Combination therapy comprising a KRAS inhibitor and an SHP2 inhibitor

Abstract

Provided herein are combinations comprising a KRAS inhibitor and an SPH2 inhibitor, and methods of treating cancer.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of priority to U.S. Provisional Application No. 63 / 427,731, filed November 23, 2022, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to combinations comprising an SHP2 inhibitor and a KRAS inhibitor, including methods of treatment using an SHP2 inhibitor in combination with a KRAS inhibitor, and the use of such combinations in the treatment of cancer. [Background technology]

[0003] SH2-containing protein tyrosine phosphatase 2 (SHP2) belongs to the protein tyrosine phosphatase family, which is involved in the regulation of cell proliferation, survival, differentiation, migration, and apoptosis. SHP2 can regulate Ras-mitogen-activated protein kinase, Janus kinase-signal transducer and activator of transcription (JAK-STAT) or phosphoinositide 3-kinase-AKT, and nuclear factor κB (NF-κB), as well as other signaling pathways. SHP2 is also a key regulator of the programmed cell death protein-1 (PD-1) and B and T lymphocyte attenuation factor (BTLA) immune checkpoint signaling pathways, which may be related to tumor immunosuppression. Therefore, activation of SHP2 is a viable antitumor strategy. Furthermore, SHP2 mutations occur rarely in tumors, making them an achievable target for cancer therapy.

[0004] Compared to SHP2, RAS genes, including H-, N-, and K-RAS variants, comprise the most frequently mutated oncogene family in cancer. KRAS is the Kirsten rat sarcoma viral oncogene homologue. Mutations in KRAS, such as the G12C mutation, are found in most pancreatic cancers, half of colorectal cancers, and a third of lung cancer cases, and therefore account for a significant proportion of cancer deaths. Therefore, compounds that inhibit KRAS activity are promising candidates for antitumor strategies.

[0005] Despite years of discovery efforts to develop effective antitumor strategies, single-agent therapy still cannot meet the need for effective antitumor strategies in many cancers. Furthermore, a significant number of tumors are either resistant or refractory to single agents.

[0006] Therefore, there is a need for new therapeutic methods, including, for example, combination therapies for the treatment of cancer. Provided herein are combinations comprising an SHP2 inhibitor and a KRAS inhibitor, including uses and methods for treating cancer comprising these combinations. Summary of the Invention

[0007] Provided herein are methods of treating and / or preventing cancer that include, inter alia, a KRAS inhibitor and an SHP2 inhibitor.

[0008] In one embodiment, provided herein is a method of treating or preventing brain metastasis, the method comprising administering a KRAS inhibitor compound of Formula I, or an acceptable salt or solvate thereof:

[0009] [ka] wherein the variables R1, R2, R3, R4, R5, L1, X1, X2, T1, T2, A, and n are described herein.

[0010] In some embodiments, treating brain metastasis comprises inhibiting growth of brain tumors, and the effective amount of the compound is an amount effective to inhibit growth of brain tumors.

[0011] In some embodiments, the brain tumor is a secondary tumor, while in some other embodiments, the primary tumor is not a brain tumor. In some embodiments, the compound of Formula I penetrates the blood-brain barrier (BBB).

[0012] In some embodiments, the KRAS inhibitor compound of formula I has formula Ia (HBI-2438):

[0013] [ka] or an enantiomer or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound of formula I is administered to a subject in an amount of about 1 to about 100 mg / kg / day for at least one day.

[0015] In some embodiments, the method further comprises administering an effective amount of a compound of formula II, wherein the compound of formula II has the formula:

[0016] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables n1, X, R 4a , and R 5a is described herein.

[0017] In some embodiments, the amount of the compound of formula II is synergistic with the amount of the compound of formula I.

[0018] In some embodiments, the amount of the compound of Formula II is synergistic with the amount of the compound of Formula I for treating brain metastases. In some other embodiments, the combined amount of the compounds of Formula I and Formula II is effective to inhibit brain tumor growth or induce brain tumor regression.

[0019] In some embodiments, the brain tumor is a secondary tumor when a compound of Formula Ia and a compound of Formula IIa are used together.

[0020] In some embodiments, the primary tumor is not a brain tumor when a compound of Formula Ia and a compound of Formula IIa are used together.

[0021] In some embodiments, the brain tumor is a secondary tumor when a compound of Formula Ia and a compound of Formula IIa are used together.

[0022] In some embodiments, the compound of Formula II has Formula IIa (HBI-2376):

[0023] [ka] or a racemic or pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the compound of Formula I is administered to a subject in an amount of about 0.5 to about 100 mg / kg / day for at least one day. In some other embodiments, the compound of Formula II is administered to a subject in an amount of about 5 to about 25 mg / kg / day. In some embodiments, the compound of Formula I is a compound of Formula Ia and the compound of Formula II is a compound of Formula IIa.

[0025] In some embodiments, provided herein are methods of treating or preventing brain metastasis, the methods comprising administering a KRAS inhibitory compound and an SPH2 inhibitory compound, or pharmaceutically acceptable salts or solvates thereof.

[0026] In some embodiments, each of the KRAS inhibitor compound and the SPH2 inhibitor compound is a small molecule compound.

[0027] In some embodiments, described herein are combinations (eg, combination therapies such as methods of treatment and uses, kits, and compositions) for treating diseases, including cancer.

[0028] Some embodiments of the present disclosure include a first pharmaceutical composition and a second pharmaceutical composition. The first pharmaceutical composition comprises a compound of Formula I, and the second pharmaceutical comprises a compound of Formula II. In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered via the same route of administration. In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered via different routes of administration.

[0029] In some embodiments, provided herein are pharmaceutical compositions comprising a first pharmaceutical composition comprising a KRAS inhibitory compound, a second pharmaceutical composition comprising an SPH2 inhibitory compound, and a pharmaceutically acceptable excipient.

[0030] In some embodiments, combinations for treating cancer (e.g., combination therapies, such as therapeutic methods and uses, kits, and compositions) are described herein. In some embodiments, the kit comprises any one of the embodiments described herein or a combination of pharmaceutical compositions of the embodiments described herein. In some embodiments, the kit further comprises at least one administration device. In some embodiments, one or more components of the kit are sterilized. In some embodiments, the combinations described herein comprise a KRAS inhibitor and an SPH2 inhibitor. In some embodiments, the combinations described herein comprise a KRAS inhibitor, an SPH2 inhibitor, and a third anti-cancer agent.

[0031] In some embodiments, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof,

[0032] [ka] and a therapeutically acceptable amount of an SPH2 inhibitor.

[0033] In some embodiments, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a KRAS inhibitor and a compound of Formula IIa (HBI-2376):

[0034] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0035] In some embodiments, the method comprises administering simultaneously or sequentially a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and a compound of formula II. In some embodiments, the method comprises administering a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and a compound of formula II as a regimen.

[0036] In some embodiments, the patient is treatment naive. In some other embodiments, the patient is treatment naive for brain tumors. In some embodiments, the method comprises administering a compound of Formula I and a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, to the patient as a first line therapy. In some embodiments, the method comprises administering a compound of Formula I and a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, to the patient as a second, third, fourth, fifth, or sixth line therapy.

[0037] In some embodiments, the method includes administering to a patient a compound of formula I and a compound of formula II, or a pharmaceutically acceptable salt or solvate thereof, after treatment with at least one other anti-cancer therapy, wherein the anti-cancer therapy is chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination of two or more thereof.

[0038] In some embodiments, the method comprises inhibiting cancer metastasis in a patient in need of such treatment. In some other embodiments, the method comprises inhibiting brain metastasis in a patient in need of such treatment. In some embodiments, the method of treating cancer extends the time to disease progression of the cancer in the patient. In some embodiments, the method of treating cancer extends survival of the patient. In some embodiments, the method of treating cancer increases progression-free survival of the patient. In some embodiments, the method of treating cancer reduces tumor or tumor burden in the patient. In some embodiments, the method reduces or prevents metastasis of a primary tumor in a patient in need of such treatment.

[0039] Other objects, features, and advantages of the combinations and methods described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0040] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0041] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Figure 1A]1 is a graph showing the effect of the compound of Formula I (HBI-2438) on tumor volume in H1373-Luc+ICA tumor-bearing mice. The results are summarized in Table 1 of Example 1. [Figure 1B] 1 is a graph showing the effect of the compound of formula I (HBI-2438) on body weight in H1373-Luc+ICA tumor-bearing mice. [Figure 2A] 1 is a graph showing the synergistic effect of a compound of Formula I (HBI-2438) and a compound of Formula II (HBI-2376) on tumor volume in H1373-Luc+ICA tumor-bearing mice. [Figure 2B] 2B is a graph showing the synergistic effect of the compound of Formula I and the compound of Formula II on tumor volume in mice bearing H1373-Luc+ICA tumors. The data shown in Figure 2B is a subset of the data in Figure 2A and represents only the combination therapy of HBI-2376 (SHP2 inhibitor) and HBI-2438 (KRAS inhibitor) at various doses. [Figure 2C] 1 is a graph showing the synergistic effect of a compound of Formula I (HBI-2438) and a compound of Formula II (HBI-2376) on body weight in H1373-Luc+ICA tumor-bearing mice. [Figure 3A] Graph showing the relative expression of ERK, pERK, and DUSP6 in different treatment groups, where G1 represents vehicle, G2 represents 5 mg / kg HBI-2376 (SHP2 inhibitor), G5-G7 represent 10, 30, and 100 mg / kg HBI-2438 (KRAS inhibitor), respectively, and G3 and G4 represent positive controls. [Figure 3B] FIG. 3B is a graph of the relative expression of ERK and pERK in the treatment groups referenced in FIG. 3A. [Figure 3C] FIG. 3B is a graph of the relative expression of DUSP6 in the treatment groups referenced in FIG. 3A. [Figure 4A]1 shows the results of Western blot analysis showing the relative expression of ERK, pERK, and DUSP6 in different treatment groups, where HBI-2376 is an inventive SHP2 inhibitor as described herein, and HBI-2438 is an inventive KRAS inhibitor as described herein. [Figure 4B] 1 is a graph depicting the relative expression of ERK and pERK in different treatment groups, where HBI-2376 is an SHP2 inhibitor of the invention described herein and HBI-2438 is a KRAS inhibitor of the invention described herein. [Figure 4C] 1 is a bar graph depicting the relative expression of DUSP6 in different treatment groups, where HBI-2376 is an SHP2 inhibitor of the invention described herein and HBI-2438 is a KRAS inhibitor of the invention described herein. [Figure 5A] 1 shows the results of Western blot analysis showing the relative expression of ERK, pERK, and DUSP6 in different treatment groups, where HBI-2376 is an inventive SHP2 inhibitor as described herein, and HBI-2438 is an inventive KRAS inhibitor as described herein. [Figure 5B] 1 is a graph depicting the relative expression of ERK and pERK in different treatment groups, where HBI-2376 is an SHP2 inhibitor of the invention described herein and HBI-2438 is a KRAS inhibitor of the invention described herein. [Figure 5C] 1 is a graph depicting the relative expression of DUSP6 in different treatment groups, where HBI-2376 is an SHP2 inhibitor of the invention described herein and HBI-2438 is a KRAS inhibitor of the invention described herein. [Figure 6A] 1 is a graph showing the relative expression of DUSP6 in different treatment groups, where HBI-2376 is an SHP2 inhibitor of the invention described herein and HBI-2438 is a KRAS inhibitor of the invention described herein. [Figure 6B]1 is a graph showing the relative gene expression of DUSP6 in the presence of vehicle alone, vehicle+HBI-2376 (SHP2 inhibitor)+HBI-2438 (KRAS inhibitor) combination treatment compared to combination treatment with positive comparator compounds, as disclosed herein. Detailed Description of the Invention

[0042] definition All patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valency known in the chemical arts. If there is a discrepancy between a depicted structure and the name given to that structure, the depicted structure shall prevail. Herein, if the stereochemistry of a structure or a portion of a structure is not shown in the depicted structure or portion of the depicted structure, the depicted structure shall be interpreted as including all of its possible stereoisomers.

[0043] Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice of the present invention. The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of the present disclosure. In the event that there are multiple definitions for a term herein, the definition in this section shall prevail unless otherwise stated. The headings used herein are for organizational purposes only and in no way limit the invention described herein.

[0044] The term "effective amount" refers to the amount of a therapy (e.g., used in the methods provided herein) sufficient to achieve a stated purpose or otherwise achieve the effect for which it is administered. An "effective amount" can be sufficient to reduce and / or ameliorate the progression, onset, recurrence, severity, and / or duration of a given disease, disorder, or condition, and / or its associated symptoms. An "effective amount" can be a "therapeutically effective amount," which refers to an amount sufficient to provide a therapeutic benefit, such as, for example, a reduction or amelioration of the advancement or progression of a given disease, disorder, or condition, a reduction or amelioration of the recurrence, development, or onset of a given disease, disorder, or condition, and / or to improve or enhance the prophylactic or therapeutic effects of another therapy. A "therapeutically effective amount" of a compound used in the methods described herein is capable of enhancing the therapeutic efficacy of another therapeutic agent.

[0045] The term "regimen" refers to a protocol regarding the dosage and timing of administration of one or more therapies (e.g., methods described herein) for treating a disease, disorder, or condition described herein. A regimen can include periods of active administration and periods of rest, as known in the art. An effective administration period includes the administration of the combinations and compositions described herein and the duration of effectiveness of such combinations and compositions. The rest periods of the regimens described herein include periods during which the compounds are not administered effectively, and in some instances, include periods during which the effectiveness of such compounds may be minimal. The combination of effective administration and rest periods in the regimens described herein can increase the effectiveness and / or duration of administration of the combinations and compositions described herein.

[0046] The terms "therapies" and "therapy" refer to any protocol(s), method(s), and / or agent(s) that can be used in the prevention, treatment, management, and / or amelioration of a disease, disorder, or condition, or one or more symptoms thereof. In some examples, the terms refer to an active agent, such as an anti-cancer agent described herein. The terms "therapy" and "treatment" can refer to antiviral therapy, antibacterial therapy, antifungal therapy, anti-cancer therapy, biological therapy, supportive care, and / or other therapies useful in the treatment, management, prevention, or amelioration of a disease, disorder, or condition, or one or more symptoms thereof, known to a medical professional of ordinary skill in the art, e.g., a physician.

[0047] The term "patient" or "subject" refers to a mammal such as a human, cow, rat, mouse, dog, monkey, ape, goat, sheep, bovine, or deer. In some embodiments, a patient described herein is a human.

[0048] The terms "inhibition," "inhibit," and "inhibiting" refer to a reduction in polypeptide activity, binding, or expression, or a reduction or amelioration of a disease, disorder, or condition or its symptoms. As used herein, "inhibiting" can include partially or completely blocking a stimulus; reducing, preventing, or delaying activation or binding; or inactivating, desensitizing, or down-regulating protein or enzyme activity or binding. In the in vivo context, "inhibit" and variants thereof can include "treat" and variants thereof.

[0049] The term "cancer" refers to any physiological condition in a mammal characterized by unregulated cell growth. Cancers, as used herein, include solid tumors and hematological (blood) cancers. "Hematological cancer" refers to any blood-borne cancer, including, for example, myeloma, lymphoma, and leukemia. "Solid tumor" or "tumor" refers to the growth or proliferation of lesions and neoplastic cells, whether malignant or benign, and all pre-cancerous and cancerous cells or tissues that result in abnormal tissue growth. As used herein, "neoplastic" refers to any form of dysregulated or unregulated cell growth that results in abnormal tissue growth, whether malignant or benign.

[0050] The terms "treat," "treating," or "treatment" refer to the administration of therapy to a subject or patient, as may be measured by any indicia of success or improvement in the progression, severity, and / or duration of a disease, condition, or illness, and include any objective or subjective parameter, such as relief, remission, or alleviation of symptoms, or making the injury, condition, or illness more tolerable to the patient, slowing the rate of degeneration or decline, making the final point of degeneration more lenient, or improving the physical or mental well-being of the subject or patient.

[0051] The term "enhance" refers to an increase or improvement in the function or activity of a first compound after a combination comprising a first compound and a second compound is administered to a subject or patient or contacted with a tissue, organ, or cell, where such increase or improvement is measured compared to administration of or contact with the first or second compound alone.

[0052] The term "administering" refers to the act of delivering a combination or composition described herein to a subject by an acceptable route of administration. Such routes may include oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration generally occurs after the onset or diagnosis of a disease, disorder, or condition, or a symptom thereof, but in some instances may occur before the onset of a disease, disorder, or condition, or a symptom thereof (e.g., prophylactic administration to a patient susceptible to such a disease, disorder, or condition).

[0053] The term "coadministration" refers to the administration of two or more agents (e.g., a combination described herein and another active agent, such as an anti-cancer agent described herein). The timing of coadministration depends in part on the combination and composition being administered and can include administration of a member of the combination simultaneously with, immediately before, or immediately after the administration of one or more additional treatments. For example, cancer therapies such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy can be administered on the same or different days, taking into account the patient's sensitivity, the toxicity of the administered agents, etc. The compounds of the present invention can be administered alone or simultaneously to a patient. Coadministration is meant to include simultaneous or sequential administration of compounds, either individually or in combination (more than one compound or agent in a single formulation). Thus, the preparation can also be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compounds described herein can be used in combination with each other and with other active agents known to be useful in the treatment of cancer.

[0054] The term "anti-cancer agent" is used according to its plain and ordinary meaning to refer to a composition having anti-neoplastic properties or the ability to inhibit the growth or proliferation of cells of one or more types of cancer. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the anti-cancer agent is an agent identified herein that has utility in methods of treating cancer. In some embodiments, the anti-cancer agent is an agent approved by the FDA or similar regulatory agency in a country other than the United States to treat cancer.

[0055] The terms "chemotherapeutic" or "chemotherapeutic agent" are used according to their plain and ordinary meaning to refer to chemical compositions or compounds that have anti-neoplastic properties or the ability to inhibit cell growth or proliferation. "Chemotherapy" refers to a treatment or regimen that includes the administration of a chemotherapeutic or anti-cancer agent as described herein.

[0056] As used herein, "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not significantly interfere with the biological activity or properties of the compound and is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0057] The term "pharmaceutically acceptable salt" refers to a salt formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not significantly interfere with the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with an acid or base, as the case may be, to form a salt.

[0058] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless specifically noted otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless specifically noted otherwise. Moreover, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0059] As used herein, "metastatic brain tumor" or "metastatic brain cancer" refers to a cancer of the brain that arises from a separate metastasized primary tumor in another organ. In some embodiments, the primary tumor begins outside the brain, metastasizes, and forms one or more metastatic colonies inside the brain after crossing the blood-brain barrier. In some embodiments, the circulating tumor lodges within the lumen of the carotid artery.

[0060] The following chemical terms, as used herein, have the following meanings unless otherwise indicated:

[0061] "Oxo" refers to an =O substituent.

[0062] "Alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing up to 10 carbon atoms includes C1-C 10 Similarly, for example, an alkyl containing up to 6 carbon atoms is referred to as a C1-C6 alkyl. Alkyl groups containing other numbers of carbon atoms (and other moieties defined herein) are similarly represented. Alkyl groups include C1-C 10Examples of alkyl include, but are not limited to, alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, alkyl is methyl or ethyl. Preferably, C1-C 10 Alkyl is any one of methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Unless stated otherwise specifically in the specification, alkyl groups may be optionally substituted as described below.

[0063] "Alkylene" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group. In some embodiments, alkylene is -CH-, -CHCH-, or -CHCHCH-. In some embodiments, alkylene is -CH-. In some embodiments, alkylene is -CHCH-. In some embodiments, alkylene is -CHCHCH-. In some embodiments, alkylene is -CHCHCH-.

[0064] "Alkoxy" refers to a group of formula -OR, where R is an alkyl group, as defined herein. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy. In some embodiments, an alkoxy is methoxy. In some embodiments, an alkoxy is ethoxy. "C1-C 10 Alkoxy (C1-C 10 The term "alkoxy"), alone or in combination, refers to the group C1-C 10alkyl-O-, where "C1-C 10 Alkyl (C1-C 10 "Alkyl" means as defined above, including, but not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy (-OCH2CH2CH3), iso-propoxy (-OCH(CH3)2), n-butoxy (-OCH2CH2CH2CH3), sec-butoxy (-OCH(CH3)CH2CH3), iso-butoxy (-OCH2CH(CH3)2), tert-butoxy (-OC(CH3)3), and the like.

[0065] "Heteroalkyl" refers to an alkyl group as defined above in which one or more carbon atoms of the alkyl have been replaced with an O, N (i.e., NH, N-alkyl), or S atom. "Heteroalkylene" refers to a straight or branched divalent heteroalkyl chain connecting the remainder of the molecule to a radical group. Unless stated otherwise specifically in the specification, a heteroalkyl or heteroalkylene group can be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOMe, or -OCHCHOCHCHNH. Representative heteroalkylene groups include, but are not limited to, -OCHCHO-, -OCHCHOCHCHO-, or -OCHCHOCHCHCHOCHCHO-.

[0066] "Alkylamino" refers to a group of the formula -NHR or -NRR, where each R is independently an alkyl group as defined above. Unless stated otherwise in the specification, an alkylamino group can be optionally substituted as described below.

[0067] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. Aromatics can be optionally substituted. The term "aromatic" includes both aryl (e.g., phenyl, naphthyl) and heteroaryl (e.g., pyridinyl, quinolinyl) groups.

[0068] "Aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless otherwise stated in this specification, the term "aryl" or the prefix "ar" (e.g., as in "aralkyl") is meant to include aryl radicals that are optionally substituted.

[0069] "Carboxy" refers to -CO2H. In some embodiments, the carboxy moiety can be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as the carboxylic acid moiety. A carboxylic acid bioisostere has biological properties similar to those of a carboxylic acid group. A compound having a carboxylic acid moiety can have the carboxylic acid moiety replaced with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, the carboxylic acid bioisostere ionizes to approximately the same extent as a carboxylic acid group at physiological pH. Examples of carboxylic acid bioisosteres include:

[0070] [ka] These include, but are not limited to:

[0071] "Cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group, in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. The cycloalkyl can be saturated or partially unsaturated. The cycloalkyl can be fused with an aromatic ring (in which case the cycloalkyl is attached via a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, bicyclic, or polycyclic. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, decalinyl, and adamantyl. In some embodiments, the cycloalkyl is monocyclic. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl is bicyclic. Bicyclic cycloalkyl groups include fused bicyclic cycloalkyl groups, spiro bicyclic cycloalkyl groups, and bridged bicyclic cycloalkyl groups.In some embodiments, the cycloalkyl group is selected from spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, 3,4-dihydronaphthalen-1(2H)-one, and decalinyl. In some embodiments, the cycloalkyl is polycyclic. Polycyclic radicals include, for example, adamantyl, and the like. In some embodiments, the polycyclic cycloalkyl is adamantyl. Unless otherwise specified in the specification, a cycloalkyl group can be optionally substituted.

[0072] "Fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring can be replaced with a nitrogen atom.

[0073] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0074] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0075] "Haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless stated otherwise specifically in the specification, a haloalkoxy group can be optionally substituted.

[0076] "Heterocycloalkyl" or "heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 14-membered non-aromatic ring radical containing 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, a heterocycloalkyl radical can be monocyclic, bicyclic (which can include fused bicyclic heterocycloalkyls (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom)), bridged heterocycloalkyl, or spiro-heterocycloalkyl), or polycyclic. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic. In some embodiments, a heterocycloalkyl is bicyclic. The nitrogen, carbon, or sulfur atoms in a heterocyclyl radical can be optionally oxidized. The nitrogen atom can be optionally quaternized. Heterocycloalkyl radicals are partially or fully saturated. Examples of such heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides.Unless otherwise specified, a heterocycloalkyl has 2-10 carbons in the ring. In some embodiments, a heterocycloalkyl has 2-8 carbons in the ring. In some embodiments, a heterocycloalkyl has 2-8 carbons and 1 or 2 N atoms in the ring. In some embodiments, a heterocycloalkyl has 2-10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heterocycloalkyl has 2-10 carbons, 1-2 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in this specification, a heterocycloalkyl group can be optionally substituted. In some embodiments, the term "3-12 membered heterocyclic group" refers to a saturated or partially unsaturated monocyclic ring or polycyclic heterocyclic group containing 3 to 12, particularly 5 to 12, and more particularly 5 to 7, carbon atoms and a heteroatom or heteroatom group, where the heteroatom or heteroatom group is N, NH, O, C(O), or S(O). m wherein m is 0, 1, or 2. In some embodiments, the 3- to 12-membered heterocyclic group includes aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholine, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamyl, valerolactam, caprolactam, butyrolactone, valerolactone, or caprolactone.

[0077] "Heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryls are monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, heteroaryls contain 0 to 4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl.In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0078] The terms "optionally substituted" or "substituted" mean that the referenced group can be substituted with one or more additional groups independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C-C alkylalkyne, halogen, acyl, acyloxy, -COH, -COalkyl, nitro, and amino, including mono- and di-substituted amino groups (e.g., -NH, -NHR, -NR), and protected derivatives thereof. In some embodiments, the optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, and -COalkyl. In some embodiments, optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0079] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom, with a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:

[0080] [ka] Includes:

[0081] combination In some embodiments, the present specification describes combinations for treating cancer (e.g., combination therapies, kits, and compositions, such as treatment methods and uses). In some embodiments, the combinations described herein include a KRAS inhibitor and an SPH2 inhibitor. In some embodiments, the combinations may include a first pharmaceutical composition and a second pharmaceutical composition. In some embodiments, the first pharmaceutical composition includes a KRAS inhibitor compound of Formula I (e.g., Formula Ia (HBI-2438)), and the second pharmaceutical composition includes an SPH2 inhibitor compound of Formula II (e.g., Formula IIa (HBI-2376)). In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are co-packaged as a kit, and the kit may further include instructions for co-administration of the first and second pharmaceutical compositions. In some embodiments, the first and second compositions can be packaged separately for combination in a clinical setting by administering them to a patient within a time frame in which the patient simultaneously receives clinical benefit from the first and second pharmaceutical compositions. In some embodiments, the combination comprises a unit dosage form of a pharmaceutical composition comprising a KRAS inhibitor and an SPH2 inhibitor. In some embodiments, the combination comprises a first pharmaceutical composition comprising a KRAS inhibitor for use in treating cancer in combination with a second pharmaceutical composition comprising an SPH2 inhibitor. In some embodiments, the combination comprises the use of a KRAS inhibitor for the preparation of a first pharmaceutical composition for use in treating cancer in combination with a second pharmaceutical composition comprising an SPH2 inhibitor.

[0082] In some embodiments, the KRAS inhibitor is a fused pyridine compound of Formula I or Formula Ia, for example, as described herein.

[0083] In some embodiments, the SHP2 inhibitor is a pyrazine derivative of Formula II or IIa, for example, as described herein.

[0084] In some embodiments, methods are described herein that include administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein formula I is:

[0085] [ka] During the ceremony, R1 and R2 are independently H, halogen, and C 1-6 alkyl, and 1-6 The alkyl is optionally substituted by 1, 2, or 3 R; R3 is H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O-, and C 3-6 cycloalkyl-O-, 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O-, or C 3-6 cycloalkyl-O- is optionally substituted by 1, 2, or 3 R; R4 is independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 the cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R5 is H, C 1-6 Alkyl, C3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 alkyl-, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl; 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; L1 is selected from -C(=O)-, -S(=O)- and -S(=O)2-; R6 is H, CN, C 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, 3-6 membered heterocycloalkyl, -C 1-6 Alkyl-3-6 membered heterocycloalkyl, and C 3-6 cycloalkyl-C(=O)-; 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, 3-6 membered heterocycloalkyl, -C 1-6 alkyl-3-6 membered heterocycloalkyl, or C 3-6 cycloalkyl-C(=O)- is optionally substituted by 1, 2, or 3 R; R7 is independently H, halogen, OH, NH2, CN, -C(=O)OH, C 1-6 Alkyl-OC(=O)-, -C(=O)-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, and -C 1-6 alkyl-3-6 membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkyl-OC(=O)- or -C 1-6alkyl-3-6 membered heterocycloalkyl is substituted by 1, 2, or 3 R; T1 and T2 are independently selected from N and -C(R8)-; R8 is H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 The cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R is independently H, halogen, OH, NH2, CN,

[0086] [ka] C 1-6 Alkyl, C 1-6 Heterocycloalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 cycloalkyl-O-, and 5- to 6-membered heterocycloalkyl-O-; 1-6 Alkyl, C 1-6 Heterocycloalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 cycloalkyl-O— or 5-6 membered heterocycloalkyl-O— is optionally substituted by 1, 2, or 3 R′; R' is selected from F, Cl, Br, I, OH, NH2, and CH3; Ring A is independently C 6-10 selected from aryl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl; n is selected from 0, 1, 2, 3, or 4;

[0087] [ka] teeth,

[0088] [ka] or

[0089] [ka] and

[0090] [ka] but,

[0091] [ka] If R2 is not present,

[0092] [ka] teeth,

[0093] [ka] Or

[0094] [ka] In the case of

[0095] [ka] teeth,

[0096] [ka] X1 and X2 are independently selected from -N=, -C(R7)=, and -C(R7)2-C(R7)=;

[0097] [ka] In the case of

[0098] [ka] teeth,

[0099] [ka] and X1 and X2 are independently selected from a single bond, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2-, and -C(R7)2-C(R7)2-; and 1-6 Heterocycloalkyl contains 1, 2, or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, and N.

[0100] The compounds of Formula I or Ia, or pharmaceutically acceptable salts thereof, are KRAS G12C inhibitors ("KRAS inhibitors"). The compounds of Formula I and Formula Ia, including their synthesis, isolation, and KRAS inhibitor utility, are substantially described in International Patent Application PCT / CN2020 / 116510, filed September 21, 2020, which is incorporated herein by reference in its entirety.

[0101] In some embodiments, a method is described herein that includes administering a therapeutically effective amount of an SHP2 inhibitor having the structure of Formula II, or a pharmaceutically acceptable salt or solvate thereof,

[0102] [ka] During the ceremony, X is selected from a chemical bond, —NH—, —CONH—; R 4a are H, D, halogen atoms, -CN, -C(O)OH, -CHO, -OH, -NO2, and -C(O)NHR. 14a , or -NHC(O)R 15a selected from -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein R 14a and R 15a are independently C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl groups, and the substituents are C-C 10 Alkyl, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, or C1-C 10 alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclic group, the substituents being optionally C-C 10 Alkyl, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, or C3-C 12 cycloalkyl;

[0103] [ka] is C6-C 10 Aryl, 5-10 membered heteroaryl, C4-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-C 14 Bridged or spirocyclic groups, or C6-C 14a bridged heterocyclic group or a spiro heterocyclic group, wherein the heterocyclic group is a 5-10 membered heteroaryl group, a 3-12 membered heterocyclic group, a C-C 14 A bridged heterocyclic or spiro heterocyclic group contains 1 to 3 heteroatoms or groups selected from N, NH, O, S, C(O), or S(O); Each R 5a are the same or different and are independently selected from H, D, a halogen atom, —CN, —C(O)OH, —CHO, —OH, —NO, or aminoacyl; C-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 aryl, or 5-10 membered heteroaryl, and the substituents are C-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, hydroxy-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaromatic group, C6-C 10 aryl, or a 3- to 12-membered heterocyclic group substituted by one or more substituents, or any two adjacent R 5a form a 3-6 membered saturated or unsaturated ring, optionally the 3-6 membered saturated or unsaturated ring containing one to three of -OH, -NH, -CN, halogen, C-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 aryl, or 5-10 membered heteroaryl, and n1 is 0, 1, 2, or 3.

[0104] In some embodiments, R 4a is H, D, halogen, -CN, unsubstituted or halogen-substituted C1-C 10 Alkyl (halogen atom substituted C1-C 10 alkyl).

[0105] In some embodiments,

[0106] [ka] is selected from phenyl, naphthyl, a 5- to 10-membered heteroaryl, or a 3- to 12-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the 3- to 12-membered heterocyclic group optionally containing 1 to 3 heteroatoms or groups selected from N, NH, O, S, or C(O).

[0107] In some embodiments, the 5-10 membered heteroaromatic ring is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indole[1,2-a]pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazo-pyrimidinyl, oxazolopyrimidinyl, isoxazopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, or furan. In some embodiments, any one of the pyrazinyl, thienopyrazinyl, pyridopyrimidinone, benzoxazolyl, and benzothiazolyl, 3-12 membered heterocyclic groups is selected from the group consisting of aziridinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxythiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactone, caprolactone, succinimide, or

[0108] [ka] is selected from.

[0109] In some embodiments, the 3-12 membered heterocyclic group is butyrolactamyl, pyrrolidinyl, succinimide, or

[0110] [ka] is selected from.

[0111] In some embodiments, each R 5aare the same or different and are independently selected from H, D, halogen, —CN, —C(O)OH, —CHO, —OH, —NO2, or aminoacyl; C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 alkoxy, or -NH2, or unsubstituted, and the substitution is C1-C 10 substituted by one or more substituents selected from alkyl, halogen, NH2, -CN, -OH, -NO2, or any two adjacent R 5a form a 3-6 membered saturated or unsaturated ring, optionally the 3-6 membered saturated or unsaturated ring containing one to three of -OH, -NH, -CN, halogen, C-C 10 Alkyl, and C1-C 10 Substituted with alkoxy.

[0112] In some embodiments, the compound of Formula II has the structure of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof, wherein Formula IIa is:

[0113] [ka] is.

[0114] In some embodiments, the compound of Formula II or IIa is N-(3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof. The compound of Formula IIa is also referred to herein as HBI-2376.

[0115] The compounds of Formula II or IIa, or pharmaceutically acceptable salts thereof, are SHP2 inhibitors. The compounds of Formula II and IIa, including their synthesis, isolation, and SHP2 inhibitory activity, are substantially as described in International Patent Application PCT / CN2020 / 077391, filed March 2, 2020, which is incorporated herein by reference in its entirety.

[0116] Some embodiments described herein provide a method of treating cancer, comprising administering to a subject having a tumor an effective amount of a combination comprising an amount of a Kirsten Rat Sarcoma oncogene homologue G12C (KRAS) inhibitor and an amount of an SH2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor, wherein the KRAS inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof, and the SHP2 inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments of the method described in the immediately preceding paragraph, Formula I is:

[0118] [ka] and R1 and R2 are independently H, halogen, and C 1-6 alkyl, and 1-6 The alkyl is optionally substituted by 1, 2, or 3 R; R3 is H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O-, and C 3-6 cycloalkyl-O-, 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O-, or C 3-6 cycloalkyl-O- is optionally substituted by 1, 2, or 3 R; R4 is independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 the cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R5 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 alkyl-, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl; 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 alkyl-, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; L1 is selected from -C(=O)-, -S(=O)-, and -S(=O)2-; R6 is H, CN, C 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, 3-6 membered heterocycloalkyl, -C 1-6Alkyl-3-6 membered heterocycloalkyl, and C 3-6 cycloalkyl-C(=O)-; 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, 3-6 membered heterocycloalkyl, -C 1-6 alkyl-3-6 membered heterocycloalkyl, or C 3-6 cycloalkyl-C(=O)- is optionally substituted by 1, 2, or 3 R; R7 is independently H, halogen, OH, NH2, CN, -C(=O)OH, C 1-6 Alkyl-OC(=O)-, -C(=O)-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, and -C 1-6 alkyl-3-6 membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkyl-OC(=O)- or -C 1-6 alkyl-3-6 membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; T1 and T2 are independently selected from N and -C(R8)-; R8 is H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 The cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R is independently H, halogen, OH, NH2, CN,

[0119] [ka] , C 1-6 Alkyl, C 1-6 Heterocycloalkyl, C 3-6Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 cycloalkyl-O-, and 5- to 6-membered heterocycloalkyl-O-; 1-6 Alkyl, C 1-6 Heterocycloalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 cycloalkyl-O— or 5-6 membered heterocycloalkyl-O— is optionally substituted by 1, 2, or 3 R′; R' is selected from F, Cl, Br, I, OH, NH2, and CH3; Ring A is independently C 6-10 selected from aryl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl; n is selected from 0, 1, 2, 3, or 4;

[0120] [ka] teeth,

[0121] [ka] or

[0122] [ka] and

[0123] [ka] but,

[0124] [ka] If R2 is not present,

[0125] [ka] teeth,

[0126] [ka] Or

[0127] [ka] In the case of

[0128] [ka] teeth,

[0129] [ka] X1 and X2 are independently selected from -N=, -C(R7)=, and -C(R7)2-C(R7)=;

[0130] [ka] In the case of

[0131] [ka] teeth,

[0132] [ka] wherein X1 and X2 are independently selected from a single bond, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2-, and -C(R7)2-C(R7)2-; The above 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or C 1-6Heterocycloalkyl contains 1, 2, or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, S(=O)2- and N, and Formula II is

[0133] [ka] and During the ceremony, X is selected from a chemical bond, —NH—, —CONH—; R 4a are H, D, halogen atoms, -CN, -C(O)OH, -CHO, -OH, -NO2, and -C(O)NHR. 14a , or -NHC(O)R 15a selected from -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 aryl, or 5- to 10-membered heteroaryl; R 14a and R 15a are independently C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl groups, and the substituents are C-C 10 Alkyl, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, or C1-C 10 alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclic group, the substituents being optionally C-C 10 Alkyl, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, C1-C 10Alkoxy, C1-C 10 Alkylamino, or C3-C 12 cycloalkyl;

[0134] [ka] is C6-C 10 Aryl, 5-10 membered heteroaryl, C4-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-C 14 Bridged or spirocyclic groups, or C6-C 14 a bridged heterocyclic group or a spiro heterocyclic group, wherein the heterocyclic group is a 5-10 membered heteroaryl group, a 3-12 membered heterocyclic group, a C-C 14 A bridged heterocyclic or spiro heterocyclic group contains 1 to 3 heteroatoms or groups selected from N, NH, O, S, C(O), or S(O); Each R 5a are the same or different and are independently selected from H, D, a halogen atom, —CN, —C(O)OH, —CHO, —OH, —NO, or aminoacyl; C-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 aryl, or 5-10 membered heteroaryl, and the substituents are C-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, hydroxy-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaromatic group, C6-C 10 aryl, or a 3- to 12-membered heterocyclic group substituted by one or more substituents, or any two adjacent R 5aform a 3-6 membered saturated or unsaturated ring, optionally the 3-6 membered saturated or unsaturated ring containing one to three of -OH, -NH, -CN, halogen, C-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 aryl, or 5-10 membered heteroaryl; and n1 is 0, 1, 2, or 3.

[0135] In some embodiments of either of the immediately preceding two paragraphs, the method includes treating tumor metastasis. In some such embodiments, treating tumors includes treating tumor metastasis to the brain. In some such embodiments, treating tumor metastasis to the brain includes inhibiting brain tumor growth, and the effective amount of the compound is an amount effective to inhibit brain tumor growth. In some such embodiments, the brain tumor is a secondary tumor. In some such embodiments, the primary tumor is not a brain tumor. In some such embodiments, the compound of Formula I penetrates the blood-brain barrier (BBB). In some such embodiments, the compound of Formula I is a compound of Formula Ia

[0136] [ka] or an enantiomer or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments of any of the immediately preceding three paragraphs, the compound of Formula I or Formula Ia is administered to a subject in an amount of about 1 to about 100 mg / kg / day for at least one day. In some such embodiments, the amount of the compound of Formula II is synergistic with the amount of the compound of Formula I. In some such embodiments, the combined amount of the compounds of Formula I and Formula II is effective to inhibit brain tumor growth or induce brain tumor regression. In some such embodiments, the combined amount of the compounds of Formula I and Formula II is effective to induce brain tumor regression. In some such embodiments, the brain tumor is a secondary tumor. In some such embodiments, the primary tumor is not a brain tumor. In some such embodiments, the compound of Formula I penetrates the blood-brain barrier (BBB).

[0138] In some embodiments of any of the immediately preceding four paragraphs, the compound of Formula II is a compound of Formula IIa, or a pharmaceutically acceptable salt or racemate thereof, wherein Formula IIa is:

[0139] [ka] is.

[0140] In some embodiments of any of the immediately preceding five paragraphs, the compound of Formula IIa or a pharmaceutically acceptable salt thereof is administered to the patient in need thereof at about 5 mg / kg to about 25 mg / kg. In some such embodiments, the compound of Formula I is administered to the subject in an amount of about 0.5 to about 100 mg / kg / day for at least 1 day.

[0141] Some embodiments described herein provide a method of treating or preventing brain metastasis, the method comprising administering to a subject having a primary tumor an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is

[0142] [ka] is selected from During the ceremony, R1 and R2 are independently H, halogen, and C 1-6 alkyl, C 1-6 The alkyl is optionally substituted by 1, 2, or 3 R; R3 is H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O-, and C 3-6 cycloalkyl-O-, 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O-, or C 3-6 cycloalkyl-O- is optionally substituted by 1, 2, or 3 R; R4 is independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 the cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R5 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 alkyl-, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl; 1-6Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; L1 is selected from -C(=O)-, -S(=O)- and -S(=O)2-; R6 is H, CN, C 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, 3-6 membered heterocycloalkyl, -C 1-6 Alkyl-3-6 membered heterocycloalkyl, and C 3-6 cycloalkyl-C(=O)-; 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, 3-6 membered heterocycloalkyl, -C 1-6 alkyl-3-6 membered heterocycloalkyl, or C 3-6 cycloalkyl-C(=O)- is optionally substituted by 1, 2, or 3 R; R7 is independently H, halogen, OH, NH2, CN, -C(=O)OH, C 1-6 Alkyl-OC(=O)-, -C(=O)-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, and -C 1-6 alkyl-3-6 membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkyl-OC(=O)- or -C 1-6 alkyl-3-6 membered heterocycloalkyl is substituted by 1, 2, or 3 R; T1 and T2 are independently selected from N and -C(R8)-; R8 is H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6cycloalkyl, and 3- to 6-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 The cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R is independently H, halogen, OH, NH2, CN,

[0143] [ka] C 1-6 Alkyl, C 1-6 Heterocycloalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 cycloalkyl-O-, and 5- to 6-membered heterocycloalkyl-O-; 1-6 Alkyl, C 1-6 Heterocycloalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 cycloalkyl-O— or 5-6 membered heterocycloalkyl-O— is optionally substituted by 1, 2, or 3 R′; R' is selected from F, Cl, Br, I, OH, NH2, and CH3; Ring A is independently C 6-10 selected from aryl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl; n is selected from 0, 1, 2, 3, or 4;

[0144] [ka] teeth,

[0145] [ka] or

[0146] [ka] and

[0147] [ka] but,

[0148] [ka] If R2 is not present,

[0149] [ka] teeth,

[0150] [ka] Or

[0151] [ka] In the case of

[0152] [ka] teeth,

[0153] [ka] X1 and X2 are independently selected from -N=, -C(R7)=, and -C(R7)2-C(R7)=;

[0154] [ka] In the case of

[0155] [ka] teeth,

[0156] [ka] wherein X1 and X2 are independently selected from a single bond, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2-, and -C(R7)2-C(R7)2-; The above 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or C 1-6 Heterocycloalkyl contains 1, 2, or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, and N.

[0157] In some embodiments of the immediately preceding paragraph, treating brain metastases includes inhibiting growth of brain tumors, and the effective amount of the compound is an amount effective to inhibit growth of brain tumors. In some such embodiments, the brain tumor is a secondary tumor. In some such embodiments, the primary tumor is not a brain tumor. In some such embodiments, the compound of Formula I penetrates the blood-brain barrier (BBB). In some such embodiments, the compound of Formula I is a compound of Formula Ia

[0158] [ka] or an enantiomer or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments of the immediately preceding two paragraphs, the compound of Formula I or Formula Ia is administered to the subject in an amount of about 1 to about 100 mg / kg / day for at least one day. Some such embodiments include administering an effective amount of a compound of Formula II, or a pharmaceutically acceptable salt or enantiomer thereof, wherein the compound of Formula II is:

[0160] [ka] During the ceremony, X is selected from a chemical bond, —NH—, —CONH—; R 4a are H, D, halogen atoms, -CN, -C(O)OH, -CHO, -OH, -NO2, and -C(O)NHR. 14a , or -NHC(O)R 15a selected from -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 aryl, or 5- to 10-membered heteroaryl; R 14a and R 15a are independently C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl groups, and the substituents are selected from C1-C 10 Alkyl, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, or C1-C 10 alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclic group, the substituents being optionally C-C 10 Alkyl, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, or C3-C 12 cycloalkyl;

[0161] [ka] is C6-C 10 Aryl, 5-10 membered heteroaryl, C4-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-C14 Bridged or spirocyclic groups, or C6-C 14 a bridged heterocyclic group or a spiro heterocyclic group, wherein the heterocyclic group is a 5-10 membered heteroaryl group, a 3-12 membered heterocyclic group, a C-C 14 A bridged heterocyclic or spiro heterocyclic group contains 1 to 3 heteroatoms or groups selected from N, NH, O, S, C(O), or S(O); Each R 5a are the same or different and are independently selected from H, D, a halogen atom, —CN, —C(O)OH, —CHO, —OH, —NO, or aminoacyl; C-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 aryl, or 5-10 membered heteroaryl, and the substituents are C-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, hydroxy-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaromatic group, C6-C 10 aryl, or a 3- to 12-membered heterocyclic group substituted by one or more substituents, or any two adjacent R 5a form a 3-6 membered saturated or unsaturated ring, optionally the 3-6 membered saturated or unsaturated ring containing one to three of -OH, -NH, -CN, halogen, C-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10aryl, or 5-10 membered heteroaryl, and n1 is 0, 1, 2, or 3.

[0162] In some embodiments of the immediately preceding three paragraphs, the amount of the compound of Formula II is synergistic with the amount of the compound of Formula I. In some such embodiments, the combined amount of the compounds of Formula I and Formula II is effective to inhibit the growth of or induce regression of a brain tumor. In some such embodiments, the combined amount of the compounds of Formula I and Formula II is effective to induce regression of a brain tumor. In some such embodiments, the brain tumor is a secondary tumor. In some such embodiments, the primary tumor is not a brain tumor. In some such embodiments, the compound of Formula I penetrates the blood-brain barrier (BBB). In some such embodiments, the compound of Formula I is a compound of Formula Ia

[0163] [ka] or an enantiomer or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments of any of the immediately preceding four paragraphs, the compound of Formula I is administered to the subject in an amount of about 1 to about 100 mg / kg / day for at least one day. In some such embodiments, the compound of Formula II is a compound of Formula IIa, or a racemate or pharmaceutically acceptable salt thereof, wherein Formula II is:

[0165] [ka] is.

[0166] In some embodiments of any of the immediately preceding five paragraphs, the compound of Formula IIa or a pharmaceutically acceptable salt thereof is administered to the patient in need thereof at about 5 mg / kg to about 25 mg / kg. In some such embodiments, the compound of Formula I is administered to the subject in an amount of about 0.5 to about 100 mg / kg / day for at least 1 day. In some such embodiments, the method is used to treat cancer in the patient.

[0167] Thus, the present invention includes a combination of a KRAS inhibitor and an SNP2 inhibitor. The present invention also includes a combination of a KRAS inhibitor and an SNP2 inhibitor for the treatment of cancer, particularly metastatic cancer, particularly metastatic cancer that has metastasized to the brain. In some such embodiments, the KRAS inhibitor is a compound of Formula I or Formula Ia described herein, particularly in any of the six paragraphs immediately preceding it, or a pharmaceutically acceptable salt thereof. In some such embodiments, the SNP2 inhibitor is a compound of Formula II or Formula IIa described herein, particularly in any of the six preceding paragraphs, or a pharmaceutically acceptable salt thereof. Thus, the present invention described herein also includes the use of any combination described herein, particularly in any of the six paragraphs immediately preceding it, for the treatment of cancer, particularly metastatic cancer, more particularly metastatic cancer that has metastasized to the brain. Thus, the present invention described herein teaches combinations, uses, and methods for the treatment of secondary brain tumors, particularly secondary brain tumors whose original tumor is outside the brain.

[0168] In some embodiments, the method includes administering a compound described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., Formula (Ia or IIa)), present in an amount greater than about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. In some other embodiments, the compound described herein is present in an amount greater than about 5 mg or about 10 mg. In some embodiments, the composition includes a compound described herein in an amount of about 1 mg to about 500 mg. In some embodiments, the composition comprises a compound described herein in an amount of about 1 mg to about 10 mg, about 1 mg to about 25 mg, about 1 mg to about 50 mg, about 5 mg to about 10 mg, about 5 mg to about 25 mg, about 5 mg to about 50 mg, about 10 mg to about 25 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, or about 200 mg to about 500 mg.

[0169] In some embodiments, the combination contains at least about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the combination contains at least about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of a compound described herein individually. In some embodiments, the compound described herein is present in the composition in an amount of at least about 5 mg or about 10 mg. In some embodiments, the combination includes at least about 1 mg to about 10 mg, about 1 mg to about 25 mg, about 1 mg to about 50 mg, about 5 mg to about 10 mg, about 5 mg to about 25 mg, about 5 mg to about 50 mg, about 10 mg to about 25 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, or about 100 mg to about 200 mg of a compound described herein.

[0170] In some embodiments, the combination comprises about 5 mg to about 500 mg, or about 5 mg to about 100 mg, of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the combination comprises about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg of a compound described herein.

[0171] In some embodiments, the methods include administering a compound described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., Formula (Ia or IIa)), in an amount relative to the patient's body weight (i.e., mg / kg). In some examples, the compound described herein is administered at a dose of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 150 mg / kg, 0.01 mg / kg to about 100 mg / kg, 0.01 mg / kg to about 50 mg / kg, 0.01 mg / kg to about 25 mg / kg, 0.01 mg / kg to about 10 mg / kg, or 0.01 mg / kg to about 5 mg / kg, 0.05 mg / kg to about 200 mg / kg, 0.05 mg / kg to about 150 mg / kg. g, 0.05 mg / kg to about 100 mg / kg, 0.05 mg / kg to about 50 mg / kg, 0.05 mg / kg to about 25 mg / kg, 0.05 mg / kg to about 10 mg / kg, or 0.05 mg / kg to about 5 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg. In other examples, the compounds described herein are present in an amount equivalent to about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg.

[0172] In some embodiments, the combination comprises about 5 mg / kg to about 25 mg / kg of patient body weight of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula Ia or Formula IIa). In some embodiments, the combination comprises about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg of body weight of a compound described herein.

[0173] In some embodiments, the compounds described herein are provided in synergistic amounts. The term synergistic refers to a combination described herein (e.g., a compound of Formula Ia and a compound of Formula IIa, including co-administration with another active agent, such as an anti-cancer agent described herein), or a combination of regimens that is more effective than the additive effects of each individual treatment or regimen.

[0174] The synergistic effect of the combinations described herein may allow for the use of lower dosages of one or more of the components of the combination (e.g., a compound of Formula Ia or a compound of Formula IIa). The synergistic effect may reduce the frequency of administration of at least one of the therapies (e.g., a compound of Formula Ia or a compound of Formula IIa) to a subject with a disease, disorder, or condition described herein. Such lower dosages and reduced administration frequency may reduce toxicity associated with administering at least one of the therapies to a subject without reducing the effectiveness of the treatment. The synergistic effect avoids or reduces adverse and undesirable side effects associated with the use of any of the therapies.

[0175] In some embodiments, the compounds described herein are metabolized upon administration, and the metabolites formed are then used to produce a desired effect, including a desired therapeutic effect.

[0176] The compounds described herein can be formed and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include: (1) salts obtained by converting the free base form of the compound into a pharmaceutically acceptable inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or a pharmaceutically acceptable acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxlic ... (1) Acid addition salts formed by reacting the parent compound with a pharmaceutically acceptable organic acid such as benzoic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, or valproic acid; (2) salts formed by replacing an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion (lithium, sodium, potassium, etc.), an alkaline earth ion (magnesium, calcium, etc.), or an aluminum ion. In some cases, the compounds described herein may be coordinated with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0177] It should be understood that the reference to pharmaceutically acceptable salts includes solvent addition forms, particularly solvates.Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and can be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc.Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of the compounds described herein can be conveniently prepared or formed during the process described herein.In addition, the compounds provided herein can exist in unsolvated form and solvated form.In general, solvated form is considered equivalent to unsolvated form for the purpose of the compounds and methods provided herein.

[0178] Pharmaceutical Composition In one embodiment, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutically usable preparations. The appropriate formulation depends on the selected route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0179] Pharmaceutical composition, as used herein, refers to a mixture of a compound disclosed herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. Pharmaceutical compositions facilitate administration of the compound to an organism.

[0180] The pharmaceutical formulations described herein can be administered to a subject in a variety of ways by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical, or transdermal routes of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0181] In some embodiments, the compounds disclosed herein are administered orally.

[0182] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation of the compounds disclosed herein is in the form of a capsule.

[0183] In one embodiment, the liquid formulation dosage form for oral administration is in the form of an aqueous suspension or liquid selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0184] For administration by inhalation, the compounds disclosed herein are formulated for use as an aerosol, mist, or powder.

[0185] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in conventional manner.

[0186] In some embodiments, the compounds disclosed herein are formulated as transdermal dosage forms.

[0187] In some embodiments, the compounds disclosed herein are formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous, or intravenous injection.

[0188] In some embodiments, the compounds disclosed herein are administered topically and can be formulated into a variety of topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments.

[0189] In some embodiments, the compounds disclosed herein are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.

[0190] Pharmaceutical compositions and dosage forms described herein typically comprise one or more excipients.Suitable excipients are well known to those skilled in the art of pharmacy.Whether a particular excipient is suitable for incorporation into pharmaceutical compositions or dosage forms depends on various factors, such as the intended route of administration to patients.Pharmaceutical compositions described herein can also comprise other agents, such as stabilizers, lubricants, buffers and disintegrants, which can reduce the rate at which active ingredients can be decomposed in certain formulations.

[0191] The pharmaceutical compositions described herein can, in certain instances, include additional active agents other than those in the combinations described herein (e.g., anti-cancer agents such as those described herein) in the amounts provided herein.

[0192] In some embodiments, the compounds described herein are provided in an oral dosage form, such as a tablet or capsule. In some embodiments, the compounds described herein are supplied as a powder (e.g., a lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration.

[0193] The combinations described herein can be provided as controlled-release pharmaceutical products, which have the goal of improving drug therapy over that achieved by their non-controlled counterparts. Controlled-release formulations can extend the activity of a drug, reduce dosing frequency, and increase subject compliance. Furthermore, controlled-release formulations can be used to affect other characteristics, such as the time of onset of action or blood levels of the drug, and therefore can affect the occurrence of side effects (e.g., adverse effects).

[0194] Treatment method The combinations and / or pharmaceutical compositions described herein are useful for treating diseases, disorders, or alleviating or eliminating symptoms of diseases and disorders such as, for example, cancer.

[0195] In some embodiments, described herein are methods of treating cancer in a patient in need thereof, comprising administering to the patient a KRAS inhibitor and SHP2 inhibitor compound described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula Ia and Formula IIa). In some other embodiments, described herein are methods of treating brain metastases in a patient in need thereof, comprising administering to the patient a KRAS inhibitor described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula Ia).

[0196] In some embodiments, described herein are methods of treating brain metastases in a patient in need thereof, comprising administering to the patient a KRAS inhibitor and SHP2 inhibitor compound described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula Ia and Formula IIa).

[0197] In some embodiments, the cancer is in the form of a tumor. In some embodiments, the cancer is selected from squamous cell carcinoma, non-squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial carcinoma, breast cancer, prostate cancer, glioblastoma, brain cancer, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant peripheral sheath tumor (MPNST). In some embodiments, the cancer is squamous cell carcinoma. In some embodiments, the cancer is non-squamous cell carcinoma. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the canola is head and neck cancer. In some embodiments, the cancer is urothelial carcinoma. In some embodiments, the cancer is breast cancer (e.g., HER2-negative or HER2-positive breast cancer). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is synovial sarcoma. In some embodiments, the cancer is malignant peripheral nephrotic tumor (MPNST).

[0198] In some embodiments, the tumor is a solid tumor. In some embodiments, the method of treating cancer reduces tumor volume or tumor burden in a patient. In some embodiments, the tumor is reduced in volume by 5% to 95%, or 5% to 50%, or any value therein. In some embodiments, the tumor is reduced in volume by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, the tumor is reduced in volume by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, the tumor is reduced by about 10% to about 99%. In some embodiments, the tumor is about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 99%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 99%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, A decrease of about 30% to about 90%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99%. In some embodiments, the tumor is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 99%. In some embodiments, the tumor is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.In some embodiments, the tumor is reduced by up to about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 99%.

[0199] In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a hematological cancer selected from lymphoma, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, Reed-Sternberg disease, multiple myeloma (MM), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is Hodgkin's lymphoma or Reed-Sternberg disease.

[0200] In some embodiments, the cancer is stage I, stage II, stage III, or stage IV cancer. In some embodiments, the cancer is stage I cancer (e.g., stage IA, IB, or IC). In some embodiments, the cancer is stage II cancer (e.g., stage IIA or IIB). In some embodiments, the cancer is stage III cancer (e.g., stage IIIA, IIIB, or IIIC). In some embodiments, the cancer is stage IV cancer (e.g., stage IVA or IVB). In some other embodiments, the cancer has metastasized.

[0201] The methods described herein can be administered to cancer patients at any time after diagnosis. For example, the cancer patient can be treatment-naive (i.e., not receiving cancer treatment for the diagnosed cancer). The cancer patient can be treatment-naive for one cancer, but can be diagnosed with one or more other cancers, for example, due to metastasis or malignancy. The cancer patient can be immune checkpoint naive for one or more cancers. The cancer patient can have refractory cancer. In certain examples, the combinations described herein are administered to patients in need of cancer treatment as first-line therapy (e.g., first-line therapy administered to treatment-naive cancer patients).

[0202] In some embodiments, the method of treating cancer inhibits metastasis of cancer in a patient. In some embodiments, metastasis is inhibited by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some other embodiments, the method of treating cancer inhibits brain metastasis.

[0203] In some embodiments, the methods of treating cancer reduce existing tumor metastases in a patient. In some other embodiments, the methods of treating cancer reduce existing brain metastases in a patient. In some embodiments, existing tumor metastases are reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0204] In some embodiments, the methods of treating cancer prolong or increase the time to disease progression of the cancer in a patient (including progression to advanced stages, e.g., progression from stage III to stage IV cancer). In some embodiments, the increase is a comparison of the time to disease progression with and without treatment. In some embodiments, the methods described herein extend the time to disease progression by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year or more, including any values ​​therebetween.

[0205] In some embodiments, the methods of treating cancer extend patient survival. In some embodiments, the methods of treating cancer increase the patient's progression-free survival. In some embodiments, the methods of treating cancer extend the time to cancer disease progression in the patient. In some embodiments, the methods of treating cancer extend patient survival. In some embodiments, the methods of treating cancer increase the patient's progression-free survival. In some embodiments, survival is extended by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or more, including values ​​therein.

[0206] In some embodiments, the patient who is a treatment-naive patient is a treatment-naive patient.

[0207] In some embodiments, the method comprises administering to a patient a compound of Formula I and a compound of Formula II described herein as a first line therapy. In some embodiments, the method comprises administering a compound of Formula I and a compound of Formula II described herein as a second, third, fourth, fifth, or sixth line therapy. In some embodiments, the method comprises administering a compound of Formula I and a compound of Formula II described herein as a second line therapy. In some embodiments, the method comprises administering a compound of Formula I and a compound of Formula II described herein as a third line therapy.

[0208] In some embodiments, the method comprises administering to a patient a compound of Formula I and a compound of Formula II described herein after treatment with at least one anti-cancer treatment. In some embodiments, the anti-cancer treatment is chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination thereof. In some embodiments, the anti-cancer treatment is chemotherapy. In some embodiments, the anti-cancer treatment is radiation therapy. In some embodiments, the anti-cancer treatment is cancer surgery. In some embodiments, the anti-cancer treatment is tumor resection or excision. In some embodiments, the anti-cancer treatment is immunotherapy.

[0209] In some embodiments, the cancer is resistant to at least one anti-cancer agent.

[0210] Administration Methods and Treatment Regimen In some embodiments, the combinations described herein are used in the preparation of a medicament for the treatment of a disease or disorder described herein.

[0211] In some embodiments, the combinations disclosed herein are administered for prophylactic and / or therapeutic treatment. In some therapeutic applications, the combinations are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0212] In prophylactic applications, the combinations disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition.

[0213] In some embodiments, the method comprises administering to a patient a combination described herein by oral administration, intraperitoneal methods (ip), or a combination thereof. In some embodiments, the combination is administered orally. In some embodiments, the combination is administered orally. In some embodiments, the combination is administered by ip methods. In some embodiments, the combination is administered intravenously (IV).

[0214] Doses of the compounds of Formula I and II used for adult human treatment typically range from 0.01 mg to 5000 mg per day, or from about 0.01 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses.

[0215] In certain embodiments, the dose of the administered drug may be temporarily reduced or temporarily suspended (ie, a "drug holiday") for a particular length of time.

[0216] In some embodiments, the method comprises administering a combination described herein to a patient daily, weekly, or monthly. In some embodiments, the combination is administered daily. In some embodiments, the combination is administered weekly. In some embodiments, the combination is administered every other week. In some embodiments, the combination is administered monthly. In some embodiments, the combination is administered every other month.

[0217] The compounds of Formula I and Formula II described herein can be administered, for example, once daily (QD), twice daily (BID), once weekly (QW), twice weekly (BID), three times weekly (TIW), or monthly (QM). In some embodiments, the method comprises administering the combination described QD, BID, or TID. In some embodiments, the combination is administered QD. In some embodiments, the combination is administered BID. In some embodiments, the combination is administered TID. In certain examples, the compounds described herein are administered 2-3 times per week. In another embodiment, the compounds described herein are administered QD. The compounds are administered for about 1 day to about 7 days, 1 day to about 14 days, 1 day to about 21 days, 1 day to about 28 days, or daily until disease progression or unacceptable toxicity. Administration of the compounds described herein may depend, in part, on the patient's tolerance; greater tolerance may allow for greater or more frequent dosing.

[0218] The term "administered simultaneously," as used herein, is not particularly limited and means that a compound of the present disclosure and an additional active agent are administered at substantially the same time, for example, as a mixture or in immediate succession.

[0219] The term "administered sequentially," as used herein, is not particularly limited and means that the compound of the present disclosure and the additional active agent are not administered simultaneously, but rather one after the other or in groups with a specific time interval between administrations. The time interval can be the same or different between each administration of the compound of the present disclosure and the additional active agent, and can be selected from the ranges of, for example, 2 minutes to 96 hours, 1 to 7 days, or 1 week, 2 weeks, or 3 weeks. Generally, the time interval between administrations can range from minutes to hours, such as 2 minutes to 72 hours, 30 minutes to 24 hours, or 1 to 12 hours. Further examples include time intervals ranging from 24 to 96 hours, 12 to 36 hours, 8 to 24 hours, and 6 to 12 hours.

[0220] In some embodiments, the KRAS inhibitor and the SHP2 inhibitor compound described herein, or a pharmaceutically acceptable salt or solvate thereof, are administered simultaneously or sequentially. In some embodiments, the SHP2 inhibitor compound described herein and the KRAS inhibitor are administered sequentially. In some embodiments, the SHP2 inhibitor described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula IIa), is administered QD, BID, or TID, and the EGFR TK inhibitor is administered QD, BID, or TID. In some other embodiments, the KRAS inhibitor described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula Ia), is administered QD, BID, or TID, and the EGFR TK inhibitor is administered QD, BID, or TID.

[0221] The combinations described herein can include administration of each therapy (e.g., a compound of Formula Ia and a compound of Formula IIa), with administration occurring simultaneously or sequentially (in either order). In some embodiments, the SHP2 inhibitor compound and the KRAS inhibitor described herein are administered simultaneously (e.g., within at least 1-5 minutes of each other). In other embodiments, the compound of Formula I and the compound of Formula IIa are administered sequentially (e.g., within at least 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 10 hours, 12 hours, 1 day, 2 days, 5 days, 7 days, 14 days, or 21 days of each other).

[0222] In some embodiments, a SHP2 inhibitor compound described herein is administered simultaneously with a KRAS inhibitor compound. In some embodiments, a SHP2 inhibitor compound described herein is administered before a KRAS inhibitor compound. In some embodiments, a SHP2 inhibitor compound described herein is administered after a KRAS inhibitor compound.

[0223] The combinations described herein can be administered in a regimen. The regimen can be designed to provide therapeutically effective amounts of the SHP2 inhibitor compound described herein and the KRAS inhibitor compound described herein over a predetermined period (e.g., administration time). The regimen can be designed to limit or prevent side effects or undesirable complications of each of the components of the combination described herein. The regimen can be designed in a manner that results in increased efficacy (e.g., synergism) of both therapies in the combination. Regimen useful for treating cancer can include any number of days of administration, which can be repeated as needed. The administration period can be interrupted by a rest period that does not include administration of at least one treatment. For example, the regimen can include an administration period that includes 2, 3, 5, 7, 10, 15, 21, 28, or more days. These periods can be repeated. For example, the regimen can include a set number of days, as described above, in which the regimen is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more times.

[0224] The regimen includes a rest period of at least 1, 2, 3, 5, 7, 10 days or more, during which at least one treatment is no longer administered to the patient.The rest period can be determined, for example, by monitoring the patient's response to the drug or by measuring the effectiveness of the treatment.The rest period can be applied to a single therapy, so that only one treatment of the combination described herein is discontinued during the rest period, while the other treatment(s) are still administered.The rest period can be applied to all the treatments administered to the subject, so that the subject does not receive treatment for the period set during the rest period.

[0225] The regimens described herein for the treatment of cancer using the combinations described herein may be continued until disease progression or unacceptable toxicity.

[0226] Biomarkers In another aspect, provided herein are methods of modulating one or more biomarkers above pre-treatment baseline levels in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a KRAS inhibitor compound and a SHP2 inhibitor compound described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula Ia and a compound of Formula IIa).

[0227] In some embodiments, one or more biomarkers are increased or decreased above pre-treatment baseline levels. In some embodiments, one or more biomarkers are increased above baseline levels. In some embodiments, one or more biomarkers are decreased above baseline levels.

[0228] In some embodiments, one or more biomarkers are increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 100%, or at least 150%. In some embodiments, one or more biomarkers are increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold. In some embodiments, one or more biomarkers are decreased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 100%, or at least 150%. In some embodiments, one or more biomarkers are decreased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold.

[0229] In some embodiments, expression of Dual-Specificity Phosphatase 6 (DUSP6) can be used as a biomarker for treatment efficiency with the compounds of Formula I and Formula II, or pharmaceutically effective salts thereof.

[0230] In some embodiments, the expression of phosphorylated Extracellular signal-Regulated Kinase (pERK) (and / or its ratio to its phosphorylated variant (ERK)) can be used as a biomarker indicative of the efficacy of treatment with the compounds of Formula I and Formula II or pharmaceutically effective salts thereof. [Example]

[0231] It will be understood that the following examples are intended to illustrate, but not limit, the present disclosure. Various other embodiments and modifications of the foregoing description and examples will be apparent to those skilled in the art after reading this disclosure without departing from the spirit and scope of the present disclosure, and all such embodiments or modifications are intended to be included within the scope of the appended claims. All publications and patents referenced herein are incorporated herein by reference in their entirety.

[0232] Example 1: The purpose of this example is to evaluate the in vivo antitumor efficacy of AMG510 (positive control KRAS G12C inhibitor), MRTX849 (positive control KRAS G12C inhibitor), and HBI-2438 (KRAS G12C inhibitor of the present invention) in NCH-H1373-luc ICA cancer cells implanted into the intracarotid artery (ICA) in Nu / Nu mice to metastasize to the brain. HBI-2438 (compound of formula Ia) was provided by Huyabio International, LLC. This intracarotid model is well recognized in the art for evaluating the ability of target compounds to treat metastatic brain tumors.

[0233] All procedures related to the handling, care, and treatment of animals in this study were performed in accordance with the guidelines of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and approved by WuXi AppTec's Institutional Animal Care and Use Committee (IACUC). During regular monitoring, animals were checked daily for tumor growth and any effects of treatment on normal behavior, such as motor ability, food and water consumption (visual appearance only), weight gain / loss (weight was measured twice weekly), eye / hair matting, and any other abnormal effects described in the protocol. Mortality and observed clinical signs were recorded based on the number of animals in each subset.

[0234] Methods: NCI-H1373-luc tumor cells were maintained in medium supplemented with 10% heat-inactivated fetal bovine serum at 37°C under a 5% CO2 atmosphere in air. Tumor cells were routinely subcultured twice weekly. Cells growing in the exponential growth phase were harvested and counted for tumor inoculation. Each mouse received 0.5 x 10 NCI-H1373-luc tumor cells in 100 μL of PBS. 5 The animals were randomized and the bioluminescent signal was measured at 8 days. * 10 6 Treatment was initiated when the luminescence intensity reached 1. After grouping, bioluminescence measurements were performed once a week using an IVIS (Lumina II).

[0235] Each mouse received 100 μL of NCI-H1373-luc tumor cells (0.5 × 10 5 The animals were randomized and the bioluminescent signal was measured at 8 days. * 10 6After grouping, bioluminescence measurements were performed once a week using an IVIS (Lumina II).

[0236] [Table 1]

[0237] Results: (a) This study evaluated the therapeutic efficacy of AMG510, MRTX849, and HBI-2438 in the NCI-H1373-luc ICA tumor model. The measured bioluminescence of all treatment groups at various time points is shown in Table 2 and Figure 1A.

[0238] After 21 days of treatment, the mean log 10 bioluminescence of vehicle treated mice reached 8.43. Compared to vehicle, AMG-510 at 30 mg / kg PO QD (log10 bioluminescence = 6.69, TGI = 111.5%, T / C = 79.3%, p<0.05), MRTX849 at 30 mg / kg PO QD (log10 bioluminescence = 6.01, TGI = 152.6%, T / C = 71.3%, p<0.001), HBI-2438 at 15 mg / kg PO QD (log10 bioluminescence = 6.58, TGI = 118.2%, T / C = 78.1%, p<0.01), 30 mg / kg PO QD (log10 bioluminescence = 6.00, TGI = 155.8%, T / C = 71.2%, p<0.001), and 100 mg / kg PO QD (log10 bioluminescence = 6.09, TGI = 150.0%, T / C = 72.2%, p < 0.01) all showed significant differences. In this study, all mice maintained their body weight well during treatment. Tumor bioluminescence measurements. See Figure 1B. Thus, HBI-2438 compared favorably with both positive controls, thereby demonstrating its usefulness in the treatment of metastatic tumors, particularly metastatic brain tumors.

[0239] The mean bioluminescence for each group at various time points is shown in Table 2.

[0240] [Table 2] (b) Tumor growth inhibition assay and bioluminescence The tumor growth inhibition rate of the test article in the NCI-H1373-luc model was calculated based on log10 bioluminescence measurements 21 days after the start of treatment, as shown in Table 3.

[0241] [Table 3]

[0242] Example 2: The purpose of this study was to preclinically evaluate the in vivo therapeutic efficacy of the test articles HBI-2376 (an SHP2 inhibitor of the present invention), HBI-2438 (a KRAS G12C inhibitor of the present invention), MRTX849 (a positive control KRAS G12C inhibitor), and TNO-155 (a positive control SHP2 inhibitor) in treating the subcutaneous HuPrime® colorectal cancer xenograft model CR2528 in female BALB / c nude mice. The test articles were administered as single agents or in specific combination settings as described in Table 4. The CR2528 model partially responds to treatment with MRTX849, making it a relevant model for testing the combination of a KRAS G12C inhibitor (HBI-2438 or MRTX849) and an SHP2 inhibitor (HBI-2376 or TNO-155). HBI-2438 and HBI-2376 (compounds of formula Ia and IIa, respectively) were supplied by Huyabio International, LLC.

[0243] The report and any amendments or procedures, including the care and use of animals in this study, were reviewed and approved by CrownBio's Institutional Animal Care and Use Committee (IACUC) prior to implementation. During the study, animal care and use was conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). All documentation related to this study, including the study protocol, protocol amendments, study reports, raw data, and supporting records, was retained at CrownBio for at least 5 years.

[0244] Methods: (a) The following dosages of formulations were used in Example 2, as shown in Table 4:

[0245] [Table 4-1]

[0246] [Table 4-2]

[0247] (b) The following model was used:

[0248] [Table 5]

[0249] (c) Tumor inoculation: Tumor fragments were collected from stock mice and used for inoculation into mice. On May 25, 2022, each mouse was subcutaneously inoculated with CR2528 model tumor fragments (2–3 mm in diameter) into the right flank for tumor development.

[0250] (d) Randomized: Mean tumor size was 160 mm 3Randomization began when the mean age of the study population reached 99. 99 mice were enrolled in the study. All animals were randomly assigned to 11 study groups, with 9 mice assigned to each group. Randomization was based on a "matched distribution" / "stratified" method (StudyDirector™ software, version 3.1.399.19) / randomized block design. The date of randomization was designated as day 0 (June 13, 2022).

[0251] Observations and Data Collection: After tumor cell inoculation, animals were checked daily for morbidity and mortality. During regular monitoring, animals were checked for tumor growth and any effects of treatment on behavior, such as mobility, food and water consumption, weight gain / loss (body weight was measured twice a week after randomization), eye / hair matting, and any other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal.

[0252] Tumor volumes were measured twice weekly after randomization in two dimensions using calipers, and volumes were reported in mm using the formula: V = (L × W × W) / 2. 3 The tumor volume is expressed as: V = ∑ L = ∑ W = ∑ ...

[0253] Treatment for both the primary and secondary studies was performed for 3 weeks. The primary study was terminated on day 21, and plasma and tumor samples were collected. For secondary analysis, tumor samples were collected after the final administration, transferred to sterile tubes, and frozen in liquid nitrogen. All frozen tumor samples were stored at -80°C.

[0254] Results: (a) This study evaluated the therapeutic efficacy of the test articles HBI-2376, HBI-2438, TNO-155, and MRTX849 as single agents and in combination in treating the subcutaneous HuPrime® colorectal cancer xenograft model CR2528 in female BALB / c nude mice. Tumor growth inhibition rates for the CR2528 model were calculated 21 days after the start of treatment, as shown in Table 5, and tumor volume growth curves between randomization grouping and the end of the study are shown in Figure 2A. Figure 2B is a subset of Figure 2A and highlights tumor growth inhibition for combined treatment with HBI-2376 and HBI-2438.

[0255] [Table 6]

[0256] (b) Tolerability and Mortality: Treatment with each compound was tolerated by the test animals. Weight loss in the treatment groups was comparable to that in the vehicle control group, likely resulting from the weight loss characteristics of the CR2528 model. No other clinical adverse signs were observed during the study. See Figure 2C and Table 7.

[0257] [Table 7]

[0258] Monotherapy with HBI-2376 at 5 mg / kg QD (Group 02), TNO-155 at 5 mg / kg QD (Group 03), MRTX849 at 100 mg / kg QD (Group 04), HBI-2438 at 30 mg / kg QD (Group 06), and HBI-2438 at 100 mg / kg QD (Group 07) significantly inhibited tumor growth, with TGI values ​​of 72.82% (P<0.001), 46.98% (P<0.01), 58.44% (P<0.001), 47.59% (P<0.01), and 56.31% (P<0.001), respectively. However, after combining HBI-2376 (5 mg / kg QD) with HBI-2438 at 10 mg / kg QD (Group 08), 30 mg / kg QD (Group 09), and 100 mg / kg QD (Group 10), tumor growth was significantly delayed, indicating synergistic behavior in the presence of HBI-2376 and HBI-2438. The TGI values ​​were 88.38%, 87.93%, and 94.51%, respectively (all P = 0). Combining TNO-155 (5 mg / kg QD) with MRTX849 (100 mg / kg QD) (Group 11) resulted in clear antitumor efficacy, with a TGI value of 76.35% (P < 0.001). See Figures 2A-2C.

[0259] Example 3: Immunoblot and gene expression analysis The purpose of this study was to evaluate protein / gene expression of pERK, ERK, and DUSP6 by Western blot and DUSP6 gene expression in the HuPrime® colorectal cancer xenograft model CR2528 in the presence of test articles HBI-2376, HBI-2438, and TNO-155. The rationale for this study is that inhibition of phosphorylation and inhibition of DUSP6 are independent indicators of reduced metastatic potential.

[0260] Methods: Treatment was performed for 3 weeks as described in Example 2. Fresh tumors were harvested 4 hours after the final administration. The tumors were transferred to sterile tubes and placed in liquid nitrogen for immediate freezing. All frozen tumors were stored at -80°C. A summary of the results is provided below. Samples were also collected for gene expression analysis.

[0261] (a) Western blot analysis: At each post-injection time point, tumors were harvested and snap-frozen in liquid nitrogen. Using a mortar and pestle, tissues were ground in liquid nitrogen and weighed. Three times the weight of RIPA buffer containing phosphatase and protease inhibitors was added, and the samples were inverted and placed on ice for 30 minutes. Cell lysates were obtained by centrifugation at 14,000 g for 15 minutes at 4°C, and the supernatants were transferred to fresh tubes. Protein was quantified using the Pierce BCA Protein Assay kit. 50 μg of protein was loaded into each well. The gel was transferred to pre-activated PVDF, and primary and secondary antibodies were diluted in TBST containing 5% dry milk. Target proteins were detected using the ECL method with a Tanon 5200 chemiluminescence imaging system. Primary antibodies: DUSP6, Abcam ab76310, β-actin CST 3700S, p-ERK CST 4370s, ERK CST 4695s. The expression of ERK, pERK, and DUSP6 in different treatment groups is shown in Figures 3A, 4A, and 5A. The ratio of pERK / ERK was measured to quantify relative expression. See Figures 3B, 4B, and 5B. DUSP6 / β-actin expression levels are quantified in Figures 3C, 4C, and 5C. (b) Gene expression analysis: Tumor tissues were harvested 4 hours after administration and flash-frozen in liquid nitrogen. The tissues were ground in liquid nitrogen using a mortar and pestle and weighed. The tissues were placed in RLT buffer containing stainless steel beads and placed in a TissueLyser. RNA was processed using an RNAeasy Mini Spin Kit (Qiagen 74106). Total RNA was quantified using a Nanodrop™ 2000 spectrophotometer. cDNA was prepared using a High Capacity cDNA Reverse Transcriptase Kit (ABI 4374966). Real-time PCR was performed using an Applied Biosystems Inc. PCR system 7900H with TaqMan Universal PCR Master Mix (ABI 4304437) and a DUSP6 probe (Thermo Fisher 4331182) and a GAPDH probe (Thermo Fisher 4351370). The raw data are analyzed by SDS2.4 and processed using the ΔCt relative quantification method. ΔCt values ​​are calculated relative to the human housekeeping gene GAPDH. ΔΔCt values ​​are calculated relative to the vehicle group. -ΔΔCt represents the expression level of the target gene DUSP6. Therefore, the expression of DUSP6 was quantified for different treatment groups. See Figures 6A and 6B.

[0262] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. 1. A method of treating or preventing brain metastasis, said method comprising administering to a subject having a primary tumor an effective amount of a compound of formula I, wherein said compound of formula I is 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein R １ , R ２ are independently H, halogen, and C １－６ alkyl, wherein C １－６ The alkyl is optionally substituted by 1, 2, or 3 R; R ３ is H, halogen, OH, NH ２ , C.N., C. １－６ Alkyl, C １－６ Heteroalkyl, 3-6 membered heterocycloalkyl, C ３－６ cycloalkyl, 3- to 6-membered heterocycloalkyl-O—, and C ３－６ cycloalkyl-O—, wherein said C １－６ Alkyl, C １－６ Heteroalkyl, 3-6 membered heterocycloalkyl, C ３－６ cycloalkyl, 3-6 membered heterocycloalkyl-O—, or C ３－６ cycloalkyl-O- is optionally substituted by 1, 2, or 3 R; R ４ are independently H, halogen, OH, NH ２ , C.N., C. １－６ Alkyl, C １－６ Heteroalkyl, C ３－６ cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl; １－６ Alkyl, C １－６ Heteroalkyl, C ３－６ the cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R ５ is H, C １－６ Alkyl, C ３－６ Cycloalkyl, 5-6 membered heterocycloalkyl-C １－３ alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl; １－６ Alkyl, C ３－６ Cycloalkyl, 5-6 membered heterocycloalkyl-C １－３ alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; L １ is -C(=O)-, -S(=O)- and -S(=O) ２ - is selected from, R ６ are H, CN, C １－６ Alkyl, C １－６ Alkyl-S(=O) ２ -, 3- to 6-membered heterocycloalkyl, -C １－６ alkyl-3-6 membered heterocycloalkyl, and C ３－６ cycloalkyl-C(═O)—, wherein C １－６ Alkyl, C １－６ Alkyl-S(=O) ２ -, 3- to 6-membered heterocycloalkyl, -C １－６ alkyl-3-6 membered heterocycloalkyl, or C ３－６ cycloalkyl-C(═O)— is optionally substituted by 1, 2, or 3 R; R ７ are independently H, halogen, OH, NH ２ , CN, -C(=O)OH, C １－６ Alkyl-O-C(=O)-, -C(=O)-NH ２ , C １－６ Alkyl, C １－６ heteroalkyl, and —C １－６ alkyl-3-6 membered heterocycloalkyl, １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Alkyl-O-C(=O)-, or -C １－６ alkyl-3-6 membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; T １ , T ２ are independently N and —C(R ８ ) - is selected from R ８ is H, halogen, OH, NH ２ , C.N., C. １－６ Alkyl, C １－６ Heteroalkyl, C ３－６ cycloalkyl, and 3- to 6-membered heterocycloalkyl; １－６ Alkyl, C １－６ Heteroalkyl, C ３－６ The cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R is independently H, halogen, OH, NH ２ , C.N., 【Chemistry 2】 , C １－６ Alkyl, C １－６ Heterocycloalkyl, C ３－６ Cycloalkyl, 5-6 membered heterocycloalkyl, C ３－６ cycloalkyl-O—, and 5-6 membered heterocycloalkyl-O—, １－６ Alkyl, C １－６ Heterocycloalkyl, C ３－６ Cycloalkyl, 5-6 membered heterocycloalkyl, C ３－６ cycloalkyl-O— or 5-6 membered heterocycloalkyl-O— is optionally substituted by 1, 2, or 3 R′; R' is F, Cl, Br, I, OH, NH ２ , and C.H. ３ is selected from Ring A is independently C ６－１０ selected from aryl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl; n is selected from 0, 1, 2, 3, or 4; 【Transformation 3】 teeth, 【Chemistry 4】 or 【Transformation 5】 and 【Transformation 6】 but, 【Transformation 7】 If R ２ does not exist, 【Transformation 8】 teeth, 【Chemistry 9】 Or 【Chemistry 10】 In the case of 【Chemistry 11】 teeth, 【Chemistry 12】 and X １ , X ２ are independently -N=, -C(R ７ ) =, and -C(R ７ ) ２ -C(R ７ ) = is selected from 【Chemistry 13】 In the case of 【Chemistry 14】 teeth, 【Chemistry 15】 and X １ , X ２ are independently a single bond, —O—, —S—, S(═O), S(═O) ２ , -N(R ６ )-, -C(=O)-, -C(R ７ ) ２ -, and -C(R ７ ) ２ -C(R ７ ) ２ - is selected from, The 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or C １－６ Heterocycloalkyl includes -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, and -S(=O) ２ -, and 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from N.

2. 10. The method of claim 1, wherein treating the brain metastasis comprises inhibiting brain tumor growth, and wherein the effective amount of the compound is an amount effective to inhibit brain tumor growth.

3. 3. The method of claim 2, wherein the brain tumor is a secondary tumor.

4. The method of claim 3 , wherein the primary tumor is not a brain tumor.

5. 5. The method of any one of claims 1 to 4, wherein said compound of formula I penetrates the blood-brain barrier (BBB).

6. The compound of formula I may be of formula Ia: 【Chemistry 16】 or an enantiomer or a pharmaceutically acceptable salt thereof.

7. 7. The method of any one of claims 1 to 6, wherein the compound of formula I or formula Ia is administered to the subject in an amount of about 1 to about 100 mg / kg / day for at least one day.

8. The method further comprises administering an effective amount of a compound of formula II, or a pharmaceutically acceptable salt or enantiomer thereof, wherein said compound of formula II is 【Chemistry 17】 and During the ceremony, X is selected from a chemical bond, —NH—, —CONH—; R ４ａ represents H, D, a halogen atom, —CN, —C(O)OH, —CHO, —OH, or —NO ２ , —C(O)NHR １４ａ or -NHC(O)R １５ａ is selected from: ２ , C １ -C １０ Alkyl, C １ -C １０ Alkylamino, C １ -C １０ Alkoxy, C ３ -C １２ cycloalkyl, 3-12 membered heterocyclic group, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, and R １４ａ and R １５ａ are each independently C １ -C １０ Alkylamino, C ３ -C １２ Cycloalkyl, C ６ -C １０ aryl or 5-10 membered heteroaryl groups, and the substituents are selected from C １ -C １０ Alkyl, halogen, -NH ２ , -CN, -C(O)OH, -CHO, -OH, -NO ２ , or C １ -C １０ alkoxy; １ -C １０ Alkylamino, C ３ -C １２ Cycloalkyl, C ６ -C １０ aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclic group, wherein the substituents are optionally substituted by one or more substituents selected from the group consisting of C １ -C １０ Alkyl, halogen, -NH ２ , -CN, -C(O)OH, -CHO, -OH, -NO ２ , C １ -C １０ Alkoxy, C １ -C １０ alkylamino, or C ３ -C １２ cycloalkyl; [Chemistry 18] is C ６ -C １０ Aryl, 5-10 membered heteroaryl, C ４ -C １２ cycloalkyl, 3-12 membered heterocyclic group, C ６ -C １４ a bridged or spirocyclic group, or C ６ -C １４ a bridged heterocyclic group or a spiro heterocyclic group, and is selected from a 5-10 membered heteroaryl group, a 3-12 membered heterocyclic group, C ６ -C １４ A bridged heterocyclic or spiro heterocyclic group contains 1 to 3 heteroatoms or groups selected from N, NH, O, S, C(O), or S(O); Each R ５ａ are the same or different and independently represent H, D, a halogen atom, —CN, —C(O)OH, —CHO, —OH, or —NO ２ or aminoacyl; １ -C １０ Alkyl, C １ -C １０ Alkylamino, C １ -C １０ Alkoxy, —NH ２ , C ３ -C １２ cycloalkyl, 3-12 membered heterocyclic group, C ６ -C １０ aryl, or 5-10 membered heteroaryl, and the substituents are １ -C １０ Alkyl, C ３ -C １２ Cycloalkyl, 3- to 12-membered heterocyclic group, halogen, —NH ２ , -CN, -C(O)OH, -CHO, -OH, -NO ２ , hydroxy-C １ -C １０ Alkyl, C １ -C １０ Alkoxy, C １ -C １０ alkylamino, 5-10 membered heteroaromatic group, C ６ -C １０ aryl, or a 3- to 12-membered heterocyclic group substituted by one or more substituents, or any two adjacent R ５ａ form a 3-6 membered saturated or unsaturated ring, optionally the 3-6 membered saturated or unsaturated ring containing 1 to 3 of -OH, -NH ２ , -CN, halogen, C １ -C １０ Alkyl, C １ -C １０ Alkoxy, C ３ -C １２ Cycloalkylamino, C １ -C １０ Alkylamino, C ３ -C １２ Cycloalkyl, halogenated C １ -C １０ Alkylamino, C ６ -C １０ aryl, or 5-10 membered heteroaryl; and The method of any one of claims 1 to 7, wherein n1 is 0, 1, 2, or 3.

9. 9. The method of claim 8, wherein the amount of said compound of formula II is synergistic with the amount of said compound of formula I.

10. 10. The method of claim 8 or claim 9, wherein the combined amount of the compounds of Formula I and Formula II is effective to inhibit the growth of or induce regression of brain tumors.

11. 11. The method of claim 10, wherein the combined amount of the compounds of Formula I and Formula II is effective to induce regression of the brain tumor.

12. 12. The method of claim 10 or claim 11, wherein the brain tumor is a secondary tumor.

13. The method of claim 12, wherein the primary tumor is not a brain tumor.

14. 14. The method of any one of claims 10 to 13, wherein said compound of formula I penetrates the blood-brain barrier (BBB).

15. 15. The method of any one of claims 10 to 14, wherein said compound of formula I is administered to said subject in an amount of about 1 to about 100 mg / kg / day for at least one day.

16. The compound of formula II is a compound of formula IIa or a racemic or pharmaceutically acceptable salt thereof, wherein formula II is 【Chemistry 19】 The method according to any one of claims 10 to 15, wherein

17. 17. The method of claim 16, wherein the compound of formula IIa or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof at about 5 mg / kg to about 25 mg / kg.

18. 18. The method of any one of claims 10 to 17, wherein said compound of formula I is administered to said subject in an amount of about 0.5 to about 100 mg / kg / day for at least one day.

19. 1. A method of treating cancer, the method comprising the step of administering to a tumor-bearing subject an effective amount of a combination comprising an amount of a Kirsten rat sarcoma oncogene homolog G12C (KRAS) inhibitor and an amount of an SH2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor, wherein the KRAS inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof, and the SHP2 inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof; Formula I is 【Chemistry 20】 and During the ceremony, R １ , R ２ are independently H, halogen, and C １－６ alkyl, wherein C １－６ The alkyl is optionally substituted by 1, 2, or 3 R; R ３ is H, halogen, OH, NH ２ , C.N., C. １－６ Alkyl, C １－６ Heteroalkyl, 3-6 membered heterocycloalkyl, C ３－６ cycloalkyl, 3- to 6-membered heterocycloalkyl-O—, and C ３－６ cycloalkyl-O—, wherein said C １－６ Alkyl, C １－６ Heteroalkyl, 3-6 membered heterocycloalkyl, C ３－６ cycloalkyl, 3-6 membered heterocycloalkyl-O—, or C ３－６ cycloalkyl-O- is optionally substituted by 1, 2, or 3 R; R ４ are independently H, halogen, OH, NH ２ , C.N., C. １－６ Alkyl, C １－６ Heteroalkyl, C ３－６ cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl; １－６ Alkyl, C １－６ Heteroalkyl, C ３－６ the cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R ５ is H, C １－６ Alkyl, C ３－６ Cycloalkyl, 5-6 membered heterocycloalkyl-C １－３ alkyl-, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl; １－６ Alkyl, C ３－６ Cycloalkyl, 5-6 membered heterocycloalkyl-C １－３ alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; L １ is -C(=O)-, -S(=O)-, and -S(=O) ２ - is selected from, R ６ are H, CN, C １－６ Alkyl, C １－６ Alkyl-S(=O) ２ -, 3- to 6-membered heterocycloalkyl, -C １－６ alkyl-3-6 membered heterocycloalkyl, and C ３－６ cycloalkyl-C(═O)—, wherein C １－６ Alkyl, C １－６ Alkyl-S(=O) ２ -, 3- to 6-membered heterocycloalkyl, -C １－６ alkyl-3-6 membered heterocycloalkyl, or C ３－６ cycloalkyl-C(═O)— is optionally substituted by 1, 2, or 3 R; R ７ are independently H, halogen, OH, NH ２ , CN, -C(=O)OH, C １－６ Alkyl-O-C(=O)-, -C(=O)-NH ２ , C １－６ Alkyl, C １－６ heteroalkyl, and —C １－６ alkyl-3-6 membered heterocycloalkyl, １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Alkyl-O-C(=O)-, or -C １－６ alkyl-3-6 membered heterocycloalkyl is substituted by 1, 2, or 3 R; T １ , T ２ are independently N and —C(R ８ ) - is selected from R ８ is H, halogen, OH, NH ２ , C.N., C. １－６ Alkyl, C １－６ Heteroalkyl, C ３－６ cycloalkyl, and 3- to 6-membered heterocycloalkyl; １－６ Alkyl, C １－６ Heteroalkyl, C ３－６ The cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R is independently H, halogen, OH, NH ２ , C.N., 【Chemistry 21】 , C １－６ Alkyl, C １－６ Heterocycloalkyl, C ３－６ Cycloalkyl, 5-6 membered heterocycloalkyl, C ３－６ cycloalkyl-O—, and 5-6 membered heterocycloalkyl-O—, １－６ Alkyl, C １－６ Heterocycloalkyl, C ３－６ Cycloalkyl, 5-6 membered heterocycloalkyl, C ３－６ cycloalkyl-O— or 5-6 membered heterocycloalkyl-O— is optionally substituted by 1, 2, or 3 R′; R' is F, Cl, Br, I, OH, NH ２ , and C.H. ３ is selected from Ring A is independently C ６－１０ selected from aryl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl; n is selected from 0, 1, 2, 3, or 4; 【Chemistry 22】 teeth, 【Chemistry 23】 or 【Chemistry 24】 and 【Chemistry 25】 but, 【Chemistry 26】 If R ２ does not exist, 【Chemistry 27】 teeth, 【Chemistry 28】 Or 【Chemistry 29】 In the case of 【Transformation 30】 teeth, 【Chemistry 31】 and X １ , X ２ are independently -N=, -C(R ７ ) =, and -C(R ７ ) ２ -C(R ７ ) = is selected from 【Chemistry 32】 In the case of 【Transformation 33】 teeth, 【Transformation 34】 and X １ , X ２ are independently a single bond, —O—, —S—, S(═O), S(═O) ２ , -N(R ６ )-, -C(=O)-, -C(R ７ ) ２ -, and -C(R ７ ) ２ -C(R ７ ) ２ - is selected from, The 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or C １－６ Heterocycloalkyl includes -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, and -S(=O) ２ -, and N; and Formula II is 【Chemistry 35】 and During the ceremony, X is selected from a chemical bond, —NH—, —CONH—; R ４ａ represents H, D, a halogen atom, —CN, —C(O)OH, —CHO, —OH, or —NO ２ , —C(O)NHR １４ａ or -NHC(O)R １５ａ is selected from: ２ , C １ -C １０ Alkyl, C １ -C １０ Alkylamino, C １ -C １０ Alkoxy, C ３ -C １２ cycloalkyl, 3-12 membered heterocyclic group, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, and R １４ａ and R １５ａ are each independently C １ -C １０ Alkylamino, C ３ -C １２ Cycloalkyl, C ６ -C １０ aryl, or 5-10 membered heteroaryl groups, and the substituents are selected from C １ -C １０ Alkyl, halogen, -NH ２ , -CN, -C(O)OH, -CHO, -OH, -NO ２ , or C １ -C １０ alkoxy; １ -C １０ Alkylamino, C ３ -C １２ Cycloalkyl, C ６ -C １０ aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclic group, wherein the substituents are optionally substituted by one or more substituents selected from the group consisting of C １ -C １０ Alkyl, halogen, -NH ２ , -CN, -C(O)OH, -CHO, -OH, -NO ２ , C １ -C １０ Alkoxy, C １ -C １０ alkylamino, or C ３ -C １２ cycloalkyl; 【Transformation 36】 is C ６ -C １０ Aryl, 5-10 membered heteroaryl, C ４ -C １２ cycloalkyl, 3-12 membered heterocyclic group, C ６ -C １４ a bridged or spirocyclic group, or C ６ -C １４ a bridged heterocyclic group or a spiro heterocyclic group, and is selected from a 5-10 membered heteroaryl group, a 3-12 membered heterocyclic group, C ６ -C １４ A bridged heterocyclic or spiro heterocyclic group contains 1 to 3 heteroatoms or groups selected from N, NH, O, S, C(O), or S(O); Each R ５ａ are the same or different and independently represent H, D, a halogen atom, —CN, —C(O)OH, —CHO, —OH, or —NO ２ or aminoacyl; １ -C １０ Alkyl, C １ -C １０ Alkylamino, C １ -C １０ Alkoxy, —NH ２ , C ３ -C １２ cycloalkyl, 3-12 membered heterocyclic group, C ６ -C １０ aryl, or 5-10 membered heteroaryl, and the substituents are １ -C １０ Alkyl, C ３ -C １２ Cycloalkyl, 3- to 12-membered heterocyclic group, halogen, —NH ２ , -CN, -C(O)OH, -CHO, -OH, -NO ２ , hydroxy-C １ -C １０ Alkyl, C １ -C １０ Alkoxy, C １ -C １０ alkylamino, 5-10 membered heteroaromatic group, C ６ -C １０ aryl, or a 3- to 12-membered heterocyclic group substituted by one or more substituents, or any two adjacent R ５ａ form a 3-6 membered saturated or unsaturated ring, optionally the 3-6 membered saturated or unsaturated ring containing 1 to 3 of -OH, -NH ２ , -CN, halogen, C １ -C １０ Alkyl, C １ -C １０ Alkoxy, C ３ -C １２ Cycloalkylamino, C １ -C １０ Alkylamino, C ３ -C １２ Cycloalkyl, halogenated C １ -C １０ Alkylamino, C ６ -C １０ aryl, or 5-10 membered heteroaryl; and n1 is 0, 1, 2, or 3.

20. 20. The method of claim 19, comprising treating tumor metastasis.

21. 21. The method of claim 19 or claim 20, wherein treating the tumor comprises treating metastasis of the tumor to the brain.

22. 22. The method of claim 21, wherein treating the brain metastasis of the tumor comprises inhibiting the growth of brain tumors, and the effective amount of the compound is an amount effective to inhibit the growth of the brain tumors.

23. 23. The method of claim 22, wherein the brain tumor is a secondary tumor.

24. 24. The method of claim 23, wherein the primary tumor is not a brain tumor.

25. 25. The method of any one of claims 19 to 24, wherein the compound of formula I penetrates the blood-brain barrier (BBB).

26. The compound of formula I is of formula Ia 【Chemistry 37】 or an enantiomer or a pharmaceutically acceptable salt thereof.

27. 27. The method of any one of claims 19 to 26, wherein the compound of formula I or formula Ia is administered to the subject in an amount of about 1 to about 100 mg / kg / day for at least one day.

28. 28. The method of claim 27, wherein the amount of said compound of formula II is synergistic with the amount of said compound of formula I.

29. 29. The method of claim 27 or claim 28, wherein the combined amount of the compounds of Formula I and Formula II is effective to inhibit the growth of or induce regression of brain tumors.

30. 30. The method of claim 29, wherein the combined amount of the compounds of Formula I and Formula II is effective to induce regression of the brain tumor.

31. 31. The method of claim 29 or claim 30, wherein the brain tumor is a secondary tumor.

32. 32. The method of claim 31, wherein the primary tumor is not a brain tumor.

33. 33. The method of any one of claims 27 to 32, wherein the compound of formula I penetrates the blood-brain barrier (BBB).

34. The compound of formula II is the compound of formula IIa, or a pharmaceutically acceptable salt or racemate thereof, wherein formula IIa is 【Transformation 38】 The method according to any one of claims 19 to 33, wherein

35. 35. The method of claim 34, wherein the compound of formula IIa or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof at about 5 mg / kg to about 25 mg / kg.

36. 36. The method of any one of claims 19 to 35, wherein said compound of formula I is administered to said subject in an amount of about 0.5 to about 100 mg / kg / day for at least one day.

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