WO2021216770A1 - Substituted tetrahydroquinazoline compounds as kras inhibitors - Google Patents

Abstract

The present disclosure relates to novel compounds that inhibits KRAS G12C, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of cancer and related diseases and conditions.

Description

NOVEL SUBSTITUTED HETEROCYCLIC COMPOUNDS AS KRAS INHIBITORS

[1] This application claims the benefit of priority to United States Provisional Patent Application No. 63/013,570, filed April 22, 2020, which is hereby incorporated by reference in its entirety.

Field of the Disclosure

[2] The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

Background of the Disclosure

[3] The KRAS, NRAS and HRAS genes encode a set of closely related small GTPase proteins KRas, NRas and HRas, collectively referred to herein as the Ras proteins or Ras, that share 82-90% overall sequence identity. The Ras proteins are critical components of signalling pathways transmitting signals from cell-surface receptors to regulate cellular proliferation, survival and differentiation. Ras functions as a molecular switch cycling between an inactive GDP -bound state and an active GTP-bound state. The GDP/GTP cycle of Ras is tightly regulated in cells by guanine nucleotide exchange factors (GEFs) such as Sosl and Sos2, which promote the exchange of GDP for GTP, and GTPase activating proteins (GAPs) such as NF-1 and pl20RasGAP which stimulate the intrinsic GTPase activity of Ras hydrolysing GTP to GDP.

[4] The Ras proteins are 188-189 amino acids in length and have a highly conserved N-terminal G- domain containing the p-loop region, which binds nucleotide, and the switch I and switch II regions which are important for regulatory and effector protein interactions. The C-terminal region of the Ras proteins are more divergent and contain elements which regulate the association of Ras with the membrane including the conserved carboxyl terminal CAXX box motif which is necessary for post- translational prenylation modifications. On binding to GTP the switch I and switch II regions of Ras undergo a conformational change which enables its interaction and activation of effector proteins to regulate down-stream signalling pathways. The best characterized effector of Ras is the serine/threonine kinase Raf which regulates the activity of the mitogen-activate protein kinase (MAPK) pathway. The PI3K pathway is another important effector pathway down-stream of Ras with the pi 10 catalytic subunit of the class I phosphoinositide 3-kinases interacting with Ras. Other effectors of Ras including RalGDS, Tiaml, PLC-e and Rassfl have been have also been described (See, Cox et al. Nature Reviews Drug Discovery, 13:828-851 (2014)).

[5] RAS mutations are frequently found in cancer and approximately 30% of all human cancers have a mutation in KRAS, NRAS or HRAS genes. Oncogenic Ras is typically, but not exclusively, associated with mutations at glycine 12, glycine 13 or glutamine 61 of Ras. These residues are located at the active site of Ras and mutations impair intrinsic and/or GAP-catalysed GTPase activity favouring the formation of GTP bound Ras and aberrant activation of down-stream effector pathways. KRAS is the most frequently mutated RAS gene in cancer followed by NRAS and then HRAS. [6] Glycine to cysteine mutation at residue 12 of Ras (the G12C mutation) is generated from a G.C to T. A base transversion at codon 12, a mutation commonly found in RAS genes that accounts for 14% of all KRAS, 2% of all NRAS and 2% of all HRAS mutations across cancer types. The G12C mutation is particularly enriched in KRAS mutant non-small cell lung cancer with approximately half carrying this mutation, which has been associated with the DNA adducts formed by tobacco smoke. The G12C mutation is not exclusively associated with lung cancer and is found in other RAS mutant cancer types including 8% of all KRAS mutant colorectal cancer.

[7] There are several tumour types that exhibit a high frequency of activating mutations in KRAS including pancreatic (~90% prevalence), colorectal (~40% prevalence) and non-small cell lung cancer (~30% prevalence). KRAS mutations are also found in other cancer types including multiple myeloma, uterine cancer, bile duct cancer, stomach cancer, bladder cancer, diffuse large B cell lymphoma, rhabdomyosarcoma, cutaneous squamous cell carcinoma, cervical cancer, testicular germ cell cancer and others.

[8] There remains an unmet medical need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, especially those who have been diagnosed to have such cancers characterized by a KRAS mutation, and including those who having cancer that progressed after chemotherapy.

Summary of The Disclosure

[9] In some embodiments, provided herein are compounds of Formula (I), stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate thereof:

wherein:

X¹ is CR¹ or N;

X² is CR² or N;

X³ is CR³ or N;

X⁴ is CR⁴ or N; each of R¹, R², R³ and R⁴ is independently hydrogen, halogen, -CN, C₁-C₅alkyl, C1- C5alkoxy, or C₁-C₅haloalkyl;

Q is a bond, -0-, -CH₂-, -OCH₂-, or -CH₂O-;

R⁵ is spirocyclopropyl, or 0, 1, or 2 R⁶; Y is C_1-6 alkoxy, O-C_0-3 alkylene-C_3-14 cycloalkyl, or O-C_0-3 alkylene-C_2-14 heterocycloalkyl, each of which is substituted with 0, 1, or 2 R⁶;

A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered ring, each of which is substituted with 0, 1, 2, or 3 R⁶;

R⁷ is C_1-6 alkyl, C_1-6 alkoxy 1, C2-6 alkenyl, C2-6 alkynyl, C_1-6 alkylene-OH, C_1-6 alkyleneamine, or C_1-6 alkylene-CN, each of which is substituted with 0,1, 2, or 3 R⁶; and R⁶ is independently hydroxy, halogen, C_1-6 alkyl, C_1-6 alkoxyl, C3-6 cycloalkyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_0-3 alkylene-CN, or C_0-3 alkylene-N-(C_1-6 alkyl)₂.

[10] In some embodiments, the compound of Formula (I) may encompass both stereoisomes and a mixture of stereoisomers. In some embodiments, the compound of Formula (I) is stereoisomer. In some embodiments, the compound of Formula (I) may encompass both racemic isomers and enantiomeric isomers. In some embodiments, the compound of Formula (I) may encompass pharmaceutically acceptable salts. In some embodiments, the compound of Formula (I) may encompass isotopic derivatives.

[11] Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of a compound disclosed herein. In some embodiments, the cancer is selected from breast cancer, lung cancer, pancreatic cancer, colorectal cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

BRIEF DESCRIPTION OF THE FIGURES

[12] The foregoing summary, as well as the following detailed description of the disclosure, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the present disclosure, the attached drawings illustrate some, but not all, alternative embodiments. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities shown. These figures, which are incorporated into and constitute part of the specification, assist in explaining the principles of the disclosures.

[13] Figures 1A and IB illustrate mobility change of KRAS-G12C mutant and wild type proteins on SDS-PAGE after 5 minutes of coincubation at 25 °C with exemplary Compounds 1 (Fig. 1 A), 2 and 3, 4, 5, 12, 26 and 27 (Fig. IB) of the present disclosure, indicative of covalent cysteine conjugation.

[14] Figure 2 illustrates phospho-ERKl/2 (Thr202/Tyr204) inhibition by exemplary Compounds 1-3 of the present disclosure in a MIA PaCa-2 cell line 4 hours after administration.

[15]

DETAILED DESCRIPTION

Definitions

[16] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CN is attached through the carbon atom. [17] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-C6 alkyl” is intended to encompass Ci, C2, C3, C4, C5, C6, C_1-6, C₁-5, C₁-4, C1-3, C1 -2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C34, C4-6, C4-5, and C5-6 alkyl.

[18] The term “acyl” as used herein refers to R-C(O)- groups such as, but not limited to, (alkyl)- C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, wherein the group is attached to the parent molecular structure through the carbonyl functionality. In some embodiments, it is a C1-10 acyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon of acyl. For example, a C4-acyl has three other ring or chain atoms plus carbonyl.

[19] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-C8)alk:enyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.

[20] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-8 carbon atoms, referred to herein as Ci-e alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl- 2-propyl, 2-methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l- pentyl, 3-methyl- 1 -pentyl, 4-methyl- 1 -pentyl, 2-methy 1-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2- pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l -butyl, 2-ethyl- 1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, “alkyl” is a straight-chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon.

[21] The term “alkoxy” means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[22] The term “alkylene” as used herein referes to a divalent alkyl radical. Representative examples of CMO alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n- butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n- hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene and n-decylene.

[23] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C₂-C₈)alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl- 1-butynyl, 4-propyl-2- pentynyl, and 4-butyl-2-hexynyl. [24] The term “aryl” as used herein refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system with 5 to 14 ring atoms. The aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, heteroaryls, and heterocyclyls. The aryl groups of this present disclosure can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “C₆-aryl.”

[25] The term “cyano” as used herein refers to -CN.

[26] The term “cycloalkyl” as used herein refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as “(C₃- C₈)cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc. The term “cycloalkyl” also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.

[27] The terms “halo” or “halogen” as used herein refer to -F, -Cl, -Br, and/or -I.

[28] “Haloalkyl” means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[29] The term “heteroaryl” as used herein refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryls can also be fused to non aromatic rings. Exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C2- C5)heteroaryl.” Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)- triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups also include, but are not limited to, a bicyclic aromatic ring, wherein the ring comprises 5-14 carbon atoms and 1-3 heteroatoms, referred to herein as "(C5-Ci4)heteroaryl.” Representative examples of heteroaryl include, but not limited to, indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[30] The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as used herein each refer to a saturated or unsaturated 3- to 18-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. Heterocycles can be aromatic (heteroaryls) or non-aromatic. Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

[31] The terms “hydroxy” and “hydroxyl” as used herein refer to -OH.

[32] “Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom. The rings can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. A (C_3-12)spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.

[33] “Spiroheterocycloalkyl” or “spiroheterocyclyl” means a spirocycle wherein at least one of the rings is a heterocycle one or more of the carbon atoms can be substituted with a heteroatom (e.g., one or more of the carbon atoms can be substituted with a heteroatom in at least one of the rings). One or both of the rings in a spiroheterocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. [34] “Isomers” means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space.

[35] “Stereoisomer” or “optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

[36] It is well-known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the disclosure from this disclosure and the knowledge of the prior art.

[37] Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S- isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S -isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S -isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, S -penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos. 5, 114,946 and 4,818,541.

[38] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration. For example, the compound mixture has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In other embodiments, the compound mixture has an (Si- enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more. In other embodiments, the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In some other embodiments, the compound mixture has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5% or more.

[39] Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods. [40] Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug and to a lower dose of an enantiomer that is possibly toxic or an inhibitor of the other enantiomer.

[41] The term “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[42] The term “pharmaceutically acceptable composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[43] The term “pharmaceutically acceptable prodrugs” as used herein represents those prodrugs of the compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure. A discussion is provided in Higuchi et al, “Prodrugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[44] The term “pharmaceutically acceptable salt(s)” refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,T-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[45] Chemical names were generated using PerkinElmer ChemDraw^® Professional, version 17.

[46] As used herein, “cancer” refers to diseases, disorders, and conditions that involve abnormal cell growth with the potential to invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

[47] As used herein, the term “subject” refers to an animal. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[48] As used herein, the term “inhibit,” “inhibition,” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[49] As used herein, the term “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically (e.g., through stabilization of a discernible symptom), physiologically, (e.g., through stabilization of a physical parameter), or both. In yet another embodiment, “treat,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.

[50] As used herein, a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

[51] Additionally, unless otherwise stated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium (²H) or tritium (¾), or the replacement of a carbon by a ¹³C- or ¹⁴C-carbon atom are within the scope of this disclosure. Such compounds may be useful as, for example, analytical tools, probes in biological assays, or therapeutic agents.

Compounds

[52] In some embodiments, provided herein are compounds of Formula (I), a stereoisomer or a mixture of stereoisomers, a isotopic derivative, a pharmaceutically acceptable salt, or hydrate thereof:

wherein:

X¹ is CR¹ or N;

X² is CR² or N;

X³ is CR³ or N;

X⁴ is CR⁴ or N; each of R¹, R², R³ and R⁴ is independently hydrogen, halogen, -CN, C₁-C₅alkyl, C₁-C₅alkoxy, or C₁-C₅haloalkyl;

Q is a bond, -O-, -CH₂-, -OCH₂-, or -CH₂O;

R⁵ is spirocyclopropyl, or 0, 1, or 2 R⁶;

Y is C_1-6 alkoxy, O-C_0-3 alkylene-C_3-14 cycloalkyl, or O-C_0-3 alkylene-C₂-i4 heterocycloalkyl, each of which is substituted with 0, 1, or 2 R⁶;

A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered ring, each of which is substituted with 0, 1, 2, or 3 R⁶;

R⁷ is C_1-6 alkyl, C _1-6 alkoxy I, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkylene-OH, C_1-6 alkyleneamine, or C_1-6 alkylene-CN, each of which is substituted with 0,1, 2, or 3 R⁶; and

R⁶ is independently hydroxy, halogen, C_1-6 alkyl, C_1-6 alkoxyl, C3-6 cycloalkyl, C_1-6haloalkyl, C_1-6 haloalkoxyl, C_0-3 alkylene-CN, orC_0-3 alkylene-N-(C_1-6 alkyl)₂.

[53] In some embodiments, X¹ is CR¹, X² is CR², X³ is CR³, and X⁴ is CR⁴.

[54] In some embodiments, R¹, R², R³ and R⁴ are each independently H, F, Cl, -CH₃, -OCH₃, or - CN. In some embodiments, R¹, R², R³ and R⁴ are each H. In some embodiments, R¹ is Cl. In some embodiments, R¹ is F. In some embodiments, R¹ is -CH₃. In some embodiments, R² is Cl. In some embodiments, R³ is F. In some embodiments, R³ is -OCH_3. In some embodiments, R³ is -CN.

[55] In some embodiments, X¹ is N. In some embodiments, X³ is N. In some embodiments, X⁴ is N.

[56] In some embodiments, R⁵ is hydrogen, halogen, -OH, or spirocyclopropyl.

[57] In some embodiments, R⁵ is 2 R⁶ and R⁶ is halogen and C₁-C₅alkyl. In some embodiments, R⁵ is 2 R⁶ and R⁶ is F and -CH₃. [58] In some embodiments, Y is seleted from OCH₂CH₂N(CH₃)₂,

. In some embodiments, Y is OCH₂CH₂N(CH₃)₂· In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

. In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

. In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

. In some embodiments, Y is

In some embodiments, Y is

. In some embodiments, Y is

[59] In some embodiments, ring A is selected from

, or

, each of which is substituted with 0, 1 or 2 R⁶.

[60] In some embodiments, ring A is selected from

In some embodiments, ring A is

In some embodiments, ring A is

In some embodiments, ring A is

In some embodiments, ring A is

In some embodiments, ring A is

. In some embodiments, ring A is

[61] In some embodiments, R⁷ is selected from -CH=CH₂, -CF=CH₂, -C≡CH, -C≡C-CH₃, -OCH₃, or

In some embodiments, R is -CH=CH₂. In some embodiments, R is -CF=CH₂. In some embodiments, R⁷ is -C≡CH. In some embodiments, R⁷ is -C≡C-CH₃. In some embodiments, R⁷ is -OCH₃. In some embodiments,

[62] In some embodiments, the compound of Formula (I) is a stereoisomer.

[63] In some embodiments, provided herein is a compound, or pharmaceutically acceptable salt thereof, chosen from the compounds listed in Table 1.

Table 1. Exemplary Compound of the Present Disclosure

Pharmaceutical Compositions

[64] Pharmaceutical compositions of t present disclosure comprise at least one compound of Formula (I), or tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.

[65] Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient. The carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound. Other pharmacologically active substances may also be present including other compounds. The formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components.

[66] For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmacologically administrable compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. In general, suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.

[67] Formulations suitable for buccal (sub-lingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.

[68] Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous preparations of at least one compound of Formula (I), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the present disclosure may contain from about 0.1 to about 5% w/w of the active compound.

[69] Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[70] Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound (i.e., at least one compound of Formula (I), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof) is generally present at a concentration of from about 0.1% to about 15% w/w of the composition, for example, from about 0.5 to about 2%. [71] The amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician. For example, a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 μg to about 1000 mg. In another embodiment, intermittent administration, such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed. Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect. In accordance with standard dosing regimens, physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.

[72] A therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used. In one embodiment, the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration. Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.

[73] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀. Compositions that exhibit large therapeutic indices are preferable.

[74] Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et ah, Cancer Chemother. Reports 50(4):219-244 (1966) and the following Table for Equivalent Surface Area Dosage Factors).

Table 2. Equivalent Surface Area Dosage Factors.

[75] The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Generally, a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

Methods of Treatment

[76] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof, is administered to treat cancer in a subject in need thereof. In some embodiments, the cancer is chosen from breast cancer, lung cancer, pancreatic cancer, colorectal cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gall bladder cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is bile duct cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the therapeutic treatment is for the treatment of KRAS G12-associated diseases and conditions.

[77] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof, is administered as a pharmaceutical composition.

[78] In some embodiments, the invention provides for methods for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[79] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a KRas G12C with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12C, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12C.

[80] In one embodiment, a cell in which inhibition of KRas G12C activity is desired is contacted with an effective amount of a compound of Formula (I) to negatively modulate the activity of KRas G12C. In other embodiments, a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of Formula (I) may be used.

[81] By negatively modulating the activity of KRas G12C, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12C activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12C. [82] The concentration and route of administration to the patient will vary depending on the cancer to be treated.

[83] In one embodiment, a compound of Formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof, is administered in combination with another therapeutic agent, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

[84] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.

[85] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.

[86] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof for use in the inhibition of KRas G12C.

[87] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12C-associated disease or disorder.

[88] Also provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[89] Also provided herein is a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of KRas G12C.

[90] Also provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12C-associated disease or disorder.

[91] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[92] One skilled in the art will further recognize that human clinical trials including first-in-human, dose ranging and efficacy trials, in healthy patients and/or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.

Examples

[93] The examples and preparations provided below further illustrate and exemplify the compounds as disclosed herein and methods of preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. [94] The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and/or techniques well known in the art. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from about - 10º C to about 200° C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10° C to about 200° C over a period that can be, for example, about 1 to about 24 hours; reactions left to run overnight in some embodiments can average a period of about 16 hours.

[95] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick- layer chromatography, or a combination of these procedures. See, e.g., Carey et al. Advanced Organic Chemistry, 3^rd Ed., 1990 New York: Plenum Press; Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2^nd Ed., 2005 Hoboken, NJ: J. Wiley & Sons. Specific illustrations of suitable separation and isolation procedures are given by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can also be used.

[96] In all of the methods, it is well understood that protecting groups for sensitive or reactive groups may be employed where necessary, in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[97] When desired, the (R)- and (S)-isomers of the nonlimiting exemplary compounds, if present, can be resolved by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts or complexes which can be separated, e.g., by crystallization; via formation of diastereoisomeric derivatives which can be separated, e.g., by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, e.g., enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas- liquid or liquid chromatography in a chiral environment, e.g., on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[98] The compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Also, the compounds described herein can be optionally contacted with a pharmaceutically acceptable base to form the corresponding basic addition salts.

[99] In some embodiments, disclosed compounds can generally be synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available, e.g., from Millipore Sigma or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.

[100] The discussion below is offered to illustrate certain of the diverse methods available for use in making the disclosed compounds and is not intended to limit the scope of reactions or reaction sequences that can be used in preparing the compounds provided herein. The skilled artisan will understand that standard atom valencies apply to all compounds disclosed herein in genus or named compound for unless otherwise specified.

The following abbreviations have the definitions set forth below:

1. ACN: Acetonitrile

2. DCE: Dichloroethane

3. DCM: Dichloromethane

4. DIEA: Diisopropylethylamine

5. DMA: N,N-dimethylacetamide

6. DMSO: Dimethyl sulfoxide

7. EA: Ethyl acetate

8. HPLC: High pressure liquid chromatography

9. LiHDMS Lithium Bis(trimethylsilyl)amide

10. LC/MS: Liquid chromatography/Mass spectroscopy

11. NMR: Nuclear magnetic resonance

12. PE: Petroleum ether

13. Pd₂(dba)₃: Tris(dibenzylideneacetone)dipalladium (0)

14. RuPhos: 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

15. RuPhos-Pd-G3: (2-Dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl) [2-(2'- amino- 1 , 1 '-biphenyl)]palladium(II) methanesulfonate

16. TEA: Triethylamine

17. TLC: Thin layer chromatography

18. TR-FRET: Time-resolved fluorescence energy transfer

19. XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

20. XPhos-Pd-G3: (2-Dicyclohexylphosphino-2',4',6'-triisopropyl- 1 , 1 '-biphenyl) [2-(2'- amino- 1 , 1 '-biphenyl)]palladium(II) methanesulfonate

General Synthetic Schemes

[101] The claimed compounds can be prepared according to the following schemes. The following schemes represent the general methods used in preparing these compounds. However, the synthesis of these compounds is not limited to these representative methods, as they can also be prepared through various other methods by those skilled in the art of synthetic chemistry.

Scheme 1 : General scheme of synthesizing claimed compounds

[102] 3-Ethoxy-2-cyclohexen- 1 -one can react with dialkyl carbonate, such as diethyl carbonate, in the presence of a strong base, such as NaH and LiHMDS, to provide a keto ester 1A. Cyclization between keto ester 1A and urea under various conditions such as heating in solvents such as EtOH, AcOH or 1,4-dioxane with or without a base such as NaOEt or tBuOK, or an acid such as p-TsOH can generate bicyclic pyrimidine intermediate IB. The hydroxyl groups of intermediate IB can be converted to leaving groups (LG) such as chloro (Cl), bromo (Br), p-toluenesulfonate (OTs) or trifluoromethansulfonate (OTf). Substitution of LG with N-protected heterocyclic amine can provide an intermediate ID. Treatment of the ethyl vinyl ether intermediate ID with an acid such as hydrochloric acid can provide ketone intermediate IE. Condensation of ketone IE with optionally substitutedl,2,3,4-tetrahydroquinoline or an oxygen containing fused heterocyclic amine can give an enamine intermediate IF, which can be reduced with reducing agent such as sodium borohydride to provide intermediate 1G. The reductive animation reaction from IE to 1G can be carried out in one- pot without isolation of enamine intermediate IF. The LG of intermediate 1G can be substituted by an alcohol R'OH or an amine HNR’R'” in the presence of a strong base such as NaH, or by coupling reaction catalyzed by transition metals such as palladium or copper to provide intermediate 1H. Deprotection of the nitrogen protective group followed by amide formation with acyl chloride R4COCI will provide final compounds of Formula (I).

Scheme 2: General scheme of synthesizing claimed compounds

[103] Alternatively, the ketone intermediate IE can be converted to triflate 2B with triflic anhydride in the presence of a base such as diisopropylethylamine. Cross coupling between triflate intermediate 2B and 1,2,3,4-tetrahydroquinoline or 3,4-dihydro-2H-benzo[b][l,4]oxazine under palladium catalysis conditions can provide intermediate IF, which can be converted to final compounds using the synthetic sequence as described in Scheme 1.

Examples 1: Synthesis of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Compound 1)

Step 1: Preparation of 7-ethoxy-5,6-dihydroquinazoline-2,4-diol

[104] To a mixture of ethyl 4-ethoxy-2-oxocyclohex-3-ene-l-carboxylate (15 g, 70.7 mmol) and urea (8.5 g, 140 mmol) in EtOH (150 mL) was added sodium ethoxide (18.6 mL, 140 mmol) carefully. The reaction was stirred for 16 h at 80 °C. The reaction mixture was concentrated under vacuum. The residue was dissolved in H₂0 (150 mL), neutralized with HC1 (1 M) to pH=7 and extracted with EtOAc (3x100 mL). The organic phases were washed with brine (100 mL), dried over sodium sulphate and evaporated in vacuo. Then crude product was purified by silica gel column chromatography (using 10% MeOH in DCM as eluent) to generate 7-ethoxy-5,6-dihydroquinazoline- 2,4-diol (9.3 g, 56.8%). LC/MS: 209.0 [M+H]⁺.

Step 2: Preparation of 2,4-dichloro-7-ethoxy-5,6-dihydroquinazoline

[105] A solution of 7-ethoxy-5,6-dihydroquinazoline-2,4-diol (9.3 g, 44.7 mmol), tetraethylammonium chloride (22.2 g, 134.1 mmol) and POCl₃ (102.81 g, 670.5 mmol) in MeCN (200 mL) was heated at 100 °C overnight. The reaction mixture was concentrated under vacuum. Ice water (200 mL) was added and the residue was extracted with EtOAc (3x100 mL). The organic phase was washed with water (300 mL), dried over sodium sulphate and evaporated in vacuo. Then crude material was purified by silica gel column chromatography (using 20% EtOAc in PE as eluent) to give 2,4-dichloro-7-ethoxy-5,6-dihydroquinazoline (4.5 g, 36.9%). LC/MS: 244.9 [M+H]⁺. Step 3: Preparation of benzyl (S)-4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)-2- (cyanomethyl)piperazine- 1 -carboxylate

[106] To a mixture of 2,4-dichloro-7-ethoxy-5,6-dihydroquinazoline (4.5 g, 18.4 mmol) and DIEA (4.7 g, 36.8 mmol) in DMSO (50 mL) was added benzyl (S)-2-(cyanomethyl)piperazine-l- carboxylate (4.8 g, 18.4 mmol) carefully. The reaction was stirred for 16 h at 50 °C. The mixture was diluted with EtOAc (500 mL). The organic layer was washed with brine, dried over Na₂SO₄, filtered and the filtrate was concentrated. Then residue was purified by silica gel column chromatography (using 50% EtOAc in PE as eluent) to afford benzyl (S)-4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin- 4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (5.5 g, 57.6%). LC/MS: 468.0 [M+H]⁺.

Step 4: Preparation of benzyl (S)-4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2- (cyanomethyl)piperazine- 1 -carboxylate

[107] To a mixture of benzyl (S)-4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)-2- (cyanomethyl)piperazine-l -carboxylate (900 mg, 1.91 mmol) in dioxane (5 mL) was added hydrochloric acid (5 mL, 30 mmol, 6 M) carefully. The reaction was stirred for 16 h at 50 °C. Then the mixture was concentrated and diluted with EtOAc (30 mL). The organic layer was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (using 50% EtOAc in PE as eluent) to provide benzyl (S)-4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2- (cyanomethyl)piperazine-l -carboxylate (600 mg, 67.4%). LC/MS: 439.7 [M+H]⁺.

Step 5: Preparation of benzyl (S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6- dihydroquinazolin-4-yl)-2-(cyanomethyl)piperazine- 1 -carboxylate

[108] To a mixture of benzyl (S)-4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2- (cyanomethyl)piperazine-l -carboxylate (600 mg, 1.37 mmol) and 1,2,3,4-tetrahydroquinoline (198 mg, 1.37 mmol) in toluene (10 mL) was added AcOH (172.6 mg, 2.74 mmol). The reaction was stirred for 16 h at 100 °C. The mixture was concentrated and diluted with EtOAc (30 mL). The organic layer was washed with sat. NaHCO:_? solution and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (using 50% EtOAc in PE as eluent) to afford benzyl (S)-4-(2-chloro-7-(3,4- dihydroquinolin-l(2H)-yl)-5,6-dihydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (410 mg, 53.8%). LC/MS: 554.7 [M+H]⁺.

Step 6: Preparation of benzyl (2S)-4-(2-chloro-7-(3, 4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate

[109] To a mixture of benzyl (S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6- dihydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (410 mg, 0.73 mmol) in AcOH (6 mL) was added NaBH₄ (55.5 mg, 1.46 mmol) carefully. The reaction was stirred for 1 h at 20 °C.

Then the mixture was diluted with EtOAc (30 mL). The organic layer was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (using 50%

EtOAc in PE as eluent) to provide benzyl (2S)-4-(2-chloro-7-(3.4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yr)-2-(cyanomethyl)piperazine-l-carboxylate (300 mg, 73.14%). LC/MS: 556.7 [M+H]⁺.

Step 7: Preparation of benzyl (2S)-2-(cyanomethyl)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l-carboxylate

[110] To a mixture of benzyl (2S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (300 mg, 0.53 mmol), [(2S)-1- methylpyrrolidin-2-yl]methanol (183. mg, 1.60 mmol) in toluene (10 mL) was added RuPhos (47.3 mg, 0.106 mmol), Pd₂(dba)3 (48.5 mg, 0.053 mmol) and CS2CO₃ (347.7 mg, 1.06 mmol). The reaction was stirred for 16 h at 100 °C under N2. Then the reaction was concentrated. The crude product was purified by silica gel column chromatography (using EtOAc as eluent) to afford benzyl (2S)-2- (cyanomethyl)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l-carboxylate (300 mg, 46.4%). LC/MS: 635.7 [M+H]⁺. Step 8: Preparation of 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpynOlidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile

[111] To a mixture of benzyl (2S)-2-(cyanomethyl)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine- 1 -carboxylate (300 mg, 0.46 mmol) in MeOH (6 mL) was added palladium on carbon (500 mg, 4.69 mmol) carefully. The reaction was stirred for 2 h at 20 °C with a balloon filled with hydrogen gas. Then the reaction mixture was filtered, and the filtrate was concentrated to afford 2-((2S)-4-(7-(3,4-dihydroquinolin- l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (60 mg, 73%). LC/MS: 502.1 [M+H]⁺.

Step 9: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Compound 1)

[112] To a mixture of 2-[(2S)-4-[7-(3,4-dihydro-2H-quinolin-l-yl)-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy}-5,6,7,8-tetrahydroquinazolin-4-yl]piperazin-2-yl]acetonitrile (200 mg, 0.40 mmol) and DIEA (155.1 mg, 1.2 mmol) in DCM (5 mL) was added prop-2-enoyl chloride (36.2 mg, 0.4 mmol) carefully. The reaction was stirred for 1 h at 0 °C. Then the reaction was diluted with DCM (10 mL). The organic layer was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude product was purified by Prep-HPLC using a gradient of 0.1% TFA/ ACN from 70:30 to 40:60, and suitable fractions were pooled and lyophilized to give a triflate salt of compound 1 (130 mg, 55.5%). LC/MS: 556.1 [M+H]⁺; 'H NMR (400 MHz, MeOH-d4) δ 7.07 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 4.0 Hz, 1H), 6.92- 6.82 (m, 2H), 6.69 - 6.67 (m, 1H), 6.33 (d, J = 16.7 Hz, 1H), 5.87 (d, J = 10.5 Hz, 1H), 5.11 - 4.97 (m, 1H), 4.95 - 4.93 (m, 1H), 4.81 - 4.75 (m, lH), 4.59 -4.29 (m, 3H), 4.17 - 4.13 (m, 1H), 3.96 - 3.78 (m, 3H), 3.67 - 3.50 (m, 2H), 3.39 - 3.35 (m, 1H), 3.30 - 3.22 (m, 2H), 3.09 - 2.90 (m, 8H), 2.86 - 2.76 (m, 3H), 2.49 - 2.39 (m, 1H), 2.21 - 1.88 (m, 7H).

Example 2: Synthesis of 2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Compound 2)

[113] Compound 1 from Example 1 (130 mg, 0.233 mmol) was separated by SFC (Column: CHIRALPAK AD-H 250 mm x 20 mm, 5 μm; Modifier: CO₂ and 35% EtOH with 0.2% NH₄OH; flow rate: 40 mL/min) and suitable fractions were pooled and lyophilized. The earlier fraction (Peak 1, Rt: 2.90 min) afforded 2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (55.7 mg, 35.8%). The stereochemistry at the piperazine stereogenic center was confirmed by co-crystals of this compound with KRAS-G12C.

LC/MS: 556.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 6.98 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 7.1 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.54 (t, J = 1.1 Hz, 1H), 6.28 (d, J = 16.6 Hz, 1H), 5.83 (d, J = 10.8 Hz, 1H),5.07 -5.01 (m, 1H), 4.77 - 4.73 (m, 1H), 4.58 - 4.53 (m, 1H), 4.31 - 4.07 (m, 4H), 3.86 - 3.74 (m, 3H), 3.61 - 3.44 (m, 1H), 3.28 - 3.18 (m, 4H), 3.05 (s, 3H), 3.01 - 2.73 (m, 8H), 2.43 - 2.34 (m, 1H), 2.15 - 1.79 (m, 7H).

Example 3: Synthesis of 2-((S)-l-acryloyl-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Compound 3)

[114] The second fraction (slow eluting peak, Rf: 3.63 min) from the chiral separation in Example 2 provided 2-((S)- 1 -acryloyl-4-((R)-7 -(3,4-dihydroquinolin- 1 (2H)-yl)-2-(((S)- 1 -methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (33.7 mg, 21.5%). The stereochemistry at the piperazine stereogenic center was assigned based on co-crystal information from Example 2.

LC/MS: 556.0 [M+H]⁺; H NMR (400 MHz, CD₃OD) δ 6.97 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 1.1 Hz, 1H), 6.28 (d, J = 16.7 Hz, 1H), 5.83 (d, J = 11.1 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.76 - 4.73 (m, 1H), 4.56 - 4.43 (m, 2H), 4.27 -4.09 (m, 3H), 3.99 - 3.83 (m, 2H), 3.48 - 3.39 (m, 1H), 3.27 -3.09 (m, 7H), 2.99-2.92 (m, 1H), 2.87 - 2.80 (m, 2H), 2.75 - 2.65 (m, 6H), 2.23-2.16 (m, 1H), 2.14 - 2.05 (m, 1H), 1.93 - 1.80 (m, 6H).

Examples 4: Synthesis of 2-((S)-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile (Compound 4)

Step 1: Preparation of2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile [115] To a mixture of 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (150 mg, 0.3 mmol), pyridine (94.6 mg, 1.2 mmol) and 2-fluoroprop-2-enoic acid (26.9 mg, 0.3mmol) in DCM (5 mL) was added phosphoryl trichloride (45.9 mg, 0.3 mmol). The reaction was stirred for 1 h at 0 °C. Then the reaction mixture was diluted with DCM (20 mL). The organic layer was washed with sat. NaHCO s solution and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The resulting crude product was purified by Prep-HPLC using a gradient of 0.1% TFA / ACN from 70:30 to 40:60, and suitable fractions were pooled and lyophilized to give a triflate salt of a mixture of compounds 4 and compound 5 (55 mg, 31.1%). LC/MS: 574.2 [M+H]⁺. This mixture (55 mg, 0.1 mmol) was separated by SFC (Column: CHIRALPAK AD-H 250 mm x 20 mm, 5 mih; Modifier: Hexane and 20% EtOH with 0.2%NH4OH; flow rate : 40 mL/min) and suitable fractions were pooled and lyophilized. The earlier fraction (Peak 1, Rt: 11.69 min) provided 2-((S)-4-((S)-7- (3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (19.8 mg, 33.9%). The chiral center at the carbon adjacent to the nitrogen atom of tetrahydroqunoline was arbitrarily assigned. LC/MS: 573.9 [M+H]⁺; H NMR (400 MHz, CD₃OD) δ 6.97 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 6.8 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.52 (t, J = 7.0 Hz, lH), 5.37-5.26 (m, 2H), 4.98 - 4.93 (m, 1H), 4.38 - 4.22 (m, 3H), 4.10 - 4.02 (m, 3H), 3.84 - 3.60 (m, 1H), 3.44 - 3.40 (m, 1H), 3.27 - 3.18 (m, 2H), 3.10 - 2.96 (m, 3H), 2.93 - 2.65 (m, 8H), 2.49 (s, 3H), 2.38 - 2.31 (m, 1H), 2.13 - 2.03 (m, 2H), 1.96 - 1.77 (m, 5H), 1.72 - 1.63 (m, 1H).

Example 5: Synthesis of 2-((S)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-(2- lluoroacryloyl)piperazin-2-yl)acetonitrile (Compound 5)

[116] The second fraction (slow eluting peak, Rf: 14.08 min) from the chiral separation in Example 4 provided 2-((S)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (20.3 mg, 34.9%). The chiral center at the carbon adjacent to the nitrogen atom of tetrahydroqunoline was arbitrarily assigned. LC/MS: 573.9 [M+H]⁺; H NMR (400 MHz, CD₃OD) δ 6.99 (t, J = 7.7 Hz, lH), 6.93 (d, J = 7.3 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.56 (t, J = 7.2 Hz, lH), 5.40 - 5.28 (m, 2H), 4.86 - 4.79 (m, 1H), 4.64 - 4.53 (m, 2H), 4.30 - 4.15 (m, 3H), 3.93 - 3.69 (m, 3H), 3.45 - 3.34 (m, 2H), 3.28 - 3.16 (m, 4H), 3.14 -2.99 (m, 5H), 2.97 - 2.83 (m, 3H), 2.78 - 2.66 (m, 3H), 2.43 - 2.34 (m, 1H), 2.21 - 2.00 (m, 4H), 1.97 - 1.81 (m, 3H).

Example 6: Synthesis of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Compound 12)

Step 1: Preparation of benzyl (S)-4-(2-chloro-7-(3,4-dihydroisoquinolin-2(lH)-yl)-5,6- dihydroquinazolin-4-yl)-2-(cyanomethyl)piperazine- 1 -carboxylate

[117] To a mixture of benzyl (S)-4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2- (cyanomethyl)piperazine-l -carboxylate (250 mg, 0.57 mmol) and 1,2,3,4-tetrahydroisoquinoline (76.7 mg, 0.57 mmol) in toluene (10 mL) was added AcOH (68.4 mg, 1.14 mmol) carefully. The reaction was stirred for 16 h at 100 °C. Then the reaction was concentrated and diluted with EA (30 mL). The organic layer was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (using 50% EtOAc in PE as eluent) to afford the desired product (220 mg, 69.5%). LC/MS: 554.7 [M+H]⁺.

Step 2: Preparation of benzyl (2S)-4-(2-chloro-7-(3, 4-dihydroisoquinolin-2(lH)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate

[118] To a mixture of S)-4-(2-chloro-7-(3,4-dihydroisoquinolin-2(lH)-yl)-5,6-dihydroquinazolin-4- yl)-2-(cyanomethyl)piperazine-l -carboxylate (220 mg, 0.39 mmol) in AcOH (5 mL) was added NaBH₄ (29.5 mg, 0.78 mmol) carefully. The reaction was stirred for 1 h at 20 °C. Then the reaction was diluted with EA (30 mL). The organic layer was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (using 50% EtOAc in PE as eluent) to afford the desired product (200 mg, 82.5%). LC/MS: 556.7 [M+H]⁺.

Step 3: Preparation of benzyl (2S)-2-(cyanomethyl)-4-(7-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l-carboxylate

[119] To a mixture of benzyl (2S)-4-(2-chloro-7-(3, 4-dihydroisoquinolin-2(lH)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (160 mg, 0.29 mmol) and [(2S)- l-methylpyrrolidin-2-yl]methanol (100 mg, 0.87 mmmol) in 1,4-dioxane (3 mL) was added RuPhos (27 mg, 0.06 mmol), Pd2(dba)3 (26.6 mg, 0.03 mmol) and CS2CO₃ (189 mg, 0.58 mmol) carefully. The reaction was stirred for 16 h at 100 °C under N2. Then the reaction was concentrated. The crude product was purified by silica gel column chromatography (using EtOAc as eluent) to afford the desired product (60 mg, 26%). LC MS: 635.9 [M+H]⁺.

Step 4: Preparation of 2-((2S)-4-(7-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile

[120] To a mixture of (2S)-2-(cyanomethyl)-4-(7-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine- 1 -carboxylate (60 mg, 0.09 mmol) in MeOH (3 mL) was added palladium/carbon (115 mg, 1.08 mmol) carefully. The reaction was stirred for 2 h at 20 °C. Then the reaction was filtered, and the filtrate was concentrated to afford the desired product (30 mg, 59.8%). LC/MS: 501.9 [M+H]⁺.

Step 5: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile

[121] To a solution of 2-[(2S)-4-[7-(3,4-dihydro-lH-isoquinolin-2-yl)-2-{[(2S)-l-methylpyrrolidin-2- yl]methoxy}-5,6,7,8-tetrahydroquinazolin-4-yl]piperazin-2-yl]acetonitrile (30 mg, 0.06 mmol) and DIEA (24 mg, 0.18 mmol) in DCM (2 mL) was added prop-2-enoyl chloride (5.4 mg, 0.06 mmol) carefully. The reaction was stirred for 1 h at 0 °C. Then the reaction was diluted with DCM (10 mL). The organic layer was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude product was purified by Prep-HPLC using a gradient of 0.1% TFA / ACN from 70:30 to 40:60, and suitable fractions were pooled and lyophilized to give the desired product (4 mg, 10.7%). LC/MS: 556.2 [M+H]⁺; 'H NMR (400 MHz, MeOD) δ 7.43 - 7.18 (m, 4H), 6.91 - 6.73 (m, 1H), 6.34 - 6.22 (m, 1H), 5.89 - 5.78 (m, 1H), 5.10 - 4.95 (m, 1H), 4.77 - 4.50 (m, 5H), 4.42 - 4.31 (m, 1H), 4.16 - 3.81 (m, 5H), 3.79 - 3.54 (m, 3H),

3.25 - 3.02 (m, 7H), 2.99 - 2.78 (m, 4H), 2.59 - 2.51 (m, 1H), 2.43 - 2.34 (m, 1H), 2.27 - 1.93 (m, 5H), 1.91 - 1.82 (m, 1H).

Example 7: Synthesis of methyl (2S)-2-(cyanomethyl)-4-[7-(3,4-dihydro-2H-quinolin-l-yl)-2- {[(2S)-l-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydroquinazolin-4-yl]piperazine-l- carboxylate (Compound 26)

[122] To a solution of 2-[(2S)-4-[7-(3,4-dihydro-2H-quinolin-l-yl)-2-{[(2S)-l-methylpyrrolidin-2- yl]methoxy}-5,6,7,8-tetrahydroquinazolin-4-yl]piperazin-2-yl]acetonitrile (120 mg, 0.24 mmol) and DIEA (93 mg, 0.72 mmol) in DCM (2 mL) was added chloro(methoxy)methanone (22.7 mg, 0.24 mmol) carefully. The reaction was stirred at 0 °C for 1 h. Then the reaction was diluted with DCM (10 mL), washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude product was purified by Prep-HPLC using a gradient of 0.1% TFA / ACN from 70:30 to 40:60, and suitable fractions were pooled and lyophilized to give a desired product (86.5 mg, 63%). LC/MS: 559.8 [M+H]⁺; 'H NMR (400 MHz, MeOD) δ 7.05 - 6.99 (m, 1H), 6.98 - 6.93 (m, 1H), 6.87 - 6.80 (m, 1H), 6.65 - 6.58 (m, 1H), 5.01 - 4.91 (m, 1H), 4.75 - 4.60 (m, 2H), 4.53 - 4.21 (m, 3H), 4.18 - 4.00 (m, 1H), 3.99 - 3.86 (m, 1H), 3.80 - 3.73 (m, 4H),

3.63 - 3.32 (m, 3H), 3.26 - 3.16 (m, 2H), 3.13 - 2.94 (m, 6H), 2.93 - 2.72 (m, 6H), 2.47 - 2.35 (m, 1H), 2.23 - 2.07 (m, 3H), 2.07 - 1.83 (m, 4H).

Example 8: Synthesis of 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin- 2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-propioloylpiperazin-2-yl)acetonitrile (Compound 27)

[123] A solution containing 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpynOlidin- 2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (100 mg, 0.2 mmol), prop-2-ynoic acid (14 mg, 0.2 mmol) and pyridine (63 mg, 0.8 mmol) in DCM (4 mL) was cooled down to 0 °C. Then phosphoryl trichloride (31 mg, 0.2 mmol) in DCM (2 mL) was added dropwise. The mixture was first stirred at 0 °C for 30 min, then quenched with ACN and a drop of water. The resulting mixture was concentrated in vacuo and the residue was purified by Prep-HPLC, using a gradient of 0.1% TFA / ACN from 70:30 to 50:50, and suitable fractions were pooled and lyophilized to give the product (44 mg, 38%) as a yellow solid. LC/MS: 554.1[M+H] ⁺; H NMR (400 MHz, MeOD) δ 7.05-6.98 (m, 1H), 6.98-6.93 (m, lH), 6.86-6.79 (m, 1H), 6.60 (t, J = 7.3 Hz, lH), 5.11- 4.99 (m, 1H), 4.98-4.90 (m, 1H), 4.85-4.57 (m, 2H), 4.55 - 4.14 (m, 5H), 3.96 - 3.66 (m, 3H), 3.63 - 3.48 (m, 1H), 3.42-3.34 (m, 1H), 3.28-3.18 (m, 2H), 3.15 - 2.82 (m, 8H), 2.84-2.66 (m, 3H), 2.46- 2.33 (m, 1H), 2.27 - 1.80 (m, 7H).

Example 9: l-(4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 16), l-(4-((S)-7- (3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 17a) and l-(4-((R)-7-(3,4- dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 17b)

Step 1: Preparation of benzyl 4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)piperazine-l- carboxylate

[124] To a mixture of 2,4-dichloro-7-ethoxy-5,6-dihydroquinazoline (4 g, 16.3 mmol) and DIEA (4.2 g, 32.7 mmol) in DMSO (50 mL) was added benzyl piperazine- 1-carboxy late (3.6 g, 16.3 mmol). The reaction was stirred for 16 h at 50 °C. Then the reaction was diluted with EA (500 mL). The organic layer was washed with brine, dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude mixture was purified by silica gel column chromatography (PE/EA = 1/1) to afford the desired compound (2.8 g, 39.9%). LC MS: 428.7 [M+H]⁺.

Step 2: Preparation of benzyl 4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l- carboxylate

[125] To a mixture of benzyl 4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)piperazine-l- carboxylate (2.8 g, 6.0 mmol) in dioxane (10 mL) was added hydrochloric acid (10 mL, 6M). The reaction was stirred for 16 h at 50 °C. The reaction mixture was concentrated and diluted with EA (30 mL). The organic layer was extracted with sat. NaHC(¾ solution, dried over Na₂S(¾, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA = 1/1) to afford the desired compound (1.1 g, 37.6%). LC/MS: 400.8 [M+H]⁺.

Step 3: Preparation of benzyl 4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6-dihydroquinazolin-4- yl)piperazine- 1 -carboxylate

[126] To a mixture of benzyl 4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l- carboxylate (1.1 g, 2.7 mmol) and 1,2,3,4-tetrahydroquinoline (365 mg, 2.7 mmol) in Toluene (10 mL) was added AcOH (329 mg, 5.8 mmol). The reaction was stirred at 100 °C for 16 h. The reaction was concentrated in vacuo and diluted with EA (30 mL). The organic layer was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, filtered under reduced pressure and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE/EA = 1/1) to afford the desired product (800 mg, 29%). LC/MS: 515.7 [M+H]⁺. Step 4: Preparation of benzyl 4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)piperazine- 1 -carboxylate

[127] To a mixture of benzyl 4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6-dihydroquinazolin-4- yl)piperazine-l -carboxylate (800 mg, 1.6 mmol) in AcOH (5 mL) was added NaBH₄ (117 mg, 3.1 mmol). The reaction was stirred at 20 °C for 1 h. The reaction was diluted with EA (30 mL). The organic layer was washed with sat. NaHCOs solution and brine. The organic layer was dried over Na₂SO₄, filtered under reduced pressure and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE/EA = 1/1) to afford the desired product (500 mg, 62.3%). LC/MS: 517.7 [M+H]⁺.

Step 5: Preparation of benzyl 4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l-carboxylate

[128] To a mixture of benzyl 4-(2-chloro-7-(3, 4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)piperazine-l -carboxylate (440 mg, 0.9 mmol) and (S)-(l-methylpyrrolidin- 2-yl)methanol (294 mg, 2.6 mmmol) in toluene (5 mL) was added RuPhos (79 mg, 0.2 mmol), Pd₂(dba)₃ (78 mg, 0.1 mmol) and Cs₂CO₃ (587 mg, 1.8 mmol). The reaction was stirred at 100 °C for 16 h under N₂. The reaction was filtered under reduced pressure and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100% EA) to afford the desired product (470 mg, 83.4%). LC/MS: 596.9 [M+H]⁺.

Step 6: Preparation of 7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-4- (piperazin- 1 -yl)-5, 6, 7, 8 -tetrahy droquinazoline

[129] To a mixture of benzyl 4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l-carboxylate (470 mg, 0.8 mmol) in MeOH (5 mL) was added palladium/carbon (168 mg, 50%). The reaction was stirred at 20 °C for 2 h. The reaction mixture was filtered under reduced pressure, and the filtrate was concentrated in vacuo to afford the desired product (290 mg, 71.6%). LC/MS: 463.0 [M+H]⁺. Step 7: Preparation of l-(4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 16)

[130] To a solution of 7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-4- (piperazin-l-yl)-5,6,7,8-tetrahydroquinazoline (290 mg, 0.6 mmol) and DIEA (244 mg, 1.8 mmol) in DCM (2 mL) was added acryloyl chloride (57 mg, 0.6 mmol). The reaction was stirred for 30 min at 0 °C. The reaction mixture was diluted with DCM (10 mL). The organic layer was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude product was purified by Prep-HPLC using a gradient of 0.1% TFA / ACN from 70:30 to 40:60, and suitable fractions were pooled and lyophilized to give compound 16 (163 mg, 50.5%). LC/MS: 517.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.05 - 6.93 (m, 2H), 6.86 - 6.74 (m, 2H), 6.64 - 6.57 (m, lH), 6.28 (dd, J = 16.8, 1.9 Hz, 1H), 5.81 (dd, J = 10.6, 1.9 Hz, 1H), 4.75 -4.66 (m, 1H), 4.35 -4.27 (m, 1H), 4.12 -4.00 (m, 2H), 4.00- 3.67 (m, 8H), 3.29 - 3.16 (m, 3H), 3.12 - 2.93 (m, 5H), 2.92 - 2.73 (m, 4H), 2.46 - 2.38 (m, 1H), 2.30 - 1.80 (m, 8H).

Step 8: Preparation of (S)-l-(4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-((l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 17a) and (S)-l-(4-(7-(3, 4-dihydroquinolin-l(2H)-yl)-2-((l-methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 17b)

[131] The racemate mixture of compound 16 was purified by Chiral-prep-HPLC (SFC, Column: CHIRALPAK AD-H 250mm 20 mm, 5μm: Modifier: 35% EtOH (0.2%NH₄OH); Total Flow: 40 g/min) and suitable fractions were pooled and lyophilized to give:

Compound 17a (first peak, 13 mg) LC/MS: 517.0 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 7.03 - 6.88 (m, 2H), 6.85 - 6.73 (m, 2H), 6.57 - 6.51 (m, 1H), 6.26 (dd, J = 16.8, 1.9 Hz, 1H), 5.80 (dd, J = 10.6, 1.8 Hz, 1H), 4.77 -4.70 (m, 1H), 4.54 -4.46 (m, lH), 4.34 - 4.21 (m, 1H), 3.93 - 3.83 (m, 3H), 3.78 - 3.67 (m, 5H), 3.56 - 3.47 (m, 2H), 3.27 - 3.21 (m, 2H), 3.06 - 2.94 (m, 4H), 2.90 - 2.80 (m, 2H), 2.77 - 2.69 (m, 3H), 2.42 - 2.33 (m, 1H), 2.24 - 1.73 (m, 8H).

Compound 17b (second peak, 38 mg) LC/MS: 517.0 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 7.03 - 6.89 (m, 2H), 6.85 - 6.74 (m, 2H), 6.57 - 6.51 (m, 1H), 6.26 (dd, J = 16.8, 1.9 Hz, 1H), 5.80 (dd, J = 10.6, 1.9 Hz, 1H), 4.77 -4.68 (m, 1H), 4.59 -4.51 (m, 1H), 4.33 -4.24 (m, 1H), 3.95 - 3.83 (m, 3H), 3.83 - 3.64 (m, 5H), 3.62 - 3.51 (m, 2H), 3.27 - 3.18 (m, 2H), 3.10 - 2.94 (m, 4H), 2.94 - 2.70 (m, 5H), 2.44 - 2.32 (m, 1H), 2.30- 1.71 (m, 8H).

Example 10: Preparation of l-((S)-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-l- yl)prop-2-en-l-one (compound 19a) and l-((S)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-l- yl)prop-2-en-l-one (compound 19b)

[132] Compounds 18, 19a and 19b were prepared analogously with the procedure described for compounds 16, 17a and 17b.

Compound 18 LC/MS: 531.0[M+H] +. ¹H NMR (400 MHz, MeOD) δ 7.01 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.88 - 6.73 (m, 2H), 6.59 (t, J = 7.0 Hz, 1H), 6.29 (d, J = 16.4 Hz, 1H), 5.82 (d, J = 10.2 Hz, 1H), 4.87 - 4.78 (m, 1H), 4.70 - 4.26 (m, 4H), 4.24 - 4.10 (m, 1H), 4.08 - 3.85 (m, 2H), 3.83 - 3.59 (m, 2H), 3.59 - 3.35 (m, 2H), 3.29 - 3.13 (m, 3H), 3.10 - 2.82 (m, 6H), 2.75 (s, 3H), 2.47 - 2.34 (m, 1H), 2.26 - 1.77 (m, 7H), 1.42 (m, 1.5H), 1.23 (m, 1.5H).

[133] The racemate mixture (80 mg) was separated by chiral prep-HPLC (EtOH/NHiOH, flow: 12.5, Temperature: 40.3, % Modifier: 40, Pressure: 101) to give:

Comound 19a (first peak, 19 mg): ¹H NMR (400 MHz, MeOD) δ 7.01 (t, J = 7.1 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.88 - 6.74 (m, 2H), 6.57 (t, J = 7.3 Hz, 1H), 6.29 (d, J = 16.5 Hz, 1H), 5.82 (dd, J = 10.6, 1.8 Hz, 1H), 4.84 - 4.77 (m, 1H), 4.71- 4.45 (m, 2H), 4.41- 4.11 (m, 2H), 4.09 - 3.83 (m, 3H), 3.79 - 3.56 (m, 3H), 3.45 - 3.23 (s, 1H), 3.29 - 3.16 (m, 3H), 3.07 - 2.82 (m, 6H), 2.80 - 2.65 (m, 3H), 2.48 - 2.33(dd, J = 13.0, 6.5 Hz, 1H), 2.27 - 1.83 (m, 7H), 1.28 - 1.19 (m, 3H). LC/MS: 530.9[M+H]⁺.

Compound 19b (second peak, 35 mg): ¹H NMR (400 MHz, MeOD) δ 6.98 (t, 7 = 7.1 Hz, 1H), 6.91 (d, J = 7.0 Hz, 1H), 6.88 - 6.71 (m, 2H), 6.53 (t, J = 7.0 Hz, 1H), 6.27 (d, J = 16.8, 1H), 5.80 (d, J = 10.8 Hz, 1H), 4.77- 4.68 (m, 1H), 4.59 - 4.21 (m, 4H), 4.19 - 3.83 (m, 3H), 3.78 - 3.66 (m, 1H), 3.⁶⁴ - 3.32(m, 2H), 3.30 - 3.15 (m, 4H), 3.08 - 2.81 (m, 6H), 2.79 - 2.61 (m, 3H), 2.47 - 2.30 (m, 1H), 2.22 - 1.98 (m, 4H), 1.97 - 1.74 (m, 3H), 1.43 - 1.33 (m, 3H). LC/MS: 531.0[M+H]⁺.

Example 11: Preparation of 2-((2S)-l-acryloyl-4-(7-(2,3-dihydro-4H-benzo[b][l,4]oxazin-4-yl)- 2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (compound 20), 2-((S)-l-acryloyl-4-((S)-7-(2,3-dihydro-4H-benzo[b][l,4]oxazin-4- yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (compound 21a) and 2-((S)-l-acryloyl-4-((R)-7-(2,3-dihydro-4H- benzo[b][l,4]oxazin-4-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 21b)

[134] Compounds 20 and 21a, 21b were prepared analogously with the procedure described for compound 1.

Compound 20: LC/MS: 558.1 [M+H]⁺. ¹H NMR (400 MHz, MeOD): δ 6.90 - 6.88 (m, lH), 6.81 - 6.77 (m, 2H), 6.73- 6.71 (m, 1H), 6.61 - 6.57 (m, 1H), 6.30 (d, J = 16.7 Hz, 1H), 5.85 (d, J = 10.5 Hz, 1H), 5.09 - 4.90 (m, 2H), 4.85 - 4.75 (m, 1H), 4.70 - 4.67 (m, 1H), 4.41 - 4.14 (m, 6H), 3.91 - 3.71 (m, 3H), 3.65 - 3.48 (m, 2H), 3.30 - 3.21 (m, 2H), 3.12 - 3.05 (m, 6H), 2.98 - 2.89 (m, 3H), 2.40- 2.36 (m, 1H), 2.25 -2.01 (m, 4H), 1.89 - 1.79 (m, 1H).

[135] The racemate mixture (40 mg) was separated by chiral SFC (Column: CHIRALPAK AD-H 250mmx20 mm, 5μm; Modifier: CO₂ and 25% EtOH (0.2%NH₄OH); Total Flow: 40 g/min) and suitable fractions were pooled and lyophilized to give:

Compound 21a (first peak, 8.3 mg) LC/MS: 558.1 [M+H]⁺. ¹H NMR (400 MHz, MeOD): δ 6.89 - 6.79 (m, 3H), 6.75 - 6.69 (m, 1H), 6.56- 6.54 (m, 1H), 6.28 (d, J = 16.6 Hz, 1H), 5.82 (d, J = 10.8 Hz, 1H), 5.07 -5.01 (m, 1H), 4.78 -4.51 (m, 1H), 4.42 -4.38 (m, 2H), 4.26 - 4.18 (m, 3H), 4.11 - 4.06 (m, 3H), 3.73 - 3.59 (m, 1H), 3.44 - 3.31 (m, 2H), 3.21 - 3.18 (m, 1H), 3.13 - 2.71 (m, 8H), 2.60 - 2.53 (m, 4H), 2.12 - 2.08 (m, 2H), 1.93 - 1.72 (m, 4H). Compound 21b (second peak, 10 mg). LC/MS: 558.1 [M+H]⁺. ¹H NMR (400 MHz, MeOD): δ 6.87 - 6.75 (m, 3H), 6.71 - 6.69 (m, 1H), 6.57 - 6.55 (m, 1H), 6.28 (d, J = 16.6 Hz, 1H), 5.83 (d, J = 10.8 Hz, 1H),5.09 - 5.01 (m, 1H), 4.77 - 4.62 (m, 1H), 4.61 - 4.39 (m, 2H), 4.21 - 4.12 (m, 4H), 4.07 - 4.01 (m, 1H), 3.99 - 3.96 (m, 1H), 3.55 - 3.47 (m, 2H), 3.30 - 3.25 (m, 2H), 3.17 - 3.00 (m, 4H), 2.98 - 2.86 (m, 3H), 2.81 - 2.65 (m, 5H), 2.19 - 2.10 (m, 1H), 2.07 - 2.02 (m, 1H), 1.97 - 1.84 (m, 2H), 1.81 - 1.77 (m, 2H).

Example 12: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((3R,4R)- 4-methoxy-l-methylpyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (compound 22), 2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2- (((3R,4R)-4-methoxy-l-methylpyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin- 2-yl)acetonitrile (compound 23a) and 2-((S)-l-acryloyl-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)- 2-(((3R,4R)-4-methoxy-l-methylpyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydroquinazolin-4- yl)piperazin-2-yl)acetonitrile (compound 23b)

[136] Compounds 22 and 23a, 23b were prepared analogously with the procedure described for compound 1.

Compound 22: LC/MS: 572.1 [M+H]+. ¹H NMR (400 MHz, MeOD) δ 7.08 - 7.01 (m, 1H), 7.01 - 6.96 (m, 1H), 6.91 - 6.73 (m, 2H), 6.70 - 6.63 (m, 1H), 6.36 - 6.26 (m, 1H), 5.91 - 5.81 (m, 1H), 5.77 - 5.64 (m, 1H), 5.13 - 4.95 (m, 1H), 4.⁷³ - 4.51 (m, 1H), 4.43 - 4.18 (m, 4H), 4.19 - 4.04 (m, 1H), 3.94 - 3.60 (m, 3H), 3.54 - 3.44 (m, 5H), 3.37 - 3.32 (m, 1H), 3.30 - 3.20 (m, 2H), 3.14 - 3.01 (m, 4H), 3.01 - 2.81 (m, 5H), 2.81 - 2.75 (m, 2H), 2.21 - 2.10 (m, 1H), 2.04 - 1.91 (m, 2H), 1.92 - 1.80 (m, 1H).

[137] The racemate mixture was separated by Chiral-prep-HPLC (SFC, Column: CHIRALPAK AD- H 250 mm 20 mm, 5μm; Modifier: 35% ETOH (0.2%NH₄OH); Total Flow: 40 g/min) and suitable fractions were pooled and lyophilized to give:

Compound 23a (first peak): LC/MS: 572.1 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 6.97 (t, J = 7.8 Hz, 1H), 6.93 - 6.79 (m, 2H), 6.76 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.1 Hz, 1H), 6.29 (d, J = 16.5 Hz, 1H), 5.84 (d, J = 10.7 Hz, 1H), 5.42- 5.35 (m, 1H), 5.18 - 5.02 (m, 1H), 4.83 - 4.53 (m, 1H), 4.40 - 4.00 (m, 4H), 3.96 - 3.85 (m, 1H), 3.54 - 3.46 (m, 1H), 3.43 (s, 3H), 3.30 - 3.17 (m, 4H), 3.15 - 2.91 (m, 6H), 2.90 - 2.77 (m, 2H), 2.76 - 2.67 (m, 3H), 2.66 -2.57 (m, 3H), 2.13 - 2.04 (m, 1H), 1.97 - 1.78 (m, 3H).

Compound 23b (second peak): LC/MS: 572.1 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 6.98 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 6.88 - 6.72 (m, 2H), 6.54 (t, J = 7.1 Hz, 1H), 6.29 (d, J = 16.7 Hz, 1H), 5.83 (d, J = 10.5 Hz, 1H), 5.67 - 5.49 (m, 1H), 5.09 - 4.98 (m, 1H), 4.85 - 4.45 (m, 1H), 4.33 - 4.20 (m, 2H), 4.18 - 4.00 (m, 3H), 3.80 - 3.69 (m, 1H), 3.67 - 3.34 (m, 6H), 3.30 - 3.17 (m, 3H), 3.16 - 3.06 (m, 1H), 3.03 (s, 3H), 3.00 - 2.67 (m, 8H), 2.16 -2.08 (m, 1H), 1.99 - 1.77 (m, 3H).

Example 13: Preparation of 2-((2S)-l-acryloyl-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4- dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 24), 2-((S)-l-acryloyl-4-((S)-2-(3-(diethylamino)azetidin-l-yl)-7-(3,4- dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 25a) and 2-((S)-l-acryloyl-4-((R)-2-(3-(diethylamino)azetidin-l-yl)-7-(3,4- dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 25b)

Step 1: Preparation of benzyl (2S)-2-(cyanomethyl)-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4- dihydroquinolin- 1 (2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine- 1 -carboxylate [138] To a mixture of benzyl (2S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (500 mg, 0.90 mmol), N,N- diethylazetidin-3-amine (542 mg, 2.70 mmol), Xphos-Pd-G₃ (152 mg, 0.18 mmol) and CS₂CO₃ (1.17 g, 3.60 mmol) in toluene (15 mL) was added Pd₂(dba)₃ (82 mg, 0.09 mmol) under N₂ atmosphere. The reaction mixture was stirred at 105 °C for 16 h, and then filtered under reduced pressure. The filtrate was concentrated in vacuo and the residue was purified by combi-Flash (4 g, DCM/MeOH = 30/1) to give benzyl (2S)-2-(cyanomethyl)-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4-dihydroquinolin- l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l-carboxylate (300 mg, 48 %) as a yellow solid. LC/MS: 649.2 [M+H]⁺.

Step 2: Preparation of 2-((2S)-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4-dihydroquinolin-l(2H)-yl)- 5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile

[139] To a solution of benzyl (2S)-2-(cyanomethyl)-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4- dihydroquinolin- 1 (2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine- 1 -carboxylate (280 mg, 0.43 mmol) in MeOH (10 mL) was added Pd/C (560 mg, 50%). The mixture was stirred at 25 °C for 2 h under H₂ atmosphere. The reaction mixture was filtered and concentrated to give 2-((2S)-4-(2-(3- (diethylamino)azetidin-l-yl)-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4- yl)piperazin-2-yl)acetonitrile (200 mg, 85%) as a brown oil. LC/MS: 515.2 [M+H]⁺.

Step 3: Preparation of2-((2S)-l-acryloyl-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4- dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile

[140] To a solution of 2-((2S)-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4-dihydroquinolin-l(2H)-yl)- 5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (210 mg, 0.41 mmol) in DCM (10 mL) was added DIEA (105 mg, 0.82 mmol), followed by prop-2-enoyl chloride (37 mg, 0.41 mmol) at 0 °C. The mixture was stirred at 0 °C for 20 min, and diluted with ACN (5 mL) followed by NaHCO₃ aqueous solution (1 mL). The reaction mixture was concentrated under vacuum and the residue was purified with Prep-HPLC using a gradient of 0.1% TFA / ACN from 75:25 to 45:55, and suitable fractions were pooled and lyophilized to give 2-((2S)-l-acryloyl-4-(2-(3-(diethylamino)azetidin-l-yl)- 7-(3,4-dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (150 mg, 58%) as an off-white solid.

Compound 24: LC/MS: 569.0 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 7.03 (t, 7 = 7.8 Hz, 1H), 6.96 (d, 7 = 7.3 Hz, 1H), 6.88 - 6.71 (m, 2H), 6.63 (t, 7 = 7.3 Hz, 1H), 6.30 (d, J = 16.7 Hz, 1H), 5.84 (d, 7 = 10.5 Hz, 1H), 5.12- 4.95 (m, 1H), 4.70 - 4.62 (m, 1H), 4.62 - 4.52 (m, 4H), 4.49 - 4.40 (m, 2H), 4.39 - 4.20 (m, 2H), 4.19 - 4.00 (m, 1H), 3.92 - 3.71 (m, 1H), 3.64 - 3.35 (m, 2H), 3.29 - 3.17 (m, 4H), 3.05 - 2.90 (m, 3H), 2.90 - 2.79 (m, 3H), 2.79 - 2.67 (m, 3H), 2.18 - 2.08 (m, 1H), 2.02 - 1.92 (m, 2H), 1.90 - 1.82 (m, 1H), 1.34 (t, 7 = 7.3 Hz, 6H).

[141] The racemate mixture was separaed by Chiral-prep-HPLC (SFC, Column: CHIRALPAK AD-H 250 mm 20 mm, 5 μm; Modifier: 35% EtOH (0.2% NH₄OH); Total Flow: 40 g/min) and suitable fractions were pooled and lyophilized to give:

Compound 25a (first peak): LC/MS: 569.0 [M+H]+. ¹H NMR (400 MHz, MeOD) δ 6.96 (t, 7 = 7.7 Hz, 1H), 6.90 (d, 7 = 7.2 Hz, 1H), 6.85 - 6.70 (m, 2H), 6.51 (t, 7 = 7.3 Hz, 1H), 6.27 (d, 7 = 16.6 Hz, 1H), 5.82 (d, 7 = 10.4 Hz, 1H), 5.12- 5.00 (m, 1H), 4.⁷⁸ - 4.45 (m, 1H), 4.22 - 4.08 (m, 4H), 3.96 - 3.81 (m, 3H), 3.74 - 3.66 (m, 1H), 3.46 - 3.34 (m, 1H), 3.27 - 3.18 (m, 2H), 3.49 - 3.33 (m, 3H), 2.98 - 2.83 (m, 2H), 2.82 - 2.60 (m, 9H), 2.10 - 2.00 (m, 1H), 1.96 - 1.86 (m, 2H), 1.85 - 1.73 (m, 1H), 1.07 (t, J = 7.2 Hz, 6H).

Compound 25b (second peak): LC/MS: 569.0 [M+H]+. ¹H NMR (400 MHz, MeOD) δ 6.99 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 6.85 - 6.70 (m, 2H), 6.55 (t, J = 7.2 Hz, 1H), 6.29 (d, J = 16.7 Hz, 1H), 5.83 (d, J = 10.6 Hz, 1H), 5.02 - 4.91 (m, 2H), 4.57 - 4.46 (m, 4H), 4.46 - 4.21 (m, 4H), 4.15 - 4.02 (m, 1H), 3.85 - 3.52 (m, 2H), 3.47 - 3.32 (m, 1H), 3.29 - 3.23 (m, 4H), 3.23 - 3.16 (m, 1H), 3.02 - 2.92 (m, 2H), 2.91 - 2.67 (m, 6H), 2.14 -2.05 (m, 1H), 1.98 - 1.81 (m, 3H), 1.36 - 1.28 (m, 6H).

Example 14: Preparation of 2-((2S)-l-(but-2-ynoyl)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)- l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 28), 2-((S)-l-(but-2-ynoyl)-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 28a) and 2-((S)-l-(but-2-ynoyl)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 28b)

[142] To a solution of 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (270 mg, 0.54 mmol) and but-2-ynoic acid (45 mg, 0.54 mmol) and pyridine (171 mg, 2.16 mmol) in DCM (4 mL) was added phosphoryl trichloride (83 mg, 0.54 mmol) in DCM (2 mL) dropwise at 0 °C. Then. The mixture was stirred at 0 °C for 30 min and then diluted with ACN and a drop of water. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC using a gradient of 0.1% TFA / ACN from 70:30 to 50:50, and suitable fractions were pooled and lyophilized to afford compound 28(125 mg, 40%) as a yellow solid. LC/MS: 568.2[M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 6.99 - 6.95 (m, 1H), 6.97 (d, J = 7.4 Hz, 1H), 6.90 - 6.82 (m, 1H), 6.67 - 6.61 (m, 1H), 5.10 - 4.98 (m, 1H), 4.79 - 4.67 (m, 1H), 4.56 - 4.25 (m, 4H), 3.97 - 3.88 (m, 1H), 3.84 - 3.76 (m, 1H), 3.72 - 3.57 (m, 1H), 3.53 - 3.36 (m, 2H), 3.28 - 3.21 (m, 2H), 3.13 -2.94 (m, 7H), 2.92 - 2.83 (m, 2H), 2.81 - 2.70 (m, 3H), 2.45 - 2.37 (m, 1H), 2.24 - 2.12 (m, 3H), 2.12 - 2.09 (m, 2H), 2.09 - 2.03 (m, 3H), 2.00 - 1.85 (m, 3H).

[143] The racemate mixture (110 mg) was separated by chiral prep-HPLC (Et0H(NH₄0H), flow:

12.5, Temperature:40.3, % Modifier: 40, Pressure: 101) to afford: 12.6 mg PI and 28.2 mg P2 as white solid.

Compound 28a (first peak, 12.6 mg): ¹H NMR (400 MHz, MeOD) δ 6.98 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 1.1 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.53 (t, J = 7.0 Hz, 1H), 5.03-4.95 (m, 1H), 4.75-4.66 (m, 1H), 4.54 - 4.45 (m, 1H), 4.43-4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.17-4.05 (m, 2H), 3.89-3.80 (m, 1H), 3.74-3.64 (m, 1H), 3.49 - 3.32 (m, 2H), 3.28 - 3.18 (m, 3H), 3.15 - 3.00 (m, 4H), 2.98-2.83 (m, 4H), 2.82-2.70 (m, 3H), 2.43-2.31 (m, 1H), 2.26 - 1.76 (m, 11H). LC/MS: 568.1[M+H]⁺.

Compound 28b (second peak, 28.2 mg): H NMR (400 MHz, MeOD) δ 6.98 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 6.8 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.2 Hz, 1H), 5.04-4.97 (m, 1H), 4.63 - 4.36 (m, 4H), 4.30-4.19 (m, 2H), 4.03-3.94 (m, 1H), 3.52-3.36 (m, 3H), 3.26-3.19 (m, 2H), 3.15 - 3.04 (m, 3H), 2.99 - 2.81 (m, 6H), 2.78-2.69 (m, 3H), 2.29-2.19 (m, 1H), 2.15 - 1.77 (m, 11H). LC/MS: 568.2[M+H]⁺.

Example 15: 2-((2S)-l-acryloyl-4-(7-(3-hydroxy-3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Compound 31)

[144] Compound 31 was prepared analogously with the procedure described for compound 1. LC/MS: 572 [M+H]⁺. Ή NMR (400 MHz, MeOD) δ 8.48 (s, 3H), 7.01 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 6.7 Hz, 1H), 6.90 - 6.67 (m, 2H), 6.58 (t, J = 12 Hz, 1H), 6.29 (d, J = 16.9 Hz, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.13 - 5.03 (m, 1H), 4.86 - 4.71 (m, 1H), 4.70 - 4.42 (m, 3H), 4.38 - 4.19 (m, 2H), 4.15 - 4.06 (m, 1H), 4.05 - 3.95 (m, 1H), 3.74 - 3.38 (m, 4H), 3.26 - 3.01 (m, 6H), 3.01 - 2.92 (m, 3H), 2.91 - 2.61 (m, 5H), 2.38 - 2.26 (m, 1H), 2.21 - 1.94 (m, 4H), 1.88 - 1.76 (m, 1H).

Example 16: Preparation of 2-((2S)-l-acryloyl-4-(7-(indolin-l-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 33)

[145] Compound 33 was prepared analogously with the procedure described for compoundl. LC/MS: 541.9 [M+H]+. ¹H NMR (400 MHz, MeOD) δ 7.14 - 7.00 (m, 2H), 6.89 - 6.72 (m, 1H), 6.71 - 6.57 (m, 2H), 6.30 (d, J = 16.7 Hz, 1H), 5.84 (d, J = 11.0 Hz, 1H), 5.05 - 4.91 (m, 1H), 4.86 -4.80 (m, 1H), 4.70 - 4.59 (m, 1H), 4.42 - 4.26 (m, 2H), 4.23 - 4.00 (m, 2H), 3.99 - 3.85 (m, 1H), 3.85 - 3.56 (m, 3H), 3.51 - 3.36 (m, 3H), 3.27 - 3.17 (m, 1H), 3.15 - 2.73 (m, 11H), 2.47 - 2.32 (m, 1H), 2.25 - 1.96 (m, 4H), 1.82 - 1.68 (m, 1H).

Example 17: 2-((2S)-l-acryloyl-4-(7-(6-fluoro-3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 37)

[146] Compound 37 was prepared analogously with the procedure described for compoundl. LC/MS: 574.3 [M+H]+. ¹H NMR (400 MHz, MeOD) δ 6.81 - 6.72 (m, 4H), 6.32 (d, J = 16.0 Hz, 1H), 5.84 (d, J = 12.0 Hz, ^1H), 4.70 - 4.65 (m, 1H), 4.42 - 4.23 (m, 4H), 3.92 - 3/74 (br, 3H), 3.48 - 3.43 (br, 2H), 3.26 - 3.17 (m, 4H), 3.09 - 2.74 (m, 10H), 2.40 (br, 1H), 2.22 - 1.84 (m, 8H)

Example 18: 2-[(2S)-4-[7-(6-methoxy-3,4-dihydro-2H-quinolin-l-yl)-2-{[(2S)-l- methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydroquinazolin-4-yl]-l-(prop-2-enoyl)piperazin-2- yljacetonitrile (compound 39)

[147] Compound 39 was prepared analogously with the procedure described for compoundl. LC/MS: 586.0 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 7.29 - 7.01 (m, 1H), 6.99 - 6.57 (m, 3H), 6.35 - 6.23 (m, 1H), 5.93 - 5.78 (m, 1H), 5.16 - 4.92 (m, 1H), 4.85 - 4.76 (m, 1H), 4.74 - 4.46 (m, 2H), 4.33 - 4.05 (m, 3H),

3.99 - 3.65 (m, 5H), 3.64 - 3.32 (m, 4H), 3.30 - 3.18 (m, 2H), 3.17 - 2.54 (m, 11H), 2.45 - 2.34 (m, 1H), 2.34 - 1.91 (m, 6H), 1.90 - 1.68 (m, 1H).

Example 19: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((2S,4R)- 4-fluoro-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (compound 69)

[148] Compound 69 was prepared analogously with the procedure described for compoundl. LC/MS: 574.1 [M+H] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.07 - 7.00 (m, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.89 - 6.71 (m, 2H), 6.63-6.60 (m, 1H), 6.30 (d, J = 16.8 Hz, 1H), 5.85 (d, J = 10.3 Hz, 1H), 5.59 - 5.40 (m, 1H), 5.20 - 4.94 (m, 2H), 4.86 - 4.74 (m, 1H), 4.62 - 4.24 (m, 4H), 4.22 - 3.95 (m, 2H), 3.93 - 3.37 (m, 4H), 3.35-3.32 (m, 1H), 3.30-3.24 (m, 1H), 3.23-3.18 (m, 1H), 3.16 (d, J = 4.6 Hz, 3H), 3.07-2.97 (m, 2H), 2.96-2.88 (m, 2H), 2.87 -2.81 (m, lH), 2.80-2.73 (m, 2H), 2.72-2.63 (m, 1H), 2.48 - 2.25 (m, 1H), 2.16 (d, J = 12.5 Hz, 1H), 2.05 - 1.81 (m, 3H).

Example 20: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((2S,4S)- 4-fluoro-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (compound 70)

[149] Compound 70 was prepared analogously with the procedure described for compoundl. LC/MS: 574.0 [M+H] ⁺. 1H NMR (400 MHz, MeOD) δ 7.06-7.03 (m, 1H), 7.01-6.95 (m, 1H), 6.90 - 6.85 (m, 1H), 6.85-6.73

(m, 1H), 6.70 - 6.62 (m, 1H), 6.30 (d, J = 16.8 Hz, 1H), 5.85 (d, J = 10.5 Hz, 1H), 5.37-5.36 (m, 1H), 5.20-4.95 (m, 2H), 4.80-4.71 (m, 1H), 4.65-4.26 (m, 3H), 4.25 - 3.96 (m, 3H), 3.96 - 3.42 (m, 4H), 3.38 - 3.32 (m, 1H), 3.30 - 3.20 (m, 2H), 3.16 (d, J = 7.6 Hz, 3H), 3.05-2.75 (m, 8H), 2.43-2.25 (m, 1H), 2.17 (d, J = 12.3 Hz, 1H), 2.06 - 1.80 (m, 3H).

Example 21: l-((2R)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-2-methylpiperazin-l-yl)prop-2-en-l-one (compound 59)

[150] Compound 59 was prepared analogously with the procedure described for compoundl. LC/MS: 531.2[M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 7.03 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.86 (m, 1H), 6.78 (m, 1H), 6.62 (t, J = 7.3 Hz, lH), 6.26 (d, J = 16.5 Hz, 1H), 5.80 (d, J = 10.6 Hz, 1H), 4.92 - 4.86 (m, 1H), 4.80 - 4.59 (m, 2H), 4.58 - 4.08 (m, 4H), 4.06 - 3.86 (m, 2H), 3.84 - 3.72 (m, 1H), 3.67 - 3.39 (m, 2H), 3.30 - 3.17 (m, 3H), 3.10 - 2.70 (m, 9H), 2.48 - 2.35 (m, 1H), 2.27 - 1.80 (m, 7H), 1.39 - 1.18 (m, 3H).

Example 22: Preparation of l-((2R,5S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazin-l- yl)prop-2-en-l-one (compound 60)

Step 1: Preparation of tert-butyl (2R,5S)-4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)-2,5- dimethylpiperazine- 1 -carboxylate

[151] To a solution of 2, 4-dichloro-7 -ethoxy-5, 6-dihydroquinazoline (4.5 g, 18.4 mmol) in DMSO (100 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-l-carboxylate (4.7 g, 22 mmol) and DIEA (4.7 g, 36.7 mmol). The mixture was stirred at 120 °C overnight. The reaction was poured into water (200 mL) and extracted with EA (100 mL X 2). The organic layer was dried over Na₂SO₄, concentrated and purified by Combi-Flash (EA/PE=0-25%) to afford tert-butyl (2R,5S)-4-(2-chloro-7- ethoxy-5,6-dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate (3.3 g, 42 %) as a yellow oil. LC/MS: 423.1 [M+H]⁺.

Step 2: Preparation of 2-chloro-4-((2S,5R)-2,5-dimethylpiperazin-l-yl)-7-ethoxy-5,6- dihydroquinazoline

[152] To a solution of tert-butyl (2R,5S)-4-(2-chloro-7-ethoxy-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5- dimethylpiperazine-1 -carboxylate (3.3 g, 7.8 mmol) in DCM (30 mL) was added TFA (7 mL). The mixture was stirred at rt for 2 h. The mixture was diluted with DCM (50 mL) and washed with aqueous NaHC03 (50 mL X 2). The organic layer was dried over Na2S04 and concentrated to afford the crude products. LC/MS: 323 [M+H]+. Step 3: Preparation of benzyl (2R,5S)-4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)-2,5- dimethylpiperazine- 1 -carboxylate

[153] To a solution of 2-chloro-4-[(2S,5R)-2,5-dimethylpiperazin-l-yl]-7-ethoxy-5,6- dihydroquinazoline (2.48 g, 7.68 mmol) in DCM (50 mL) was added DIEA (3 g, 23.04 mmol) and benzyl chloroformate (1.97 g, 11.52 mmol). The mixture was stirred for lh at rt. The reaction was concentrated and purified by Combi-flash (PE/EA= from 5:1 to 3:1) to afford benzyl (2R,5S)-4-(2- chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate (3.3 g, 94%) as a yellow oil. LC/MS: 457.0 [M+H]⁺.

Step 4: Preparation of benzyl (2R,5S)-4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5- dimethylpiperazine- 1 -carboxylate

[154] To a solution of benzyl (2R,5S)-4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)-2,5- dimethylpiperazine-1 -carboxylate (1.8 g, 3.94 mmol) in dioxane (20 mL) was added HC1 (6 N in H₂0, 20 mL). The mixture was stirred at 50 °C for 16 h. The mixture was concentrated, poured into ice NaHCO₃ (50 mL) and extracted with EA (50 mL X2). The combined organic layers were dried over Na₂SO₄, concentrated and purified by Combi-Flash (EA/PE = 0-30%) to afford benzyl (2R,5S)-4-(2- chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate (1.3 g, 77 %) as a yellow oil. LC/MS: 429.1[M+H]⁺.

Step 5: Preparation of benzyl (2R,5S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6- dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate

[155] To a solution of benzyl (2R,5S)-4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5- dimethylpiperazine-1 -carboxylate (1.3 g, 3.03 mmol) in toluene (20 mL) was added 1,2, 3, 4- tetrahydroquinoline (404 mg, 3.03 mmol) and AcOH (364 mg, 6.06 mmol). The reaction was stirred overnight at 105 °C. The mixture was concentrated in vacuo and used for next step without further purification. LC/MS: 544.0[M+H]⁺.

Step 6: Preparation of benzyl (2R,5S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate

[156] To a solution of benzyl (2R,5S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6- dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate (1.5 g, 2.76 mmol) in AcOH (10 mL) was added NaBHi (524 mg, 13.78 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was quenched with aq. NaHCO₃ (50 mL) and extracted with EA (50 mL X 2). The combined organic layers were dried over Na₂SO₄, concentrated and purified by Combi-flash (EA/PE = 0-35%) to afford benzyl (2R,5S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5- dimethylpiperazine-1 -carboxylate (425 mg, 28%) as an off-white solid. LC/MS: 546.0 [M+H]⁺.

Step 7: Preparation of benzyl (2R,5S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate

[157] To a solution of benzyl (2R,5S)-4-(2-chloro-7-(3,4-dihydroquinolin- l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate (400 mg, 0.88 mmol) in Toluene (10 mL) was added [(2R)-l-methylpyrrolidin-2-yl]methanol (166 mg, 1.44 mmol), RuPhos (67 mg, 0.14 mmol), CS2CO₃ (703 mg, 2.16 mmol) and Pd2(dba)3 (66 mg, 0.07 mmol). The mixture was stirred at 100 °C overnight. The mixture was filtered, concentrated and purified by Combi-Flash (4 g, EA/PE=0-60%) to afford benzyl (2R,5S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate (400 mg, 87%) as a yellow solid. LC/MS: 625.2 [M+H]⁺.

Step 8: Preparation of7-(3,4-dihydroquinolin-l(2H)-yl)-4-((2S,5R)-2,5-dimethylpiperazin-l-yl)-2- (((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazoline

[158] To a solution of benzyl (2S)-2-(cyanomethyl)-4-[7-(3,4-dihydro-2H-quinolin-l-yl)-2-{[(2R)-l- methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydroquinazolin-4-yl]piperazine-l-carboxylate (400 mg, 0.64 mmol) in MeOH (10 mL) was added Pd/C (600 mg). The mixture was stirred for 1 h at rt under H₂ atmosphere. The mixture was filtered and the filtrate was concentrated to afford 7-(3,4- dihydroquinolin-l(2H)-yl)-4-((2S,5R)-2,5-dimethylpiperazin-l-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazoline (230 mg, 73%) as a colorless oil. LC/MS: 490.9[M+H]⁺. Step 9: Preparation of l-((2R,5S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazin-l-yl)prop-2-en-l-one

[159] To a solution of 7-(3,4-dihydro-2H-quinolin-l-yl)-4-[(2S,5R)-2,5-dimethylpiperazin-l-yl]-2- {[(2S)-l-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydroquinazoline (100 mg, 0.2 mmol) in DCM (5 mL) was added DIEA (52 mg, 0.4 mmol) and prop-2-enoyl chloride (18 mg, 0.2 mmol). The mixture was stirred for 25 min at 0 °C. The mixture was added MeCN (5 mL) and NaHCO₃ (1 mL), concentrated and purified by Prep-HPLC (0.2% TFA in water/ MeCN = from 75% to 45%) to afford compound 60 (65 mg, 59%) as a white solid.

LC/MS: 545.2 [M+H]⁺. lH NMR (400 MHz, MeOD) δ 7.07 - 7.00 (m, 1H), 6.99 - 6.93 (m, 1H), 6.90 - 6.71 (m, 2H), 6.62 (d, J = 7.3 Hz, 1H), 6.32 - 6.24 (m, 1H), 5.86 - 5.78 (m, 1H), 5.08 - 4.91 (m, 2H), 4.74 - 4.51 (m, 2H), 4.49 - 4.23 (m, 2H), 4.10-3.98 (m, 1H), 3.95-3.85 (m, 2H), 3.82-3.73 (m, 1H), 3.67 - 3.52 (m, 1H), 3.27 - 3.17 (m, 2H), 3.12 - 2.95 (m, 5H), 2.92-2.83 (m, 1H), 2.81-2.68 (m, 3H), 2.48 - 2.35 (m, 1H), 2.24 - 1.84 (m, 8H), 1.48 - 1.37 (m, 2H), 1.34-1.15 (m,4H).

Example 23: 7-(3,4-dihydroquinolin-l(2H)-yl)-4-((S)-3-methylpiperazin-l-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazoline (compound 61)

[160] Compound 61 was prepared analogously with the procedure described for compound 1.

LC/MS: 531.0 [M+H]⁺.

1H NMR (400 MHz, MeOD) δ 7.01 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.87 - 6.73 (m, 2H), 6.59 (t, J = 7.3 Hz, 1H), 6.26 (d, J = 16.9 Hz, 1H), 5.80 (d, J = 10.9 Hz, 1H), 4.87 - 4.78 (m, 1H), 4.70-4.68 (m, 1H), 4.53 (d, J = 13.8 Hz, 1H), 4.35-4.32 (m, 3H), 4.14-4.12 (m, 1H), 3.87-3.85 (m,

1H), 3.75-3.73 (m, 1H), 3.68 - 3.33 (m, 3H), 3.29 - 3.11 (m, 3H), 3.06-3.04 (m, 3H), 2.94-2.92 (m, 4H), 2.76 (m, 2H), 2.48 - 2.35 (m, lH), 2.26 - 1.84 (m, 7H), 1.31-1.30 (m, 3H).

Example 24: l-((2S,5S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazin-l-yl)prop-2-en-l-one (Compound 62)

[161] Compound 62 was also prepared by procedures similar to the one described in compound 60, replacing tert-butyl (2R,5S)-2,5-dimethylpiperazine-l-carboxylate in step 1 with tert-butyl (2S,5S)- 2,5-dimethylpiperazine- 1 -carboxylate.

LC/MS:545.5[M+H]⁺.

1H NMR (400 MHz, MeOD) δ 7.01 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.87 - 6.68 (m, 2H), 6.63-6.56 (m, 1H), 6.25 (d, J = 16.0 Hz, 1H), 5.79 (dd, J = 10.7, 3.3 Hz, 1H), 4.95 -4.90 (m, 1H), 4.89 - 4.78 (m, 2H), 4.71 - 4.45 (m, 3H), 4.29 (s, 2H), 3.91 (s, 1H), 3.75 (d, J = 9.1 Hz, 1H), 3.61 -

3.46 (m, 1H), 3.29 - 3.15 (m, 3H), 3.14 - 2.98 (m, 4H), 2.97 - 2.80 (m, 3H), 2.79 - 2.70 (m, 2H),

2.47 - 2.35 (m, 1H), 2.26 - 1.81 (m, 7H), 1.43 (d, J = 6.0 Hz, 2H), 1.28 (d, J = 6.2 Hz, 4H).

Example 25: Preparation of 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-((E)-4- (dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile (compound 63), 2-((S)-4-((S)-7-(3,4- dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)-l-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile (compound 64) and 2-((S)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-((E)-4-(dimethylamino)but-2-enoyl)piperazin- 2-yl)acetonitrile (compound 65)

Step 1: Preparation of2-((2S)-4-(7-(3,4-dihydroqumolm-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2- yl)acetonitrile

[162] To a solution of 2-[(2S)-4-[7-(3,4-dihydro-2H-quinolin-l-yl)-2-{[(2S)-l-methylpyrrolidin-2- yl]methoxy}-5,6,7,8-tetrahydroquinazolin-4-yl]piperazin-2-yl]acetonitrile (240 mg, 0.48 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid (62 mg, 0.48 mmol) in DCM was added pyridine (190 mg, 2.4 mmol) and POCl₃ (74 mg, 0.48 mmol). The mixture was stirred at rt for 6 h. The mixture was diluted with MeCN (5 mL) and quenched with lmL aq. NaHCO₃. The mixture was concentrated and purified with Prep-HPLC to give 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-((E)-4-(dimethylamino)but-2- enoyl)piperazin-2-yl)acetonitrile (50 mg, 17%) as a yellow oil. LC/MS: 613.3[M+H]⁺.

[163] The racemate mixture (43 mg) was separated with by SFC ( Column: CHIRALPAK OJ-H 250mm X 20 mm, 5μm; Modifier: CO₂ and 40% MeOH (0.2%NH₄OH); Total Flow: 40g/min) and suitable fractions were pooled and lyophilized to give:

Compound 64 (Peak 1, 5.5 mg). LC/MS: 613.2 [M+H]+. lH NMR (400 MHz, MeOD) δ 6.98 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 6.1 Hz, 1H), 6.89 - 6.71 (m, 3H), 6.53 (t, J = 7.0 Hz, 1H), 5.09 (s, 1H), 4.84-4.79 (m, lH), 4.61 (s, 1H), 4.49-4.43 (m, 1H), 4.29-4.23 (m, 2H), 4.06-4.01 (m, 2H), 3.65 - 3.52 (m, 2H), 3.47-3.42 (m, 2H), 3.29 - 3.21 (m, 2H), 3.21 - 3.01 (m, 5H), 3.01 - 2.80 (m, 6H), 2.75-2.71 (m, 3H), 2.53-2.48 (m, 6H), 2.34 - 2.26 (m, 1H), 2.20 - 1.76 (m, 7H).

Compound 65 (Peak 2, 6.3 mg). lH NMR (400 MHz, MeOD) δ 6.97 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 6.9 Hz, 1H), 6.87 - 6.65 (m, 3H), 6.53 (t, J = 7.0 Hz, 1H), 5.12-4.97 (m, 1H), 4.85-4.72 (m, 1H), 4.56-4.50 (m, 1H), 4.46-4.41 (m, 1H), 4.26 (d, J = 4.5 Hz, 1H), 4.11-4.06 (m, 3H), 3.79-3.74 (m, 1H), 3.48-3.45 (m, 3H), 3.29 - 3.13 (m,

3H), 3.12-3.02 (m, 1H), 3.01 -2.65 (m, 12H), 2.45-2.32 (m, 6H), 2.27-2.21 (m, 1H), 2.13-2.09 (m,

1H), 2.05 - 1.80 (m, 6H).

Example 26: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(2- (dimethylamino)ethoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 50b), 2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(2- (dimethylamino)ethoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 50) and 2-((S)-l-acryloyl-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(2- (dimethylamino)ethoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 50a)

[164] Compound 50b, 50 and 50a are prepared analogously with the procedure described for compound 1.

Compound 50b: LC/MS: 530.0 [M+H]+. 1H NMR (400 MHz, MeOD) 7.02 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 6.83 (m, 2H), 6.61 (t, J = 7.3 Hz, 1H), 6.31 (d, J = 16.8 Hz, 1H), 5.85 (d, J = 10.0 Hz, 1H), 5.09-5.08 (m, 1H), 4.88-4.86 (m, lH), 4.47-4.45 (m, 2H), 4.24-4.21 (m, 3H), 3.92-3.90 (m, 1H), 3.67-3.64 (m, 2H), 3.50-3.47 (m, 2H), 3.29 - 3.18 (m, 2H), 3.15 - 2.80 (m, 12H), 2.78-2.76 (m, 2H), 2.16-2.14 (m, 1H), 2.03 - 1.80 (m, 3H).

[165] The racemate mixture was separated by SFC (Column: CHIRALPAK AD-H 250 mm 20 mm,

5 μm; Modifier: 35% EtOH (0.2%NH₄OH); Total Flow: 40 g/min) and suitable fractions were pooled and lyophilized to give:

Compound 50 (peak 1)

1H NMR (400 MHz, MeOD) δ 6.98 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 6.79 (m, 2H), 6.54 (t, J = 7.2 Hz, 1H), 6.29 (d, J = 16.9 Hz, 1H), 5.83 (d, J = 10.7 Hz, 1H), 5.04 (s, 1H), 4.81 - 4.66 (m, 2H), 4.34 - 4.01 (m, 4H), 3.75-3.77 (m, 1H), 3.64 - 3.46 (m, 3H), 3.28 - 3.10 (m, 3H), 3.06 - 2.93 (m, 7H), 2.87-2.84 (m, 4H), 2.81 - 2.65 (m, 3H), 2.14-2.11 (m, 1H), 2.01 - 1.78 (m, 3H).

LC/MS: 530.0 [M+H]+.

Compound 50a (peak 2) lH NMR (400 MHz, MeOD) δ 6.99 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.82-6.79 (m, 2H), 6.55 (t, J = 7.3 Hz, 1H), 6.29 (d, J = 17.3 Hz, 1H), 5.84 (d, J = 10.9 Hz, 1H), 5.09 (s, 1H), 4.59-4.56 (m, 4H), 4.32 - 4.00 (m, 3H), 3.79-3.76 (m, 1H), 3.63 - 3.56 (m, 2H), 3.49-3.47 (m, 1H), 3.29 - 3.14 (m, 4H), 3.13-3.10 (m, 1H), 3.04 - 2.91 (m, 7H), 2.91 - 2.71 (m, 4H), 2.11-2.10 (m, 1H), 2.00 - 1.80 (m, 3H).

Example 27: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((R)-l- methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 66)

[166] Compound 66 was prepared analogously with the procedure described for compound 1.

LC/MS :556.2 [M+H]⁺.

1H NMR (400 MHz, MeOD) δ 7.02 - 6.99 (m, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.86-6.73 (m, 2H), 6.60 - 6.58 (m, 1H), 6.31 (d, J = 16.8 Hz, 1H), 5.85 (d, J = 10.6 Hz, 1H), 5.14-4.96 (m, 1H), 4.75 -4.39

(m, 4H), 4.35-4.12 (m, 2H), 4.06 - 3.61 (m, 5H), 3.52-3.43 (m, 1H), 3.29-3.25 (m, 1H), 3.24 - 3.16 (m, 2H), 3.15-3.11 (m, 1H), 3.04-2.95 (m, 5H), 2.95 -2.83 (m, 3H), 2.78-2.72 (m, 2H), 2.55 - 2.41

(m, 1H), 2.33 - 2.11 (m, 2H), 2.03-1.81 (m, 4H).

Example 28: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(2- (dimethylamino)-2-methylpropoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (compound 67)

[167] Compound 67 was prepared analogously with the procedure described for compound 1.

LC/MS: 558.0 [M+H]⁺. lH NMR (400 MHz, MeOD) δ 7.02 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.90 - 6.74 (m, 2H), 6.64-6.60 (m, 1H), 6.30 (d, J = 17.1 Hz, 1H), 5.84 (d, J = 11.5 Hz, 1H), 4.98-4.9 (m, 1H), 4.78 -4.51 (m, 3H), 4.20-4.16 (m, 4H), 3.80-3.75 (m, 2H), 3.54 - 3.35 (m, 2H), 3.26 - 3.19 (m, 1H), 2.95-2.90 (m, 13H), 2.14-2.12 (m, 1H), 1.93-1.90 (m, 3H), 1.53-1.50 (m, 6H).

Example 29: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpiperidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 68)

[168] Compound 68 was prepared analogously with the procedure described for compound 1.

LC/MS: 569.8 [M+H]⁺.

1H NMR (400 MHz, MeOD) δ 7.02 (t, J = 7.7 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.92 - 6.72 (m, 2H),

6.61 (t, J = 7.3 Hz, 1H), 6.30 (d, J = 16.8 Hz, 1H), 5.84 (d, J = 9.7 Hz, 1H), 5.09-5.07 (m, 1H), 4.63-

4.61 (m, 3H), 4.27-4.25 (m, 4H), 3.87 - 3.36 (m, 5H), 3.28 - 3.06 (m, 3H), 3.06 - 2.81 (m, 8H), 2.76- 2.74 (m, 2H), 2.20 - 2.03 (m, 2H), 2.02 - 1.59 (m, 8H).

Example 302-((2S)-l-acryloyl-4-(2-(((S)-4,4-difluoro-l-methylpyrrolidin-2-yl)methoxy)-7-(3,4- dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 71)

[169] Compound 71 was prepared analogously with the procedure described for compound 1.

LC/MS: 592.0 [M+H] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.09 - 6.92 (m, 2H), 6.88-6.70 (m, 2H), 6.63 - 6.60 (m, 1H), 6.31 (d, J = 16.7 Hz, 1H), 5.85 (d, J = 10.2 Hz, 1H), 5.03-4.96 (m, 1H), 4.90-4.80 (m, 1H), 4.79 - 4.67 (m, 1H), 4.52 -4.24 (m, 3H), 4.21-3.97 (m, 3H), 3.92-3.75 (m, 1H), 3.67 - 3.39 (m, 3H), 3.30 - 3.27 (m, 1H), 3.27-3.18 (m, 1H), 3.15-2.95 (m, 6H), 2.95-2.80 (m, 4H), 2.80-2.72 (m, 2H), 2.67-2.55 (m, 1H), 2.17

- 2.13 (m, 1H), 2.03 - 1.83 (m, 3H).

Example 31: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((R)-4- methylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 72)

[170] Compound 72 was prepared analogously with the procedure described for compound 1. LC/MS: 571.8 [M+H]⁺.

1H NMR (400 MHz, MeOD) δ 7.01 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 6.7 Hz, 1H), 6.82-6.80 (m, 2H), 6.58 (t, J = 7.3 Hz, 1H), 6.31 (d, J = 16.9 Hz, 1H), 5.86-5.84 (m, 1H), 5.04-5.02 (m, 1H), 4.87-4.85

(m, 1H), 4.64-4.62 (m, 2H), 4.36-4.35 (m, 3H), 4.12-4.10 (m, 3H), 3.87-3.85 (m, 2H), 3.64-3.62 (m, 2H), 3.50-3.49 (m, 2H), 3.19-3.17 (m, 5H), 2.98-2.97 (m, 4H), 2.89-2.85 (m, 3H), 2.77-2.75 (m, 2H),

2.16-2.14 (m, 1H), 1.93-1.91 (m, 3H).

Example 32: Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((R)-l- methylpiperidin-3-yl)oxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 73)

[171] Compound 73 was prepared analogously with the procedure described for compound 1. LC/MS: 556.2 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 7.03 - 7.01 (m, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.88 - 6.73 (m, 2H), 6.62-6.60 (m, 1H), 6.31 (d, J = 16.8 Hz, 1H), 5.73-5.56 (m, 1H), 5.64 (d, J = 52.1 Hz, 1H), 5.11-4.98 (m, 0.5 H), 4.74-4.63 (m, 0.5H), 4.57 - 4.00 (m, 4H), 3.95-3.70 (m, 2H), 3.68 - 3.34 (m, 4H), 3.29- 3.19 (m, 2H), 3.15 - 2.68 (m, 12H), 2.27-2.09 (m, 3H), 2.06 - 1.80 (m, 5H).

Example 33: Gel shift assay to determine the activity of the exemplary compounds in modifying mutant KRAS (KRAS-G12C) and wild type KRAS [172] 0.5 mM compounds were incubated with 1 mM GDP-bound untagged KRAS (G12C or wild type) proteins at 25 °C for 5 minutes in 40 μl reaction buffer (50 mM Tris, pH 7.5, 100 mM NaCl, 1 mM MgCl₂, 1 mM DTT). The reactions were quenched with 10 μl SDS-PAGE sample loading buffer (250 mM Tris-HCl, pH 6.8, 10% SDS, 0.5% bromophenol blue, 50% glycerol and 50 mM DTT) and then analyzed via SDS-PAGE using 4%-20% gradient polyacrylamide gel followed by Coomassie blue stain.

[173] Table 3 summarizes molecular weight shift of KRAS-G12C mutant on SDS-PAGE after 5 mins of coincubation at 25 °C with exemplary compounds of the present disclosure, indicative of cov alent cysteine conjugation.

Table 3: Molecular weight shift of KRAS-G12C mutant on SDS-PAGE

Example 34: TR-FRET assay to determine the activity of the claimed compounds in inhibiting KRAS-GDP to KRAS-GTP exchange induced by SOS1

[174] GDP form of 6*His tagged KRAS-G12C was diluted to 40 nM and incubated with 8 nM LanthaScreen™ Elite Terbium-anti-HIS Antibody (Thermo, catalog number PV5863) in reaction buffer containing 20 mM Tris, pH 7.5, 100 mM NaCl, 1 mM DTT, 0.1% Tween20, 0.05% BSA, 2% DMSO, 1 mM MgCl₂. After 1 hour-incubation at 4 °C, proteins were placed in 384 well plate (PerkinElmer, PROXIPLATE-384 PLUS). Then compounds with different concentrations were added to the proteins. BODIPY labeled GTP (Thermo, catalog number G12411) and SOS-1 (or reaction buffer as control) were then added to reactions at 200 nM and 1 mM to trigger the exchange of GDP to BODIPY-GTP. TR-FRET emission signals were determined at 520 nm and 620 nm on a EnVision® Multilabel Plate Reader (PerkinElmer) using a 337 nm laser as light source. All data were analyzed and plotted using GraphPad Prism software (version 8.0.1). Raw TR-FRET data were converted to percentage of inhibition (relative to DMSO) using the following equations: a) Emission ratio = Em520/Em620 b) For a given test compound concentration X:

Signal (X) = Emission ratio (SOS-1 & GTP) - Emission ratio (buffer & GTP) c) Percentage of inhibition at concentration X = [1 - Signal(X)/Signal (DMSO)] *100%

[175] The IC50 values were determined by nonlinear regression of plots of [inhibitor] vs. percentage of inhibition with variable slope.

[176] Table 4 summarizes inhibition of SOSl-assisted GDP/GTP exchanging activity of KRAS- G12C mutant with exemplary compounds of the present disclosure.

Table 4: Inhibition of SOSl-assisted GDP/GTP exchanging activity of KRAS-G12C mutant

Example 35: pERK and ERK western blot analysis

[177] MIA PaCa-2 (ATCC) cells were plated in 24-well plates at 2x10⁵ cells/well in RPMI growth medium containing 10% FBS and lx Penicillin Streptomycin. They were then incubated at 37°C overnight. The following day, the test compound was administered to the cells by using 1000x compound stock solution prepared in DMSO at various concentrations. After administration of the compound, the cells were then incubated at 37°C for 4 hours.

[178] Upon completion, the cells were washed with PBS and protein was collected in Laemmli sample buffer (lx; VWR International). Proteins in cell lysate were separated by SDS-PAGE and transferred to Odyssey nitrocellulose membranes (Licor) with iblot® dry blotting transfer system (ThermoFisher). Nonspecific binding was blocked by incubating membranes with Intercept Blocking Buffer (Licor) for 1 hour at room temperature with gentle shaking. The membranes were then incubated overnight at 4°C with primary antibodies rabbit anti-phospho p44/42 MAPK (Erkl/2) (1:2,000, Cell Signaling, 4370) and mouse anti-p44/42 MAPK (Erkl/2) (1:1,000, Cell Signaling, 4696) diluted in Intercept Blocking Buffer containing 0.1% Tween 20. After washing 3 times with TBS-T, the membranes were incubated with IRDye® 800CW goat anti-rabbit IgG (1:20,000, Licor) or IRDye® 680CW goat anti-mouse IgG (1:20,000, Licor) for 1 hour. After TBS-T washes, membranes were rinsed in TBS and scanned on Odyssey® CLx Imaging System (Licor). The bands were quantified using Image Studio™ Software (Licor).

[179] Table 5 summarizes phospho-ERKl/2 (Thr202/Tyr204) inhibition by exemplary compounds of the present disclosure in a MIA PaCa-2 cell line 4 hours after administration. A: <100 nM; B: >100 nM and <1,000 nM; C: >1,000 nM.

Table 5: Phospho-ERKl/2 (Thr202/Tyr204) inhibition in MIA PaCa-2 cell line

Example 36: 3D cell growth assay

[180] MIA PaCa-2 (ATCC), NCI-H358 (ATCC), NCI-H23 (ATCC), SW837 and A549 (ATCC) cells were plated in round bottom 96-well spheroid microplates (Corning. 4520) at 3000 cells/well in 90 μl of RPMI growth medium containing 10% FBS and 1% Penicillin Streptomycin. Calu-1 (ATCC) cells were plated in round bottom 96-well spheroid microplates (Corning. 4520) at 3000 cells/well in 90 μl of DMEM growth medium containing 10% FBS and 1% Penicillin Streptomycin. Cells were incubated at 37°C overnight. The following day, the test compound was administered to the cells by using 10x compound stock solution prepared in growth medium at various concentrations. After administration of the compound, cells were then incubated at 37°C for 6 days. Before CellTiter-Glo assay, the plates were equilibrated at room temperature for approximately 10 minutes. 100 μl of CellTiter-Glo® Reagent (Promega, G7573) was added to each well. The plates were then incubated at room temperature for 10 minutes and luminescence was recorded by EnSpire plate reader (PerkinElmer).

[181] Table 6 illustrates growth inhibition (GI50) by exemplary Compound 1 of the present disclosure in multiple cell lines 6 days after administration in 3D cell culture.

Table 6: Growth inhibition (GI50) of compounds in multiple cell lines in 3D cell assay

[182] The many features and advantages of the present disclosure are apparent from the detailed specification, and thus it is intended by the appended claims to cover all such features and advantages of the present disclosure that fall within the true spirit and scope of the present disclosure. Further, since numerous modifications and variations will readily occur to those skilled in the art, it is not desired to limit the present disclosure to the exact construction and operation illustrated and described and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the present disclosure.

[183] Moreover, those skilled in the art will appreciate that the conception upon which this disclosure is based may readily be used as a basis for designing other structures, methods, and systems for carrying out the several purposes of the present disclosure. Accordingly, the claims are not to be considered as limited by the foregoing description or examples.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I) a isotopic derivative or a pharmaceutically acceptable salt thereof:

wherein:

X¹ is CR¹ or N;

X² is CR² or N;

X³ is CR³ or N;

X⁴ is CR⁴ or N; each of R¹, R², R³ and R⁴ is independently hydrogen, halogen, -CN, C₁-C₅alky I, C₁-C₅alkoxy, or C₁-C₅haloalkyl;

Q is a bond, -O-, -CH₂-, -OCH2-, or -CH₂O-;

R⁵ is spirocyclopropyl, or 0, 1, or 2 R⁶;

Y is C_1-6 alkoxy, O-C_0-3 alkylene-C_3-14 cycloalkyl, or O-C_0-3 alkylene-C_2-14 heterocycloalkyl, each of which is substituted with 0, 1, or 2 R⁶;

A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered ring, each of which is substituted with 0, 1, 2, or 3 R⁶;

R⁷ is C_1-6 alkyl, C_1-6 alkoxy I, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkylene-OH, C_1-6 alkyleneamine, or C_1-6 alkylene-CN, each of which is substituted with 0,1, 2, or 3 R⁶; and

R⁶ is independently hydroxy, halogen, C_1-6 alkyl, C_1-6 alkoxyl, C_3-6 cycloalkyl, C_1-6haloalkyl, C_1-6 haloalkoxyl, C_0-3 alkylene-CN, orC_0-3 alkylene-N-(C_1-6 alkyl)₂.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X¹ is CR¹,

X² is CR², X³ is CR³, and X⁴ is CR⁴.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴ are each independently H, F, Cl, -CH₃, -OCH₃, or -CN.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴ are each H.

5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R¹ is Cl, F or -CH₃.

6. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R² is Cl.

7. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R³ is F, - OCH₃or -CN.

8. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein X¹ is N.

9. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein X³ is N.

10. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein X⁴ is N.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen, halogen, -OH, or spirocyclopropyl.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ is 2 R⁶ and R⁶ is halogen and C₁-C₅alkyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R³ is 2 R⁶ and R⁶ is F and -CH₃.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is

, each of which is substituted with 0, 1 or 2 R⁶.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein A is

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is -

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is stereoisomer.

19. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolm-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroqumolin-l(2H)-yl)-2-(((S)-l-(methyl-d3)pyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((R)-7-(3,4-dihydroquinolm-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-

5.6.7.8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile;

2-((S)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yr)acetomtrile;

2-((S)-l-acryloyl-4-((S)-7-(8-methyl-3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolm-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((R)-7-(8-methyl-3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((S)-7-(8-chloro-3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S) - 1 -acryloyl-4-((R)-7-(8 -chloro-3,4-dihydroquinolin- 1 (2H)-yl)-2-(((S) - 1 -methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-4-((S)-7-(8-chloro-3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-

5.6.7.8-tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-((R)-7-(8-chloro-3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-

5.6.7.8-tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-

5.6.7.8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(2,2-dimethyl-2,3-dihydro-4H-benzo[b][l,4]oxazin-4-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)- 1 -acryloyl-4-(2-(((S)- 1 -methylpyrrolidin-2-yl)methoxy)-7-(spiro [benzo [b] [ 1 ,4]oxazine-2, 1 cyclopropan]-4(3H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)- 1 -acryloyl-4-(7-(5-fluoro-2, 3-dihydro-4H-benzo [b] [ 1 ,4]oxazin-4-yl)-2-(((S)- 1 - methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile; l-(4-(7-(3,4-dihydioquinoUn-l(2H)-yl)-2-(((S)-l-methylpym)Udm-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one; l-(4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one; l-(4-((R)-7-(3,4-dihydroqumolm-l(2H)-yl)-2-(((S)-l-methylpynOlidm-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one; l-((3S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpynolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-3-methylpiperazin- 1 -yl)prop-2-en- 1 -one; l-((S)-4-((S)-7-(3,4-dihydroqumolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidm-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-3-methylpiperazin- 1 -yl)prop-2-en- 1 -one;

1-((S)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpynOlidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-3-methylpiperazin- 1 -yl)prop-2-en- 1 -one;

2-((2S)-l-acryloyl-4-(7-(2,3-dihydro-4H-benzo[b][l,4]oxazin-4-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)- 1 -acryloyl-4-((S)-7-(2, 3-dihydro-4H-benzo [b] [ 1 ,4]oxazin-4-yl)-2-(((S)- 1 -methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((R)-7-(2,3-dihydro-4H-benzo[b][l,4]oxazin-4-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((3R,4R)-4-methoxy-l-methylpyrrolidin-

3-yl)oxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((3R,4R)-4-methoxy-l- methylpyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S) - 1 -acryloyl-4-((R)-7-(3,4-dihydroquinolin- 1 (2H)-yl)-2-(((3R,4R)-4-methoxy- 1 - methylpyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((2S)-l-acryloyl-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((S)-2-(3-(diethylamino)azetidin-l-yl)-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((R)-2-(3-(diethylamino)azetidin-l-yl)-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile; methyl (2S)-2-(cyanomethyl)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l-carboxylate;

2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-l-propioloylpiperazin-2-yl)acetonitrile;

2-((2S)-l-(but-2-ynoyl)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-l-(but-2-ynoyl)-4-((S)-7-(3,4-dihydroquinoIin-l(2H)-yl)-2-(((S)-l-methylpyrroUdin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-(but-2-ynoyr)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(7-(4-hydroxy-3,4-dihydroquinolm-l(2H)-yl)-2-(((S)-l-methylpynOlidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(7-(4,4-difluoro-3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(7-(3-hydroxy-3,4-dihydroquinolm-l(2H)-yl)-2-(((S)-l-methylpynOlidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(7-(3-fluoro-3,4-dihydroqumolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(7-(indolin-l-yl)-2-(((S)-l -methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydro-l,5-naphthyridin-l(2H)-yl)-2-(((S)-l-methylpyrrolidm-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydro-l,6-naphthyridin-l(2H)-yl)-2-(((S)-l-methylpyrrolidm-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydro-l,8-naphthyridin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(7-(6-fluoro-3,4-dihydroqumolm-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(7-chloro-3,4-dihydroqumolin-l(2H)-yl)-2-(((S)-l-methylpynOlidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(6-methoxy-3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

1-(4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-l-yl)-2-(((S)-l-methylpyrrolidin-2-yr)methoxy)- 5,6,7,8-tetrahydroquinazolin-7-yl)-l,2,3,4-tetrahydroquinoline-6-carbonitrile;

2-((2S)-l-acryloyl-4-(7-(2,3-dihydrobenzo[e][l,4]oxazepin-l(5H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile; 2-((2S)-l-acryloyl-4-(7-(3,4-dihydrobenzo[b][l,4]oxazepin-5(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroqumolin-l(2H)-yl)-2-(((2S,4R)-4-fluoro-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroqumolm-l(2H)-yl)-2-(((2S,4S)-4-fluoro-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile; 2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(3-morpholinopropoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile; l-((3S,5S)-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-

5.6.7.8-tetrahydroquinazolin-4-yl)-3,5-dimethylpiperazin-l-yl)prop-2-en-l-one; l-(7-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yr)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-l-one; l-(6-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-l-one;

1-((R)-4-((S)-7-(3,4-dihydroqumolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-2-methylpiperazin- 1 -yl)prop-2-en- 1 -one;

2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(2-(dimethylammo)ethoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((S)-l-acryloyl-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8- tetrahydroqumazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(7-(3, 4-dihydroqumolin-l(2H)-yl)-2-(2-(dimethylamino)ethoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-((tetrahydro-lH-pyrrolizm-7a(5H)- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-((2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-((l-(pyrrolidm-l- ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-((l-

((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile;

2-((2S)-4-(7-(3,4-dihydroqumolm-l(2H)-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-

5.6.7.8-tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-((2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5,6,7,8-tetrahydroquinazolm-4-yl)-l-(2-fluoroacryloyl)piperazm-2-yl)acetomtrile; 2-((2S)-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-((l-(pyrrolidm-l-ylmethyl)cyclopropyl)methoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-((l-((dimethylammo)methyl)cyclopropyl)methoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; l-((2R)-4-(7-(3, 4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpynolidm-2-yl)methoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2-methylpiperazin- 1 -yl)prop-2-en- 1 -one; l-((2R,5S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpynOlidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazin-l-yl)prop-2-en-l-one; l-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-2-methylpiperazin- 1 -yl)prop-2-en- 1 -one;

1-((2S,5S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazin-l-yl)prop-2-en-l-one;

2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-l-((E)-4-(dimethylainino)but-2-enoyl)piperazin-2-yl)acetomtrile; 2-((S)-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-l-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile; 2-((S)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-l-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2-yl)acetomtrile; 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((R)-l-methylpyrrolidin-3-yl)methoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-(2-(dimethylamino)-2-methylpropoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-(((S)-l-methylpiperidm-2-yl)methoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-(((2S,4R)-4-fluoro-l-methylpynOlidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((2S,4S)-4-fluoro-l-methylpyrrolidm-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetomtrile;

2-((2S)-l-acryloyl-4-(2-(((S)-4,4-difluoro-l-methylpyrrolidin-2-yl)methoxy)-7-(3,4-dihydroquinolin- l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroqumolin-l(2H)-yl)-2-(((R)-4-methylmorpholin-2-yl)methoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile; or

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((R)-l-methylpiperidin-3-yl)oxy)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-(methyl-d3)pyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-l-acryloyl-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-

5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile;

2-((S)-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpynOlidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)- 1 -(2-fluoroacryloyl)piperazin-2-yl)acetomtrile; or 2-((S)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile.

21. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and one or more of a pharmaceutically acceptable carrier, a pharmaceutically acceptable vehicle, a pharmaceutically acceptable excipient, or combinations thereof.

22. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or the pharmaceutical composition of claim 21.

23. The method of claim 22, wherein the cancer is breast cancer, lung cancer, pancreatic cancer, colorectal cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.

24. The method of claim 23, wherein the cancer is lung cancer.

25. The method of claim 23, wherein the cancer is pancreatic cancer.

26. The method according to claim 23, wherein the cancer is colorectal cancer.

27. A use of the compound of claim 1 or of the pharmaceutical composition of claim 21 in the preparation of a medicament.

28. A method of inhibiting KRAS G12C in a cell, comprising contacting the cell with the compound of claim 1 or the pharmaceutical composition of claim 21.

29. The method of claim 23, comprising administering to the subject combination therapy wherein the composition of claim 1 or the pharmaceutical composition of claim 21 is administered with an additional anti-cancer agent.

30. The method of claim 29, wherein the composition of claim 1 or the pharmaceutical composition of claim 21 and the additional anti-cancer agent are administered concomitantly.

31. The method of claim 29, wherein the composition of claim 1 or the pharmaceutical composition of claim 21 and the additional anti-cancer agent are administered sequentially.