Pan-KRas inhibitor

Abstract

The present invention relates to a compound that inhibits at least one of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H, a pharmaceutical composition containing the compound, and a method of using the same.

Description

Technical Field

[0001] The present invention relates to compounds that inhibit multiple mutant forms of KRas, i.e., pan-KRas inhibitors. In particular, the present invention relates to pan-KRas compounds, pharmaceutical compositions containing such compounds, and methods of using the same.

Background Art

[0002] Kirsten rat sarcoma 2 virus oncogene homolog (「KRas」) is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch cycling between an inactive (GDP-bound) state and an active (GTP-bound) state, and transmits upstream cell signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes including cell proliferation (see, for example, Non-Patent Document 1).

[0003] The role of activated KRas in malignant tumors was observed over 30 years ago (see, for example, Non-Patent Document 2). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and result in constitutive activation of KRas. KRas mutations at codons 12, 13, 61 and other positions in the primary amino acid sequence of KRas are present in 88% of all pancreatic adenocarcinoma patients, 50% of all colorectal / rectal adenocarcinoma patients, and 32% of lung adenocarcinoma patients (see, for example, Non-Patent Document 3). Recent publications have also suggested that wild-type KRas inhibition may be a viable therapeutic strategy for treating KRas WT dependent cancers (see, for example, Non-Patent Document 4).

[0004] Due to the well-known role of KRas in malignant tumors and the discovery of these frequent mutations in KRas in various tumor types, KRas has become a very attractive target for the pharmaceutical industry in cancer therapy. Despite 30 years of extensive discovery efforts to develop inhibitors of KRas for treating cancer, KRas inhibitors have still not demonstrated sufficient safety and / or efficacy to obtain regulatory approval (see, for example, Non-Patent Document 5).

[0005] Compounds that inhibit KRas activity are still highly desirable and under investigation, including compounds that disrupt effectors such as guanine nucleotide exchange factors (see, for example, Non-Patent Document 6), as well as recent advances in the covalent targeting of the allosteric pocket of KRas G12C (see, for example, Non-Patent Documents 7 and 8). Clearly, there remains a continuing interest and effort in developing inhibitors of KRas, particularly inhibitors of the activated KRas mutants.

[0006] Therefore, there is a need to develop new pan-KRas inhibitors that demonstrate sufficient efficacy for the treatment of KRas-mediated cancers.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non - Patent Document 6

Non - Patent Document 7

Non - Patent Document 8

Summary of the Invention

Means for Solving the Problems

[0008] In one aspect of the present invention, a compound that inhibits KRas activity is provided. In certain embodiments, the compound has the formula (I):

Chemical Formula

[0009] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0010] In yet another aspect of the present invention, there is provided a method for inhibiting the activity of cells in a cell that contain wild-type KRas or one or more KRas mutations, such as KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H, the method comprising contacting the cell with a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0011] Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0012] Also provided is a method for treating cancer in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present invention, or a pharmaceutically acceptable salt thereof.

[0013] Also provided herein is a method for treating a KRas wild-type, KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0014] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in therapy.

[0015] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of cancer.

[0016] Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, for use in inhibiting wild-type KRas or multiple types of KRas mutations, such as KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations.

[0017] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of diseases or disorders associated with wild-type KRas or diseases or disorders associated with KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0018] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0019] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the activity of wild-type KRas or mutant forms of KRas including mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0020] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases or disorders associated with wild-type KRas or diseases or disorders associated with KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0021] Methods for the treatment of cancer in patients in need thereof are also provided herein, the methods comprising (a) determining that the cancer is associated with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (i.e., KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0022] One potential utility of the pan-KRas inhibitors described herein is for the treatment of cancers that develop resistance after prolonged treatment with a KRas G12C inhibitor. Thus, embodiments of the invention include those patients afflicted with cancer who are treated with a pan-KRas inhibitor described herein that has become ineffective or has decreased efficacy due to the emergence of resistance-conferring mutations after treatment with a G12C inhibitor.

[0023] Treatment of KRas G12C mutant cancers with covalent KRas G12C inhibitors such as adagrasib (MRTX849) or sotorasib (AMG510) can result in the incorporation of additional mutations that confer resistance to adagrasib. These mutations can confer resistance through a number of mechanisms.

[0024] Mutations that change the mutant cysteine at codon 12 to another amino acid will render current covalent KRas G12C inhibitors ineffective because the current inhibitors covalently bind to the mutant cysteine amino acid side chain. Similarly, in patients with one wild-type KRas allele in addition to the KRas G12C mutant allele, mutations of the wild-type codon 12 glycine to another codon will likely allow bypass of signaling in these tumors via the newly mutated protein. The repertoire of codon 12 mutations that can occur by single nucleotide substitutions in the wild-type gene (glycine codon) includes mutations commonly observed in cancer, such as G12S, G12V, G12R, G12C, etc. The repertoire of codon 12 mutations that can occur by single nucleotide base substitutions in the cysteine codon 12 includes, in addition to G12S and G12R, mutations not frequently observed in cancer, such as G12Y, G12F, and G12W.

[0025] Secondary site mutations can also occur at another position within the KRas G12C mutant gene that confers resistance to KRas G12C inhibitor treatment. These mutations can confer resistance through various mechanisms. The RAS protein is a small GTPase that normally cycles between an active GTP-bound state and an inactive GDP-bound state. The RAS protein is loaded with GTP via a guanine nucleotide exchange factor (GEF; e.g., SOS1) activated by an upstream receptor tyrosine kinase, inducing its subsequent interaction with effector proteins that activate RAS-dependent signaling. The RAS protein hydrolyzes GTP to GDP by its intrinsic GTPase activity, which is dramatically enhanced by a GTPase activating protein (GAP). Mutations at codons 12 and 13 of the RAS protein impair GAP-stimulated GTP hydrolysis, and RAS predominantly assumes the GTP-bound active state. The covalent KRas G12C inhibitors currently in clinical development bind only to GDP-bound KRas G12C. Mutations such as those at codon Q61, which may or may not be present on the same allele as the G12C mutation, can reduce the intrinsic GTPase activity of KRas and shift KRas to a GTP-loaded state that is less susceptible to the effects of covalent inhibition, serving as a mechanism of resistance to KRas G12C inhibitor treatment. Co-mutations such as R68, H95, and Y96 may be present with the KRas G12C mutation and may reduce the binding affinity of the KRas G12C inhibitor to the Switch II binding pocket.

[0026] The pan-KRas inhibitors described herein can exhibit activity against common and uncommon codon 12 mutations that occur in the KRas protein, which reduce the binding of the KRas G12C inhibitor to the KRas protein.

[0027] Also provided herein is a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0028] Also provided herein are compounds of formula (I) obtained by the process for preparing the compounds defined herein, or pharmaceutically acceptable salts thereof.

BRIEF DESCRIPTION OF THE INVENTION

[0029] The present invention relates to inhibitors of wild-type KRas and / or multiple mutant forms of KRas, such as the KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations. In particular, the present invention relates to compounds that inhibit the activity of wild-type KRas and / or KRas mutations such as G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of using the same.

[0030] DEFINITIONS Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0031] As used herein, "wild-type KRas" refers to the non-mutated form of the mammalian KRas protein. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "wild-type KRas inhibitor" refers to the compounds of the present invention represented by formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of wild-type KRas G12A. As used herein, "wild-type KRas-related disease or disorder" refers to a disease or disorder that is associated with, mediated by, or has wild-type KRas. Non-limiting examples of wild-type KRas-related diseases or disorders are wild-type KRas-related cancers.

[0032] As used herein, "KRas G12A" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by alanine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12 inhibitor" refers to the compounds of the invention represented by formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12A. As used herein, "KRas G12A-related disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12A mutation. Non-limiting examples of KRas G12A-related diseases or disorders are KRas G12A-related cancers.

[0033] As used herein, "KRas G12C" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by cysteine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12C inhibitor" refers to the compounds of the invention represented by formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12C. As used herein, "KRas G12C-related disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12C mutation. Non-limiting examples of KRas G12C-related diseases or disorders are KRas G12C-related cancers.

[0034] As used herein, "KRas G12D" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by aspartic acid at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12D inhibitor" refers to a compound of the invention represented by formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12D. As used herein, "KRas G12D-related disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12D mutation. Non-limiting examples of KRas G12D-related diseases or disorders are KRas G12D-related cancers.

[0035] As used herein, "KRas G12R" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by arginine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12R inhibitor" refers to a compound of the invention represented by formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12R. As used herein, "KRas G12R-related disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12R mutation. Non-limiting examples of KRas G12R-related diseases or disorders are KRas G12R-related cancers.

[0036] As used herein, "KRas G12S" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by serine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12S inhibitor" refers to a compound of the invention represented by formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12S. As used herein, "KRas G12S-related disease or disorder" refers to a disease or disorder that is associated with, or mediated by, or has a KRas G12S mutation. Non-limiting examples of KRas G12S-related diseases or disorders are KRas G12S-related cancers.

[0037] As used herein, "KRas G12V" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by valine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12V inhibitor" refers to a compound of the invention represented by formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12V. As used herein, "KRas G12V-related disease or disorder" refers to a disease or disorder that is associated with, or mediated by, or has a KRas G12V mutation. Non-limiting examples of KRas G12V-related diseases or disorders are KRas G12V-related cancers.

[0038] As used herein, "KRas G13D" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by aspartic acid at amino acid position 13. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G13D inhibitor" refers to a compound of the invention represented by formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G13D. As used herein, "KRas G13D-related disease or disorder" refers to a disease or disorder that is associated with, mediated by, or has a KRas G13D mutation. Non-limiting examples of KRas G13D-related diseases or disorders are KRas G13D-related cancers.

[0039] As used herein, "KRas Q61H" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by histidine at amino acid position 61. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas Q61H inhibitor" refers to a compound of the invention of formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas Q61H. As used herein, "KRas Q61H-related disease or disorder" refers to a disease or disorder that is associated with, mediated by, or has a KRas Q61H mutation. Non-limiting examples of KRas Q61H-related diseases or disorders are KRas Q61H-related cancers.

[0040] As used herein, the terms "subject", "individual", or "patient", which are used interchangeably, refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is human. In some embodiments, the subject has experienced and / or presented with at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having cancer with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., determined using an assay or kit approved by a regulatory authority, such as the FDA). In some embodiments, the subject has a tumor that is positive for wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., determined using an assay or kit approved by a regulatory authority, such as the FDA). The subject can be a subject having a tumor that is positive for wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., determined using an assay or kit approved by a regulatory authority, such as the FDA). The subject can be a subject in which the subject's tumor has a wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., the tumor is so identified using an assay or kit approved by a regulatory authority, such as the FDA). In some embodiments, the subject is suspected of having cancer associated with wild-type KRas or the KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H gene.In some embodiments, the subject has a clinical record indicating that the subject has a tumor having wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0041] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a patient (e.g., a patient suspected of having wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-related cancer, a patient having one or more symptoms of wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-related cancer, and / or a patient at high risk of developing wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-related cancer) has a wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation using a sample from the patient (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample)), and the assay can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, an assay is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or an antigen-binding fragment thereof.

[0042] The term "regulatory authority" is a national agency for approving the medical use of a medicine country by country. For example, a non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0043] The term "acyl" refers to -C(O)CH3.

[0044] As used herein, the terms "C1-C6 alkyl", "C1-C4 alkyl", and "C1-C3 alkyl" refer to straight-chain and branched-chain aliphatic groups having 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0045] The terms "C1-C3 haloalkyl" and "C1-C4 haloalkyl" refer to a C1-C3 alkyl chain or a C1-C4 alkyl chain as defined herein, in which one or more hydrogens are replaced by halogen. Examples include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0046] The "C1-C4 alkylene" group refers to a C1-C4 alkyl group as defined above herein, which is disposed between two other chemical groups and serves to connect the chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0047] The terms "C1-C3 alkoxy" and "C1-C4 alkoxy" refer to -OC1-C3 alkyl and -OC1-C4 alkyl, respectively, and the alkyl portion is as defined above herein.

[0048] As used herein, the term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbons having 3 to 12 carbon atoms, such as 3 to 8 carbon atoms, and more specifically 3 to 6 carbon atoms. The cycloalkyl group may further include one or more R as defined herein 8 or R 9The base is optionally substituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkyl" also includes bridged cycloalkyl such as bicyclo[1.1.1]pentanyl.

[0049] As used herein, the terms "C1-C3 hydroxyalkyl" and "C1-C4 hydroxyalkyl" refer to -C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0050] As used herein, the term "C2-C4 hydroxyalkynyl" refers to -C2-C4 alkynylene-OH.

[0051] The "aryl" group is a C6-C containing 1 to 3 aromatic rings optionally substituted with one or more R 8 or R 9 groups as defined herein. The "aryl" group is an aromatic moiety. In one embodiment, the aryl group is a C6-C 14 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. "Aryl" also refers to a bicyclic or tricyclic ring system, where one or two of the aryl ring systems can be saturated or partially saturated, and when the ring system contains two saturated rings, the saturated rings can be fused or spirocyclic. Examples of aryl ring systems containing two saturated rings that are spirocyclic include the following ring systems: 10

Chemical formula

[0052] ​The "aralkyl C1-C6 alkyl" or "arylalkyl" group contains an aryl group covalently bonded to an alkyl group, and each of them can independently be optionally substituted or unsubstituted. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, and naphthylmethyl (C6-C 10 ) aryl (C1-C6) alkyl-. Examples of substituted aralkyl C1-C6 alkyl are those in which the alkyl group is substituted with hydroxyalkyl.

[0053] The "heterocyclyl" or "heterocyclic" group is a ring structure having 3 to 12 atoms, for example 4 to 8 atoms, and one or more atoms are selected from the group consisting of N, O, and S. Ring N atoms can be oxidized to N-O, ring S atoms can be oxidized to SO or SO2, and the remaining ring atoms are carbon. Heterocyclyl can be monocyclic, bicyclic, spirocyclic or a bridged ring system. The heterocyclic group is optionally substituted at one or more positions on the ring carbon or ring nitrogen with one or more R 8 or R 9 groups, and R 6is as defined for formula I. The heterocyclic group is also optionally substituted, independently, on the ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on sulfur with lower alkyl. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl (e.g., octahydroindolizinyl), azaspiroheptanyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1’H,3’H-spiro[cyclopropane-1,2’-pyrrolidine], hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyl, oxaazaspirooctanyl s, diazaspirononanyl, oxaazabicycloheptanyl, hexahydropyrrolidinyl 4(1H)-oxide, tetrahydro-2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide. Compounds having adjacent cyclic O and / or S atoms are specifically excluded from the scope of this term.

[0054] As used herein, the term "heteroaryl" has 3 to 14 ring atoms, preferably 5, 6, 6, 9, or 10 ring atoms, selected from the group consisting of N, O, and S; has 5, 10, or 14 π electrons shared in a cyclic arrangement; and refers to a group having 1 to 3 heteroatoms per ring or 1 to 3 heteroatoms in at least one ring in addition to carbon atoms.Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,3,4-oxadiazolyl, 1,4,4-oxadiazolyl, 1,5,4-oxadiazolyl, 1,4,5-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,5,4-thiadiazinyl, 1,3,4-thiadiazolyl, 1,4,4-thiadiazolyl, 1,5,4-thiadiazolyl, 1,4,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,3,4-triazolyl, 1,4,4-triazolyl, 1,5,4-triazolyl, 1,4,4-triazolyl, and xanthenyl, and are selected from the group consisting of them."Heteroaryl" also refers to a bicyclic ring system having, in addition to carbon atoms, 1 to 3 heteroatoms selected from the group consisting of N, O, and S per ring, where one of the ring systems may be saturated or partially saturated.

[0055] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H. Such an amount may be administered as a single dose or may be administered according to a regimen in which it is effective.

[0056] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to relieve symptoms, or to reduce symptoms in any way, or to stop or reverse the progression of a condition, or to negatively regulate or inhibit the activity of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H. Such an amount may be administered as a single dose or may be administered according to a regimen in which it is effective.

[0057] As used herein, treatment means any method by which the symptoms or pathology of a condition, disorder, or disease are alleviated or otherwise beneficially modified. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0058] As used herein, remission of the symptoms of a particular disorder due to the administration of a particular pharmaceutical composition refers to any alleviation that may result from or be associated with the administration of the composition, whether permanent or temporary, continuous or transient.

[0059] Compound In one aspect of the invention, a compound represented by formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof is provided (wherein: X is CR, O or N; Y is CR or N; Z is O or S; n is an integer from 1 to 4; each R is independently H or C1-C3 alkyl; R 1 is C1-C3 alkyl or hydroxy; or n is at least 2, and two R 1 are optionally joined to form a methylene or ethylene bridge; or n is at least 2, and two R 1 are optionally joined to form a spiro or fused ring, where the ring is heterocyclic or heteroaryl, and the ring is optionally substituted with 1-2 substituents selected from oxo and -C(O)N(CH3)(CH3); each R 2 is independently C1-C3 alkyl).

[0060] In a particular embodiment of the present invention, n is 2, and two R 1 form a saturated heterocyclic ring containing S and N atoms.

[0061] In a particular embodiment of the present invention, the saturated heterocyclic ring formed by two R 1 is substituted with two oxo groups.

[0062] In a particular embodiment of the present invention, n is 2; one R 1 is OH, and the other R 1 is CH3.

[0063] Non-limiting examples of the compounds of formula (I) are: [Chemical formula] [Chemistry] It is selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0064] In one embodiment, the compound of formula (I) includes bis-hydrochloride, tris-hydrochloride, trifluoroacetate, bis-trifluoroacetate, and tris-trifluoroacetate of the above compound. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition.

[0065] Pharmaceutical composition In another aspect, the present invention provides a pharmaceutical composition comprising a wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H inhibitor according to the present invention, and a pharmaceutically acceptable carrier, excipient, or diluent. The compounds of the present invention can be formulated by any method well known in the art and can be prepared for administration by any route including, but not limited to, parenteral, intraperitoneal, intradermal, intracardiac, intracerebroventricular, intracranial, intrathecal, intra-articular, intramedullary, intramuscular injection, intravitreal injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intranasal, intratracheal, rectal, subcutaneous, and local administration. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In one embodiment, the administration can be by the oral route. In some embodiments, the pharmaceutical composition provided can be administered to a subject in need of treatment by systemic injection such as intravenous injection; or by injection or application to the injection or related site, for example, direct injection by syringe or direct application to the site when the site is surgically exposed; or by local administration.

[0066] Parenteral administration can be by bolus injection or continuous infusion. Injectable pharmaceutical compositions can be presented in unit dosage form, with preservatives added, for example, in ampoules or multi-dose containers.

[0067] The pharmaceutical composition provided can also be formulated as a depot preparation. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the formulation can be modified with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion-exchange resin, or as a poorly soluble derivative, such as a poorly soluble salt.

[0068] The pharmaceutical composition can be presented in a medical device, including but not limited to, a vial, a pack, or a dispenser device that can contain one or more unit dosage forms containing the active ingredient. In one embodiment, the dispenser device can include a syringe having a single dose of a liquid formulation ready for injection. The syringe can be accompanied by instructions for administration.

[0069] The properties of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, the compositions according to the invention can include, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizing agents and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington’s Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0070] As used herein, the term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the compounds identified above and exhibit minimal or no undesirable toxicological effects. Examples of such salts include acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, but are not limited thereto. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly including quaternary ammonium salts of the formula -NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzyloate, and diphenylacetate, etc.).

[0071] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing significant toxic effects in the patient being treated. In one embodiment, the dosage of the active compound for all of the above-described conditions (states) ranges from about 0.01 to 300 mg / kg per day, such as 0.1 to 100 mg / kg, and as a further example, is 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound being delivered. If the derivative is itself active, the effective dosage can be estimated as described above using the weight of the derivative or by other means known to those skilled in the art.

[0072] The pharmaceutical composition containing the compound of the present invention can be used in the methods of use described herein.

[0073] Method of use In yet another aspect, the present invention provides a method for inhibiting wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V and / or KRas Q61H activity in cells, the method comprising contacting a cell in which inhibition of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V and / or Q61H activity is desired with an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0074] As used herein, the term "contacting" refers to bringing the designated moieties together in an in vitro or in vivo system. For example, "contacting" wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H with the compounds provided herein includes administering the compounds provided herein to an individual or patient, such as a human, having wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H mutation, and also includes introducing, for example, the compounds provided herein into a sample containing cells or a purified preparation containing wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H mutation.

[0075] In one embodiment, a cell in which inhibition of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity is desired is contacted with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to negatively regulate the activity of one or more of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H.

[0076] By negatively regulating the activity of wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H, the methods described herein are designed to inhibit unwanted cell proliferation, which results in enhanced wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H activity in cells. Cells can be contacted with a single dose or multiple doses according to a specific treatment regimen to affect the desired negative regulation of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H. The ability of a compound to bind to one or more of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H can be monitored in vitro using well-known methods, including those described in Examples A and B below. In addition, the inhibitory activity of exemplary compounds in cells can be monitored, for example, by measuring the inhibition of one or more of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H activity by the amount of phosphorylated ERK, using, for example, the methods described in Example C below.

[0077] In another aspect, there is provided a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0078] The compositions and methods provided herein can be used for the treatment of wild-type KRas-related or KRas G12A-, KRas G12C-, KRas G12D-, KRas G12R-, KRas G12S-, KRas G12V-, KRas G13D- and / or KRas Q61H-related cancers in a patient in need thereof, and comprise administering to the patient a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the wild-type KRas-related or KRas G12A-, KRas G12C-, KRas G12D-, KRas G12R-, KRas G12S-, KRas G12V-, KRas G13D- and / or KRas Q61H-related cancer is lung cancer.

[0079] The compositions and methods provided herein can be used for the treatment of a wide variety of cancers, including tumors such as lung, prostate, breast, brain, skin, cervical cancer, testicular cancer, and the like. More specifically, cancers that can be treated by the compositions and methods of the present invention include tumor types such as astrocytoma, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers, as well as sarcomas, but are not limited thereto. More specifically, these compounds are: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, bipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, adenoma, hamartoma, leiomyosarcoma); Genitourinary: kidney (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: gallbladder carcinoma, ampulla carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochronfroma) (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, gliocytoma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal nerve fibroma, meningioma, gliocytoma, sarcoma); Gynecology: uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa-theca cell tumor, sertoli-leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (cancer); Hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; And adrenal gland: can be used to treat neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In certain embodiments, the cancer is non-small cell lung cancer.;

[0080] The dosing concentration and route of administration to the patient will vary depending on the cancer being treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may also be co-administered with other anti-cancer compounds, such as chemotherapy, or used in combination with other treatments, such as radiation or surgical procedures, as adjuvants before or after surgery.

[0081] Also provided herein are the compounds of formula (I) as defined herein for use in a treatment method, or their pharmaceutically acceptable salts, or pharmaceutical compositions thereof.

[0082] Also provided herein are the compounds of formula (I) as defined herein for use in the treatment of cancer, or their pharmaceutically acceptable salts, or pharmaceutical compositions thereof.

[0083] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the inhibition of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0084] Also provided herein are compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of diseases or disorders associated with wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0085] Also provided herein is the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.

[0086] Also provided herein is the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the inhibition of the activity of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0087] Also provided herein is the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diseases or disorders associated with wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0088] Methods for the treatment of cancer in patients in need thereof are also provided herein, the method comprising: (a) determining that the cancer is associated with wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H mutation (e.g., determined using an assay or kit approved by a regulatory authority, e.g., approved by the FDA); (b) administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0089] One of ordinary skill in the art will recognize that both in vivo and in vitro testing using suitable known and generally accepted cell and / or animal models can predict the ability of a test compound to treat or prevent a given disorder.

[0090] One of ordinary skill in the art will further recognize that human clinical trials, including first-in-human, dose range and efficacy testing in healthy and / or patients suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0091] Reaction Schemes and Examples The compounds of the present invention can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those of skill in the art. For example, the compounds of the present invention can be prepared according to the reaction schemes and examples outlined below.

[0092] The compounds of the present invention may have one or more chiral centers and can be synthesized as mixtures of stereoisomers, isomers of the same constitution with different arrangements of their atoms in space. The compounds can be used as a mixture, or the individual components / isomers can be isolated using conventional methods for the isolation of stereoisomers and enantiomers well known to those skilled in the art, commercially available reagents, and, for example, using Chiralpak® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention can be synthesized using optically pure chiral reagents and intermediates to prepare the individual isomers or enantiomers. Unless otherwise indicated, all chiral forms (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise indicated, whenever the specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to encompass all chiral (enantiomers and diastereomers) and racemic forms.

[0093] The compounds of the present invention can be in anhydrous, solvated or hydrated forms, and all such forms are included within the scope of the present invention.

[0094] The following intermediates are intended to illustrate further specific embodiments of the present invention and are not intended to limit the scope of the present invention.

Example

[0095] Example 1

Chem.

Chem.

[0096] Project B. 6-((R)-3-Hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carbonitrile: To a solution of (R)-2-chloro-6-(3-hydroxy-3-methylpiperidin-1-yl)pyrimidine-4-carbonitrile (500 mg, 1.98 mmol, 1.00 eq) in ACN (5.00 mL) were added DIPEA (767 mg, 5.94 mmol, 1.03 mL, 3.00 eq) and (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (383 mg, 2.97 mmol, 1.50 eq) dropwise. The reaction mixture was stirred at 80 °C for 14 h. Another batch of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (256 mg, 1.98 mmol, 1.00 eq) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (10.0 mL) and extracted with DCM (5.00 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to DCM / MeOH 50:1) to give the title compound (400 mg, 1.07 mmol, yield 53.8%, purity 92.0%) as a yellow oil. 1 1H NMR: (400 MHz, CDCl3) δ 6.59 (s, 1H), 5.30 - 5.19 (m, 1H), 3.80 - 3.70 (m, 1H), 3.50 - 3.30 (m, 1H), 3.25 - 3.05 (m, 3H), 2.74 - 2.60 (m, 1H), 2.48 (s, 3H), 2.30 - 2.25 (m, 1H), 2.10 - 1.75 (m, 8H), 1.60 - 1.50 (m, 3H), 1.30 - 1.25 (m, 6H).

[0097] Project C. (Z)-N'-Hydroxy-6-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboximidamide: To a solution of 6-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carbonitrile (500 mg, 1.45 mmol, 1.00 eq) in EtOH (5.00 mL) were added Na2CO3 (199 mg, 1.88 mmol, 1.30 eq) and NH2OH·HCl (262 mg, 3.76 mmol, 2.60 eq). The resulting solution was stirred at 80 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (540 mg, crude) as a yellow solid. LCMS (ESI): m / z = 379.3 (M+1) + ;

[0098] Project D. (Z)-N'-((2-Amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-6-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboximidamide: A solution of (Z)-N'-hydroxy-6-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboximidamide (120 mg, 317 μmol, 1.00 equiv) and 2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carboxylic acid (82.4 mg, 349 μmol, 1.10 equiv) in DMF (1.00 mL) was added with DIEA (123 mg, 951 μmol, 165.68 μL, 3.00 equiv) and PyBOP (248 mg, 476 μmol, 1.50 equiv) at 0 °C. The resulting solution was stirred at 0 °C to room temperature for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 38% - 68%, 8 minutes) to obtain the title compound (100 mg, 153 μmol, yield 48.2%, purity 91.2%) as a yellow solid. LCMS (ESI): m / z = 597.3 (M+1) + 。

[0099] Project E.2 - Amino - 4 - (3 - (6 - ((R) - 3 - hydroxy - 3 - methylpiperidin - 1 - yl) - 2 - ((S) - 1 - ((S) - 1 - methylpyrrolidin - 2 - yl)ethoxy)pyrimidin - 4 - yl) - 1,2,4 - oxadiazol - 5 - yl) - 4 - methyl - 4,5,6,7 - tetrahydrobenzo[b]thiophene - 3 - carbonitrile: (Z) - N’ - ((2 - amino - 3 - cyano - 4 - methyl - 4,5,6,7 - tetrahydrobenzo[b]thiophene - 4 - carbonyl)oxy) - 6 - ((R) - 3 - hydroxy - 3 - methylpiperidin - 1 - yl) - 2 - ((S) - 1 - ((S) - 1 - methylpyrrolidin - 2 - yl)ethoxy)pyrimidine - 4 - carboximidamide (100 mg, 153 μmol, purity 91.2%, 1.00 equivalent) in THF (1.00 mL) was added Triton B (56.2 mg, 134 μmol, 61.1 μL, purity 40.0%, 0.9 equivalent) at 0 °C. The resulting solution was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (NH4HCO3) - ACN]; B%: 45% - 75%, 8 minutes) and lyophilized to give the title compound (5.20 mg, 9.60 μmol, yield 6.28%, purity 92.6%) as a yellow solid. LCMS (ESI): m / z = 579.3 (M + 1) + ; 1 1H NMR (400 MHz, MeOD) δ 7.13 (s, 1H), 5.27 - 5.10 (m, 1H), 4.73 - 4.51 (m, 5H), 3.91 - 3.68 (m, 1H), 3.13 (s, 1H), 2.90 - 2.72 (m, 1H), 2.64 - 2.55 (m, 4H), 2.50 - 2.45 (m, 1H), 2.25 - 2.18 (m, 1H), 2.10 - 2.00 (m, 2H), 1.98 - 1.92 (m, 2H), 1.90 - 1.68 (m, 9H), 1.65 - 1.56 (m, 1H), 1.38 - 1.32 (m, 3H), 1.25 (s, 3H).

[0100] Example 2

Chemical Structure

Chemical Structure

[0101] Step E. 2-Amino-4-(3-(6-(2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile: To a solution of (Z)-N'-((2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-6-(2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-carboximidamide (110 mg, 149 μmol, purity 88.0%, 1.00 equivalent) in DMF (1.00 mL) was added K2CO3 (41.12 mg, 297.50 μmol, 2.00 equivalents). The mixture was stirred at 60 - 100 °C for 12 hours. The reaction mixture was filtered, and then the organic layer was concentrated under reduced pressure to obtain a residue. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge 150×25 mm×5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 29% - 59%, 8 minutes) to obtain the title compound (15.0 mg, 22.2 μmol, yield 14.9%, purity 93.5%) as a yellow solid. LCMS (ESI): m / z = 633.3 (M+1) + ; 11H NMR (400 MHz, MeOD) δ 7.17 (s, 1H), 3.18 - 3.15 (m, 8H), 3.14 (s, 1H), 2.60 (s, 1H), 2.61 (m, 1H), 2.52 (m, 2H), 2.39 - 2.35 (m, 1H), 2.24 - 2.12 (m, 2H), 1.98 - 1.93 (m, 3H), 1.88 - 1.69 (m, 14H), 1.32 (d, J = 6 Hz, 3H).

[0102] Example 3

Chemical formula

Chemical formula

[0103] Engineering F.4-(3-(6-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile: To a solution of tert-butyl (1R,5S)-3-(6-(5-(2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)-1,2,4-oxadiazol-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 28.7 μmol, purity 97.0%, 1.00 eq) in dioxane (1.00 mL) was added HCl / dioxane (4.0 M, 0.50 mL, 92.9 eq). The mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (4.00 mL) and extracted with DCM (4.00 mL × 3). The pH of the aqueous phase was adjusted to 8 with solid NaHCO3 and extracted with DCM (4.00 mL × 4). The combined organic layers were washed with brine (4.00 mL × 2), dried over Na2SO4, filtered, and concentrated to give a residue. ACN / H2O (1 / 5, 20 V) was added, triturated at 25 °C for 1 h, and then lyophilized to give the title compound (10.0 mg, 15.8 μmol, yield 54.9%) as a yellow solid. LCMS (ESI): m / z = 576.3 (M+1) + ; 1 1H NMR (400 MHz, MeOD) δ 7.08 (s, 1H), 5.27 - 5.21 (m, 1H), 3.68 - 3.66 (m, 2H), 3.31 - 3.30 (m, 1H), 3.29 - 3.28 (m, 1H), 3.06 (m, 1H).2.69 - 2.62 (m, 3H), 2.61 (m, 2H), 2.22 - 2.19 (m, 2H), 2.00 - 1.79 (m, 11H), 1.76 (m, 2H), 1.40 - 1.37 (m, 3H), 1.33 - 1.29 (m, 4H).

[0104] Example 4 [Chemistry] 2-Amino-4-(3-(6-(2,2-dioxide-2-thia-1,3,7-triazaspiro[4.5]decane-7-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile Synthesized according to Example 2. The title compound was obtained as a yellow solid. LCMS: M / Z = 655.4 [M+1] + . 1 H NMR: 400 MHz MeOD-d 4 , δ 8.52(s,1H), 7.28 - 7.26(m,1H), 5.34 - 5.33(m,1H), 4.05 - 3.99(m,1H), 3.71 - 3.59(m,3H), 3.50 - 3.34(m,3H), 3.21 - 3.13(m,2H), 3.03 - 2.99(m,3H), 2.63(t,J = 6.00Hz 2H), 2.37 - 2.34(m,1H), 2.26 - 2.09(m,3H), 2.04 - 1.92(m,6H), 1.90(s,3H), 1.84 - 1.78(m,2H), 1.48 - 1.47(d,J = 6.00Hz 3H).

[0105] Example 5 [Chemistry] 2-Amino-4-(3-(6-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octane-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile Synthesized according to Example 2. The title compound was obtained as a yellow solid (500 mg, 0.804 mmol, yield 30.5%, purity 94.3%, formate). LCMS(ESI): m / z = 591.3 [M+1] + . 11H NMR (400 MHz, MeOD-d 4 ) δ 8.53 (s, 1H), 7.17 - 7.15 (m, 1H), 5.27 (s, 1H), 4.76 - 4.47 (m, 2H), 4.33 - 4.30 (m, 1H), 4.20 - 4.18 (m, 1H), 3.69 - 3.60 (m, 2H), 3.16 - 3.08 (m, 3H), 3.07 - 3.05 (m, 3H), 2.81 - 2.61 (m, 2H), 2.27 - 2.22 (m, 2H), 2.19 - 2.08 (m, 4H), 2.06 - 1.98 (m, 5H), 1.90 (s, 2H), 1.85 - 1.75 (m, 2H), 1.49 - 1.44 (m, 3H), 1.24 - 1.21 (m, 1H).

[0106] Example 6

Chem.

[0107] Example 7

Chem.

[0108] Process B: Lithium 6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboxylate. To a solution of methyl 6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboxylate (18.0 g, 48.7 mmol) in MeOH (180 mL) and H2O (90.0 mL) was added LiOH.H2O (2.92 g, 121 mmol). The reaction mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (200 mL) and washed with MTBE (300 mL×2). The aqueous mixture was lyophilized to obtain the title compound (14.0 g, 41.3 mmol, yield 84.9%, purity 83.1%) as a yellow solid.

[0109] Process C: N,6-Dimethoxy-N-methyl-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboxamide. To a solution of lithium 6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboxylate (14.0 g, 49.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (9.71 g, 99.5 mmol) in DMF (100 mL) were added DIEA (32.1 g, 248 mmol) and HATU (22.7 g, 59.7 mmol). The reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (500 mL) and extracted with dichloromethane (100 mL×2). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse-phase HPLC (0.1% FA conditions) to obtain the title compound (8.70 g, 26.8 mmol, yield 53.9%) as a yellow oil.

[0110] Project D: (E)-N'-(3-cyano-4-(3-(6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-3-oxoprop-1-yn-1-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformimidamide. To a solution of (E)-N'-(3-cyano-4-ethynyl-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformimidamide (8.01 g, 29.50 mmol) in THF (50.0 mL) was added dropwise LiHMDS (1 M, 67.0 mL) at -78 °C. The mixture was stirred at -78 °C for 0.5 h. A solution of N,6-dimethoxy-N-methyl-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-carboxamide (8.70 g, 26.8 mmol) in THF (50.0 mL) was added at -78 °C. The reaction was stirred at -78 °C for 2 h. The residue was poured into NH4Cl(aq) (50.0 mL), stirred, and the mixture was extracted with ethyl acetate (50.0 mL × 2). The combined organic phases were washed with brine (50.0 mL), dried over anhydrous Na2SO4, filtered, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate: 10:1~0:1) to give the title compound (11.0 g, 18.1 mmol, yield 67.5%, purity 84.2%) as a yellow solid. LCMS: m / z = 535.3 (M+1) + .

[0111] Project E: (E)-N'-(3-Cyano-4-(3-(6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)isothiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformimidamide. To a solution of (E)-N'-(3-cyano-4-(3-(6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-3-oxoprop-1-yn-1-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformimidamide (1.00 g, 1.87 mmol) in MeOH (10.0 mL) was added NH2OSO3H (232 mg, 2.06 mmol) portionwise. The reaction mixture was stirred at 25 °C for 4 h. To this reaction mixture were added NaHS (262 mg, 4.68 mmol) and NaHCO3 (172 mg, 2.06 mmol). The reaction mixture was stirred at 50 °C for 1 h. The residue was diluted with water (20.0 mL) and extracted with dichloromethane (20.0 mL × 2). The combined organic phases were washed with brine (20.0 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse-phase HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 23% - 53%, 10 min) to give the title compound as a yellow solid (200 mg, 0.33 mmol, yield 17.8%, purity 85.0%). 1 H NMR: (400 MHz MeOD-d 4 ) δ 7.90 (s, 1H), 7.75 (d, J = 10.8 Hz 1H), 7.17 (d, J = 2.00 Hz 1H), 5.35 - 5.31 (m, 1H), 4.02 (s, 3H), 3.14 (s, 3H), 3.07 (s, 3H), 2.78 - 2.70 (m, 3H), 2.58 - 2.53 (m, 3H), 2.39 - 2.38 (m, 1H), 2.09 - 2.03 (m, 2H), 2.02 - 2.00 (m, 1H), 1.95 (s, 3H), 1.92 - 1.86 (m, 2H), 1.83 - 1.77 (m, 4H), 1.39 - 1.37 (m, 3H)

[0112] Project F: (E)-N'-(3-cyano-4-(3-(6-hydroxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)isothiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformimidamide. To a mixture of (E)-N'-(3-cyano-4-(3-(6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)isothiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformimidamide (2.00 g, 3.54 mmol) and ACN (4.00 mL) were added TMSCl (1.92 g, 17.68 mmol, 2.24 mL) and NaI (2.65 g, 17.6 mmol) at once at 20 °C under N2. The reaction mixture was heated at 60 °C for 2 h. The reaction mixture was poured into ice water (20.0 mL), and the mixture was extracted with dichloromethane (10.0 mL × 2). The combined organic phases were washed with brine (10.0 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to give the title compound (600 mg, 1.02 mmol, yield 28.9%, purity 94.7%) as a yellow solid. LCMS: m / z = 552.2 (M+1) + 。

[0113] Project G: 6-(5-(3-cyano-2-(((E)-(dimethylamino)methylene)amino)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)isothiazol-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)trifluoromethanesulfonate. To a mixture of (E)-N'-(3-cyano-4-(3-(6-hydroxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)isothiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformimidamide (400 mg, 725 μmol) and DCM (4.00 mL) were added DIEA (18.7 mg, 145 μmol) and Tf2O (40.9 mg, 145 μmol, 23.92 uL) at once at 20 °C under N2. The reaction mixture was stirred for 4 hours. The mixture was poured into ice water (10.0 mL), and the aqueous mixture was extracted with dichloromethane (10.0 mL × 2). The combined organic phases were washed with brine (10.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (400 mg, 584 μmol, 80.6% yield) as a yellow solid.

[0114] Project H. (E)-N'-(3-cyano-4-(3-(6-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)isothiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformimidamide. A mixture of the compound (R)-3-methylpiperidin-3-ol (25.9 mg, 171 μmol, HCl) and 6-(5-(3-cyano-2-(((E)-(dimethylamino)methylene)amino)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)isothiazol-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl trifluoromethanesulfonate (65.0 mg, 95.0 μmol) in THF (2.00 mL) was added DIEA (36.8 mg, 285 μmol, 49.6 μL) at once at 25 °C under N2. The reaction mixture was stirred at 25 °C for 2 h and poured into water (2.00 mL). The aqueous mixture was extracted with ethyl acetate (2.00 mL × 3). The combined organic phases were washed with brine (2.00 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a yellow solid. LCMS: m / z = 649.4 (M+1) +

[0115] Step I: 2-Amino-4-(3-(6-((R)-3-Hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-Methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)isothiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile. To a solution of (E)-N'-(3-cyano-4-(3-(6-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)isothiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformimidamide (50.0 mg, crude) in MeOH (2.00 mL) was added HCl (12 M, 1.00 mL) at once under N2 at 20 °C. The reaction mixture was stirred at 100 °C for 2 h. The mixture was concentrated and purified by reverse-phase HPLC (column: Phenomenex Luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 15% - 45%, 9 min) to give the title compound as an off-white solid (12.0 mg, 16.5 μmol, yield 17.3%, purity 98.8%, FA salt). LCMS: m / z = 594.3 (M+1) + 1 1H NMR: 400 MHz MeOD-d 4 : δ 7.73 (d, J = 6.40 Hz, 1H), 7.17 (s, 1H), 5.30 - 5.27 (m, 1H), 3.83 (d, J = 13.2 Hz, 1H), 3.47 - 3.41 (m, 2H), 3.25 (s, 1H), 3.02 (s, 1H), 2.69 (s, 3H), 2.62 - 2.59 (m, 3H), 2.05 - 2.02 (m, 4H), 1.91 (s, 3H), 1.88 - 1.75 (m, 7H), 1.65 - 1.62 (m, 2H), 1.40 (d, J = 2.00 Hz, 1H), 1.26 (s, 3H).

[0116] Example 8 [Chemical Structure Diagram] 2-Amino-4-(3-(6-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)isothiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile Synthesized according to Example 7. The title compound was obtained as an off-white solid (formate). 1 H NMR: 400 MHz MeOD-d 4 : δ 7.73 (d, J = 6.40 Hz, 1H), 7.12 (s, 1H), 5.32 - 5.28 (m, 1H), 4.32 - 4.29 (s, 1H), 3.48 - 3.36 (m, 2H), 3.17 - 3.08 (m, 3H), 2.77 (s, 3H), 2.74 - 2.62 (m, 1H), 2.61 - 2.58 (m, 2H), 2.36 (s, 1H), 2.28 - 2.19 (m, 3H), 2.05 - 2.03 (m, 2H), 1.99 - 1.95 (m, 2H), 1.90 (s, 3H), 1.87 - 1.76 (m, 5H), 1.42 (d, J = 6.00 Hz, 3H), 1.28 - 1.24 (m, 2H). LCMS: m / z = 606.3 (M + 1) + 。

[0117] Example 9

Chemical formula

[0118] Example 10

Chem.

[0119] Example 11

Chem.

[0120] Example 12

Chemical formula

[0121] Example 13

Chem.

Chem.

[0122] Step B. 6-Methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carbonitrile: To a solution of 2-chloro-6-methoxypyrimidine-4-carbonitrile (15.8 g, 1.0 eq) and (1S)-1-[(2S)-1-methylpyrrolidin-2-yl]ethanol (12.0 g, 1.0 eq) in acetonitrile (200 mL) was added DIEA (36.1 g, 3.0 eq). The reaction mixture was stirred at 70 °C for 12 h. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 20 / 1 - 0 / 1] to give the title compound (17.8 g, 73% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 263.3.

[0123] Step C. (Z)-N’-Hydroxy-6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboximidamide: To a solution of 6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carbonitrile (12.5 g, 1.0 eq) in ethanol (300 mL) were added NH2OH·HCl (4.30 g, 1.3 eq) and Na2CO3 (13.1 g, 2.6 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. The mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (13.8 g, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 296.2.

[0124] Project D. (Z)-N'-((2-Amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboximidamide: To a solution of 2-amino-3-cyano-4-methyl-6,7-dihydro-5H-benzo[b]thiophene-4-carboxylic acid (9.94 g, 0.9 eq) in DMF (150 mL) were added TEA (14.2 g, 3.0 eq), HOBt (9.47 g, 1.5 eq) and EDCI (11.2 g, 1.3 eq). The reaction mixture was stirred at 25 °C for 0.5 h. Then, a solution of (Z)-N'-hydroxy-6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboximidamide (13.8 g, 1.0 eq) in DMF (150 mL) was added to this mixture. The reaction mixture was stirred at 45 °C for 12 h. The mixture was diluted with water (1 L) and extracted with ethyl acetate (2 × 1 L). The combined organic layers were washed with brine (1 L), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1] to give the title compound (20.0 g, yield 71%) as a yellow solid; LCMS (ESI, M+1): m / z = 514.2.

[0125] Project E. 2-Amino-4-(3-(6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile: To a solution of (Z)-N’-((2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboximidamide (20.0 g, 1.0 equiv) in THF (200 mL) was added Cs2CO3 (21.6 g, 2.0 equiv). The reaction mixture was stirred at 70 °C for 1 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 10 / 1~0 / 1] to give the title compound (15.0 g, 74% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 496.4.

[0126] Project F. 2-Amino-4-(3-(6-hydroxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile: To a solution of 2-amino-4-(3-(6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (8.00 g, 1.0 equivalent) in DMAc (80 mL) was added NaSEt (5.47 g, 5.0 equivalents). The reaction mixture was stirred at 60 °C for 1 hour. The mixture was diluted with water (250 mL) and washed with ethyl acetate (2 × 250 mL). The aqueous phase was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 (250 × 70 mm, 10 μm); mobile phase: water (FA)-ACN; B%: 7% - 37% for 20 minutes] to give the title compound (3.80 g, 61% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 482.3.

[0127] G.6-(5-(2-Amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)-1,2,4-oxadiazol-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl 4-methylbenzenesulfonate: To a solution of 2-amino-4-(3-(6-hydroxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3.80 g, 1.0 equiv) and TEA (2.40 g, 3.0 equiv) in DCM (40 mL) was added 4-methylbenzenesulfonyl chloride (2.26 g, 1.5 equiv) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The mixture was diluted with water (200 mL) and extracted with DCM (2 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [Al2O3, ethyl acetate] to afford the title compound (4.00 g, 80% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 636.2.

[0128] Project H. 2-Amino-4-(3-(6-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile: To a solution of 6-(5-(2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)-1,2,4-oxadiazol-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl 4-methylbenzenesulfonate (100 mg, 1.0 equiv) and 4 Å molecular sieves (100 mg) in DMF (1 mL) were added 6-methyl-1,4-oxazepan-6-ol (39.5, 1.5 equiv, HCl) and DIEA (102 mg, 5.0 equiv). The reaction mixture was stirred at 80 °C for 1 hour. The mixture was filtered. The filtrate was diluted with water (5 mL) and extracted with ethyl acetate (3 × 8 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 um; mobile phase: water (NH4HCO3)-ACN; gradient: 30% - 60% B in 9 minutes] to give the title compound (5.50 mg, yield 5.8%) as an off-white solid; 1 H NMR (400 MHz, methanol-d4) δ = 7.36 - 7.04 (m, 1H), 5.29 - 5.19 (m, 1H), 4.05 - 3.82 (m, 4H), 3.75 - 3.50 (m, 4H), 3.10 - 3.05 (m, 1H), 2.75 - 2.67 (m, 1H), 2.63 (br t, J = 6.0 Hz, 2H), 2.54 (s, 3H), 2.37 (q, J = 8.4 Hz, 1H), 2.28 - 2.20 (m, 1H), 2.05 - 1.95 (m, 4H), 1.90 (s, 3H), 1.83 - 1.74 (m, 3H), 1.37 - 1.33 (m, 3H), 1.26 (s, 3H); LCMS (ESI, M + 1): m / z = 595.4.

[0129] Example A KRas Binding Assay This example shows that the exemplary compounds of the invention can bind to KRas and replace a labeled tracer ligand that occupies the KRas binding site. KRas WT 、KRas G12A 、KRas G12C 、KRas G12D 、KRas G12R 、KRas G12S 、KRas G12V 、KRas G13D 、or KRas Q61H was used in the assay.

[0130] The ability of a compound to bind to KRas was measured using a TR-FRET displacement assay. Biotinylated KRas (corresponding to amino acids 1 - 169, manufactured by Accelegan Inc.) was incubated with a custom Cy5-labeled tracer, terbium streptavidin (Cisbio Inc.), and the compound (1% DMSO final) in buffer (50 mM HEPES, pH 7.5, 5 mM MgCl2, 0.005% Tween-20 and 1 mM DTT). After a 60-minute incubation at room temperature, the reaction was measured via TR-FRET using a BMG LABTECH CLARIO star Plus. 100 percent of the control (POC) was determined by using a DMSO control, and 0 POC was determined using the concentration of a control compound that completely inhibits the binding of the tracer to KRas. The POC values were fit to a 4-parameter IC 50 equation, and the IC 50 was reported.

[0131]

Table 1

[0132] Example B Inhibition of KRas phosphorylation of ERK (HTRF) by an exemplary compound of formula (I) Cisbio HTRF Advanced pERK assay catalog #64AERPEH Cells: MKN1, PSN1

[0133] Procedure: · Day 1: 384-well white solid bottom plate; Seed with 6,000 cells / well - 25 μl / well in RPMI 1_10% FBS. Incubate overnight at 37 °C / 5% CO2. · Day 2: Echo transfer 25 nl of 10-point dilutions of 10 mM compound at 1:3 (Cf = 10 μM) and incubate at 37 °C / 5% CO2 for 3 hours. · Add 8.5 μl / well of 4X lysis buffer / 25X blocking reagent (do not discard the medium) and incubate on a shaker at room temperature for 30 minutes. · Add a total of 8.5 μl / well of 1X-pERK-D2 and 1X-pERK-K conjugate compounds diluted in detection buffer. · Cover and incubate at room temperature for 4 hours. · Read HTRF using ClarioStar Cells: ASPC1, H727, A549, H460, HCT116, H358 Culture / assay medium: RPMI - 1640 + 10% FBS

[0134] Procedure: Cell seeding 1. To harvest cells from the flask, use 0.05% trypsin / EDTA solution. Add 10 mL of medium to stop the trypsinization. Pipette the cells into a conical bottom 50 mL centrifuge tube and centrifuge at 1000 rpm for 5 minutes. 2. Resuspend the cell pellet in medium, obtain the cell count, and then adjust the cell density using fresh medium. 3. Seed 6,000 cells into a cell culture plate with 50 μL of medium. 4. Incubate the cell plate overnight in a 37 °C, 5% CO2 incubator.

[0135] Compound titration 1. Complete compound addition using Tecan. The compounds start at up to 10 uM, 3-fold dilutions, and 10 doses. The final DMSO concentration is 0.8%. 0.2 uM trametinib was dispensed as the minimum control. 2. Incubate the cell plates in an incubator for 3 hours.

[0136] Detection using the Cisbio pERK HTRF kit 1. Dilute 1 volume of 4x lysis buffer with 3 volumes of deionized water. Then add 100X blocking reagent. Keep the lysis buffer on ice. 2. At the end of compound treatment, flick off the medium. 3. Using a Multidrop Combi, add 35 μL of lysis buffer / well. Then place on a plate shaker and shake at 300 rpm at 4 °C for 40 minutes. 4. Prepare the HTRF antibody buffer. For each assay plate, mix 50 μL of d2-conjugated antibody with 950 μL of detection buffer. Similarly, mix 50 μL of Cryptate antibody with 950 μL of detection buffer. Then mix the two diluted antibodies together. 5. Dispense 3.4 μL of antibody buffer into the wells of an empty assay plate. Seal the plate and centrifuge the plate at 1000 rpm for 30 seconds. 6. At the end of the 4 °C lysis, centrifuge the lysate plate at 1500 rpm for 3 minutes. 7. Using Bravo, transfer 13.6 μL of lysate from the cell culture plate to the assay plate. Then incubate the assay plate at room temperature for 2 hours. 8. At the end of the incubation, centrifuge the plate at 1000 rpm for 30 seconds and then read the plate on an Envision.

[0137]

Table 2

[0138] Although the present invention has been described in connection with its particular embodiments, it is capable of further modification, and this application is intended to cover any variations, uses, or adaptations of the invention, generally following the principles of the invention and including within the scope of the known or customary practice in the art to which the invention pertains, departing from the disclosure shown herein only insofar as they come within the scope of the essential features shown herein and are as described in the following claims appended hereto.

Claims

1. Compound of formula (I): 【Chemistry 1】 or its pharmaceutically acceptable salt (in the formula: X is CR, O, or N; Y is either CR or N; Z is either O or S; n is an integer between 1 and 4; Each R is independently H or C1-C3 alkyl; R1 is a C1-C3 alkyl or hydroxyl group; or n is at least 2, and there are two R １ They may combine to form methylene or ethylene crosslinks; or n is at least 2, and there are two R １ These may be bonded to form a spiro or fused ring, the ring being heterocyclic or heteroaryl, and the ring being optionally substituted with one or two substituents selected from oxo and -C(O)N(CH3)(CH3); Each R ２ These are independently C1-C3 alkyl groups.

2. n is 2, and there are two R １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compounds form a saturated heterocyclic ring containing S and N atoms.

3. The two R's mentioned above １ The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the saturated heterocyclic ring formed by is substituted with two oxos.

4. n is 2, and on the other hand, R １ OH is OH, and the other R is １ CH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Request Item 5】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 Compounds selected from, and their pharmaceutically acceptable salts.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition according to claim 6 for inhibiting the activity of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H in cells.

8. A pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, wherein the therapeutically effective dose of the compound is approximately 0.01 to 100 mg / kg per day.

10. The pharmaceutical composition according to claim 9, wherein the therapeutically effective dose of the compound is approximately 0.1 to 50 mg / kg per day.

11. The aforementioned cancers include: cardiac sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (Adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminocarcinoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampulla carcinoma, cholangiocarcinoma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (retinocellular sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrogenic exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glial cell tumor, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, Schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glial cell tumor, sarcoma); Gynecology: Uterus (endometrial cancer (serous cystadenoma, mucinous cystadenoma, unclassified) A pharmaceutical composition according to claim 8, selected from the group consisting of: cancer, granulosa-encapsular cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma, vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

12. The pharmaceutical composition according to claim 11, wherein the cancer is a KRas G12A-related cancer.

13. The pharmaceutical composition according to claim 11, wherein the cancer is a KRas G12C-related cancer.

14. The pharmaceutical composition according to claim 11, wherein the cancer is a KRas G12D-related cancer.

15. The pharmaceutical composition according to claim 11, wherein the cancer is a KRas G12R-related cancer.

16. The pharmaceutical composition according to claim 11, wherein the cancer is a KRas G12S-related cancer.

17. The pharmaceutical composition according to claim 11, wherein the cancer is a KRas G12V-related cancer.

18. The pharmaceutical composition according to claim 11, wherein the cancer is a KRas G13D-related cancer.

19. The pharmaceutical composition according to claim 11, wherein the cancer is a KRas Q61H-related cancer.

20. The pharmaceutical composition according to claim 11, wherein the cancer is related to at least one of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H.

21. The pharmaceutical composition according to claim 8, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

22. The pharmaceutical composition according to claim 6 for treating cancer determined to be associated with wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H mutations.

23. The pharmaceutical composition according to claim 8, administered via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasacral, intrathecal, intramuscular, intravitreous, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.

24. The pharmaceutical composition according to claim 23, wherein the route of administration is orally.

25. The pharmaceutical composition according to claim 23, wherein the administration is by intravenous injection.

26. The pharmaceutical composition according to claim 23, wherein the administration route is intramuscular injection.

27. The pharmaceutical composition according to claim 23, wherein the administration route utilizes a delivery device.

28. The pharmaceutical composition according to claim 23, wherein the administration is carried out in a hospital setting.

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