Tricyclic pyridones and pyrimidinones

Abstract

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

Description

[0001] Reference to a sequence listing

[0002] This application incorporates by reference a sequence listing in ASCII text format in a computer readable form (CRF) filed with this application, named 2023-04-24Sequence_Listing_ST26 055745-542001WO.xml, created on April 24, 2023, and 5,290 bytes in size. Background Art

[0003] Embodiments herein relate to compounds and methods for treating RAS-mediated diseases. In particular, embodiments herein relate to compounds and methods for treating diseases such as cancer by targeting oncogenic mutants of K-RAS isoforms.

[0004] Ras protein is a small guanine nucleotide binding protein that acts as a molecular switch by cycling between active GTP-bound and inactive GDP-bound conformations. Ras signaling is regulated by a balance between activation by guanine nucleotide exchange factors (GEFs, most commonly son of sevenless (SOS)) and inactivation by GTPase-activating proteins (GAPs, such as neurofibromin or p120GAP). Ras protein plays an important role in regulating cell proliferation, differentiation and survival. Disregulation of the Ras signaling pathway is almost always associated with disease. Hyperactivated somatic mutations in Ras are among the most common lesions found in human cancers. It has been shown that most of these mutations reduce the sensitivity of Ras to GAP stimulation and reduce its intrinsic GTPase activity, resulting in an increase in the active GTP-bound population. Although mutations in any of the three Ras isoforms (K-Ras, N-Ras or H-Ras) have been shown to lead to oncogenic transformation, K-Ras mutations are by far the most common in human cancers. For example, it is known that K-Ras mutations are often associated with pancreatic cancer, colorectal cancer, and non-small cell lung cancer. Similarly, H-Ras mutations are common in cancers such as papillary thyroid cancer, lung cancer, and skin cancer. Finally, N-Ras mutations often occur in hepatocellular carcinoma.

[0005] There is a need for potent Ras inhibitors that could provide a new class of anticancer compounds. These and other advantages will be apparent to those skilled in the art based on the embodiments and disclosure herein. Summary of the invention

[0006] In some aspects, the embodiments disclosed herein relate to compounds of formula (I)

[0007]

[0008] in:

[0009] Each R 1 are independently methyl or cyanomethyl;

[0010] n is an integer from 0 to 2;

[0011] X is -CCF3 or -C-halogen;

[0012] Ar 1 is aryl or heteroaryl, which is optionally substituted with one or more alkyl, halogen, hydroxyl or amino; and

[0013] Ar 2 is C-linked aryl or heteroaryl, which is optionally substituted by alkyl or halogen.

[0014] In some aspects, embodiments herein relate to methods of treating a subject having a cancer associated with a G12C Kras mutation, comprising administering to the subject a compound as disclosed herein in a pharmaceutically acceptable vehicle. DETAILED DESCRIPTION

[0015] I. Overview

[0016] Disclosed herein are potent and selective tricyclic quinazoline-2-one compounds that have been found to be useful as inhibitors of oncogenic mutants of RAS proteins. Among the various advantages, the compounds disclosed herein have superior selectivity for oncogenic RAS mutants over wild-type RAS proteins. In addition, the compounds disclosed herein may exhibit selectivity for oncogenic mutants of K-RAS over other mutant K-RAS proteins and mutants of N-RAS and H-RAS isoforms. Specifically, the compounds disclosed herein may exhibit selectivity for K-RAS, N-RAS, and H-RAS mutants with a common G12C mutation. Also disclosed herein are pharmaceutical compositions comprising these compounds, and their use in treating diseases such as cancer. Also provided are methods for inhibiting the activity of oncogenic mutant K-RAS, N-RAS, and H-RAS, and methods for treating oncogenic mutant RAS-mediated diseases, especially those involving elevated levels of oncogenic mutant RAS, particularly cancer.

[0017] Disclosed herein is a class of compounds useful for treating oncogenic RAS-mediated conditions and disorders, defined by structural formula (I):

[0018]

[0019] in:

[0020] Each R 1 are independently methyl or cyanomethyl;

[0021] n is an integer from 0 to 2;

[0022] X is -CCF3 or -C-halogen;

[0023] Ar 1 is aryl or heteroaryl, which is optionally substituted with one or more alkyl, halogen, hydroxyl or amino; and

[0024] Ar 2 is C-linked aryl or heteroaryl, which is optionally substituted by alkyl or halogen.

[0025] The compounds according to the various embodiments disclosed herein have useful oncogenic mutant RAS inhibitory or regulatory activity and can be used to treat or prevent diseases or disorders in which oncogenic mutant RAS plays an active role. Therefore, in a broad aspect, the embodiments disclosed herein also provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable carrier, as well as methods for preparing and using the compounds and compositions. The embodiments disclosed herein provide methods for selectively inhibiting RAS, wherein the RAS is an oncogenic mutant with a G12C mutation. In some embodiments, a method for treating an oncogenic mutant K-RAS-mediated disorder in a subject is provided, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition according to the various embodiments disclosed herein. Related embodiments disclose the use of the compounds disclosed herein as therapeutic agents, such as in the treatment of cancer and other diseases involving elevated levels of oncogenic mutant K-RAS. The various embodiments disclosed herein also contemplate the use of the compounds disclosed herein for the manufacture of medicaments for treating diseases or disorders improved by inhibiting oncogenic mutant K-RAS. In some such embodiments, the disease or disorder is cancer.Each of the above-mentioned methods is equally applicable to N-RAS carrying the G12C mutation and similar mutations in H-RAS.

[0026] The compounds of the various embodiments disclosed herein may be selective in RAS oncogenic mutant forms in various ways. For example, the compounds described herein may be selective for G12C mutants of K-RAS, N-RAS or H-RAS. In certain embodiments, the compounds of the various embodiments disclosed herein may be selective for K-RAS G12C over other K-RAS mutants and wild-type K-RAS. Similarly, the compounds of the various embodiments disclosed herein may be selective for N-RAS and H-RAS with the same G12C mutation.

[0027] Various embodiments disclosed herein also relate to methods of inhibiting at least one RAS function, comprising the step of contacting an oncogenic mutant RAS with a compound of formula I as described herein. Cellular phenotype, cell proliferation, activity of mutant RAS, changes in biochemical output produced by active mutant RAS, expression of mutant RAS, or binding of mutant RAS to natural binding partners may be affected. Such methods may encompass disease treatment models, bioassays, cell assays, biochemical assays, and the like.

[0028] II. Definitions

[0029] A. General Definition

[0030] As used herein, the following terms have the indicated meanings.

[0031] When a numerical range is disclosed and the notation "n1 ... to n2" is used (where n1 and n2 are numerical values), then unless otherwise specified, this notation is intended to include the numerical value itself and the range therebetween. This range can be an integer between the end values ​​or be continuous and include the end values. For example, the range "2 to 6 carbons" is intended to include two, three, four, five, and six carbons, because carbon is in integer units. In contrast, for example, the range "1 to 3 μM (micromolar concentration)" is intended to include 1 μM, 3 μM, and all numbers therebetween to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0032] As used herein, the term "about" is intended to qualify the numerical value it modifies, indicating that this value is variable within a margin of error. When a specific margin of error (e.g., the standard deviation of the mean value given in a data chart or table) is not listed, the term "about" should be understood to mean a range that covers the listed values ​​and the range that is included by rounding up or down to the number taking into account significant figures.

[0033] As used herein, "a," "an," or "the" include not only aspects having one member, but also aspects having more than one member. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, and reference to "an agent" includes reference to one or more agents known to those skilled in the art, and so forth.

[0034] B. Chemical Definition

[0035] The following chemical functional group definitions are provided to guide understanding of their meaning and scope. Those skilled in the art will recognize that the use of these functional groups is consistent with the practice of the chemical field. Any of the following chemical functional groups may be optionally substituted as defined below, and each chemical functional group below itself may be an optional substitution.

[0036] The term "acyl" as used herein, alone or in combination, refers to a carbonyl (C=O) attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or any other moiety, wherein the atom attached to the carbonyl is carbon. "Acetyl" is a type of acyl group, which refers to a (--C(=O)CH3) group. "Alkylcarbonyl" or "alkanoyl" refers to an alkyl group attached to the parent molecular moiety via a carbonyl group. Examples of such groups include, but are not limited to, methylcarbonyl and ethylcarbonyl. Similarly, "arylcarbonyl" or "aroyl" refers to an aryl group attached to the parent molecular moiety via a carbonyl group. Examples of such groups include, but are not limited to, benzoyl and naphthoyl. Thus, general examples of acyl include alkanoyl, aroyl, heteroaroyl, and the like. Specific examples of acyl include, but are not limited to, formyl, acetyl, acryloyl, benzoyl, trifluoroacetyl, and the like.

[0037] The term "alkenyl" as used herein, alone or in combination, refers to a straight or branched hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkenyl group may contain 2 to 6 carbon atoms or 2 to 4 carbons, any of which may be referred to as a "lower alkenyl group". The term "alkenylene" refers to a carbon-carbon double bond system connected at two or more positions, such as vinylene (--CH=CH--). The alkenyl group may include any number of carbons, such as C2, C 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 5-6and C6, etc., up to 20 carbon atoms. Alkenyl groups may 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 may be substituted or unsubstituted. Unless otherwise specified, the term "alkenyl" may include "alkenylene".

[0038] The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Alkoxy groups may have the general formula: alkyl-O-. Like alkyl groups, alkoxy groups may have any suitable number of carbon atoms, such as C 1-6 Alkoxy includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Alkoxy may be further optionally substituted as defined herein.

[0039] The term "alkyl" (sometimes abbreviated as Alk) as used herein, alone or in combination, refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms. In certain embodiments, the alkyl group may contain 1 to 10 carbon atoms. In other embodiments, the alkyl group may contain 1 to 6 carbon atoms or 1 to 4 carbon atoms. The alkyl group may include any number of carbon atoms, such as C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , 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 C 5-6 For example, C 1-6Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl may also refer to an alkyl having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl may 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 saturated hydrocarbon and connected at two or more positions, such as methylene (--CH2--). Unless otherwise specified, the term "alkyl" may include "alkylene". When the alkyl is methyl, it may be structurally represented as CH3, Me, or terminated with a single bond only, without terminal substitution.

[0040] The term "alkylamino" as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety via an amino group. Suitable alkylamino groups may be mono- or di-alkylated, forming, for example, the following groups: N-methylamino (--NHMe), N-ethylamino (--NHEt), N,N-dimethylamino (--NMe2), N,N-ethylmethylamino (--NMeEt), etc. The term "aminoalkyl" refers to the reverse orientation in which the amino group appears at the distal end of the parent molecular moiety and is attached to the parent molecular moiety via an alkyl group. For example, NH2(CH2) n - describes an aminoalkyl group in which the terminal amine is located at the end of the alkyl group attached to the parent molecular moiety. The two terms alkylamino and aminoalkyl can be combined to describe "alkylaminoalkyl" in which the alkyl group is located on the nitrogen atom distal to the parent molecular moiety, such as MeNH(CH2) n --. In a similar manner, aryl groups as defined herein may be combined in a similar manner to provide arylaminoalkyl ArNH(CH2) n For greater clarity, nomenclature may be provided in which the group attached to the nitrogen is indicated by "N-" in the name, such as 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 group is attached to the parent molecular moiety.

[0041] The term "alkylene" as used herein, alone or in combination, refers to an alkenyl group wherein one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[0042] The term "alkylthio" as used herein, alone or in combination, refers to an alkylthioether (AlkS-) group, wherein the term alkyl is as defined above and wherein the sulfur may be mono- or di-oxidized. Examples of suitable alkylthioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methylsulfonyl, ethylsulfinyl, and the like. Similarly, "arylthio" refers to an arylthioether (ArS-) group, wherein the term aryl is as defined herein and wherein the sulfur may be mono- or di-oxidized.

[0043] The term "alkynyl" as used herein, alone or in combination, refers to a straight or branched hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkynyl group contains 2 to 6 carbon atoms. In other embodiments, the alkynyl group contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene. Alkynyl groups may include any number of carbon atoms, such as C2, C 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. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentenyl, 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 may be substituted or unsubstituted. Unless otherwise specified, the term "alkynyl" may include "alkynylene".

[0044] The term "acylamino" as used herein, alone or in combination, refers to an amino group that is connected to the parent molecular moiety via a carbonyl group as described below. The term "C-acylamino" as used herein, alone or in combination, refers to a --C(=O)N(R)2 group, wherein R is as defined herein. The term "N-acylamino" as used herein, alone or in combination, refers to a RC(=O)N(R')-- group, wherein R and R' are as defined herein. The term "acylamino" as used herein, alone or in combination, encompasses an acyl group that is connected to the parent moiety via an amino group. An example of an "acylamino" is acetylamino (CH3C(O)NH--).

[0045] The term "amino" as used herein, alone or in combination, refers to --N(R)(R') or --N + (R)(R')(R"), wherein 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 itself be optionally substituted.

[0046] 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 with N (e.g., in the case of 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, thiolalkyl, alkylthioalkyl, and alkylthio, any of which may be optionally substituted. The term "amino acid" includes all naturally occurring amino acids as well as synthetic analogs.

[0047] The term "aryl" as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings, wherein such rings may be attached together in a pendant manner or may be fused. The term "aryl" encompasses aromatic groups such as benzyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, dihydroindenyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl and biphenyl.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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 alkynyl group.

[0052] The term "arylalkanoyl" or "aralkanoyl" or "aroyl" as used herein, alone or in combination, refers to an acyl group derived from an aryl-substituted alkanecarboxylic acid, such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyroyl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0053] 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.

[0054] The terms "benzo" and "benz" as used herein, alone or in combination, refer to a divalent radical C6H4- derived from benzene. Examples include benzothiophene and benzimidazole.

[0055] The term "carbamate" as used herein, alone or in combination, refers to an ester of a carbamic acid (--NHCOO--) which can be attached to the parent molecular moiety from either the nitrogen terminus or the acid (oxygen) terminus, and which can be optionally substituted as defined herein.

[0056] The term "O-carbamyl," as used herein, alone or in combination, refers to an --OC(O)NRR' group, where R and R' are as defined herein.

[0057] The term "N-carbamyl" as used herein, alone or in combination, refers to a ROC(O)NR'-- group, where R and R' are as defined herein.

[0058] As used herein, the term "carbonyl" when alone includes formyl [--C(=O)H] and in combination is a -C(=O)- group.

[0059] As used herein, the term "carboxyl" or "carboxyl" refers to --C(=O)OH, O-carboxyl, C-carboxyl, or the corresponding "carboxylate" anion, such as in a carboxylate. "O-carboxyl" refers to a RC(=O)O-- group, where R is as defined herein. "C-carboxyl" refers to a --C(=O)OR group, where R is as defined herein.

[0060] The term "cyano" as used herein, alone or in combination, refers to -CN.

[0061] 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, wherein each cyclic moiety contains 3 to 12 carbon atom ring members and it may optionally be a benzo fused ring system optionally substituted as defined herein. In some embodiments, the cycloalkyl may contain 3 to 7 carbon atoms or 5 to 7 carbon atoms. Examples of such cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, etc. "Bicyclic" and "tricyclic" as used herein are intended to include both fused ring systems (such as decahydronaphthalene, octahydronaphthalene) and polycyclic (multi-center) saturated or partially unsaturated types. The latter isomer is generally exemplified by bicyclo[1.1.1]pentane, camphor, adamantane and bicyclo[3.2.1]octane.

[0062] As used herein, the term "electrophilic moiety" is used according to its ordinary common chemical meaning and refers to an electrophilic chemical group. Exemplary electrophilic moieties include, but are not limited to, compounds containing unsaturated carbonyl groups, such as acrylamides, acrylates, unsaturated (i.e., vinyl) sulfones or phosphates, epoxides, and vinyl epoxides.

[0063] The term "ester" as used herein, alone or in combination, refers to a carboxyl group bridging two moieties linked at carbon atoms (--CRR'C(=O)OCRR'--), wherein each R and R' is independent and defined herein.

[0064] The term "ether" as used herein, alone or in combination, generally refers to an oxy group bridging two moieties connected at a carbon atom. "Ether" may also include polyethers, such as --RO(CH2)2O(CH2)2O(CH2)2OR', --RO(CH2)2O(CH2)2OR', --RO(CH2)2OR' and --RO(CH2)2OH.

[0065]

[0046] The term "halo" or "halogen" as used herein, alone or in combination, refers to fluoro, chloro, bromo or iodo.

[0066] 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.

[0067] The term "haloalkyl" as used herein alone or in combination refers to an alkyl group with the meaning as defined above, wherein one or more hydrogens are replaced by halogen. Specifically encompassing monohaloalkyl, dihaloalkyl, trihaloalkyl and polyhaloalkyl. The monohaloalkyl of an example may have iodine, bromine, chlorine or fluorine atoms within the group. Dihaloalkyl and polyhaloalkyl may have a combination of two or more identical halogen atoms or different halogens. The example of haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "haloalkylene" refers to a haloalkyl group connected at two or more positions. Examples include fluoromethylene (--CFH--), difluoromethylene (--CF2--), chloromethylene (--CHCl--) etc.

[0068] The term "heteroalkyl" as used herein, alone or in combination, refers to a stable straight or branched or cyclic hydrocarbon radical that is fully saturated or contains 1 to 3 degrees of unsaturation, or a combination thereof, which consists of a specified number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized (i.e., bonded to 4 groups). The heteroatoms O, N and S may be located at any interior position of the heteroalkyl. Up to two heteroatoms may be consecutive, for example --CH2NHOCH3. The term heteroalkyl may include ethers.

[0069] The term "heteroaryl" or "heteroaromatic" as used herein, alone or in combination, refers to a 3- to 7-membered unsaturated heteromonocyclic ring or a fused polycyclic ring, each of which is 3- to 7-membered, wherein at least one fused ring is unsaturated, wherein at least one atom is selected from the group consisting of O, S, and N. In some embodiments, the heteroaryl group may contain 5 to 7 carbon atoms. The term also encompasses fused polycyclic groups, wherein the heterocyclic group is fused to an aryl group, wherein the heteroaryl group is fused to other heteroaryl groups, or wherein the heteroaryl group is fused to a cycloalkyl group. Non-limiting examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, phenyl The invention also includes benzotriazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzothiophenyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, etc. Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, etc.

[0070] The heteroaryl or heteroaromatic group can include any number of ring atoms, for example, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl group, for example, 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. The heteroaryl group can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups may include, for example, the following groups: 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 benzene rings, to form members including, but not limited to, the following: benzopyrroles such as indole and isoindole; benzopyridines such as quinoline and isoquinoline; benzopyrazines (quinoxalines); benzopyrimidines (quinazolines); benzopyridazines such as phthalazine and cinnoline; benzothiophene; and benzofurans. Other heteroaryl groups include heteroaryl rings connected by bonds, such as bipyridine. Heteroaryl groups may be substituted or unsubstituted.

[0071] The heteroaryl or heteroaromatic group may be attached via any position on the ring. For example, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3- and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazole includes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5- and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2- and 3-thiophene, furan includes 1- and 2-thiophene, includes 2- 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-quinazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran.

[0072] Some heteroaryl or heteroaromatic groups include those having 5 to 10 ring members and 1 to 3 ring atoms (including 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 with 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Other heteroaryl groups include those with 5 to 6 ring members and 1 to 2 ring atoms (including N, O or S), such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0073] The terms "heterocycloalkyl" and "heterocycle" or "heterocyclyl" as used herein, alone or in combination, each refer to a saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each heteroatom can be independently selected from the group consisting of nitrogen, oxygen and sulfur. In certain embodiments, the heterocycloalkyl may contain 1 to 4 heteroatoms as ring members. In other embodiments, the heterocycloalkyl may contain 1 to 2 heteroatom ring members. In some embodiments, the heterocycloalkyl may contain 3 to 8 ring members in each ring. In other embodiments, the heterocycloalkyl may contain 3 to 7 ring members in each ring. In other embodiments, the heterocycloalkyl may contain 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include N-oxides of sugars, sulfones, sulfoxides, tertiary nitrogen ring members, and carbocyclic fused rings and benzofused ring systems; in addition, the two terms also include systems in which the heterocycle is fused to an aryl or another heterocyclic group as defined herein. Examples of heterocycloalkyl 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, isoindolyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, etc. Unless specifically prohibited, the heterocycloalkyl group may be optionally substituted.

[0074] "Heterocycloalkyl" may refer to a saturated ring system having 3 to 12 ring members and 1 to 5 N, O and S heteroatoms. The heteroatoms may also be oxidized, such as, but not limited to, S(O) and S(O)2. Heterocycloalkyl may include any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Heterocycloalkyl may include any suitable number of heteroatoms, such as 1, 2, 3, 4 or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4 or 3 to 5. Heterocycloalkyl may include any number of carbon atoms, such as 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 3-12The heterocycloalkyl group may include, for example, 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), thiolane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane or dithiane. The heterocycloalkyl group may also be fused with an aromatic or non-aromatic ring system to form members including, but not limited to, indoline, diazabicycloheptane, diazabicyclooctane, diazaspirooctane, or diazaspironane. The heterocycloalkyl group may be unsubstituted or substituted. For example, the heterocycloalkyl group may be substituted with, in particular, C16 alkyl or oxo (=O). The heterocycloalkyl group may also include double or triple bonds, such as, but not limited to, dihydropyridine or 1,2,3,6-tetrahydropyridine.

[0075] The heterocycloalkyl group may be attached via any position on the ring. For example, the aziridine may be 1- or 2-aziridine, the azetidine may be 1- or 2-azetidine, the pyrrolidine may be 1-, 2- or 3-pyrrolidine, the piperidine may be 1-, 2-, 3- or 4-piperidine, the pyrazolidine may be 1-, 2-, 3- or 4-pyrazolidine, the imidazolidine may be 1-, 2-, 3- or 4-imidazolidine, the piperazine may be 1-, 2-, The tetrahydrofuran may be 1- or 2-tetrahydrofuran, the oxazolidine may be 2-, 3-, 4- or 5-oxazolidine, the isoxazolidine may be 2-, 3-, 4- or 5-isoxazolidine, the thiazolidine may be 2-, 3-, 4- or 5-thiazolidine, the isothiazolidine may be 2-, 3-, 4- or 5-isothiazolidine, and the morpholine may be 2-, 3- or 4-morpholine.

[0076] When the heterocycloalkyl group includes 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiacyclohexane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. The heterocycloalkyl group can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, and representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0077] The term "hydrazino," as used herein, alone or in combination, refers to two amino groups joined by a single bond, ie, --N--N--. Generally, the hydrazino group has an optional substitution on at least one of the NH hydrogens to impart stability.

[0078] As used herein, the term "hydroxamic acid" or an ester thereof refers to --C(O)ON(R)O(R'), wherein R and R' are as defined herein, or the corresponding "hydroxamate" anion, including any corresponding hydroxamate salt.

[0079] The term "hydroxyl" as used herein, alone or in combination, refers to OH.

[0080] 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 hydrogen atom is replaced by a hydroxy group. As with alkyl, hydroxyalkyl or alkylhydroxy can have any suitable number of carbon atoms, for example, C 1-6 . Example C 1-4 Hydroxyalkyl includes, but is not limited to, hydroxymethyl, hydroxyethyl (wherein the hydroxyl group is at the 1- or 2-position), hydroxypropyl (wherein the hydroxyl group is at the 1-, 2-, or 3-position), hydroxybutyl (wherein the hydroxyl group is at the 1-, 2-, 3-, or 4-position), 1,2-dihydroxyethyl, and the like.

[0081] The term "imino" as used herein, alone or in combination, refers to C=NR.

[0082] The term "iminohydroxy" as used herein, alone or in combination, refers to C=N(OH) and its O-ether C=N--OR.

[0083] The term "isocyanato" refers to an --NCO group.

[0084] The term "isothiocyanato" refers to the --NCS group.

[0085] The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0086] As used herein, the term "linker" refers to any nitrogen-containing organic fragment used to connect the pyrimidine or pyridone core of the compounds disclosed herein to the electrophilic moiety E as defined herein. Exemplary linkers include piperazine, aminoalkyl, alkyl-based or aryl-based diamines, aminocycloalkyl, amine-containing spiro rings, any of which may be optionally substituted as defined herein. In some embodiments, the linker may comprise a substructure LQ-L'-E, wherein Q is a 4- to 7-membered monocyclic or bicyclic, bridged or fused or spiro 6- to 11-membered ring, any of which optionally includes one or more nitrogen atoms, E is an electrophilic group, and L is a bond, C 1-6 Alkylene, -OC 0-5 Alkylene, -SC 0-5 Alkylene or -NH-C 0-5 Alkylene, and for C 2-6 Alkylene, -OC2-5 Alkylene, -SC 2-5 Alkylene and NH-C 2-5 For alkylene, one carbon atom of any of the alkylene may be optionally replaced by O, S or NH; and when Q comprises a nitrogen attached to E, L' is a bond, otherwise L' is NR, wherein R is hydrogen or alkyl.

[0087] The term "lower" as used herein, alone or in combination, means containing 1 to 6 (and including 6) carbon atoms or 1 to 4 carbon atoms.

[0088] The term "thiol" as used herein, alone or in combination, refers to an RS-- group, where R is as defined herein.

[0089] The term "nitro" as used herein, alone or in combination, refers to --NO2.

[0090] The term "oxy" or "oxa," as used herein, alone or in combination, refers to --O--.

[0091] The term "oxo" as used herein, alone or in combination, refers to =0.

[0092] The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms.

[0093] The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0094] The term "phosphoramide" as used herein, alone or in combination, refers to a phosphate group [(OH)2P(=O)O--], wherein one or more hydroxyl groups are replaced by nitrogen, amino or amido groups.

[0095] The term "phosphonate group" as used herein, alone or in combination, refers to a group of the form ROP(OR')(OR)O--, wherein R and R' are selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, any of which may itself be optionally substituted. "Phosphonate group" includes "phosphate ester group [(OH)2P(O)O--] and the associated phosphate anion that can form a salt.

[0096] The terms "sulfonate," "sulfonic acid," and "sulfonic acid group," as used herein, alone or in combination, refer to the -SO3H group and its anion when the sulfonic acid is used in salt formation, or to a sulfonate ester when OH is replaced by OR, wherein R is not hydrogen, but is otherwise as defined herein, and is typically alkyl or aryl.

[0097] The term "sulfanyl" as used herein, alone or in combination, refers to -S-.

[0098] The term "sulfinyl" as used herein, alone or in combination, refers to --S(O)--.

[0099] The term "sulfonyl" as used herein, alone or in combination, refers to --S(O)2--.

[0100] The term "N-sulfonamido" refers to a RS(=0)2NR'-- group, where R and R' are as defined herein.

[0101] The term "S-sulfonamido" refers to a --S(=0)2NRR' group, where R and R' are as defined herein.

[0102] The terms "thia" and "thio" as used herein, alone or in combination, refer to an --S-- group or an ether in which the oxygen is replaced by sulfur. The oxygenated derivatives of thio, namely, sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0103] The term "thiol" as used herein, alone or in combination, refers to a --SH group.

[0104] As used herein, the term "thiocarbonyl" when alone includes the thiocarbonyl group --C(=S)H, and in combination is a --C(=S)-- group.

[0105] The term "N-thiocarbamyl" refers to a ROC(=S)NR'-- group, where R and R' are as defined herein.

[0106] The term "O-thiocarbamyl" refers to an --OC(=S)NRR' group, where R and R' are as defined herein.

[0107] The term "thiocyanato" refers to the --CNS group.

[0108] The term "trihalomethanesulfonamido" refers to a X3CS(=O)2NR-- group, where X is a halogen and R is as defined herein.

[0109] The term "trihalomethanesulfonyl" refers to a X3CS(=O)2- group, where X is a halogen.

[0110] The term "trihalomethoxy" refers to a X3CO-- group where X is a halogen.

[0111] The term "trisubstituted silyl" as used herein, alone or in combination, refers to a polysiloxy group in which three free valencies are substituted with groups as listed herein below the definition of substituted amino. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, and the like.

[0112] In the embodiments of the present disclosure, any position understood to have hydrogen may also be present or understood to be isotopically enriched. In the compounds of the present disclosure, any atom that is not explicitly designated as a specific isotope is intended to represent any stable isotope of the atom. It may be difficult to obtain 100% deuteration at any relevant site of a compound of milligrams or more. Therefore, it should be understood that even if deuterium atoms are explicitly shown in the chemical structure, a certain percentage of hydrogen may still be present. Therefore, when a chemical structure contains "D", the compound represented by the structure is enriched in deuterium at the site represented by "D". Unless otherwise stated, when a position is explicitly designated as "H" or "hydrogen", it should be understood that the position has hydrogen of natural abundance isotopic composition. Furthermore, unless otherwise noted, when a position is specifically designated as "D" or "deuterium", it is understood that the position has deuterium at an abundance of at least 3340 times the natural abundance of deuterium, which is 0.015% (i.e., the term "D" or "deuterium" indicates at least 50.1% deuterium is incorporated). In embodiments, the benzene ring may optionally be present as -C6D5, -C6DH4, -C6D2H3, -C6D3H2, and -C6D4H. In embodiments, the cyclohexyl group may optionally be present as -C6D 11 exist.

[0113] Any definition herein can be used in combination with any other definition to describe a composite structural group. By convention, the following components of any such definition are those that are attached to the parent moiety. For example, the composite group alkylamido will represent an alkyl group that is attached to the parent molecule via an acylamino group, and the term alkoxyalkyl will represent an alkoxy group that is attached to the parent molecule via an alkyl group.

[0114] When a group is defined as "empty", this means that the group does not exist. An "empty" group that appears between two other groups can also be understood as a folding of the side groups. For example, if in --(CH2) x G 1 G 2 G 3 In the component G 2 is empty, the group will become --(CH2) x G 1 G 3 .

[0115] The term "optionally substituted" means that one or more preceding groups may be substituted or unsubstituted. The groups constituting the optional substitution may themselves be optionally substituted. For example, if an alkyl group is encompassed by optional substitution, the alkyl group itself may also be optionally substituted. When substituted, the substituents of the "optionally substituted" group may include, but are not limited to, one or more substituents independently selected from the following groups or a specific specified group set, 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, carboxylate, carboxamido, cyano, hydrogen, halogen, hydroxyl, amino, alkylamino, arylamino, amido, nitro, thiol, alkylthio, haloalkylthio, perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridyl, 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) hydroxy, alkyl, halo, alkoxy, and cyano. Provided that the optional substitution comprises a heteroatom-hydrogen bond (-NH-, SH, OH), other optional substitutions of heteroatom hydrogen are contemplated, and include, but are not limited to, optional substitution with alkyl, acyl, alkoxymethyl, alkoxyethyl, arylsulfonyl, alkylsulfonyl, any of which is further optionally substituted. These subsets of optional substitutions are intended to be exemplary only, and any combination of 2 to 5, or 2 to 10, or 2 to 20 of the above-listed groups up to all of the above-listed groups and any subranges therebetween are contemplated. "Optionally substituted" may include any chemical functional group as defined above and throughout this disclosure. Two optional substituents can be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, such as methylenedioxy or ethylenedioxy. An optionally substituted group can be unsubstituted (e.g., --CH2CH3), fully substituted (e.g., --CF2CF3), monosubstituted (e.g., --CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., --CH2CF3).

[0116] The various optional substitutions need not be identical, and any combination of optional substituents may be combined. For example, the carbon chain may be substituted by alkyl, halo, and alkoxy. Where a substituent is not specifically listed in terms of substitution, both substituted and unsubstituted forms are contemplated. Where a substituent is defined as "substituted", the substituted form is explicitly intended. Additionally, different groups of optional substituents for a particular moiety may be defined as desired; in these cases, the optional substitution will be as defined, typically immediately following the phrase "optionally substituted by...".

[0117] Unless otherwise defined, the term R or the term R', when present alone and without a numerical designation, refers to a moiety selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted. Each such R and R' group is understood to be optionally substituted as defined herein. R and R' are understood to be independent at each occurrence. Regardless of whether the R group has a numerical designation, each R group (including R, R', and R') is independently substituted. n , wherein n=(1, 2, 3, ..., n)), each substituent and each term should be understood to be independent of each other with respect to the group selected from. If any variable, substituent or term (e.g., aryl, heterocycle, R, etc.) appears more than once in a formula or general structure, its definition at each occurrence is independent of its definition at each other occurrence. Those skilled in the art will further recognize that certain groups may be attached to the parent molecule or may occupy positions in the component chain starting from either end as written. Thus, by way of example only, an asymmetric group (e.g., --C(O)N(R)--) may be attached to the parent moiety at carbon or nitrogen.

[0118] Asymmetric centers, axial asymmetry (non-interchangeable rotational isomers), etc. may be present in the compounds of the various embodiments disclosed herein. This chirality may be specified by the symbol "R" or "S", depending on the configuration of the substituents around the chiral carbon atom or the relevant axis. It should be understood that the embodiments encompass all stereochemical isomeric forms, including diastereoisomers, enantiomers and epimeric forms, d-isomers and l-isomers and mixtures thereof. Individual stereoisomers of compounds may be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products, followed by separation, such as conversion into a mixture of diastereoisomers, followed by separation or recrystallization, chromatography, direct separation of enantiomers on a chiral chromatographic column, or any other suitable method known in the art. Starting compounds with specific stereochemistry are commercially available or can be prepared and resolved by techniques known in the art. In addition, the compounds of the various embodiments disclosed herein may exist as geometric isomers. The various embodiments disclosed herein include all cis, trans, cis, trans, hetero (E) and homo (Z) isomers and suitable mixtures thereof. In addition, compounds may exist as tautomers, including keto-enol tautomers; the embodiments disclosed herein encompass all tautomeric isomers.

[0119] Additionally, the compounds of the various embodiments disclosed herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the various embodiments disclosed herein.

[0120] The term "bond" refers to a covalent linkage between two atoms, or between two moieties when the atoms joined by the bond are considered part of a larger substructure. Unless otherwise specified, a bond may be a single bond, a double bond, or a triple bond. 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 location.

[0121] 1. Salts of Compounds

[0122] The compounds disclosed herein may exist as pharmaceutically acceptable salts, including acid addition salts. Suitable salts include those formed with organic acids and inorganic acids. Such acid addition salts will generally be pharmaceutically acceptable. However, salts that are not pharmaceutically acceptable salts can be used to prepare and purify the compounds in question. Base addition salts may also be formed and are pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002). It should be understood that each compound disclosed herein and each embodiment of the compounds described herein include pharmaceutically acceptable salts of such compounds.

[0123] As used herein, the term "pharmaceutically acceptable salt" represents a salt or zwitterionic form of a compound disclosed herein that is water-soluble or oil-soluble, or dispersible, and is pharmaceutically acceptable as defined herein. The salt can be prepared during the final isolation and purification of the compound, or prepared separately by reacting an appropriate compound in free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (benzenesulfonate / besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (hydroxyethyl sulfonate), lactate, maleate The present invention also provides the following quaternary ammonium salts: quaternary ammonium salts, ... 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 compounds with alkali metal or alkaline earth metal ions. Therefore, various embodiments disclosed herein contemplate sodium salts, potassium salts, magnesium salts and calcium salts of the compounds disclosed herein, etc.

[0124] Base addition salts can be prepared by reacting the carboxyl group with a suitable base (e.g., hydroxide, carbonate, or bicarbonate of a metal cation) or with ammonia or an organic primary, secondary, or tertiary amine during the final separation and purification of the compound. The cation of the pharmaceutically acceptable salt includes lithium, sodium, potassium, calcium, magnesium, and aluminum, and 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 that can be used to form base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0125] C. Treatment-Related Definitions

[0126] The term "disease" as used herein is intended to be generally synonymous with the terms "disorder" and "condition" (as in medical conditions) and to be used interchangeably because all of the terms reflect an abnormal condition in the body or a part thereof that impairs normal function and usually manifests itself by distinctive signs and symptoms.

[0127] As used herein, the term "cancer" refers to all types of cancers, neoplasms or malignancies found in mammals (e.g., but not limited to humans), including leukemias, lymphomas, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, pancreatic cancer. Other examples include Hodgkin's Disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer / medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0128] The term "leukemia" refers broadly to progressive malignant diseases of the blood-forming organs and is generally characterized by dysmorphic proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias are generally clinically classified based on: (1) the duration and nature of the disease (acute or chronic); (2) the cell types involved; myeloid (myeloid), lymphoid (lymphogenic), or monocytic; and (3) the absence or increase in the number of abnormal cells in the blood (leukemic or leukopenic (subleukemic)). Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, leukopenia leukemia, leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, blast cell leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, Hemoblastic leukemia, hematoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelomorphic leukemia, myelomonocytic leukemia, Negri's leukemia leukemia), plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia or undifferentiated cell leukemia.

[0129] As used herein, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphoid tissues. It begins in lymphocytes, i.e., blood cells found primarily in lymph nodes, spleen, thymus, and bone marrow. Two major types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. It is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the rate of cancer growth and the cell types involved. NHL has aggressive (high-grade) and indolent (low-grade) types. Based on the cell types involved, there are B-cell NHL and T-cell NHL. Exemplary B-cell lymphomas that can 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 lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B lymphoblastic lymphoma. Exemplary T-cell lymphomas that can 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.

[0130] The term "sarcoma" generally refers to a tumor composed of material resembling embryonic connective tissue and usually composed of tightly packed cells embedded in a fibrous or homogeneous substance. Sarcomas treatable with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, amelogenin sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, extraperiosteal sarcoma, reticular cell sarcoma, Roussarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0131] The term "melanoma" means a tumor of the melanocyte system originating from the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral punctate melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0132] The term "carcinoma" refers to a malignant new growth composed of epithelial cells that tends to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that can be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma (carcinoma basocellulare), basaloid carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, cutaneous carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, adenoid epithelial cell carcinoma, exophytic carcinoma, ulcerative carcinoma, and ulcerative carcinoma. ulcere), fibrocarcinoma, gelatinous carcinoma (gelatinous carcinoma), giant cell carcinoma (giant cell carcinoma / carcinoma gigantocellulare), adenocarcinoma, granulosa cell carcinoma, maternal carcinoma, hematogenous carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma (lenticulare), lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma (carcinoma medullare / medullary carcinoma), melanoma, carcinoma molle, mucinous carcinoma noma), carcinoma muciparum, carcinomamuco cellulare, mucoepidermoid carcinoma, carcinoma mucosum / mucous car cinoma, carcinoma mucosus / mucous car cinoma,myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthocyte carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet-ring cell carcinoma, carcinoma simplex, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectasia telangiectaticum / carcinomatelangiectodes), transitional cell carcinoma, carcinoma tuberosum / tuberouscarcinoma, verrucous carcinoma, or carcinoma villosum.

[0133] "Ras-related cancer" (also referred to herein as "Ras-related cancer") refers to a cancer caused by abnormal Ras activity or signaling. "Cancer associated with abnormal K-Ras activity" (also referred to herein as "K-Ras-related cancer") is a cancer caused by abnormal K-Ras activity or signaling (e.g., mutant K-Ras). K-Ras-related cancers may include lung cancer, non-small cell lung cancer, breast cancer, leukemia, pancreatic cancer, colon cancer, colorectal cancer. Other cancers associated with abnormal activity of one or more of Ras, K-Ras, H-Ras, N-Ras, mutant K-Ras (including K-Ras G12C, K-Ras G12V, K-Ras G13C, K-Ras G12D, K-Ras G13D mutants), mutant N-Ras, and mutant H-Ras (including N-Ras G12C and H-Ras G12C) are well known in the art, and determining such cancers is within the capabilities of those skilled in the art.

[0134] The term "administering or administering a Ras inhibitor" means administering to a subject a compound that inhibits the activity or level (e.g., amount) of one or more Ras proteins or the level of their signaling pathways (e.g., Ras inhibitors, K-Ras inhibitors, N-Ras inhibitors, H-Ras inhibitors, mutant K-Ras inhibitors, K-Ras G12C inhibitors, K-RasG12V inhibitors, K-Ras G13C inhibitors, K-Ras G12D inhibitors, K-Ras G13D inhibitors). Without being limited by mechanism, administration may include allowing the Ras inhibitor enough time to reduce the activity of one or more Ras proteins, or allowing the Ras inhibitor enough time to reduce one or more symptoms of a disease (e.g., cancer, where the Ras inhibitor can block the cell cycle, slow the cell cycle, reduce DNA replication, reduce cell replication, reduce cell growth, reduce metastasis, or cause 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, mutant K-Ras, K-Ras G12C, K-Ras G12V, K-Ras G12D, K-Ras G13C, K-Ras G13D) or the level of its signaling pathway. In an embodiment, administration does not include administration of any active agent other than the listed active agents.

[0135] The term "associated" or "associated with..." in the context of a substance or substance activity or function associated with a disease (e.g., Ras (e.g., human K-Ras or human H-Ras) activity, a protein-related disease, a cancer associated with abnormal Ras activity, a K-Ras-related cancer, a mutant K-Ras-related cancer, an activated K-Ras-related cancer, a K-RasG12C-related cancer, a K-Ras G12V-related cancer, a K-Ras G13C-related cancer, a K-Ras G12D-related cancer, a K-Ras G13D-related cancer) means that the disease (e.g., cancer) is (wholly or partially) caused by the substance or substance activity or function, or the symptoms of the disease are (wholly or partially) caused by the substance or substance activity or function. For example, a cancer associated with abnormal Ras activity or function may be a cancer that is (wholly or partially) derived from abnormal Ras activity or function (e.g., enzymatic activity, protein-protein binding, signaling pathway), or a cancer in which a particular symptom of the disease is (wholly or partially) caused by abnormal Ras activity or function. As used herein, a substance described as being associated with a disease may be a target for treating the disease if it is a pathogenic agent. For example, in the case where increased Ras activity or function (e.g., signaling pathway activity) causes a cancer associated with abnormal Ras activity or function or a Ras-related cancer, the cancer may be treated with a Ras modulator or Ras inhibitor. For example, a cancer associated with K-Ras G12C may be a cancer that a subject with K-Ras G12C is at a higher risk of developing compared to a subject without K-Ras G12C. For example, a cancer associated with K-RasG12V may be a cancer that a subject with K-Ras G12V is at a higher risk of developing compared to a subject without K-Ras G12V.

[0136] The term "Ras" refers to one or more of the human Ras GTPase protein family (e.g., K-Ras, H-Ras, N-Ras). The term "K-Ras" refers to a nucleotide sequence or protein of human K-Ras (e.g., human K-Ras4A (NP_203524.1), human K-Ras4B (NP_004976.2), or both K-Ras4A and K-Ras4B). The term "K-Ras" includes wild-type forms of nucleotide sequences or proteins 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 nucleotide sequence or protein of a mutant K-Ras, wherein the Y-numbered amino acid of K-Ras that has an X amino acid in the wild type has a Z amino acid in the mutant instead (e.g., K-Ras G12C has a G in the wild type protein but has 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 comprising (e.g., consisting of) the following amino acid sequence or comprising the following sequence with one or more mutations (e.g., G12C, G12V, or G13C):

[0137] MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAFYTLVREIRKHKEK(SEQ ID NO:1)

[0138] In some embodiments, K-Ras refers to a protein comprising (e.g., consisting of) the following amino acid sequence, or comprising (e.g., consisting of) the following sequence with one or more mutations (e.g., G12C, G12V, or G13C):

[0139] MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAFYTLVREIRKHKEKMSKDGKKKKKKSKTKCVIM(SEQ ID NO:2)

[0140] 1mteyklvvvg aggvgksalt iqliqnhfvd eydptiedsy rkqvvidget clldil dtag61qeeysamrdq ymrtgegflc vfainntksf edihhyreqi krvkdsedvp mvlvgnkcdl121psrtvdtkqa qdlarsygip fietsaktrq gvddafytlv reirkhkekm skdgkkkkkk181sktkcvim(SEQ ID NO:3)

[0141] The term "combination therapy" means the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described in this disclosure. This administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule with a fixed ratio of active ingredients or in multiple separate capsules of each active ingredient. In addition, this administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0142] "K-RAS inhibitor" is used herein to refer to an inhibitor that exhibits an IC 50 Compounds that do not exceed about 100 mM, and more typically do not exceed about 50 mM, as measured in the K-RAS assay outlined below. 50 " is the concentration of inhibitor that reduces the activity of an enzyme (e.g., K-RAS) to half-maximal levels. It has been found that the compounds of various embodiments disclosed herein exhibit inhibition of oncogenic mutant K-RAS isoforms. As measured in the K-RAS assay described herein, in some embodiments, the compounds exhibit an IC of 1.0 for oncogenic mutant K-RAS. 50 In other embodiments, the compound exhibits an IC of no more than about 10 mM with respect to K-RAS. 50 In other embodiments, the compound exhibits an IC of no more than about 5 mM with respect to K-RAS.50 In other embodiments, the compound exhibits an IC of 50 No more than about 200 nM. Without being bound by theory, in some embodiments, the K-RAS inhibitor is an irreversible inhibitor via forming a covalent bond with the cysteine ​​at the G12C mutation site.

[0143] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used in the treatment of a disease or condition. This amount will achieve the goal of reducing or eliminating the disease or condition.

[0144] As used herein, reference to "treatment" of a subject is intended to include prevention. The term "subject" means 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.

[0145] The term "prodrug" refers to a compound that is active in vivo via an in vivo chemical reaction, thereby releasing an active compound. As described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003), the compounds disclosed herein may be modified to exist as prodrugs. The prodrug of the compound described herein is a structurally modified form of the compound that is susceptible to chemical changes under physiological conditions to provide an active compound. In addition, the prodrug can be converted into an active compound by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent, the prodrug can be slowly converted into a compound. The reason why prodrugs are generally useful is that, in some cases, they are easier to administer than active compounds or parent drugs. For example, prodrugs can be bioavailable by oral administration, while parent drugs cannot. Prodrugs may also have improved solubility relative to the parent drug in a pharmaceutical composition. Numerous prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug is a compound administered as an ester ("prodrug"), which is then metabolically hydrolyzed to a carboxylic acid as the active entity. Other examples include peptidyl derivatives of the compound. The term "therapeutically acceptable prodrug" refers to those prodrugs or zwitterions that are suitable for contact with subject tissues without excessive toxicity, irritation, and allergic reactions, commensurate with a reasonable benefit / risk ratio, and effective for its intended use.

[0146] III. Compound Embodiments

[0147] A. Class I - Overview

[0148] In some embodiments, compounds of formula (I) are provided:

[0149]

[0150] in:

[0151] Each R 1 are independently methyl or cyanomethyl;

[0152] n is an integer from 0 to 2;

[0153] X is -CCF3 or -C-halogen;

[0154] Ar 1 is aryl or heteroaryl, which is optionally substituted with one or more alkyl, halogen, hydroxyl or amino; and

[0155] Ar 2 is C-linked aryl or heteroaryl, which is optionally substituted by alkyl or halogen.

[0156] In some embodiments, Ar 1 is phenyl optionally substituted by one or more halogens.

[0157] In one or more of the foregoing embodiments, X is -CCl or -CCF3.

[0158] In one or more of the foregoing embodiments, Ar 1 is phenyl substituted by one or more halogens.

[0159] In one or more of the foregoing embodiments, n is 2 and each R 1 It is methyl.

[0160] In one or more of the foregoing embodiments, Ar 2 Selected from:

[0161] Any of them is optionally substituted with halogen.

[0162] In embodiments, other compounds are provided:

[0163]

[0164]

[0165]

[0166] or a pharmaceutically acceptable salt thereof.

[0167] IV. General Synthetic Methods for Preparing Compounds

[0168] The following schemes can be used to practice the various embodiments disclosed herein. It should be understood that these schemes are merely exemplary and that they are readily accessible to core structures with variable functional groups.

[0169] V. Mode of Administration

[0170] Although the compounds disclosed herein can be administered in the form of raw chemicals, they can also be presented in the form of pharmaceutical compositions (i.e., in the form of preparations). Therefore, pharmaceutical compositions are provided herein, comprising one or more of the compounds disclosed herein or one or more pharmaceutically acceptable salts, esters, prodrugs, amides or solvates thereof, and one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients. The carrier should be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and does not harm its recipient. Suitable formulations depend on the selected route of administration. Any well-known techniques, carriers and excipients can be used when appropriate and as understood in the art; for example, see Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein can be manufactured in any manner known in the art, for example, by means of conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or compression processes.

[0171] Pharmaceutical compositions may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including skin, buccal, sublingual and intraocular) administration, but the most suitable route may depend on, for example, the recipient's illness and condition. Pharmaceutical compositions may be suitably presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. Generally, these methods include the step of associating a compound disclosed herein or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with a carrier constituting one or more auxiliary ingredients. In general, the formulation is prepared by uniformly and adequately associating the active ingredient with a liquid carrier or a finely powdered solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0172] The pharmaceutical compositions of the various embodiments disclosed herein suitable for oral administration can be presented in the following ways: 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 liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, elixir or paste.

[0173] Orally usable pharmaceutical compositions include tablets. Tablets can be made by compression or molding, optionally containing one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (e.g., powder or granules) in a suitable machine, optionally mixed with a binder, an inert diluent or lubricant, a surfactant or a dispersant. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored and can be formulated to provide a slow or controlled release of the active ingredient therein. The dosage of all preparations for oral administration should be suitable for such administration.

[0174] The compounds disclosed herein can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable preparations can be presented in unit dosage form (e.g., in ampoules or in multi-dose containers), and preservatives are added. The composition can be in the form of a suspension, solution, or emulsion, for example, in an oily or aqueous vehicle, and can contain formulations such as suspending agents, stabilizers, and / or dispersants. The preparation can be presented in unit doses or multi-dose containers (e.g., sealed ampoules and vials), and can be stored in powder form or under freeze-dried (lyophilized) conditions, so that only a sterile liquid carrier, such as saline or sterile pyrogen-free water, needs to be added just before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the types previously described.

[0175] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include 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 polydextrose. Optionally, the suspension may also contain a suitable stabilizer or an agent that increases the solubility of the compound to allow the preparation of a high concentration solution.

[0176] dose

[0177] The compounds disclosed herein can be administered orally or via injection at a dose of 0.1 to 500 mg / kg per day. Common dosage ranges for adults are generally 5 mg / day to 2 g / day. Tablets or other presentation forms provided as discrete units may suitably contain an amount of one or more compounds that are effective at this dose or as multiples of this dose, for example, units containing 5 mg to 500 mg, typically 10 mg to 200 mg or so.

[0178] The amount of active ingredient that may 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.

[0179] The compounds disclosed herein can be administered in various modes, such as orally, topically or by injection. The exact amount of the compound administered to the subject will be the responsibility of the attending physician. The specific dosage level for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, administration time, administration route, excretion rate, drug combination, the exact condition being treated, and the severity of the indication or illness being treated. In addition, the administration route may vary depending on the illness and its severity.

[0180] In certain cases, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient when receiving one of the compounds herein is high blood pressure, it may be appropriately administered. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be the sum of the two therapeutic agents or the patient may experience a synergistic benefit.

[0181] In any case, multiple therapeutic agents (at least one of which is a compound of the various embodiments disclosed herein) can be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents can be provided in a single unified form or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents can be given in multiple doses, or both can be given in multiple doses. If not administered simultaneously, the time between multiple doses can be any duration ranging from a few minutes to four weeks.

[0182] VI. Treatment Methods

[0183] On the one hand, the embodiments herein provide a method for treating a subject with cancer, comprising administering to the subject a certain amount of a compound of each embodiment disclosed herein or a pharmaceutically 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 embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In other 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 a glioma, a meningioma, a medulloblastoma, a ganglioglioma, a schwannoma, and a craniopharyngioma. In embodiments, the glioma comprises one or more of an astrocytoma, a glioblastoma, an oligodendroglioma, and an ependymoma. In embodiments, the CNS cancer comprises a metastatic or secondary cancer. In other embodiments, the CNS cancer comprises cancer metastasized from one or more of melanoma, breast cancer, colon cancer, kidney cancer, nasopharyngeal carcinoma, leukemia, lymphoma, myeloma, and other cancers of unknown primary site.

[0184] On the other hand, embodiments herein provide methods for treating a K-RAS-mediated disorder in a human or animal subject in need of such treatment, comprising administering to the subject a compound of the various embodiments disclosed herein in an amount effective to reduce or prevent the disorder of the subject, optionally in combination with at least one additional agent known in the art for treating the disorder. In a related aspect, various embodiments disclosed herein provide a therapeutic composition comprising at least one compound of the various embodiments disclosed herein in combination with one or more additional agents for treating a K-RAS-mediated disorder. In some such embodiments, the K-RAS-mediated disease is cancer, and the K-RAS is presented in the form of an oncogenic mutation.

[0185] The compounds disclosed herein can be used to treat K-RAS mediated diseases, disorders and conditions. In some embodiments, the compounds disclosed herein can be used to treat cancers as disclosed above. In some such embodiments, the type of cancer may depend on the specific type of K-RAS oncogenic mutation present. For example, in some embodiments, oncogenic K-RAS mutations may be associated with human pancreatic cancer, lung cancer and / or colon cancer.

[0186] 1. Combination therapy

[0187] The compounds disclosed herein can be used in combination therapy. For example, the compounds disclosed herein can 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. September 18, 2019 11:510eaaw7999, stm.sciencemag.org / content / 11 / 510 / eaaw7999. The compounds disclosed herein can be combined with regulators of the ULK protein family that regulate autophagy. Other compounds of interest in combination therapy include SHP2 inhibitors. Other SHP2 inhibitors include those disclosed 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, WO 2020061103 and WO2020061101. All references and patent applications, including compositions, methods of use and methods of preparing compounds disclosed therein, are incorporated herein by reference in their entirety.

[0188] In embodiments, compounds disclosed herein can be combined with EGFR inhibitors. In embodiments, the EGFR inhibitors are selective to mutant EGFR, including but not limited to C797X, L718Q, G724S, S768I, G719X, L792X, G796X, T263P, A289D / V, G598V and EGFRvIII high expression. In embodiments, the combination therapy with EGFR agents tracked by mutation and indication is shown in Table CT-1 below.

[0189] Table 1

[0190] mutation Indications EGFR agents mEGFR NSCLC Osimertinib mEGFR NSCLC Afatinib mEGFR NSCLC Erlotinib mEGFR NSCLC Gefitinib mEGFR NSCLC Lazertinib mEGFR NSCLC Nazartinib mEGFR NSCLC Dacomitinib mEGFR NSCLC BLU-945 mEGFR NSCLC Icotinib wtEGFR Esophagus / CRC Cetuximab wtEGFR CRC Paninitumab wtEGFR NSCLC Amivantamab wtHER2 / wtEGFR Breast cancer Lapatinib wtHER2 / wtEGFR Breast cancer Neratinib wtEGFR NSCLC Zorifertinib mEGFR NSCLC Mobicertinib

[0191] EGFR inhibitors include those disclosed in U.S. Pat. Nos. 5,747,498, 8,946,235, and 9,732,058, WO2002030926, US 20040048880, US20050165035, and WO2019067543. All patents and applications, including compositions, methods of use, and methods of preparing compounds disclosed therein, are incorporated herein by reference in their entirety.

[0192] Other combination therapies based on target biomarkers are shown in Table CT-2 below.

[0193] Table 2.

[0194]

[0195]

[0196] The second agent in the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compounds disclosed herein so that they do not adversely affect each other. The compounds may be administered together or separately in a single pharmaceutical composition. In one embodiment, the compounds or pharmaceutically acceptable salts may be co-administered with cytotoxic agents to treat proliferative diseases and cancer.

[0197] The term "co-administration" refers to simultaneous administration or any manner of separate sequential administration of a compound disclosed herein or a salt thereof and one or more additional active pharmaceutical ingredients, including cytotoxic agents and radiation therapy. If the administration is not simultaneous, the compounds are administered in close proximity to each other. In addition, 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.

[0198] Those additional agents may be administered separately from the composition containing the compounds of the invention as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the disclosure in a single composition. If administered as part of a multiple dosage regimen, the two active agents may be presented simultaneously, sequentially, or within a certain time period of each other, typically within five hours of each other.

[0199] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the compounds disclosed herein can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form comprising a compound of Formula I, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0200] The amount of both the compound and the additional therapeutic agent (in those compositions comprising additional therapeutic agents as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. In certain embodiments, the compositions of the present disclosure are formulated so that a dosage of 0.01-100 mg / kg body weight / day of the compound of the invention can be administered.

[0201] Generally, any agent active against the disease or condition being treated may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology, VT Devita and S. Hellman (eds.), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. One skilled in the art will be able to discern which combination of agents to use based on the specific properties of the drugs and the disease involved.

[0202] In one embodiment, the method of treatment comprises co-administering a compound disclosed herein or a pharmaceutically acceptable salt thereof and 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, but are not limited to, radioactive isotopes (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 inhibitory agents; enzymes and fragments thereof, such as nucleolytic enzymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof.

[0203] Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-A inhibitors; fatty acid biosynthesis inhibitors; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and cancer metabolism inhibitors.

[0204] "Chemotherapeutic agents" include compounds that are useful in treating cancer. Examples of chemotherapeutic agents include erlotinib ( Genentech / OSIPharm.), bortezomib ( Millennium Pharm.), disulfiram, epigallocatechin gallate, halophilic actinomycinamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant ( AstraZeneca, sunitinib ( Pfizer / Sugen), letrozole ( Novartis), imatinib mesylate ( Novartis, finasunate ( Novartis), oxaliplatin ( Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, Wyeth), lapatinib ( GSK572016, GlaxoSmith Kline), Lonafamib (SCH 66336), sorafenib ( Bayer Labs), gefitinib ( AstraZeneca), AG1478, alkylating agents such as thiotepa and Cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including topotecan ( topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocortical steroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase inhibitors, including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, and sedative agents. obinostat), valproic acid, mocetinostat, dolastatin; aldesleukin, talcduocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; stoloniferol; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, clofosamide, estramustine, ifosfamide, methyldi(chloroethyl)amine, methyldi(chloroethyl)amine oxide hydrochloride, melphalan, novembichin, cholesterol p-phenylacetic acid mustard (phenesterine), prednimustine, trofosfamide, uracil mustard;Nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne antibiotics (e.g. calicheamicin, especially calicheamicin gamma 1I and calicheamicin omega 1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azoserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, actinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIA; doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrroline-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tuberculin, ubenimex, zinostatin, zorubicin n); antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluridine, enocitabine, floxuridine; androgens such as calusterone, dromos propionate tanolonepropionate, epitiostanol, mepitiostane, testolactone; antiadrenal drugs such as aminoglutethimide, mitotan e, trilostane; folic acid supplements such as folinic acid; aceglucuronolide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine;elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine ne); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), (Cremophor-free), an albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and (docetaxel, doxetaxel; Sanofi-Aventis); chlorambucil; GE (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine Ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

[0205] Chemotherapeutic agents also include (i) antihormonal agents, which are used to regulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including (for example) tamoxifen (including tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and (toremifenecitrate); (ii) aromatase inhibitors, which inhibit aromatase, the enzyme that regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, (megestrol acetate), (exemestane; Pfizer), formestanie, fadrozole, (vorozole), (letrozole; Novartis) and (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, acid), fenretinide, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways associated with abnormal cell proliferation, such as PKC-α, Ralf, and H-Ras; (vii) ribozymes, such as inhibitors of VEGF expression (e.g. ) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, e.g. and rIL-2; topoisomerase 1 inhibitors, such as LU rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

[0206] Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab ( Genentech; Cetuximab ( Imclone; panitumumab ( Amgen), rituximab ( Genentech / Biogen Idec), pertuzumab ( 2C4, Genentech), trastuzumab ( Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate gemtuzumab ozo gamicin ( Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the present disclosure include: apolizumab, aselizumab, atlizumab, bapi neuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegylated pegol), cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab b, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab b), nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab b, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizu mab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibr otuzumab, siplizumab, sontuzumab, tacatuzumab

[00136] The invention relates to the treatment of leukemia / inflammatories comprising: tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urt oxazumab, ustekinumab, visilizumab, and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a recombinant, exclusively human sequence, full-length IgG1λ antibody genetically modified to recognize the interleukin-12p40 protein.

[0207] Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to EGFR or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and are 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 CR L HB8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Pat. No. 4,943,533 to Mendelsohn et al.), and variants thereof, such as chimeric 225 (C225 or cetuximab; ) and remodeled human 225 (H225) (see WO 96 / 40210, Imcl one Systems Inc.); IMC-11F8, which is a fully human, EGFR-targeting antibody (Imcl one); 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; and human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (see WO 98 / 50433, Abgenix / Amgen); EMD55900 (Stragliotto et al., Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody to EGFR that competes with EGF and TGF-α for EGFR binding (EMD / Merck); the human EGFR antibody HuMax-EGFR (GenMab); fully human antibodies, referred to as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3 and described in U.S. Pat. 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 can be conjugated to cytotoxic agents to generate immunoconjugates (eg, see EP 659,439 A2, Merck Patent GmbH). EGFR antagonists include small molecules, such as those disclosed in U.S. Pat. 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, 6,140,33 2, 5,866,572, 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 the compounds described in the following PCT publications: WO98 / 14451, WO98 / 50038, WO99 / 09016 and WO99 / 24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, Genentech / OSI Pharmaceuticals); PD 183805 (CI 1033, 2-acrylamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-dihydrochloride, Pfizer Inc.); ZD1839, gefitinib 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((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-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib ( GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2-methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine).

[0208] Chemotherapeutic agents also include "tyrosine kinase inhibitors", including the EGFR targeted drugs described in the preceding paragraphs; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724,714, which is 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 HER2 and EGFR overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), which is an 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-5132, an antisense agent that inhibits Raf-1 signaling, available from ISIS Pharmaceuticals; non-HER targeted TK inhibitors, such as imatinib mesylate ( available from Glaxo SmithKline); multitargeted tyrosine kinase inhibitors, such as sunitinib ( available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines such as PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloyl methane, 4,5-bis(4-fluoroanilino)phthalimide); tyrosine phosphorylation inhibitors containing a nitrothiophene moiety (ty rphostine); PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxalines (U.S. Pat. No. 5,804,396); tyrosine phosphorylation inhibitors (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis / Lilly); imatinib mesylate PK I 166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, ); or as described in any of the following patent publications: U.S. Pat. No. 5,804,396; WO 1999 / 09016 (American Cyanamid); WO 1998 / 43960 (American Cyanamid); WO 1997 / 38983 (Warner Lambert); WO 1999 / 06378 (Warner Lambert); WO 1999 / 06396 (Warner Lambert); WO 1996 / 30347 (Pfizer, Inc); WO 1996 / 33978 (Zeneca); WO 1996 / 3397 (Zeneca) and WO 1996 / 33980 (Zeneca).

[0209] Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, and dapoxetine. alfa, denileukin, dexrazoxane, epoetinalfa, elotinib, filgrastim, histrelinacetate, ibritumomab, interferon alfa-2a, 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.

[0210] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcho l, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone butyrate-17, hydrocortisone valerate-17, aclometasone dipropionate, and 1,1-dipropionate. e), betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate; immunoselective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamyl-glycine (FEG) and its D-isomer (feG) (IMULAN BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, ciclosporin (cyclosporin A), D-penicillamine, gold salts, hydroxychloroquine (hydroxychloroquine), and hydroxychloroquine. ine), leflunomide, minocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi); interleukin 1 (IL-1) blockers such as anakinra (Kineret); T cell costimulation blockers such as abatacept (Orencia);Interleukin-6 (IL-6) blockers such as tocilizumab; Interleukin-13 (IL-13) blockers such as lebrikizumab; interferon α (IFN) blockers such as Rontalizumab; β7 integrin blockers such as rhuMAbβ7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin α (LTa); radioisotopes (e.g. At 211 ,I 131 ,I 125 , Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 , P 32 , Pb 212 and radioisotopes of Lu); various test agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3 or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavin, flavanol, procyanidin, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MA ); beta-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin; podophyllotoxin; tegafur Bexarotene Bisphosphonates such as clodronate (e.g. or ), etidronate NE-58095, Zoledronic Acid / Zoledronate Alendronate Pamidronate Tiludronate or risedronate and epidermal growth factor receptor (EGF-R); vaccines such as Vaccines; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteasome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium pixantrone; farnesyl transferase inhibitors such as lonafar nib (SCH 6636, SARASAR TM ); and a pharmaceutically acceptable salt, acid or derivative of any of the foregoing; and a combination of two or more of the foregoing, such as CHOP (an abbreviation for a combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone); and FOLFOX (oxaliplatin (ELOXATIN TM ) combined with 5-FU and leucovorin).

[0211] Chemotherapeutic agents also include nonsteroidal anti-inflammatory drugs which have analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives (e.g., ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, and naproxen), acetic acid derivatives (e.g., indomethacin, sulindac, etodolac, diclofenac), enolic acid derivatives (e.g., piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, and isoxicam), fenamic acid derivatives (e.g., mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), and fenamic acid derivatives. NSAIDs are used for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory joint disease, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, postoperative pain, mild to moderate pain caused by inflammation and tissue damage, fever, intestinal obstruction and renal colic.

[0212] 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, dorastatin 10, colchicine, trimetrexate, chlorpheniramine, cyclosporine, daunomycin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, camptothecin, cisplatin, metronidazole, and imatinib mesylate. In other embodiments, the compounds disclosed herein are administered in combination with a biological agent (e.g., bevacizumab or panitumumab).

[0213] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable compositions thereof, are administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretinoin, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, live BCG, bevacizumab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, captestosterone, capecitabine, camptothecin, carboplatin, carmoplatin, statins, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, actinomycin D, darepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, drostanolone propionate, epirubicin, epoetin alfa, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea , ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprorelin acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofizumab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegaspargase, pegfilgrastim tin, pemetrexed disodium, pentostatin, pipobroman, prinomycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozotocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronic acid, or zoledronic acid.

[0214] Chemotherapeutic agents also include treatments for Alzheimer's Disease, such as donepezil hydrochloride and rivastigmine; treatments for Parkinson's Disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents used to treat multiple sclerosis (MS), such as beta interferon (e.g., and ), glatiramer acetate, and mitoxantrone; treatments for asthma, such as albuterol and montelukast sodium; agents used to treat schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine agents for treating cardiovascular disease, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antiviral agents; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; and agents for treating immunodeficiency disorders, such as gamma globulin.

[0215] Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any chemotherapeutic agent described herein, and combinations of two or more thereof.

[0216] VII. Examples

[0217] The following examples are provided to illustrate exemplary embodiments of the compounds disclosed herein and their preparation.

[0218] Unless otherwise indicated, various starting materials and other reagents are purchased from commercial suppliers, such as Aldrich Chemical Company, and are used without further purification. Compounds are prepared according to the exemplary procedures provided herein and modifications thereof known to those skilled 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, "BOC", "Boc" or "boc" means N-tert-butyloxycarbonyl, "Bn" means benzyl, "Bu" means butyl, "nBu" means n-butyl, "tBu" means tert-butyl, "Cbz" means benzyloxycarbonyl, "DBU" means 1,8-diazabicyclo[5.4.0]11-7-ene, "DCM" (CH2Cl2) means dichloromethane (methylene chloride) "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 dimethyl sulfoxide, "DPPP" means 1,3-bis(diphenylphosphino)propane, and "ee" means para- "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 hexafluorophosphate 3-oxide, "HOAc" or "AcOH" means acetic acid, "i-Pr" means isopropyl, "IPA" means isopropyl alcohol, "LDA" means lithium diisopropylamide, and "LiHMDS" or "LHMDS" means hexafluorophosphate. Lithium methyl disilazide, "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-pyrrolidone, "Ph" means phenyl, "sat." means saturated, "SFC" means supercritical fluid chromatography, "TBME" or "MTBE" means tert-butyl methyl ether, "TEA" means triethylamine, "TF" means tert-butyl methyl ether, "TEA" means triethylamine, "TFE ... "A" means trifluoroacetic acid, "THF" means tetrahydrofuran, "TLC" means thin layer chromatography, "Rf" means retention fraction, "about" means about, "rt" means retention time, "RT" means room temperature, "h" means hour, "min" means minute, "N" means positive, "M" means molarity, "mL" means milliliter, "mmol" means millimole, "μmol" means micromolar, "eq." means equivalent, "℃." means degrees Celsius, and "Pa" means Pascals.1 H-NMR spectra are reported in ppm and are obtained as solutions in CDCl3 (7.25 ppm), DMSO-D6 (2.50 ppm), or CD3OD (3.4 ppm and 4.8 ppm), either of which may use internal tetramethylsilane (0.00 ppm) as an internal standard when appropriate. Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplet). Coupling constants are reported in Hertz (Hz) when given.

[0219] Synthesis Scheme 1

[0220]

[0221] 2. Preparation of Compound 2

[0222] To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (2.68 g, 10 mmol, 1.0 eq.) in DMF (27 mL) was added DIPEA (6.45 g, 50 mmol, 10 eq.), NH4Cl (3.20 g, 60 mmol, 6 eq.) and HATU (7.6 g, 20 mmol, 2 eq.) at room temperature under N2 atmosphere. The reaction mixture was then stirred for 2 hours, diluted with MTBE (100 mL), washed with 0.5 N HCl aqueous solution (50 mL), brine (50 mL) and dried over Na2SO4. The organic layer was concentrated in vacuo. The obtained residue was purified by chromatography (0-50% EtOAc / petroleum ether) to give the product 2 (2.3 g, yield: 86%) as a yellow solid. LC-MS: [M+H] + =267

[0223] 3. Preparation of Compound 3

[0224] To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzamide (2.67 g, 10 mmol, 1.0 eq.) in CFCOOH (27 mL) was added hydrogen peroxide (5.7 g, 5 0 mmol, 5 eq.). The reactant was stirred at 50 ° C for 0.5 hours. It was then diluted with MTBE (150 mL), washed with water (100 mL), brine (100 mL), and then dried over NaSO. The organic layer was concentrated in vacuo, and the obtained residue was purified by chromatography (0-100% EtOAc / petroleum ether) to give the product 3 (1.8 g, yield: 60%) as a yellow solid. LC-MS: [M+H] + =297

[0225] 4. Preparation of Compound 5

[0226] To a solution of 4-bromo-5-chloro-3-fluoro-2-nitrobenzamide (3.0 g, 10 mmol, 1.0 eq) in EtOH (30 ml) and water (6 mL) was added 2-((tert-butyldiphenylsilyl)oxy)ethane-1-thiol (3.2 g, 10 mmol, 1.0 eq), potassium carbonate (4.2 g, 30 mmol, 3.0 eq). The reaction mixture was then stirred at 50 °C for 2 hours. The solvent was removed to give 6.5 g of crude product, which was used in the subsequent step without further purification. LC-MS: [M+H] + =593

[0227] 5. Preparation of Compound 6

[0228] Iron powder (2.8 g, 50 mmol, 5 eq.) was added to a solution of compound 5 (6.5 g crude, 10 mmol, 1.0 eq.) in CH3COOH (120 mL). 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 of water, 300 mL of brine, and concentrated in vacuo. The obtained residue was purified by chromatography (0-100% EtOAc / petroleum ether) to give product 6 (2.8 g, yield: 50%) as a yellow solid. LC-MS: [M+H] + =563

[0229] 6. Preparation of Compound 7

[0230] To a solution of compound 6 (5.6 g, 10 mmol, 1.0 eq.) in DCM (110 mL) was added DIPEA (2.6 g, 20 mmol, 2 eq.), CDI (4.9 g, 30 mmol, 3.0 eq.) at room temperature. The reaction mixture was stirred for 16 hours. After filtration, the filter cake was washed with petroleum ether (50 mL) and dried to give product 7 (4.7 g, yield: 80%) as an off-white solid. LC-MS: [M+H] + =589

[0231] 7. Preparation of Compound 8

[0232] Tetrabutylammonium fluoride (10 mL, 10 mmol, 1.0 eq.) was added to a solution of compound 7 (5.9 g, 10 mmol, 1.0 eq.) in THF (60 mL). The reaction mixture was stirred for 3 hours. 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 the crude product 8 (3.16 g, yield: 90%) as an off-white solid.

[0233] 8. Preparation of Compound 9

[0234] To a solution of 7-bromo-6-chloro-8-((2-hydroxyethyl)thio)quinazoline-2,4-diol (3.5 g, 10 mmol, 1.0 eq.) in THF (100 mL) was added PPh3 (4.5 g, 17 mmol, 1.7 eq.), and then DEAD (3.0 g, 17 mmol, 1.7 eq.) was added at -10°C to 0°C. The reaction mixture was stirred for 1 hour. After dilution with EtOAc (100 mL), it was washed with water (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The obtained residue was diluted with DCM (100 mL) and stirred for 2 hours. After filtration, the filter cake was washed with DCM (50 mL) and dried to give the product 9 (1.5 g, yield: 45%) as an off-white solid. LC-MS: [M+H]+=333.

[0235] Compounds of the present disclosure having substituted fused 7-membered rings can be prepared in a similar manner.

[0236] Example

[0237] 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]thiazepine 2,3,4-ij]quinazolin-6-one (Example 100a) and (3S)-8-((3S,5R)-4-acryloyl-3,5-dimethyl Piperazine-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)

[0238]

[0239] Step 1: 2,4,7-Trichloro-8-iodo-6-(trifluoromethyl)quinazoline

[0240]

[0241] Phosphorus oxychloride (12 mL) was added 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). The mixture was stirred at 110 ° C for 12 hours 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 resulting crude material 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] +.

[0242] Step 2: (2S,6R)-tert-butyl 4-(2,7-dichloro-8-iodo-6-(trifluoromethyl)quinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

[0243]

[0244] 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 (2S,6R)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.83 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour, and the volatiles were removed under reduced pressure. The residue was purified by silica gel column chromatography (5%-15% ethyl acetate in petroleum ether) to give the title compound as a white solid in 82% yield. MS (ESI) m / z: 605.2 [M+1] +.

[0245] Step 3: (2S,6R)-tert-butyl 4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

[0246]

[0247] To a solution of (2S,6R)-4-(2,7-dichloro-8-iodo-6-(trifluoromethyl)quinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (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 hours 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] +.

[0248] Step 4: 2-(Pyridin-4-yl)propane-1,3-diol

[0249]

[0250] A mixture of 4-methylpyridine (430 mmol) in 37% formaldehyde (1.72 mol) was stirred at 100 °C for 12 hours. 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 as a colorless oil in 88% yield. 1H NMR (400 MHz, methanol-d4) δ ppm 2.99 (q, J = 6.4 Hz, 1H) 3.77-3.91 (m, 4H) 7.29-7.47 (m, 2H) 8.33-8.54 (m, 2H).

[0251] Step 5: 3-Hydroxy-2-(pyridin-4-yl)propyl 4-methylbenzenesulfonate

[0252]

[0253] To a 0°C solution of 2-(pyridin-4-yl)propane-1,3-diol (65.3 mmol) in dichloromethane (100 mL) 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 hours, quenched with water and extracted three times with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was used in the next step without further purification.

[0254] Step 6: S-(3-hydroxy-2-(pyridin-4-yl)propyl)thioacetate

[0255]

[0256] 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 hours, 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, 3H) 2.99 (quintet, J = 6.4 Hz, 1H) 3.15-3.24 (m, 1H), 3.37 (dd, J = 14.0, 7.2 Hz, 1H) 3.79-3.90 (m, 2H) 7.14-7.24 (m, 2H), 8.48-8.59 (m, 2H).

[0257] Step 7: (2S,6R)-tert-butyl 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

[0258]

[0259] To a solution of S-(3-hydroxy-2-(pyridin-4-yl)propyl)thioacetate (0.95mmol) and (2S,6R)-4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazoline-4-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.42mmol) in 1,2-ethylene glycol (2mL) and isopropanol (2mL) was added potassium carbonate (2.84mmol) and cuprous iodide (0.47mmol). The mixture was stirred at 85°C for 2 hours, 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 which 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] +.

[0260] Step 8: (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-carboxylic acid tert-butyl ester (Int-1a) and (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-carboxylic acid tert-butyl ester (Int-1b)

[0261]

[0262] 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 minutes, and diethyl azodicarboxylate (10.6 mmol) was added. After 12 hours, the volatiles were removed under reduced pressure to give a residue that was purified by silica gel chromatography (0-10% methanol in ethyl acetate). Compounds Int-1a and Int-1b were isolated as a 1:1 mixture of diastereomers in 65% yield. The above mixture was purified by SFC (Daicel Chiralcel OD 250mmx30mm, 10um, using 50% methanol in CO2 as mobile phase) to obtain pure diastereomers Int-1a and Int-1b, and characterized by SFC (Chiracel OD-3, 50x4.6 mm, 3um, using 40% methanol in CO2 (containing 0.05% diethylamine) as mobile phase, 3mL / min.).

[0263] Int-1a: SFC Rt=1.03min; MS(ESI)m / z:609.9[M+1] +

[0264] Int-1b: SFC Rt=1.40min; MS(ESI)m / z:609.9[M+1] +

[0265] Step 9: (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-carboxylic acid tert-butyl ester

[0266]

[0267] To a solution of (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepine[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (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 minutes and the reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by preparative TLC and semi-preparative reverse phase-HPLC. The title compound was isolated as a yellow solid in 33% yield. MS (ESI) m / z: 722.1 [M+1] +.

[0268] 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

[0269]

[0270] 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]thiazepine[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 minutes, then the volatiles were evaporated 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]+.

[0271] Step 11: (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 1 00a) 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)

[0272]

[0273] To a 0°C 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]thiazepine[2,3,4-ij]quinazolin-6-one (0.16 mmol) in dichloromethane (3 mL) was added triethylamine (0.05 mmol) and prop-2-enoyl chloride (0.32 mmol). The mixture was stirred at 0°C for 30 minutes and the volatiles were removed under reduced pressure to give a residue that was purified by preparative TLC. Compounds 1a and 1b were isolated as a 1:1 mixture of diastereomers in 54% yield. The above mixture was purified by SFC (Daicel Chiralpak AD 250mmx30mm, 10um, using 50% isopropanol in CO2 as the mobile phase) to obtain pure diastereomers 1a and 1b, and characterized by SFC (Chiralpak AD-3, 50x4.6mm, 3um. Using 5%-40% isopropanol (containing 0.05% diethylamine) in CO2 as the mobile phase, 3mL / min.).

[0274] Compound 100a: SFC Rt=1.79 min; MS (ESI) m / z: 676.0 [M+1]+. 1H NMR (400MHz, CDCl3) δppm 1.51-1.59 (m, 6H) 3.15 (br d,J=13.6Hz,1H)3.41(td,J=12.8,4.8Hz,2H)3.70-3.87(m,2H)4.12-4.27(m,2H)4.53-4.91(m,4H)5.80(dd,J=10.4,2.0Hz,1H) 6.43 (dd, J = 16.8, 2.0 Hz, 1H) 6.64 (dd, J = 16.4, 10.4 Hz, 1H) 7.06 (t, J = 8.8 Hz, 1H) 7.28-7.34 (m, 3H) 8.14 (s, 1H) 8.49-8.67 (m, 2H).

[0275] Compound 100b: SFC Rt=3.30 min; MS (ESI) m / z: 676.0 [M+1]+. 1H NMR (400MHz, CDCl3) δppm 1.53 (br d,J=6.8Hz,6H)3.06-3.27(m,1H)3.41(ddd,J=17.6,13.2,4.4Hz,2H)3.61-3.83(m,2H)4.14-4.23(m,2H)4.53-4.90(m,4H)5.80( dd,J=10.4,2.0Hz,1H)6.43(dd,J=16.8,1.6Hz,1H)6.64(dd,J=16.8,10.4Hz,1H)7.10(t,J=8.8Hz,1H)7.23-7.27(m,1H)7.30(br d,J=5.2Hz,2H)8.15(s,1H)8.59(d,J=6.0Hz,2H).

[0276] 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]thiazepine [2,3,4-ij]quinazolin-6-one (101a) and (3R,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazine- 1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-((S)-3,4-dihydropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydropyridin-4-yl Hydrogen-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (101b)

[0277]

[0278] Step 1: (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-carboxylic acid tert-butyl ester

[0279]

[0280] Potassium phosphate (1.18 mmol) and Ruphos Pd G4 (0.04 mmol) were added to a solution of (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepine[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.39 mmol) and (5-chloro-2,4-difluoro-phenyl)boronic acid (1.57 mmol) in dioxane (5 mL) and water (0.1 mL). The mixture was stirred at 80 °C for 30 minutes, cooled to room temperature and the insoluble material was filtered. The volatiles were evaporated under reduced pressure to give a residue that was purified by preparative TLC. The title compound was isolated as a yellow solid in 61% yield. MS (ESI) m / z: 722.1 [M+1] +.

[0281] 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

[0282]

[0283] Trifluoroacetic acid (1 mL) was added to a 0°C 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). The reaction was stirred at 0°C for 30 minutes and the volatiles were removed under reduced pressure to give the title compound as a yellow oil in 97% yield. MS (ESI) m / z: 622.0 [M+1]+.

[0284] 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]quinazolin-6-one (101b)

[0285]

[0286] To a 0°C 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]thiazepine[2,3,4-ij]quinazolin-6-one (0.16 mmol) in dichloromethane (3 mL) was added triethylamine (0.05 mmol) and prop-2-enoyl chloride (0.32 mmol). The mixture was stirred at 0°C for 30 minutes and the volatiles were removed under reduced pressure to give a residue that was purified by preparative TLC. Compounds 101a and 101b were isolated as a 1:1 mixture of diastereomers in 94% yield.

[0287] The above mixture was purified by SFC (column: Daicel Chiralpak IG 250 mm x 30 mm, 10 um, using 55% isopropanol / acetonitrile (4:1) in CO2 as mobile phase) to obtain pure diastereomers 101a and 101b. 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 mobile phase, 3 mL / min).

[0288] 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, 6H) 3.16 (br d,J=12.8Hz,1H)3.41(td,J=12.4,4.8Hz,2H)3.67-3.95(m,2H)4.12-4.25(m,2H)4.42-5.05(m,4H)5.72-5.90(m,1H)6.43(dd,J=16 .8,1.6Hz,1H)6.56-6.72(m,1H)7.06(t,J=8.8Hz,1H)7.31(t,J=7.6Hz,1H)7.38(d,J=6.0Hz,2H)8.14(s,1H)8.62(d,J=6.0Hz,2H).

[0289] Compound 101b: SFC Rt=2.23 min; MS (ESI) m / z: 676.0 [M+1]+. 1H NMR (400MHz, CDCl3) δppm=1.48-1.61(m,6H)2.99-3.24(m,1H)3.41(ddd,J=17.6,13.2,4.6Hz,2H)3.57-3.89(m,2H)4.19(br dd,J=13.2,5.6Hz,2H)4.46-5.00(m,4H)5.80(dd,J=10.4,1.6Hz,1H)6.43(dd,J=16. 8,1.6Hz,1H)6.64(dd,J=16.8,10.4Hz,1H)7.10(t,J=8.8Hz,1H)7.25(s,1H)7.31(br d,J=5.6Hz,2H)8.15(s,1H)8.52-8.67(m,2H).

[0290] 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]thiazepine[2,3,4- ij]quinazolin-6-one

[0291]

[0292] Step 1: (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-carboxylic acid tert-butyl ester

[0293]

[0294] The title compound was prepared in a manner analogous to Example 100, Step 9, 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 as a yellow solid in 78% yield. MS (ESI) m / z: 703.2 [M+1]+.

[0295] Step 2: (2S,6R)-4-((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-carboxylic acid tert-butyl ester

[0296]

[0297] To a solution of copper bromide (0.14 mmol) and tert-butyl nitrite (0.17 mmol) in acetonitrile (1 mL) was added (2R,6S)-4-[(12S)-8-(5-amino-2,4-difluoro-phenyl)-2-oxo-12-(4-pyridinyl)-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-carboxylic acid tert-butyl ester (0.11 mmol) in acetonitrile (1 mL) and the reaction was stirred at 60°C for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by preparative TLC followed by semi-preparative reverse phase-HPLC. The title compound was isolated as a yellow solid in 40% yield. MS (ESI) m / z: 768.2 [M+1] +.

[0298] 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

[0299]

[0300] The title compound was prepared in a manner analogous to Example 100, Step 10, using (2S,6R)-4-((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-carboxylic acid tert-butyl ester was used instead of (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-carboxylic acid tert-butyl ester. The title compound was isolated as a yellow oil in 99% yield. MS (ESI) m / z: 668.1 [M+1]+.

[0301] 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

[0302]

[0303] The title compound was prepared in an analogous manner to Example 100 Step 11, replacing (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]thiazepin[2,3,4-ij]quinazolin-6-one with (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]thiazepin[2,3,4-ij]quinazolin-6-one. The title compound was isolated as a yellow oil in 97% yield. MS (ESI) m / z: 722.1 [M+1]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.54 (br d, J = 6.8 Hz, 6H) 3.04-3.25 (m, 1H) 3.34-3.46 (m, 2H) 3.57-3.89 (m, 2H) 4.19 (br dd, J = 13.6, 6.8 Hz, 2H) 4.50-4.93 (m, 4H) 5.80 (dd, J = 10.4, 1.6 Hz, 1H) 6.38-6.49 (m, 1H) 6.56-6.71 (m, 1H) 6.99-7.15 (m, 1H) 7.31 (br dd,J=4.4,2.0Hz,2H)7.43(dt,J=14.4,7.2Hz,1H)8.14(d,J=3.6Hz,1H)8.51-8.68(m,2H).

[0304] 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]thiazepine [2,3,4-ij]quinazolin-6-one (Example 104a) and (3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethoxyquinazolin-6-one methylpiperazin-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)

[0305]

[0306] Step 1: 2-(Pyridin-3-yl)prop-2-en-1-ol

[0307]

[0308] 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 hours. 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 (35%-80% ethyl acetate in hexanes). The title compound was isolated as a colorless oil in 53% yield. MS (ESI) m / z: 136.1 [M+H] +.

[0309] Step 2: 2-(Pyridin-3-yl)propane-1,3-diol

[0310]

[0311] A 10 M THF solution of borane dimethyl sulfide 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 minutes, 1 M aqueous NaOH (6.5 mL) was added dropwise, followed by 35% aqueous hydrogen peroxide (86 mmol). After 2 hours, methanol (50 mL) was added, and the resulting reaction was stirred at 70° C. for 12 hours. 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 (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).

[0312] Step 3: 3-((tert-Butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propan-1-ol

[0313]

[0314] 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 reactants were stirred at room temperature for 30 minutes, cooled to 0°C, and a solution of TBDPSCl (10.4 mmol) in THF (20 mL) was added. After 30 minutes, the reaction was terminated by adding saturated aqueous ammonium chloride solution, 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 as a colorless oil in 47% yield. 1H NMR (400MHz, CDCl3) δ8.49(d,J=4.4Hz,1H),8.45(s,1H),7.61(dd,J=7.6,11.2Hz,4H),7.54(d,J=8.0Hz,1H),7.49-7.33(m ,6H),7.21(dd,J=4.8,7.6Hz,1H),4.11-4.05(m,1H),3.99-3.89(m,3H),3.08(quintet,J=6.0Hz,1H),2.14(s,1H),1.05(s,9H).

[0315] Step 4: S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)thioacetate

[0316]

[0317] A solution of triphenylphosphine (8.20 mmol) and DIAD (8.17 mmol) in THF (50 mL) was stirred at 0 °C for 30 minutes. 3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propan-1-ol (4.09 mmol) and thioacetic acid (9.81 mmol) were added, and the mixture was stirred at room temperature for one hour. The volatiles were evaporated under reduced pressure to give a residue that was purified by silica gel chromatography (10%-25% ethyl acetate in hexanes). The title compound was isolated as a colorless oil in 98% yield. MS (ESI) m / z: 450.1 [M+H]+.

[0318] Step 5: (2S,6R)-tert-butyl 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

[0319]

[0320] The title compound was prepared in an analogous manner to Example 100, Step 7, replacing S-(3-hydroxy-2-(pyridin-4-yl)propyl)thioacetate with (3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)thioacetate. The title compound was isolated as a brown solid in 97% yield. MS (ESI) m / z: 866.3 [M+H]+.

[0321] Step 6: (2S,6R)-tert-butyl 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

[0322]

[0323] A solution of 1 M TBAF in THF (4.4 mL) was added 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). After 2 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 as a brown solid in 80% yield. MS (ESI) m / z: 628.2 [M+H]+.

[0324] Step 7: (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-carboxylic acid tert-butyl ester and (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-carboxylic acid tert-butyl ester

[0325]

[0326] The title compound was prepared in an analogous manner to Example 100, Step 8, replacing (2S,6R)-tert-butyl 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 with 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. The title compound was isolated as a 1:1 mixture of diastereomers in 98% yield. The mixture was purified by SFC (ChiracelChiralpak AD 250x30 mm, 10um, using 40% methanol in CO2 as mobile phase) to separate each individual diastereomer. Each individual diastereomer was characterized by analytical SFC (Chiralpak AD-3, 50x4.6 mm, 3um, using 5%-40% ethanol (containing 0.05% diethylamine) in CO2 as mobile phase, 3mL / min.).

[0327] (2S,6R)-tert-butyl 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(400MHz,DMSO-d6)δ9.38-8.16(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, 12.4Hz, 2H), 1.44 (s, 9H), 1.42-1.26 (m, 6H).

[0328] (2S,6R)-tert-butyl 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 (400MHz, DMSO-d6) δ8.63(d,J=7.6Hz,1H),8.01(s,1H),7.87(d,J=3.2Hz,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=4.0,12.4Hz,2H),1.44(s,9H),1.41-1.26(m,6H).

[0329] Step 8: (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-carboxylic acid tert-butyl ester

[0330]

[0331] The title compound was prepared in a manner analogous to Example 100, Step 9, replacing 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 with 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. The title compound was isolated as a white solid in 52% yield. MS (ESI) m / z: 722.1 [M+H]+.

[0332] Step 9: (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

[0333]

[0334] The title compound was prepared in a manner analogous to Example 100, Step 10, using (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-carboxylic acid tert-butyl ester instead of (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-carboxylic acid tert-butyl ester. The title compound was isolated as a yellow oil in 99% yield. MS (ESI) m / z: 622.1 [M+H]+.

[0335] 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 104) a) 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)

[0336]

[0337] The title compound was prepared in a manner analogous to Example 100 Step 11, replacing (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]thiazepin[2,3,4-ij]quinazolin-6-one with (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]thiazepin[2,3,4-ij]quinazolin-6-one. The title compound was isolated as a white solid in 66% yield as a 1:1 mixture of diastereomers. The mixture was purified by SFC (Chiracel Chiralpak IC 250x30mm, 10um, using 65% methanol in CO2 as mobile phase) to obtain each individual diastereomer. Each individual diastereomer was characterized by analytical SFC (Chiralpak IC-3, 50x4.6 mm, 3um, using 60% methanol in CO2 (containing 0.05% diethylamine) as mobile phase, 3mL / min.).

[0338] (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 (400MHz, CDCl3) δ8.87-8.39 (m, 2H), 8.15 (s, 1H), 7.74 (d, J = 6.8Hz, 1H), 7. 40-7.28(m,2H),7.10(t,J=8.8Hz,1H),6.64(dd,J=10.4,16.4Hz,1H),6.43(dd, J=2.0,16.4Hz,1H),5.83-5.76(m,1H),5.11-4.48(m,4H),4.19(d,J=13.2Hz,2 H),3.89-3.58(m,2H),3.46-3.36(m,2H),3.27-3.00(m,1H),1.61-1.53(m,6H).

[0339] (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 (400MHz, CDCl3) δ8.91-8.30 (m, 2H), 8.14 (s, 1H), 7.75 (d, J = 7.6Hz, 1H), 7.32 (t,J=7.6Hz,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= 4.4,13.2Hz,2H),3.22-3.03(m,1H),1.60(d,J=6.8Hz,3H),1.54(d,J=6.8Hz,3H).

[0340] Example 106: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)- 1-(trifluoromethyl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazole 6-Phenyline

[0341]

[0342] Step 1: (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-carboxylic acid tert-butyl ester and (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-carboxylic acid tert-butyl ester

[0343]

[0344] The title compound was prepared in a similar manner to Example 100, wherein 2-picoline was used instead of 4-picoline in step 4. The title compound was isolated as a 1:1 mixture of diastereomers. The mixture was purified by SFC (ChiracelChiralpak AS, 250x50 mm, 10um, using 40% methanol in CO2 as mobile phase) to obtain each individual diastereomer and characterized by analytical SFC (Chiralpak IC-3, 50x4.6 mm, 3um, using 5%-40% methanol (containing 0.05% diethylamine) in CO2 as mobile phase, 3 mL / min.).

[0345] (2S,6R)-tert-butyl 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]+.

[0346] (2S,6R)-tert-butyl 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]+.

[0347] Step 2: (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-carboxylic acid tert-butyl ester

[0348]

[0349] The title compound was prepared in a manner analogous to Example 100, Step 9, replacing 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 with 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. The title compound was isolated as a yellow solid in 91% yield. MS (ESI) m / z: 670.2 [M+H]+.

[0350] 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

[0351]

[0352] The title compound was prepared in an analogous manner to Example 100, Step 10, replacing 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 with 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 isolated as a yellow solid in 95% yield. MS (ESI) m / z: 570.2 [M+H]+

[0353] Step 4: (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

[0354]

[0355] The title compound was prepared in an analogous manner to Example 100 Step 11 by replacing (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]thiazepin[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester 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]thiazepin[2,3,4-ij]quinazolin-6-one. The title compound was isolated as a yellow solid in 33% yield. MS (ESI) m / z: 624.3 [M+H]+. 1H NMR (400 MHz, CDCl3-d) δ, 8.46 (br d,J=4.4Hz,1H),8.03(s,1H),7.59(dt,J=1.6,7.6Hz,1H),7.23(d,J=7.6Hz, 1H),7.17-7.06(m,5H),6.57(dd,J=10.4,16.8Hz,1H),6.35(dd,J=1.6,16.8H z,1H),5.76-5.65(m,1H),4.92(brd,J=4.4Hz,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).

[0356] Example 107a and Example 107b: (3R,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazine- 1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4] Thiazepine [2,3,4-ij] quinazolin-6-one and (3R,11R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperidin Oxazine-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

[0357]

[0358] The title compound was prepared in an analogous manner to Example 102, replacing 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 with 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. The title compound was obtained as a 1:1 mixture of diastereomers. The mixture was purified by SFC (Chiracel Chiralpak AD, 250x30mm, 10um, using 45% isopropanol (containing 0.1% ammonium hydroxide) in CO2 as the mobile phase) to obtain each individual diastereomer, and characterized by analytical SFC (Chiralpak AD, 50x4.6mm, 3um, using 40% isopropanol (containing 0.05% diethylamine) in CO2 as the mobile phase, 3mL / min.).

[0359] Example 107a: Rt = 0.46 min. MS (ESI) m / z: 721.9 [M+H] +. 1 HNMR 1 H NMR(400MHz,CDCl3-d)δ,8.57(br d,J=4.4Hz,1H),8.12(s,1H),7.73-7.64(m,1H),7.42(t,J=7.2Hz,1H),7.36-7.30(m ,1H),7.23-7.16(m,1H),7.06-6.97(m,1H),6.64(dd,J=10.4,16.8Hz,1H),6.43(dd,J =2.0,16.8Hz,1H),5.79(dd,J=2.0,10.4Hz,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=7.2Hz,6H).

[0360] Example 107b: Rt = 0.83 min. MS (ESI) m / z: 721.9 [M+H] +. 1HNMR(400MHz, 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=7.2Hz,1H),7.26(br d,J=7.2Hz,1H),7.15-7.10(m,1H),6.95(t,J=8.8Hz,1H),6.56(dd,J=10.4,16.8Hz,1H),6.35(dd,J=2.0,16.8Hz,1H),5.74-5.68(m,1H),4.92(br d,J=4.4Hz,2H),4.74-4.23(m,2H),4.09(br d,J=12.8Hz,2H),3.95-3.76(m,1H),3.70-3.35(m,2H),3.34-3.21(m,2H),1.49(br s,6H).

[0361] Examples 108a and 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]thiazepine 2,3,4-ij]quinazolin-6-one and (3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazine-1- 1-(5-bromo-2,4-difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]sulfur Aza[2,3,4-ij]quinazolin-6-one

[0362]

[0363] The title compound was prepared in an analogous manner to Example 102, replacing 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 with 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. The title compound was obtained as a 1:1 mixture of diastereomers. The mixture was purified by SFC (Phenomenex cellulose-2, 250x30mm, 10um, using 70% methanol in CO2 as the mobile phase) to obtain each individual diastereomer, and characterized by analytical SFC (Unichiral OZ-5H, 50x4.6mm, 3um, using 60% methanol in CO2 (containing 0.05% diethylamine) as the mobile phase, 3mL / min).

[0364] Example 108a: Rt = 1.89 minutes. 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=2.0,10.4Hz,1H),5.09-4.31(m,4H),4.19(d,J=12.8Hz,2H),3.97-3.54 (m,2H),3.46-3.34(m,2H),3.29-2.97(m,1H),1.60(d,J=6.8Hz,3H),1.53(d,J=6.8Hz,3H).

[0365] Example 108b: Rt = 3.03 min. MS (ESI) m / z: 720.0 [M+H] +. 1 HNMR(400MHz, CDCl3)δ9.10-8.29(m,1H),8.14(s,1H),7.84-7.73(m,1H),7.46(t,J=7.0Hz, 1H),7.38-7.27(m,2H),7.04(t,J=8.4Hz,1H),6.64(dd,J=10.4,16.4Hz,1H),6.48-6.38(m,1 H),5.80(dd,J=1.6,10.4Hz,1H),5.07-4.42(m,4H),4.19(dd,J=5.2,13.6Hz,2H),3.98-3.7 1(m,2H),3.45-3.36(m,2H),3.17-3.09(m,1H),1.59(d,J=6.8Hz,3H),1.54(d,J=6.8Hz,3H).

[0366] Example 109: (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]thiazepine[2, 3,4-ij]quinazolin-6-one

[0367]

[0368] Step 1: (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-carboxylic acid tert-butyl ester and (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-carboxylic acid tert-butyl ester

[0369]

[0370] The title compound was prepared in an analogous manner 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 the mixture was purified by SFC (Chiracel Chiralpak IC 250x30mm, 10um, using 65% ethanol in CO2 as mobile phase) to separate each individual diastereomer and characterized by analytical SFC (Chiralpak IC-3, 50x4.6mm, 3um, using 60% ethanol in CO2 (containing 0.05% diethylamine) as mobile phase, 3mL / min).

[0371] (2S,6R)-tert-butyl 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]+.

[0372] (2S,6R)-tert-butyl 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]+.

[0373] Step 2: (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-carboxylic acid tert-butyl ester

[0374]

[0375] The title compound was prepared in a manner analogous to Example 100, Step 9, replacing 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 with 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. The title compound was isolated as a yellow solid in 85% yield. MS (ESI) m / z: 740.0 [M+H] +.

[0376] 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

[0377]

[0378] The title compound was prepared in a manner analogous to Example 100, Step 10, using (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, Tert-butyl 6-dimethylpiperazine-1-carboxylate replaced (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)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated as a yellow solid in 99% yield. MS (ESI) m / z: 640.0 [M+H]+.

[0379] 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

[0380]

[0381] The title compound was prepared in an analogous manner to Example 100, Step 11, replacing (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]thiazepin[2,3,4-ij]quinazolin-6-one with (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]thiazepin[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=11.6Hz,1H),4.97-4.54(m,4H),4.19(dd,J=5.2,12.0Hz,2H),3.96-3.67(m,2H),3.4 1(t,J=4.4,12.4Hz,2H),3.20-3.04(m,1H),1.59(d,J=6.8Hz,3H),1.54(d,J=6.8Hz,3H).

[0382] Example 112a and Example 112b: (3S,11S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazine- 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 (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)

[0383]

[0384] Step 1: (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-carboxylic acid tert-butyl ester and (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-carboxylic acid tert-butyl ester

[0385]

[0386] The title compound was prepared in an analogous manner to Example 100, substituting 3-fluoro-4-methyl-pyridine for 4-methylpyridine in step 4. The two compounds were obtained as a 1:1 mixture of diastereomers. The mixture was purified by SFC (Chiracel Chiralpak IC 250x30 mm, 10um, using 60% methanol in CO2 (containing 0.1% ammonium hydroxide) as mobile phase) to separate each individual diastereomer and characterized by analytical SFC ((S,S) Whelk-O1, 50x4.6 mm, 1.8um, 50% methanol / acetonitrile (4:1) in CO2 (containing 0.05% diethylamine) as mobile phase, 3 mL / min).

[0387] (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-carboxylic acid tert-butyl ester: Rt = 1.41 minutes. MS (ESI) m / z: 628.4 [M+H]+

[0388] (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-carboxylic acid tert-butyl ester: Rt = 1.81 minutes. MS (ESI) m / z: 628.4 [M+H]+

[0389] Step 2: (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-carboxylic acid tert-butyl ester

[0390]

[0391] The title compound was prepared in a manner analogous to Example 100, Step 9, replacing 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 with 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. The title compound was isolated as a yellow solid in 44% yield. MS (ESI) m / z: 740.5 [M+H] +.

[0392] 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

[0393]

[0394] The title compound was prepared in a manner analogous to Example 100, Step 10, using (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, Tert-butyl 6-dimethylpiperazine-1-carboxylate replaced (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)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated as a yellow solid in 98% yield. MS (ESI) m / z: 640.5 [M+H]+.

[0395] 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)

[0396]

[0397] The title compound was prepared in an analogous manner to Example 100, Step 11, replacing (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]thiazepin[2,3,4-ij]quinazolin-6-one with (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]thiazepin[2,3,4-ij]quinazolin-6-one. The two compounds were isolated as a 1:1 diastereoisomer mixture in 51% yield. The mixture was purified by SFC (Chiracel OD 250x30mm, 10um, using 50% methanol in CO2 as mobile phase), each individual diastereomer was separated, and characterized by analytical SFC (Chiralpak IC-3, 50x4.6mm, 3um, using 60% methanol / acetonitrile (containing 0.05% diethylamine) in CO2 as mobile phase, 3mL / min).

[0398] (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 (112a) (Example 112a): Rt=0.92 min. MS (ESI) m / z: 694.1 [M+H]+. 1H NMR (400MHz, CDCl3) δppm 1.54(d,J=6.8Hz,3H)1.59(d,J=6.8Hz,3H)3.02-3.23(m,1H)3.42(td,J=12.4,4.4Hz,2H)3.65-3.86(m,1H)4.11-4.24(m,3H)4.54-5.0 1(m,4H)5.74-5.84(m,1H)6.38-6.48(m,1H)6.58-6.70(m,1H)7.05(t,J=8.8Hz,1H)7.30(t,J=7.6Hz,2H)8.14(s,1H)8.32-8.61(m,2H).

[0399] (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 (400MHz, CDCl3) δppm 1.53 (d, J = 6.4Hz, 3H) 1.59 (br s,3H)2.97-3.27(m,1H)3.36-3.46(m,2H)3.54-3.83(m,1H)4.05-4.26(m,3H)4.49-5.05(m,4H)5.80(dd,J =10.4,2.0Hz,1H)6.43(dd,J=16.8,2.0Hz,1H)6.64(dd,J=16.8,10.4Hz,1H)7.09(t,J=8.8Hz,1H)7.25(br s,1H)7.29(br s,1H)8.14(s,1H),8.44(d,4.8Hz),8.47(s,1H).

[0400] Example 113: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazine-1-yl)-11-(4-fluorophenyl)- 1-(trifluoromethyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazole 6-Phenyline

[0401]

[0402] Step 1: (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-carboxylic acid tert-butyl ester

[0403]

[0404] The title compound was prepared in a manner analogous to Example 100, Step 9, substituting (4-fluorophenyl)boronic acid for (5-chloro-2,4-difluoro-phenyl)boronic acid. The title compound was isolated as a yellow solid in 73% yield. MS (ESI) m / z: 670.2 [M+1]+.

[0405] 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

[0406]

[0407] The title compound was prepared in an analogous manner to step 10 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 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. The title compound was isolated as a yellow solid in 99% yield. MS (ESI) m / z: 570.1 [M+1] +

[0408] Step 3: (S)-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

[0409]

[0410] The title compound was prepared in a manner analogous to Example 100, Step 11, 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] +. 1 H NMR (400MHz, CDCl3) δppm 1.53(d,J=7.2Hz,3H)1.61(d,J=6.8Hz,3H)3.01-3.18(m,1H)3.41(ddd,J =17.2,13.2,4.0Hz,2H)3.60-3.83(m,2H)4.20(dd,J=12.8,6.4Hz,2H)4. 56-4.95(m,4H)5.74-5.85(m,1H)6.43(dd,J=16.8,2.0Hz,1H)6.59-6.71 (m,1H)7.17-7.26(m,4H)7.29-7.38(m,2H)8.13(s,1H)8.49-8.71(m,2H).

[0411] Example 114: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazine-1-yl)-11-(4-fluorophenyl)- 1-(3-fluoropyridin-4-yl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij] Quinazolin-6-one

[0412]

[0413] Step 1: (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-carboxylic acid tert-butyl ester

[0414]

[0415] The title compound was prepared in a manner analogous to Example 100, Step 9, using 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 as a yellow solid. MS (ESI) m / z: 688.2 [M+1] +.

[0416] 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

[0417]

[0418] The title compound was prepared in an analogous manner to step 10 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 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. The title compound was isolated as a yellow solid in 99% yield. MS (ESI) m / z: 588.2 [M+1]+.

[0419] Step 3: (S)-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

[0420]

[0421] The title compound was prepared in a manner analogous to Example 100, Step 11, 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 (400MHz, CDCl3) δppm 1.53(d,J=6.8Hz,3H)1.60(d,J=6.0Hz,3H)2.91-3.20(m,1H)3.34-3.48(m,2H)3.53-3.81(m,1H)3.97-4.26(m, 3H)4.45-5.07(m,4H)5.73-5.85(m,1H)6.43(dd,J=16.8,2.0Hz,1H)6.58-6.69(m,1H)7.14-7.23(m,3H)7.25(br s,1H)7.30(br s,1H)8.12(s,1H)8.29-8.57(m,2H).

[0422] Example 115: 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazine-1-yl)-3,11-bis(4-fluorophenyl) 1,4-dihydro-10-(trifluoromethyl)-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

[0423]

[0424] Reaction scheme

[0425]

[0426]

[0427] Methyl 2-(4-fluorophenyl)-3-hydroxypropionate (2)

[0428] To a mixture of 2-(4-fluorophenyl)acetic acid methyl ester (5g, 29.76mmol) and sodium methoxide (0.08031g, 1.49mmol) in DMSO (10mL) was added polyoxymethylene (0.93g, 31.25mmol) at 20°C for 16 hours. The mixture was quenched with water and neutralized with 2N hydrochloric acid and extracted with ethyl acetate (100mL×3). The combined organic phases were washed with brine (50mL) and dried over anhydrous sodium sulfate. After filtering and concentrating, the residue was purified by a silica gel column using petroleum ether / ethyl acetate = 5% to 40% to obtain 2-(4-fluorophenyl)-3-hydroxypropionic acid methyl ester 2 (4.5g, yield 76%) as a white solid.

[0429] 2-(4-Fluorophenyl)propane-1,3-diol (3)

[0430] 1.0M DIBAL-H (166.68mmol, 166.68mL) was added to a solution of methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (11g, 55.56mmol) in THF (100mL) at -78°C under N2 atmosphere. The mixture was stirred for 3 hours at -78°C under a nitrogen atmosphere. After completion, the mixture was quenched with sodium sulfate decahydrate and filtered. The solution was concentrated, and the residue was purified by a silica gel column (PE / EA=10% to 100%) to give 2-(4-fluorophenyl)propane-1,3-diol 3 (5.05g, 53% yield) as a yellow oil.

[0431] 2-(4-Fluorophenyl)-3-hydroxypropyl 4-methylbenzenesulfonate (4)

[0432] Tosyl chloride (3.35 g, 17.6 mmol) was added 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) at 0 ° C. The mixture was stirred at 20 ° C for 12 hours. 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 4-methylbenzenesulfonic acid 2-(4-fluorophenyl)-3-hydroxypropyl ester 4 (3.58 g, 38% yield) as a white solid.

[0433] S-(2-(4-Fluorophenyl)-3-hydroxypropyl)thioacetate (5)

[0434] 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 hour. 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-thioacetic acid (2-(4-fluorophenyl)-3-hydroxypropyl) ester 5 (1.7 g, yield 67%) as a yellow oil.

[0435] 7-Chloro-8-((2-(4-fluorophenyl)-3-hydroxypropyl)thio)-4-hydroxy-6-(trifluoromethyl)quinazolin-2(1H)-one (6)

[0436] To a mixture of S-thioacetic acid (2-(4-fluorophenyl)-3-hydroxypropyl) ester (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) was added CuI (551 mg, 2.90 mmol) and KCO (3 g, 21.72 mmol) at 20 ° C under N2 atmosphere. The mixture was stirred at 85 ° C for 3 hours. 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% to 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 solid.

[0437] 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)

[0438] To a mixture of 7-chloro-8-((2-(4-fluorophenyl)-3-hydroxypropyl)thio)-4-hydroxy-6-(trifluoromethyl)quinazoline-2(1H)-one (160 mg, 0.36 mmol) and triphenylphosphine (189 mg, 0.72 mmol) in tetrahydrofuran (20 mL) at 0 ° C. under N2 atmosphere, diethyl azodicarboxylate (125 mg, 0.72 mmol) was added. The mixture was stirred at 20 ° C. for 1 hour. After completion, the mixture was concentrated under reduced pressure, and the residue was quickly purified by reverse phase to give 11-chloro-3-(4-fluorophenyl)-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepine[2,3,4-ij]quinazoline-6(2H)-one 7 (100 mg, 73% yield) as a yellow solid.

[0439] (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-carboxylic acid tert-butyl ester (8)

[0440] 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) at 0°C was added 4-methylbenzenesulfonic anhydride (112 mg, 0.345 mmol). The mixture was stirred at 30°C for 4 hours. Then, tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate (98 mg, 0.46 mmol) was added to the reaction mixture. 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 (PE / EA=0% to 100%) to give (2S,6R)-tert-butyl 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.

[0441] (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-carboxylic acid tert-butyl ester (9)

[0442] To a solution of 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), (4-fluorophenyl)boronic acid (90 mg, 0.64 mmol) and potassium phosphate (64 mg, 0.24 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (12 mg, 0.016 mmol) at 20 °C under N2 atmosphere. The mixture was stirred at 80° C. under a nitrogen atmosphere for 2 h. After completion, the mixture was concentrated under reduced pressure, and the residue was purified by a silica gel column (DCM / MeOH=0% to 20%) to give (2S,6R)-tert-butyl 4-(3,11-bis(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepine[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate 9 (40 mg, yield: 73%) as a yellow solid.

[0443] 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)

[0444] To a solution of (2S,6R)-4-(3,11-bis(4-fluorophenyl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepine[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester 9 (40 mg, 0.058 mmol) in dichloromethane (5 ml) at 0°C was added trifluoroacetic acid (5 mL). 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% to 20%) to give the product 10 (20 mg, yield: 59%) as a yellow solid.

[0445] 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)

[0446] 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 hour. After completion, the mixture was concentrated and the residue was purified by preparative HPLC to afford 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. 1 HNMR(400MHz, CDCl3)δ8.11(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=16.8Hz,2.0Hz,1H),5.78(dd,J=10 .8Hz,2.4Hz,1H),4.78-4.63(m,4H),4.21-4.15(m,2H),3.75-3.63(m,2H),3.4 2-3.33(m,2H),3.06-3.03(m,1H),1.60(d,J=6.8Hz,3H),1.51(d,J=6.8Hz,3H).

[0447] Example 122: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)- 6-(trifluoromethyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazoline (2H)-ketone (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]quinazoline- 6(2H)-Keto(P2)

[0448]

[0449] Reaction scheme

[0450]

[0451] 3-(Thiophen-3-yl)oxetane (2)

[0452] Thiophene-3-ylboronic acid (20 g, 101 mmol), nickel(II) bromide diethanol dimethyl ether complex (3.12 g, 10.1 mol), (1S,2S)-N-(2-(2-(2-phenyl)-1-yl)-boronic acid (20 g, 101 mmol), nickel(II) bromide diethanol dimethyl ether complex (3.12 g, 10.1 mol), 1 ,N 2-dimethylcyclohexane-1,2-diamine (2.15g, 15.15mmol) and potassium tert-butoxide (22.62g, 202mmol) in 1,4-dioxane (350mL) were added 3-iodooxetane (27.88g, 151.5mmol). The mixture was stirred at 60 ° C for 18 hours. After completion, the mixture was poured into ice-water (300mL) and extracted with ethyl acetate (150mL x 3). After concentration, the residue was purified by silica gel column using petroleum ether / ethyl acetate = 20 / 1 to obtain 3- (thiophene-3-yl) oxetane (2) (1.38g, 10% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.35-7.33(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).

[0453] 3-Bromo-2-(thiophen-3-yl)propan-1-ol (3)

[0454] 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, 1 M in dichloromethane) at -78 °C under nitrogen atmosphere. The mixture was stirred at 0 °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 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 HNMR (400MHz, CDCl3) δ7.26-7.24(m,1H),7.07(d,J=2.0Hz,1H),6.94(d,J=4.8Hz,1H),3.88-3.81(m,2H),3.68-3.55(m,2H),3.27-3.21(m,1H).

[0455] 3-Mercapto-2-(thiophen-3-yl)propan-1-ol (4)

[0456] To a solution of 3-bromo-2-(thiophene-3-yl)propan-1-ol (3) (2.1 g 9.54 mmol) in N,N-dimethylformamide (30 mL) was added sodium bisulfide (1.6 g, 28.62 mmol). The mixture was stirred at room temperature for 2 hours. 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 using dichloromethane / methanol=30 / 1 to obtain 3-mercapto-2-(thiophene-3-yl)propan-1-ol (4) (1.42 g, 85% yield). 1 HNMR (400MHz, CDCl3) δ7.35-7.33(m,1H),7.11(d,J=2.0Hz,1H),7.00(d,J=5.2Hz,1H),3.87(d,J=6.0Hz,2H),3.16-3.12(m,1H),2.91-2.83(m,2H).

[0457] 7-Chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (5)

[0458] 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-dimethyldibenzopyran (472 mg, 0.816 mmol) and tris(dibenzylideneacetone)dipalladium (498 mg, 0.544 mmol). The mixture was stirred at 60° C. under a nitrogen atmosphere for 18 hours. 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] + .

[0459] 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)

[0460] 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 min. Upon 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 using 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] + .

[0461] (2S,6R)-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-carboxylic acid tert-butyl ester (7)

[0462] 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-tri(propan-2-yl)benzenesulfonyl chloride (675 mg, 2.19 mmol). The mixture was stirred at 35° C. for 4 hours. After completion, tert-butyl (2S,6R)-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×3). The residue was concentrated and purified by C18 column using 20%-95% aqueous acetonitrile 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 light yellow solid. MS (ESI) m / z 615.2 [M+H] + .

[0463] (2S,6R)-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-carboxylic acid tert-butyl ester (8)

[0464] To a solution of (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, 0.29 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) were added potassium 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). The mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. 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)-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-carboxylic acid tert-butyl ester (8) (210 mg, crude) as a yellow solid. MS (ESI) m / z 675.1 [M+H] + .

[0465] 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)

[0466] 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 hour. 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 light yellow solid. MS (ESI) m / z 575.1 [M+H] + .

[0467] 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)

[0468] 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 hour. After completion, the mixture was poured into ice-water (10 mL) and extracted with dichloromethane (10 mL x 3). The residue was concentrated and purified by preparative HPLC (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] + .

[0469] The above racemate (70 mg) was dissolved in ethanol (5 mL) and separated by chiral supercritical fluid chromatography (separation conditions: column: IF 5 μm 20x 250 mm; mobile phase: MeOH / DCM=90 / 10, 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 analytical HPLC: using 5 μm 4.6×250 mm column on IF, mobile phase: MeOH / DCM=90 / 10, 1 mL / min; temperature: 30°C; wavelength: 254 nm).

[0470] (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)

[0471] 1 H NMR (400MHz, CDCl3) δ8.10(s,1H),7.31-7.29(m,1H),7.24(s,1H),7.20-7.15(m,4H),7.10(d,J=4.8Hz, 1H),6.63(dd,J=16.4Hz,10.8Hz,1H),6.42(dd,J=16.8Hz,1.6Hz,1H),5.78(dd,J=10.4Hz,1.6Hz,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.

[0472] (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)

[0473] 1H NMR (400MHz, CDCl3) δ8.10(s,1H),7.31-7.29(m,1H),7.24(s,1H),7.20-7.15(m,4H),7.10(d,J=4.0Hz, 1H),6.63(dd,J=16.0Hz,10.0Hz,1H),6.42(dd,J=16.4Hz,1.6Hz,1H),5.78(dd,J=10.4Hz,1.6Hz,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.

[0474] Example 124: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)- 1-(trifluoromethyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazole 6-Phenyl-1-one (P1)

[0475] Example 125: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)- 1-(trifluoromethyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazole 6-Phenyl-1-one(P2)

[0476]

[0477] Reaction scheme

[0478]

[0479] 3-(Thiophen-2-yl)oxetan-3-ol (2)

[0480] Isopropylmagnesium chloride lithium chloride solution (49.6mL, 64.42mmol, 1.3M tetrahydrofuran) was added to a solution of 2-bromothiophene (10g, 61.35mmol) in tetrahydrofuran (205mL) at -78°C under a nitrogen atmosphere. The mixture was stirred at -78°C for 1 hour. Then oxetane-3-one (5.3g, 73.62mmol) was slowly added. The mixture was slowly warmed to room temperature and stirred for 2 hours. Saturated aqueous ammonium chloride solution (200mL) was slowly added and extracted with ethyl acetate (300mL x 3). After concentration, the residue was purified by silica gel column (petroleum ether / ethyl acetate=3 / 1) to obtain 3-(thiophene-2-yl)oxetane-3-ol (2) (6.9g, 72% yield) as a light yellow oil. 1H NMR (400MHz, CDCl3) δ7.31-7.30(m,1H),7.19-7.18(m,1H),7.05-7.04(m,1H),4.93-2.89(m,4H).

[0481] 3-(Thiophen-2-yl)oxetane (3)

[0482] To a mixture of 3-(thiophene-2-yl)oxetane-3-ol (2) (6.9 g, 44.17 mmol) and trifluoroacetic acid (15.4 mL, 200.85 mmol) in dichloromethane (75 mL) at 0 ° C. triethylsilane (32.1 mL, 200.85 mmol) was added. The mixture was stirred at 30 ° C. for 3 hours. After completion, the mixture was poured into ice-water (150 mL) and extracted with dichloromethane (150 mL x 3). After concentration, the residue was purified by silica gel column (petroleum ether / ethyl acetate=10 / 1) to obtain 3-(thiophene-2-yl)oxetane (3) (5.8 g, 94% yield) as a colorless oil. 1 HNMR (400MHz, CDCl3) δ7.23-7.21(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).

[0483] 3-Bromo-2-(thiophen-2-yl)propan-1-ol (4)

[0484] Boron tribromide (41.4 mL, 41.4 mmol, 1.0 M in dichloromethane) was slowly added to a solution of 3-(thiophene-2-yl)oxetane (3) (5.8 g, 41.37 mmol) in dichloromethane (140 mL) at -78 ° C under a nitrogen atmosphere. The mixture was stirred at -78 ° C for 2 hours. After completion, the mixture was poured into ice-water (150 mL) and extracted with dichloromethane (150 mL x 3). After concentration, the residue was purified by silica gel column (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-bromo-2-(thiophene-2-yl)propan-1-ol (4) (5.3 g, 58% yield). 1 H NMR (400MHz, CDCl3) δ7.25-7.23(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).

[0485] 3-Mercapto-2-(thiophen-2-yl)propan-1-ol (5)

[0486] To a solution of 3-bromo-2-(thiophene-2-yl)propan-1-ol (4) (5.3 g, 23.97 mmol) in N,N-dimethylformamide (48 mL) was added sodium hydrosulfide (5.76 g, 71.91 mmol, 70%) at 0 ° C. The mixture was stirred at 30 ° C under a nitrogen atmosphere for 4 hours. After completion, the mixture was poured into ice-water (200 mL) and extracted with ethyl acetate (200 mL x 3). After concentration, the residue was purified by silica gel column (petroleum ether / ethyl acetate = 2 / 1) to obtain 3-mercapto-2-(thiophene-2-yl)propan-1-ol (5) (2.5 g, 60% yield) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ7.23-7.22(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).

[0487] 7-Chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (6)

[0488] 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(diphenyl-phosphino)-9,9-dimethyldibenzopyran (498 mg, 0.86 mmol) and tris(dibenzylideneacetone)dipalladium (522 mg, 0.57 mmol). The mixture was stirred at 60° C. under a nitrogen atmosphere for 18 hours. 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] - .

[0489] 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)

[0490] 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) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. Upon completion, the mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was concentrated and the residue was purified by C18 using 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, two steps) as a yellow solid. MS (ESI): m / z 419.2 [M+H] + .

[0491] (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-carboxylic acid tert-butyl ester (8)

[0492] To a mixture of 11-chloro-8-hydroxy-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepine[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, tert-butyl (2S,6R)-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 using 20%-95% aqueous acetonitrile to give (2S,6R)-tert-butyl 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 light yellow solid. MS (ESI) m / z 615.2 [M+H] + .

[0493] (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-carboxylic acid tert-butyl ester (9)

[0494] 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-carboxylic acid tert-butyl ester (8) (150 mg, 0.24 mmol) in 1,4-dioxane and water at 25 °C were added [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)boric acid (101 mg, 0.72 mmol). 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 (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-carboxylic acid tert-butyl ester (9) (220 mg, crude) as a yellow solid. (ESI) m / z 675.2 [M+H] + .

[0495] 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)

[0496] 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 hour. Upon completion, the mixture was concentrated and the pH was adjusted to 8 at 0°C with ammonia in methanol. 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] + .

[0497] 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)

[0498] 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, methanol was added to the mixture at 25°C and concentrated. The mixture was purified by preparative HPLC (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, three steps) as a light yellow powder. MS (ESI) m / z 629.0 [M+H] + .

[0499] The above racemate (50 mg) was dissolved in ethanol (5 mL) and separated by chiral supercritical fluid chromatography (separation conditions: column: IC 5 μm 20x 250 mm; mobile phase: MeOH / DCM=90 / 10, 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 analytical HPLC: using a 5 μm 4.6×250 mm column on IC, mobile phase: MeOH / DCM=90 / 10, 1 mL / min; temperature: 30°C; wavelength: 254 nm).

[0500] (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)

[0501] 1 H NMR(400MHz, CDCl3)δ8.09(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=16.4Hz, 10.4Hz, 1H), 6.41 (dd, J=16.8Hz, 2.0Hz, 1H), 5.78 (dd, J=10.4Hz, 2.0Hz, 1H), 4.8 7-4.84 (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.

[0502] (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)

[0503] 1H NMR(400MHz, CDCl3)δ8.09(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=16.8Hz,10.4Hz,1H),6.41(dd,J=16.8Hz,2.0Hz,1H),5.78(dd,J=10.4Hz,1.6Hz,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.

[0504] Example 126: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)- 1-(trifluoromethyl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij] Quinazolin-6-one

[0505]

[0506] Step 1: (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-carboxylic acid tert-butyl ester and (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-carboxylic acid tert-butyl ester

[0507]

[0508] The title compound was prepared in an analogous manner 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. The mixture was purified by SFC (column = Daicel Chiralpak IC 250 mm x 30 mm, 10 um; phase A: ethanol, phase B: CO2; gradient: 65% A in B for 7.45 min run time) to afford (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 as a single diastereomer. -1-carboxylic acid tert-butyl ester and (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-carboxylic acid tert-butyl ester and characterized by SFC (column: Chiralpak IC-3, 50x4.6 mm, ID=3um, stable at 35°C, back pressure of 100 bar. Mobile phase: 60% ethanol in CO2 (containing 0.05% diethylamine), flow rate=3 mL / min. Detector: photodiode array). Int-a: SFC Rt=1.58 min; MS (ESI) m / z: 628.2 [M+H]+. Int-b: SFC Rt=2.87min; MS (ESI) m / z: 628.2[M+H]+.

[0509] Step 2: (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-carboxylic acid tert-butyl ester

[0510]

[0511] The title compound was prepared in a manner analogous to Example 100, Step 9, replacing tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepin[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-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepin[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated as a yellow solid in 36% yield. MS (ESI) m / z: 688.2 [M+H]+.

[0512] 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

[0513]

[0514] The title compound was prepared in an analogous manner to step 10 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 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. The title compound was isolated as a yellow solid in 99% yield. MS (ESI) m / z: 588.2 [M+H]+.

[0515] Step 4: (S)-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

[0516]

[0517] The title compound was prepared in an analogous manner to Example 100, Step 11, 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] +.

[0518] 1H-NMR (400MHz, CDCl3) = 8.47 (s, 1H), 8.42 (s, 1H), 8.13 (S, 1H), 7.46 (m, 1H), 7.25-7.19 (m, 4H), 6.61 (dd, J = 16Hz, J = 6Hz, 1 H), 6.44 (d, J = 16Hz, 1H), 5.80 (d, J = 6Hz, 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).

[0519] Those skilled in the art will appreciate that the above compounds have chiral centers as well as potential axial asymmetry, ie atropisomers. Each compound may be provided as a mixture of diastereoisomers or in any diastereoisomerically pure form.

[0520] Other embodiments are provided herein as follows:

[0521]

[0522]

[0523]

[0524]

[0525] Inhibition of KRAS G12C by compounds of Formula I mediates phospho-ERK1 / 2 inhibition

[0526] This example demonstrates that various compounds of the present disclosure inhibit KRAS G12C, thereby mediating downstream inhibition of phospho-ERK1 / 2.

[0527] 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 in 5% CO2. Phospho-ERK HTRF assays were performed following the supplier's protocol (CisBio No. 64AERPEH). NCI-H358 or RI KRAS G12C cells were plated at a density of 50,000 cells / well in a 96-well plate (Corning No. 3903) in the corresponding culture 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 in 5% CO2. The cells were allowed to adhere overnight and treated the next day with an 11-point dose response of exemplary compounds using a Tecan D300e digital dispenser (Tecan Group Ltd., Switzerland), starting at 2,500 nM, followed by a continuous 1:3 dilution, and the treatment lasted for 4 hours or 16 hours. After compound treatment, the cells were washed once with ice-cold PBS. The cells were lysed by adding 50 μl of lysis buffer (1×) supplemented with 1× Pierce Halt protease and phosphatase inhibitors, and incubated at 4°C for 30 minutes with shaking. After lysis, 16 μL of cell lysate from a 96-well cell culture plate was transferred to a 384-well plate (Perkin Elmer No. 6007290). A premixed antibody solution was prepared by mixing (volume / volume) advanced phospho-ERK1 / 2d2 antibody and advanced phospho-ERK1 / 2Eu cryptate antibody. The premixed antibody solution (4 μL) was added to the detection plate containing the cell lysate. The assay plates were incubated overnight at 4°C, and the HTRF signals were read the next day by 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.

[0528] Compounds prepared according to previous procedures and characterized for inhibition of p-ERK according to the protocols provided herein are summarized in Table 3:

[0529] Table 3

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542] 0.5-2.0 nM=++++; 2.0 nM-20 nM=+++; 20 nM-250 nM=++; >250nM=+

[0543] Although the foregoing embodiments have been described in detail by way of illustration and example for the purpose of clear understanding, it will be appreciated by those skilled in the art that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. If there is a conflict between the present application and the reference provided herein, the present application shall prevail.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: Each R 1 are independently methyl or cyanomethyl; n is an integer from 0 to 2; X is -CCF3 or -C-halogen; Ar 1 is aryl or heteroaryl, which is optionally substituted with one or more alkyl, halogen, hydroxyl or amino; and Ar 2 is C-linked aryl or heteroaryl, which is optionally substituted by alkyl or halogen.

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

3. The compound of claim 1 or 2, wherein X is -CCl or -CCF3.

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

5. A compound as claimed in any one of claims 1 to 4, wherein n is 2 and each R 1 It is methyl.

6. The compound according to any one of claims 1 to 5, wherein Ar 2 Selected from: Any of them is optionally substituted with halogen.

7. The compound according to any one of claims 1 to 5, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

9. A method of treating a subject suffering from cancer, the method comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or a pharmaceutical composition thereof.

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

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

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

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

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

20. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for treating cancer.

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

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

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

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

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

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

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

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

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

30. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the manufacture of a medicament for preventing or reducing the spread of cancer via a CNS pathway.

Images