Tricyclic pyridones and pyrimidones

Abstract

Compounds having KRAS G12C inhibitory activity and methods of using same to treat cancers containing the K-Ras G12C mutation are disclosed.

Description

[Technical field]

[0001] Sequence Listing Reference This application incorporates by reference the computer readable form (CRF) of the Sequence Listing submitted with this application in ASCII text format, entitled 2023-04-24 Sequence_Listing_ST26 055745-542001WO.xml, created on April 24, 2023, and having a size of 5,290 bytes. [Background technology]

[0002] FIELD OF THE DISCLOSURE Embodiments herein relate to compounds and methods for the treatment of RAS-mediated diseases. In particular, embodiments herein relate to compounds and methods for treating diseases such as cancer by targeting oncogenic mutants of the K-RAS isoform.

[0003] Ras proteins are small guanine nucleotide-binding proteins that function as molecular switches by cycling between an active GTP-bound conformation and an inactive GDP-bound conformation. Ras signaling is controlled by a balance between activation by guanine nucleotide exchange factors (GEFs), usually by Sons of Sevenless (SOS), and inactivation by GTPase-activating proteins (GAPs), such as neurofibromin or p120GAP. Ras proteins play a key role in controlling cell proliferation, differentiation, and survival. Dysregulation of the Ras signaling pathway is almost exclusively associated with disease. Hyperactivating somatic mutations of Ras are among the most common lesions in human cancers. Most of these mutations have been shown to reduce the sensitivity of Ras to GAP stimulation, reducing its intrinsic GTPase activity and leading to an increase in the active GTP-bound population. Mutations in any one of the three Ras isoforms (K-Ras, N-Ras, or H-Ras) have been shown to cause oncogenic transformation, although K-Ras mutations are the most common in human cancers. For example, K-Ras mutations are known to be frequently associated with pancreatic, colon, and non-small cell lung cancers. Similarly, H-Ras mutations are common in cancers such as papillary thyroid cancer, lung cancer, and skin cancer. Finally, N-Ras mutations occur frequently in hepatocellular carcinoma.

[0004] There is a need for effective Ras inhibitors that could provide a new class of anti-cancer compounds. These and other advantages will become apparent to those skilled in the art based on the embodiments and disclosure herein. Summary of the Invention

[0005] In some aspects, embodiments disclosed herein relate to compounds of formula (I): [ka] During the ceremony, Each R 1 is independently methyl or cyanomethyl; n is an integer from 0 to 2, X is -CCF3 or -C-halogen; Ar 1 is aryl or heteroaryl optionally substituted with one or more alkyl, halogen, hydroxy, or amino; Ar 2 is a C-linked aryl or heteroaryl optionally substituted with alkyl or halogen.

[0006] In some aspects, embodiments herein relate to a method of treating a subject having a cancer associated with a G12C Kras mutation, the method comprising administering to the subject a compound disclosed herein in a pharma- ceutically acceptable vehicle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] I. Overview Disclosed herein are potent and selective tricyclic quinazolin-2-one compounds that have been found to be useful as inhibitors of oncogenic mutants of RAS proteins. Among other advantages, the compounds disclosed herein are selective for oncogenic RAS mutants over wild-type RAS proteins. Furthermore, the compounds disclosed herein may exhibit selectivity for oncogenic mutants of K-RAS over other mutant K-RAS proteins, as well as mutants of N-RAS and H-RAS isoforms. In particular, the compounds disclosed herein may exhibit selectivity for K-RAS, N-RAS, and H-RAS mutants that share the common G12C mutation. Also disclosed herein are pharmaceutical compositions that include these compounds, and their application in treating diseases such as cancer. Also provided are methods for inhibiting oncogenic mutant K-RAS, N-RAS, and H-RAS activity, as well as methods for treating oncogenic mutant RAS-mediated diseases, particularly diseases associated with elevated levels of oncogenic mutant RAS, particularly in cancer.

[0008] Disclosed herein is a class of compounds useful for the treatment of oncogenic RAS-mediated disorders and conditions, the class of compounds being defined by structural formula (I): [ka] During the ceremony, Each R 1 is independently methyl or cyanomethyl; n is an integer from 0 to 2, X is -CCF3 or -C-halogen; Ar 1 is aryl or heteroaryl optionally substituted with one or more alkyl, halogen, hydroxy, or amino; Ar 2 is a C-linked aryl or heteroaryl optionally substituted with alkyl or halogen.

[0009] The compounds according to various embodiments disclosed herein have useful oncogenic mutant RAS inhibitory or modulating activity and can be used to treat or prevent diseases or conditions in which oncogenic mutant RAS plays an active role. Thus, in a broad aspect, the embodiments disclosed herein also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharma- ceutically acceptable carrier, as well as methods of making and using the compounds and compositions. The embodiments disclosed herein provide methods for selectively inhibiting an oncogenic mutant RAS having a G12C mutation. In some embodiments, methods are provided for treating oncogenic mutant K-RAS-mediated disorders in a subject, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition according to various embodiments disclosed herein. Related embodiments disclose the use of the compounds disclosed herein as therapeutic agents, for example, in the treatment of cancer and other diseases associated with elevated levels of oncogenic mutant K-RAS. The various embodiments disclosed herein also contemplate the use of the compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the inhibition of oncogenic mutant K-RAS. In some embodiments, the disease is cancer. Each of the above methods applies equally to similar mutations in N-RAS and H-RAS with a G12C mutation.

[0010] The compounds of various embodiments disclosed herein may be selective among RAS oncogenic mutations in various ways. For example, the compounds described herein may be selective for the G12C mutant of K-RAS, N-RAS, or H-RAS. In certain embodiments, the compounds of various embodiments disclosed herein may be selective for K-RAS G12C compared to other K-RAS mutants and wild-type K-RAS. Similarly, the compounds of various embodiments disclosed herein may be selective for N-RAS and H-RAS with the same G12C mutation.

[0011] Various embodiments disclosed herein also relate to a method for inhibiting at least one RAS function, comprising contacting oncogenic mutant RAS with a compound of formula I described herein.Cell phenotype, cell proliferation, activity of mutant RAS, change in biochemical output produced by active mutant RAS, expression of mutant RAS, or binding of mutant RAS to natural binding partner may be affected.Such methods may include disease treatment modalities, biological assays, cellular assays, or biochemical assays, etc.

[0012] II. Definition A. General definition As used herein, the following terms have the meanings indicated.

[0013] When a range of numerical values ​​is disclosed and the notation "from n1 to ... n2" is used, where n1 and n2 are numbers, the notation is intended to include the numbers themselves and the range therebetween, unless otherwise specified. The range may be integer or continuous between and including the end values. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. As an example, compare the range "1 to 3 μM (micromolar)" to any number of significant digits (e.g., 1.255 μM, 2.1 M, 2.9999 M, etc.), which is intended to include 1 μM, 3 μM, and everything in between.

[0014] The term "about" as used herein is intended to modify the numerical value it modifies and indicates a value that is variable within an acceptable error. In the absence of a specific acceptable error, such as a standard deviation for an average value shown in a data chart, the term "about" should be understood to mean a range that encompasses the recited value and the range encompassed by rounding up or down to that number, taking into account the significant digits.

[0015] As used herein, "a," "an," or "the" includes embodiments with one member as well as embodiments with multiple members. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, reference to "the agent" includes reference to one or more agents known to those of skill in the art, and so forth.

[0016] B. Chemical definition The following definitions of chemical functional groups are provided to provide guidance in understanding their meaning and scope. Those of ordinary skill in the art will recognize that these functional groups are used in a manner consistent with the practice of the chemical arts. Any of the following chemical functional groups may be optionally substituted as defined below, and each of the following chemical functional groups may itself be optionally substituted.

[0017] The term "acyl," as used herein alone or in combination, refers to a carbonyl (C=O) bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or any other moiety where the atom bonded to the carbonyl is carbon. An "acetyl" group, which is a type of acyl, refers to the (--C(=O)CH3) group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group bonded to the parent molecular moiety through a carbonyl group. Examples of such groups include, but are not limited to, methylcarbonyl and ethylcarbonyl. Similarly, an "arylcarbonyl" or "aroyl" group refers to an aryl group bonded to the parent molecular moiety through a carbonyl group. Examples of such groups include, but are not limited to, benzoyl and naphthoyl. Thus, general examples of acyl groups include alkanoyl, aroyl, heteroaroyl, and the like. Specific examples of acyl groups include, but are not limited to, formyl, acetyl, acryloyl, benzoyl, trifluoroacetyl, and the like.

[0018] The term "alkenyl" as used herein alone or in combination refers to a straight or branched chain hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkenyl may contain 2 to 6 carbon atoms, or 2 to 4 carbons, either of which may be referred to as a lower alkenyl. The term "alkenylene" refers to a carbon-carbon double bond system bonded at two or more positions, such as ethenylene (--CH=CH--). Alkenyl refers to any number of carbons, e.g., C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C36, C37, C38, C39, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C51, C52, C53, C54, C55, C56, C57, C58, C59, C61, C62, C63, C64, C65, C66, C67, C68, C69, C71, C72, C73, C74, C75, C75, C76, C77, C78, ​​C79, C81, C92, C93, C94, C95, C96, C97, C98, C99, C101, C112, C123, C132, C143, C144, C151, C152, C163, C164, C175, C185, C196, C197, C198, C199, C213, C1 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6, and C6. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted. Unless otherwise specified, the term "alkenyl" can include "alkenylene" groups.

[0019] The term "alkoxy" as used herein alone or in combination refers to an alkyl ether radical, where the term alkyl is as defined below. An alkoxy group can have the general formula: alkyl-O-. With respect to the alkyl group, the alkoxy group can be any of the following: C 1~6 Alkoxy groups can have any suitable number of carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. Alkoxy groups can be further optionally substituted as defined herein.

[0020] The term "alkyl" (sometimes abbreviated as Alk), as used herein alone or in combination, refers to a straight or branched chain alkyl radical containing 1 to 20 carbon atoms. In certain embodiments, an alkyl can contain 1 to 10 carbon atoms. In further embodiments, an alkyl can contain 1 to 6 carbon atoms, or 1 to 4 carbon atoms. An alkyl is any of the groups represented by C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 1~7 , C 1~8 , C1~9 , C 1~10 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C5~6 For example, C 1~6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, and the like. Alkyl groups can be substituted or unsubstituted. The term "alkylene" as used herein alone or in combination refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon bonded at two or more positions, such as methylene (--CH2--). Unless otherwise specified, the term "alkyl" can include an "alkylene" group. When alkyl is methyl, it can be structurally represented as CH3, Me, or just a single bond terminating without end group substitution.

[0021] The term "alkylamino," as used herein alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups are, for example, N-methylamino (--NHMe), N-ethylamino (--NHEt), N,N-dimethylamino (--NMe2), N,N-ethylmethylamino (--NMeEt), and the like. The term "aminoalkyl" refers to the reverse orientation in which the amino group appears distal to the parent molecular moiety and the bond to the parent molecular moiety is through the alkyl group. For example, NH2(CH2) n-describes an aminoalkyl group having a terminal amine at the end of the alkyl group attached to the parent molecular moiety. The two terms alkylamino and aminoalkyl can be combined to describe an "alkylaminoalkyl" group, where the alkyl group is MeNH(CH2) n In a similar manner, aryl groups as defined herein can be attached in a similar manner to the arylaminoalkyl group ArNH(CH2), n For added clarity, a nomenclature may be provided in which groups attached to a nitrogen are designated using "N-" in the name, e.g., N-arylaminoalkyl, which is understood to mean that the aryl group is a substituent on the nitrogen atom of the aminoalkyl group and the alkyl is attached to the parent molecular moiety.

[0022] The term "alkylidene," as used alone or in combination herein, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[0023] The term "alkylthio", as used herein alone or in combination, refers to an alkylthioether (AlkS-) radical, where the term alkyl is as defined above and sulfur may be singly or doubly oxidized. Examples of suitable alkylthioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like. Similarly, "arylthio" refers to an arylthioether (ArS-) radical, where the term aryl is as defined herein and sulfur may be singly or doubly oxidized.

[0024] The term "alkynyl" as used herein alone or in combination refers to a straight or branched chain hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkynyl contains 2 to 6 carbon atoms. In further embodiments, the alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene. Alkynyl includes C2, C6, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C21, C22, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C51, C52, C53, C54, C55, C56, C57, C58, C59, C61, C62, C63, C64, C65, C66, C67, C68, C69, C71, C72, C73, C74, C75, C75, C76, C77, C78, ​​C79, C81, C92, C93, C94, C95, C96, C97, C98, C99, C100, C111, C122, C132, C142, C150, C151, C163, C174, C185, C195, C196, C197, C198, C199, C200, C211, C222, C33, C34, C45, C56, C67, C78, ​​C79, 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6 , and any number of carbons, such as C6. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted. Unless otherwise specified, the term "alkynyl" can include "alkynylene" groups.

[0025] The term "amido", as used herein alone or in combination, refers to an amino group, as described below, attached to the parent molecular moiety through a carbonyl group. The term "C-amido", as used herein alone or in combination, refers to a -C(=O)N(R) group, where R is as defined herein. The term "N-amido", as used herein alone or in combination, refers to a RC(=O)N(R')-- group, where R and R' are as defined herein. The term "acylamino", as used herein alone or in combination, includes an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH3C(O)NH-).

[0026] The term "amino" as used herein, alone or in combination, means --N(R)(R') or --N + (R)(R')(R''), where R, R', and R'' are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted.

[0027] The term "amino acid" as used herein alone or in combination means a substituent of the form --NRCH(R')C(O)OH, where R is typically hydrogen but may be cyclized at N (e.g., as in the amino acid proline), and R' is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, amido, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, thiol, thioalkyl, alkylthioalkyl, and alkylthio, any of which may be substituted. The term "amino acid" includes all naturally occurring amino acids, as well as synthetic analogues.

[0028] The term "aryl" as used herein alone or in combination means a carbocyclic aromatic system containing one, two, or three rings, which may be linked together in a pendant manner or may be fused. The term "aryl" encompasses aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, and biphenyl.

[0029] The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

[0030] The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

[0031] The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

[0032] The term "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

[0033] The terms "arylalkanoyl" or "aralkanoyl" or "aroyl" as used herein alone or in combination refer to an acyl radical derived from an aryl substituted alkanecarboxylic acid, such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0034] The term "aryloxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy group.

[0035] The terms "benzo" and "benz", as used herein, alone or in combination, refer to the divalent radical CH derived from benzene. Examples include benzothiophene and benzimidazole.

[0036] The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (--NHCOO--), which may be attached to the parent molecular moiety through either the nitrogen or the acid (oxygen) terminus, and which may be optionally substituted as defined herein.

[0037] The term "O-carbamyl," as used herein, alone or in combination, refers to a --OC(O)NRR' group, with R and R' as defined herein.

[0038] The term "N-carbamyl," as used herein, alone or in combination, refers to a ROC(O)NR'-- group, with R and R' as defined herein.

[0039] The term "carbonyl" as used herein alone includes formyl [--C(=O)H] and in combination the group -C(=O)--.

[0040] The term "carboxyl" or "carboxyl" as used herein refers to --C(=O)OH, O-carboxy, C-carboxy, or the corresponding "carboxylate" anion, such as in a carboxylate salt. An "O-carboxy" group refers to a RC(=O)O-- group, where R is as defined herein. A "C-carboxy" group refers to a --C(=O)OR group, where R is as defined herein.

[0041] The term "cyano," as used herein, alone or in combination, refers to --CN.

[0042] The term "cycloalkyl" or alternatively "carbocycle", as used herein alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl radical, each cyclic moiety containing 3 to 12 carbon atom ring members, which may optionally be a benzo-fused ring system, optionally substituted as defined herein. In some embodiments, a cycloalkyl may contain 3 to 7 carbon atoms, or 5 to 7 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic" and "tricyclic" are intended to include both fused ring systems, e.g., decahydronaphthalene, octahydronaphthalene, and polycyclic (multi-center) saturated or partially unsaturated types. The latter type of isomers are commonly exemplified by bicyclo[1.1.1]pentane, camphor, adamantane, and bicyclo[3.2.1]octane.

[0043] As used herein, the term "electrophilic moiety" is used according to its plain and ordinary chemical meaning to refer to a chemical group that is electrophilic. Exemplary electrophilic moieties include, but are not limited to, unsaturated carbonyl-containing compounds, such as acrylamides, acrylates, unsaturated (i.e., vinyl) sulfones or phosphates, epoxides, and vinyl epoxides.

[0044] The term "ester," as used herein alone or in combination, refers to a carboxyl group bridging two moieties joined at a carbon atom (--CRR'C(=O)OCRR'--), where each R and R' is independent and defined herein.

[0045] The term "ether" as used herein alone or in combination refers to an oxy group that typically bridges two moieties attached at a carbon atom. "Ether" can also include polyethers such as, for example, --RO(CH2)2O(CH2)2O(CH2)2OR', --RO(CH2)2O(CH2)2OR', --RO(CH2)2OR', and --RO(CH2)2OH.

[0046] The terms "halo" or "halogen," as used herein, alone or in combination, refer to fluorine, chlorine, bromine, and iodine.

[0047] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0048] The term "haloalkyl", as used herein alone or in combination, refers to an alkyl radical having the meaning defined above, in which one or more hydrogens are replaced by halogen. Specifically, monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl radicals are included. For example, monohaloalkyl radicals can have iodo, bromo, chloro, or fluoro atoms in the radical. Dihalo and polyhaloalkyl radicals can have two or more of the same halo atoms, or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group that is attached at two or more positions. Examples include fluoromethylene (--CFH--), difluoromethylene (--CF2--), chloromethylene (--CHCl--), and the like.

[0049] The term "heteroalkyl" as used herein alone or in combination means a stable linear or branched chain, or cyclic hydrocarbon group, or combination thereof, consisting of the specified number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized (i.e., bonded to four groups). The heteroatom(s) O, N, and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, --CH2NHOCH3. The term heteroalkyl may include ethers.

[0050] The terms "heteroaryl" or "heteroaromatic," as used herein alone or in combination, refer to a 3- to 7-membered unsaturated heteromonocyclic ring or fused polycyclic ring, each of which is 3- to 7-membered and at least one of the fused rings is unsaturated, where at least one atom is selected from the group consisting of O, S, and N. In some embodiments, a heteroaryl may contain 5 to 7 carbon atoms. The term also encompasses fused polycyclic groups in which a heterocyclic radical is fused to an aryl radical, a heteroaryl radical is fused to another heteroaryl radical, or a heteroaryl radical is fused to a cycloalkyl radical. Non-limiting examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0051] Heteroaryl or heteroaromatic groups can contain any number of ring atoms, for example, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Heteroaryl groups can contain any suitable number of heteroatoms, for example, 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5, etc. Heteroaryl groups can have 5-8 ring members and 1-4 heteroatoms, or 5-8 ring members and 1-3 heteroatoms, or 5-6 ring members and 1-4 heteroatoms, or 5-6 ring members and 1-3 heteroatoms. Heteroaryl groups may include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups may also be fused to aromatic ring systems, such as phenyl rings, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings joined by bonds, such as bipyridine. Heteroaryl groups may be substituted or unsubstituted.

[0052] The heteroaryl or heteroaromatic group can be attached through any position on the ring, for example, pyrrole is 1-, 2-, and 3-pyrrole, pyridine is 2-, 3-, and 4-pyridine, imidazole is 1-, 2-, 4-, and 5-imidazole, pyrazole is 1-, 3-, 4-, and 5-pyrazole, triazole is 1-, 4-, and 5-triazole, tetrazole is 1- and 5-tetrazole, pyrimidine is 2-, 4-, 5-, and 6-pyrimidine, pyridazine is 3- and 4-pyridazine, 1,2,3-triazine is 4- and 5-triazine, 1,2,4-triazine is 3-, 5-, and 6-triazine, 1,3,5-triazine is 2-triazine, thiophene is 2- and 3-thiophene, furan is 2- and and 3-furan, thiazole includes 2-, 4-, and 5-thiazole, isothiazole includes 3-, 4-, and 5-isothiazole, oxazole includes 2-, 4-, and 5-oxazole, isoxazole includes 3-, 4-, and 5-isoxazole, indole includes 1-, 2-, and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3-, and 4-quinoline, isoquinoline includes 1-, 3-, and 4-isoquinoline, quinazoline includes 2- and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran.

[0053] Some heteroaryl or heteroaromatic groups include those having 5 to 10 ring members and 1 to 3 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Additionally, other heteroaryl groups include those having 5 to 6 ring members and 1 to 2 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0054] The terms "heterocycloalkyl" and, interchangeably, "heterocycle" or "heterocyclyl", as used herein alone or in combination, refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic radical containing at least one heteroatom as a ring member, where each heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, a heterocycloalkyl may contain 1 to 4 heteroatoms as ring members. In certain embodiments, a heterocycloalkyl may contain 1 to 2 heteroatoms as ring members. In some embodiments, a heterocycloalkyl may contain 3 to 8 ring members in each ring. In certain embodiments, a heterocycloalkyl may contain 3 to 7 heteroatoms as ring members. In certain embodiments, a heterocycloalkyl may contain 5 to 6 heteroatoms as ring members. "Heterocycloalkyl" and "heterocycle" are intended to include sugars, sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzofused ring systems, and both terms also include systems in which a heterocycle is fused to an aryl group, as defined herein, or an additional heterocyclic group. Examples of heterocycloalkyl groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, epoxy, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Heterocycloalkyl groups may be optionally substituted unless specifically prohibited.

[0055] "Heterocycloalkyl" refers to a saturated ring system having 3-12 ring members and 1-5 N, O, and S heteroatoms. Heteroatoms such as, but not limited to, S(O) and S(O)2 can also be oxidized. Heterocycloalkyl groups can contain any number of ring atoms, for example, 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl group, such as 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. Heterocycloalkyl groups include those having C 3~6 , C 4~6 , C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 , and C 3~12Heterocycloalkyl groups may contain any number of carbons, such as aziridine, azetidine, pyrrolidine, piperidine, azepane, diazepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups may also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline, diazabicycloheptane, diazabicyclooctane, diazaspirooctane, or diazaspirononane. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with C1-6 alkyl or oxo (=O), among others. Heterocycloalkyl groups can also contain double or triple bonds, such as, but not limited to, dihydropyridine or 1,2,3,6-tetrahydropyridine.

[0056] The heterocycloalkyl group can be attached via any position on the ring. For example, the aziridine can be 1- or 2-aziridine, the azetidine can be 1- or 2-azetidine, the pyrrolidine can be 1-, 2-, or 3-pyrrolidine, the piperidine can be 1-, 2-, 3-, or 4-piperidine, the pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine, the imidazolidine can be 1-, 2-, 3-, or 4-imidazolidine, the piperazine can be 1-, 2-, 3-, or 4-piperazine, the tetrahydrofuran can be 1- or 2-tetrahydrofuran, the oxazolidine can be 2-, 3-, 4-, or 5-oxazolidine, the isoxazolidine can be 2-, 3-, 4-, or 5-isoxazolidine, the thiazolidine can be 2-, 3-, 4-, or 5-thiazolidine, the isothiazolidine can be 2-, 3-, 4-, or 5-isothiazolidine, and the morpholine can be 2-, 3-, or 4-morpholine.

[0057] When a heterocycloalkyl contains 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyls can also form rings with 5 to 6 ring members and 1 to 2 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0058] The term "hydrazinyl," as used herein alone or in combination, refers to two amino groups joined by a single bond, i.e., --N--N--. Generally, hydrazinyl groups have an optional substitution on at least one of the NH hydrogens to impart stability.

[0059] As used herein, the term "hydroxamide" or ester thereof refers to the corresponding "hydroxamate" anion, including --C(O)ON(R)O(R'), where R and R' are as defined herein, or any corresponding hydroxanoate salt.

[0060] The term "hydroxy", as used herein, alone or in combination, refers to OH.

[0061] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group. "Hydroxyalkyl" or "alkylhydroxy" refers to an alkyl group, as defined above, in which at least one of the hydrogen atoms is replaced with a hydroxy group. With respect to the alkyl group, the hydroxyalkyl or alkylhydroxy group can have any suitable number of carbon atoms, such as C1-6. Exemplary C 1~4 Hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (hydroxy in the 1- or 2-position), hydroxypropyl (hydroxy in the 1-, 2- or 3-position), hydroxybutyl (hydroxy in the 1-, 2-, 3- or 4-position), 1,2-dihydroxyethyl, and the like.

[0062] The term "imino," as used herein, alone or in combination, refers to C=NR.

[0063] The term "iminohydroxy" as used herein, alone or in combination, refers to C=N(OH) and O-ether C=N--OR.

[0064] The term "isocyanato" refers to the group --NCO.

[0065] The term "isothiocyanato" refers to the group --NCS.

[0066] The phrase "linear chain of atoms" refers to the longest linear chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0067] The term "linking group" as used herein refers to any nitrogen-containing organic fragment that serves to connect the pyrimidine or pyridone core of the compounds disclosed herein to an electrophilic moiety, E, as defined herein. Exemplary linking groups include piperazine, aminoalkyl, alkyl- or aryl-based diamines, aminocycloalkyl, amine-containing spiro rings, any of which may be optionally substituted as defined herein. In some embodiments, the linking group may comprise the moiety LQ-L'-E, where Q is a monocyclic 4-7 membered ring, or a bicyclic, bridged, or fused, or spiro 6-11 membered ring, any of which may optionally contain one or more nitrogen atoms, E is an electrophilic group, L is a bond, C1-6 alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5 Alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 For alkylene, any one carbon atom of the alkylene group can be optionally replaced with O, S or NH, and L' is a bond when Q contains a nitrogen to bond to E, otherwise L' is NR and R is hydrogen or alkyl.

[0068] The term "lower" as used herein alone or in combination means containing 1 to 6 carbon atoms, or 1 to 4 carbon atoms.

[0069] The term "mercaptyl," as used herein, alone or in combination, refers to an RS-- group, where R is as defined herein.

[0070] The term "nitro" as used herein, alone or in combination, means --NO 2を Point.

[0071] The terms "oxy" or "oxa", as used herein, alone or in combination, refer to --O--.

[0072] The term "oxo" as used herein, alone or in combination, refers to =O.

[0073] "Helhaloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms have been replaced by halogen atoms.

[0074] The term "perhaloalkyl," as used herein, alone or in combination, refers to an alkyl group in which all of the hydrogen atoms have been replaced with halogen atoms.

[0075] The term “phosphoroamido,” as used herein alone or in combination, refers to a phosphate group [(OH)P(=O)O—] in which one or more of the hydroxyl groups have been replaced with nitrogen, amino, or amide.

[0076] The term "phosphate," as used herein alone or in combination, refers to a group of the form ROP(OR')(OR)O--, where R and R' are selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. "Phosphate" includes "phosphoric acid [(OH)2P(O)O--] and related phosphate anions which may form salts.

[0077] The terms "sulfonate", "sulfonic acid", and "sulfonic acid", as used herein alone or in combination, refer to the -SOH group and its anion, where sulfonic acid is used in salt formation or sulfonate ester formation, where OH is replaced by OR, where R is not hydrogen, but is otherwise as defined herein, and is typically alkyl or aryl.

[0078] The term "sulfanyl," as used herein, alone or in combination, refers to --S--.

[0079] The term "sulfinyl," as used herein, alone or in combination, refers to --S(O)--.

[0080] The term "sulfonyl," as used herein, alone or in combination, refers to --S(O)2--.

[0081] The term "N-sulfonamido" refers to a RS(=O)2NR'-- group, with R and R' as defined herein.

[0082] The term "S-sulfonamido" refers to a -S(=O)2NRR' group, with R and R' as defined herein.

[0083] The terms "thia" and "thio" as used herein, alone or in combination, refer to an --S-- group or an ether where the oxygen is replaced by sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0084] The term "thiol", as used herein, alone or in combination, refers to a --SH group.

[0085] The term "thiocarbonyl" as used herein alone includes thioformyl --C(=S)H and in combination the group --C(=S)--.

[0086] The term "N-thiocarbamyl" refers to the group ROC(=S)NR'--, with R and R' as defined herein.

[0087] The term "O-thiocarbamyl" refers to a --OC(.dbd.S)NRR'-- group, with R and R' as defined herein.

[0088] The term "isothiocyanato" refers to the group --CNS.

[0089] The term “trihalomethanesulfonamide” refers to a X 3 CS(═O) 2 NR— group, where X is halogen and R is defined herein.

[0090] The term "trihalomethanesulfonyl" refers to a X3CS(=O)2-- group where X is a halogen.

[0091] The term "trihalomethoxy" refers to a X3CO-- group where X is a halogen.

[0092] The term "trisubstituted silyl" as used herein alone or in combination refers to a silicone group substituted in its three free valences with a group listed herein under the definition of substituted amino. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, etc.

[0093] In embodiments of the present disclosure, any one of the positions understood to have hydrogen may be present or may be understood to be isotopically enriched. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. It may be difficult to obtain 100% deuteration at any relevant site of a compound in milligram or larger quantities. Thus, even if a deuterium atom is specifically shown in a chemical structure, it is understood that some percentage of hydrogen may still be present. Thus, when a chemical structure contains a "D", the compound represented by that structure is deuterium enriched at the site represented by the "D". Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen at its naturally occurring isotopic composition. Also, unless otherwise noted, when a position is specifically designated as "D" or "deuterium," it is understood that the position has deuterium in an abundance at least 3340 times greater than the natural abundance of deuterium, i.e., 0.015% (i.e., the term "D" or "deuterium" indicates an incorporation of at least 50.1% deuterium). In embodiments, the benzene ring may optionally be present as -CD, -CDH, -CDH, -CDH, -CDH, and -CDH. In embodiments, the cyclohexyl group may optionally be present as -CD 11 It can exist as:

[0094] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is the one that is attached to the parent moiety. For example, an alkylamide composite group represents an alkyl group that is attached to the parent molecule through an amide group, and the term alkoxyalkyl represents an alkoxy group that is attached to the parent molecule through an alkyl group.

[0095] When a group is defined as "null", what is meant is that the group is not present. A "null" group occurring between two other groups may also be understood to be a collapse of the adjacent groups. For example, -(CH2) x G 1 G2 G 3 In the above, element G 2 When is null, the group is --(CH2) x G 1 G 3 become.

[0096] The term "optionally substituted" means that the preceding group(s) may be substituted or unsubstituted. The group that constitutes the optional substitution may itself be optionally substituted. For example, if an alkyl group is encompassed by an optional substitution, the alkyl group itself may also be optionally substituted. When substituted, substituents on an "optionally substituted" group include, but are not limited to, one or more substituents independently selected from the following groups or a specific set of specified groups, alone or in combination: alkyl, alkenyl, alkynyl, alkanoyl, heteroalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, lower perhaloalkyl, perhaloalkoxy, cycloalkyl, phenyl, aryl, aryloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, alkylcarbonyl, carboxyester, carboxamido, cyano, hydrogen, halogen, hydroxy, amino, alkylamino, arylamino, amido, nitro, thiol, alkylthio, haloalkylthio, perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N, SH, SCH, C(O)CH, COCH, COH, pyridinyl, thiophene, furanyl, carbamate, and urea. Specific subsets of optional substitutions include, but are not limited to, (1) alkyl, halo, and alkoxy, (2) alkyl and halo, (3) alkyl and alkoxy, (4) alkyl, aryl, and heteroaryl, (5) halo and alkoxy, and (6) hydroxyl, alkyl, halo, alkoxy, and cyano. When an optional substitution involves a heteroatom-hydrogen bond (-NH-, SH, OH), further optional substitution of the heteroatom hydrogen is contemplated, including, but not limited to, optional substitution with alkyl, acyl, alkoxymethyl, alkoxyethyl, arylsulfonyl, alkylsulfonyl, any of which are further optionally substituted.These subsets of optional substitutions are intended to be merely exemplary, and any combination of 2-5, or 2-10, or 2-20 of the groups listed above (up to all of the groups listed above and any subranges therebetween) is contemplated. "Optionally substituted" may include any of the chemical functional groups defined above and throughout this disclosure. Two optional substituents may be joined together to form a fused 5-, 6-, or 7-membered carbocyclic or heterocyclic ring of 0-3 heteroatoms, for example, methylenedioxy or ethylenedioxy. Optionally substituted groups may be unsubstituted (e.g., --CH2CH3), fully substituted (e.g., --CF2CF3), monosubstituted (e.g., --CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., --CH2CF3).

[0097] The various optional substitutions do not have to be the same, and any combination of optional substituents can be combined. For example, a carbon chain can be substituted with alkyl, halo, and alkoxy groups. When a substituent is recited without modification regarding substitution, both substituted and unsubstituted forms are included. When a substituent is modified as "substituted", the substituted form is specifically intended. Furthermore, different sets of optional substituents for a particular moiety can be defined as necessary, and in these cases, the optional substitutions are as defined, often immediately following the phrase "optionally substituted with".

[0098] The term R or R', appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted. Each such R and R' group should be understood to be optionally substituted as defined herein. Each occurrence of R and R' should be understood to be independent. Whether or not an R group has a number designation, R, R', and R n All R groups, including (where n is (1, 2, 3, ...), all substituents, and all terms should be understood to be independent of each other in terms of selection from a group. When any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than once in a formula or generic structure, its definition at each occurrence is independent of its definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in the chain of elements from either end as described. Thus, by way of example only, an unsymmetrical group such as --C(O)N(R)-- may be attached to the parent moiety at either the carbon or the nitrogen.

[0099] Asymmetric centers, axial asymmetry (non-interchangeable rotamers), and the like may be present in the compounds of various embodiments disclosed herein. Such chirality may be indicated by the symbols "R" or "S", depending on the configuration of the substituents around the chiral carbon atom or related axis. It is to be understood that the embodiments encompass all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing chiral centers, or by preparation of a mixture of enantiomeric products followed by separation, such as conversion to a diastereomeric mixture, followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers by chiral chromatographic columns, or any other suitable method known in the art. Starting compounds of a particular stereochemistry are commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of various embodiments disclosed herein may exist as geometric isomers. The various embodiments disclosed herein include all cis, trans, syn, anti, entogen (E), and zusanmen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers, including keto-enol tautomers, and all tautomers are encompassed within the embodiments disclosed herein.

[0100] Additionally, the compounds of the various embodiments disclosed herein can exist in unsolvated as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the embodiments disclosed herein.

[0101] The term "bond" refers to a covalent bond between two atoms, or between two moieties when the atoms joined by the bond are considered part of a larger substructure. The bond may be a single, double, or triple bond, unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may or may not be present at that position.

[0102] 1. Salts of compounds The compounds disclosed herein may exist as pharma- ceutically acceptable salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts are usually pharma- ceutically acceptable. However, salts of non-pharma- ceutically acceptable salts may be useful in the preparation and purification of the desired compound. Base addition salts may also be formed and are pharma- ceutically acceptable. For a more complete discussion of salt preparation and selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VSHA, Zurich, Switzerland, 2002). It is to be understood that each of the compounds disclosed herein and each embodiment of the compounds presented herein includes pharma- ceutically acceptable salts of such compounds.

[0103] The term "pharmaceutically acceptable salt" as used herein refers to a water- or oil-soluble or dispersible, pharmaceutically acceptable salt or zwitterionic form of the compounds disclosed herein, as defined herein. The salts can be prepared during the final isolation and purification of the compounds, or separately by reacting the appropriate compounds in the form of a free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, These include DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate (p-tosylate), and undecanoate. In addition, the compounds of various embodiments disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, dimethyl, diethyl, dibutyl, and diamyl sulfates, decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides, and benzyl and phenethyl bromides. Examples of acids that can be used to form pharmaceutically acceptable addition salts include inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids, such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination of the compounds with alkali metal or alkaline earth ions.Thus, the various embodiments disclosed herein contemplate sodium, potassium, magnesium, calcium salts, and the like, of the compounds disclosed herein.

[0104] Base addition salts can be prepared by reacting the carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary, or tertiary amine during the final isolation and purification of the compound. Pharmaceutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, piperidine, and piperazine.

[0105] C. Treatment-Related Definitions The term "disease" as used herein is generally synonymous with, and intended to be used interchangeably with, the terms "disorder" and "condition" (as in medical conditions), all of which reflect an abnormal condition of the body or one of its parts that impairs normal functioning and are typically manifested by distinguishing signs and symptoms.

[0106] As used herein, the term "cancer" refers to all types of cancer, neoplasms, or malignant tumors found in mammals (e.g., but not limited to, humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that may be treated with the compounds or methods provided herein include thyroid, endocrine, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovarian, sarcoma, stomach, uterine, medulloblastoma, colon cancer, and pancreatic cancer. Additional examples include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, uterine cancer, adrenal cortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0107] The term "leukemia" refers broadly to progressive malignant diseases of the blood-forming organs and is generally characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and nature of the disease: acute or chronic, (2) the type of cells involved: bone marrow (myeloid), lymph (lymphoid), or monocytic, and (3) the increase or absence of an increase in the number of abnormal cells in the blood: leukemic or non-leukemic (subleukemic). Exemplary leukemias that may be treated with the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, erythroblastic leukemia, hematoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

[0108] As used herein, the term "lymphoma" refers to a group of cancers that affect the hematopoietic and lymphatic tissues. Lymphomas begin in lymphocytes, which are blood cells found primarily in lymph nodes, spleen, thymus, and bone marrow. There are two main types of lymphoma: non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all lymphoma diagnoses. It is a Reed-Sternberg malignant B-lymphocyte-related cancer. Non-Hodgkin's lymphoma (NHL) can be classified based on how fast the cancer grows and the type of cells involved. There are aggressive and indolent types of NHL. Based on the type of cells involved, there are B-cell NHL and T-cell NHL. Exemplary B-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0109] The term "sarcoma" generally refers to tumors composed of embryonic connective tissue-like material and generally consists of closely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastoma, botryoid sarcoma, chlorosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibro ...sarcoma, These include blastic cell sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multifocal pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cell, lymphoma, immunoblastic sarcoma of T cell, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0110] The term "melanoma" is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with the compounds or methods provided herein include, for example, atopic melanoma, black melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo malignant melanoma, malignant melanoma, nodular melanoma, sublingual melanoma, or superficial spreading melanoma.

[0111] The term "carcinoma" refers to a malignant new growth composed of epithelial cells that tend to invade surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolocarcinoma, bronchogenic carcinoma, encephalomyeloma, cholangiocarcinoma, trophoblastic tumor, and colloid carcinoma. , comedocarcinoma, uterine cancer, cribriform carcinoma, armor carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, scirrhous carcinoma, embryonal carcinoma, cerebro-like carcinoma, epithelioid carcinoma, glandular epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinous carcinoma, mucinous carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Chrompecher carcinoma, Kruczykki cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipoma-like carcinoma, lymphoepithelial carcinoma, medullary carcinoma carcinoma), melanoma, soft carcinoma, mucinous carcinoma, mucosecreting carcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, soft carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, beaded carcinoma, telangiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma, nodular carcinoma, verrucous carcinoma, or choriocarcinoma.

[0112] "Ras associated cancer" (also referred to herein as "Ras related cancer") refers to cancer caused by aberrant Ras activity or signaling. "Cancer associated with aberrant K-Ras activity" (also referred to herein as "K-Ras related cancer") is cancer caused by aberrant K-Ras activity or signaling (e.g., mutant K-Ras). K-Ras related cancers can include lung cancer, non-small cell lung cancer, breast cancer, leukemia, pancreatic cancer, colon cancer, and colorectal cancer. Other cancers associated with abnormal activity of one or more of Ras, K-Ras, H-Ras, N-Ras, mutated K-Ras (including K-Ras G12C, K-Ras G12V, K-Ras G13C, K-Ras G12D, K-Ras G13D mutants), mutated N-Ras, and mutated H-Ras are well known in the art and it is within the skill of one of ordinary skill in the art to determine such cancers, including G12C in both N-Ras and H-Ras.

[0113] The term "administering (or administering) a Ras inhibitor" refers to administering to a subject a compound (e.g., a Ras inhibitor, a K-Ras inhibitor, an N-Ras inhibitor, an H-Ras inhibitor, a mutant K-Ras inhibitor, a K-Ras G12C inhibitor, a K-Ras G12V inhibitor, a K-Ras G13C inhibitor, a K-Ras G12D inhibitor, a K-Ras G13D inhibitor) that inhibits the activity or level (e.g., amount) of one or more Ras proteins or the level of a signaling pathway. Administration can include, but is not limited by mechanism, allowing a sufficient time for the Ras inhibitor to reduce the activity of one or more Ras proteins or for the Ras inhibitor to alleviate one or more symptoms of a disease (e.g., cancer), where the Ras inhibitor stops the cell cycle, slows the cell cycle, reduces DNA replication, reduces cell replication, reduces cell proliferation, reduces metastasis, or causes cell death. The term "administering (or administering) a K-Ras inhibitor" means administering a compound that inhibits the activity or level (e.g., amount) of one or more K-Ras proteins (K-Ras, mutated K-Ras, Ras, K-Ras G12C, K-Ras G12V, K-Ras G12D, K-Ras G13C, K-Ras G13D) or the level of a signaling pathway. In embodiments, administration does not include administration of any active agent other than the listed active agents.

[0114] The term "associated" or "related to" in the context of a substance or activity or function of a substance associated with a disease (e.g., Ras (e.g., human K-Ras or human H-Ras) activity, a protein-associated disease, a cancer associated with aberrant Ras activity, K-Ras-associated cancer, mutant K-Ras-associated cancer, activated K-Ras-associated cancer, K-RasG12C-associated cancer, K-Ras G12V-associated cancer, K-Ras G13C-associated cancer, K-Ras G12D-associated cancer, K-Ras G13D-associated cancer) means that the disease (e.g., cancer) is caused (in whole or in part) or a symptom of the disease is caused (in whole or in part) by the substance or activity or function of the substance. For example, a cancer associated with aberrant Ras activity or function can be a cancer that results (in whole or in part) from aberrant Ras activity or function (e.g., enzymatic activity, protein-protein binding, signaling pathways) or a cancer in which a particular symptom of the disease is caused (in whole or in part) by aberrant Ras activity or function. As used herein, what is described as being related to a disease can be a target for the treatment of the disease if it is a causative agent.For example, cancers related to the abnormality of Ras activity or function, or Ras-related cancers can be treated with Ras modulators or Ras inhibitors if the increase in Ras activity or function (e.g., signal transduction pathway activity) causes cancer.For example, K-Ras G12C-related cancers can be cancers that subjects with K-Ras G12C have a higher risk of developing compared to subjects without K-Ras G12C.For example, K-Ras G12V-related cancers can be cancers that subjects with K-Ras G12V have a higher risk of developing compared to subjects without K-Ras G12V.

[0115] The term "Ras" refers to one or more of the family of human Ras GTPase proteins (e.g., K-Ras, H-Ras, N-Ras). The term "K-Ras" refers to the nucleotide sequence or protein of human K-Ras4A (NP_203524.1), human K-Ras4B (NP_004976.2), or both K-Ras4A and K-Ras4B. The term "K-Ras" includes both the wild type of the nucleotide sequence or protein and any mutants thereof. In some embodiments, "K-Ras" is wild type K-Ras. In some embodiments, "K-Ras" is one or more mutant forms. The term "K-Ras" XYZ refers to a mutant K-Ras nucleotide sequence or protein, where the Y-numbered amino acid of K-Ras that has an X amino acid in the wild type has instead a Z amino acid in the mutant (e.g., K-Ras G12C has a G in the wild type protein but a C in the K-Ras G12C mutant protein). In some embodiments, K-Ras refers to K-Ras4A and K-Ras4B. In some embodiments, K-Ras refers to K-Ras4A. In some embodiments, K-Ras refers to K-Ras4B (e.g., NM_004985.4 or NP_004976.2). In some embodiments, K-Ras refers to a protein that comprises (e.g., consists of) the following amino acid sequence, or that includes one or more mutations (e.g., G12C, G12V, or G13C):

[0116] MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAFYTLVREIRKHKEK (SEQ ID NO: 1)

[0117] In some embodiments, K-Ras refers to a protein that comprises (e.g., consists of) the following amino acid sequence, or a protein that comprises (e.g., consists of) the following sequence with one or more mutations (e.g., G12C, G12V, or G13C):

[0118] MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAFYTLVREIRKHKEKMSKDGKKKKKKSKTKCVIM (SEQ ID NO: 2)

[0119] 1 mteyklvvvg aggvgksalt iqliqnhfvd eydptiedsy rkqvvidget clldildtag 61 qeeysamrdq ymrtgegflc vfainntksf edihhyreqi krvkdsedvp mvlvgnkcdl 121 psrtvdtkqa qdlarsygip fietsaktrq gvddafytlv reirkhkekm skdgkkkkkk 181 sktkcvim (sequence number 3)

[0120] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents substantially simultaneously, for example, in a single capsule having a fixed ratio of active ingredients, or in multiple separate capsules for each active ingredient. Moreover, such administration also includes sequential use of each type of therapeutic agent. In either case, the treatment regimen provides the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0121] A "K-RAS inhibitor" is an inhibitor that has an IC50 of about 100 mM or less, more typically about 50 mM or less, with respect to K-RAS activity, as measured in the K-RAS assay outlined below.50 "IC" is used herein to refer to compounds that exhibit 50 " is the concentration of an inhibitor that reduces the activity of an enzyme (e.g., K-RAS) to half-maximal levels. Compounds of various embodiments disclosed herein have been found to exhibit inhibition against oncogenic mutant K-RAS isoforms. In some embodiments, the compounds have an IC of about 10 mM or less with respect to oncogenic mutant K-RAS as measured in the K-RAS assay described herein. 50 and in further embodiments, the compound has an IC 50 and in yet further embodiments, the compound has an IC 50 In yet further embodiments, the compound has a potency of about 200 nM or less with respect to K-RAS. IC50 Without being bound by theory, in some embodiments, the K-RAS inhibitor is an irreversible inhibitor via covalent bond formation to the cysteine ​​at the G12C mutation site.

[0122] The phrase "therapeutically effective" is intended to modify the amount of active ingredient used to treat a disease or disorder, which amount achieves the goal of reducing or eliminating the disease or disorder.

[0123] As used herein, reference to "treatment" of a subject is intended to include prophylaxis. The term "subject" refers to all mammals, including humans. Examples of subjects include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. In some embodiments, the subject is a human.

[0124] The term "prodrug" refers to a compound that is activated in vivo by a chemical reaction in vivo, thereby releasing the active compound. The compounds disclosed herein can be modified to exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the active compound. Furthermore, prodrugs can be converted to active compounds by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to compounds when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because in some situations they can be easier to administer than the active compound or parent drug. For example, prodrugs can be bioavailable by oral administration even if the parent drug is not bioavailable by oral administration. A prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, including those that rely on hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug is a compound that is administered as an ester ("prodrug"), which is then metabolically hydrolyzed to a carboxylic acid as the active entity. Additional examples include peptidyl derivatives of a compound. The term "pharmaceutical acceptable prodrug" refers to a prodrug or zwitterion that is suitable for use in contact with the tissues of a subject without undue toxicity, irritation, and allergic response, is commensurate with a reasonable benefit / risk ratio, and is effective for its intended use.

[0125] III. Compound Embodiments A. Genus I - General In some embodiments, provided is a compound of formula I: [ka] During the ceremony, Each R 1 is independently methyl or cyanomethyl; n is an integer from 0 to 2, X is -CCF3 or -C-halogen; Ar 1 is aryl or heteroaryl optionally substituted with one or more alkyl, halogen, hydroxy, or amino; Ar 2 is a C-linked aryl or heteroaryl optionally substituted with alkyl or halogen.

[0126] In some embodiments, Ar 1 is phenyl optionally substituted with one or more halogens.

[0127] In one or more of the preceding embodiments, X is -CCl or -CCF3.

[0128] In one or more of the preceding embodiments, Ar 1 is phenyl substituted with one or more halogens.

[0129] In one or more of the preceding embodiments, n is 2 and each R 1 is methyl.

[0130] In one or more of the preceding embodiments, Ar 2 is selected from: [ka] Any of these are optionally substituted with halogen.

[0131] In an embodiment, a further compound: [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0132] IV. General Synthetic Methods for Preparing Compounds The following schemes can be used to implement the various embodiments disclosed herein. It will be understood that these schemes are merely exemplary and that they provide easy access to core structures with variable functionality.

[0133] V. Mode of Administration Although the compounds disclosed herein may be administered as raw chemicals, they can also be presented as pharmaceutical compositions (i.e., as formulations). Thus, provided herein are pharmaceutical compositions that include one or more compounds disclosed herein, or one or more pharma-ceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharma-ceutically acceptable carriers and, optionally, one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Appropriate formulations depend on the route of administration selected. Any of the well-known techniques, carriers, and excipients may be suitably used, as understood in the art, e.g., Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein can be manufactured in a manner known in the art, such as by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0134] Pharmaceutical compositions may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including cutaneous, buccal, sublingual, and ocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. Pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound disclosed herein, or a pharma-ceutically acceptable salt, ester, amide, prodrug, or solvate thereof ("active ingredient"), with the carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0135] The pharmaceutical compositions of the various embodiments disclosed herein may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0136] Pharmaceutical compositions that can be used orally include tablets. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form as a powder or granules, optionally mixed with a binder, an inert diluent, or a lubricant, surface active agent, or dispersant, etc., in a suitable machine. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or grooved and can be formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.

[0137] The compounds disclosed herein can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Injectable preparations can be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with the addition of a preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The preparations can be presented in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and can be stored in powder form or in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, e.g., saline or pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described.

[0138] Preparations for parenteral administration include aqueous and non-aqueous (oily) isotonic sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Dosage

[0139] The compounds disclosed herein may be administered orally or by injection at a dose of 0.1 to 500 mg / kg per day. The general dose range for adult humans is generally 5 mg to 2 g / day. Tablets or other presentation forms provided in individual units may conveniently contain an effective amount of one or more compounds at such dosage amounts or multiples thereof, for example, a unit containing 5 mg to 500 mg, usually about 10 mg to about 200 mg.

[0140] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0141] The compounds disclosed herein can be administered in various ways, for example, orally, topically, or by injection.The exact amount of compound administered to a subject is the responsibility of the attending physician.The specific dose level for any particular patient depends on a variety of factors, including the activity of the specific compound used, the patient's age, weight, general health, sex, diet, administration time, administration route, excretion rate, drug combination, the exact disorder being treated, and the severity of the indication or condition being treated.In addition, the administration route may vary depending on the condition and its severity.

[0142] In certain cases, it may be appropriate to administer at least one of the compounds described herein (or its pharma- ceutically acceptable salt, ester, or prodrug) in combination with another therapeutic agent.By way of example only, when one of the side effects that a patient experiences when administered one of the compounds described herein is hypertension, it may be appropriate to administer.In any case, regardless of the disease, disorder, or condition that is treated, the overall benefit that the patient experiences may simply be the additive benefit of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0143] In either case, the multiple therapeutic agents (at least one of which is a compound of various embodiments disclosed herein) may be administered in any order, or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either a single pill or two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneously, the timing between the multiple doses may be any period ranging from a few minutes to four weeks.

[0144] VI. Treatment method In one aspect, embodiments herein provide a method of treating a subject having cancer, comprising administering to the subject an amount of a compound of various embodiments disclosed herein, or a pharma- ceutically acceptable salt thereof. In embodiments, the cancer comprises a K-Ras G12 mutation. In embodiments, the G12 mutation is G12C. In embodiments, the cancer is one or more of pancreatic cancer, lung cancer, and colorectal cancer. In other embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In further embodiments, the cancer is a CNS cancer. In embodiments, the CNS cancer is a primary cancer. In embodiments, the primary cancer comprises one or more of glioma, meningioma, medulloblastoma, ganglioglioma, schwannoma, and craniopharyngioma. In embodiments, the glioma comprises one or more of astrocytoma, glioblastoma, oligodendroglioma, and ependymoma. In embodiments, the CNS cancer comprises a metastatic or secondary cancer. In further embodiments, the CNS cancer includes cancers metastasized from one or more of melanoma, breast cancer, colon cancer, renal cancer, nasopharyngeal cancer, leukemia, lymphoma, myeloma, and other cancers of unknown primary site.

[0145] In another aspect, the embodiments herein provide a method for treating a K-RAS-mediated disorder in a human or animal subject in need of such treatment, comprising administering to the subject an amount of a compound of various embodiments disclosed herein, optionally in combination with at least one additional agent known in the art for treating the disorder, effective to reduce or prevent the disorder. In a related aspect, the various embodiments disclosed herein provide a therapeutic composition comprising at least one compound of various embodiments disclosed herein, in combination with one or more additional agents for treating the K-RAS-mediated disorder. In some such embodiments, the K-RAS-mediated disease is cancer, and K-RAS is present in an oncogenic mutant form.

[0146] The compounds disclosed herein may be useful for treating K-RAS-mediated diseases, disorders, and conditions. In some embodiments, the compounds disclosed herein may be used for treating cancer, as disclosed above. In some such embodiments, the type of cancer may depend on the presence of a particular type of oncogenic mutation in K-RAS. For example, in some embodiments, oncogenic K-RAS mutations may be associated with human cancer of the pancreas, lung, and / or colon.

[0147] 1. Combination therapy The compounds disclosed herein may be used in combination therapy. For example, the compounds disclosed herein may be used in combination with inhibitors of mammalian target of rapamycin (mTOR), insulin growth factor 1 receptor (IGF1R), and combinations thereof. Such combination therapy may be particularly suitable for certain cancer types, such as lung cancer. See Molinas-Arcas et al. Sci. Trans. Med. 18 Sep. 2019 11:510 eaaw7999 at stm.sciencemag.org / content / 11 / 510 / eaaw7999. The compounds disclosed herein may be combined with regulators of the ULK family of proteins that regulate autophagy. Other compounds of interest in combination therapy include inhibitors of SHP2. Other SHP2 inhibitors include those described in WO2016 / 203404, WO2018 / 136264, WO2018 / 057884, WO2019 / 067843, WO2019 / 183367, WO2016 / 203405, WO2019 / 051084, WO2018 / 081091, WO2019 / 165073, WO2017 / 216706, WO2018 / 218133, WO2019 / 183364, WO2020061103, and WO2020061101. All references and patent applications, including those relating to the compositions, methods of use, and methods of making the compounds disclosed herein, are hereby incorporated by reference in their entirety.

[0148] In embodiments, the compounds disclosed herein can be combined with EGFR inhibitors. In embodiments, the EGFR inhibitors are selective for EGFR mutations, including but not limited to C797X, L718Q, G724S, S768I, G719X, L792X, G796X, T263P, A289D / V, G598V, and EGFRvIII high expression. In embodiments, combination therapy with EGFR drugs tracked by mutation and indication is shown in Table CT-1 below. [Table 1]

[0149] EGFR inhibitors include those described in U.S. Patent Nos. 5,747,498, 8,946,235, and 9,732,058, WO2002030926, US20040048880, US20050165035, and WO2019067543. All patents and applications containing compositions, methods of use, and methods of making the compounds disclosed herein are hereby incorporated by reference in their entirety.

[0150] Other combination therapies based on target biomarkers are shown in Table CT-2 below. [Table 2-1] [Table 2-2]

[0151] The second agent of the pharmaceutical combination formulation or administration regimen may have a complementary activity to the compound disclosed herein so that they do not adversely affect each other. The compounds may be administered together as a single pharmaceutical composition or separately. In one embodiment, the compound or a pharmaceutically acceptable salt may be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

[0152] The term "co-administration" refers to simultaneous administration or any other method of separate sequential administration of a compound disclosed herein or its salt with additional active pharmaceutical ingredient(s), including cytotoxic agents and radiotherapy. If administration is not simultaneous, the compounds are administered in close time proximity to each other. Furthermore, it does not matter whether the compounds are administered in the same dosage form, for example, one compound may be administered topically and another compound may be administered orally.

[0153] These additional agents can be administered separately from the compound-containing composition of the present invention as part of a multiple dose regimen.Alternatively, these agents can be part of a single dosage form, mixed with the compound of the present disclosure in a single composition.When administered as part of a multiple dose regimen, the two active agents can be administered simultaneously, sequentially, or within a period of time that is usually within 5 hours of each other.

[0154] As used herein, the terms "concomitant," "concomitant," and related terms refer to simultaneous or sequential administration of a therapeutic agent according to the present disclosure. For example, a compound disclosed herein may be administered simultaneously with another therapeutic agent, or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present embodiments provide a single unit dosage form that includes a compound of formula I, an additional therapeutic agent, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0155] The amount of both the compound and additional therapeutic agent that can be combined with the carrier materials to produce a single dosage form (in compositions containing additional therapeutic agents as described above) can vary depending on the host treated and the particular mode of administration. In certain embodiments, the compositions of the present disclosure are formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the present invention can be administered.

[0156] Typically, any agent that has activity against the disease or condition being treated can be co-administered. Examples of such agents are found in V.T. Davida and S. Hellman (eds.), 6 thedition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

[0157] In one embodiment, the method of treatment involves co-administration of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, with at least one cytotoxic agent. As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu), chemotherapeutic agents, growth inhibitors, enzymes such as nucleases and fragments thereof, and toxins such as small molecule or enzymatically active toxins (including fragments and / or variants thereof) of bacterial, fungal, plant, or animal origin.

[0158] Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutics, pro-apoptotic agents, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signal inhibitors, HDAC inhibitors, proteasome inhibitors, and cancer metabolism inhibitors.

[0159] "Chemotherapeutic agent" includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents are erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium). Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), Smith Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide, alkylsulfonates such as busulfan, improsulfan, and piposulfan, aziridines such as benzodopa, carboquone, meturedopa, and uredopa, ethylenimines and methylamelanamines (altretamine, triethylenemelamine, triethylenephosphoramine, acetogenins (especially bullatacin and bullatacinone), camptothecins (including topotecan and irinotecan), bryostatin, kallistatin, CC-1065 (including its azozelesin, carzelesin, and bizelesin synthetic analogues), cryptophycins (especially cryptophycin 1 and cryptophycin 8), corticosteroids (including prednisone and prednisolone), cyproterone acetate,5α-reductase (including finasteride and dutasteride), vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatins, aldesleukin, talc duocarmycins (including synthetic analogs KW-2189 and CB1-TM1), eloterobin, pancratistatin, sarcodictiin, spongiostatins, nitrogen mustards, e.g., chlorambucil, chromafazine, chlorophosphamide, estrastatins, mustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicine, phenesterine, prednimustine, trofosfamide, uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine, antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ1I and calicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994) 33:183-186), dynemicins including dynemicin A, bisphosphonates such as clodronate, esperamicins, and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), antibiotics such as aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomonoacin, cyanococc ... rufolino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), mitomycins such as epirubicin, esorubicin, idarubicin, marcelomycin, and mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, puromycin, keramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, antimetabolites such as methotrexate and 5-fluorouracil (5-FU), folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate,Purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid replacement fluids such as floric acid; aceglatone, aldophosphamide glycosides; aminolevulinic acid; Eniluracil, amsacrine, bestravcil, bisantrene, edatrexate, defofamine, demecolcine, diaziquone, elfomitin, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidain, maytansinoids such as maytansine and ansamitocin, mitoguazone, mitoxantrone, mopidanol, nitraelin, pentostatin, fenameth, pirarubicin, losoxantrone, podophyllic acid, 2-ethylhydrazide, procarbazine, PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.), razoxane, rhizoxin, schizofiran, spirogermanium, tenuazonic acid, triazicon, 2,2',2''-trichlorotriethylamine, trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine), urethanes, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, taxoids such as TAXOL (paclitaxel, Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (chromophore-free), albumin engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel, doxetaxel, Sanofi-Aventis), chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine, methotrexate,Platinum analogues such as cisplatin and carboplatin, vinblastine, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE® (vinorelbine), novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine (XELODA®), ibandronate, CPT-11, the topoisomerase inhibitor RFS 2000, difluoromethylornithine (DMFO), retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0160] Chemotherapeutic agents include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®, tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxyfene, ketoxifene, LY117018, onapristone, and FARESTON® (including toremifine citrate); (ii) anti-hormonal agents that inhibit estrogen production in the adrenal glands; Aromatase inhibitors, which inhibit the aromatase enzyme they regulate, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane, Pfizer), formestany, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole, Novartis), and ARIMIDEX® (anastrozole, AstraZeneca), (iii) antiandrogens, such as flutamide, nilutamide, bicalcitabine, etc. (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, e.g., PKC-alpha, Ralf, and Goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, fenretinide, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (vi) acetylcholinesterase inhibitors; ... and H-Ras, (vii) ribozymes, such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors, (viii) vaccines such as gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®, and VAXID®, PROLEUKIN®, rIL-2, topoisomerase 1 inhibitors, such as LURTOTECAN®, ABARELIX® rmRH, and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0161] Chemotherapeutic agents also include antibodies, such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies that have therapeutic potential as drugs in combination with the compounds of the disclosure include apolizumab, acelizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidofusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, natavizumab, and the like. tuzumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resivizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), an exclusively human sequence recombinant full-length IgG1λ antibody genetically modified to recognize the p40 protein.

[0162] Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise directly interact with EGFR and prevent or reduce its signaling activity, alternatively referred to as "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Pat. No. 4,943,533 (Mendelsohn et al.)), as well as mutant forms thereof, such as chimeric 225 (C225 or cetuximab, ERBUTIX®) and reshaped human 225 (H225) (see WO 96 / 40210 (Imclone Systems, Inc., U.S. Pat. No. 6,225-6,325). Inc.), IMC-11F8, fully human EGFR targeting antibodies (Imclone), antibodies that bind to type II mutant EGFR (U.S. Pat. No. 5,212,290), humanized and chimeric antibodies that bind to EGFR as described in U.S. Pat. No. 5,891,996, as well as human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (see WO 98 / 50433 (Abgenix / Amgen)), EMD 55900 (Stragliotto et al. Eur. J. Cancer 2002, 14:131-135), and / or human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (see WO 98 / 50433 (Abgenix / Amgen)). 32A:636-640 (1996)), the humanized EGFR antibody EMD7200 (matuzumab) (EMD / Merck) directed against EGFR which competes with both EGF and TGF-alpha for EGFR binding, the human EGFR antibody HuMax-EGFR (GenMab), the fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3 and described in US 6,235,883, MDX-447 (Medarex Inc), and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).Anti-EGFR antibodies may be conjugated to a cytotoxic agent, thereby producing an immunoconjugate (see, for example, European Patent No. 659,439 A2, Merck Patent GmbH). EGFR antagonists are disclosed in U.S. Patent Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5, Nos. 8,666,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, and small molecules such as those compounds described in PCT publications such as WO 98 / 14451, WO 98 / 50038, WO 99 / 09016, and WO 99 / 24037.Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech / OSI Pharmaceuticals), PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.), ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol), (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine), CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinazolinyl]-4-(dimethylamino)-2-butynamide) (Wyeth), AG1478 (Pfizer), AG1571 (SU 5271, Pfizer), and dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2 methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

[0163] Chemotherapeutic agents include EGFR targeted drugs as described in the previous paragraph, small molecule HER2 tyrosine kinase inhibitors such as TAK165 available from Takeda, CP-724,714 (an oral selective inhibitor of ErbB2 receptor tyrosine kinase) (Pfizer and OSI), dual HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds to EGFR but inhibits both HER2 and EGFR overexpressing cells, lapatinib (GSK572016, available from Glaxo-SmithKline), oral HER2 and EGFR tyrosine kinase inhibitor, PKI-166 (available from Novartis), pan-HER inhibitors such as canertinib (CI-1033, Pharmacia), Raf-1 inhibitors such as ISIS which inhibit Raf-1 signaling. antisense drug ISIS-5132 available from GlaxoSmithKline; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from GlaxoSmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitors CI-1040 (available from Pharmacia); quinazolines such as PD 153035, 4-(3-chloroanilino)quinazolines; pyridopyrimidines, pyrimidopyrimidines, pyrrolopyrimidines such as CGP 59326, CGP 60261, and CGP 62706, pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines, curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide), tyrphostins containing a nitrothiophene moiety, PD-0183805 (Warner-Lamber), antisense molecules (e.g., those that bind to HER-encoding nucleic acids), quinoxalines (U.S. Pat. No. 5,804,396), tryphostins (U.S. Pat. No. 5,804,396), ZD6474 (AstraZeneca), PTK-787 (Novartis / Schering AG), CI-1033 (Pfizer), pan-HER inhibitors such as Affinitac (ISIS 3521, Isis / Lilly), imatinib mesylate (GLEEVEC®), PKI 166 (Novartis), GW2016 (Glaxo SmithKline), CI-1033 (Pfizer), EKB-569 (Wyeth), semaxinib (Pfizer), ZD6474 (AstraZeneca), PTK-787 (Novartis / Schering AG), INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®), or those disclosed in U.S. Pat. No. 5,804,396, WO 1999 / 09016 (American The present invention also includes "tyrosine kinase inhibitors" including those described in any of the patent publications such as WO1997 / 38983 (Warner Lambert), WO1999 / 06378 (Warner Lambert), WO1999 / 06396 (Warner Lambert), WO1996 / 30347 (Pfizer, Inc.), WO1996 / 33978 (Zeneca), WO1996 / 3397 (Zeneca), and WO1996 / 33980 (Zeneca).

[0164] Chemotherapeutic agents include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, and ibuprofen. Also included are interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0165] Chemotherapeutic agents include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, and hydrocortisone. 17-valerate, aclomethasone propionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate, immunoselective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomer form (feG) (IMULAN Antirheumatic drugs (e.g., azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers (e.g., etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi )), interleukin 1 (IL-1) blockers (e.g., anakinra (Kineret)), T cell costimulation blockers (e.g., abatacept (Orencia)), interleukin 6 (IL-6) blockers (e.g., tocilizumab (ACTEMERA®)), interleukin 13 (IL-13) blockers (e.g., lebrikizumab), interferon alpha (IFN) blockers (e.g., rontalizumab), beta 7 integrin blockers (e.g., rhuMAb Beta7), IgE pathway blockers (e.g., anti-M1 prime), secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers (e.g., anti-lymphotoxin alpha (LTa)), radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re186 、Re 188 、Sm 153 、Bi 212 、P 32 、Pb 212and radioisotopes of Lu), various investigational drugs (e.g., thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832)), polyphenols (e.g., quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavin, flavanols, procyanidins, betulinic acid and its derivatives), autophagy inhibitors (e.g., chloroquine, roquinol), delta-9-tetrahydrocannabinol (dronabinol, MARINOL®), beta-lapachone, lapachol, colchicine, betulinic acid, acetylcamptothecin, scopolectin, and 9-aminocamptothecin), podophyllotoxin, tegafur (UFTORAL®), bexarotene (TARGRETIN®), bisphosphonates (e.g., clodronate (e.g., BONEFOS®), or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®)), as well as epidermal growth factor receptor (EGF-R), vaccines (e.g., THERATOPE® vaccine), perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341), CCI-779, tipifarnib (R11577), orafenib, ABT510, Bcl-2 inhibitors such as oblimersen sodium (GENASENSE®), pixantrone, farnesyltransferase inhibitors such as lonafarnib (SCH6636, SARASAR™), and pharma- ceutically acceptable salts, acids, or derivatives of any of the above, as well as combinations of two or more of the above, such as CHOP (short for a combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone), and FOLFOX (short for a treatment regimen using oxaliplatin (ELOXATIN™) in combination with 5-FU and leucovorin).

[0166] Chemotherapeutic agents may also include nonsteroidal anti-inflammatory drugs that have analgesic, antipyretic and anti-inflammatory effects.NSAIDs include nonselective inhibitors of the enzyme cyclooxygenase.Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib and valdecoxib. NSAIDs may be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headaches and migraines, post-operative pain, mild to moderate pain due to inflammation and tissue injury, fever, ileus, and renal colic.

[0167] In certain embodiments, chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferon, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, mTOR inhibitors (e.g., rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, camptothecin, cisplatin, metronidazole, and imatinib mesylate, among others. In another embodiment, the compounds disclosed herein are administered in combination with a biologic agent, such as bevacizumab or panitumumab.

[0168] In certain embodiments, the compounds disclosed herein or pharma- ceutically acceptable compositions thereof are selected from the group consisting of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calsterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclospor ... Phosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, dromostanolone propionate, epirubicin, epoetin alfa, eroticinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, hitrelin acetate, hydroxyurea, ibritumomab, idarubicin , ifosfamide, imatinib mesylate, interferon alpha-2a, interferon alpha-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegaspar Gauze, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine,It is administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of vincristine, vinorelbine, zoledronic acid, or zoledronic acid.

[0169] Chemotherapeutic agents also include drugs for treating Alzheimer's disease, such as donepezil hydrochloride and rivastigmine; drugs for treating Parkinson's disease, such as L-dopa / carbidopa, entacapone, lopinrol, pramipexole, bromocriptine, pergolide, trihexefendyl, and amantadine; drugs for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; drugs for treating asthma, such as albuterol and montelukast sodium; drugs for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; corticosteroids, TNF inhibitors, IL-1 Also included are anti-inflammatory drugs such as RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's drugs; drugs to treat cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; drugs to treat liver disease such as corticosteroids, cholestyramine, interferons, and antivirals; drugs to treat blood disorders such as corticosteroids, antileukemias, and growth factors; and drugs to treat immune deficiencies such as gamma globulin.

[0170] Additionally, the chemotherapeutic agents include pharma- ceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents described herein, as well as combinations of two or more thereof. EXAMPLES

[0171] IV. Working Examples The following examples are provided to illustrate exemplary embodiments of the compounds disclosed herein and their preparation.

[0172] Various starting materials were purchased from commercial suppliers such as Aldrich Chemical Company and used without further purification unless otherwise indicated. Compounds are prepared according to the exemplary procedures provided herein and modifications thereof known to those of skill in the art. The following abbreviations are used throughout the examples: "Ac" means acetyl, "AcO" or "OAc" means acetoxy, "ACN" means acetonitrile, "aq" means aqueous, "atm" means atmosphere(s), "BOC" means "Boc" or "boc" means N-tert-butoxycarbonyl, "Bn" means benzyl, "Bu" means butyl, "nBu" means normal butyl, "tBu" means tert-butyl, "Cbz" means benzyloxycarbonyl, "DBU" means 1,8-diazabicyclo[5.4.0]undec-7-ene, "DCM" (CH2Cl2) means methylene chloride / dichloromethane, "de" means diastereomeric excess, "DEA" means diethylamine, "DIPEA" means diisopropylethylamine, "DMA" means N,N-dimethylacetamide, "DMAP" means 4-dimethylaminopyridine, "DMF" means N,N-dimethylformamide, "DMSO" means dimethylsulfoxide, "DPPP" means 1,3-bis(diphenylphosphino)propane, "ee" means enantiomeric excess, "Et" means ethyl, "EtOAc" means ethyl acetate, "EtOH" means ethanol, "HATU" means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, "HOAc" or "AcOH" means acetic acid, "i-Pr" means isopropyl, "IPA" means isopropyl alcohol, "LDA" means lithium diisopropylamide, "LiHMDS" or "LHMDS" " means lithium hexamethyldisilazide, "Me" means methyl, "MeOH" means methanol, "MgSO4" means magnesium sulfate, "MS" means mass spectrometry, "MTBE" means methyl tert-butyl ether, "Na2SO4" means sodium sulfate, "NMP" means 1-methyl 2-pyrrolidinone, "Ph" means phenyl, "sat." means saturated, "SFC" means supercritical fluid chromatography, "TBME" or "MTBE" means tert-butyl methyl ether, "TEA" means triethylamine, "TFA" means trifluoroacetic acid, "THF" means tetrahydrofuran, "TLC" means thin layer chromatography, "Rf" means retention, "about" means approximately, "rt" means retention time, "RT" means room temperature, "h" means hour, "min" means minute, "N" means standard, "M" means molar, "mL" means milliliter, "mmol" means millimole, "μmol" means micromole, "eq." means equivalent, and ". o"C" stands for degrees Celsius and "Pa" stands for Pascal. 1 H-NMR spectra are reported in ppm and were obtained as CDCl3 (7.25 ppm), DMSO-D6 (2.50 ppm), or CD3OD (3.4 ppm and 4.8 ppm) solutions, all using tetramethylsilane (0.00 ppm) as an internal standard where appropriate. Other NMR solvents were used as required. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet, br (broad), dd (double doublet), dt (double triplet). Coupling constants, when given, are reported in Hertz (Hz). [ka]

[0173] 2. Preparation of Compound 2 To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (2.68 g, 10 mmol, 1.0 equiv.) in DMF (27 mL) were added DIPEA (6.45 g, 50 mmol, 10 equiv.), NH4Cl (3.20 g, 60 mmol, 6 equiv.) and HATU (7.6 g, 20 mmol, 2 equiv.) at room temperature under N2 atmosphere. The reaction mixture was then stirred for 2 h, diluted with MTBE (100 mL), washed with 0.5 N aqueous HCl (50 mL), brine (50 mL) and dried over Na2SO4. The organic layer was concentrated in vacuo. The resulting residue was purified by chromatography (0-50% EtOAc / petroleum ether) to give the product 2 as a yellow solid (2.3 g, yield: 86%). LC-MS: [M+H] + = 267

[0174] 3. Preparation of Compound 3 To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzamide (2.67 g, 10 mmol, 1.0 equiv) in CF3COOH (27 mL) was added hydrogen peroxide (5.7 g, 50 mmol, 5 equiv). The reaction was stirred at 50 °C for 0.5 h. It was then diluted with MTBE (150 mL), washed with water (100 mL), brine (100 mL), and then dried over Na2SO4. The organic layer was concentrated in vacuo and the resulting residue was purified by chromatography (0-100% EtOAc / petroleum ether) to give the product 3 as a yellow solid (1.8 g, yield: 60%). LC-MS: [M+H] + = 297

[0175] 4. Preparation of Compound 5 To a solution of 4-bromo-5-chloro-3-fluoro-2-nitrobenzamide (3.0 g, 10 mmol, 1.0 equiv.) in EtOH (30 ml) and water (6 mL), 2-((tert-butyldiphenylsilyl)oxy)ethane-1-thiol (3.2 g, 10 mmol, 1.0 equiv.), potassium carbonate (4.2 g, 30 mmol, 3.0 equiv.) were added. The reaction mixture was then stirred at 50° C. for 2 h. The solvent was removed to give 6.5 g of crude product, which was used in the next step without further purification. LC-MS: [M+H] + = 593

[0176] 5. Preparation of Compound 6 To a solution of compound 5 (6.5 g crude, 10 mmol, 1.0 equiv) in CH3COOH (120 mL) was added iron powder (2.8 g, 50 mmol, 5 equiv). The reaction mixture was stirred at 50 °C for 2 h. After filtration, the collected solid was washed with EtOAc (500 mL). The organic phase was washed with 300 mL water, 300 mL brine, and concentrated in vacuo. The resulting residue was purified by chromatography (0-100% EtOAc / petroleum ether) to give product 6 as a yellow solid (2.8 g, yield: 50%). LC-MS: [M+H] + = 563

[0177] 6. Preparation of Compound 7 To a solution of compound 6 (5.6 g, 10 mmol, 1.0 equiv.) in DCM (110 mL) was added DIPEA (2.6 g, 20 mmol, 2 equiv.) CDI (4.9 g, 30 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred for 16 h. After filtration, the filter cake was washed with petroleum ether (50 mL) and dried to give product 7 as an off-white solid (4.7 g, yield: 80%). LC-MS: [M+H] + = 589

[0178] 7. Preparation of Compound 8 To a solution of compound 7 (5.9 g, 10 mmol, 1.0 equiv) in THF (60 mL) was added tetrabutylammonium fluoride (10 mL, 10 mmol, 1.0 equiv). The reaction mixture was stirred for 3 h. After dilution with EtOAc (150 mL), it was washed with H2O (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give crude product 8 as an off-white solid (3.16 g, yield: 90%).

[0179] 8. Preparation of Compound 9 To a solution of 7-bromo-6-chloro-8-((2-hydroxyethyl)thio)quinazoline-2,4-diol (3.5 g, 10 mmol, 1.0 equiv.) in THF (100 mL) was added PPh3 (4.5 g, 17 mmol, 1.7 equiv.) followed by DEAD (3.0 g, 17 mmol, 1.7 equiv.) at -10 to 0 °C. The reaction mixture was stirred for 1 h. After dilution with EtOAc (100 mL), it was washed with water (100 mL), brine (100 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was diluted with DCM (100 mL) and stirred for 2 h. After filtration, the filter cake was washed with DCM (50 mL) and dried to give the product 9 as an off-white solid (1.5 g, yield: 45%). LC-MS: [M+H]+ = 333.

[0180] Compounds of the disclosure having a substituted fused seven-membered ring can be prepared in a similar manner.

[0181] Working Example Examples 100a and 100b: (3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one ( Example 100a) and (3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 100b). [ka]

[0182] Step 1: 2,4,7-trichloro-8-iodo-6-(trifluoromethyl)quinazoline [ka]

[0183] To a mixture of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (5.1 mmol) in N,N-diisopropylethylamine (17.9 mmol) was added phosphoryl trichloride (12 mL). The mixture was stirred at 110° C. for 12 h, and the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in cold water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material obtained was purified by silica gel chromatography (0-15% ethyl acetate in petroleum ether) to give the title compound as a white solid in 44% yield. MS (ESI) m / z: 427.0 [M+1]+.

[0184] Step 2: tert-Butyl (2S,6R)-4-(2,7-dichloro-8-iodo-6-(trifluoromethyl)quinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0185] To a solution of 2,4,7-trichloro-8-iodo-6-(trifluoromethyl)quinazoline (2.04 mmol) and triethylamine (6.11 mmol) in dichloromethane (10 mL) was added tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate (1.83 mmol) at 0° C. The mixture was stirred at room temperature for 1 h and the volatiles were removed under reduced pressure. The residue was purified by silica gel column chromatography (5-15% ethyl acetate in hexanes) to give the title compound as a white solid in 82% yield. MS (ESI) m / z: 605.2 [M+1]+.

[0186] Step 3: tert-Butyl (2S,6R)-4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0187] To a solution of tert-butyl (2S,6R)-4-(2,7-dichloro-8-iodo-6-(trifluoromethyl)quinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (1.73 mmol) in acetonitrile (50 mL) was added 2-(methylsulfonyl)ethan-1-ol (3.47 mmol), cesium carbonate (3.47 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.17 mmol). The mixture was stirred at 80° C. for 2 h and the volatiles were removed under reduced pressure to give a solid which was redissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with a 10:1 mixture of tert-butyl methyl ether and ethyl acetate (60 mL). The yellow solid was filtered and dried under vacuum to give the title compound in 88% yield. MS (ESI) m / z: 587.2 [M+1]+.

[0188] Step 4: 2-(pyridin-4-yl)propane-1,3-diol [ka]

[0189] A mixture of 4-methylpyridine (430 mmol) in 37% formaldehyde (1.72 mol) was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (1-10% methanol in ethyl acetate). The title compound was isolated in 88% yield as a colorless oil. 1H NMR (400 MHz, methanol-d4) δ ppm 2.99 (q, J = 6.4 Hz, 1H) 3.77-3.91 (m, 4 H) 7.29-7.47 (m, 2 H) 8.33-8.54 (m, 2 H).

[0190] Step 5: 3-Hydroxy-2-(pyridin-4-yl)propyl-4-methylbenzenesulfonate [ka]

[0191] To a solution of 2-(pyridin-4-yl)propane-1,3-diol (65.3 mmol) in dichloromethane (100 mL) at 0° C. was added p-toluenesulfonyl chloride (65.3 mmol), N,N′-dimethylaminopyridine (6.53 mmol) and pyridine (65.3 mmol). The mixture was stirred at 25° C. for 3 h, quenched with water and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was used in the following step without further purification.

[0192] Step 6: S-(3-hydroxy-2-(pyridin-4-yl)propyl)ethanethioate [ka]

[0193] To a solution of 3-hydroxy-2-(pyridin-4-yl)propyl-4-methylbenzenesulfonate (55.3 mmol) in dimethylformamide (150 mL) was added potassium thioacetate (81.9 mmol). The mixture was stirred at 50 °C for 2 h, quenched with water, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (50-100% ethyl acetate in petroleum ether). The title compound was isolated as a yellow oil in 15% yield. 1H NMR (400 MHz, CDCl3) δ ppm 2.35 (s, 3 H) 2.99 (quintet, J= 6.4 Hz, 1 H) 3.15-3.24 (m, 1 H), 3.37 (dd, J= 14.0, 7.2 Hz, 1H) 3.79-3.90 (m, 2 H) 7.14-7.24 (m, 2H), 8.48-8.59 (m, 2H).

[0194] Step 7: tert-Butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-4-yl)propyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0195] To a solution of S-(3-hydroxy-2-(pyridin-4-yl)propyl)ethanethioate (0.95 mmol) and tert-butyl (2S,6R)-4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (1.42 mmol) in 1,2-ethanediol (2 mL) and isopropanol (2 mL) was added potassium carbonate (2.84 mmol) and cuprous iodide (0.47 mmol). The mixture was stirred at 85° C. for 2 h, quenched with water, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative TLC. The title compound was isolated as a yellow solid in 65% yield. MS (ESI) m / z: 627.9 [M+1]+.

[0196] Step 8: tert-Butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (Int-1a) and tert-Butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (Int-1b) [ka]

[0197] To a 0° C. solution of tert-butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-4-yl)propyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (2.11 mmol) in tetrahydrofuran (100 mL) was added triphenylphosphine (10.6 mmol). The mixture was stirred at 0° C. for 30 min and diethyl azodicarboxylate (10.6 mmol) was added. After 12 h, the volatiles were removed under reduced pressure to give a residue which was purified by silica gel chromatography (0-10% methanol in ethyl acetate). Compounds Int-1a and Int-1b were isolated in 65% yield as a 1:1 mixture of diastereomers. The pure diastereomers Int-1a and Int-1b were obtained by purification of the above mixture by SFC (Dacel Chiralcel OD 250 mm x 30 mm, 10 um, using 50% methanol in CO2 as the mobile phase) and characterized by SFC (Chiracel OD-3, 50 x 4.6 mm, 3 um, using 40% methanol (containing 0.05% diethylamine) in CO2 as the mobile phase at 3 mL / min).

[0198] Int-1a:SFC Rt=1.03 min;MS (ESI) m / z: 609.9 [M+1] +

[0199] Int-1b:SFC Rt=1.40 min;MS (ESI) m / z: 609.9 [M+1] +

[0200] Step 9: tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0201] To a solution of tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (0.46 mmol) and (5-chloro-2,4-difluoro-phenyl)boronic acid (1.84 mmol) in dioxane (5 mL) and water (0.1 mL) was added potassium phosphate (1.38 mmol) and Ruphos Pd G4 (0.05 mmol). The mixture was stirred at 80° C. for 30 min, the reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC and semi-preparative reversed phase HPLC. The title compound was isolated as a yellow solid in 33% yield. MS (ESI) m / z: 722.1 [M+1]+.

[0202] Step 10: (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0203] To a solution of tert-butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (0.17 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 0° C. The mixture was stirred at 0° C. for 30 min followed by evaporation of volatiles under reduced pressure. The title compound was isolated as a yellow oil in 87% yield and used in the next step without further purification. MS (ESI) m / z: 622.0 [M+1]+.

[0204] Step 13: (3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 100a) and (3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 100b). [ka]

[0205] To a solution of (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (0.16 mmol) in dichloromethane (3 mL) at 0° C. was added triethylamine (0.05 mmol) and prop-2-enoyl chloride (0.32 mmol). The mixture was stirred at 80° C. for 30 min and the volatiles were removed under reduced pressure to give a residue which was purified by preparative TLC. Compounds 1a and 1b were isolated in 54% yield as a 1:1 mixture of diastereomers. The pure diastereomers 1a and 1b were obtained by purification of the aforementioned mixture by SFC (Daicel Chiralpak AD 250 mm × 30 mm, 10 um, 50% isopropanol in CO2 used as mobile phase) and characterized by SFC (Chiralpak AD-3, 50 × 4.6 mm, 3 um) using 5-40% isopropanol in CO2 (containing 0.05% diethylamine) at 3 mL / min as mobile phase.

[0206] Compound 100a: SFC Rt=1.79 min; MS (ESI) m / z: 676.0 [M+1]+. 1 H NMR (400 MHz,CDCl3) δ ppm 1.51 - 1.59 (m,6 H) 3.15 (br d, J =13.6 Hz,1 H) 3.41 (td, J = 12.8,4.8 Hz,2 H) 3.70 - 3.87 (m, 2 H) 4.12 - 4.27 (m, 2 H) 4.53 - 4.91 (m, 4 H) 5.80 (dd, J = 10.4, 2.0 Hz, 1 H) 6.43 (dd, J = 16.8, 2.0 Hz, 1 H) 6.64 (dd, J = 16.4, 10.4 Hz, 1 H) 7.06 (t, J = 8.8 Hz, 1H) 7.28 - 7.34 (m, 3H) 8.14 (s, 1H) 8.49 - 8.67 (m, 2H).

[0207] Compound 100b: SFC Rt=3.30 min; MS (ESI) m / z: 676.0 [M+1]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.53 (br d, J = 6.8Hz, 6 H) 3.06 - 3.27 (m, 1 H) 3.41 (ddd, J = 17.6, 13.2, 4.4 Hz, 2 H) 3.61 - 3.83 (m, 2 H) 4.14 - 4.23 (m, 2 H) 4.53 - 4.90 (m, 4 H) 5.80 (dd, J = 10.4, 2.0 Hz, 1 H) 6.43 (dd, J = 16.8, 1.6Hz, 1H) 6.64 (dd, J = 16.8, 10.4 Hz, 1 H) 7.10 (t, J = 8.8 Hz, 1 H) 7.23 - 7.27 (m, 1 H) 7.30 (br d, J = 5.2 Hz, 2 H) 8.15 (s, 1 H) 8.59 (d, J = 6.0 Hz, 2 H).

[0208] Examples 101a and 101b: (3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (101a) and and (3R,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-((S)-3,4-dihydropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6-1 (101b) [ka]

[0209] Step 10: tert-Butyl (2S,6R)-4-((3R)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0210] To a solution of tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (0.39 mmol) and (5-chloro-2,4-difluorophenyl)boronic acid (1.57 mmol) in dioxane (5 mL) and water (0.1 mL) was added potassium phosphate (1.18 mmol) and Ruphos Pd G4 (0.04 mmol). The mixture was stirred at 80° C. for 30 min, cooled to room temperature and the insoluble material was filtered. Evaporation of the volatiles under reduced pressure gave a residue which was purified by preparative TLC. The title compound was isolated in 61% yield as a yellow solid. MS (ESI) m / z: 722.1 [M+1]+.

[0211] Step 2: (3R)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0212] To a solution of tert-butyl (2S,6R)-4-((3R)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (0.25 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL) at 0° C. The reaction was stirred at 0° C. for 30 min and the volatiles were removed under reduced pressure to give the title compound in 99% yield as a yellow oil. MS (ESI) m / z: 622.0 [M+1]+.

[0213] Step 3: (3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (101a) and (3R ,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-((S)-3,4-dihydropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6-1 (101b) [ka]

[0214] To a solution of (3R)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (0.16 mmol) in dichloromethane (3 mL) at 0° C. was added triethylamine (0.05 mmol) and prop-2-enoyl chloride (0.32 mmol). The mixture was stirred at 80° C. for 30 min and the volatiles were removed under reduced pressure to give a residue which was purified by preparative TLC. Compounds 101a and 101b were isolated in 94% yield as a 1:1 mixture of diastereomers.

[0215] The pure diastereomers 101a and 101b were obtained by purification of the above mixture by SFC (column: Dacel Chiralpak IG 250 mm x 30 mm, 10 um, using 55% isopropanol / acetonitrile (4:1) in CO2 as the mobile phase). Each individual diastereomer was analyzed by SFC (Chiralpak AD-3, 50 x 4.6 mm, 3 um, using 40% isopropanol (containing 0.05% diethylamine) in CO2 as the mobile phase at 3 mL / min).

[0216] Compound 101a: SFC Rt = 1.25 min; MS (ESI) m / z: 676.0 [M+1]+. 1H NMR (400 MHz, CDCl3) δ ppm = 1.50 - 1.61 (m, 6 H) 3.16 (br d, J = 12.8 Hz, 1 H) 3.41 (td, J = 12.4, 4.8 Hz, 2 H) 3.67 - 3.95 (m, 2 H) 4.12 - 4.25 (m, 2 H) 4.42 - 5.05 (m, 4 H) 5.72 - 5.90 (m, 1 H) 6.43 (dd, J = 16.8, 1.6 Hz, 1 H) 6.56 - 6.72 (m, 1 H) 7.06 (t, J = 8.8 Hz, 1 H) 7.31 (t, J = 7.6 Hz, 1 H) 7.38 (d, J = 6.0 Hz, 2 H) 8.14 (s, 1 H) 8.62 (d, J = 6.0 Hz, 2 H).

[0217] Compound 101b: SFC Rt = 2.23 min; MS (ESI) m / z: 676.0 [M+1]+. 1H NMR (400 MHz, CDCl3) δ ppm = 1.48 - 1.61 (m, 6 H) 2.99 - 3.24 (m, 1 H) 3.41 (ddd, J = 17.6, 13.2, 4.6 Hz, 2 H) 3.57 - 3.89 (m, 2 H) 4.19 (br dd, J = 13.2, 5.6 Hz, 2 H) 4.46 - 5.00 (m, 4 H) 5.80 (dd, J = 10.4, 1.6 Hz, 1 H) 6.43 (dd, J = 16.8, 1.6 Hz, 1 H) 6.64 (dd, J = 16.8, 10.4 Hz, 1 H) 7.10 (t, J = 8.8 Hz, 1 H) 7.25 (s, 1 H) 7.31 (br d, J = 5.6 Hz, 2 H) 8.15 (s, 1 H) 8.52 - 8.67 (m, 2 H).

[0218] Example 102: (3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0219] Step 1: tert-Butyl (2S,6R)-4-((3S)-11-(5-amino-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0220] The title compound was prepared similarly to step 9 of example 100, substituting 2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for (5-chloro-2,4-difluoro-phenyl)boronic acid. The title compound was isolated in 78% yield as a yellow solid. MS (ESI) m / z: 703.2 [M+1]+.

[0221] Step 2: tert-Butyl (2S,6R)-4-((3S)-11-(5-amino-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0222] To a solution of copper bromide (0.14 mmol) and tert-butyl nitrite (0.17 mmol) in acetonitrile (1 mL) was added a solution of tert-butyl (2R,6S)-4-[(12S)-8-(5-amino-2,4-difluoro-phenyl)-2-oxo-12-(4-pyridyl)-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo[7.4.1.05,14]tetradeca-3,5,7,9(14)-tetraen-4-yl]-2,6-dimethyl-piperazine-1-carboxylate (0.11 mmol) in acetonitrile (1 mL) and stirred at 60° C. for 30 min. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by preparative TLC followed by semi-preparative reversed phase HPLC. The title compound was isolated as a yellow solid in 40% yield. MS (ESI) m / z: 768.2 [M+1]+.

[0223] Step 3: (3S)-11-(5-bromo-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0224] tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared similarly to step 10 of example 100, substituting -((3S)-11-(5-bromo-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow oil. MS (ESI) m / z: 668.1 [M+1]+.

[0225] Step 4: (3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0226] The title compound was prepared analogously to step 11 of example 100, replacing (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one with (3S)-11-(5-bromo-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 97% yield as a yellow oil. MS (ESI) m / z: 722.1 [M+1]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.54 (br d, J = 6.8 Hz, 6 H) 3.04 - 3.25 (m, 1 H) 3.34 - 3.46 (m, 2 H) 3.57 - 3.89 (m, 2 H) 4.19 (br dd, J = 13.6, 6.8 Hz, 2 H) 4.50 - 4.93 (m, 4 H) 5.80 (dd, J = 10.4, 1.6 Hz, 1 H) 6.38 - 6.49 (m, 1 H) 6.56 - 6.71 (m, 1 H) 6.99 - 7.15 (m, 1H) 7.31 (br dd, J = 4.4, 2.0 Hz, 2 H) 7.43 (dt, J = 14.4, 7.2 Hz, 1 H) 8.14 (d, J = 3.6 Hz, 1 H) 8.51 - 8.68 (m, 2 H).

[0227] Examples 104a and 104b: (3S,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (exemplified Example 104a) and (3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 104b). [ka]

[0228] Step 1: 2-(pyridin-3-yl)prop-2-en-1-ol [ka]

[0229] A mixture of pyridin-3-ylboronic acid (41 mmol), 2-bromoprop-2-en-1-ol (49 mmol), potassium phosphate (122 mmol) and XPhosPd G2 (1.0 mmol) in THF (50 mL) and water (50 mL) was stirred at 60 °C for 12 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (35-80% ethyl acetate in hexanes). The title compound was isolated in 53% yield as a colorless oil. MS (ESI) m / z: 136.1 [M+H]+.

[0230] Step 2: 2-(pyridin-3-yl)propane-1,3-diol [ka]

[0231] A 10 M THF solution of borane dimethylsulfide complex (8.6 mL) was added to a 0 °C solution of 2-(pyridin-3-yl)prop-2-en-1-ol (22 mmol) in THF (30 mL). After 5 min, 1 M aqueous NaOH (6.5 mL) was added dropwise, followed by 35% aqueous hydrogen peroxide (86 mmol). After 2 h, methanol (50 mL) was added and the resulting reaction was stirred at 70 °C for 12 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0-20% methanol in ethyl acetate). The title compound was isolated as a colorless oil in 73% yield. 1H NMR (400MHz, CDCl3) δ8.58-8.48(m, 2H), 7.68-7.59(m, 1H), 7.32-7.28(m, 1H), 4.10-3.96(m, 4H), 3.16-3.07(m, 1H).

[0232] Step 3: 3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propan-1-ol [ka]

[0233] 2-(Pyridin-3-yl)propane-1,3-diol (13.0 mmol) was added to a 0 °C suspension of NaH (13.1 mmol) in THF (20 mL). The reaction was stirred at room temperature for 30 min, cooled to 0 °C, and a solution of TBDPSCl (10.4 mmol) in THF (20 mL) was added. After 30 min, the reaction was quenched with a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (20-50% ethyl acetate in hexanes). The title compound was isolated in 47% yield as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 4.4 Hz, 1H), 8.45 (s, 1H), 7.61 (dd, J = 7.6, 11.2 Hz, 4H), 7.54 (d, J = 8.0 Hz, 1H), 7.49 - 7.33 (m, 6H), 7.21 (dd, J = 4.8, 7.6 Hz, 1H), 4.11 - 4.05 (m, 1H), 3.99 - 3.89 (m, 3H), 3.08 (quintet, J = 6.0 Hz, 1H), 2.14 (s, 1H), 1.05 (s, 9H).

[0234] Step 4: S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)ethanethioate [ka]

[0235] A solution of triphenylphosphine (8.20 mmol) and DIAD (8.17 mmol) in THF (50 mL) was stirred at 0° C. for 30 min. 3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propan-1-ol (4.09 mmol) and ethanethioic S-acid (9.81 mmol) were added and the mixture was stirred at room temperature for 1 h. The volatiles were evaporated under reduced pressure to give a residue which was purified by silica gel chromatography (10-25% ethyl acetate in hexanes). The title compound was isolated in 98% yield as a colorless oil. MS (ESI) m / z: 450.1 [M+H]+.

[0236] Step 5: tert-Butyl (2S,6R)-4-(8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)thio)-7-chloro-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0237] The title compound was prepared similarly to step 7 of example 100, substituting S-(3-hydroxy-2-(pyridin-4-yl)propyl)ethanethioate with S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)ethanethioate. The title compound was isolated in 97% yield as a brown solid. MS (ESI) m / z: 866.3 [M+H]+.

[0238] Step 6: tert-Butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-3-yl)propyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0239] To a solution of tert-butyl (2S,6R)-4-(8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)thio)-7-chloro-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (3.69 mmol) in THF (50 mL) was added a 1 M solution of TBAF in THF (4.4 mL). After 3 h, the reaction mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (20% methanol in ethyl acetate). The title compound was isolated in 80% yield as a brown solid. MS (ESI) m / z: 628.2 [M+H]+.

[0240] Step 7: tert-Butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate and tert-Butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0241] The title compound was prepared analogously to step 8 of example 100, substituting tert-butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-4-yl)propyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate for tert-butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-3-yl)propyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 98% yield as a 1:1 mixture of diastereomers. Each individual diastereomer was isolated by purification of the aforementioned mixture by SFC (Chiracel Chiralpak AD2 50 x 30 mm, 10 um, using 40% methanol in CO2 as the mobile phase). Each individual diastereomer was characterized by analytical SFC (Chiralpak AD-3, 50 x 4.6 mm, 3 um, using 5-40% ethanol in CO2 (containing 0.05% diethylamine) as the mobile phase at 3 mL / min).

[0242] tert-Butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate: Rt=1.94 min. MS (ESI) m / z: 610.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.38 - 8.16 (m, 2H), 8.01 (s, 1H), 7.86 (s, 1H), 7.63 - 7.25 (m, 1H), 4.85 - 4.40 (m, 2H), 4.32 - 4.16 (m, 2H), 4.04 - 3.95 (m, 3H), 3.68 (br s, 2H), 3.17 (dt, J = 4.0, 12.4 Hz, 2H), 1.44 (s, 9H), 1.42 - 1.26 (m, 6H).

[0243] tert-Butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate: Rt = 2.42 min. MS (ESI) m / z: 610.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 7.6 Hz, 1H), 8.01 (s, 1H), 7.87 (d, J = 3.2 Hz, 1H), 7.64 - 7.29 (m, 1H), 5.01 - 4.42 (m, 2H), 4.29 - 4.16 (m, 2H), 4.05 - 3.99 (m, 3H), 3.94 - 3.59 (m, 2H), 3.17 (dt, J = 4.0, 12.4 Hz, 2H), 1.44 (s, 9H), 1.41 - 1.26 (m, 6H).

[0244] Step 8: tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0245] The title compound was prepared analogously to step 9 of example 100, replacing tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 52% yield as a white solid. MS (ESI) m / z: 722.1 [M+H]+.

[0246] Step 4: (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0247] tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared similarly to step 10 of example 100, substituting -((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow oil. MS (ESI) m / z: 622.1 [M+H]+.

[0248] Step 10: (3S,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 10) 4a) and (3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 104b) [ka]

[0249] The title compound was prepared analogously to step 11 of operation 100, substituting (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one for (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 68% yield as a white solid and as a 1:1 mixture of diastereomers. Each individual diastereomer was obtained by purification of the above mixture by SFC (Chiracel Chiralpak IC 250×30 mm, 10 um, using 65% methanol in CO2 as the mobile phase). Each individual diastereomer was characterized by analytical SFC (Chiralpak IC-3, 50×4.6 mm, 3 um, using 60% ethanol in CO2 (containing 0.05% diethylamine) as the mobile phase at 3 mL / min).

[0250] (3S,11R)-8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 104a): Rt=2.98 min. MS (ESI) m / z: 676.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.87 - 8.39 (m, 2H), 8.15 (s, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.40 - 7.28 (m, 2H), 7.10 (t, J = 8.8 Hz, 1H), 6.64 (dd, J = 10.4, 16.4 Hz, 1H), 6.43 (dd, J = 2.0, 16.4 Hz, 1H), 5.83 - 5.76 (m, 1H), 5.11 - 4.48 (m, 4H), 4.19 (d, J = 13.2 Hz, 2H), 3.89 - 3.58 (m, 2H), 3.46 - 3.36 (m, 2H), 3.27 - 3.00 (m, 1H), 1.61 - 1.53 (m, 6H).

[0251] (3S,11S)-8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 104b): Rt=3.62 min. MS (ESI) m / z: 676.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.91 - 8.30 (m, 2H), 8.14 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.10 - 7.02 (m, 1H), 6.70 - 6.58 (m, 1H), 6.47 - 6.39 (m, 1H), 5.83 - 5.76 (m, 1H), 4.91 - 4.54 (m, 4H), 4.23 - 4.15 (m, 2H), 3.91 - 3.72 (m, 2H), 3.40 (dt, J = 4.4, 13.2 Hz, 2H), 3.22 - 3.03 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H).

[0252] Example 106: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0253] Step 1: tert-Butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate and tert-Butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0254] The title compound was prepared similarly to Example 100, substituting 2-methylpyridine for 4-methylpyridine in step 4. The title compound was isolated as a 1:1 mixture of diastereomers. Each individual diastereomer was obtained by purification of the aforementioned mixture by SFC (Chiracel Chiralpak AS, 250×50 mm, 10 um, using 40% methanol in CO2 as the mobile phase) and characterized by analytical SFC (Chiralpak IC-3, 50×4.6 mm, 3 um, using 5-40% methanol in CO2 (containing 0.05% diethylamine) as the mobile phase at 3 mL / min).

[0255] tert-Butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate: Rt=1.12 min. MS (ESI) m / z: 610.2 [M+H]+.

[0256] tert-Butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate: Rt=1.39 min. MS (ESI) m / z: 610.2 [M+H]+.

[0257] Step 2: tert-Butyl (2S,6R)-4-((R)-11-(4-fluorophenyl)-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0258] The title compound was prepared analogously to step 9 of Example 100, replacing tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 91% yield as a yellow solid. MS (ESI) m / z: 670.2 [M+H]+.

[0259] Step 3: (R)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0260] tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate was reacted with tert-butyl (2S, The title compound was prepared similarly to step 10 of example 100, substituting 6R)-4-((R)-11-(4-fluorophenyl)-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 95% yield as a yellow solid. MS (ESI) m / z 570.2 [M+H]+.

[0261] Step 4: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0262] The title compound was prepared analogously to step 11 of example 100, replacing tert-butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with (R)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 33% yield as a yellow solid. MS (ESI) m / z: 624.3 [M+H]+.1H NMR (400 MHz, CDCl3-d) δ, 8.46 (br d, J = 4.4 Hz, 1H), 8.03 (s, 1H), 7.59 (dt, J = 1.6, 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.17 - 7.06 (m, 5H), 6.57 (dd, J = 10.4, 16.8 Hz, 1H), 6.35 (dd, J = 1.6, 16.8 Hz, 1H), 5.76 - 5.65 (m, 1H), 4.92 (br d, J = 4.4 Hz, 2H), 4.76 - 4.39 (m, 2H), 4.15 - 4.07 (m, 2H), 3.92 - 3.75 (m, 1H), 3.59 - 3.40 (m, 2H), 3.32 - 3.23 (m, 2H), 1.46 (br d, J = 6.8 Hz, 6H).

[0263] Example 107a and Example 107b: (3R,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quina Zolin-6-one and (3R,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0264] The title compound was prepared analogously to Example 102, replacing tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was obtained as a 1:1 mixture of diastereomers. Each individual diastereomer was obtained by purification of the aforementioned mixture by SFC (Chiracel Chiralpak AD, 250 x 30 mm, 10 um, using 45% isopropanol in CO2 (containing 0.1% ammonium hydroxide) as the mobile phase) and characterized by analytical SFC (Chiralpak AD, 50 x 4.6 mm, 3 um, using 40% isopropanol in CO2 (containing 0.05% diethylamine) as the mobile phase at 3 mL / min).

[0265] Example 107a: Rt = 0.46 min. MS (ESI) m / z: 721.9 [M+H]+. 1 1H NMR 1 1H NMR (400 MHz, CDCl3-d) δ, 8.57 (br d, J = 4.4 Hz, 1H), 8.12 (s, 1H), 7.73 - 7.64 (m, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.36 - 7.30 (m, 1H), 7.23 - 7.16 (m, 1H), 7.06 - 6.97 (m, 1H), 6.64 (dd, J = 10.4, 16.8 Hz, 1H), 6.43 (dd, J = 2.0, 16.8 Hz, 1H), 5.79 (dd, J = 2.0, 10.4 Hz, 1H), 5.08 - 4.93 (m, 2H), 4.84 - 4.49 (m, 2H), 4.22 - 4.13 (m, 2H), 4.01 - 3.91 (m, 1H), 3.71 - 3.52 (m, 2H), 3.41 - 3.32 (m, 2H), 1.55 (br d, J = 7.2 Hz, 6H).

[0266] Example 107b: Rt=0.83 min. MS (ESI) m / z: 721.9 [M+H]+. 1H NMR (400 MHz, CDCl3-d) δ, 8.47 (br s, 1H), 8.11 - 8.01 (m, 1H), 7.67 - 7.55 (m, 1H), 7.35 (br t, J = 7.2 Hz, 1H), 7.26 (br d, J = 7.2 Hz, 1H), 7.15 - 7.10 (m, 1H), 6.95 (t, J = 8.8 Hz, 1H), 6.56 (dd, J = 10.4, 16.8 Hz, 1H), 6.35 (dd, J = 2.0, 16.8 Hz, 1H), 5.74 - 5.68 (m, 1H), 4.92 (br d, J = 4.4 Hz, 2H), 4.74 - 4.23 (m, 2H), 4.09 (br d, J = 12.8 Hz, 2H), 3.95 - 3.76 (m, 1H), 3.70 - 3.35 (m, 2H), 3.34 - 3.21 (m, 2H), 1.49 (br s, 6H).

[0267] Example 108a and Example 108b: (3S,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quina Zolin-6-one and (3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0268] The title compound was prepared analogously to Example 102, replacing tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was obtained as a 1:1 mixture of diastereomers. Each individual diastereomer was obtained by purification of the aforementioned mixture by SFC (Phenomenex cellulose-2, 250×30 mm, 10 um, using 70% methanol in CO2 as the mobile phase) and characterized by analytical SFC (Unichiral OZ-5H, 50×4.6 mm, 3 um, using 60% methanol in CO2 (containing 0.05% diethylamine) as the mobile phase at 3 mL / min).

[0269] Example 108a: Rt = 1.89 min. MS (ESI) m / z: 720.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.15 - 8.23 ​​(m, 1H), 8.15 (s, 1H), 7.75 (d, J = 6.8 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.08 (t, J = 8.4 Hz, 1H), 6.70 - 6.58 (m, 1H), 6.43 (dd, J = 2.0, 16.4 Hz, 1H), 5.80 (dd, J = 2.0, 10.4 Hz, 1H), 5.09 - 4.31 (m, 4H), 4.19 (d, J = 12.8 Hz, 2H), 3.97 - 3.54 (m, 2H), 3.46 - 3.34 (m, 2H), 3.29 - 2.97 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.53 (d, J = 6.8 Hz, 3H).

[0270] Example 108b: Rt = 3.03 min. MS (ESI) m / z: 720.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.10 - 8.29 (m, 1H), 8.14 (s, 1H), 7.84 - 7.73 (m, 1H), 7.46 (t, J = 7.0 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.04 (t, J = 8.4 Hz, 1H), 6.64 (dd, J = 10.4, 16.4 Hz, 1H), 6.48 - 6.38 (m, 1H), 5.80 (dd, J = 1.6, 10.4 Hz, 1H), 5.07 - 4.42 (m, 4H), 4.19 (dd, J = 5.2, 13.6 Hz, 2H), 3.98 - 3.71 (m, 2H), 3.45 - 3.36 (m, 2H), 3.17 - 3.09 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H).

[0271] Example 102: (3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0272] Step 1: tert-Butyl (2S,6R)-4-((R)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate and tert-Butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0273] The title compound was prepared similarly to Examples 104a and 104b, substituting (5-fluoropyridin-3-yl)boronic acid for pyridin-3-ylboronic acid in step 1. The title compound was obtained as a 1:1 mixture of diastereomers, and each individual diastereomer was isolated by purification of the previous mixture by SFC (Chiracel Chiralpak IC 250×30 mm, 10 um, using 65% ethanol in CO2 as the mobile phase) and characterized by analytical SFC (Chiralpak IC-3, 50×4.6 mm, 3 um, using 60% ethanol in CO2 (containing 0.05% diethylamine) as the mobile phase at 3 mL / min).

[0274] tert-Butyl (2S,6R)-4-((R)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate: Rt=1.58 min. MS (ESI) m / z: 628.1 [M+H]+.

[0275] tert-Butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate: Rt=2.87 min. MS (ESI) m / z: 628.1 [M+H]+.

[0276] Step 2: tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0277] The title compound was prepared analogously to step 9 of example 100, replacing tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 85% yield as a yellow solid. MS (ESI) m / z: 740.0 [M+H]+.

[0278] Step 3: (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0279] tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate was reacted with tert-butyl (2S,6R)-4-(( The title compound was prepared similarly to step 10 of example 100, substituting 3S)-11-(5-chloro-2,4-difluorophenyl)-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow solid. MS (ESI) m / z: 640.0 [M+H]+.

[0280] Step 4: (3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0281] The title compound was prepared analogously to step 9 of example 100, replacing (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one with (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated as a white solid in 21% yield. MS (ESI) m / z: 694.4 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.36 - 7.27 (m, 1H), 7.14 - 7.03 (m, 1H), 6.68 - 6.60 (m, 1H), 6.47 - 6.40 (m, 1H), 5.80 (d, J = 11.6 Hz, 1H), 4.97 - 4.54 (m, 4H), 4.19 (dd, J = 5.2, 12.0 Hz, 2H), 3.96 - 3.67 (m, 2H), 3.41 (t, J = 4.4, 12.4 Hz, 2H), 3.20 - 3.04 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H).

[0282] Example 112a and Example 112b: (3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6- (112a) and (3S,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (112b). [ka]

[0283] Step 1: tert-butyl (2S,6R)-4-((S)-11-chloro-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate and tert-butyl (2S,6R)-4-((R)-11-chloro-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0284] The title compound was prepared similarly to Example 100, substituting 3-fluoro-4-methylpyridine for 4-methylpyridine in step 4. The two compounds were obtained as a 1:1 mixture of diastereomers. Each individual diastereomer was obtained by purification of the previous mixture by SFC (Chiracel Chiralpak IC 250×30 mm, 10 um, using 60% methanol in CO2 (containing 0.1% ammonium hydroxide) as the mobile phase) and characterized by analytical SFC ((S,S)Whelk-O1, 50×4.6 mm, 1.8 um, 50% methanol / acetonitrile (4:1) in CO2 (containing 0.05% diethylamine) as the mobile phase at 3 mL / min).

[0285] tert-Butyl (2S,6R)-4-((S)-11-chloro-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate: Rt=1.41 min. MS (ESI) m / z 628.4 [M+H]+.

[0286] tert-Butyl (2S,6R)-4-((R)-11-chloro-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate: Rt=1.81 min. MS (ESI) m / z: 628.4 [M+H]+

[0287] Step 2: tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0288] The title compound was prepared analogously to step 9 of example 100, replacing tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-((S)-11-chloro-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 44% yield as a yellow solid. MS (ESI) m / z: 740.5 [M+H]+.

[0289] Step 2: (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0290] tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate was reacted with tert-butyl (2S,6R)-4-(( The title compound was prepared similarly to step 10 of example 100, substituting 3S)-11-(5-chloro-2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 98% yield as a yellow solid. MS (ESI) m / z: 640.5 [M+H]+.

[0291] Step 3: (3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 112 a) and (3S,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 112b) [ka]

[0292] The title compound was prepared analogously to step 11 of operation 100, substituting (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one for (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The two compounds were isolated as a 1:1 mixture of diastereomers in 51% yield. Each individual diastereomer was isolated by purification of the mixture by SFC (Chiracel OD 250×30 mm, 10 um, using 50% methanol in CO2 as the mobile phase) and characterized by analytical SFC (Chiralpak IC-3, 50×4.6 mm, 3 um, using 60% methanol / acetonitrile (containing 0.05% diethylamine) in CO2 at 3 mL / min as the mobile phase).

[0293] (3S,11S)-8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 112a): Rt=0.92 min. MS (ESI) m / z: 694.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.54 (d, J = 6.8 Hz, 3 H) 1.59 (d, J = 6.8 Hz, 3 H) 3.02 - 3.23 (m, 1 H) 3.42 (td, J = 12.4, 4.4 Hz, 2 H) 3.65 - 3.86 (m, 1 H) 4.11 - 4.24 (m, 3 H) 4.54 - 5.01 (m, 4 H) 5.74 - 5.84 (m, 1 H) 6.38 - 6.48 (m, 1 H) 6.58 - 6.70 (m, 1 H) 7.05 (t, J = 8.8 Hz, 1 H) 7.30 (t, J = 7.6 Hz, 2 H) 8.14 (s, 1 H) 8.32 - 8.61 (m, 2 H).

[0294] (3S,11R)-8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 112b): Rt=1.37 min. MS (ESI) m / z: 694.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.53 (d, J=6.4 Hz, 3 H) 1.59 (br s, 3 H) 2.97 - 3.27 (m, 1 H) 3.36 - 3.46 (m, 2 H) 3.54 - 3.83 (m, 1 H) 4.05 - 4.26 (m, 3 H) 4.49 - 5.05 (m, 4 H) 5.80 (dd, J = 10.4, 2.0 Hz, 1 H) 6.43 (dd, J = 16.8, 2.0 Hz, 1 H) 6.64 (dd, J = 16.8, 10.4 Hz, 1 H) 7.09 (t, J = 8.8 Hz, 1 H) 7.25 (br s, 1 H) 7.29 (br s, 1 H) 8.14 (s, 1 H), 8.44 (d, 4.8 Hz), 8.47 (s, 1H).

[0295] Example 113: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0296] Step 1: tert-Butyl (2S,6R)-4-((S)-11-(4-fluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0297] The title compound was prepared similarly to step 9 of example 100, substituting (4-fluorophenyl)boronic acid for (5-chloro-2,4-difluoro-phenyl)boronic acid. The title compound was isolated in 73% yield as a yellow solid. MS (ESI) m / z: 670.2 [M+1]+.

[0298] Step 2: (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0299] tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate was reacted with tert-butyl (2S, The title compound was prepared similarly to step 10 of example 100, substituting 6R)-4-((S)-11-(4-fluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow solid. MS (ESI) m / z: 570.1 [M+1]+

[0300] Step 3: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0301] The title compound was prepared analogously to step 11 of example 100, replacing (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one with (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated as a yellow solid in 91% yield. MS (ESI) m / z: 624.2 [M+1]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.53 (d, J = 7.2 Hz, 3 H) 1.61 (d, J = 6.8 Hz, 3 H) 3.01 - 3.18 (m, 1 H) 3.41 (ddd, J = 17.2, 13.2, 4.0 Hz, 2 H) 3.60 - 3.83 (m, 2 H) 4.20 (dd, J = 12.8, 6.4 Hz, 2 H) 4.56 - 4.95 (m, 4 H) 5.74 - 5.85 (m, 1 H) 6.43 (dd, J = 16.8, 2.0Hz, 1H) 6.59 - 6.71 (m, 1 H) 7.17 - 7.26 (m, 4 H) 7.29 - 7.38 (m, 2 H) 8.13 (s, 1 H) 8.49 - 8.71 (m, 2 H).

[0302] Example 114: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0303] Step 1: tert-Butyl (2S,6R)-4-((S)-11-(4-fluorophenyl)-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0304] tert-Butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate and (5-chloro-2,4-difluoro-phenyl)boronic acid were reacted with tert-butyl (2S,6R The title compound was prepared similarly to step 9 of example 100, substituting 4-((S)-11-chloro-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate and (4-fluorophenyl)boronic acid. The title compound was isolated as a yellow solid. MS (ESI) m / z: 688.2 [M+1]+.

[0305] Step 2: (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0306] tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared similarly to step 10 of example 100, substituting -4-((S)-11-(4-fluorophenyl)-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow solid. MS (ESI) m / z: 588.2 [M+1]+.

[0307] Step 3: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0308] The title compound was prepared analogously to step 11 of example 100, replacing (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one with (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated as a yellow solid in 61% yield. MS (ESI) m / z: 642.2 [M+1]+. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 1.53 (d, J = 6.8 Hz, 3 H) 1.60 (d, J = 6.0 Hz, 3 H) 2.91 - 3.20 (m, 1 H) 3.34 - 3.48 (m, 2 H) 3.53 - 3.81 (m, 1 H) 3.97 - 4.26 (m, 3 H) 4.45 - 5.07 (m, 4 H) 5.73 - 5.85 (m, 1 H) 6.43 (dd, J = 16.8, 2.0 Hz, 1 H) 6.58 - 6.69 (m, 1 H) 7.14 - 7.23 (m, 3 H) 7.25 (br s, 1 H) 7.30 (br s, 1H) 8.12 (s, 1 H) 8.29 - 8.57 (m, 2 H).

[0309] Example 115: 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3,11-bis(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka] [ka] [ka]

[0310] Methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (2)

[0311] To a mixture of methyl 2-(4-fluorophenyl)acetate (5 g, 29.76 mmol) and sodium methanolate (0.08031 g, 1.49 mmol) in DMSO (10 mL) was added polyformaldehyde (0.93 g, 31.25 mmol) at 20 °C for 16 h. The mixture was quenched with water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column with petroleum ether / ethyl acetate = 5% to 40% to give methyl 2-(4-fluorophenyl)-3-hydroxypropanoate 2 (4.5 g, 76% yield) as a white solid.

[0312] 2-(4-fluorophenyl)propane-1,3-diol (3)

[0313] To a solution of methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (11 g, 55.56 mmol) in THF (100 mL) was added 1.0 M DIBAL-H (166.68 mmol, 166.68 mL) at −78 °C under N2 atmosphere. The mixture was stirred at −78 °C for 3 h under nitrogen atmosphere. After completion, the mixture was quenched with sodium sulfate decahydrate and filtered. The solution was concentrated and the residue was purified by silica gel column (PE / EA = 10% to 100%) to give 2-(4-fluorophenyl)propane-1,3-diol 3 (5.05 g, 53% yield) as a yellow oil.

[0314] 2-(4-Fluorophenyl)-3-hydroxypropyl 4-methylbenzenesulfonate (4)

[0315] To a mixture of 2-(4-fluorophenyl)propane-1,3-diol (5.0 g, 29.4 mmol) and TEA (5.94 g, 58.82 mmol) in DCM (50 mL) was added tosyl chloride (3.35 g, 17.6 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column (PE / EA = 0-2:1) to give 2-(4-fluorophenyl)-3-hydroxypropyl 4-methylbenzenesulfonate 4 (3.58 g, 38% yield) as a white solid.

[0316] S-(2-(4-fluorophenyl)-3-hydroxypropyl)ethanethioate (5)

[0317] To a mixture of 2-(4-fluorophenyl)-3-hydroxypropyl 4-methylbenzenesulfonate (3.6 g, 11.11 mmol) in acetone (10 mL) was added potassium methanesulfinate (2.53 g, 22.2 mmol) at 20 °C. The mixture was stirred at 50 °C for 1 h. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column (DCM / MeOH = 0-20:1) to give S-(2-(4-fluorophenyl)-3-hydroxypropyl)ethanethioate 5 (1.7 g, 67% yield) as a yellow oil.

[0318] 7-Chloro-8-((2-(4-fluorophenyl)-3-hydroxypropyl)thio)-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one (6)

[0319] To a mixture of S-(2-(4-fluorophenyl)-3-hydroxypropyl)ethanethioate (1.65 g, 7.24 mmol) and 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2.82 g, 7.24 mmol) in ethylene glycol (10 mL) and isopropanol (10 mL), CuI (551 mg, 2.90 mmol) and K2CO3 (3 g, 21.72 mmol) were added at 20° C. under N2 atmosphere. The mixture was stirred at 85° C. for 3 h. After completion, the mixture was extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The organics were concentrated under reduced pressure, and the residue was purified by silica gel column with DCM / MeOH=0%-20% to give 7-chloro-8-((2-(4-fluorophenyl)-3-hydroxypropyl)thio)-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one 6 (160 mg) as a yellow oil.

[0320] 11-Chloro-3-(4-fluorophenyl)-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (7)

[0321] To a mixture of 7-chloro-8-((2-(4-fluorophenyl)-3-hydroxypropyl)thio)-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one (160 mg, 0.36 mmol) and triphenylphosphine (189 mg, 0.72 mmol) in tetrahydrofuran (20 mL) was added diethyl azodicarboxylate (125 mg, 0.72 mmol) under N2 atmosphere at 0° C. The mixture was stirred at 20° C. for 1 h. After completion, the mixture was concentrated under reduced pressure and the residue was purified by back-flash to give 11-chloro-3-(4-fluorophenyl)-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one 7 (100 mg, 73% yield) as a yellow solid.

[0322] tert-Butyl (2S,6R)-4-(11-chloro-3-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8)

[0323] To a mixture of 11-chloro-3-(4-fluorophenyl)-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one 7 (100 mg, 0.23 mmol) and potassium carbonate (254 mg, 1.84 mmol) in acetonitrile (10 mL), 4-methylbenzenesulfonic anhydride (112 mg, 0.345 mmol) was added at 0° C. The mixture was stirred at 30° C. for 4 hours. Then, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (98 mg, 0.46 mmol) was added to the reaction solution. The reaction mixture was stirred at 30° C. for another 2 hours. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE / EA=0%~100%) to give tert-butyl (2S,6R)-4-(11-chloro-3-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate 8 (50 mg, 35% yield) as a yellow solid.

[0324] tert-Butyl (2S,6R)-4-(3,11-bis(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9)

[0325] tert-Butyl (2S,6R)-4-(11-chloro-3-(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate 8 (50 mg, 0.08 mmol) in 1,4-dioxane (4 mL) and water (1 mL). To a solution of (4-fluorophenyl)boronic acid (90 mg, 0.64 mmol), and tripotassium phosphate (64 mg, 0.24 mmol) was added chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (12 mg, 0.016 mmol) under N2 atmosphere at 20° C. The mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM / MeOH=0%~20%) to give tert-butyl (2S,6R)-4-(3,11-bis(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate 9 (40 mg, 73% yield) as a yellow solid.

[0326] 8-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-3,11-bis(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (10)

[0327] To a solution of tert-butyl (2S,6R)-4-(3,11-bis(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate 9 (40 mg, 0.058 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 mL) at 0° C. The reaction solution was stirred at room temperature for 1 h. After completion, the mixture was concentrated and the residue was purified by silica gel column (dichloromethane / methanol=0%-20%) to give product 10 (20 mg, yield: 59%) as a yellow solid.

[0328] 8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-3,11-bis(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (11)

[0329] To a mixture of 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3,11-bis(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one 10 (20 mg, 0.034 mmol) and triethylamine (10 mg, 0.102 mmol) in dichloromethane (5 ml) was added acrylic anhydride (9 mg, 0.068 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. After completion, the mixture was concentrated and the residue was purified by preparative HPLC to give 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3,11-bis(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one 11 (7 mg, yield: 32%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.35-7.29 (m, 3H), 7.25-7.16 (m, 3H), 7.04-6.99 (m, 2H), 6.67-6.60 (m, 1H), 6.42 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J = 10.8 Hz, 2.4 Hz, 1H), 4.78-4.63 (m, 4H), 4.21-4.15 (m, 2H), 3.75-3.63 (m, 2H), 3.42-3.33 (m, 2H), 3.06-3.03 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.51 (d, J = 6.8 Hz, 3H).

[0330] Example 122: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (P1) and Example 123: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (P2) [ka] [ka]

[0331] 3-(Thiophen-3-yl)oxetane (2)

[0332] Thiophen-3-ylboronic acid (20 g, 101 mmol), nickel(II) bromide ethylene glycol dimethyl ether complex (3.12 g, 10.1 mol), (1S,2S)-N in 1,4-dioxane (350 mL). 1 ,N2 To a mixture of 1,2-dimethylcyclohexane-1,2-diamine (2.15 g, 15.15 mmol) and potassium tert-butoxide (22.62 g, 202 mmol), 3-iodooxetane (27.88 g, 151.5 mmol) was added under nitrogen atmosphere at 0° C. The mixture was stirred at 60° C. for 18 h. After completion, the mixture was poured into ice water (300 mL) and extracted with ethyl acetate (150 mL×3). After concentration, the residue was purified by silica gel column with petroleum ether / ethyl acetate=20 / 1 to give 3-(thiophen-3-yl)oxetane (2) (1.38 g, 10% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.35-7.33 (m, 1H), 7.20-7.18 (m, 1H), 7.12-7.11 (m,1H), 5.04-5.00 (m, 2H), 4.77-4.74 (m, 2H), 4.35-4.27 (m, 1H).

[0333] 3-Bromo-2-(thiophen-3-yl)propan-1-ol (3)

[0334] To a solution of 3-(thiophen-3-yl)oxetane (2) (1.38 g, 9.86 mmol) in dichloromethane (30 mL) was added boron tribromide (10 mL, 9.86 mmol, 1M in dichloromethane) under nitrogen atmosphere at -78°C. The mixture was stirred at 0°C for 1 h. After completion, the mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3), and the mixture was concentrated to give the product 3-bromo-2-(thiophen-3-yl)propan-1-ol (3) (2.1 g, crude) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.26-7.24 (m, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 4.8 Hz, 1H), 3.88-3.81 (m, 2H), 3.68-3.55 (m, 2H), 3.27-3.21 (m, 1H).

[0335] 3-Mercapto-2-(thiophen-3-yl)propan-1-ol (4)

[0336] To a solution of 3-bromo-2-(thiophen-3-yl)propan-1-ol (3) (2.1 g, 9.54 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydrogen sulfide (1.6 g, 28.62 mmol). The mixture was stirred at room temperature for 2 h. After completion, the mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). After concentration, the residue was purified by silica gel column with dichloromethane / methanol = 30 / 1 to give 3-mercapto-2-(thiophen-3-yl)propan-1-ol (4) (1.42 g, 85% yield). 1 H NMR (400 MHz, CDCl3) δ 7.35-7.33 (m, 1H), 7.11 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 5.2 Hz, 1H), 3.87 (d, J = 6.0 Hz, 2H), 3.16-3.12 (m, 1H), 2.91-2.83 (m, 2H).

[0337] 7-Chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (5)

[0338] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol (2.12 g, 5.44 mmol) in 1,4-dioxane (70 mL) was added potassium carbonate (1.5 g, 10.88 mmol), 3-mercapto-2-(thiophen-3-yl)propan-1-ol (4) (1.42 g, 8.16 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (472 mg, 0.816 mmol) and tris(dibenzylideneacetone)dipalladium (498 mg, 0.544 mmol). The mixture was stirred at 60° C. under nitrogen atmosphere for 18 h. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate=4 / 1) to give 7-chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (5) (1.0 g, 42% yield) as a pale yellow solid. MS (ESI) m / z 435.1 [MH] + .

[0339] 11-Chloro-8-hydroxy-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (6)

[0340] To a mixture of 7-chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (5) (1.0 g, 2.29 mmol) and triphenylphosphine (1.2 g, 4.58 mmol) in tetrahydrofuran (40 mL) was added diethyl azodicarboxylate (797 mg, 4.58 mmol) at 0° C. The mixture was stirred at 0° C. for 45 minutes. After completion, the mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL×3). The residue was concentrated and purified by C18 with 30-95% acetonitrile in water to give 11-chloro-8-hydroxy-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (6) (610 mg, 64% yield) as a yellow solid. MS (ESI) m / z 417.1 [MH] + .

[0341] (2S,6R)-tert-Butyl 4-(11-chloro-6-oxo-3-(thiophen-3-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (7)

[0342] To a mixture of 11-chloro-8-hydroxy-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (6) (610 mg, 1.46 mmol) and potassium carbonate (2.01 g, 14.6 mmol) in acetonitrile (50 mL) was added 2,4,6-tris(prop-2-yl)benzenesulfonyl chloride (675 mg, 2.19 mmol). The mixture was stirred at 35° C. for 4 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (625 mg, 2.92 mmol) was added to the reaction solution. The reaction mixture was stirred at 35° C. for 1 hour. After completion, the mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The residue was concentrated and purified by C18 column with 20-95% acetonitrile in water to give (2S,6R)-tert-butyl 4-(11-chloro-6-oxo-3-(thiophen-3-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (7) (630 mg, 70% yield) as a pale yellow solid. MS (ESI) m / z 615.2[M+H] + .

[0343] (2S,6R)-tert-butyl 4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-3-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8)

[0344] (2S,6R)-tert-butyl 4-(11-chloro-6-oxo-3-(thiophen-3-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (7) (180 mg, To a solution of 0.29 mmol of 4-fluorophenylboronic acid (162 mg, 1.16 mmol), tripotassium phosphate (120 mg, 0.87 mmol), (4-fluorophenyl)boronic acid (162 mg, 1.16 mmol), and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (23 mg, 0.03 mmol) were added. The mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane / methanol=50 / 1) to give (2S,6R)-tert-butyl 4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-3-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (210 mg, crude) as a yellow solid. MS (ESI) m / z: 675.1 [M+H] + .

[0345] 8-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (9)

[0346] To a mixture of (2S,6R)-tert-butyl 4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-3-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (210 mg, crude) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) at 0° C. The reaction solution was stirred at room temperature for 1 h. After completion, the mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol=15 / 1) to give 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (9) (160 mg, crude) as a pale yellow solid. MS (ESI) m / z 575.1[M+H] + .

[0347] 8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (10)

[0348] To a mixture of 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (9) (160 mg, 0.28 mmol) and triethylamine (57 mg, 0.56 mmol) in dichloromethane (4 ml) was added acrylic anhydride (53 mg, 0.42 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. After completion, the mixture was poured into ice water (10 mL) and extracted with dichloromethane (10 mL×3). The residue was concentrated and purified by preparative high performance liquid chromatography (20% to 95% acetonitrile in water) to give 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (10) (70 mg, 40% yield) as a white solid. MS (ESI) m / z: 629.2 [M+H] + .

[0349] The above racemic compound (70 mg) was dissolved in ethanol (5 mL) and separated by chiral supercritical fluid chromatography (separation conditions: column: IF 5 μm 20×250 mm; mobile phase: MeOH / DCM=90 / 10 at 25 mL / min; temperature: 30° C.; wavelength: 254 nm) to give the title compounds P1 (20 mg, yield: 29%, 100% ee) and P2 (22 mg, yield: 31%, 99.6% ee); chiral HPLC analysis: using a 5 μm 4.6×250 mm column on IF, mobile phase: MeOH / DCM=90 / 10 at 1 mL / min; temperature: 30° C.; wavelength: 254 nm).

[0350] (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (P1)

[0351] 1 H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.31-7.29 (m, 1H), 7.24 (s, 1H), 7.20-7.15 (m, 4H), 7.10 (d, J = 4.8 Hz, 1H), 6.63 (dd, J = 16.4 Hz, 10.8 Hz, 1H), 6.42 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 4.87-4.60 (m, 4H), 4.17 (t, J = 12.0 Hz, 2H), 3.89-3.85 (m, 1H), 3.62 (d, J = 10.4 Hz, 1H), 3.41-3.32 (m, 2H), 3.07 (d, J = 14.8 Hz, 1H), 1.60 (d, J = 7.2 Hz, 3H), 1.51 (d, J = 6.8 Hz, 3H); Chiral HPLC fraction 1: ee=100%, Rt=7.610 min.

[0352] (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (P2)

[0353] 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.31-7.29 (m, 1H), 7.24 (s, 1H), 7.20-7.15 (m, 4H), 7.10 (d, J = 4.0 Hz, 1H), 6.63 (dd, J = 16.0 Hz, 10.0 Hz, 1H), 6.42 (dd, J = 16.4 Hz, 1.6 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 4.85-4.60 (m, 4H), 4.18 (t, J = 11.6 Hz, 2H), 3.88-3.84 (m, 1H), 3.62 (d, J = 8.8 Hz, 1H), 3.41-3.32 (m, 2H), 3.07 (d, J = 16.4 Hz, 1H), 1.60 (d, J = 7.2 Hz, 3H), 1.51 (d, J = 6.8 Hz, 3H); Chiral HPLC fraction 1: ee=99.6%, Rt=9.489 min.

[0354] Example 124: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (P1)

[0355] Example 125: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (P2) [ka] [ka]

[0356] 3-(Thiophen-2-yl)oxetan-3-ol (2)

[0357] To a solution of 2-bromothiophene (10 g, 61.35 mmol) in tetrahydrofuran (205 mL) was added lithium isopropylmagnesium chloride solution (49.6 mL, 64.42 mmol, 1.3 M tetrahydrofuran) under nitrogen atmosphere at −78° C. The mixture was stirred at −78° C. for 1 h. Then oxetan-3-one (5.3 g, 73.62 mmol) was added slowly. The mixture was slowly warmed to room temperature and stirred for 2 h. Saturated aqueous ammonium chloride solution (200 mL) was added slowly and extracted with ethyl acetate (300 mL×3). After concentration, the residue was purified by silica gel column (petroleum ether / ethyl acetate=3 / 1) to give 3-(thiophen-2-yl)oxetan-3-ol (2) (6.9 g, 72% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.31-7.30 (m, 1H), 7.19-7.18 (m, 1H), 7.05-7.04 (m, 1H), 4.93-2.89 (m, 4H).

[0358] 3-(Thiophen-2-yl)oxetane (3)

[0359] To a mixture of 3-(thiophen-2-yl)oxetan-3-ol (2) (6.9 g, 44.17 mmol) and trifluoroacetic acid (15.4 mL, 200.85 mmol) in dichloromethane (75 mL) was added triethylsilane (32.1 mL, 200.85 mmol) at 0° C. The mixture was stirred at 30° C. for 3 h. After completion, the mixture was poured into ice water (150 mL) and extracted with dichloromethane (150 mL×3). After concentration, the residue was purified by silica gel column (petroleum ether / ethyl acetate=10 / 1) to give 3-(thiophen-2-yl)oxetane (3) (5.8 g, 94% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.23-7.21 (m, 1H), 7.00-6.96 (m, 2H), 5.06-5.02 (m, 2H), 4.82-2.79 (m, 2H), 4.56-4.48 (m, 1H).

[0360] 3-Bromo-2-(thiophen-2-yl)propan-1-ol (4)

[0361] To a solution of 3-(thiophen-2-yl)oxetane (3) (5.8 g, 41.37 mmol) in dichloromethane (140 mL) was slowly added boron tribromide (41.4 mL, 41.4 mmol, 1.0 M in dichloromethane) under nitrogen atmosphere at −78° C. The mixture was stirred at −78° C. for 2 h. After completion, the mixture was poured into ice water (150 mL) and extracted with dichloromethane (150 mL×3). After concentration, the residue was purified by silica gel column (petroleum ether / ethyl acetate=2 / 1) to give 3-bromo-2-(thiophen-2-yl)propan-1-ol (4) (5.3 g, 58% yield). 1 H NMR (400 MHz, CDCl3) δ 7.25-7.23 (m, 1H), 7.01-6.99 (m, 1H), 6.97-6.96 (m, 1H), 3.97-3.96 (m, 2H), 3.74-3.64 (m, 2H), 3.51-3.48 (m, 1H).

[0362] 3-Mercapto-2-(thiophen-2-yl)propan-1-ol (5)

[0363] To a solution of 3-bromo-2-(thiophen-2-yl)propan-1-ol (4) (5.3 g, 23.97 mmol) in N,N-dimethylformamide (48 mL) was added sodium disulfide (5.76 g, 71.91 mmol, 70%) at 0° C. The mixture was stirred at 30° C. for 4 h under nitrogen atmosphere. After completion, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate (200 mL×3). After concentration, the residue was purified by silica gel column (petroleum ether / ethyl acetate=2 / 1) to give 3-mercapto-2-(thiophen-2-yl)propan-1-ol (5) (2.5 g, 60% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.23-7.22 (m, 1H), 7.00-6.98 (m, 1H), 6.93-6.92 (m, 1H), 3.89-3.87 (m, 2H), 3.32-3.26 (m, 1H), 2.95-2.82 (m, 2H), 1.44-1.40 (m, 1H).

[0364] 7-Chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (6)

[0365] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol (2.24 g, 5.74 mmol) in 1,4-dioxane (60 mL) was added potassium carbonate (2.38 g, 17.22 mmol), 3-mercapto-2-(thiophen-2-yl)propan-1-ol (5) (2.5 g, 14.34 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (498 mg, 0.86 mmol) and tris(dibenzylideneacetone)dipalladium (522 mg, 0.57 mmol). The mixture was stirred at 60° C. under nitrogen for 18 h. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane / methanol=30 / 1) to give 7-chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (6) (2.2 g, crude) as a pale yellow solid. MS (ESI) m / z 435.0 [MH] - .

[0366] 11-Chloro-8-hydroxy-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (7)

[0367] To a mixture of 7-chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (6) (2.2 g, 5.04 mmol) and triphenylphosphine (2.64 g, 10.08 mmol) in tetrahydrofuran (100 mL) was added diethyl azodicarboxylate (1.76 g, 10.08 mmol) under nitrogen atmosphere at 0° C. The mixture was stirred at room temperature for 3 hours. After completion, the mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic phase was concentrated and the residue was purified by C18 with 30-95% acetonitrile in water to give 11-chloro-8-hydroxy-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (7) (665 mg, 28% yield for two steps) as a yellow solid. MS (ESI) m / z: 419.2 [M+H] + .

[0368] tert-Butyl (2S,6R)-4-(11-chloro-6-oxo-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8)

[0369] To a mixture of 11-chloro-8-hydroxy-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (7) (665 mg, 1.59 mmol) and potassium carbonate (1.10 g, 7.95 mmol) in acetonitrile (60 mL) was added 4-methylbenzenesulfonic anhydride (1.30 g, 3.98 mmol). The mixture was stirred at 35° C. for 8 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (1.02 g, 4.77 mmol) was added to the reaction solution. The reaction mixture was stirred at 35° C. overnight. After completion, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate (100 mL×3). The residue was concentrated and purified by C18 column with 20-95% acetonitrile in water to give (2S,6R)-4-(11-chloro-6-oxo-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (720 mg, 74% yield) as a pale yellow solid. MS (ESI) m / z: 615.2 [M+H] + .

[0370] tert-Butyl (2S,6R)-4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9)

[0371] To a mixture of (2S,6R)-4-(11-chloro-6-oxo-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (150 mg, 0.24 mmol) in 1,4-dioxane and water, [2'-( Amino)[1,1'-biphenyl]-2-yl][[2',6'-bis(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]chloropalladium (38 mg, 0.048 mmol), potassium phosphate trihydrate (320 mg, 1.2 mmol) and (4-fluorophenyl)boronic acid (101 mg, 0.72 mmol) were added at 25° C. The mixture was stirred at 80° C. for 2 hours. After completion, the mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol=50 / 1) to give tert-butyl (2S,6R)-4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (220 mg, crude) as a yellow solid. MS (ESI) m / z: 675.2 [M+H] + .

[0372] 8-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (10)

[0373] To a mixture of tert-butyl (2S,6R)-4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (220 mg, crude) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 25° C. The mixture was stirred at 25° C. for 1 h. After completion, the mixture was concentrated and the PH was adjusted to 8 with ammonia in methanol at 0° C. The mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol=20 / 1) to give 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (10) (130 mg, crude) as a yellow solid. MS (ESI) m / z: 575.2 [M+H] + .

[0374] 8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (11)

[0375] To a mixture of 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (10) (130 mg, 0.23 mmol) in dichloromethane (6 ml) was added triethylamine (46 mg, 0.46 mmol) and acrylic anhydride (44 mg, 0.35 mmol) at 0° C. The mixture was stirred at 25° C. for 1 hour. After completion, the mixture was added methanol at 25° C. and concentrated. The mixture was purified by preparative high performance liquid chromatography (20% to 95% acetonitrile in water) to give 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (11) (50 mg, 33% yield for three steps) as a pale yellow powder. MS (ESI) m / z: 629.0 [M+H] + .

[0376] The above racemic compound (50 mg) was dissolved in ethanol (5 mL) and separated by chiral supercritical fluid chromatography (separation conditions: column: IC 5 μm 20 × 250 mm; mobile phase: MeOH / DCM = 90 / 10 at 20 mL / min; temperature: 30 °C; wavelength: 254 nm) to give the title compounds CA-5578-F1 (18 mg, yield: 36%, 100% ee) and CA-5578-F2 (16 mg, yield: 32%, 99.8% ee); chiral HPLC analysis: using a 5 μm 4.6 × 250 mm column on IC, mobile phase: MeOH / DCM = 90 / 10 at 1 mL / min; temperature: 30 °C; wavelength: 254 nm).

[0377] (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (P1)

[0378] 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.28-7.27 (m, 1H), 7.21-7.15 (m, 4H), 7.00-6.99 (m, 1H), 6.97-6.95 (m, 1H), 6.63 (dd, J = 16.4 Hz, 10.4 Hz, 1H), 6.41 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 4.87-4.84 (m, 1H), 4.76-4.53 (m, 3H), 4.21-4.15 (m, 2H), 4.11-4.03 (m, 1H), 3.71-3.61 (m, 1H), 3.41-3.32 (m, 2H), 3.13-3.02 (m, 1H), 1.60 (d, J = 7.2 Hz, 3H), 1.52 (d, J = 6.8 Hz, 3H); Chiral HPLC fraction 1: ee=100%, Rt=10.566 min.

[0379] (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (P2)

[0380] 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.31-7.29 (m, 1H), 7.20-7.17 (m, 4H), 7.00-6.99 (m, 1H), 6.97-6.95 (m, 1H), 6.63 (dd, J = 16.8 Hz, 10.4 Hz, 1H), 6.41 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 4.94-4.83 (m, 1H), 4.78-4.54 (m, 3H), 4.21-4.15 (m, 2H), 4.11-4.02 (m, 1H), 3.72-3.60 (m, 1H), 3.41-3.33 (m, 2H), 3.10-3.03 (m, 1H), 1.60-1.57 (m, 3H), 1.52 (d, J = 6.8 Hz, 3H); Chiral HPLC fraction 2: ee=99.8%, Rt=12.223 min.

[0381] Example 126: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0382] Step 1: tert-Butyl (2S,6R)-4-((R)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate and tert-Butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0383] The title compound was prepared similarly to Example 104, substituting (5-fluoropyridin-3-yl)boronic acid for pyridin-3-ylboronic acid in step 1. The title compound was isolated as a 1:1 mixture of diastereomers. tert-Butyl (2S,6R)-4-((R)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate and tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate were purified by SFC (column: Daicel Chiralpak IC Purification of the mixture by HPLC (250mm x 30mm, 10um; phase A: ethanol, phase B: CO2; gradient: 65% A / B, 7.45 min runtime) afforded single diastereomers and characterized by SFC (column: Chiralpak IC-3, 50 x 4.6mm, ID = 3um, stabilized at 35 °C with 100 bar back pressure). Mobile phase: 60% ethanol with 0.05% diethylamine in CO2, flow rate = 3mL / min, detector: photodiode array). Int-a: SFC Rt = 1.58 min; MS (ESI) m / z: 628.2 [M+H]+. Int-b: SFC Rt = 2.87 min; MS (ESI) m / z: 628.2 [M+H]+.

[0384] Step 2: tert-Butyl (2S,6R)-4-((S)-11-(4-fluorophenyl)-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0385] The title compound was prepared analogously to step 9 of example 100, replacing tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 36% yield as a yellow solid. MS (ESI) m / z: 688.2 [M+H]+.

[0386] Step 3: (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0387] tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared similarly to step 10 of example 100, substituting -4-((S)-11-(4-fluorophenyl)-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow solid. MS (ESI) m / z: 588.2 [M+H]+.

[0388] Step 4: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one [ka]

[0389] The title compound was prepared analogously to step 11 of example 100, replacing (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one with (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated as a yellow solid in 84% yield. MS (ESI) m / z: 642.2 [M+1]+.

[0390] 1H-NMR (400 MHz, CDCl3)= 8.47 (s, 1H), 8.42 (s, 1H), 8.13 (S, 1H), 7.46 (m, 1H), 7.25-7.19 (m, 4 H), 6.61 (dd, J= 16 Hz, J= 6 Hz, 1H), 6.44 (d, J= 16 Hz, 1H), 5.80 (d, J= 6 Hz, 1H), 4.80 (m, 4H), 4.21 (m, 2H), 3.75 (m, 2H), 3.40 (m, 2H), 3.06 (m, 1H), 1.57 (m, 6H).

[0391] Those skilled in the art will recognize that the above compounds have chiral centers as well as potential axial chirality, i.e., atropisomers. Each of the compounds may be provided as a mixture of diastereomers or in any diastereomerically pure form.

[0392] Additional embodiments are provided herein as follows: [ka] [ka] [ka]

[0393] Inhibition of KRAS G12C by compounds of formula (I) mediates inhibition of phospho-ERK1 / 2

[0394] This example demonstrates that various compounds of the disclosure inhibit KRAS G12C, thereby mediating downstream inhibition of phospho-ERK1 / 2.

[0395] KRAS G12C mutant cell lines, NCI H358 (ATCC, CRL-5807) and Ras Initiative (RI) KRAS G12C, were cultured according to published protocols and maintained at 37°C with 5% CO2. Phospho-ERK HTRF assays were performed according to the provider's protocol (CisBio#64AERPEH). NCI-H358 or RI KRAS G12C cells were seeded at a density of 50,000 cells per well in 96-well plates (Corning#3903) in the respective medium (RPMI+10% FBS+1% Pen / Strep for NCI-H358 and DMEM+10% FBS+1% Pen / Strep+4ug / ml Blasticidin for RI KRAS G12C) and maintained at 37°C with 5% CO2. Cells were allowed to adhere overnight and treated the next day using an 11-point dose response starting with 2,500 nM of exemplary compound followed by serial 1:3 dilutions for 4 or 16 hours using a Tecan D300e digital dispenser (Tecan Group Ltd., Switzerland). After compound treatment, cells were washed once with ice-cold PBS. Cells were lysed by adding 50 μl of lysis buffer (1x) supplemented with 1x Pierce Halt protease and phosphatase inhibitors and incubated for 30 minutes at 4°C with shaking. After lysis, 16 μL of cell lysate was transferred from the 96-well cell culture plate to a 384-well plate (Perkin Elmer #6007290). A premixed antibody solution was prepared by mixing (volume / volume) Advanced Phospho-ERK1 / 2 d2 antibody and Advanced Phospho-ERK1 / 2 Eu Cryptate antibody. Premixed antibody solution (4 μL) was added to the detection plate containing the cell lysates. The detection plate was incubated overnight at 4°C, and the HTRF signal was read the next day using a Spectramax M5 or Spectramax i3 microplate reader (Molecular Devices, San Jose, CA, USA), and the data were processed according to the manufacturer's protocol.

[0396] Compounds prepared according to the preceding procedures and characterized by inhibition of p-ERK according to the protocols provided herein are summarized in Table 3: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17]

[0397] Although the foregoing embodiments have been described in some detail through illustration and example for purposes of clarity of understanding, those skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims.Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.In the event of any inconsistency between this application and the references provided herein, this application shall control.

Claims

1. A compound of formula (I), or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, Each R １ is independently methyl or cyanomethyl; n is an integer from 0 to 2, X is -CCF ３ or —C-halogen, Ar １ is aryl or heteroaryl optionally substituted with one or more alkyl, halogen, hydroxy, or amino; Ar ２ is a C-linked aryl or heteroaryl optionally substituted with alkyl or halogen.

2. Ar １ 2. The compound of claim 1, wherein is phenyl optionally substituted with one or more halogens.

3. X is -CCl or -CCF ３ 3. The compound according to claim 1 or 2,

4. Ar １ The compound according to any one of claims 1 to 3, wherein is phenyl substituted with one or more halogens.

5. n is 2, and each R １ The compound according to any one of claims 1 to 4, wherein is methyl.

6. Ar ２ but, 【Chemistry 2】 The compound of any one of claims 1 to 5, selected from: any of which is optionally substituted with halogen.

7. The compound is 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 【Chemistry 3-4】 or a pharma- ceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, in a pharma- ceutically acceptable carrier.

9. A method of treating a subject having cancer, comprising administering to the subject a compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

10. 10. The method of claim 9, wherein the cancer comprises a K-Ras G12 mutation.

11. 11. The method of claim 10, wherein the G12 mutation is G12C.

12. The method of any one of claims 9 to 11, wherein the cancer is one or more of pancreatic cancer, lung cancer, and colorectal cancer.

13. 13. The method of claim 12, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

14. The method of any one of claims 9 to 13, wherein the cancer is a CNS cancer.

15. 15. The method of claim 14, wherein the CNS cancer is a primary cancer.

16. 16. The method of claim 15, wherein the primary cancer comprises one or more of a glioma, a meningioma, a medulloblastoma, a ganglioglioma, a schwannoma, and a craniopharyngioma.

17. 17. The method of claim 16, wherein the glioma comprises one or more of astrocytoma, glioblastoma, oligodendroglioma, and ependymoma.

18. 15. The method of claim 14, wherein the CNS cancer comprises a metastatic or secondary cancer.

19. 20. The method of claim 18, wherein the CNS cancer comprises cancer metastasized from one or more of the following: melanoma, breast cancer, colon cancer, renal cancer, nasopharyngeal cancer, leukemia, lymphoma, myeloma, and other cancers of unknown primary site.

20. 13. Use of a compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, in the treatment of cancer.

21. 21. The use of claim 20, wherein the cancer is one or more of pancreatic cancer, lung cancer, and colorectal cancer.

22. 21. The use of claim 20, wherein the cancer is a CNS cancer.

23. 23. The use of claim 22, wherein the CNS cancer comprises a primary cancer.

24. 24. The use of claim 23, wherein the primary cancer comprises one or more of glioma, meningioma, medulloblastoma, ganglioglioma, schwannoma, and craniopharyngioma.

25. 25. The use of claim 24, wherein the glioma comprises one or more of astrocytoma, glioblastoma, oligodendroglioma, and ependymoma.

26. 23. The use of claim 22, wherein the CNS cancer comprises a metastatic or secondary cancer.

27. 27. The use of claim 26, wherein the CNS cancer comprises cancer metastasized from one or more of melanoma, breast cancer, colon cancer, renal cancer, nasopharyngeal cancer, leukemia, lymphoma, myeloma, and other cancers of unknown primary site.

28. 23. The use of claim 22, wherein the CNS cancer comprises a RAS-associated cancer.

29. 13. A method of preventing or reducing the spread of cancer through CNS pathways, comprising administering to a subject a compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

30. 13. Use of a compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or reducing the spread of cancer via CNS pathways.

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