Pan-kras inhibitors

Abstract

The present invention relates to compounds that inhibit at least one of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H, pharmaceutical compositions comprising these compounds, and methods of use thereof.

Description

Technical Field

[0001] The present invention relates to compounds that inhibit multiple mutant forms of KRas, ie, pan-KRas inhibitors. In particular, the present invention relates to pan-KRas compounds, pharmaceutical compositions comprising these compounds, and methods of use thereof. Background Art

[0002] Kirsten rat sarcoma type 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras oncogene family. KRas acts as a molecular switch that cycles between an inactive (GDP-bound) and an active (GTP-bound) state to convert upstream cellular signals received from a variety of tyrosine kinases to downstream effectors to regulate a variety of processes, including cell proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancy was observed more than three decades ago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas. KRas mutations at codons 12, 13, 61 and other positions in the KRas primary amino acid sequence are present in 88% of all pancreatic cancer patients, 50% of all colon / rectal adenocarcinoma patients, and 32% of lung adenocarcinoma patients (e.g., see Prior et al., (2020) Cancer Res 80:2969–74). Recent publications have also suggested that wild-type Kras inhibition may be a therapeutic approach for KRas. WT A viable treatment strategy for cancers with PD-1 dependence (e.g., see Bery et al., (2020) Nat. Commun. 11:3233).

[0004] The well-known role of KRas in malignancies and the discovery of these frequent mutations in KRas in various tumor types make KRas a highly attractive target for cancer therapy by the pharmaceutical industry. Despite three decades of extensive discovery efforts to develop KRas inhibitors for the treatment of cancer, no KRas inhibitor has demonstrated sufficient safety and / or efficacy to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. [Clinical Cancer Research] 21(8): 1797-1801).

[0005] Compounds that inhibit KRas activity remain highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie201201358) and recent advances in covalently targeting the allosteric pocket of KRas G12C (e.g., see Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234). Clearly, there remains a continuing interest and effort in developing KRas inhibitors, particularly inhibitors that activate KRas mutants.

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

[0007] In one aspect of the present invention, compounds that inhibit KRas activity are provided. In certain embodiments, these compounds are represented by formula (I):

[0008] Formula (I)

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] X is CR, O or N;

[0011] Y is CR or N;

[0012] Z is O or S;

[0013] n is an integer from 1 to 4;

[0014] Each R is independently H or C1-C3 alkyl;

[0015] R 1 is C1-C3 alkyl or hydroxy; or

[0016] n is at least two, and both R 1 Optionally linked to form a methylene or ethylene bridge; or

[0017] n is at least two, and both R 1 optionally linked to form a spiro or fused ring, wherein the ring is heterocyclic or heteroaryl, and wherein the ring is optionally substituted with 1-2 substituents selected from oxo and -C(O)N(CH3)(CH3);

[0018] Each R 2 are independently C1-C3 alkyl.

[0019] In another aspect of the present invention, pharmaceutical compositions are provided, which contain a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0020] In yet another aspect of the invention, a method for inhibiting the activity of a cell containing wild-type KRas or one or more KRas mutations (e.g., KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H) in the cell is provided, 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 contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0021] Also provided herein is a method of 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.

[0022] Also provided are methods for treating cancer in a patient, 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.

[0023] Also provided herein is a method of 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.

[0024] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein, for use in therapy.

[0025] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein, for use in treating cancer.

[0026] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof for use in inhibiting KRas wild type or various types of KRas mutations, such as KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations.

[0027] 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 treating a KRas wild-type-associated disease or disorder or a KRas mutant G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated disease or disorder.

[0028] 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 treating cancer.

[0029] 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 a wild-type form of KRas or a mutant form of KRas, comprising mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0030] 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 treating a KRas wild-type associated disease or disorder or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H associated disease or disorder.

[0031] Also provided herein are methods for treating cancer in a patient in need thereof, the methods comprising (a) determining that the cancer is associated with KRas wild type or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations (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 having formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0032] One potential utility of the pan-KRas inhibitors described herein is for treating cancers that develop resistance following long-term treatment with a KRas G12C inhibitor. Thus, embodiments of the invention include those in which a patient with a cancer that has been treated with a G12C inhibitor becomes ineffective or less effective with a pan-KRas inhibitor described herein due to the emergence of a resistance-conferring mutation.

[0033] Treatment of KRas G12C mutant cancers with covalent KRas G12C inhibitors such as adagrasib (MRTX849) or sotograciib (AMG510) may result in the incorporation of additional mutations that confer resistance to adagrasib. These mutations may confer resistance through a number of mechanisms.

[0034] The mutation of the mutant cysteine ​​at codon 12 to another amino acid will make the current covalent KRasG12C inhibitor invalid because the current inhibitor forms a covalent bond with the mutant cysteine ​​amino acid side chain. Similarly, in patients with a wild-type KRas allele in addition to the KRas G12C mutant allele, the mutation of the wild-type codon 12 glycine to another codon will allow bypass signaling by novel mutant proteins in these tumors. The library of codon 12 mutations that can occur with single nucleotide substitutions in the wild-type gene (glycine codon) includes mutations commonly observed in cancer, such as G12S, G12V, G12R, G12C. In addition to G12S and G12R, the library of codon 12 mutations that can occur with single nucleotide base substitutions of cysteine ​​codon 12 includes mutations that are not often observed in cancer, G12Y, G12F and G12W.

[0035] Second site mutations can also occur in another position in the KRas G12C mutant gene that confers resistance to KRas G12C inhibitor treatment. These mutations can confer resistance through different mechanisms. RAS proteins are small GTPases that usually cycle between an active GTP-bound state and an inactive GDP-bound state. RAS proteins are loaded with GTP through guanine nucleotide exchange factors (GEFs; e.g., SOS1), which are activated by upstream receptor tyrosine kinases, thereby triggering subsequent interactions with effector proteins that activate RAS-dependent signaling. RAS proteins hydrolyze GTP to GDP through their intrinsic GTPase activity, which is significantly enhanced by GTPase activating proteins (GAPs). Mutations at codons 12 and 13 in RAS proteins impair GAP-stimulated GTP hydrolysis, leaving RAS primarily in a GTP-bound active state. In current clinical development, covalent KRas G12C inhibitors only bind to GDP-bound KRas G12C. Mutations such as the Q61 codon mutation (which may or may not occur on the same allele as the G12C mutation) reduce the intrinsic GTPase activity of KRas and may represent a mechanism of resistance to treatment with KRas G12C inhibitors by shifting KRas to a GTP-loaded state where it is less susceptible to covalent inhibition. Co-mutations such as R68, H95, and Y96 may be present with KRas G12C mutations and may reduce the binding affinity of KRas G12C inhibitors to the Switch II binding pocket.

[0036] The pan-KRas inhibitors described herein may exhibit activity against one or more common and uncommon codon 12 mutations occurring in the KRas protein that reduce binding of the KRas G12C inhibitor to the KRas protein.

[0037] Also provided herein is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0038] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof obtained by a process for preparing a compound of formula (I) as defined herein. DETAILED DESCRIPTION

[0039] The present invention relates to inhibitors of KRas wild type and / or various mutant forms of KRas (e.g., 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 KRas wild type and / or KRas mutations such as G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H, pharmaceutical compositions comprising therapeutically effective amounts of these compounds, and methods of use thereof. definition

[0040] 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 the invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0041] As used herein, "wild-type KRas" refers to a non-mutated form of the mammalian KRas protein. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, "wild-type KRas inhibitors" refer to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of wild-type KRas G12A. As used herein, "wild-type KRas-related diseases or disorders" refer to diseases or disorders associated with, mediated by, or having wild-type KRas. A non-limiting example of a wild-type KRas-related disease or disorder is a wild-type KRas-related cancer.

[0042] As used herein, "KRas G12A" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of alanine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12A inhibitors" refers to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12A. As used herein, "KRas G12A-related diseases or disorders" refers to diseases or disorders associated with or mediated by KRas G12A mutations or having KRas G12A mutations. A non-limiting example of a KRas G12A-related disease or disorder is a KRas G12A-related cancer.

[0043] As used herein, "KRas G12C" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of cysteine ​​in place of glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12C inhibitors" refers to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12C. As used herein, "KRas G12C-related diseases or disorders" refers to diseases or disorders associated with or mediated by KRas G12C mutations or having KRas G12C mutations. A non-limiting example of a KRas G12C-related disease or disorder is a KRas G12CD-related cancer.

[0044] As used herein, "KRas G12D" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of aspartic acid in place of glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12D inhibitors" refers to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12D. As used herein, "KRas G12D-related diseases or disorders" refers to diseases or disorders associated with or mediated by KRas G12D mutations or having KRas G12D mutations. A non-limiting example of a KRas G12D-related disease or disorder is a KRas G12D-related cancer.

[0045] As used herein, "KRas G12R" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of arginine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12R inhibitors" refers to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12R. As used herein, "KRas G12R-related diseases or disorders" refers to diseases or disorders associated with or mediated by KRas G12R mutations or having KRas G12R mutations. A non-limiting example of a KRas G12R-related disease or disorder is a KRas G12R-related cancer.

[0046] As used herein, "KRas G12S" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of serine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12S inhibitors" refer to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12S. As used herein, "KRas G12S-related diseases or disorders" refers to diseases or disorders associated with or mediated by KRas G12S mutations or having KRas G12S mutations. A non-limiting example of a KRas G12S-related disease or disorder is a KRas G12S-related cancer.

[0047] As used herein, "KRas G12V" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of valine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, "KRas G12V inhibitors" refer to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12V. As used herein, "KRas G12V-related diseases or disorders" refers to diseases or disorders associated with or mediated by KRas G12V mutations or having KRas G12V mutations. A non-limiting example of a KRas G12V-related disease or disorder is a KRas G12V-related cancer.

[0048] As used herein, "KRas G13D" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of aspartic acid in place of glycine at amino acid position 13. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G13D inhibitors" refers to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G13D. As used herein, "KRas G13D-related diseases or disorders" refers to diseases or disorders associated with or mediated by KRas G13D mutations or having KRas G13D mutations. A non-limiting example of a KRas G13D-related disease or disorder is a KRas G13D-related cancer.

[0049] As used herein, "KRas Q61H" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of histidine for glutamine at amino acid position 61. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas Q61H inhibitors" refer to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas Q61H. As used herein, "KRas Q61H-related diseases or disorders" refers to diseases or disorders associated with or mediated by KRas Q61H mutations or having KRas Q61H mutations. A non-limiting example of a KRas Q61H-related disease or disorder is a KRas Q61H-related cancer.

[0050] As used herein, the terms "subject", "individual", or "patient" are used interchangeably and 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 a human. In some embodiments, the subject has experienced and / or exhibits 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 with cancer having wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., as determined using a regulatory agency-approved assay or kit, such as an FDA-approved assay or kit). 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., as determined using a regulatory agency-approved assay or kit). The subject can be a subject having one or more tumors that are positive for wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., identified as positive using a regulatory agency-approved assay or kit, such as an FDA-approved assay or kit). The subject can be a subject whose tumor has a wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., where the tumor is so identified using a regulatory agency-approved kit or assay, such as an FDA-approved kit or assay). In some embodiments, the subject is suspected of having cancer associated with wild-type KRas or a 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 a 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).

[0051] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a patient has wild-type KRas-associated or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-associated cancer, a patient having one or more symptoms of a wild-type KRas-associated or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-associated cancer, and / or a patient at increased risk of developing a wild-type KRas-associated or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-associated cancer. G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations, the assays can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, resolved FISH analysis, Southern blotting, protein immunoblotting, FACS analysis, RNA blotting, and PCR-based amplification (such as RT-PCR and quantitative real-time RT-PCR). As is well known in the art, these assays are typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0052] The term "regulatory body" is an agency that is responsible for the medical use of a drug approved by a country. For example, a non-limiting example of a regulatory body is the U.S. Food and Drug Administration (FDA).

[0053] The term "acyl" refers to -C(O)CH3.

[0054] As used herein, the terms "C1-C6 alkyl", "C1-C4 alkyl" and "C1-C3 alkyl" refer to straight and branched aliphatic groups having 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 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.

[0055] The terms "C1-C3 haloalkyl" and "C1-C4 haloalkyl" refer to a C1-C3 alkyl chain or a C1-C4 alkyl chain, respectively, as defined herein, in which one or more hydrogens have been replaced by halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.

[0056] "C1-C4 alkylene" is a C1-C4 alkyl group as defined above, which is located between two other chemical groups and is used to connect the two chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0057] The terms "C1-C3 alkoxy" and "C1-C4 alkoxy" refer to -OC1-C3 alkyl and -OC1-C4 alkyl, respectively, wherein the alkyl portion is as defined above.

[0058] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons (e.g., 3 to 8 carbons), and as a further example, 3 to 6 carbons, wherein the cycloalkyl group is further optionally substituted by one or more R as defined herein. 8 or R 9 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkyl" also includes bridged cycloalkyls, such as bicyclo[1.1.1]pentyl.

[0059] As used herein, the terms "C1-C3 hydroxyalkyl" and "C1-C4 hydroxyalkyl" refer to -C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0060] As used herein, the term "C2-C4 hydroxyalkynyl" refers to -C2-C4 alkynylene-OH.

[0061] An "aryl" group is a C 6 -C 14 The aromatic moiety is optionally substituted with one or more R as defined herein. 8 or R 9 As an example, the aryl group is C 6 -C 10 Aryl groups. 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, wherein one or both rings of the aryl ring system may be saturated or partially saturated, respectively, and wherein if the ring system includes two saturated rings, the saturated rings may be fused or spirocyclic. Examples of aryl ring systems comprising two saturated rings, wherein the rings are spirocyclic, include the following ring systems:

[0062] An "aryl C1-C6 alkyl" or "aralkyl" group includes an aryl group covalently linked to an alkyl group, either of which may be independently optionally substituted or unsubstituted. Examples of aralkyl groups are (C 6 -C 10)Aryl (C 1 -C 6 )alkyl-, including but not limited to benzyl, phenethyl, and naphthylmethyl. An example of a substituted aryl C1-C6 alkyl is one in which the alkyl group is substituted with a hydroxyalkyl group.

[0063] A "heterocyclyl" or "heterocyclic" group is a ring structure having 3 to 12 atoms, such as 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O and S, wherein the ring N atom can be oxidized to NO and the ring S atom can be oxidized to SO or SO 2 , the remaining ring atoms are carbon. The heterocyclic group can be a monocyclic, bicyclic, spirocyclic or bridged ring system. The heterocyclic group is optionally replaced at one or more positions by one or more R 8 or R 9 Group substitution, where R 6 As defined in Formula I. The heterocyclic group is also independently optionally substituted by an alkyl, aralkyl, alkylcarbonyl group on the ring nitrogen atom, or by a lower alkyl group on sulfur. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidone, 4-piperidone, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxaazepanyl, azabicyclohexane, azabicycloheptane, azabicyclooctanyl, azabicyclononane Compounds with adjacent cyclic O and / or S atoms are specifically excluded from the scope of this term.

[0064] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms; sharing 6, 10 or 14 π electrons in the cyclic array; and having, in addition to carbon atoms, one to three heteroatoms per ring, or one to three heteroatoms selected from N, O and S in at least one ring. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, benzopyranyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidine 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, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. "Heteroaryl" also refers to a bicyclic ring system having, in addition to carbon atoms, one to three heteroatoms per ring selected from the group consisting of N, O and S, wherein one of the ring systems may be saturated or partially saturated.

[0065] As used herein, an "effective amount" of a compound refers to 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 can be administered as a single dose or can be administered according to a regimen such that it is effective.

[0066] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or in some way reduce the symptoms of a disorder or to stop or reverse the progression of a disorder, 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 can be administered as a single dose or can be administered according to a regimen, such that it is effective.

[0067] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder, or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0068] As used herein, relief of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, long-lasting or transient, resulting from or associated with the administration of the composition. Compound

[0069] In one aspect of the present invention, there is provided a compound represented by formula (I):

[0070] Formula (I)

[0071] or a pharmaceutically acceptable salt thereof, wherein:

[0072] X is CR, O or N;

[0073] Y is CR or N;

[0074] Z is O or S;

[0075] n is an integer from 1 to 4;

[0076] Each R is independently H or C1-C3 alkyl;

[0077] R 1 is C1-C3 alkyl or hydroxy; or

[0078] n is at least two, and both R 1Optionally linked to form a methylene or ethylene bridge; or

[0079] n is at least two, and both R 1 optionally linked to form a spiro or fused ring, wherein the ring is heterocyclic or heteroaryl, and wherein the ring is optionally substituted with 1-2 substituents selected from oxo and -C(O)N(CH3)(CH3);

[0080] Each R 2 are independently C1-C3 alkyl.

[0081] In certain embodiments of the present invention, n is 2, and both R 1 A saturated heterocyclic ring containing S and N atoms is formed.

[0082] In some embodiments of the present invention, two R 1 The resulting saturated heterocyclic ring is substituted with two oxo groups.

[0083] In certain embodiments of the present invention, n is 2; and an R 1 is OH and another R 1 Yes CH 3。

[0084] Non-limiting examples of compounds having formula (I) are selected from the group consisting of:

[0100] and pharmaceutically acceptable salts thereof.

[0085] In one embodiment, the compound of formula (I) includes dihydrochloride, trihydrochloride, trifluoroacetate, bistrifluoroacetate and tristrifluoroacetate of the above compounds. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition. Pharmaceutical composition

[0086] In another aspect, the present invention provides pharmaceutical compositions comprising wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRasG13D and / or KRas Q61H inhibitors 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 known in the art and can be prepared for administration by any route, including but not limited to parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral, oral, sublingual, transdermal, topical, intranasal, intratracheal, rectal, subcutaneous and topical administration. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In one embodiment, administration can be performed by an oral route. In some embodiments, provided pharmaceutical compositions can be administered to a subject in need of treatment by systemic injection (e.g., by intravenous injection); or by injection or application to the relevant site, such as by direct injection via a syringe, or direct application to the site when the site is exposed during surgery; or by topical administration.

[0087] Parenteral administration may be by bolus injection or continuous infusion. Pharmaceutical compositions for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative.

[0088] The pharmaceutical composition provided can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, the formulation can be modified with suitable polymerization or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or with ion exchange resins, or as a poorly soluble derivative, for example, as a poorly soluble salt.

[0089] If desired, the pharmaceutical composition can be present in a vial, package or medical device, including but not limited to a dispenser device, which 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 liquid formulation ready for injection. The syringe can be accompanied by instructions for use.

[0090] The characteristics 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 one or more active ingredients. Therefore, in addition to the inhibitor, the composition according to the present invention may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, for example, Remington's Pharmaceutical Sciences, 18th edition, edited by A. Gennaro, Mack Publishing Co., Easton, Pennsylvania, 1990.

[0091] As used herein, the term pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of the compound identified above and exhibits minimal or no undesirable toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts formed with organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid). These compounds can also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, which particularly include 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, tosylate, methanesulfonate, sulfonate, phosphate or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzyloate and diphenylacetate).

[0092] 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 severe toxic effects in the treated patient. In one embodiment, the range of the active compound dosage for all the above-mentioned conditions is about 0.01 to 300 mg / kg, for example 0.1 to 100 mg / kg per day, and as another example 0.5 to about 25 mg / kg recipient body weight / day. In a suitable carrier, a typical local dose range is 0.01%-3% wt / wt. The effective dose range of the pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, the effective dose can be estimated by the weight of the derivative as above or by other means known to those skilled in the art.

[0093] Pharmaceutical compositions comprising compounds of the invention can be used in the methods of use described herein. How to use

[0094] In yet another aspect, the invention provides a method of inhibiting wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, and / or KRas Q61H activity in a cell, the method comprising contacting the cell (where inhibition of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, and / or KRas Q61H activity is desired) with an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0095] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro system 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 a compound provided herein includes administering a compound provided herein to an individual or patient (e.g., a human having a wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H mutation), as well as, for example, introducing a compound provided herein into a sample containing cells or purified preparations containing wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H mutations. G12V, KRas G13D, or KRas Q61H mutations.

[0096] 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 having Formula (I) or a pharmaceutically acceptable salt thereof to down-regulate 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.

[0097] The methods described herein are designed to inhibit unwanted cell proliferation caused by enhanced wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H activity in cells by negatively regulating 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. Cells can be contacted with a single dose or multiple doses according to a particular 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 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 can be monitored in vitro using well-known methods, including those described in Examples A and B below. In addition, the inhibitory activity of the 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 in a certain amount of phosphorylated ERK, for example, using the method described in Example C below.

[0098] In another aspect, methods of treating cancer in a patient in need thereof are provided, 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.

[0099] The compositions and methods provided herein can be used to treat 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 patients in need thereof, the method comprising 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, KRasG12V, KRas G13D and / or KRas Q61H-related cancer is lung cancer.

[0100] The compositions and methods provided herein can be used to treat a variety of cancers, including tumors, such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer and sarcoma. More specifically, these compounds can be used to treat: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial lung cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilage hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, smooth muscle sarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor Tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary carcinoma, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant Lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa cell tumors, Sertoli-Leydig cell tumors tumor), dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: 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.;

[0101] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts may also be co-administered with other anti-tumor compounds (e.g., chemotherapy), or used in combination with other treatments (e.g., radiation or surgical intervention), either as an adjunct before or after surgery.

[0102] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein, for use in therapy.

[0103] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein, for use in treating cancer.

[0104] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in inhibiting wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRasG12V, KRas G13D and / or KRas Q61H.

[0105] 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 treating a wild-type KRas-associated or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H-associated disease or disorder.

[0106] 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 treating cancer.

[0107] 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 KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRasG12V, KRas G13D and / or KRas Q61H.

[0108] 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 treating a wild-type KRas-associated or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H-associated disease or disorder.

[0109] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRasG12V, KRas G13D and / or KRas Q61H mutations (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay); and (b) administering to the patient a therapeutically effective amount of a compound having Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0110] Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0111] Those skilled in the art will further recognize that human clinical trials (including first-in-human, dose-ranging and efficacy trials) in healthy patients and / or patients suffering from a given disorder can be performed according to methods well known in the clinical and medical arts. Reaction schemes and examples

[0112] 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 skilled in the art. For example, the compounds of the present invention can be prepared according to the following reaction schemes and examples outlined.

[0113] The compounds of the present invention may have one or more chiral centers and may be synthesized as a mixture of stereoisomers, which have the same constitution but differ in the arrangement of the atoms in space. These compounds may be used as a mixture, or the individual components / isomers may be separated according to the manufacturer's instructions using commercially available reagents and conventional methods for separating stereoisomers and enantiomers well known to those skilled in the art, for example using (Sigma-Aldrich) or (Diacel Corp) chiral chromatography HPLC column. Alternatively, the compounds of the present invention can be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (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 the compounds of the present invention, the term "compound" should be understood to cover all chiral (enantiomers and diastereomers) and racemic forms.

[0114] The compounds of the present invention may be in anhydrous, solvated or hydrated form, and all such forms are encompassed within the scope of the present invention.

[0115] The following intermediates are intended to further illustrate certain embodiments of the invention and are not intended to limit the scope of the invention. Example 1 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

[0116] Step A (R)-2-Chloro-6-(3-hydroxy-3-methylpiperidin-1-yl)pyrimidine-4-carbonitrile:To a solution of 2,6-dichloropyrimidine-4-carbonitrile (2.00 g, 11.5 mmol, 1.00 eq) in DCM (20.0 mL) was added DIEA (2.97 g, 23.0 mmol, 4.00 mL, 2.00 eq) dropwise at 0°C. Then (3R)-3-methylpiperidin-3-ol (1.74 g, 11.5 mmol, 1.00 eq, HCl) was added to the mixture at 0°C. The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was mixed with H 2 O (10.0 mL) and then extracted with DCM 15.0 mL (10.0 mL×3). The combined organic layers were washed with brine (20.0 mL) and purified by Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate 20:1 to 1:1) to give the title compound (1.70 g, 6.66 mmol, 57.9% yield, 99.0% purity) as a yellow solid. 1 HNMR:(400MHz,CDCl 3 )δ6.83(s,1H),4.60-3.50(m,2H),3.20-3.12(m,2H),2.00-1.65(m,2H),1.64-1.51(m,2H),1.33(s,3H).

[0117] Step 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) was 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 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. 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) and purified by Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate=10:1 to DCM / MeOH 50:1) to give the title compound (400 mg, 1.07 mmol, 53.8% yield, 92.0% purity) as a yellow oil. 1 H NMR: (400MHz, CDCl3) δ6.59(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).

[0118] Step C (Z)-N'-hydroxy-6-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methyl (2-pyrrolidin-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 equiv) in EtOH (5.00 mL) was added Na 2 CO 3 (199 mg, 1.88 mmol, 1.30 equiv) and NH 2 OH·HCl (262 mg, 3.76 mmol, 2.60 equiv). The resulting solution was stirred at 80°C for 1 hour. 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) + ;

[0119] Step 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 Pyridine-4-carboxamidineTo 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 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 rt for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 38%-68%, 8 min) to give the title compound as a yellow solid (100 mg, 153 μmol, 48.2% yield, 91.2% purity). LCMS (ESI): m / z=597.3 (M+1) + .

[0120] Step E 2-amino-4-(3-(6-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methyl pyrrolidin-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-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboximidamide (100 mg, 153 μmol, 91.2% purity, 1.00 equiv) in THF (1.00 mL) was added Triton B (56.2 mg, 134 μmol, 61.1 μL, 40.0% purity, 0.9 equiv) at 0°C. The resulting solution was stirred at 0°C for 1 hour. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 45%-75%, 8 min) and lyophilized to give the title compound as a yellow solid (5.20 mg, 9.60 μmol, 6.28% yield, 92.6% purity). LCMS (ESI): m / z=579.3 (M+1) + ; 1H NMR(400MHz,MeOD)δ7.13(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). Example 2 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

[0121] Steps A to D were carried out as steps A to D of Example 1.

[0122] 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]decan-7-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboximidamide (110 mg, 149 μmol, 88.0% purity, 1.00 equiv) in DMF (1.00 mL) was added K 2 CO 3 (41.12 mg, 297.50 μmol, 2.00 equiv.). The mixture was stirred at 60°C to 100°C for 12 hours. The reaction mixture was filtered, and the organic layer was then concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 29%-59%, 8 min) to give the title compound as a yellow solid (15.0 mg, 22.2 μmol, 14.9% yield, 93.5% purity). LCMS (ESI): m / z=633.3 (M+1) + ; 1 H NMR(400MHz,MeOD)δ7.17(s,1H),3.18-3.15(m,8H),3.14(s,1H),2.60(s,1H),2.61(m,1H),2.52(m,2 H), 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 = 6Hz, 3H). Example 3 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

[0123] Steps A to E were carried out as steps A to E of Example 1.

[0124] Step 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 (1R,5S)-3-(6-(5-(2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-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-carboxylic acid tert-butyl ester (20.0 mg, 28.7 μmol, 97.0% purity, 1.00 equiv) in dioxane (1.00 mL) was added HCl / dioxane (4.0 M, 0.50 mL, 92.9 equiv). The mixture was stirred at 25 °C for 4 hours. 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 using solid NaHCO 3 The mixture was adjusted to 8 and extracted with DCM (4.00 mL×4). The combined organic layers were washed with brine (4.00 mL×2), purified by Na 2 SO 4Dry, filter, and concentrate to give a residue. Add ACN / H2O (1 / 5, 20V) and grind at 25°C for 1 hour, then freeze-dry to give the title compound as a yellow solid (10.0 mg, 15.8 μmol, 54.9% yield). LCMS (ESI): m / z=576.3 (M+1) + ; 1 H NMR (400MHz, MeOD) δ7.08(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). Example 4 2-Amino-4-(3-(6-(2,2-dioxido-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

[0125] Synthesized according to Example 2. The title compound was obtained as a yellow solid. LCMS: M / Z=655.4 [M+1] + . 1 H NMR: 400MHz MeOD-d 4 ,δ8.52(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). Example 5 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)-1,2,4-oxadiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile

[0126] Synthesized according to Example 2. The title compound was obtained as a yellow solid (500 mg, 0.804 mmol, 30.5% yield, 94.3% purity, formate salt). LCMS (ESI): m / z=591.3 [M+1] + . 1 H NMR (400MHz MeOD-d 4 )δ8.53(s,1H),7.17-7.15(m,1H),5.27(s,1H),4.76-4.47(m,2H),4.33-4.3 0(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). Example 6 5-(6-(5-(2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-1,2,4-oxadiazol-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide

[0127] Synthesized according to Example 2. The title compound was obtained as a white solid (15.4 mg, 21.6 μmol, 14.9% yield, 94.5% purity, formate salt). LCMS (ESI): m / z=672.3 [M+1]+. 1 H NMR (400MHz MeOD-d 4)δ8.53(s,1H),7.23(s,1H),6.68(s,1H),5.24(s,1H),4.78(m,8H),4.10(m,1H),3.31-3.30(m,2H ), 3.05 (s, 3H), 2.85 (m, 4H), 2.61 (t, J = 4.00Hz, 2H), 2.23 (m, 2H), 2.09-1.85 (m, 11H), 1.44 (s, 3H). Example 7 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

[0128] Step A: 6-Methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboxylic acid ester .In N 2 To a mixture of methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (20.0 g, 98.7 mmol) and (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (15.3 g, 118 mmol) in ACN (200 mL) was added DIPEA (25.5 g, 197 mmol, 34.3 mL) at 20°C. The reaction was heated to 80°C and stirred for 40 hours. The residue was poured into water (200 mL). The aqueous mixture was extracted with dichloromethane (100 mL x 2). The combined organic phases were washed with brine (100 mL), washed with anhydrous Na 2 SO 4 Dry, filter, concentrate and analyze by column chromatography (SiO 2 , petroleum ether:ethyl acetate=10:1-1:0) to give the title compound (18.0 g, 48.7 mmol, 49.4% yield, 80.0% purity) as a yellow solid. LCMS: m / z=296.2 (M+1) + .

[0129] Step B: Lithium 6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine-4-carboxylate . To 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 H 2 O (90.0 mL) was added with LiOH. 2O (2.92 g, 121 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was diluted with water (200 mL) and washed with MTBE (300 mL x 2). The aqueous mixture was lyophilized to give the title compound (14.0 g, 41.3 mmol, 84.9% yield, 83.1% purity) as a yellow solid.

[0130] Step C: N,6-dimethoxy-N-methyl-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine 4-pyridinecarboxamide .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) was added DIEA (32.1 g, 248 mmol) and HATU (22.7 g, 59.7 mmol). The reaction was stirred at 25 °C for 1 hour. The mixture was diluted with water (500 mL) and extracted with dichloromethane (100 mL x 2). The combined organic phases were washed with brine (500 mL) and washed with anhydrous Na 2 SO 4 Dried, filtered, concentrated, and purified by reverse phase HPLC (0.1% FA conditions) to give the title compound (8.70 g, 26.8 mmol, 53.9% yield) as a yellow oil.

[0131] Step 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-Dimethylformamidine .To a solution of (E)-N'-(3-cyano-4-ethynyl-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformamidine (8.01 g, 29.50 mmol) in THF (50.0 mL) at -78°C was added LiHMDS (1 M, 67.0 mL) dropwise. 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)pyrimidine-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 NH 4 Cl (aqueous solution) (50.0 mL) was added and stirred, and the mixture was extracted with ethyl acetate (50.0 mL×2). The combined organic phase was washed with brine (50.0 mL), washed with anhydrous Na 2 SO 4 Dry, filter, and analyze by column chromatography (SiO 2, petroleum ether / ethyl acetate: 10:1-0:1) to give the title compound (11.0 g, 18.1 mmol, 67.5% yield, 84.2% purity) as a yellow solid. LCMS: m / z=535.3 (M+1) + .

[0132] Step 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-dimethyl Formamidine 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-dimethylformamidine (1.00 g, 1.87 mmol) in MeOH (10.0 mL) was added NH 2 OSO 3 H (232 mg, 2.06 mmol). The reaction was stirred at 25 °C for 4 h. NaHS (262 mg, 4.68 mmol) and NaHCO were added to the reaction mixture. 3 (172 mg, 2.06 mmol). The reaction was stirred at 50 °C for 1 hour. The residue was diluted with water (20.0 mL) and extracted with dichloromethane (20.0 mL x 2). The combined organic phases were washed with brine (20.0 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, concentrated and purified by reverse phase HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; B%: 23%-53%, 10 min) to give the title compound (200 mg, 0.33 mmol, 17.8% yield, 85.0% purity) as a yellow solid. 1 H NMR: (400MHz MeOD-d 4 )δ7.90(s,1H),7.75(d,J=10.8Hz 1H),7.17(d,J=2.00Hz 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)

[0133] Step F: (E)-N'-(3-cyano-4-(3-(6-hydroxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethyl) oxy)pyrimidin-4-yl)isothiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformamide Amidine .In N 2 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]thiophene-2-yl)-N,N-dimethylformamidine (2.00 g, 3.54 mmol) and ACN (4.00 mL) at 20 °C was added TMSCl (1.92 g, 17.68 mmol, 2.24 mL) and NaI (2.65 g, 17.6 mmol) in one portion. The reaction was heated at 60 °C for 2 hours. The reaction was poured into ice water (20.0 mL) and the mixture was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were washed with brine (10.0 mL) and washed with anhydrous Na 2 SO 4 Dried, filtered, concentrated, and purified by column chromatography to give the title compound as a yellow solid (600 mg, 1.02 mmol, 28.9% yield, 94.7% purity). LCMS: m / z=552.2 (M+1) + .

[0134] Step G: 6-(5-(3-cyano-2-(((E)-(dimethylamino)methylene)amino)-4-methyl-trifluoromethanesulfonic acid 4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)isothiazol-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethyl Oxy)pyrimidin-4-yl ester .In N 2 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-dimethylformamidine (400 mg, 725 μmol) and DCM (4.00 mL) at 20°C was added DIEA (18.7 mg, 145 μmol) and Tf 2 O (40.9 mg, 145 μmol, 23.92 uL). The reaction 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 phase was washed with brine (10.0 mL) and washed with anhydrous Na 2 SO 4 Dried, filtered, and concentrated to give the title compound (400 mg, 584 μmol, 80.6% yield) as a yellow solid.

[0135] Step 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-dimethylformamidine.In N 2 To a mixture of 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 uL) in one portion at 25°C. The reaction was stirred at 25°C for 2 hours and poured into water (2.00 mL). The aqueous mixture was extracted with ethyl acetate (2.00 mL x 3). The combined organic phases were washed with brine (2.00 mL) and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate to give the title compound as a yellow solid. LCMS: m / z = 649.4 (M+1) +

[0136] Step I: 2-amino-4-(3-(6-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-1-((S)-1-methyl 4-Methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-yl)-4-methyl-2-(4-(2-(2-((4-( ...((-(-(-pyrrolidin-2-yl-ethoxy-pyrimidin-4-yl-isothiazol-5-yl-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3 Formonitrile .In N 2 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-dimethylformamidine (50.0 mg, crude) in MeOH (2.00 mL) was added HCl (12 M, 1.00 mL) in one portion at 20° C. The reaction was stirred at 100° C. for 2 h. The mixture was concentrated and purified by reverse phase HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 9 min) to give the title compound (12.0 mg, 16.5 μmol, 17.3% yield, 98.8% purity, FA salt) as an off-white solid. LCMS: m / z=594.3 (M+1) +1 H NMR: 400MHz MeOD-d 4:δ7.73(d,J=6.40Hz,1H),7.17(s,1H),5.30-5.27(m,1H),3.83(d,J=13.2Hz,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=2.00Hz,1H),1.26(s,3H). Example 8 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

[0137] Synthesized according to Example 7. The title compound (formate salt) was obtained as an off-white solid. 1 H NMR: 400MHzMeOD-d 4 :δ7.73(d,J=6.40Hz,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,2 H), 1.90 (s, 3H), 1.87-1.76 (m, 5H), 1.42 (d, J = 6.00Hz, 3H), 1.28-1.24 (m, 2H). LCMS: m / z=606.3 (M+1) + . Example 9 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)isothiazol-5-yl)-2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile

[0138] Synthesized according to Example 7. The title compound (formate salt) was obtained as an off-white solid. 1 H NMR: 400MHzMeOD-d 4 :δ8.55(s,1H),7.75(d,J=7.20Hz,1H),7.15(s,1H),5.30-5.27(m,1H),3.79 (s,2H),3.41-3.39(m,3H),3.25-3.24(m,2H),2.85(s,4H),2.61(t,J=6.40Hz 2H), 2.26 (s, 1H), 2.06-2.04 (m, 3H), 1.98-1.93 (m, 3H), 1.91-1.88 (m, 5H), 1.82-1.80 (m, 4H), 1.44 (d, J = 6.00Hz, 3H). LCMS: m / z=591.3(M+1) + . Example 10 2-Amino-4-(3-(6-(2,2-dioxido-2-thia-1,3,7-triazaspiro[4.5]decane-7-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

[0139] Synthesized according to Example 7. The title compound (formate salt) was obtained as an off-white solid. 1H NMR: 400 MHz MeOD-d 4 :δ7.76-7.74(m,1H),7.23-7.22(m,1H),5.37-5.34(m,1H),3.72(s,1H),3.39-3.35(m,4H),3.19-3.16(m,2H),2.74 -2.61(m,4H),2.61(s,2H),2.31-2.15(m,1H),2.03-1.96(m,6H),1.91(s,3H),1.86-1.81(m,6H),1.44-1.39(m,3H). LCMS: m / z=670.2(M+1) + . Example 11 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)isothiazol-5-yl)-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile

[0140] Synthesized according to Example 7. The title compound (formate salt) was obtained as an off-white solid. 1H NMR: 400 MHz MeOD-d 4 :δ7.76-7.74(m,1H),7.24(s,1H),5.25-5.22(m,1H),3.55-3.46(m,2H),2.92-2.88(m,1H),2.82(s,3H),2.63-2.59(m ,3H),2.23-2.17(m,3H),2.05-1.98(m,6H),1.91(s,3H),1.87-1.80(m,4H),1.42(d,J=6.00Hz,3H),1.35-1.30(m,2H). LCMS: m / z=648.3(M+1) + . Example 12 5-(6-(5-(2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)isothiazol-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide

[0141] Synthesized according to Example 7. The title compound (formate salt) was obtained as an off-white solid. 1H NMR: 400 MHz MeOD-d 4 :δ7.62(d,J=6.40Hz,1H),7.13(s,1H),6.61(s,1H),5.18(s,1H),4.05(s,2H),3.34-3.22(m,2H),3.17(s,3H),2.95(s,3H),2.74(s, 4H),2.50-2.41(m,3H),2.05-2.02(m,2H),1.94-1.90(m,7H),1.78(s,3H),1.71-1.66(m,2H),1.34-1.33(m,3H),1.31-1.19(m,2H). LCMS: m / z=687.3(M+1) - . Example 13 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

[0142] Step A 2-Chloro-6-methoxypyrimidine-4-carbonitrile: To a solution of 2,6-dichloropyrimidine-4-carbonitrile (18.6 g, 1.0 eq.) in MeOH (200 mL) was added CH 3 ONa (19.3 g, 30% purity, 1.0 equiv.). The reaction was stirred at -40 °C for 2 h. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO 2 , petroleum ether / ethyl acetate=20 / 1 to 5 / 1] to give the title compound (15.8 g, 87% yield) as a yellow solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.04 (s, 1H), 4.10 (s, 3H).

[0143] 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 equiv) and (1S)-1-[(2S)-1-methylpyrrolidin-2-yl]ethanol (12.0 g, 1.0 equiv) in acetonitrile (200 mL) was added DIEA (36.1 g, 3.0 equiv). The reaction was stirred at 70 °C for 12 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO 2 , petroleum ether / ethyl acetate=20 / 1 to 0 / 1] to give the title compound (17.8 g, 73% yield) as a yellow oil; LCMS (ESI, M+1): m / z=263.3.

[0144] Step C (Z)-N'-Hydroxy-6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine Pyridine-4-carboxamidine: 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) was added NH 2 OH·HCl (4.30 g, 1.3 eq.) and Na 2 CO3 (13.1 g, 2.6 eq.). The reaction was stirred at 25 °C for 3 h. The mixture was concentrated, diluted with water (50 mL) and extracted with ethyl acetate (2 x 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.

[0145] Step 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-benzothiophene-4-carboxylic acid (9.94 g, 0.9 eq.) in DMF (150 mL) was 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 was stirred at 25 °C for 0.5 h. 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 then added to the mixture. The reaction was stirred at 45 °C for 12 h. The mixture was diluted with water (1 L) and extracted with ethyl acetate (2 x 1 L). The combined organic layers were washed with brine (1 L), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO 2 , petroleum ether / ethyl acetate=10 / 1 to 0 / 1] to give the title compound (20.0 g, 71% yield) as a yellow solid; LCMS (ESI, M+1): m / z=514.2.

[0146] Step E 2-amino-4-(3-(6-methoxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine 4-pyridin-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 Cs 2 CO 3 (21.6 g, 2.0 equiv.). The reaction was stirred at 70 °C for 1 hour. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO 2, petroleum ether / ethyl acetate=10 / 1 to 0 / 1] to give the title compound (15.0 g, 74% yield) as a yellow solid; LCMS (ESI, M+1): m / z=496.4.

[0147] Step F 2-amino-4-(3-(6-hydroxy-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidine 4-pyridin-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 equiv) in DMAc (80 mL) was added NaSEt (5.47 g, 5.0 equiv). The reaction was stirred at 60 °C for 1 hour. The mixture was diluted with water (250 mL) and washed with ethyl acetate (2 x 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%, 20 min] to give the title compound (3.80 g, 61% yield) as a yellow solid; LCMS (ESI, M+1): m / z=482.3.

[0148] Step G 4-Methylbenzenesulfonic acid 6-(5-(2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 4-yl)-1,2,4-oxadiazol-3-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyrimidin-4-yl ester : 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 eq) and TEA (2.40 g, 3.0 eq) in DCM (40 mL) was added 4-methylbenzenesulfonyl chloride (2.26 g, 1.5 eq) dropwise at 0 °C. The reaction was stirred at 20 °C for 1 hour. The mixture was diluted with water (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [Al 2 O 3 , ethyl acetate] to give the title compound (4.00 g, 80% yield) as a yellow solid; LCMS (ESI, M+1): m / z=636.2.

[0149] Step 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: 6-(5-(2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-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 Molecular sieves (100 mg) were added to a solution of DMF (1 mL) with 6-methyl-1,4-oxazacycloheptane-6-ol (39.5, 1.5 eq., HCl) and DIEA (102 mg, 5.0 eq.). The reaction 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 (NH 4 HCO 3 )-ACN; gradient: 30%-60% B over 9 min] to give the title compound as an off-white solid (5.50 mg, 5.8% yield); 1 H NMR (400 MHz, methanol-d 4 )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=6.0Hz,2H),2.54(s,3H),2.37(q,J=8.4Hz,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. Example A KRas binding assay

[0150] This example illustrates that exemplary compounds of the invention bind to KRas and are able to displace a labeled tracer ligand occupying a KRas binding site. WT 、KRas G12A 、KRas G12C 、KRas G12D 、KRas G12R 、KRas G12S 、KRas G12V 、KRas G13D KRasQ61H .

[0151] The ability of the compounds to bind to KRas was measured using a TR-FRET displacement assay. Biotinylated KRas (corresponding to amino acids 1-169, manufactured by Accelegan) was incubated with a custom Cy5-labeled tracer, terbium streptavidin (Cisbio), and the compounds (1% DMSO final concentration) in a buffer (50 mM HEPES, pH 7.5, 5 mM MgCl 2 , 0.005% Tween-20 and 1 mM DTT). After incubation for 60 min at room temperature, the reaction was measured by TR-FRET using BMG LABTECH CLARIO starPlus. The 100% control (POC) was determined by using a DMSO control, and the 0POC was determined using a control compound concentration that completely inhibited the binding of the tracer to KRas. The POC values ​​were fitted to a 4-parameter IC 50 equation, and report the IC 50 value. Table 1 Binding of exemplary compounds of formula (I) to KRas (IC 50 nM) Example B Inhibition of ERK (HTRF) KRas Phosphorylation by Exemplary Compounds of Formula (I) Cisbio HTRF Advanced pERK Assay Catalog No. 64AERPEH Cell: MKN1, PSN1 program: Day 1: Seed 6,000 cells / well in 384-well white solid bottom plate - 25 μl / well; RPM1_10% FBS. Incubate overnight at 37°C / 5% CO2. • Day 2: echo transfer 25 nl of 10 mM compound, 10 point dilution, 1:3 (Cf = 10 uM) and incubate for 3 hours at 37°C / 5% CO2. - Add 8.5 μl / well of 4X Lysis Buffer / 25X Blocker (do not pour off the medium) and incubate on a shaker at room temperature for 30 min. - Add 4.25ul / well of the conjugate mix of 1X-pERK-D2 and 1X-pERK-K, diluted in assay buffer to a total of 8.5ul / well. Incubate covered at room temperature for 4 hours. HTRF reading using ClarioStar Cells: ASPC1, H727, A549, H460, HCT116, H358 Culture / Assay Medium: RPMI-1640 + 10% FBS program: Cell seeding 1. Harvest cells from flask using 0.05% trypsin / EDTA solution. Add 10 mL of culture medium to stop trypsinization. Pipette cells into a conical bottom 50 mL centrifuge tube and centrifuge for 5 min x 1000 rpm. 2. Resuspend the cell pellet in culture medium, perform a cell count, and then adjust the cell density using fresh culture medium. 3. Seed 6,000 cells into a cell culture plate containing 50 μL of culture medium. 4. Incubate the cell plate in a 37°C, 5% CO2 incubator overnight. Titration of compounds 1.Compound addition was done using Tecan.Compounds started at 10uM top, diluted 3-fold, 10 doses. Final DMSO concentration was 0.8%. 0.2uM trametinib was dispensed as a minimum control. 2. Incubate the cell plate in the incubator for 3 hours. Detection with cisbio pERK HTRF kit 1. Dilute 1 volume of 4x lysis buffer with 3 volumes of deionized water. Then, add 100X blocking agent. Keep the lysis buffer on ice. 2. At the end of compound treatment, flick off the culture medium. 3. Using the Multidrop Combi, add 35 μL of lysis buffer to each well, and then place on a plate stirrer and shake at 300 rpm for 40 min at 4°C. 4. Prepare 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 for 30 seconds x 1000 rpm. 6. At the end of lysis at 4°C, centrifuge the lysate plate for 3 min x 1500 rpm. 7. Use Bravo to 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, read the plate on the Envision after centrifuging the plate for 30 seconds x 1000 rpm. Table 2 Inhibition of KRas-mediated ERK phosphorylation by exemplary compounds of formula (I) 50 nM)

[0152] Although the invention has been described in conjunction with specific embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention which generally follow the principles of the invention and which involve departures from the invention which come within the known or customary practice of the art to which the invention pertains and which are applicable to the basic characteristics as set forth above and which appear within the scope of the appended claims.

Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt thereof, in: 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; R1 is C1-C3 alkyl or hydroxyl; or n is at least two, and both R 1 optionally linked to form a methylene or ethylene bridge; or n is at least 2, and both R 1 optionally linked to form a spiro or fused ring, wherein the ring is heterocyclic or heteroaryl, and wherein the ring is optionally substituted with 1-2 substituents selected from oxo and -C(O)N(CH3)(CH3); and Each R 2 are independently C1-C3 alkyl.

2. The compound or salt of claim 1, wherein n is 2, and both R 1 A saturated heterocyclic ring containing S and N atoms is formed.

3. The compound or salt as claimed in claim 2, wherein two R 1 The resulting saturated heterocyclic ring is substituted with two oxo groups.

4. The compound or salt of claim 1, wherein n is 2, one R 1 is OH and another R 1 Yes CH 3。 5. A compound selected from: and pharmaceutically acceptable salts thereof.

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

7. A method 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 a cell, the method comprising contacting the cell in which the KRas activity is desired to be inhibited with an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, or a pharmaceutical composition as described in claim 6.

8. A method for treating cancer, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 6 to a patient suffering from cancer.

9. The method of claim 8, wherein the therapeutically effective amount of the compound is about 0.01 to 100 mg / kg / day.

10. The method of claim 9, wherein the therapeutically effective amount of the compound is about 0.1 to 50 mg / kg / day.

11. The method of claim 8, wherein the cancer is selected from the group consisting of: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma ； Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous 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), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealoma), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecology: uterus (endometrial carcinoma (serous =The following are some of the following: malignant tumors: ovarian (epidermal, ovarian, genital, ovarian, ureteral), cervical (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands: neuroblastoma.

12. The method of claim 11, wherein the cancer is a KRas G12A-associated cancer.

13. The method of claim 11, wherein the cancer is a KRas G12C-associated cancer.

14. The method of claim 11, wherein the cancer is a KRas G12D-associated cancer.

15. The method of claim 11, wherein the cancer is a KRas G12R-associated cancer.

16. The method of claim 11, wherein the cancer is a KRas G12S-associated cancer.

17. The method of claim 11, wherein the cancer is a KRas G12V-associated cancer.

18. The method of claim 11, wherein the cancer is a KRas G13D-associated cancer.

19. The method of claim 11, wherein the cancer is a KRas Q61H-associated cancer.

20. The method of claim 11, wherein the cancer is a KRas G12A-associated cancer.

21. The method of claim 11, wherein the cancer is associated with at least one of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H.

22. The method of any one of claims 7-21, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

23. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H mutation; and (b) administering to the patient a therapeutically effective amount of a compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 6.

24. The method of any one of claims 7-23, wherein the administration is carried out via a route selected from the group consisting of composition: Parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous and local administration.

25. The method of claim 24, wherein the route of administration is oral.

26. The method of claim 24, wherein the administration is intravenous injection.

27. The method of claim 24, wherein the route of administration is intramuscular injection.

28. The method of claim 24, wherein the route of administration utilizes a delivery device.

29. The method of claim 24, wherein administering is performed in a hospital setting.

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