WO2023205794A1 - Combination therapy using a pyrimidone derivative as ptpn11 inhibitor and a pd-1/pd-l1 inhibitor and its use in the treatment of cancer - Google Patents

Abstract

The present disclosure provides a method of treating a disease or disorder (e.g., cancer) in a subject. The method including administering to the subject: a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PTPN11 inhibitor is represent by formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein the subscripts a and b, Y₁, Y₂, and R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₃ are as provided herein. In particular, the present disclosure provides a method of treating a solid tumor (e.g., an advanced non-small cell lung cancer) with a therapeutically effective amount of a compound of formula (10b) (i.e., 6-((3S,4JS)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(R _a )-(2,3- dichlorophenyl)-2, 5 -dimethyl-4(3H)-pyrimidinone) in combination with a PD-1/PD-L1 inhibitor (except for nivolumab) in a subject, wherein the subject has one or more mutations in KRAS.

Description

COMBINATION THERAPY USING A PTPN11 INHIBITOR AND A PD-1/PD-L1 INHIBITOR CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/333,958 filed April 22, 2022, which is incorporated herein in its entirety for all purposes. BACKGROUND [0002] Programmed Death-1 (PD-1) is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family. PD-L1 is expressed on antigen-presenting cells as well as many human cancers and has been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1. Inhibition of the PD-1/PD-L1 interaction mediates potent antitumor activity in preclinical models and multiple antibody inhibitors of the PD-1/PD-L1 interaction for treating cancer have been approved for clinical use. Among them, pembrolizumab, which targets PD-1 receptors, has been suggested for treatment of a variety of indications including melanoma, lung cancers, head and neck cancer, Hodgkin lymphoma, and stomach cancer. In particular, pembrolizumab is used to treat inoperable or metastatic melanoma and metastatic non-small cell lung cancer (NSCLC); as a first-line treatment for metastatic bladder cancer in patients who can’t receive cisplatin-based chemotherapy and have high levels of PD-L1; as a second-line treatment for head and neck squamous cell carcinoma (HNSCC), after platinum-based chemotherapy; for the treatment of adult and pediatric patients with refractory classic Hodgkin's lymphoma (cHL); and for recurrent locally advanced or metastatic esophageal squamous cell carcinoma. Pembrolizumab is also approved for use in treating any unresectable or metastatic solid tumor with certain genetic anomalies (mismatch repair deficiency or high microsatellite instability, and high tumor mutational burden). [0003] Protein-tyrosine phosphatase non-receptor type 11 (PTPN11, also known as Src Homology-2 phosphatase (SHP2)) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 plays a key role in the RTK-mediated MAPK signal transduction pathway. This PTP contains two tandem Src homology-2 (SH2) domains, which function as phospho- tyrosine binding domains, a catalytic domain, and a C-terminal tail. In the basal state the protein typically exists in an inactive, self-inhibited conformation with the N-terminal SH2 domain blocking the active site. When stimulated by signal transduction mediated by cytokines and growth factor binding of phosphorylated proteins to the SH2 domains the auto-inhibition is relieved, this makes the active site available for dephosphorylation of PTPN11 substrates (MG Mohl, BG Neel, Curr. Opin. Genetics Dev.2007, 17, 23–30. KS Grossmann, Adv. Cancer Res. 2010, 106, 53-89. W.Q. Huang et. al. Curr. Cancer Drug Targets 2014, 14, 567-588. C. Gordon et. al. Cancer Metastasis Rev.2008, 27, 179-192.). [0004] Germ-line and somatic mutations in PTPN11 have been reported in several human diseases resulting in gain-of-function in the catalytic activity, including Noonan Syndrome and Leopard Syndrome; as well as multiple cancers such as juvenile myelomonocytic leukemia, neuroblastoma, myelodysplastic syndrome, B cell acute lymphoblastic leukemia/lymphoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon (MG Mohl, BG Neel, Curr. Opin. Genetics Dev. 2007, 17, 23–30). Recent studies have demonstrated that single PTPN11 mutations are able to induce Noonan syndrome, JMML-like myeloproliferative disease and acute leukemia in mice. These mutations disrupt the auto-inhibition between the N-SH2 domains and the catalytic site allowing constitutive access of substrates to the catalytic site of the enzyme (E. Darian et al, Proteins, 2011, 79, 1573-1588. Z-H Yu et al, JBC, 2013, 288, 10472, W Qiu et al BMC Struct. Biol.2014, 14, 10). [0005] PTPN11 is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions that includes proliferation, differentiation, cell cycle maintenance, epithelial-mesenchymal transition (EMT), mitogenic activation, metabolic control, transcription regulation, and cell migration, through multiple signaling pathways including the Ras-MAPK, the JAK-STAT or the PI3K-AKT pathways (Tajan, M. et. al. Eur. J. Medical Genetics, 2015, 58, 509-525. Prahallad, A. et. al. Cell Reports, 2015, 12, 1978-1985). [0006] Additionally there is growing evidence that PTPN11/SHP2 is implicated in immune evasion during tumorigenesis, and hence a SHP2 inhibitor could stimulate the immune response in cancer patients (Cancer Res.2015 Feb 1;75(3):508-18. T Yokosuka T, J Exp Med. 2012, 209(6), 1201. S Amarnath Sci Transl Med.2011, 3, 111ra120. T Okazaki, PNAS 2001, 98:24, 13866-71). [0007] However, notwithstanding the treatment options with PD-1/PD-L1 inhibitors, cases of resistance occur. Thus, there remains a need for effective and safe therapeutic agents to treat such cases of resistance. BRIEF SUMMARY [0008] The present disclosure provides methods of treating diseases and disorders (e.g., cancers) by administering both a PTPN11 inhibitor (e.g., a compound of formula (10b), as described herein) and a PD-1/PD-L1 inhibitor. [0009] In one aspect, the present disclosure provides a method of treating cancer in a subject, the method including administering to the subject: a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PTPN11 inhibitor is represent by Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein the subscripts a and b, Y₁, Y₂, and R₁, R₂, R₃, R_4, R₅, R₆, R_7, R₈, R₉, R₁₀, R₁₁, and R₁₃ are as provided herein; and the PD-1/PD-L1 inhibitor is as defined and described herein. [0010] In aother aspect, the present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PD-1/PD-L1 inhibitor is as defined and described herein. In some embodiments, the PD-1/PD-L1 inhibitor is not nivolumab. [0011] In another aspect, the present disclosure provides a method of treating a solid tumor (e.g., an advanced non-small cell lung cancer) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the subject has a KRAS mutation (e.g., as described herein). In some embodiments, the PD-1/PD-L1 inhibitor is not nivolumab. BRIEF DESCRIPTION OF THE DRAWINGS [0012] FIG.1A-FIG.1B show results from a study of the effect of Compound (10b) on CD107a expression of CD8+ T cells. FIG.1A: Donors 1 and 3; and FIG. 1B: Donors 2 and 4. [0013] FIG.2 shows an overall design of a clinical study of Compound (10b) in combination with a PD-1/PD-L1 inhibitor in patients with advanced non-small cell lung cancer with a KRAS mutation, as described in Example 2. [0014] FIG.3 shows a flowchart for a trial conducted using the BOIN Design. Abbreviations: BOIN=Bayesian optimal interval design; DLT=dose limiting toxicity; MTD=maximum tolerated dose. Note: e = 19.7% and d = 29.8%. In practice, with 6 patients/cohort, if the DLT rate is [0015] FIG.4 shows progression-free to tumor burden endpoint after CT-26 KRAS D12C KI tumor-bearing female Balb/c mice were treated with formula (10b) and ANTIBODY A (as an anti-PD-1 therapy), alone or in combination. [0016] FIG.5 shows a statistically significant delay in tumor progression to burden, when CT- 26 KRAS D12C KI tumor-bearing female Balb/c mice were treated with a combination of formula (10b) and ANTIBODY A. [0017] FIG.6 shows tumor volumes after CT-26 KRAS D12C KI tumor-bearing female Balb/c mice were treated with formula (10b) and ANTIBODY A (as an anti-PD-1 therapy), alone or in combination. DETAILED DESCRIPTION I. GENERAL [0018] The present disclosure provides a combination therapy method of treating a disease or disorder (e.g., cancer, such as a solid tumor) in a subject. The method includes administering to the subject a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PTPN11 inhibitor is represented by Formula (I) as defined and described herein (e.g., a compound represented by formula (10b)). The PD-1/PD-L1 inhibitor may at least partially inhibit PD-1/PD-L1 proteins. The PD-1/PD-L1 inhibitor may be a PD-1 inhibitor. The PD-1/PD-L1 inhibitor may be a PD-L1 inhibitor. The PD-1/PD-L1 inhibitor may be a selective PD-1/PD-L1 inhibitor, selectively inhibiting PD-1 and/or PD-L1. The PD-1/PD-L1 inhibitor may inhibit both PD-1 and PD-L1. The PD-1/PD-L1 inhibitor may additionally inhibit PD-L2. Also provided are a pharmaceutical composition thereof and a kit thereof for treating a disease or disorder (e.g., cancer) in a subject. [0019] The present disclosure also provides a method of treating a solid tumor (e.g., an advanced non-small cell lung cancer) with a therapeutically effective amount of a compound of formula (10b) in combination of with a PD-1/PD-L1 inhibitor in a subject, wherein the subject has one or more mutations in KRAS. In particular, the solid tumor is an advanced non-small cell lung cancer (NSCLC) caused by a mutation in KRAS. In some embodiments, the PD-1/PD-L1 inhibitor is not nivolumab. In some embodiments, the cancer is characterized by a KRAS mutation other than a Q61X mutation. II. DEFINITIONS [0020] As used herein, the terms below have the meanings indicated. [0021] Unless specifically indicated otherwise, the group “

as used herein in any one of formulae (e.g., (2b), (10b)), refers to methyl. [0022] “Comprise,” “include,” and “have,” and the derivatives thereof, are used herein interchangeably as comprehensive, open-ended terms. For example, use of “comprising,” “including,” or “having” means that whatever element is comprised, had, or included, is not the only element encompassed by the subject of the clause that contains the verb. [0023] When ranges of values are disclosed, and the notation “from n1 … to n2” or “between n1 … and n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 µM (micromolar),” which is intended to include 1 µM, 3 µM, and everything in between to any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.). [0024] “About,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures. [0025] “Alkenyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms. The term “alkenylene” refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(-CH⁼CH-),(-C::C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups. [0026] “Alkynyl” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond and having the number of carbon atom indicated (i.e., C_2-6 means to two to six carbons). Alkynyl can include any number of carbons, such as C₂, C_2-3, C_2-4, C_2-5, C_2-6, C_2-7, C_2-8, C_2-9, C_2-10, C₃, C_3-4, C_3-5, C_3-6, C₄, C_4-5, C_4-6, C₅, C_5-6, and C₆. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, and 1,3,5-hexatriynyl. [0027] “Alkoxy,” as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like. [0028] “Alkyl,” as used herein, alone or in combination, refers to a straight-chain or branched- chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 8 carbon atoms. Alkyl groups are unsubstituted or substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH₂-). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. [0029] “Alkylamino,” as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N- ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like. [0030] “Amido” and “carbamoyl,” as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The “amido” group as used herein incudes a “C-amido” and “N-amido” groups. The term “C-amido” as used herein, alone or in combination, refers to a -C(O)N(RR’) group with R and R’ as defined herein or as defined by the specifically enumerated “R” groups designated. In some embodiments, the “amido” group includes -C(O)NH₂, C_1-4alkylamido, and di(C_{1- 4}alkyl)amido. The term “C_1-4alkylamido”, as used herein, refers to -C(O)NH(C_1-4alkyl), wherein C_1-4alkyl is as defined herein. The term “N-amido” as used herein, alone or in combination, refers to a RC(O)N(R’)- group, with R and R’ as defined herein or as defined by the specifically enumerated “R” groups designated. The term "acylamino" as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH₃C(O)NH-). [0031] “Amino,” as used herein, alone or in combination, refers to -NRR^’, wherein R and R^’ are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be unsubstituted or substituted. Additionally, R and R’ may combine to form heterocycloalkyl, either of which is unsubstituted or substituted. [0032] “Aryl,” as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl. [0033] “Cyano,” as used herein, alone or in combination, refers to -CN. [0034] “Cycloalkyl,” or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is unsubstituted or substituted as defined herein. The term “cycloalkenyl” refers to a cycloalkyl group having one or two double bonds. In certain embodiments, said cycloalkyl (or cycloalkenyl) will comprise from 5 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3- dihydro-1H-indenyl, adamantyl and the like. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane. [0035] “Halo,” or “halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine. [0036] “Haloalkoxy,” as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. [0037] “Haloalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro, or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF₂ -), chloromethylene (-CHCl-) and the like. [0038] “Heteroaryl,” as used herein, alone or in combination, refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from N, O, and S. In certain embodiments, said heteroaryl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heteroaryl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heteroaryl will comprise from 5 to 7 atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like. [0039] “Heterocycloalkyl” and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, said heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said heterocycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups are unsubstituted or substituted unless specifically prohibited. [0040] “Hydroxy,” as used herein, alone or in combination, refers to -OH. [0041] “Hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group. [0042] “Oxo,” as used herein, alone or in combination, refers to =O. [0043] “Ring,” or equivalently, “cycle,” as used herein, in reference to a chemical structure or portion thereof, means a group in which every atom is a member of a common cyclic structure. A ring can be saturated or unsaturated, including aromatic, unless otherwise provided, and may have between 3 and 9 members. If the ring is a heterocycle, it may contain between 1 and 4 heteroatoms or heteroatom-comprising groups selected from B, N, O, S, C(O), S(O)m. Unless specifically prohibited, a ring is unsubstituted or substituted. [0044] “Sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein, alone or in combination, refer to the –SO₃H group and its anion as the sulfonic acid is used in salt formation. [0045] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group. [0046] “Bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position. [0047] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the present disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by various techniques. Additionally, the compounds disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this disclosure. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms. [0048] “Tautomer”, as use herein, alone or in combination, refers to one of two or more isomers that rapidly interconvert. Generally, this interconversion is sufficiently fast so that an individual tautomer is not isolated in the absence of another tautomer. The ratio of the amount of tautomers can be dependent on solvent composition, ionic strength, and pH, as well as other solution parameters. The ratio of the amount of tautomers can be different in a particular solution and in the microenvironment of a biomolecular binding site in said solution. Examples of tautomers include keto / enol, enamine / imine, and lactam / lactim tautomers. Additional examples of tautomers include 2-hydroxypyridine / 2(1H)-pyridone and 2-aminopyridine / 2(1H)-iminopyridone tautomers. [0049] Conformational isomers exist in the compounds disclosed herein. When R₁ is aryl or heteroaryl in the formula:

, the aryl or heteroaryl group can orient in different conformations in relation to the pyrimidinone moiety, as represented by:

These forms are designated by the symbols “S_a” or “R_a”, depending on the conformation of the aryl or heteroaryl group in relation to the pyrimidinone moeity. Examples of “S_a” and “R_a” forms can be found in Examples 1-20 of International Patent Application No. PCT/US2019/045903, which is incorporated herein in its entirety for all purposes. The compound of formula (10b) is substantially in a “R_a” form. [0050] “Pharmaceutically acceptable” refers to those compounds (salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The compounds disclosed herein can exist as pharmaceutically acceptable salts, as defined and described herein. [0051] “Salt” refers to acid or base salts of the compounds of the present disclosure. Illustrative examples of pharmaceutically acceptable acid addition salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts and organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference. [0052] “Solvate” refers to a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. [0053] “Hydrate” refers to a compound that is complexed to a water molecule. The compounds of the present disclosure can be complexed with ½ water molecule or from 1 to 10 water molecules. [0054] “ Combination therapy” means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0055] ‘ ‘PTPN11 inhibitor” is used herein to refer to a compound that exhibits an IC₅₀ with respect to PTPN11 activity of no more than about 100 micromolar (pM) and more typically not more than about 50 pM, as measured in the PTPN11 assay described generally in International Patent Application No. PCT/US2019/045903 (e.g., the enzymatic activity of recombinant human PTPN11 proteins of Example 21). “IC₅₀” is that concentration of inhibitor which reduces the activity of an enzyme (e.g., PTPN11) to half-maximal level. In certain embodiments, compounds exhibit disclosed in PCT/US2019/045903 exhibit an IC₅₀ of no more than about 10 pM for inhibition of PTPN11; in further embodiments, compounds exhibit an IC₅₀ of no more than about 1 pM for inhibition of PTPN11; in yet further embodiments, compounds exhibit an IC₅₀ of not more than about 200 nM for inhibition of PTPN11; in yet further embodiments, compounds exhibit an IC₅₀ of not more than about 100 nM for inhibition of PTPN11; and in yet further embodiments, compounds exhibit an IC₅₀ of not more than about 50 nM for inhibition of PTPN11, as measured in the PTPN11 assay described therein. In certain embodiments, the compound of formula (2b) exhibits an IC₅₀ of no more than 150 nM for inhibition of PTPN11 (e.g., a PTPN11-E76K mutant enzyme). In certain embodiments, the compound of formula (10b) exhibits an IC₅₀ of no more than 50 nM for inhibition of PTPN11 (e.g., a PTPN11-E76K mutant enzyme).

[0056] “Therapeutically effective amount” refers to an amount of a compound or of a pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0057] “Treat”, “treating”, and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; and/or improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, assay (e.g., analysis of a fluid of a subject, such as blood, plasma, or urine), imaging analysis, neuropsychiatric exams, and/or a psychiatric evaluation. [0058] “Administering” refers to therapeutic provision of the compound or a form thereof to a subject, such as by oral administration or intravenous administration. [0059] “Patient” or “subject” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, non-human primates (e.g., monkeys), goats, pigs, sheep, cows, deer, horses, bovines, rats, mice, rabbits, hamsters, guinea pigs, cats, dogs, and other non-mammalian animals. In some embodiments, the subject is human. In some embodiments, a subject is an adult (e.g., at least 18 years of age). [0060] “Composition,” as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. [0061] “Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors. Other pharmaceutical excipients can be useful in the present disclosure. [0062] “Tablet” refers to solid pharmaceutical formulations with and without a coating. The term “tablet” also refers to tablets having one, two, three or even more layers, wherein each of the before mentioned types of tablets may be without or with one or more coatings. In some embodiments, tablets of the present disclosure can be prepared by roller compaction or other suitable means known in the art. The term “tablet” also comprises mini, melt, chewable, effervescent, and orally disintegrating tablets. Tablets include the compound of Formula (I) or formula (10b) and one or more pharmaceutical excipients (e.g., fillers, binders, glidants, disintegrants, surfactants, binders, lubricants, and the like). Optionally, a coating agent can be also included. For the purposes of calculating percent weight of the tablet formulation, the amount of coating agent is not included in the calculation. That is, the percent weights reported herein are of the uncoated tablet. [0063] Unless specifically indicated otherwise, the content of the compound of Formula (I) or formula (10b) in, e.g., a tablet formulation is calculated based on the normalized weight of the compound of Formula (I) or formula (10b) on a salt-free and anhydrous basis. That is, the salt and/or water content in the compound of Formula (I) or formula (10b) is not included in the calculation. [0064] “PD-1/PD-L1 inhibitor” (also known as immune checkpoint inhibitors) as used herein refers to a compound which targets, decreases, or inhibits the synthesis or biological activity of programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1). PD-1 has two ligands, PD-L1 and PD-L2. The PD-1/PD-L1 inhibitor blocks PD-L1 and/or PD-L2 binding to PD-1. The PD-1/PD-L1 inhibitor may at least partially inhibit PD-1 and/or PD-L1. The PD- 1/PD-L1 inhibitor may be a PD-1 inhibitor. The PD-1/PD-L1 inhibitor may be a PD-L1 inhibitor. The PD-1/PD-L1 inhibitor may be a selective PD-1/PD-L1 inhibitor. In those cases, the selective PD-1/PD-L1 inhibitor may have high potency for PD-1/PD-L1, along with low affinity for related programmed death-ligand 2 (PD-L2). [0065] “PD-L1-positive cancer” refers to a cancer with expression or overexpression of PD-L1. [0066] “A cancer resistant to a PD-1/PD-L1 inhibitor”, “a cancer that is a PD-1/PD-L1- positive cancer resistant to a PD-1/PD-L1 inhibitor”, and/or “a cancer that is a KRAS-positive cancer resistant to a PD-1/PD-L1 inhibitor” refer to a cancer or tumor that either fails to respond favorably to treatment with a prior PD-1/PD-L1 inhibitor, or alternatively, recurs or relapses after responding favorably to a PD-1/PD-L1 inhibitor. [0067] “KRAS-positive cancer” refers to a cancer with the KRAS gene rearranged, mutated, or amplified. “KRAS G12C-positive cancer” refers to a cancer with the KRAS G12C gene rearranged, mutated, or amplified. [0068] “A cancer resistant to a KRAS inhibitor” and/or “a cancer that is a KRAS-positive cancer resistant to a KRAS inhibitor” refer to a cancer or tumor that either fails to respond favorably to treatment with a prior KRAS inhibitor, or alternatively, recurs or relapses after responding favorably to a KRAS inhibitor. “A cancer resistant to a KRAS G12C inhibitor” and/or “a cancer that is a KRAS G12C-positive cancer resistant to a KRAS G12C inhibitor” refer to a cancer or tumor that either fails to respond favorably to treatment with a prior KRAS G12C inhibitor, or alternatively, recurs or relapses after responding favorably to a KRAS G12C inhibitor. [0069] “Jointly therapeutically effective amount” as used herein means the amount at which the therapeutic agents, when given separately (in a chronologically staggered manner, especially a sequence-specific manner) to a warm-blooded animal, especially to a human to be treated, show an (additive, but preferably synergistic) interaction (joint therapeutic effect). Whether this is the case can be determined inter alia by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals. [0070] “Synergistic effect” as used herein refers to an effect of at least two therapeutic agents: a PTPN11 inhibitor as defined herein; and a PD-1/PD-L1 inhibitor as defined herein, which is greater than the simple addition of the effects of each drug administered by themselves. The effect can be, for example, slowing the symptomatic progression of a proliferative disease, such as cancer, particularly lung cancer (e.g., non-small cell lung cancer), or symptoms thereof. Analogously, a “synergistically effective amount” refers to the amount needed to obtain a synergistic effect. [0071] “A,” “an,” or “a(n)”, when used in reference to a group of substituents or “substituent group” herein, mean at least one. For example, where a compound is substituted with “an” alkyl or aryl, the compound is substituted with at least one alkyl and/or at least one aryl, wherein each alkyl and/or aryl is optionally different. In another example, where a compound is substituted with “a” substituent group, the compound is substituted with at least one substituent group, wherein each substituent group is optionally different. III. COMBINATION THERAPY [0072] In one aspect, the present disclosure provides a method of cancer in a subject. The method includes administering to the subject: a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PTPN11 inhibitor is represent by formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: subscript a is 0 or 1; subscript b is 0 or 1; Y₁ is a direct bond or CR₁₇R₁₈; Y₂ is selected from the group consisting of C_1-4alkyl, amino, C_1-4alkylC(O)O-, C_1-4alkylamino and C_1-4aminoalkyl; R₁ is selected from the group consisting of C_6-10aryl, C_3-8cycloalkyl, C_3-8cycloalkenyl, and a 5-10 membered heteroaryl group having 1 to 4 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S; said aryl or heteroaryl of R₁ is unsubstituted or substituted with 1 to 5 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di( C_1-4alkyl)amino, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4haloalkyl, C_1-4aminoalkyl, C_3-8cycloalkyl, C_3-8cycloalkenyl, NR₁₅C(O)R₁₄, NR₁₅C(O)OR₁₄, NR₁₄C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₄, NR₁₅S(O)₂R₁₄, C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R_16, C(O)R_14, C(O)OR_14, OR₁₄, SR₁₄, S(O)R₁₄, and S(O)₂R₁₄; R₂, R₃, R₁₀, and R₁₁ are each independently selected from the group consisting of hydrogen, C_1-4alkyl, and C_3-8cycloalkyl; R₄, R₅, R₈, and R₉ are each independently selected from the group consisting of hydrogen, cyano, C_1-4alkyl, C_1-4alkoxy, amino, hydroxy, C_3-8cycloalkyl, halo, and C_1-4alkylamino; R₆ is selected from the group consisting of amino, C_1-4aminoalkyl, and C_1-4alkylamino; R₇ is selected from the group consisting of hydrogen, amido, cyano, halo, and hydroxy, or is selected from the group consisting of C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino, and C_1-4aminoalkyl; or R₆ and R₇ together with the carbon atom to which they are both attached form a 3- to 7- membered saturated or unsaturated ring, having 0 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O)_m; subscript m is 0, 1, or 2; and said saturated or unsaturated ring formed by R₆ and R₇ is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; any two groups of R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₁ can form a 5 to 6 membered ring, having 0 to 2 heteroatoms as ring vertices elected from N, O and S; any two groups of R₂, R₄, R₆, R₈ and R₁₀ can form a direct bond, or a 1 or 2 atom carbon bridge; R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6 dihydroxyalkyl, -NH-NHR₁₉, -NHR₁₉, -OR₁₉, -NHC(O)R₁₉, -NHC(O)NHR₁₉, -NHS(O)2NHR₁₉, -NHS(O)2R₁₉, -C(O)OR₁₉, -C(O)NR₁₉R₂₀, -C(O)NH(CH₂)qOH, -C(O)NH(CH₂)qR₂₁, -C(O)R₂₁, -NH₂, -OH, -S(O)2NR₁₉R₂₀, C_3-8cycloalkyl, aryl, heterocyclyl having 1-5 heteroatoms as ring vertices selected from N, O, S and P, and heteroaryl having 1-5 heteroatoms as ring vertices selected from N, O, S and P; subscript q is an integer of from 0 to 6; and each of aryl, heteroaryl, heterocyclyl and cycloalkyl of R₁₃ is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of C_1-4alkyl, –OH, -NH₂, -OR₂₁, halo, cyano, and oxo; R₁₄, R₁₅ and R₁₆ are each independently selected from the group consisting of hydrogen, C_1-4alkyl, C_3-8cycloalkyl, C_6-10aryl and 5-10 membered heteroaryl, any of which is unsubstituted or substituted with one or more groups independently selected from the group consisting of amido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; R₁₇ and R₁₈ are each independently selected from the group consisting of hydrogen, C_1-4alkyl, and CF₃; R₁₉ and R₂₀ are each independently selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl and C_3-6cycloalkyl; and each R₂₁ is independently selected from the group consisting of hydrogen, -OH, C_1-6 alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl and C_3-6cycloalkyl. [0073] In aother aspect, the present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PD-1/PD-L1 inhibitor is as defined and described herein. [0074] In another aspect, the present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the subject has a KRAS mutation (e.g., as described herein). III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors [0075] The PTPN11 inhibitor represented by Formula (I) is further described according to Section IV. Compounds. In some embodiments, the PTPN11 inhibitor of Formula (I) is any one of embodiments as described in Section IV. Compounds. [0076] In some embodiments, the PTPN11 inhibitor is represented by formula (2b):

or a pharmaceutically acceptable salt, stereoisomer, conformational isomer, or a combination thereof. [0077] In some embodiments, the PTPN11 inhibitor is represented by formula (2b):

having the name of 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(R_a)-(2,3- dichlorophenyl)-2-methyl-4(3H)-pyrimidinone. [0078] In some embodiments, the PTPN11 inhibitor is represented by formula (10b):

or a pharmaceutically acceptable salt, stereoisomer, conformational isomer, or a combination thereof. [0079] The compound of any one of Formula (I), formula (2b), and formula (10b) can be in a pharmaceutically acceptable salt form or in a neutral form, each of which is optionally in a solvate or a hydrate form. [0080] In some embodiments, the compound of any one of Formula (I), formula (2b), and formula (10b) is in a pharmaceutically acceptable salt form. In some embodiments, a pharmaceutically acceptable acid addition salt of the compound of formula (10b) is represented by formula (10b-HX):

wherein HX is a pharmaceutically acceptable acid addition. [0081] Examples of acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. [0082] In some embodiments, the compound of any one of Formula (I), formula (2b), and formula (10b) is in a neutral form. In some embodiments, the compound of formula (10b) is in a neutral form. [0083] In some embodiments, the compound of formula (10b) has a substantially moiety of 6- ((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl) with stereochemistry as shown in formula (10b):

[0084] In some embodiments, the compound of formula (10b) is substantially in a R_a conformation as shown in formula (10b):

[0085] In some embodiments, the compound of formula (10b) is represented by the formula:

having the name of 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(R_a)-(2,3- dichlorophenyl)-2,5-dimethyl-4(3H)-pyrimidinone. [0086] In some embodiments, the compound of formula (10b) includes one or more corresponding enantiomer, diastereomers, and/or conformational isomers, as represented by formulae, respectively:

[0087] In some embodiments, the compound of formula (10b) has a purity of at least about 95 area% determined by a chiral high-performance liquid chromatography (HPLC). In some embodiments, the compound of formula (10b) has a purity of from about 95 area% to about 99 area%, from about 96 area% to about 99 area%, from about 97 area% to about 99 area%, or from about 98 area% to about 99 area%, determined by a chiral high-performance liquid chromatography (HPLC). In some embodiments, the compound of formula (10b) has a purity of from about 98 area% to about 99 area%. [0088] In some embodiments, the compound of formula (10b) includes one or more corresponding enantiomer, diastereomers, and/or conformational isomers, as represented by the formulae above; and a total of the one or more isomers is no more than about 5 area% determined by a chiral high-performance liquid chromatography (HPLC). [0089] In some embodiments, the corresponding enantiomer, diastereomers, and/or conformational isomers of the compound of formula (10b) are present in the compound of formula (10b) meet acceptance criteria as follows: enantiomer (3R, 4R, S_a) ≤ 0.5 area%; diastereomer (3R, 4S, R_a) ≤ 1.2 area%; diastereomer (3S, 4R, S_a) ≤ 0.5 area%; diastereomer (3R, 4R, R_a) ≤ 0.5 area%; diastereomer (3S, 4S, S_a) ≤ 0.5 area%; diastereomer (3S, 4R, R_a) ≤ 0.5 area%; and diastereomer (3R, 4S, S_a) ≤ 0.5 area%, each of which is determined by a chiral high- performance liquid chromatography (HPLC). In some embodiments, the compound of formula (10b) has a purity of at least about 95 area%, wherein enantiomer (3R, 4R, S_a) < 0.5 area%; diastereomer (3R, 4S, R_a) < 1.2 area%; diastereomer (3S, 4R, S_a) < 0.5 area%; diastereomer (3R, 4R, R_a) < 0.5 area%; diastereomer (3S, 4S, S_a) < 0.5 area%; diastereomer (3S, 4R, R_a) < 0.5 area%; and diastereomer (3R, 4S, S_a) < 0.5 area%, each of which is determined by a chiral high- performance liquid chromatography (HPLC). In some embodiments, the compound of formula (10b) has a purity of from about 95 area% to about 99 area%, from about 96 area% to about 99 area%, from about 97 area% to about 99 area%, or from about 98 area% to about 99 area%, wherein enantiomer (3R, 4R, S_a) < 0.5 area%; diastereomer (3R, 4S, R_a) < 1.2 area%; diastereomer (3S, 4R, S_a) < 0.5 area%; diastereomer (3R, 4R, R_a) < 0.5 area%; diastereomer (3S, 4S, S_a) < 0.5 area%; diastereomer (3S, 4R, R_a) < 0.5 area%; and diastereomer (3R, 4S, S_a) < 0.5 area%, each of which is determined by a chiral high-performance liquid chromatography (HPLC). In some embodiments, the compound of formula (10b) has a purity of from about 98 area% to about 99 area%, wherein enantiomer (3R, 4R, S_a) is not detected; diastereomer (3R, 4S, R_a) is about 0.86 area%; diastereomer (3S, 4R, S_a) is not detected; diastereomer (3R, 4R, R_a) is about 0.07 area%; diastereomer (3S, 4S, S_a) is not detected; diastereomer (3S, 4R, R_a) is not detected; and diastereomer (3R, 4S, S_a) is not detected, each of which is determined by a chiral high-performance liquid chromatography (HPLC). [0090] In some embodiments, the compound of any one of Formula (I), formula (2b), formula (10b), and formula (10b-HX) is in a solvate and/or a hydrate form. [0091] The PD-1/PD-L1 inhibitor can be an inhibitor described for use in the treatment of a cancer. In some embodiments, the PD-1/PD-L1 inhibitor at least partially inhibits PD-1 and/or PD-L1 proteins. In some embodiments, the PD-1/PD-L1 inhibitor additionally inhibits PD-L2. In some embodiments, the PD-1/PD-L1 inhibitor is a selective PD-1/PD-L1 inhibitor, selectively inhibiting PD-1 and/or PD-L1. In some embodiments, the PD-1/PD-L1 inhibitor is a PD-1 inhibitor. In some embodiments, the PD-1/PD-L1 inhibitor is a PD-L1 inhibitor. In some embodiments, the PD-1/PD-L1 inhibitor inhibits both PD-1 and PD-L1. [0092] In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, or tebotelimab. In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab. In some embodiments, the PD-1/PD-L1 inhibitor is not nivolumab, when the PTPN11 inhibitor is a compound of formula (10b). [0093] In some embodiments, the PTPN11 inhibitor is represented by formula (2b); and the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, or tebotelimab. In some embodiments, the PTPN11 inhibitor is represented by formula (2b); and the PD-1/PD-L1 inhibitor is pembrolizumab. In some embodiments, the PTPN11 inhibitor is represented by formula (2b); and the PD-1/PD-L1 inhibitor is nivolumab. [0094] In some embodiments, the PTPN11 inhibitor is represented by formula (10b); and the PD-1/PD-L1 inhibitor is pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab- rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, or tebotelimab. In some embodiments, the PTPN11 inhibitor is represented by formula (10b); and the PD-1/PD-L1 inhibitor is pembrolizumab. III-2. Cancer/Solid Tumor [0095] The cancer can be any cancer that responds to the treatment of a PTPN11 inhibitor and/or a PD-1/PD-L1 inhibitor. In some embodiments, the cancer expresses PD-L1. In some embodiments, the cancer is characterized by a high level of microsatellite instability (MSI-H), a deficient mismatch repair (dMMR), a high level of tumor mutational burden (TMB-H), or a combination thereof. In some embodiments, the cancer is characterized by a high level of microsatellite instability (MSI-H). In some embodiments, the cancer is characterized by a deficient mismatch repair (dMMR). In some embodiments, the cancer is characterized by a high level of tumor mutational burden (TMB-H). In some embodiments, the cancer is caused and/or characterized by a KRAS mutation, such as a KRAS G12C mutation. In some embodiments, the cancer is characterized by a KRAS mutation other than a Q61X mutation. In some embodiments, the cancer is a PD-L1-positive cancer. In some embodiments, the cancer is a KRAS-positive cancer. In some embodiments, the cancer is a KRAS G12C-positive cancer (e.g., a cancer characterized by a G12C mutation in KRAS). [0096] In some embodiments, the cancer is characterized by a KRAS mutation, such as a mutation in codon 12, 13, or 61 (e.g., a G12C, G12D, G12S, G12V, G12R, G12A, G12F, G12I, G12L, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation). In some embodiments, the cancer is characterized by a KRAS mutation selected from a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, and a combination thereof. In some embodiments, the cancer is characterized by a KRAS G12C mutation. In some embodiments, the KRAS protein does not comprise a mutation at Q61. [0097] The cancer can be characterized by a solid tumor and/or a liquid tumor. In some embodiments, the cancer includes a solid tumor. In some embodiments, the cancer includes a liquid tumor. [0098] In some embodiments, the cancer is anal cancer, biliary tract cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer (CRC), endometrial cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), merkel cell carcinoma, melanoma, mesothelioma, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, renal cell carcinoma (RCC), small cell lung cancer (SCLC), squamous cell carcinoma (SCC), triple negative breast cancer (TNBC), Hodgkin’s lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), diffuse large B-cell lymphoma (DLBCL), or a combination thereof. In some embodiments, the cancer is anal cancer, biliary tract cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer (CRC), endometrial cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), merkel cell carcinoma, melanoma, mesothelioma, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, renal cell carcinoma (RCC), small cell lung cancer (SCLC), squamous cell carcinoma (SCC), triple negative breast cancer (TNBC), or a combination thereof. In some embodiments, the cancer is Hodgkin’s lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), diffuse large B-cell lymphoma (DLBCL), or a combination thereof. In some embodiments, the cancer is Hodgkin’s lymphoma. In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). [0099] In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). [0100] In some embodiments, the cancer is colorectal cancer (CRC) characterized by a KRAS mutation, such as a mutation in codon 12 (e.g., KRAS G12C, G12D, or G12R). [0101] In some embodiments, the cancer is NSCLC characterized by a KRAS mutation, such as a KRAS G12C mutation. In some embodiments, a KRAS protein includes a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation. In some embodiments, a KRAS protein includes a G12C, G12D, or G12V mutation. In some embodiments, the cancer is NSCLC characterized by a G12C, G12D, or G12V mutation in KRAS. In some embodiments, the cancer is NSCLC characterized by a mutation in an epidermal growth factor receptor (EGFR) protein. In some embodiments, the cancer is NSCLC that is not characterized by a mutation in EGFR, KRAS, or anaplastic lymphoma kinase (ALK). [0102] The cancer can also be any cancer that is resistant to the treatment of a PD-1/PD-L1 inhibitor. In some embodiments, the cancer is resistant to a PD-1/PD-L1 inhibitor as defined and described herein. In some embodiments, the cancer is characterized by intrinsic and/or acquired resistance to a PD-1/PD-L1 inhibitor. In some embodiments, the cancer is a PD-1/PD-L1- positive cancer resistant to a PD-1/PD-L1 inhibitor. In some embodiments, the cancer is a PD- 1/PD-L1-positive cancer characterized by intrinsic and/or acquired resistance to a PD-1/PD-L1 inhibitor. In some embodiments, the cancer is a KRAS-positive cancer resistant to a PD-1/PD- L1 inhibitor. In some embodiments, the cancer is a KRAS-positive cancer characterized by intrinsic and/or acquired resistance to a PD-1/PD-L1 inhibitor. [0103] In some embodiments, the cancer is resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, and tebotelimab. In some embodiments, the cancer is resistant to pembrolizumab. In some embodiments, the cancer is resistant to nivolumab. [0104] In some embodiments, the cancer is a PD-L1-positive cancer resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, and tebotelimab. In some embodiments, the cancer is a PD-L1-positive cancer resistant to pembrolizumab. In some embodiments, the cancer is a PD-L1-positive cancer resistant to nivolumab. [0105] In some embodiments, the cancer is a KRAS-positive cancer resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, and tebotelimab. In some embodiments, the cancer is a KRAS-positive cancer resistant to pembrolizumab. In some embodiments, the cancer is a KRAS-positive cancer resistant to nivolumab. [0106] In some embodiments, the cancer is characterized by intrinsic and/or acquired resistance to another therapy such as a KRAS modulator, platinum-based therapy, or taxane therapy. [0107] The solid tumor can be any solid tumor that responds to the treatment of a PTPN11 inhibitor and an anti-PD-1/PD-L1 agent (e.g., nivolumab). In some embodiments, the solid tumor is a tumor with one or more genes in KRAS rearranged, mutated, or amplified, provided that the tumor is other than caused by one or more additional activating mutations in BRAF V600X, PTPN11 (SHP2), or KRAS Q61X. [0108] In some embodiments, the solid tumor is an advanced non-small cell lung cancer (NSCLC) caused by a mutation in KRAS. In some embodiments, the solid tumor is an advanced non-small cell lung cancer (NSCLC) caused by a mutation in KRAS, provided that the tumor is other than caused by one or more additional activating mutations in BRAF V600X, PTPN11 (SHP2), or KRAS Q61X. In some embodiments, the solid tumor is a KRAS G12C-positive solid tumor. In some embodiments, the solid tumor is an advanced or metastatic KRASG12C-positive non-small cell lung cancer (NSCLC). [0109] The solid tumor can also be any tumor that is resistant to the treatment of a KRAS G12C inhibitor (e.g., sotorasib (AMG-510), adagrasib (MRTX-849), MRTX1257, ARS-853, ARS-1620, JNJ-74699157(ARS-3248), LY3537982, and LY3499446). In some embodiments, the solid tumor is resistant to a KRAS G12C inhibitor. In some embodiments, the solid tumor is characterized by intrinsic and/or acquired resistance to a KRAS G12C inhibitor as defined and described herein. In some embodiments, the solid tumor is a KRAS G12C-positive solid tumor resistant to a KRAS G12C inhibitor. In some embodiments, the solid tumor is a KRAS G12C- positive solid tumor characterized by intrinsic and/or acquired resistance to a KRAS G12C inhibitor. In some embodiments, the solid tumor is resistant to the treatment of a KRAS G12C inhibitor selected from the group consisting of sotorasib (AMG-510), adagrasib (MRTX-849), MRTX1257, ARS-853, ARS-1620, JNJ-74699157(ARS-3248), LY3537982, and LY3499446. In some embodiments, the solid tumor is resistant to sotorasib (AMG-510). In some embodiments, the solid tumor is resistant to adagrasib (MRTX-849). In some embodiments, the solid tumor is a KRAS-positive solid tumor resistant to the treatment of a KRAS G12C inhibitor selected from the group consisting of sotorasib (AMG-510), adagrasib (MRTX-849), MRTX1257, ARS-853, ARS-1620, JNJ-74699157(ARS-3248), LY3537982, and LY3499446. In some embodiments, the solid tumor is a KRAS-positive solid tumor resistant to sotorasib (AMG-510). In some embodiments, the solid tumor is a KRAS-positive solid tumor resistant to adagrasib (MRTX-849). In some embodiments, the solid tumor is a KRAS G12C-positive solid tumor resistant to the treatment of a KRAS G12C inhibitor selected from the group consisting of sotorasib (AMG-510), adagrasib (MRTX-849), MRTX1257, ARS-853, ARS-1620, JNJ- 74699157(ARS-3248), LY3537982, and LY3499446. In some embodiments, the solid tumor is a KRAS G12C-positive solid tumor resistant to sotorasib (AMG-510). In some embodiments, the solid tumor is a KRAS G12C-positive solid tumor resistant to adagrasib (MRTX-849). [0110] The solid tumor can also be any tumor that is resistant to the treatment of a PD-1/PD- L1 inhibitor (e.g., pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, and tebotelimab). In some embodiments, the solid tumor is resistant to a PD-1/PD-L1 inhibitor as defined and described herein. In some embodiments, the solid tumor is characterized by intrinsic and/or acquired resistance to a PD-1/PD-L1 inhibitor as defined and described herein. In some embodiments, the solid tumor is a PD-1/PD-L1-positive solid tumor resistant to a PD-1/PD-L1 inhibitor. In some embodiments, the solid tumor is a PD-1/PD-L1-positive solid tumor characterized by intrinsic and/or acquired resistance to a PD-1/PD-L1 inhibitor. In some embodiments, the solid tumor is a KRAS-positive solid tumor resistant to a PD-1/PD-L1 inhibitor. In some embodiments, the solid tumor is a KRAS-positive solid tumor characterized by intrinsic and/or acquired resistance to a PD-1/PD-L1 inhibitor. [0111] In some embodiments, the solid tumor is resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, and tebotelimab. In some embodiments, the solid tumor is resistant to pembrolizumab. In some embodiments, the solid tumor is resistant to nivolumab. In some embodiments, the solid tumor is a PD-L1-positive solid tumor resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, and tebotelimab. In some embodiments, the solid tumor is a PD-L1-positive solid tumor resistant to pembrolizumab. In some embodiments, the solid tumor is a PD-L1-positive solid tumor resistant to nivolumab. [0112] In some embodiments, the solid tumor is a KRAS-positive solid tumor resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, and tebotelimab. In some embodiments, the solid tumor is a KRAS- positive solid tumor resistant to pembrolizumab. In some embodiments, the solid tumor is a KRAS-positive solid tumor resistant to nivolumab. [0113] In any one of embodiments, a standard of care or curative therapy is unavailable for treating cancer or a solid tumor, as described herein. III-3: Subject [0114] In some embodiments, the subject is human. In some embodiments, the subject is under the care of a medical practitioner, such as a physician. In some embodiments, the subject has been diagnosed with the cancer. In some embodiments, the subject has relapsed. In some embodiments, the subject has previously entered remission. In some embodiments, the subject has previously undergone, is undergoing, or will undergo a monotherapy course of treatment. In some embodiments, the subject has previously undergone, is undergoing, or will undergo radiation therapy. In some embodiments, the subject has previously undergone, is undergoing, or will undergo immunotherapy. In some embodiments, the subject has previously undergone, is undergoing, or will undergo chemotherapy. In some embodiments, the subject has previously undergone, is undergoing, or will undergo a platinum-based chemotherapy. In some embodiments, the subject has previously undergone, is undergoing, or will undergo a therapeutic regimen comprising administration of a KRAS modulator (e.g., KRAS inhibitor). In some embodiments, the subject has previously undergone, is undergoing, or will undergo a therapeutic regimen comprising administration of an anti-PD-1/PD-L1 inhibitor (e.g., checkpoint inhibitor). [0115] The subject can have an advanced (e.g., primary or recurrent) solid tumor with a KRAS mutation (e.g., excluding KRAS Q61X) as assessed by molecular diagnostic using an appropriate clinically validated and/or FDA approved test and with no available standard of care or curative therapies. In some embodiments, the subject has a mutation in KRAS (excluding KRAS Q61X), as assessed by molecular diagnostic using an appropriate clinically validated and/or FDA approved test within at least one (1) year prior to the admission to the treatment as described herein. [0116] In some embodiments, the subject has a mutation in KRAS, provided that the mutation is other than KRAS Q61X (e.g., the subject has a cancer characterized by a mutation in KRAS other than KRAS Q61X). In some embodiments, a KRAS protein includes a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, and/or G13V mutation (e.g., the subject has a cancer characterized by a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, and/or G13V mutation in KRAS). In some embodiments, subject has a KRAS mutation including a KRAS G12C mutation. In some embodiments, subject has a KRAS mutation including a KRAS G12A mutation, a KRAS G12D mutation, a KRAS G12F mutation, a KRAS G12I mutation, a KRAS G12L mutation, a KRAS G12R mutation, a KRAS G12S mutation, a KRAS G12V mutation, a KRAS G12Y mutation, a KRAS G13D mutation, or a combination thereof (e.g., the subject has a cancer characterized by a KRAS mutation including a KRAS G12C mutation, a KRAS G12A mutation, a KRAS G12D mutation, a KRAS G12F mutation, a KRAS G12I mutation, a KRAS G12L mutation, a KRAS G12R mutation, a KRAS G12S mutation, a KRAS G12V mutation, a KRAS G12Y mutation, a KRAS G13D mutation, or a combination thereof). [0117] In some embodiments, the subject has the solid tumor progressed or recurred on or after at least one prior line of a systemic therapy including a platinum-based doublet chemotherapy and/or an anti-PD-1/PD-L1 therapy, each of which is given in monotherapy or both of which are given in combination therapy. [0118] In some embodiments, the subject has the solid tumor progressed or recurred during a treatment of an anti-PD-1/PD-L1 therapy or within about 90 days after discontinuing an anti-PD- 1/PD-L1 therapy. [0119] In some embodiments, the subject has a measurable disease according to response evaluation criteria in solid tumors (RECIST). [0120] In some embodiments, the subject has not previously participated in an interventional clinical study within a period of at least about four (4) weeks or five (5) half-lives of an agent used in the interventional clinical study, whichever is shorter prior to initiation of the treatment with the compound of Formula (I) or formula (10b) in combination with the PD-1/PD-L1 inhibitor. [0121] In some embodiments, the subject has not previously received a radiotherapy or a proton therapy including i) a limited field of radiation for palliation within a period of about one (1) week, or ii) a radiation to more than about 30% of bone marrow or a wide field of radiation within a period of about four (4) weeks, prior to initiation of the treatment with the compound of Formula (I) or formula (10b) in combination with the PD-1/PD-L1 inhibitor. [0122] In some embodiments, the subject has not taken or is not taking a) one or more of strong or moderate inducers or inhibitors of CYP3A4 and/or P-gp inducers or inhibitors (including herbal supplements or food products containing grapefruit juice, star fruit, or Seville oranges) within a period of about 14 days or five (5) half-lives, whichever is longer prior to initiation of the treatment with the compound of Formula (I) or formula (10b) in combination with the PD-1/PD-L1 inhibitor; and/or b) a drug that is a known substrate of P-gp, breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein (MATE)1, and/or MATE2-K transporters within a period of about 7 days prior to initiation of the treatment with the compound of Formula (I) or formula (10b) in combination with the PD-1/PD-L1 inhibitor. [0123] In some embodiments, the subject does not have inadequate organ functions including adequate hematological, renal, hepatic, and coagulating functions, as defined below: Hematological a. White blood cell count <2,000/µL; b. Absolute neutrophil count <1,500/µL; c. Platelets <100,000/µL; and d. Renal d. calculated using the Cockcroft-Gault formula) Hepatic e. institutional ULN if the patient has a diagnosis of Gilbert syndrome or hemolytic anemia as confirmed by the investigator; and f. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) and/or alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) >2.5×ULN. Coagulation g. International normalized ratio (INR) or prothrombin time (PT) >1.5×ULN unless the patient is receiving anticoagulant therapy and as long as PT or activated partial thromboplastin time (aPTT) is within the therapeutic range of intended use of anticoagulants; and h. Activated partial thromboplastin time >1.5×ULN unless the patient is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants. [0124] In some embodiments, the subject does not have active hepatitis B infection, hepatitis C infection, or human immunodeficiency virus (HIV) infection with measurable viral load. [0125] In some embodiments, the subject does not have has a life-threatening illness, medical condition, an active uncontrolled infection, or an organ system dysfunction (e.g., ascites, coagulopathy, or encephalopathy). [0126] In some embodiments, the subject does not have one or more cardiac-related diseases or findings: a) History of significant cardiovascular disease (e.g., cerebrovascular accident, myocardial infarction or unstable angina), within the last 6 months before starting the treatment; b) Clinically significant cardiac disease, including New York Heart Association Class II or higher heart failure; c) History of left ventricular ejection fraction (LVEF) <50% within the previous 12 months before starting the treatment; d) Resting corrected QT interval (QTc) >470 msec, derived as the averaged from three electrocardiograms (ECGs), using the ECG machines provided; and/or e) Any clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., third degree heart block, Mobitz Type II heart block, ventricular arrhythmias, uncontrolled atrial fibrillation). [0127] In some embodiments, the subject has not been diagnosed of an additional invasive malignancy within the previous 3 years, provided that the additional invasive malignancy is other than curatively treated non-melanomatous skin cancer, superficial urothelial carcinoma, in situ cervical cancer, or any other curatively treated malignancy that is not expected to require treatment for recurrence during the course of the treatment with the compound of Formula (I) or formula (10b) in combination with the PD-1/PD-L1 inhibitor. [0128] In some embodiments, the subject does not have one or more untreated brain metastases from non-brain tumors. [0129] In some embodiments, the subject who has had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to the initiation of the treatment (e.g., Cycle 1, Day 1) with the compound of Formula (I) or formula (10b) in combination with the PD- 1/PD-L1 inhibitor is eligible, provided that the subject meets all of the following criteria prior to the initiation of the treatment: a) residual neurological symptoms related to the CNS treatment least 2 weeks prior to Cycle 1, Day 1, if applicable; and c) follow-up magnetic resonance imaging (MRI) within 4 weeks prior to Cycle 1, Day 1 shows no new lesions appearing. [0130] In some embodiments, the subject has not undergone a major surgery within 4 weeks prior to the enrollment for the treatment with the compound of Formula (I) or formula (10b) in combination with the PD-1/PD-L1 inhibitor, provided that the surgery or procedure is other than peripherally inserted central catheter line placement, thoracentesis, paracentesis, biopsies, or abscess drainage. [0131] In some embodiments, the subject does not have a history of hypersensitivity to the PD- 1/PD-L1 inhibitor or the compound of Formula (I) or formula (10b), active or inactive excipients of the PD-1/PD-L1 inhibitor or the compound of Formula (I) or formula (10b) or drugs with a similar chemical structure or class to either the PD-1/PD-L1 inhibitor or the compound of Formula (I) or formula (10b), dependent on which combination the subject could receive. [0132] In some embodiments, the subject does not have one or more additional activating mutations in BRAF V600X, PTPN11 (SHP2), and/or KRAS Q61X. In some embodiments, the subject does not have a tumor harboring one or more additional activating mutations in BRAF V600X, PTPN11 (SHP2), and/or KRAS Q61X. [0133] In some embodiments, the subject is not previously treated with a PTPN11 inhibitor (e.g., SHP2 inhibitor), provided that the PTPN11 inhibitor is other than the compound of Formula (I) or formula (10b). In some embodiments, the subject is not previously treated with a PTPN11 inhibitor selected from the group consisting of TNO-155, RMC-4630, RLY-1971, JAB- 3068, JAB-3312, PF-07284892, and ERAS601. In some embodiments, the subject is not previously treated with the compound of Formula (I) or formula (10b). In some embodiments, the subject has previously been treated with a SHP2 inhibitor including any one of TNO-155, RMC-4630, RLY-1971, JAB-3068, JAB-3312, PF-07284892, ERAS601, and the compound of Formula (I) or formula (10b). [0134] In some embodiments, the subject does not have a gastrointestinal illness (e.g., post gastrectomy, short bowel syndrome, uncontrolled Crohn’s disease, celiac disease with villous atrophy, or chronic gastritis), which may preclude absorption of the compound of Formula (I) or formula (10b). [0135] In some embodiments, the subject is not on dialysis. [0136] In some embodiments, the subject does not have a history of allogenic bone marrow transplant. [0137] In some embodiments, the subject has not experienced a progressive disease (PD) within the first 120 days of initiating a treatment with an anti-PD-1/PD-L1 agent (e.g., primary refractory). [0138] related to prior anti-PD-1/PD-L1 treatment, which required discontinuation of therapy. [0139] In some embodiments, the subject does not have a known or suspected autoimmune disease, provided that the autoimmune disease is other than type 1 diabetes, hypothyroidism only requiring hormone replacement, skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger. [0140] In some embodiments, the subject does not have a condition requiring a systemic treatment with either corticosteroids (>10 mg prednisone equivalent) or other immunosuppressive medication within 14 days prior to the initiation of the treatment (e.g., Cycle 1, Day 1). In some embodiments, the subject is allowed to be on inhaled or topical steroids, and adrenal replacement steroids >10 mg prednisone equivalent, when the subject does not an active autoimmune disease. [0141] In some embodiments, the subject has not received a live/attenuated vaccine within 30 days prior to the initiation of the treatment. [0142] Further inclusion and exclusion criteria for subjects who may benefit from treatment with the compound of Formula (I) or formula (10b) in combination with nivolumab, such as subjects enrolled in a clinical study of the SHP2 Inhibitor Compound (10b) in Combination with the PD-1/PD-L1 inhibitor, are described in Example 2. [0143] In some embodiments, the subject meets all of inclusion criteria of 1) to 10) as described in Example 2. In some embodiments, the subject meets all of inclusion criteria of 1) to 10) as described in Example 2, provided that the subject does not meet any one of exclusion criteria of 1) to 22) as described in Example 2. III-4: Treatment Cycle and Dose Adjustment [0144] Treatment with the compound of Formula (I) or formula (10b) in combination with the KRAS G12C inhibitor can include one or more treatment cycles (e.g., at least 1, 2, 3, or more treatment cycles). In some embodiments, the treatment includes one or more treatment cycles (e.g., at least 1, 2, 3, or more treatment cycles). In some embodiments, the treatment includes at least 2, 3, or more treatment cycles. In some embodiments, the treatment includes 2 to 3 treatment cycles. In some embodiments, the treatment includes 3 treatment cycles. In some embodiments, the treatment includes more than 3 treatment cycles. [0145] In some embodiments, each of one or more treatment cycles has a duration of about 28 days; and the compound of Formula (I) or formula (10b) is administered daily. In some embodiments, each of one or more treatment cycles has a duration of about 28 days; and the PD- 1/PD-L1 inhibitor is administered every 1, 2, 3, 4, 5, or 6 weeks, such as every 3 weeks or every 6 weeks. In some embodiments, each of one or more treatment cycles has a duration of about 28 days; the compound of Formula (I) or formula (10b) is administered daily; and the PD-1/PD-L1 inhibitor is administered every 1, 2, 3, 4, 5, or 6 weeks, such as every 3 weeks or every 6 weeks. [0146] The treatment includes a dose escalation period, during which, after a previous treatment cycle, a dose of the compound of Formula (I) or formula (10b) can be adjusted (e.g., dose escalation or de-escalation) or retained. Dose adjustment may be based at least in part on a safety evaluation (e.g., a dose-limiting toxicity (DLT) assessment). In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes one or more dose escalations, a dose retention, or a dose de-escalation, each of which is determined by a dose- limiting toxicity (DLT) assessment. In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes one or more dose escalations, a dose retention, or a dose de-escalation, each of which is determined by a dose-limiting toxicity (DLT) assessment, as described in Example 2 and FIG.3. [0147] In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes a dose escalation after a previous treatment cycle, when a dose-limiting toxicity (DLT) rate is less than, e.g., about 19.7% determined by a DLT assessment. In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes a dose escalation in a second treatment cycle after a first treatment cycle, when a dose-limiting toxicity (DLT) rate is less than, e.g., about 19.7% determined by a DLT assessment. In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes a dose escalation in a third treatment cycle after a second treatment cycle, when a dose-limiting toxicity (DLT) rate is less than, e.g., about 19.7% determined by a DLT assessment. [0148] In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes a dose de-escalation after a previous treatment cycle, when a dose-limiting toxicity rate is more than, e.g., about 29.8% determined by a DLT assessment. In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes a dose retention in a second treatment cycle after a first treatment cycle, when a dose-limiting toxicity rate is more than, e.g., about 29.8% determined by a DLT assessment. In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes a dose retention in a third treatment cycle after a second treatment cycle, when a dose-limiting toxicity rate is more than, e.g., about 29.8% determined by a DLT assessment. [0149] In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes a dose retention after a previous treatment cycle, when a dose-limiting toxicity rate is in a range of from about 21.9% to about 29.8% determined by a DLT assessment. In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes a dose retention in a second treatment cycle after a first treatment cycle, when a dose-limiting toxicity rate is in a range of from about 21.9% to about 29.8% determined by a DLT assessment. In some embodiments, the administration of the compound of Formula (I) or formula (10b) includes a dose retention in a third treatment cycle after a second treatment cycle, when a dose- limiting toxicity rate is in a range of from about 21.9% to about 29.8% determined by a DLT assessment. [0150] After the dose escalation period, the treatment further includes a dose expansion/optimization period. In some embodiments of the dose expansion/optimization period, the compound of Formula (I) or formula (10b) is administered at at a dose regimen (e.g., Dose Regimen 1 or Dose Regimen 2) determined during the dose escalation period. [0151] In some embodiments, during the dose expansion/optimization period, the administration of the compound of Formula (I) or formula (10b) optionally includes one or more dose adjustments. In some embodiments, during the dose expansion/optimization period, the administration of the compound of Formula (I) or formula (10b) optionally includes one or more dose adjustments; and the one or more dose adjustments are determined according to a safety evaluation by Safety Review Committee (SRC). [0152] In any one of embodiments as described herein, the the PD-1/PD-L1 inhibitor in a total daily dosage is not adjusted (e.g., any dose escalation and/or de-escalation are not allowed during the treatment). [0153] In some embodiments, dosing adjustments, delays, and discontinuations of the compound of Formula (I) or formula (10b) and/or the the PD-1/PD-L1 inhibitor are further based on the criteria of Example 2. III-5: Therapeutically Effective Amount/Administration [0154] The compound of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor can be provided in jointly therapeutically effective amounts or in synergistically effective amounts, or each of which can be used at a dose less than when each is used alone. In some embodiments, the compound of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor are provided in jointly therapeutically effective amounts. In some embodiments, the compound of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor are provided in synergistically effective amounts. In some embodiments, the compound of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor are each used at a dose less than when each is used alone. [0155] The compound of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor can be administered concomitantly or sequentially. In some embodiments, the compound of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor are administered concomitantly. In some embodiments, the compound of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor are administered in a pharmaceutical composition including the compound of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor. In some embodiments, the compound of Formula (I) or formula (10b) and the KRAS G12C inhibitor are administered sequentially. In some embodiments, the compound of Formula (I) or formula (10b) is administered prior to the administration of the PD-1/PD-L1 inhibitor. In some embodiments, the the compound of Formula (I) or formula (10b) is administered after the administration of the PD-1/PD-L1 inhibitor. [0156] The therapeutically effective amount of the compound of Formula (I) or formula (10b) can be a total daily dosage of no more than about 2000 mg, on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount of the compound of Formula (I) or formula (10b) is a total daily dosage of no more than about 2000 mg, on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg, from about 50 mg to about 2000 mg, from about 80 mg to about 2000 mg, from about 80 mg to about 1000 mg, from about 80 mg to about 700 mg, from about 80 mg to about 550 mg, from about 80 mg to about 400 mg, from about 80 mg to about 250 mg, or from about 80 mg to about 150 mg of the compound of Formula (I) or formula (10b), on a salt-free and anhydrous basis, or any useful range therein. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 80 mg to about 700 mg, from about 80 mg to about 550 mg, from about 80 mg to about 400 mg, from about 80 mg to about 250 mg, or from about 80 mg to about 150 mg of the compound of Formula (I) or formula (10b), on a salt-free and anhydrous basis, or any useful range therein. [0157] In some embodiments, the therapeutically effective amount of the compound of Formula (I) or formula (10b) is a total daily dosage of about 100 mg to about 2000 mg, from about 150 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 250 mg to about 700 mg, from about 250 mg to about 550 mg, from about 250 mg to about 400 mg, from about 400 mg to about 550 mg, or from about 550 mg to about 700 mg, on a salt-free and anhydrous basis, or any useful range therein. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 250 mg to about 400 mg, from about 400 mg to about 550 mg, or from about 550 mg to about 700 mg of the compound of Formula (I) or formula (10b), on a salt-free and anhydrous basis, or any useful range therein. [0158] The therapeutically effective amount of the compound of formula (10b) can be a total daily dosage of no more than about 2000 mg, on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of no more than about 2000 mg, on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg, from about 50 mg to about 2000 mg, from about 80 mg to about 2000 mg, from about 80 mg to about 1000 mg, from about 80 mg to about 700 mg, from about 80 mg to about 550 mg, from about 80 mg to about 400 mg, from about 80 mg to about 250 mg, or from about 80 mg to about 150 mg of the compound of formula (10b), on a salt-free and anhydrous basis, or any useful range therein. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 80 mg to about 700 mg, from about 80 mg to about 550 mg, from about 80 mg to about 400 mg, from about 80 mg to about 250 mg, or from about 80 mg to about 150 mg of the compound of formula (10b), on a salt-free and anhydrous basis, or any useful range therein. [0159] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 100 mg to about 2000 mg, from about 150 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 250 mg to about 700 mg, from about 250 mg to about 550 mg, from about 250 mg to about 400 mg, from about 400 mg to about 550 mg, or from about 550 mg to about 700 mg of the compound of formula (10b), on a salt-free and anhydrous basis, or any useful range therein. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 250 mg to about 400 mg, from about 400 mg to about 550 mg, or from about 550 mg to about 700 mg, on a salt-free and anhydrous basis, or any useful range therein. [0160] In some embodiments, the therapeutically effective amount is a total daily dosage of about 80 mg, about 150 mg, about 250 mg, about 400 mg, about 550 mg, or about 700 mg of the compound of formula (10b), on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dosage of about 80 mg of the compound of formula (10b), on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dosage of about 150 mg of the compound of formula (10b), on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dosage of about 250 mg of the compound of formula (10b), on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dosage of about 400 mg of the compound of formula (10b), on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dosage of about 550 mg of the compound of formula (10b), on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dosage of about 700 mg of the compound of formula (10b), on a salt-free and anhydrous basis. [0161] The therapeutically effective amount of the PD-1/PD-L1 inhibitor can be the recommended dosage according to the product’s dosing information. In some embodiments, the PD-1/PD-L1 inhibitor in a total dosage of about between about 10-2000 mg every 1, 2, 3, 4, 5, or 6 weeks, such as 480 mg every 4 weeks, 400 mg every 6 weeks or 200 mg every 3 weeks (e.g., for pembrolizumab), 350 mg every 3 weeks (e.g., for cemiplimab), 1200 mg every 3 weeks (e.g., for atezolizumab), 800 mg every 2 weeks (e.g., for avelumab), or 1500 mg every 3-4 weeks (e.g., for durvalumab). In some embodiments, the PD-1/PD-L1 inhibitor is not adjusted (e.g., any dose escalation and/or de-escalation are not allowed during the treatment). [0162] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of no more than about 2000 mg, on a salt-free and anhydrous basis; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor is a total dosage of between about 10-2000 mg every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 100 mg to about 2000 mg, from about 150 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 250 mg to about 700 mg, from about 250 mg to about 550 mg, from about 250 mg to about 400 mg, from about 400 mg to about 550 mg, or from about 550 mg to about 700 mg, on a salt-free and anhydrous basis, or any useful range therein; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor is a total dosage of between about 10-2000 mg every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of from about 250 mg to about 400 mg, from about 400 mg to about 550 mg, or from about 550 mg to about 700 mg, on a salt-free and anhydrous basis, or any useful range therein; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor is a total dosage of between about 10-2000 mg every 1, 2, 3, 4, 5, or 6 weeks. [0163] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg of the compound of formula (10b), on a salt-free and anhydrous basis; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor is a total dosage of between about 10-2000 mg every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments, the therapeutically effective amount can be a total daily dosage of about 250 mg of the compound of formula (10b), on a salt-free and anhydrous basis; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor is a total dosage of between about 10-2000 mg every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments, the therapeutically effective amount can be a total daily dosage of about 400 mg of the compound of formula (10b), on a salt-free and anhydrous basis; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor is a total dosage of between about 10-2000 mg every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments, the therapeutically effective amount can be a total daily dosage of about 550 mg of the compound of formula (10b), on a salt-free and anhydrous basis; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor is a total dosage of between about 10-2000 mg every 1, 2, 3, 4, 5, or 6 weeks. [0164] The PTPN11 inhibitor as described herein and the PD-1/PD-L1 inhibitor as described herein can be administered orally or the PTPN11 inhibitor as described herein can be administered orally and the PD-1/PD-L1 inhibitor as described herein can be administered intravenously. In some embodiments, the PTPN11 inhibitor and/or the PD-1/PD-L1 inhibitor are administered orally. In some embodiments, the PTPN11 inhibitor administered orally and the PD-1/PD-L1 inhibitor is administered intravenously. [0165] In general, the compound of Formula (I) or formula (10b) can be administered orally. In some embodiments, the compound of Formula (I) or formula (10b) is administered orally. In some embodiments, the compound of formula (10b) is administered orally. In some embodiments, the compound of formula (10b) in a tablet formulation is administered orally. [0166] In general, the PD-1/PD-L1 inhibitor can be administered intravenously. In some embodiments, the PD-1/PD-L1 inhibitor is administered intravenously. [0167] In general, the compound of Formula (I) or formula (10b) can be administered once or multiple times (e.g., 2, 3, 4, or more times) daily. In some embodiments, the compound of Formula (I) or formula (10b) is administered once, twice, three times, or four times daily. In some embodiments, the compound of formula (10b) is administered once, twice, three times, or four times daily. In some embodiments, the compound of formula (10b) is administered once daily. In some embodiments, the compound of formula (10b) is administered twice daily. [0168] In general, the PD-1/PD-L1 inhibitor can be administered once or twice every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments, the PD-1/PD-L1 inhibitor is administered once every 1, 2, 3, 4, 5, or 6 weeks. [0169] In some embodiments, the compound of Formula (I) or formula (10b) is administered orally; and the PD-1/PD-L1 inhibitor is administered intravenously. In some embodiments, the compound of formula (10b) is administered once daily; and the PD-1/PD-L1 inhibitor is administered once every 1, 2, 3, 4, 5, or 6 weeks. [0170] The compound of Formula (I) or formula (10b) can be in an oral dosage form in one or more dosage strengths, where the compound of Formula (I) or formula (10b) is present in an amount of at least about 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, 90 mg, 100 mg, 120 mg, 180 mg, 200 mg, 300 mg, 400 mg, or 500 mg, on a salt-free and anhydrous basis. In some embodiments, the oral dosage form is a tablet formulation in one or more dosage strengths. In some embodiments of the tablet formulation, the compound of Formula (I) or formula (10b) is present in an amount of from 1 to 1000 mg, from 1 to 750 mg, from 1 to 500 mg, from 1 to 250 mg, from 30 to 1000 mg, from 30 to 750 mg, from 30 to 500 mg, from 30 to 200 mg, from 30 to 180 mg, from 30 to 120 mg, from 30 to 90 mg, from 50 to 1000 mg, from 50 to 750 mg, from 50 to 500 mg, from 50 to 250 mg, from 100 to 1000 mg, from 100 to 750 mg, from 100 to 500 mg, from 100 to 250 mg, from 200 to 1000 mg, from 200 to 750 mg, from 200 to 500 mg, from 300 to 1000 mg, from 300 to 750 mg, from 300 to 500 mg, from 400 to 1000 mg, from 400 to 750 mg, from 500 to 1000 mg, from 500 to 750 mg, from 600 to 1000 mg, from 5 to 250 mg, or from 5 to 100 mg in each tablet, on a salt-free and anhydrous basis. In some embodiments of the tablet formulation, the compound of Formula (I) or formula (10b) is present in an amount of about 5 mg, 10 mg, 30 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg in each tablet, on a salt-free and anhydrous basis. In some embodiments of the tablet formulation, the compound of Formula (I) or formula (10b) is present in an amount of about 30 mg, 50 mg, or 100 mg in each tablet, on a salt-free and anhydrous basis. [0171] The compound of formula (10b) can be in an oral dosage form in one or more dosage strengths, where the compound of formula (10b) is present in an amount of at least about 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, 90 mg, 100 mg, 120 mg, 180 mg, 200 mg, 300 mg, 400 mg, or 500 mg, on a salt-free and anhydrous basis. In some embodiments, the oral dosage form is a tablet formulation in one or more dosage strengths. In some embodiments of the tablet formulation, the compound of formula (10b) is present in an amount of from 1 to 1000 mg, from 1 to 750 mg, from 1 to 500 mg, from 1 to 250 mg, from 30 to 1000 mg, from 30 to 750 mg, from 30 to 500 mg, from 30 to 200 mg, from 30 to 180 mg, from 30 to 120 mg, from 30 to 90 mg, from 50 to 1000 mg, from 50 to 750 mg, from 50 to 500 mg, from 50 to 250 mg, from 100 to 1000 mg, from 100 to 750 mg, from 100 to 500 mg, from 100 to 250 mg, from 200 to 1000 mg, from 200 to 750 mg, from 200 to 500 mg, from 300 to 1000 mg, from 300 to 750 mg, from 300 to 500 mg, from 400 to 1000 mg, from 400 to 750 mg, from 500 to 1000 mg, from 500 to 750 mg, from 600 to 1000 mg, from 5 to 250 mg, or from 5 to 100 mg in each tablet, on a salt-free and anhydrous basis. In some embodiments of the tablet formulation, the compound of formula (10b) is present in an amount of about 5 mg, 10 mg, 30 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg in each tablet, on a salt-free and anhydrous basis. In some embodiments of the tablet formulation, the compound of formula (10b) is present in an amount of about 30 mg, 50 mg, or 100 mg in each tablet, on a salt-free and anhydrous basis. In some embodiments of the tablet formulation, the compound of formula (10b) is present in an amount of about 30 mg in each tablet, on a salt-free and anhydrous basis. In some embodiments of the tablet formulation, the compound of formula (10b) is present in an amount of about 50 mg in each tablet, on a salt-free and anhydrous basis. In some embodiments of the tablet formulation, the compound of formula (10b) is present in an amount of about 100 mg in each tablet, on a salt-free and anhydrous basis. [0172] In some embodiments, the compound of formula (10b) is administered once daily to provide a total daily dosage of no more than about 2000 mg of the compound of formula (10b). In some embodiments, the compound of formula (10b) is administered once daily to provide a total daily dosage of from about 100 mg to about 2000 mg, from about 150 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 250 mg to about 700 mg, from about 250 mg to about 550 mg, from about 250 mg to about 400 mg, from about 400 mg to about 550 mg, or from about 550 mg to about 700 mg of the compound of formula (10b), on a salt-free and anhydrous basis. In some embodiments, the compound of formula (10b) is administered once daily to provide a total daily dosage of from about 250 mg to about 400 mg, from about 400 mg to about 550 mg, or from about 550 mg to about 700 mg of the compound of formula (10b), on a salt-free and anhydrous basis. In some embodiments, the compound of formula (10b) is administered once daily to provide a total daily dosage of about 250 mg, about 400 mg, about 550 mg of the compound of formula (10b), on a salt-free and anhydrous basis. [0173] In some embodiments, the compound of formula (10b) is administered once daily to provide a total daily dosage of no more than about 2000 mg of the compound of formula (10b); and the PD-1/PD-L1 inhibitor is administered once every 1, 2, 3, 4, 5, or 6 weeks to provide a total dosage of between about 10-2000 mg. In some embodiments, the compound of formula (10b) is administered once daily to provide a total daily dosage of from about 100 mg to about 2000 mg, from about 150 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 250 mg to about 700 mg, from about 250 mg to about 550 mg, from about 250 mg to about 400 mg, from about 400 mg to about 550 mg, or from about 550 mg to about 700 mg of the compound of formula (10b), on a salt-free and anhydrous basis; and the PD-1/PD-L1 inhibitor is administered once every 1, 2, 3, 4, 5, or 6 weeks to provide a total dosage of between about 10-2000 mg. In some embodiments, the compound of formula (10b) is administered once daily to provide a total daily dosage of from about 250 mg to about 400 mg, from about 400 mg to about 550 mg, or from about 550 mg to about 700 mg of the compound of formula (10b), on a salt-free and anhydrous basis; and the PD-1/PD-L1 inhibitor is administered once every four (4) weeks to provide a total dosage of between about 10-2000 mg. In some embodiments, the compound of formula (10b) is administered once daily to provide a total daily dosage of about 250 mg, about 400 mg, about 550 mg of the compound of formula (10b), on a salt-free and anhydrous basis; and the PD-1/PD-L1 inhibitor is administered once every 1, 2, 3, 4, 5, or 6 weeks to provide a total dosage of between about 10- 2000 mg. [0174] In some embodiments, the compound of formula (10b) is administered once daily during each of one or more treatment cycles, as described herein. In some embodiments, the PD- 1/PD-L1 inhibitor is administered once every 1, 2, 3, 4, 5, or 6 weeks during each of one or more treatment cycles, as described herein. In some embodiments, the compound of formula (10b) is administered once daily and the PD-1/PD-L1 inhibitor is administered once every 1, 2, 3, 4, 5, or 6 weeks during each of one or more treatment cycles, as described herein. [0175] In general, the compound of formula (10b) is recommended to be administered to a subject without food (e.g., after an overnight fast (minimum 8 hours) followed by 2 hours of fasting after the dose is taken). The subject is allowed to have water except for one (1) hour before and after the administration and the subject is given with water (e.g., 240 mL) at the administration. In some embodiments, the compound of formula (10b) is administered to the subject without food, at least about 8 hours prior to the administration and at least about 2 hours post the administration. [0176] In some embodiments, the PD-1/PD-L1 inhibitor is administered once every 1, 2, 3, 4, 5, or 6 weeks intravenously, within about 30 minutes after administration of the compound of formula (10b). III-6: Efficacy [0177] A clinical study of a PTPN inhibitor (e.g., a compound represented by formula (10b)) in combination with a PD-1/PD-L1 inhibitor can be performed to evaluate the safety, tolerability, and efficacy of the combination to reduce or stabilize cancers (e.g., cancers comprising solid tumors) in subjects. In some embodiments, the subjects have a solid tumor including non-small cell lung cancer (NSCLC). In some embodiments, the subjects have non-small cell lung cancer (NSCLC). In some embodiments, the subjects have NSCLC characterized by a KRAS mutation. [0178] Administration of a therapeutically effective amount of the compound of Formula (I) or formula (10b) in combination with a therapeutically effective amount of a PD-1/PD-L1 inhibitor can reduce or substantially eliminate cancers or solid tumors in subjects. In some embodiments, the therapeutically effective amount of Formula (I) or formula (10b) in combination with a PD- 1/PD-L1 inhibitor substantially eliminates the solid tumor. In some embodiments, the therapeutically effective amount of Formula (I) or formula (10b) in combination with a PD- 1/PD-L1 inhibitor reduces a volume of the solid tumor at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more. In some embodiments, the therapeutically effective amount of Formula (I) or formula (10b) in combination with a PD-1/PD-L1 inhibitor reduces a volume of the solid tumor in a size of from about 10% to about 90%, from about 10% to about 80%, from about 10% to about 70%, from about 10% to about 60%, from about 10% to about 50%, from about 10% to about 40%, from about 10% to about 30%, from about 10% to about 20%, from about 20% to about 90%, from about 20% to about 80%, from about 20% to about 70%, from about 20% to about 60%, from about 20% to about 50%, from about 20% to about 40%, from about 20% to about 30%, from about 30% to about 90%, from about 30% to about 80%, from about 30% to about 70%, from about 30% to about 60%, from about 30% to about 50%, from about 30% to about 40%, from about 40% to about 90%, from about 40% to about 80%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 50%, from about 50% to about 90%, from about 50% to about 80%, from about 50% to about 70%, from about 50% to about 60%, from about 60% to about 90%, from about 60% to about 80%, from about 60% to about 70%, from about 70% to about 90%, from about 70% to about 80%, from about 80% to about 90%, or any range therein. In some embodiments, the therapeutically effective amount of Formula (I) or formula (10b) in combination with a PD-1/PD-L1 inhibitor reduces a volume of the solid tumor about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. [0179] Administration of a therapeutically effective amount of the compound of Formula (I) or formula (10b) in combination with a therapeutically effective amount of a PD-1/PD-L1 inhibitor can stabilize cancers or solid tumors in subjects. In some embodiments, the therapeutically effective amount of Formula (I) or formula (10b) in combination with a PD-1/PD-L1 inhibitor stabilize the solid tumor. [0180] Administration of a therapeutically effective amount of the compound of Formula (I) or formula (10b) in combination with a therapeutically effective amount of a PD-1/PD-L1 inhibitor can maintain a reduction or stabilization of cancers or solid tumors in subjects for a period of time (e.g., 1 to 12 months). In some embodiments, the solid tumor is reduced or stabilized for a period of at least about one month with the therapeutically effective amount of the compound of Formula (I) or formula (10b) in combination with a PD-1/PD-L1 inhibitor. In some embodiments, the solid tumor is reduced or stabilized for a period of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months with the therapeutically effective amount of the compound of Formula (I) or formula (10b) in combination with a PD-1/PD-L1 inhibitor. In some embodiments, the solid tumor is reduced or stabilized for a period of from about 1 to about 12 months, from about 1 to about 6 months, from about 1 to about 3 months, or from about 1 to about 2 months. [0181] In some embodiments, the subject is further evaluated to by one or more tests to provide overall assessments including plasma pharmacokinetic and/or pharmacodynamic profiles. [0182] In some embodiments, the subject is further evaluated for one or more biomarkers to determine a correlation of the one or more biomarkers to an antitumor response. III-7: Embodiments [0183] Embodiment 1A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of pembrolizumab. [0184] Embodiment 1B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of pembrolizumab, wherein the subject has a KRAS mutation (e.g., as described herein). [0185] Embodiment 2A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of atezolizumab. [0186] Embodiment 2B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of atezolizumab, wherein the subject has a KRAS mutation (e.g., as described herein). [0187] Embodiment 3A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of durvalumab. [0188] Embodiment 3B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of durvalumab, wherein the subject has a KRAS mutation (e.g., as described herein). [0189] Embodiment 4A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of avelumab. [0190] Embodiment 4B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of avelumab, wherein the subject has a KRAS mutation (e.g., as described herein). [0191] Embodiment 5A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of cemiplimab-rwlc. [0192] Embodiment 5B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of cemiplimab-rwlc, wherein the subject has a KRAS mutation (e.g., as described herein). [0193] Embodiment 6A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of camrelizumab. [0194] Embodiment 6B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of camrelizumab, wherein the subject has a KRAS mutation (e.g., as described herein). [0195] Embodiment 7A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of toripalimab. [0196] Embodiment 7B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of toripalimab, wherein the subject has a KRAS mutation (e.g., as described herein). [0197] Embodiment 8A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of prolgolimab. [0198] Embodiment 8B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of prolgolimab, wherein the subject has a KRAS mutation (e.g., as described herein). [0199] Embodiment 9A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of tislelizumab. [0200] Embodiment 9B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of tislelizumab, wherein the subject has a KRAS mutation (e.g., as described herein). [0201] Embodiment 10A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of balstilimab. [0202] Embodiment 10B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of balstilimab, wherein the subject has a KRAS mutation (e.g., as described herein). [0203] Embodiment 11A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of dostarlimab. [0204] Embodiment 11B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of dostarlimab, wherein the subject has a KRAS mutation (e.g., as described herein). [0205] Embodiment 12A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of M7824. [0206] Embodiment 12B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of M7824, wherein the subject has a KRAS mutation (e.g., as described herein). [0207] Embodiment 13A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of spartalizumab. [0208] Embodiment 13B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of spartalizumab, wherein the subject has a KRAS mutation (e.g., as described herein). [0209] Embodiment 14A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of sasanlimab. [0210] Embodiment 14B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of sasanlimab, wherein the subject has a KRAS mutation (e.g., as described herein). [0211] Embodiment 15A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of retifanlimab. [0212] Embodiment 15B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of retifanlimab, wherein the subject has a KRAS mutation (e.g., as described herein). [0213] Embodiment 16A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of BMS-986213. [0214] Embodiment 16B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of BMS-986213, wherein the subject has a KRAS mutation (e.g., as described herein). [0215] Embodiment 17A: The present disclosure provides a method of treating cancer in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of tebotelimab. [0216] Embodiment 17B: The present disclosure provides a method of treating a solid tumor (e.g., as described herein) in a subject, the method including administering to a subject in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof; and b) a therapeutically effective amount of tebotelimab, wherein the subject has a KRAS mutation (e.g., as described herein). [0217] With reference to any one of Embodiments 1A-17A and1B to 17B, the compound of formula (10b) is described according to Section III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors. In some embodiments, the compound of formula (10b) is any of embodiments as described in Section III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors. In some embodiments, the compound of formula (10b) is represented by the formula:

or a pharmaceutically acceptable salt, stereoisomer, conformational isomer, or a combination thereof. In some embodiments, the compound of formula (10b) has the name of 6-((3S,4S)-4- amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(R_a)-(2,3-dichlorophenyl)-2,5-dimethyl- 4(3H)-pyrimidinone. [0218] With reference to any one of Embodiments 1A to 17A and 1B to 17B, the caner or solid tumor is described according to Section III-2: Cancer/Solid Tumor. In some embodiments, the caner or solid tumor is any one of embodiments as described in Section III-2: Cancer/Solid Tumor. In some embodiments, the cancer or solid tumor is colorectal cancer (CRC). In some embodiments, the cancer or solid tumor is non-small cell lung cancer (NSCLC). [0219] With reference to any one of Embodiments 1A to 17A and 1B to 17B, the subject is described according to Section III-3: Subject. In some embodiments, the subject is any one of embodiments as described in Section III-3: Subject. In some embodiments, the subject has a mutation in KRAS, provided that the mutation is other than KRAS Q61X (e.g., the subject has a cancer or solid tumor characterized by a mutation in KRAS other than KRAS Q61X). [0220] With reference to any one of Embodiments 1A to 17A and 1B to 17B, the treatment cycle and dose adjustment are described according to Section III-4: Treatment Cycle and Dose Adjustment. In some embodiments, the therapeutically effective amount and/or administration are any one of embodiments as described in Section III-4: Treatment Cycle and Dose Adjustment. [0221] With reference to any one of Embodiments 1A to 17A and 1B to 17B, the therapeutically effective amount and/or administration are described according to Section III-5: Therapeutically Effective Amount/Administration. In some embodiments, the therapeutically effective amount and/or administration are any one of embodiments as described in Section III- 5: Therapeutically Effective Amount/Administration. Pembrolizumab [0222] With reference to Embodiment 1A or 1B, the therapeutically effective amount of pembrolizumab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of pembrolizumab is in a dosage of 200 mg every three weeks (q3week) or 400 mg every six weeks (q6week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of pembrolizumab is in a dosage of 200 mg every three weeks by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of pembrolizumab is in a dosage of 400 mg every six weeks by intravenous (IV) administration. [0223] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of pembrolizumab is in a dosage of 200 mg every three weeks (q3week) or 400 mg every six weeks (q6week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of pembrolizumab is in a dosage of 200 mg every three weeks (q3week) or 400 mg every six weeks (q6week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of pembrolizumab is in a dosage of 200 mg every three weeks (q3week) or 400 mg every six weeks (q6week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of pembrolizumab is in a dosage of 200 mg every three weeks (q3week) or 400 mg every six weeks (q6week) by intravenous (IV) administration. [0224] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of pembrolizumab in a q3week dosage or a q6week doasage can be adjusted, according to cancer progression and/or toxicity. [0225] In some embodiments, the compound of formula (10b) is administered orally; and pembrolizumab is administered intravenously. [0226] In some embodiments, the compound of formula (10b) and pembrolizumab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and pembrolizumab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and pembrolizumab are each used at a dose lower than when each is used alone. Atezolizumab [0227] With reference to Embodiment 2A or 2B, the therapeutically effective amount of atezolizumab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of atezolizumab is in a dosage of 840 mg every two weeks (q2week), 1200 mg every three weeks (q3week), or 1680 mg every four weeks (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of atezolizumab is in a dosage of 840 mg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of atezolizumab is in a dosage of 1200 mg every three weeks (q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of atezolizumab is in a dosage of 1680 mg every four weeks (q4week) by intravenous (IV) administration. [0228] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of atezolizumab is in a dosage of 840 mg every two weeks (q2week), 1200 mg every three weeks (q3week), or 1680 mg every four weeks (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of atezolizumab is in a dosage of 840 mg every two weeks (q2week), 1200 mg every three weeks (q3week), or 1680 mg every four weeks (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of atezolizumab is in a dosage of 840 mg every two weeks (q2week), 1200 mg every three weeks (q3week), or 1680 mg every four weeks (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of atezolizumab is in a dosage of 840 mg every two weeks (q2week), 1200 mg every three weeks (q3week), or 1680 mg every four weeks (q4week) by intravenous (IV) administration. [0229] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of atezolizumab in a q2week dosage, q3week dosage, or q4week doasage can be adjusted, according to cancer progression and/or toxicity. [0230] In some embodiments, the compound of formula (10b) is administered orally; and atezolizumab is administered intravenously. [0231] In some embodiments, the compound of formula (10b) and atezolizumab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and atezolizumab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and atezolizumab are each used at a dose lower than when each is used alone. Durvalumab [0232] With reference to Embodiment 3A or 3B, the therapeutically effective amount of durvalumab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of durvalumab is in a dosage of 1500 mg every three weeks (q3week) or every four weeks (q4week) for a subject (with > 30 kg body weight) by intravenous (IV) administration. [0233] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of durvalumab is in a dosage of 1500 mg every three weeks (q3week) or every four weeks (q4week) for a subject (with > 30 kg body weight) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of durvalumab is in a dosage of 1500 mg every three weeks (q3week) or every four weeks (q4week) for a subject (with > 30 kg body weight) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of durvalumab is in a dosage of 1500 mg every three weeks (q3week) or every four weeks (q4week) for a subject (with > 30 kg body weight) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of durvalumab is in a dosage of 1500 mg every three weeks (q3week) or every four weeks (q4week) for a subject (with > 30 kg body weight) by intravenous (IV) administration. [0234] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of durvalumab in a q3week dosage or a q4week doasage can be adjusted, according to cancer progression and/or toxicity. [0235] In some embodiments, the compound of formula (10b) is administered orally; and durvalumab is administered intravenously. [0236] In some embodiments, the compound of formula (10b) and durvalumab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and durvalumab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and durvalumab are each used at a dose lower than when each is used alone. Avelumab [0237] With reference to Embodiment 4A or 4B, the therapeutically effective amount of avelumab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of avelumab is in a dosage of 800 mg every two weeks (q2week) by intravenous (IV) administration. [0238] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of avelumab is in a dosage of 800 mg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of avelumab is in a dosage of 800 mg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of avelumab is in a dosage of 800 mg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of avelumab is in a dosage of 800 mg every two weeks (q2week) by intravenous (IV) administration. [0239] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of avelumab in a biweekly dosage can be adjusted, according to cancer progression and/or toxicity. [0240] In some embodiments, the compound of formula (10b) is administered orally; and avelumab is administered intravenously. [0241] In some embodiments, the compound of formula (10b) and avelumab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and avelumab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and avelumab are each used at a dose lower than when each is used alone. Cemiplimab-rwlc [0242] With reference to Embodiment 5A or 5B, the therapeutically effective amount of avelumab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of cemiplimab-rwlc is in a dosage of 350 mg every three weeks (q3week) by intravenous (IV) administration. [0243] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of cemiplimab-rwlc is in a dosage of 350 mg every three weeks (q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of cemiplimab-rwlc is in a dosage of 350 mg every three weeks (q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of cemiplimab-rwlc is in a dosage of 350 mg every three weeks (q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of cemiplimab-rwlc is in a dosage of 350 mg every three weeks (q3week) by intravenous (IV) administration. [0244] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of cemiplimab-rwlc in a q3week dosage can be adjusted, according to cancer progression and/or toxicity. [0245] In some embodiments, the compound of formula (10b) is administered orally; and cemiplimab-rwlc is administered intravenously. [0246] In some embodiments, the compound of formula (10b) and cemiplimab-rwlc are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and cemiplimab-rwlc are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and cemiplimab-rwlc are each used at a dose lower than when each is used alone. Camrelizumab [0247] With reference to Embodiment 6A or 6B, the therapeutically effective amount of camrelizumab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of camrelizumab is in a dosage of from about 60 mg to about 400 mg every two or three weeks (q2week or q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of camrelizumab is in a dosage of about 200 mg every two weeks (q2week) by intravenous (IV) administration. [0248] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of camrelizumab is in a dosage of from about 60 mg to about 400 mg every two or three weeks (q2week or q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of camrelizumab is in a dosage of about 200 mg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of camrelizumab is in a dosage of about 200 mg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of camrelizumab is in a dosage of about 200 mg every two weeks (q2week) by intravenous (IV) administration. [0249] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of camrelizumab in a q2week or q3week dosage can be adjusted, according to cancer progression and/or toxicity. [0250] In some embodiments, the compound of formula (10b) is administered orally; and camrelizumab is administered intravenously. [0251] In some embodiments, the compound of formula (10b) and camrelizumab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and camrelizumab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and camrelizumab are each used at a dose lower than when each is used alone. Toripalimab [0252] With reference to Embodiment 7A or 7B, the therapeutically effective amount of toripalimab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of toripalimab is in a dosage of 240 mg every three weeks (q3week) by intravenous (IV) administration. [0253] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of toripalimab is in a dosage of 240 mg every three weeks (q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of toripalimab is in a dosage of 240 mg every three weeks (q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of toripalimab is in a dosage of 240 mg every three weeks (q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of toripalimab is in a dosage of 240 mg every three weeks (q3week) by intravenous (IV) administration. [0254] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of toripalimab in a q3week dosage can be adjusted, according to cancer progression and/or toxicity. [0255] In some embodiments, the compound of formula (10b) is administered orally; and toripalimab is administered intravenously. [0256] In some embodiments, the compound of formula (10b) and toripalimab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and toripalimab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and toripalimab are each used at a dose lower than when each is used alone. Prolgolimab [0257] With reference to Embodiment 8A or 8B, the therapeutically effective amount of prolgolimab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of prolgolimab is in a dosage of 250 mg every three weeks (q3week) or 1 mg/kg every two weeks (q2week) by intravenous (IV) administration. [0258] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of prolgolimab is in a dosage of 250 mg every three weeks (q3week) or 1 mg/kg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of prolgolimab is in a dosage of 250 mg every three weeks (q3week) or 1 mg/kg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of prolgolimab is in a dosage of 250 mg every three weeks (q3week) or 1 mg/kg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of prolgolimab is in a dosage of 250 mg every three weeks (q3week) or 1 mg/kg every two weeks (q2week) by intravenous (IV) administration. [0259] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of prolgolimab in a q2week or q3week dosage can be adjusted, according to cancer progression and/or toxicity. [0260] In some embodiments, the compound of formula (10b) is administered orally; and prolgolimab is administered intravenously. [0261] In some embodiments, the compound of formula (10b) and prolgolimab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and prolgolimab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and prolgolimab are each used at a dose lower than when each is used alone. Tislelizumab [0262] With reference to Embodiment 9A or 9B, the therapeutically effective amount of tislelizumab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of tislelizumab is in a dosage of 200 mg every three weeks (q3week) by intravenous (IV) administration. [0263] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of tislelizumab is in a dosage of 200 mg every three weeks (q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of tislelizumab is in a dosage of 200 mg every three weeks (q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of tislelizumab is in a dosage of 200 mg every three weeks (q3week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of tislelizumab is in a dosage of 200 mg every three weeks (q3week) by intravenous (IV) administration. [0264] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of tislelizumab in a q3week dosage can be adjusted, according to cancer progression and/or toxicity. [0265] In some embodiments, the compound of formula (10b) is administered orally; and tislelizumab is administered intravenously. [0266] In some embodiments, the compound of formula (10b) and tislelizumab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and tislelizumab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and tislelizumab are each used at a dose lower than when each is used alone. Balstilimab [0267] With reference to Embodiment 10A or 10B, the therapeutically effective amount of balstilimab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of balstilimab is in a dosage of 300 mg every three weeks (q3week) or 3 mg/kg every two week (q2week) by intravenous (IV) administration. [0268] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of balstilimab is in a dosage of 300 mg every three weeks (q3week) or 3 mg/kg every two week (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of balstilimab is in a dosage of 300 mg every three weeks (q3week) or 3 mg/kg every two week (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of balstilimab is in a dosage of 300 mg every three weeks (q3week) or 3 mg/kg every two week (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of balstilimab is in a dosage of 300 mg every three weeks (q3week) or 3 mg/kg every two week (q2week) by intravenous (IV) administration. [0269] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of balstilimab in a q2 week or q3week dosage can be adjusted, according to cancer progression and/or toxicity. [0270] In some embodiments, the compound of formula (10b) is administered orally; and balstilimab is administered intravenously. [0271] In some embodiments, the compound of formula (10b) and balstilimab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and balstilimab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and balstilimab are each used at a dose lower than when each is used alone. Dostarlimab [0272] With reference to Embodiment 11A or 11B, the therapeutically effective amount of dostarlimab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of dostarlimab is in a dosage of 500 mg every three weeks (q3week) or 1000 mg every six week (q6week) by intravenous (IV) administration. [0273] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of dostarlimab is in a dosage of 500 mg every three weeks (q3week) or 1000 mg every six week (q6week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of dostarlimab is in a dosage of 500 mg every three weeks (q3week) or 1000 mg every six week (q6week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of dostarlimab is in a dosage of 500 mg every three weeks (q3week) or 1000 mg every six week (q6week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of dostarlimab is in a dosage of 500 mg every three weeks (q3week) or 1000 mg every six week (q6week) by intravenous (IV) administration. [0274] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of dostarlimab in a q3week or q6week dosage can be adjusted, according to cancer progression and/or toxicity. [0275] In some embodiments, the compound of formula (10b) is administered orally; and dostarlimab is administered intravenously. [0276] In some embodiments, the compound of formula (10b) and dostarlimab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and dostarlimab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and dostarlimab are each used at a dose lower than when each is used alone. Spartalizumab [0277] With reference to Embodiment 13A or 13B, the therapeutically effective amount of spartalizumab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of spartalizumab is in a dosage of 300 mg every three weeks (q3week) or 400 mg every four week (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of spartalizumab is in a dosage of 400 mg every four week (q4week) by intravenous (IV) administration. [0278] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of spartalizumab is in a dosage of 300 mg every three weeks (q3week) or 400 mg every four week (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of spartalizumab is in a dosage of 300 mg every three weeks (q3week) or 400 mg every four week (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of spartalizumab is in a dosage of 300 mg every three weeks (q3week) or 400 mg every four week (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of spartalizumab is in a dosage of 300 mg every three weeks (q3week) or 400 mg every four week (q4week) by intravenous (IV) administration. [0279] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of spartalizumab in a q3week or q4week dosage can be adjusted, according to cancer progression and/or toxicity. [0280] In some embodiments, the compound of formula (10b) is administered orally; and spartalizumab is administered intravenously. [0281] In some embodiments, the compound of formula (10b) and spartalizumab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and spartalizumab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and spartalizumab are each used at a dose lower than when each is used alone. Sasanlimab [0282] With reference to Embodiment 14A or 14B, the therapeutically effective amount of sasanlimab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of sasanlimab is in a dosage of from 0.5 mg to10 mg/kg every three weeks (q3week) by intravenous (IV) administration, or 300 mg every four week (q4week) by subcutaneous(SC) administration. In some embodiments, the therapeutically effective amount of sasanlimab is in a dosage of 300 mg every four week (q4week) by subcutaneous(SC) administration. [0283] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of sasanlimab is in a dosage of from 0.5 mg to10 mg/kg every three weeks (q3week) by intravenous (IV) administration, or 300 mg every four week (q4week) by subcutaneous(SC) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of sasanlimab is in a dosage of from 0.5 mg to10 mg/kg every three weeks (q3week) by intravenous (IV) administration, or 300 mg every four week (q4week) by subcutaneous(SC) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of sasanlimab is in a dosage of from 0.5 mg to10 mg/kg every three weeks (q3week) by intravenous (IV) administration, or 300 mg every four week (q4week) by subcutaneous(SC) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of sasanlimab is in a dosage of from 0.5 mg to10 mg/kg every three weeks (q3week) by intravenous (IV) administration, or 300 mg every four week (q4week) by subcutaneous(SC) administration. [0284] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of sasanlimab in a q3week or q4week dosage can be adjusted, according to cancer progression and/or toxicity. [0285] In some embodiments, the compound of formula (10b) is administered orally; and sasanlimab is administered intravenously. In some embodiments, the compound of formula (10b) is administered orally; and sasanlimab is administered subcutaneously. [0286] In some embodiments, the compound of formula (10b) and sasanlimab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and sasanlimab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and sasanlimab are each used at a dose lower than when each is used alone. Retifanlimab [0287] With reference to Embodiment 15A or 15B, the therapeutically effective amount of retifanlimab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of retifanlimab is in a dosage of 500 mg every four weeks (q4week) by intravenous (IV) administration. [0288] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of retifanlimab is in a dosage of 500 mg every four weeks (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of retifanlimab is in a dosage of 500 mg every four weeks (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of retifanlimab is in a dosage of 500 mg every four weeks (q4week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of retifanlimab is in a dosage of 500 mg every four weeks (q4week) by intravenous (IV) administration. [0289] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of retifanlimab in a q4week dosage can be adjusted, according to cancer progression and/or toxicity. [0290] In some embodiments, the compound of formula (10b) is administered orally; and retifanlimab is administered intravenously. [0291] In some embodiments, the compound of formula (10b) and retifanlimab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and retifanlimab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and retifanlimab are each used at a dose lower than when each is used alone. BMS-986213 [0292] With reference to Embodiment 16A or 16B, the therapeutically effective amount of BMS-986213 can be a recommended dosage according to the product’s dosing information when used alone. [0293] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of BMS-986213 is a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of BMS-986213 is a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of BMS-986213 is a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of BMS-986213 is a recommended dosage according to the product’s dosing information when used alone. [0294] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of BMS-986213 in a recommended dosage can be adjusted, according to cancer progression and/or toxicity. [0295] In some embodiments, the compound of formula (10b) is administered orally; and BMS-986213 is administered intravenously. [0296] In some embodiments, the compound of formula (10b) and BMS-986213 are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and BMS-986213 are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and BMS-986213 are each used at a dose lower than when each is used alone. Tebotelimab [0297] With reference to Embodiment 17A or 17B, the therapeutically effective amount of tebotelimab can be a recommended dosage according to the product’s dosing information when used alone. In some embodiments, the therapeutically effective amount of tebotelimab is in a dosage of 120 mg, 240 mg, 400, or 600 mg every two weeks (q2week) by intravenous (IV) administration. [0298] In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg, about 400 mg, or about 550 mg, on a salt- free and anhydrous basis; and the therapeutically effective amount of tebotelimab is in a dosage of 120 mg, 240 mg, 400, or 600 mg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of tebotelimab is in a dosage of 120 mg, 240 mg, 400, or 600 mg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of tebotelimab is in a dosage of 120 mg, 240 mg, 400, or 600 mg every two weeks (q2week) by intravenous (IV) administration. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of tebotelimab is in a dosage of 120 mg, 240 mg, 400, or 600 mg every two weeks (q2week) by intravenous (IV) administration. [0299] The therapeutically effective amount of the compound of formula (10b) in a total daily dosage; and the therapeutically effective amount of tebotelimab in a biweekly dosage can be adjusted, according to cancer progression and/or toxicity. [0300] In some embodiments, the compound of formula (10b) is administered orally; and tebotelimab is administered intravenously. [0301] In some embodiments, the compound of formula (10b) and tebotelimab are provided in jointly therapeutically effective amounts. In some embodiments, the compound of formula (10b) and tebotelimab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and tebotelimab are each used at a dose lower than when each is used alone. [0302] With reference to any one of Embodiments 1A to 17A and 1B to 17B, the efficay of the treatment is described according to Section III-6: Efficacy. In some embodiments, the efficay of the treatment is any one of embodiments as described in Section III-6: Efficacy. IV. COMPOUNDS [0303] The present disclosure provides a PTPN11 inhibitor represent by Formula (I) for use in a method of treating a disease or disorder (e.g., cancer) in a subject as described in Section III: Combination Therapy, a pharmaceutical composition for treating a disease or disorder (e.g., cancer) in a subject as described in Section V: Composition; and a kit for treating a disease or disorder (e.g., cancer) in a subject as described in Section VI: Kits. The PTPN11 inhibitor is as defined and described in WO 2020/033828, the entirety of which is hereby incorporated for all purposes. [0304] The PTPN11 inhibitor is represent by Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: subscript a is 0 or 1; subscript b is 0 or 1; Y₁ is a direct bond or CR₁₇R₁₈; Y₂ is selected from the group consisting of C_1-4alkyl, amino, C_1-4alkylC(O)O-, C_1-4alkylamino and C_1-4aminoalkyl; R₁ is selected from the group consisting of C_6-10aryl, C_3-8cycloalkyl, C_3-8cycloalkenyl, and a 5-10 membered heteroaryl group having 1 to 4 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S; said aryl or heteroaryl of R₁ is unsubstituted or substituted with 1 to 5 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4haloalkyl, C_1-4aminoalkyl, C_3-8cycloalkyl, C_3-8cycloalkenyl, NR₁₅C(O)R₁₄, NR₁₅C(O)OR₁₄, NR₁₄C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₄, NR₁₅S(O)2R₁₄, C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)2NR₁₅R₁₆, C(O)R₁₄, C(O)OR₁₄, OR₁₄, SR₁₄, S(O)R₁₄, and S(O)2R₁₄; R₂, R₃, R₁₀, and R₁₁ are each independently selected from the group consisting of hydrogen, C_1-4alkyl, and C_3-8cycloalkyl; R₄, R₅, R₈, and R₉ are each independently selected from the group consisting of hydrogen, cyano, C_1-4alkyl, C_1-4alkoxy, amino, hydroxy, C_3-8cycloalkyl, halo, and C_1-4alkylamino; R₆ is selected from the group consisting of amino, C_1-4aminoalkyl, and C_1-4alkylamino; R₇ is selected from the group consisting of hydrogen, amido, cyano, halo, and hydroxy, or is selected from the group consisting of C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino, and C_1-4aminoalkyl; or R₆ and R₇ together with the carbon atom to which they are both attached form a 3- to 7- membered saturated or unsaturated ring, having 0 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O)m; subscript m is 0, 1, or 2; and said saturated or unsaturated ring formed by R₆ and R₇ is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; any two groups of R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₁ can form a 5 to 6 membered ring, having 0 to 2 heteroatoms as ring vertices elected from N, O and S; any two groups of R₂, R₄, R₆, R₈ and R₁₀ can form a direct bond, or a 1 or 2 atom carbon bridge; R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6 dihydroxyalkyl, -NH-NHR₁₉, -NHR₁₉, -OR₁₉, -NHC(O)R₁₉, -NHC(O)NHR₁₉, -NHS(O)₂NHR₁₉, -NHS(O)₂R₁₉, -C(O)OR₁₉, -C(O)NR₁₉R₂0, -C(O)NH(CH₂)qOH, -C(O)NH(CH₂)qR₂₁, -C(O)R₂₁, -NH₂, -OH, -S(O)2NR₁₉R₂₀, C_3-8cycloalkyl, aryl, heterocyclyl having 1-5 heteroatoms as ring vertices selected from N, O, S and P, and heteroaryl having 1-5 heteroatoms as ring vertices selected from N, O, S and P; subscript q is an integer of from 0 to 6; and each of aryl, heteroaryl, heterocyclyl and cycloalkyl of R₁₃ is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of C_1-4alkyl, –OH, -NH₂, -OR₂₁, halo, cyano, and oxo; R₁₄, R₁₅ and R₁₆ are each independently selected from the group consisting of hydrogen, C_1-4alkyl, C_3-8cycloalkyl, C_6-10aryl and 5-10 membered heteroaryl, any of which is unsubstituted or substituted with one or more groups independently selected from the group consisting of amido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; R₁₇ and R₁₈ are each independently selected from the group consisting of hydrogen, C_1-4alkyl, and CF₃; R₁₉ and R₂₀ are each independently selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl and C_3-6cycloalkyl; and each R₂₁ is independently selected from the group consisting of hydrogen, -OH, C_1-6 alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl and C_3-6cycloalkyl. [0305] In some embodiments of formula (I), Y₁ is a direct bond. In some ebodiments, Y₁ is CR₁₇R₁₈. In some embodiments, R₁₇ and R₁₈ are each independently selected from the group consisting of hydrogen, C_1-4alkyl, and CF₃. In some embodiments, R₁₇ and R₁₈ are each independently hydrogen or C_1-4alkyl. In some embodimetns, Y₁ is -CH₂. [0306] In some embodiments of formula (I), Y₂ is C_1-4alkyl. In some embodiments, Y₂ is methyl. [0307] In some embodiments, the compound is represented by Formula (Ia):

wherein the subscripts a and b, Y₁, R₁, R₂, R₃, R_4, R₅, R₆, R_7, R₈, R₉, R₁₀, R₁₁, and R₁₃ are as defined and described herein. [0308] In some embodiments, the compound is represented by Formula (Ib):

wherein the subscripts a and b, Y₂, R₁, R₂, R₃, R_4, R₅, R₆, R_7, R₈, R₉, R₁₀, R₁₁, and R₁₃ are as defined and described herein. [0309] In some embodiments, the compound is represented by Formula (Ic):

wherein the subscripts a and b, R₁, R₂, R₃, R_4, R₅, R₆, R_7, R₈, R₉, R₁₀, R₁₁, and R₁₃ are as defined and described herein. [0310] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), subscripts a and b are each 1. [0311] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁₃ is selected from the group consisting of hydrogen, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, C_3-8cycloalkyl, 3- or 6-membered heterocyclyl having 1-3 heteroatoms as ring vertices selected from N, O and S; wherein heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from the group consisting of C_1-4alkyl, –OH, -NH₂, -OR₂₁, halo, cyano and oxo. In some embodiments, R₁₃ is selected from the group consisting of hydrogen, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl. In some embodiments, R₁₃ is selected from the group consisting of hydrogen, halo, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments, R₁₃ is selected from the group consisting of hydrogen, halo, C_1-4alkyl, and C_1-4haloalkyl. In some embodiments, R₁₃ is selected from the group consisting of -CH₂OH, CF2OH, and –CHFOH. In some embodiments, R₁₃ is selected from the group consisting of hydrogen, Cl, Br, methyl, and CF₃. In some embodiments, R₁₃ is hydrogen. In some embodiments, R₁₃ is Cl. In some embodiments, R₁₃ is Br. In some embodiments, R₁₃ is methyl. In some embodiments, R₁₃ is CF₃. [0312] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is selected from the group consisting of C_6-10aryl and a 5- to 9- membered heteroaryl group having 1 to 4 heteroatoms groups as ring vertices independently selected from N, C(O), O, and S; and is unsubstituted or substituted with 1 to 5 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4haloalkyl, C_1-4aminoalkyl, C_3-8cycloalkyl, C_3-8cycloalkenyl, NR₁₅C(O)R₁₄, NR₁₅C(O)OR₁₄, NR₁₄C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₄, NR₁₅S(O)2R₁₄, C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R_16, C(O)R_14, C(O)OR_14, OR₁₄, SR₁₄, S(O)R₁₄, and S(O)₂R₁₄. [0313] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is selected from the group consisting of C_6-10aryl and a 5- to 9- membered heteroaryl group having 1 to 4 heteroatoms groups as ring vertices independently selected from N, C(O), O, and S; and is unsubstituted or substituted with 1 to 5 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4haloalkyl, C_1-4aminoalkyl, C_3-8cycloalkyl, C_3-8cycloalkenyl, NR₁₅C(O)R₁₄, NR₁₅C(O)OR₁₄, NR₁₄C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₄, NR₁₅S(O)2R₁₄, C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)2NR₁₅R₁₆, C(O)R₁₄, C(O)OR₁₄, OR₁₄, SR₁₄, S(O)R₁₄, and S(O)2R₁₄; and R₁₄, R₁₅ and R₁₆ are each independently selected from the group consisting of hydrogen, C_1-4alkyl, C_3-8cycloalkyl, C_6-10aryl and 5-10 membered heteroaryl, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of amido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0314] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is selected from the group consisting of C_6-10aryl and a 5- to 9- membered heteroaryl group having 1 to 4 heteroatoms groups as ring vertices independently selected from N, C(O), O, and S; and is unsubstituted or substituted with 1 to 5 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4haloalkyl, C_1-4aminoalkyl, C_3-8cycloalkyl, C_3-8cycloalkenyl, NR₁₅C(O)R₁₄, NR₁₅C(O)OR₁₄, NR₁₄C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₄, NR₁₅S(O)2R₁₄, C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)2NR₁₅R₁₆, C(O)R₁₄, C(O)OR₁₄, OR₁₄, SR₁₄, S(O)R₁₄, and S(O)2R₁₄; and R₁₄, R₁₅ and R₁₆ are each independently selected from the group consisting of hydrogen, C_1-4alkyl, C_3-8cycloalkyl, C_6-10aryl and 5-10 membered heteroaryl, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of halo, hydroxy, cyano, and C_1-4alkyl. [0315] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄. [0316] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_{1- 4}alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; and R₁₄ is selected from the group consisting of hydrogen, C_1-4alkyl, C_3-8cycloalkyl, C_6-10aryl and 5-10 membered heteroaryl, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of amido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0317] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; and R₁₄ is selected from the group consisting of hydrogen, C_1-4alkyl, C_3-8cycloalkyl, C_6-10aryl and 5-10 membered heteroaryl, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of halo, hydroxy, cyano, and C_1-4alkyl. [0318] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; and R₁₄ is selected from the group consisting of C_6-10aryl and a 5-10 membered heteroaryl, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of C_1-4alkylamido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0319] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; and R₁₄ is selected from the group consisting of C_6-10aryl and a 5-10 membered heteroaryl, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of halo, hydroxy, cyano, and C_1-4alkyl. [0320] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; and R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0321] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; and R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of halo, hydroxy, cyano, and C_1-4alkyl. [0322] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; and R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. [0323] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; and R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of C_1-4alkylamido and C_1-4alkyl. [0324] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl. [0325] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₂, R₃, R₁₀, and R₁₁ are independently hydrogen or C_1-4alkyl. In certain embodiments, R₂, R₃, R₁₀, and R₁₁ are each hydrogen. [0326] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₄, R₅, R₈, and R₉ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, amino, hydroxy, C_3-8cycloalkyl, and C_1-4alkylamino. In certain embodiments, R4, R5, R8, and R9 are independently hydrogen or C_1-4alkyl. In certain embodiments, R4, R5, R8, and R9 are each hydrogen. [0327] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl; and R₄, R₅, R₈, and R₉ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, amino, hydroxy, C_3-6cycloalkyl, and C_1-4alkylamino. [0328] In some embodiments of any one of Formulae (I), (Ia), (Ib), and (Ic), R₂, R₃, R₄, R₅, R₈, R₉, R₁₀ and R₁₁ are each hydrogen. [0329] In some embodiments, the compound is represented by Formula (II):

wherein R₁, R₆, R_7, and R₁₃ are as defined and described herein. [0330] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ is selected from the group consisting of amino, C_1-4aminoalkyl, and C_1-4alkylamino; and R₇ is selected from the group consisting of hydrogen, amido, cyano, halo, and hydroxy, or is selected from the group consisting of C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with one to three substituents selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. In some embodiments, R₆ is selected from the group consisting of amino, C_1-4aminoalkyl, and C_1-4alkylamino; and R₇ is selected from the group consisting of hydrogen, amido, halo, and hydroxy, or is selected from the group consisting of C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with one or two substituents selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. [0331] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ is selected from the group consisting of amino, C_1-4aminoalkyl, and methylamino. In some embodiments, R₆ is amino or C_1-4aminoalkyl. In certain embodiments, R₆ is amino, aminomethyl, or methylamino. In certain embodiments, R₆ is amino or aminomethyl. In certain embodiments, R₆ is amino. In certain embodiments, R₆ is aminomethyl. [0332] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₇ is selected from the group consisting of hydroxy, C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with one or two groups selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. In some embodiments, R₇ is selected from the group consisting of hydroxy, C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl. In some embodiments, R₇ is hydroxy, C_1-4alkyl, or C_1-4hydroxyalkyl. In certain embodiments, R₇ is C_1-4alkyl. In certain embodiments, R₇ is methyl. In certain embodiments, R₇ is ethyl. [0333] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ is C_1-4aminoalkyl; and R₇ is selected from the group consisting of hydroxy, C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with one to three groups independently selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. [0334] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ is aminomethyl; and R₇ is selected from the group consisting of hydroxy, C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl. [0335] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ is amino; and R₇ is selected from the group consisting of hydroxy, C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with one to three groups independently selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. [0336] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ is amino; and R₇ is selected from the group consisting of hydroxy, C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl. [0337] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ is amino; and R₇ is C_1-4hydroxyalkyl. In some embodiments, R₆ is amino; and R₇ is hydroxymethyl. In some embodiments, R₆ is amino; and R₇ is C_1-4alkyl. In certain embodiments, R₆ is amino; and R₇ is methyl. In some embodiments, R₆ is amino; and R₇ is ethyl. In some embodiments, R₆ is aminomethyl; and R₇ is C_1-4alkyl. In certain embodiments, R₆ is aminomethyl; and R₇ is methyl. In some embodiments, R₆ is aminomethyl; and R₇ is ethyl. [0338] In any of the above embodiments, the amido of R₇ may specifically be –C(O)NH₂. [0339] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ and R₇ together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring having 1 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O)m, and that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0340] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ and R₇ together with the carbon atom to which they are both attached form a 4- to 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), and O, and that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0341] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ and R₇ together with the carbon atom to which they are both attached form a 3- to 7-membered saturated ring having 1 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O)m, and that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0342] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ and R₇ together with the carbon atom to which they are both attached form a 4- to 6-membered saturated ring having 1 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), and O, and that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0343] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ and R₇ together with the carbon atom to which they are both attached form a 4- to 6-membered saturated ring having 1 to 3 heteroatoms or groups as ring vertices independently selected from N and O, and that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0344] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ and R₇ together with the carbon atom to which they are both attached form a 3- to 7- membered cycloalkyl ring that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0345] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₆ and R₇ together with the carbon atom to which they are both attached form a 4- to 6- membered cycloalkyl ring that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0346] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; R₆ is selected from the group consisting of amino, C_1-4aminoalkyl, and C_1-4alkylamino; and R₇ is selected from the group consisting of hydrogen, halo, and hydroxy, or is selected from the group consisting of amido, C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with one or two substituents selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. [0347] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; R₆ is amino or aminomethyl; and R₇ is selected from the group consisting of hydroxy, C_1-4alkyl, and C_1-4hydroxyalkyl. [0348] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; and R₆ and R₇ together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring having 1 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O)_m, and that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0349] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; and R₆ and R₇ together with the carbon atom to which they are both attached form a 4- to 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), and O, and that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0350] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄; R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; and R₆ and R₇ together with the carbon atom to which they are both attached form a 3- to 7- membered cycloalkyl ring that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0351] In some embodiments of any one of Formulae(I), (Ia)-(Ic), and (II), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl; R₆ is selected from the group consisting of amino, C_1-4aminoalkyl, and C_1-4alkylamino; and R₇ is selected from the group consisting of hydrogen, halo, and hydroxy, or is selected from the group consisting of amido, C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with one or two substituents selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_{1- 4}alkoxy. [0352] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl; R₆ is amino or aminomethyl; and R₇ is selected from the group consisting of hydroxy, C_1-4alkyl, and C_1-4hydroxyalkyl. [0353] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl; and R₆ and R₇ together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring having 1 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O)m, and that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0354] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl; and R₆ and R₇ together with the carbon atom to which they are both attached form a 4- to 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), and O, and that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0355] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is unsubstituted or substituted with 1, 2 or 3 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl; and R₆ and R₇ together with the carbon atom to which they are both attached form a 3- to 7- membered cycloalkyl ring that is unsubstituted or substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0356] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is selected from the group consisiting of phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazinyl, pyridazinyl, and 1,2,4-triazinyl; and is unsubstituted or substituted with 1, 2, or 3 R₁₂, wherein each R₁₂ is as defined and described herein, In some embodiments, R₁ is selected from the group consisiting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and 1,2,4-triazinyl; and is unsubstituted or substituted with 1, 2, or 3 R₁₂, wherein each R₁₂ is as defined and described herein. In some embodiments, R₁ is phenyl or pyridyl; and is unsubstituted or substituted with 1, 2, or 3 R₁₂, wherein each R₁₂ is as defined and described herein. [0357] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and 1,2,4-triazinyl; and is unsubstituted or substituted with 1, 2, or 3 R₁₂ independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄. [0358] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and 1,2,4-triazinyl; and is unsubstituted or substituted with 1, 2, or 3 R₁₂ independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl. [0359] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or pyridyl, each of which is unsubstituted or substituted with 1, 2, or 3 R₁₂ independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄. [0360] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl or pyridyl, each of which is unsubstituted or substituted with 1, 2, or 3 R₁₂ independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl. [0361] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is phenyl and is unsubstituted or substituted with 1-3 R₁₂, each of which is independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄. In some embodiments, R₁ is phenyl and is unsubstituted or substituted with 1-3 R₁₂, each of which is independently selected from the group consisting of halo, hydroxy, amino, methylamino, dimethylamino, cyano, C_1-4alkyl, C_1-4haloalkyl, and C_1-4alkoxy. In some embodiments, R₁ is phenyl and is unsubstituted or substituted with 1-3 R₁₂, each of which is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, and C_1-4alkoxy. [0362] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is pyridyl and is unsubstituted or substituted with 1-3 R₁₂, each of which is independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄. In some embodiments, R₁ is pyridyl and is unsubstituted or substituted with 1-3 R₁₂, each of which is independently selected from the group consisting of halo, hydroxy, amino, methylamino, dimethylamino, cyano, C_1-4alkyl, C_1-4haloalkyl, and C_1-4alkoxy. In some embodiments, R₁ is pyridyl and is unsubstituted or substituted with 1-3 R₁₂, each of which is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, and C_1-4alkoxy. [0363] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is selected from the group consisting of:

,

wherein each R₁₂ is as defined and described herein. [0364] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is selected from the group consisting of:

,

each R₁₂ is independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄, wherein R₁₄ is as defined and described herein. [0365] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is selected from the group consisting of:

each R₁₂ is independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl. [0366] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is selected from the group consisting of:

each R₁₂ is independently selected from the group consisting of halo, hydroxy, amino, methylamino, dimethylamino, cyano, C_1-4alkyl, C_1-4haloalkyl, and C_1-4alkoxy. [0367] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is selected from the group consisting of:

each R₁₂ is independently selected from the group consisting of halo, hydroxy, amino, methylamino, dimethylamino, cyano, C_1-4alkyl, C_1-4haloalkyl, and C_1-4alkoxy. [0368] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is selected from the group consisting of: ,

each R₁₂ is independently selected from the group consisting of halo, hydroxy, amino, methylamino, dimethylamino, cyano, C_1-4alkyl, C_1-4haloalkyl, and C_1-4alkoxy. [0369] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), each R₁₂ is independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄. In some embodiments, each R₁₂ is independently selected from the group consisting of halo, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄. In some embodiments, each R₁₂ is independently selected from the group consisting of halo, hydroxy, amino, methylamino, dimethylamino, cyano, C_1-4alkyl, C_1-4haloalkyl, and C_1-4alkoxy. In some embodiments, each R₁₂ is independently selected from the group consisting of halo, C_1-4alkyl, C_1-4alkoxy, and C_1-4haloalkyl. In some embodiments, each R₁₂ is independently selected from the group consisting of F, Cl, Br, CH₃, OCH₃, and CF₃. [0370] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), each R₁₂ is independently selected from the group consisting of F, Cl, Br, CH₃, OCH₃, CF₃,

. [0371] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is selected from the group consisting of:

each R₁₂ is independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4aminoalkyl, and OR₁₄, wherein R₁₄ is as defined and described herein. [0372] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), each R₁₂ is independently selected from the group consisting of F, Cl, Br, CH3, OCH3, CF₃, and OR₁₄; and R₁₄ is selected from the group consisting of:

[0373] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is represented by:

each R₁₂ is independently selected from the group consisting of halo, C_1-4alkyl, C_1-4alkoxy, and C_1-4haloalkyl. In some embodiments, each R₁₂ is independently selected from the group consisting of F, Cl, Br, CH3, OCH3, and CF₃. In some embodiments, each R₁₂ is Cl. [0374] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is represented by:

each R₁₂ is independently selected from the group consisting of halo, C_1-4alkyl, C_1-4alkoxy, and C_1-4haloalkyl. In some embodiments, each R₁₂ is independently selected from the group consisting of F, Cl, Br, CH3, OCH3, and CF₃. In some embodiments, each R₁₂ is independently Cl or Br. [0375] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁₄ is independently selected from the group consisting of C_6-10aryl and a 5-10 membered heteroaryl, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of C_1-4alkylamido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl. In some embodiments, R₁₄ is independently selected from the group consisting of C_6-10aryl and a 5-10 membered heteroaryl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. In some embodiments, R₁₄ is independently selected from the group consisting of C_6-10aryl and a 5-10 membered heteroaryl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of halo, hydroxy, cyano, and C_1-4alkyl. [0376] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁₄ is independently phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of C_1-4alkylamido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl. In some embodiments, R₁₄ is independently phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. In some embodiments, R₁₄ is independently phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of halo, hydroxy, cyano, and C_1-4alkyl. [0377] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. In some embodiments, R₁₄ is phenyl, unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. In some embodiments, R₁₄ is phenyl, substituted with C_1-4alkylamido. In some embodiments, R₁₄ is phenyl substituted with -C(O)NHMe. In some embodiments, R₁₄ is phenyl. In some embodiments, R₁₄ is pyrazolyl, unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. In some embodiments, R₁₄ is pyrazolyl substituted with C_1-4alkyl. In some embodiments, R₁₄ is pyrazolyl substituted with methyl. In some embodiments, R₁₄ is N- methylpyrazolyl. In some embodiments, R₁₄ is pyrazolyl. [0378] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is represented by:

each R₁₂ is independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and C_1-4aminoalkyl; and R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. [0379] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is represented by:

each R₁₂ is independently selected from the group consisting of halo, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; and R₁₄ is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. [0380] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is represented by:

each R₁₂ is independently selected from the group consisting of halo, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; and R₁₄ is selected from the group consisting of phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. [0381] In some embodiments of any one of Formulae (I), (Ia)-(Ic), and (II), R₁ is represented by:

each R₁₂ is independently selected from the group consisting of halo, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; and R₁₄ is selected from the group consisting of phenyl, phenyl substituted with C_1-4alkylamido, pyrazolyl, and pyrazolyl substituted with C_1-4alkyl. In some embodiments, each R₁₂ is independently selected from the group consisting of F, Cl, Br, CH3, OCH3, and CF₃; and R₁₄ is selected from the group consisting of phenyl, MeNHC(O)-phenyl, pyrazolyl, and N-methylpyrazolyl. In some embodiments, each R₁₂ is Cl; and R₁₄ is selected from the group consisting of phenyl, MeNHC(O)-phenyl, pyrazolyl, and N-methylpyrazolyl. [0382] In certain embodiments, the compound is represented by Formula (II):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: R₁ is phenyl or pyridyl, each of which is substituted with 0 to 3 R₁₂; each R₁₂ is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; R₆ is selected from the group consisting of amino, C_1-4aminoalkyl, and C_1-4alkylamino; R₇ is selected from the group consisting of hydrogen, cyano, amido, halo, and hydroxy, or is selected from the group consisting of C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy; R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl; and R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. [0383] In certain embodiments, the compound is represented by Formula (III):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: R₁ is phenyl or pyridyl, each of which is substituted with 0 to 3 R₁₂; each R₁₂ is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; R₆ is selected from the group consisting of amino, C_1-4aminoalkyl, and C_1-4alkylamino; R₇ is selected from the group consisting of hydrogen, cyano, amido, halo, and hydroxy, or is selected from the group consisting of C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy; R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6 dihydroxyalkyl, and C_3-8cycloalkyl; and R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. [0384] In certain embodiments, the compound is represented by Formula (IV):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: R₁ is phenyl or pyridyl, each of which is substituted with 0 to 3 R₁₂; each R₁₂ is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl; R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl; and each R^a is independently selected from the group consisting of amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0385] In certain embodiments, the compound is represented by Formula (V):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: R₁ is phenyl or pyridyl, each of which is substituted with 0 to 3 R₁₂; each R₁₂ is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; and R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl; R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl; and R^a is selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. [0386] In certain embodiments, the compound is represented by Formula (VI):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: R₁ is phenyl or pyridyl, each of which is substituted with 0 to 3 R₁₂; each R₁₂ is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; and R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl; R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl; and each R^a is independently selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. [0387] In certain embodiments, the compound is represented by Formula (VII):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: R₁ is phenyl or pyridyl, each of which is substituted with 0 to 3 R₁₂; each R₁₂ is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; and R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl; R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl; and each R^a is independently selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. [0388] In certain embodiments, the compound is represented by Formula (VIII):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: R₁ is phenyl or pyridyl, each of which is substituted with 0 to 3 R₁₂; each R₁ is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; and R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl; R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl; and each R^a is independently selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. [0389] In certain embodiments, the compound is represented by Formula (IX):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: R₁ is phenyl or pyridyl, each of which is substituted with 0 to 3 R₁₂; each R₁₂ is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; and R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl; R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl; and R^a is selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkyl, and C_1-4alkoxy. [0390] In certain embodiments, the compound is represented by Formula (X):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: R₁ is phenyl or pyridyl, each of which is substituted with 0 to 3 R₁₂; each R₁₂ is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; and R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl; R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl; and each R^a is independently selected from the group consisting of amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0391] In certain embodiments, the compound is represented by Formula (XI):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: R₁ is phenyl or pyridyl, each of which is substituted with 0 to 3 R₁₂; each R₁₂ is independently selected from the group consisting of halo, hydroxy, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄; and R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl; R₁₄ is phenyl or pyrazolyl, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl; and each R^a is independently selected from the group consisting of amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl. [0392] In some embodiement of any one of Formulae (II)-(XI), R₁, R₆, R₇, R₁₂, R₁₃, and R₁₄ may have the meanings set forth in any one or more of the selected embodiments noted above. [0393] In some embodiments of any one of Formulae (II)-(XI), R₁₃ is selected from the group consisting of hydrogen, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6dihydroxyalkyl, and C_3-8cycloalkyl. In some embodiments, R₁₃ is selected from the group consisting of hydrogen, halo, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments, R₁₃ is selected from the group consisting of hydrogen, halo, C_1-4alkyl, and C_1-4haloalkyl. In some embodiments, R₁₃ is selected from the group consisting of hydrogen, Cl, Br, methyl, and CF₃. In some embodiments, R₁₃ is hydrogen. In some embodiments, R₁₃ is Cl. In some embodiments, R₁₃ is Br. In some embodiments, R₁₃ is methyl. In some embodiments, R₁₃ is CF₃. [0394] In some embodiments of any one of Formulae (II)-(XI), R₁ is phenyl or pyridyl, each of which is substituted with 1 to 3 R₁₂. In some embodiments, R₁ is phenyl or pyridyl, each of which is substituted with 2 or 3 R₁₂. In some embodiments, R₁ is phenyl substituted with 2 or 3 R₁₂. In some embodiments, R₁ is phenyl substituted with 2 R₁₂. In some embodiments, R₁ is phenyl substituted with 3 R₁₂. In some embodiments, R₁ is pyridyl substituted with 2 R₁₂. [0395] In some embodiments of any one of Formulae (II)-(XI), each R₁₂ is independently selected from the group consisting of halo, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, and OR₁₄. In some embodiments, each R₁₂ is independently selected from the group consisting of halo, hydroxy, amino, methylamino, dimethylamino, cyano, C_1-4alkyl, C_1-4haloalkyl, and C_1-4alkoxy. In some embodiments, each R₁₂ is independently selected from the group consisting of halo, C_1-4alkyl, C_1-4alkoxy, and C_1-4haloalkyl. In some embodiments, each R₁₂ is independently selected from the group consisting of F, Cl, Br, CH3, OCH3, and CF₃. [0396] In some embodiments of any one of Formulae (II)-(XI), each R₁₂ is independently selected from the group consisting of F, Cl, Br, CH3, OCH3, CF₃,

[0397] In some embodiments of any one of Formulae (II)-(XI), R₁ is phenyl substituted with 2 R₁₂; and each R₁₂ is independently selected from the group consisting of F, Cl, Br, CH₃, OCH₃, and CF₃. In some embodiments, R₁ is phenyl substituted with 2 R₁₂; and each R₁₂ is Cl. [0398] In some embodiments of any one of Formulae (II)-(XI), R₁ is phenyl substituted with 3 R₁₂; and each R₁₂ is independently selected from the group consisting of F, Cl, Br, CH₃, OCH₃, CF₃,

[0399] In some embodiments of any one of Formulae (II)-(XI), R₁ is phenyl substituted with 3 R₁₂; the first and second R₁₂ are each Cl; and the third R₁₂ is Br. In some embodiments, R₁ is phenyl substituted with 3 R₁₂; the first and second R₁₂ are each Cl; and the third R₁₂ is selected from the group consisting of:

. [0400] In some embodiments of any one of Formulae (II)-(XI), In some embodiments, R₁₄ is phenyl, unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. In some embodiments, R₁₄ is phenyl, substituted with C_1-4alkylamido. In some embodiments, R₁₄ is phenyl substituted with -C(O)NHMe. In some embodiments, R₁₄ is phenyl. In some embodiments, R₁₄ is pyrazolyl, unsubstituted or substituted by one or two groups independently selected from the group consisting of C_1-4alkylamido, halo, hydroxy, cyano, and C_1-4alkyl. In some embodiments, R₁₄ is pyrazolyl substituted with C_1-4alkyl. In some embodiments, R₁₄ is pyrazolyl substituted with methyl. In some embodiments, R₁₄ is N-methylpyrazolyl. In some embodiments, R₁₄ is pyrazolyl. [0401] In some embodiments of Formula (II) or (III), R₆ is amino or C_1-4aminoalkyl. In certain embodiments, R₆ is amino or aminomethyl. In certain embodiments, R₆ is amino. In certain embodiments, R₆ is aminomethyl. [0402] In some embodiments of Formula (II) or (III), R₇ is hydroxy, C_1-4alkyl, or C_1-4hydroxyalkyl. In certain embodiments, R₇ is C_1-4alkyl. In certain embodiments, R₇ is methyl. In certain embodiments, R₇ is ethyl. [0403] In some embodiments of Formula (II) or (III), R₆ is amino; and R₇ is C_1-4alkyl. In certain embodiments, R₆ is amino; and R₇ is methyl. In some embodiments, R₆ is amino; and R₇ is ethyl. In some embodiments, R₆ is aminomethyl; and R₇ is C_1-4alkyl. In certain embodiments, R₆ is aminomethyl; and R₇ is methyl. [0404] In some embodiments of any one of Formulae (IV)-(XI), each R^a is independently selected from the group consisting of amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, and C_1-4haloalkyl. In some embodiments, each R^a is independently amino or C_1-4alkyl. In some embodiments, each R^a is independently amino or methyl. [0405] In some embodiments, the compound is represented by the formula selected from the group consisting of:

[0406] Also provided are embodiments wherein any embodiment above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive. [0407] As used herein, two embodiments are “mutually exclusive” when one is defined to be something which is different than the other. For example, an embodiment wherein two groups combine to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl the other group is hydrogen. Similarly, an embodiment wherein one group is CH₂ is mutually exclusive with an embodiment wherein the same group is NH. [0408] The compounds disclosed herein can exist as pharmaceutically acceptable salts. The present disclosure includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. [0409] The term “pharmaceutically acceptable” refers to those compounds (or salts, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. [0410] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and pharmaceutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L- tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like. [0411] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N- dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine. [0412] A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid. V. COMPOSITION [0413] The oral dosage form including the compound of Formula (I) or formula (10b) can be in any oral dosage forms including one or more pharmaceutically acceptable carriers and/or excipients. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. [0414] For preparing oral dosage forms including the compound of Formula (I) or formula (10b), pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA (“Remington’s”). [0415] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. [0416] The powders, capsules and tablets preferably contain from 5% to 70% of the compound of Formula (I) or formula (10b), or from about 10% to about 70% of the compound of Formula (I) or formula (10b). Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other excipients, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. [0417] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. [0418] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). Pharmaceutical preparations of the dosage forms can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the compound of Formula (I) or formula (10b) mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the compound of Formula (I) or formula (10b) may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers. [0419] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compound of Formula (I) or formula (10b) are dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. [0420] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. [0421] Aqueous solutions suitable for oral use can be prepared by dissolving the compound of Formula (I) or formula (10b) in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity. [0422] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. [0423] Oil suspensions can be formulated by suspending the compound of Formula (I) or formula (10b) in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.281:93-102, 1997. The pharmaceutical formulations including the compound of Formula (I) or formula (10b) can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent. [0424] In one aspect, the present disclosure provides a pharmaceutical composition for treating cancer in a subject, the composition including: a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, together with a pharmaceutically acceptable carrier or excipient, wherein the PTPN11 inhibitor is represented by Formula (I) as defined and described herein. [0425] The cancer and/or solid tumor are described according to Section III-2: Cancer/Solid Tumor. In some embodiments, the cancer and/or solid tumor are any of embodiments as described in Section III-2: Cancer/Solid Tumor. [0426] The subject is described according to Section III-3: Subject. In some embodiments, the subject is any of embodiments as described in Section III-3: Subject. [0427] The PTPN11 inhibitor represented by Formula (I) is described according to Section III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors. In some embodiments, the PTPN11 inhibitor of formula (I) is any of embodiments as described in Section III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors. In some embodiments, the PTPN11 inhibitor of Formula (I) is the compound of formula (10b). [0428] The PTPN11 inhibitor of Formula (I) is further described according to Section IV. Compounds. In some embodiments, the PTPN11 inhibitor of Formula (I) is any of embodiments as described in Section IV. Compounds. [0429] The PD-1/PD-L1 inhibitor is described according to Section III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors. In some embodiments, the PD-1/PD-L1 inhibitor is any of embodiments as described in Section III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors. [0430] In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, or tebotelimab. In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab. In some embodiments, when the PTPN11 inhibitor is represented by formula (10b), the PD-1/PD-L1 inhibitor is other than nivolumab. [0431] The compositions of the present disclosure (including the compound of Formula (I) and the PD-1/PD-L1 inhibitor) can be prepared in a wide variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. The compositions of the present disclosure can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compositions described herein can be administered by inhalation, for example, intranasally. Additionally, the compositions of the present disclosure can be administered transdermally. The compositions of this disclosure can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). [0432] For preparing pharmaceutical compositions of the present disclosure (including the compound of Formula (I) and the PD-1/PD-L1 inhibitor), pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA (“Remington’s”). [0433] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active components are mixed with the carrier having the necessary binding properties in suitable proportions and compacted in a particular shape and size. [0434] The powders, capsules and tablets preferably contain from about 5% to about 70% of the active compounds, such as from about 10% to about 70% of the active compounds (e.g., the compound of Formula (I) and the PD-1/PD-L1 inhibitor). Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other excipients, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. [0435] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen. Disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. [0436] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). Pharmaceutical preparations of the present disclosure can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the active compounds (e.g., the compound of Formula (I) and the PD-1/PD-L1 inhibitor) mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds (e.g., the compound of Formula (I) and the PD-1/PD-L1 inhibitor) may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers. [0437] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active compounds (e.g., the compound of Formula (I) and the PD-1/PD-L1 inhibitor) are dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. [0438] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. [0439] Aqueous solutions suitable for oral use can be prepared by dissolving the active compounds (e.g., the compound of Formula (I) and the PD-1/PD-L1 inhibitor), as defined and described herein, in water and adding optional suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity. [0440] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. [0441] Oil suspensions can be formulated by suspending the active compounds (e.g., the compound of Formula (I) and the PD-1/PD-L1 inhibitor) in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the present disclosure can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent. [0442] The compositions of the present disclosure (including the compound of Formula (I) and the PD-1/PD-L1 inhibitor) can be delivered by any suitable means, including oral, parenteral and topical methods. Transdermal administration methods, by a topical route, can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. [0443] The compositions of the present disclosure (including the compound of Formula (I) and the PD-1/PD-L1 inhibitor) can also be delivered as microspheres for slow release in the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed.7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol.49:669-674, 1997). Both transdermal and intradermal routes afford constant delivery for weeks or months. [0444] In another embodiment, the compositions of the present disclosure can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. The formulations for administration will commonly comprise a solution of the compositions of the present disclosure dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by various sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present disclosure in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol. [0445] In another embodiment, the formulations of the compositions of the present disclosure can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present disclosure into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698- 708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). [0446] Lipid-based drug delivery systems include lipid solutions, lipid emulsions, lipid dispersions, self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). In particular, SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants and co-surfactants that can disperse spontaneously in aqueous media and form fine emulsions (SEDDS) or microemulsions (SMEDDS). Lipids useful in the formulations of the present disclosure include any natural or synthetic lipids including, but not limited to, sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerol esters, Labrafil®, Labrasol®, Cremophor®, Solutol®, Tween®, Capryol®, Capmul®, Captex®, and Peceol®. [0447] The pharmaceutical formulations of the present disclosure can be provided as a salt and can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in, e.g., 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use. [0448] The pharmaceutical formulations of the present disclosure can be provided as a salt and can be formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts. VI. KITS [0449] In another aspect, the present disclosure provides a kit for treating cancer in a subject, the kit including: a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, together with instruction for effective administration, wherein the PTPN11 inhibitor is represented by Formula (I) as defined and described herein. [0450] The cancer and/or solid tumor are described according to Section III-2: Cancer/Solid Tumor. In some embodiments, the cancer and/or solid tumor are any of embodiments as described in Section III-2: Cancer/Solid Tumor. [0451] The subject is described according to Section III-3: Subject. In some embodiments, the subject is any of embodiments as described in Section III-3: Subject. [0452] The PTPN11 inhibitor represented by Formula (I) is described according to Section III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors. In some embodiments, the PTPN11 inhibitor of formula (I) is any of embodiments as described in Section III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors. In some embodiments, the PTPN11 inhibitor of Formula (I) is the compound of formula (10b). [0453] The PTPN11 inhibitor of Formula (I) is further described according to Section IV. Compounds. In some embodiments, the PTPN11 inhibitor of Formula (I) is any of embodiments as described in Section IV. Compounds. [0454] The PD-1/PD-L1 inhibitor is described according to Section III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors. In some embodiments, the PD-1/PD-L1 inhibitor is any of embodiments as described in Section III-1: PTPN11 Inhibitors and/or PD-1/PD-L1 Inhibitors. [0455] In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, or tebotelimab. In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab. In some embodiments, when the PTPN11 inhibitor is represented by formula (10b), the PD-1/PD-L1 inhibitor is other than nivolumab. [0456] In some embodiments, the kit includes instructions for administration of the compound of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor. In some embodiments, the kit includes instructions for administration of the compound of formula (10b) and the PD-1/PD-L1 inhibitor. In some embodiments, such instructions include directions relating to safety provisions as well as timing and amounts of administration of the compound of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor. In some embodiments, such instructions include directions relating to safety provisions as well as timing and amounts of administration of the compound of formula (10b) and the PD-1/PD-L1 inhibitor. [0457] The PTPN11 inhibitor represented by Formula (I) or formula (10b) as described herein and the PD-1/PD-L1 inhibitor as described herein can be are formulated for concomitant administration or sequential administration. In some embodiments, the PTPN11 inhibitor of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor are formulated for concomitant administration. In some embodiments, the PTPN11 inhibitor of Formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor are formulated for sequential administration. In some embodiments, the PTPN11 inhibitor of Formula (I) or formula (10b) is administered prior to the administration of the PD-1/PD-L1 inhibitor. In some embodiments, the PTPN11 inhibitor of Formula (I) or formula (10b) is administered after the administration of the PD-1/PD-L1 inhibitor. VII. LIST OF ABBREVIATIONS

VIII. EXAMPLES Example 1: Evaluation of Combination of PD-1/PD-L1 Inhibitor and PTPN11 Inhibitor CD8+ activation in peripheral blood mononuclear cells (PBMCs) [0458] A study was performed to evaluate the effect of the SHP2 inhibitor Compound (10b) response to antigenic stimulation. PBMCs from four healthy donors were stimulated with a After the initial CEFT stimulation, the cultures were rested and cytokines were added to expand the number of responding CD8+ T cells. Cells were then restimulated with the CEFT peptide pool for 24 hours, and the frequency of CD107a+ cells as a percentage of total CD8+ T cells was assessed by flow cytometry. In addition, at 5 days post stimulation, the supernatents were FIG. 1A-FIG.1B include results from this study. The results showed that donors 2 and 4 had strong recall responses to CEFT stimulation, while donors 1 and 3 had milder responses. The addition of the SHP2 inhibitor Compound (10b) to the assay resulted in mixed effects between donors, which was likely to be caused by the variability in antigen-specific precursor frequencies between donors. [0459] For donor 1, there was a clear Compound (10b) dose-dependent effect and the of CD8+ T cells, as indicated by higher levels of CD107a+CD8+ T cells. For donor 3, there was synergy, resulting in improved activation of CD8+ T cells, as indicated by higher levels of CD107a+CD8+ T cells. For donor 2, the addition of Compound (10b) resulted in a dose dependent decrease in the percentage of CD107a+CD8+ T cells, and there was no synergy with were inconsistent across donors (data not shown). These results indicate a possible role for weak or sub-optimal CD8+ T cell responses. Example 2: A Clinical Study of the SHP2 Inhibitor Compound (10b) in Combination with a Programmed Death Receptor-1 Blocking Antibody in Patients with a Solid Tumor [0460] A clinical study of the SHP2 inhibitor compound (10b) in combination with a PD- 1/PD-L1 inhibitor (e.g., a PD-1/PD-L1 inhibitor other than nivolumab) can be performed. Subjects of the study have a solid tumor such as non-small cell lung cancer (NSCLC), such as NSCLC characterized by a KRAS mutation (e.g., a KRAS mutation other than a Q61 mutation, such as a mutation at codon 12 or 13). The subject may have previously completed a standard of care treatment. [0461] The clinical study may include a dose escalation phase to evaluate the safety, tolerability, and recommended phase 2 dose (RP2D) of compound (10b) when used in combination with the PD-1/PD-L1 inhibitor. Additional objectives for the dose escalation study may include assessment of preliminary antitumor activity of Compound (10b) in combination with the PD-1/PD-L1 inhibitor (as defined by objective response rate [ORR, complete response (CR) + partial response (PR) rate], duration of response [DOR], and progression free survival [PFS] according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and as assessed by investigator, and overall survival [OS]); characterization of the pharmacokinetics (PK) of Compound (10b) and the PD-1/PD-L1 inhibitor given in combination (e.g., area under the curve [AUC], maximum drug concentration [C_max], time to C_max [T_max], half-life) of Compound (10b) and the PD-1/PD-L1 inhibitor from plasma or serum concentration-time data); characterization of circulating and intratumoral target engagement (pharmacodynamic activity) of Compound (10b) in combination with the PD-1/PD-L1 inhibitor (e.g., raw, normalized, and/or baseline adjusted analyte signal in circulating and intratumoral target engagement biomarkers of Compound (10b) activity in combination with the PD-1/PD-L1 inhibitor); and characterization of the immunogenicity of the PD-1/PD-L1 inhibitor when given in combination with Compound (10b). Peripheral and intratumoral biomarkers may also be assessed. The dose escalation phase may include, e.g., 5-10 patients. [0462] The clinical study may also include a dose expansion/optimization period to evaluate the antitumor activity of Compound (10b), as defined by the ORR (per investigator) according to RECIST v1.1, when used in combination with the PD-1/PD-L1 inhibitor in subjects (e.g., subjects with advanced NSCLC with a KRAS mutation who have failed standard of care treatment). Additional objectives for the dose expansion/optimization study may include assessment of additional measures of antitumor activity of Compound (10b) in combination with the PD-1/PD-L1 inhibitor, including ORR (per blinded independent central review [BICR]) and DOR and PFS (per investigator and BICR), as defined by RECIST v1.1, and OS; assessment of safety and tolerability of Compound (10b) at the RP2D, in combination with the PD-1/PD-L1 inhibitor; characterization of the PK of Compound (10b) and the PD-1/PD-L1 inhibitor given in combination; characterization of circulating and intratumoral target engagement (pharmacodynamic activity) of Compound (10b) in combination with the PD-1/PD-L1 inhibitor; and characterization of the immunogenicity of the PD-1/PD-L1 inhibitor when given in combination with Compound (10b). Peripheral and intratumoral biomarkers may also be assessed. The dose expansion/optimization phase may include, e.g., 10-30 patients. [0463] The PD-1/PD-L1 inhibitor used in the clinical study may be, for example, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, or tebotelimab. The PD-1/PD-L1 inhibitor may be administered by IV infusion. [0464] Compound (10b) is as described herein. Compound (10b) may be administered as oral capsules of, e.g., 50 and 100 mg. [0465] Subjects in the study may have had had at least one previous line of treatment which included platinum-based doublet chemotherapy and anti-PD-(L)1 therapy, either given as one line or individual lines of therapy. Subjects in the study may have a solid tumor, such as a solid tumor characterized by a KRAS mutation (e.g., a mutation in codon 12 or 13, as described herein). For examples, subjects in the study may have NSCLC with a KRAS mutation. Inclusion Criteria [0466] Patients participating in the clinical study will meet the inclusion criteria listed below (as applicable): 1. the Screening visit as well as comply with all study visits and requirements through the end of the study. 2. Have documentation of a KRAS mutation from local or central laboratory testing in tumor samples collected within the 1 year prior to screening. 3. Have measurable disease by RECIST v1.1. 4. Have minimum life expectancy of >12 weeks. 5. Women must have a negative serum human chorionic gonadotropin test if of childbearing hysterectomy, or have had menopause (defined as 12 consecutive months of amenorrhea and confirmed by follow up hormone level assessment). 6. Patients of childbearing potential must use 2 methods of contraception for the duration of the study and for at least 5 months after the last dose of study treatment for female patients or 105 days after the last dose of study treatment for male patients, whichever is later for the individual patient. Female patients should not become pregnant or breastfeed while on this study. Female and male patients must also agree not to donate eggs (ova, oocytes) or sperm for the purpose of reproduction for at least 5 months or 105 days after the last dose of study treatment, respectively. 7. Have histologically documented, locally advanced and unresectable, or metastatic NSCLC. 8. Have progression or disease recurrence on or after at least one prior line of systemic therapy, which must include platinum-based doublet chemotherapy and anti-PD-(L)1 therapy, either given as one line or individual lines of therapy. 9. Experienced radiologically documented progressive or recurrent disease occurring either during treatment or within 90 days after discontinuing anti-PD-(L)1 therapy. 10. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 with no deterioration over the previous 2 weeks. Exclusion Criteria [0467] Patients who meet any of the exclusion criteria listed below will not be eligible for participation in the study. 1. Have participated in an interventional clinical study within the last 4 weeks OR, if applicable, be within 5 times the half-life of the investigational study drug, whichever is lesser, prior to the C₁D1 visit. Patients should always adhere to other eligibility criteria that apply to specified concomitant medication regarding washout periods as specified below. 2. Have received radiotherapy or proton therapy with a limited field of radiation for palliation within 1 week of the start of study treatment, OR radiation to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the start of study treatment. 3. Have taken any of the following: a. Strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4 or P- glycoprotein (P-gp) inducers or inhibitors (including herbal supplements or food products containing grapefruit juice, star fruit, or Seville oranges) within 14 days or 5 half-lives (whichever is longer) of Cycle 1 Day 1, and/or b. Drugs that are known substrates of P-gp, breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein (MATE) 1 or MATE2-K, unless stopped 7 days prior to Cycle 1 Day 1 and for the study duration. 4. Have inadequate organ function as defined below: Hematological e. White blood cell count <2,000/µL f. Absolute neutrophil count <1,500/µL g. Platelets <100,000/µL h. Renal e. (measured or calculated using the Cockcroft-Gault formula) Hepatic g. institutional ULN if the patient has a diagnosis of Gilbert syndrome or hemolytic anemia as confirmed by the investigator h. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) and/or alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) >2.5×ULN Coagulation i. International normalized ratio (INR) or prothrombin time (PT) >1.5×ULN unless the patient is receiving anticoagulant therapy and as long as PT or activated partial thromboplastin time (aPTT) is within the therapeutic range of intended use of anticoagulants j. Activated partial thromboplastin time >1.5×ULN unless the patient is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants 5. Have active Hepatitis B infection (defined by the presence of hepatitis B surface antigen [HBsAg] or the presence of hepatitis B virus [HBV] DNA), hepatitis C infection (defined by the presence of hepatitis C virus [HCV] antibody and positive HCV RNA), or human immunodeficiency virus (HIV) infection with measurable viral load. 6. Have a life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction (such as ascites, coagulopathy, or encephalopathy), or other reasons which, in the investigator’s opinion, could compromise the participating patient’s safety, or interfere with or compromise the integrity of the study outcomes. 7. Have any of the following cardiac-related issues or findings: a. History of significant cardiovascular disease, such as cerebrovascular accident, myocardial infarction or unstable angina, within the last 6 months before starting study treatment. b. Clinically significant cardiac disease, including New York Heart Association Class II or higher heart failure. c. History of left ventricular ejection fraction (LVEF) <50% within the previous 12 months before starting study treatment. d. Resting corrected QT interval (QTc) >470 msec, derived as the averaged from three electrocardiograms (ECGs), using the ECG machines provided by the sponsor for study purposes. e. Any clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., third degree heart block, Mobitz Type II heart block, ventricular arrhythmias, uncontrolled atrial fibrillation). 8. Have a diagnosis of another invasive malignancy within the previous 3 years other than curatively treated non-melanomatous skin cancer, superficial urothelial carcinoma, in situ cervical cancer, or any other curatively treated malignancy that is not expected to require treatment for recurrence during the course of the study. 9. Have untreated brain metastases from non-brain tumors. Patients who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to Cycle 1, Day 1 are eligible if they meet all of the following criteria prior to first dose of study medication: a) residual neurological symptoms related to the CNS treatment Grade least 2 weeks prior to Cycle 1, Day 1, if applicable; and c) follow-up magnetic resonance imaging (MRI) within 4 weeks prior to C1D1 shows no new lesions appearing. 10. Have undergone major surgery within 4 weeks prior to study enrollment. Note: This does not include patients who have had procedures such as peripherally inserted central catheter line placement, thoracentesis, paracentesis, biopsies, or abscess drainage. 11. Have a history of hypersensitivity to the PD-1/PD-L1 inhibitor or Compound (10b), active or inactive excipients of the PD-1/PD-L1 inhibitor or Compound (10b) or drugs with a similar chemical structure or class to either the PD-1/PD-L1 inhibitor or Compound (10b), dependent on which combination the patient could receive. 12. Have tumors harboring known activating mutations in BRAF V600X, PTPN11 (SHP2), or KRAS Q61X. 13. Have previously received a SHP2 inhibitor (eg, TNO-155, RMC-4630, RLY-1971, JAB- 3068, JAB-3312 and PF-07284892). 14. Have gastrointestinal illness that, in the opinion of the investigator, would preclude absorption of Compound (10b) (e.g., post gastrectomy, short bowel syndrome, uncontrolled Crohn’s disease, celiac disease with villous atrophy, or chronic gastritis). 15. Are on dialysis. 16. Have a history of allogenic bone marrow transplant. 17. Are unable to swallow oral medications (capsules, tablets) without chewing, breaking, crushing, opening, or otherwise altering the product dosage form. 18. Experienced progressive disease (PD) within the first 120 days of initiating treatment with an anti-PD-(L)1 agent (e.g., primary refractory). 19. required discontinuation of therapy. 20. Have known or suspected autoimmune disease, except patients are permitted to enroll in cases of type 1 diabetes, hypothyroidism only requiring hormone replacement, skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions no expected to recur in the absence of an external trigger. 21. Have a condition requiring systemic treatment with either corticosteroids (>10 mg prednisone equivalent) or other immunosuppressive medication within 14 days of Cycle 1 Day 1. Inhaled or topical steroids, and adrenal replacement steroids >10 mg prednisone equivalent are permitted in the absence of active autoimmune disease. 22. Have received any live/attenuated vaccine within 30 days of first study treatment. Study Design [0468] A study may include an initial screening period (e.g., a 30 day screening period), followed by a treatment period including multiple consecutive treatment cycles and a subsequent post-treatment follow up period. Dosing may continue for 1 or more years unless a patient is discontinued from study treatment or withdrawn from the study. [0469] A dose escalation phase of a clinical study may follow a Bayesian optimal interval (BOIN) design. Three dose levels of Compound (10b) may be used in the dose escalation study, such as 250mg, 400mg, and 550mg. The PD-1/PD-L1 inhibitor will be administered in combination with Compound (10b) at appropriate dosing, such as dosing approved by the Food and Drug Administration. Such dosing may be, e.g., between about 10-2000 mg every 1, 2, 3, 4, 5, or 6 weeks. The dose escalation phase will be used to determine an RP2D that will be used in the dose escalation phase of the study. [0470] In a dose escalation phase of a clinical study, subjects will receive compound (10b) at the RP2D from the dose escalation phase in combination with the PD-1/PD-L1 inhibitor. Depending on the results of the dose escalation phase, one or more additional cohorts including dosing of compound (10b) at different dosing levels may be used. [0471] Dosing of compound (10b) or the PD-1/PD-L1 inhibitor may be adjusted, e.g., in the event of drug-related adverse events. [0472] The clinical study may be further expanded to incorporate a “triplet” therapy including the PTPN11 inhibitor, the PD-1/PD-L1 inhibitor, and a KRAS G12C inhibitor such as sotorasib (AMG-510), adagrasib (MRTX-849), MRTX1257, ARS-853, ARS-1620, JNJ-74699157(ARS- 3248), LY3537982, or LY3499446. [0473] FIG.2 shows a clinical study of the SHP2 Inhibitor Compound (10b) in combination with a PD-1/PD-L1 inhibitor in patients with solid tumors (e.g., non-small cell lung cancer (NSCLC)). The study design includes a dose escalation and a dose expansion/optimization. [0474] FIG.3 shows a flowchart for a trial conducted using the BOIN Design. Abbreviations: BOIN=Bayesian optimal interval design; DLT=dose limiting toxicity; MTD=maximum tolerated dose. Note: e = 19.7% and d = 29.8%. In practice, with 6 patients/cohort, if the DLT rate is Example 3: Combination of Formula (10b) and anti-PD-1 in CT-26 CRISPR Knock-In KRAS D12C - In Vivo Efficacy A. MATERIALS [0475] Test article #1 - formula (10b) [0476] Test article #2 – ANTIBODY A; Variable region epitope: Mouse PD-1; Constant region: Mouse Immunoglobulin G1 (IgG1); engineered with a single amino acid substitution, aspartic acid to alanine at codon 265 (D265A), which prevents Fc receptor binding; and Molecular weight: ~150 kDa. [0477] Isotype Control article #1 - MOPC-21, InVivoMAb mouse IgG1 Isotype Control; Variable region epitope: unknown specificity; Constant region: Mouse Immunoglobulin G1 (IgG1); and Molecular weight: ~150 kDa. B. EXPERIMENTAL PROCEDURES [0478] Animal Receipt and Housing. For the CT-26 CRISPR knock-in KRAS D12C study, protocols and procedures involving the care and use of animals were reviewed and approved by the Charles River Accelerator and Development Lab (CRADL) Institutional Animal Care and Use Committee (IACUC) prior to execution. The animal care and use program has been fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). Balb/c female mice (Envigo; Inotiv Inc.) were ordered, aged six to eight weeks at receipt, and identified by ear notch. Animals were acclimated for a period of eleven days prior to tumor inoculation. For the duration of the acclimation period and throughout the study, mice were group-housed up to five animals per cage in disposable polycarbonate IVC cages (Innovive; San Diego, CA) which consisted of a layer of Alpha-Dri bedding (Sheppard Specialty Papers, Inc., Kalamazoo, MI), a certified enrichment block and diamond-twist, and a certified polycarbonate housing device. Mice were presented with rodent diet pellet and irradiated reverse-osmosis Aquavive^® drinking water (Innovive; San Diego, CA), ad libitum. The vivarium temperature was maintained between 20°C through 26°C and an environmental humidity between 30% through 70%. The interior room lighting was cycled twelve hours on and twelve hours off. [0479] Tumor Cell Line Culture and Inoculation. The murine colon carcinoma CT-26 cell line was genetically engineered by CRISPR technology to edit the three endogenous loci of KRAS with D12C, and internally registered at BMS as BXA-229794-02-001. Cells were screened and confirmed negative for mouse pathogens (IDEXX) and maintained in-vitro at 37°C, 5% CO2 atmosphere in 10% (v/v) fetal bovine serum (FBS, Invitrogen) and 90% (v/v) Roswell Park Memorial Institute (RPMI) 1640 Medium (Gibco) on T150 flasks. For implantation, cells were harvested with 0.25% Trypsin-EDTA (Gibco), washed in DPBS (Gibco), counted and viability determined with trypan blue exclusion using Vi-Cell XR (Beckman Coulter), then brought up in a 1:1 ratio of DPBS:Matrigel to a final concentration of 3x10⁶ cells/mL. The single-cell suspension was implanted into the subcutaneous right hind flank region of each mouse, 3 x 10⁵ cells, at a volume of 0.1 mL per mouse. [0480] Group Assignment and Dosing. Following sixteen days post inoculation, Balb/c mice were assigned to a treatment group, with each group consisting of n=10 mice. A ‘stratified’ randomization method by tumor volume was selected (StudyLog^® Desktop software, version 4.5.5.523) whereby group mean tumor volumes averaged about 191 mm³. [0481] CT-26 KRAS D12C KI tumor-bearing female Balb/c mice (10 animals/group) were administered one of the following treatment regimens until reaching an experimental endpoint: 1) a combination of vehicle control (0.5% v/v methyl cellulose in sterile deionized water) (PO, QDx35) and MOPC-21 isotype control antibody (10 mg/kg PO, Q4Dx4), 2) ANTIBODY A (10 mg/kg IP, Q4Dx4), 3) formula (10b) (100 mg/kg PO, QDx35), 4) a combination of ANTIBODY A (10 mg/kg IP, Q4Dx4) and formula (10b) (100 mg/kg PO, QDx35). [0482] Formula (10b) Formulation. Formula (10b) formulation buffer (0.5% v/v methyl cellulose in sterile deionized water) was prepared once per month by weighing the desired amount of methyl cellulose 400 cp (e.g., Sigma-Aldrich, catalog M0262, viscosity 400 cP) into a glass bottle. Sterile deionized water equivalent to 75% v/v of the intended final volume was added under continuous magnetic stirring with a stir bar and stirred at room temperature until complete dissolution. The buffer was then brought to the final volume with sterile deionized water. [0483] Formula (10b) working suspensions of 10 mg/mL of active pharmaceutical ingredient (10.22 mg/mL with correction factor) were prepared weekly and administered daily for up to 35 days at a 10 mL/kg dose volume by oral gavage to mice for the 100 mg/kg dose level, starting on Study Day 1. A correction factor of 1.022 was applied to the formula (10b) formulation to accommodate for the purity (97.8%). To prepare formula (10b) formulations, compound was accurately weighed into a glass vial. Formula (10b) formulation buffer equivalent to 70% v/v of the intended final volume was added to the glass vial containing drug substance and mixed well using a 1/4-inch probe for 4 to 9 minutes until a homogeneous suspension was achieved with no large visible agglomerates or particles. The rest of the suspending vehicle was added to reach the intended final volume to the dispersion containing drug substance. The suspension was throughout dosing each day. [0484] ANTIBODY A Formulation. ANTIBODY A is a murine anti-PD-1 murine engineered with a single amino acid substitution, aspartic acid to alanine at codon 265 (D265A), which prevents Fc receptor binding. Stock solution was stored in a monitored 2°C through 8°C refrigerator. Dosing solutions were prepared once per study to a 1 mg/mL concentration by dilution into PBS, pH 7.2, aliquoted and stored into sterile containers, and kept at 2°C through 8°C for the length of the dosing period. The 1 mg/mL ANTIBODY A formulation was administered every four days for four doses (Q4Dx4), starting on Study Day 1, at 10 mL/kg dose volume by intraperitoneal to mice for a 10 mg/kg dose level. [0485] MOPC-21 Isotype Control Antibody Formulation. MOPC-21 is a mouse IgG1 isotype control antibody, manufactured by BioXCell, lot 78512101 and stock concentration 10.22 mg/mL. The fragment antigen-binding site (Fab) size has unknown specificity to an antigen. Stock material was stored in a monitored 2°C through 8°C refrigerator. Dosing solutions were prepared to 1 mg/mL concentration by dilution into PBS, pH 7.2, aliquoted and stored into sterile containers, and kept at 2°C through 8°C for the length of the dosing period. The 1 mg/mL MOPC-21 formulation was administered every four days for four doses (Q4Dx4), starting on Study Day 1, at 10 mL/kg dose volume by intraperitoneal to mice for a 10 mg/kg dose level. [0486] Tumor and Body Weight Measurements. Tumor length [mm] and width [mm] were measured two times per week using a caliper, and the tumor volume [mm³] calculated using the formula: Tumor volume = (length x width²)/2, where length was defined as the longest tumor diameter and width was defined as the shortest tumor diameter. [0487] Mouse body weights were recorded once weekly following randomization. [0488] Calculations and Statistical Analyses. Median tumor volume and progression-free to tumor burden endpoint graphs, as well as median progression-free, hazard ratio and statistical analyses, were generated from GraphPad Prism software (version 9). [0489] Median tumor volumes were calculated from each group to qualify efficacy of treatment prior to mice reaching tumor burden. If a mouse reached tumor burden in a particular group, the last recorded tumor volume was extended and included in later median calculations until the calculated median was greater than any single extended value, or until 50% or more of the mice in that group reached tumor burden. If a decedent was discovered prior to reaching an experimental endpoint, such as dosing error, individual tumor volume values from that subject were not included in the median for any timepoint. [0490] A Kaplan-Meier plot was generated to evaluate the cumulative percentage to tumor burden endpoint of mice following treatment. A tumor burden endpoint was defined as a subject reaching an experimental endpoint of tumor burden with a recorded volume of 1,500 mm³ or greater. A hazard ratio, identifying the tumor burden incidence rate was calculated using the Mantel-Haenszel method. [0491] A p-value of less than 0.05 was considered statistically significant following a Log- rank (Mantel-Cox) test comparing the combination formula (10b) plus ANTIBODY A against ANTIBODY A alone. [0492] Experimental Endpoints. Following tumor cell inoculation, animals were checked daily for morbidity and mortality. During routine monitoring, animals were checked for any effects of tumor growth and treatments on behavior such as mobility, food and water consumption, body weight gain/loss, eye/hair matting and any other abnormalities. Mice were euthanized if they lost over 20% of their body weight relative to the weight on the first day of treatment. Additionally, mice were euthanized if significant adverse changes were noted to the animal’s general welfare. A mouse was euthanized for tumor burden if the calculated tumor 3. The study commenced once all mice reached tumor burden, determined as Study Day 35. C. RESULTS [0493] This study was performed to determine if the combination of the SHP2 inhibitor, formula (10b), and the murine anti-PD-1, ANTIBODY A, enhanced anti-tumor activity over either agent alone in vivo. The study was performed in the syngeneic CRC CT-26 model with a CRISPR engineered KRAS D12C knock-in mutation at all three endogenous loci. [0494] Treatment with the combination of SHP2i, formula (10b), and anti-PD-1, ANTIBODY A, resulted in delayed progression to tumor burden in the subcutaneous CT- 26 syngeneic model harboring KRAS D12C KI mutations. An in vivo study was conducted to evaluate the impact of formula (10b) in combination with the murine anti-PD-1 antibody, ANTIBODY A, on tumor volume in Balb/c mice bearing the cell line-derived CT-26 CRC syngeneic model, which harbored a KRAS D12C mutation at all three endogenous loci. [0495] Following once daily oral administration of formula (10b) (100 mg/kg) for 35 days, or intraperitoneal administration of ANTIBODY A (10 mg/kg) every-four days for four doses, or in combination with formula (10b) (100 mg/kg) plus ANTIBODY A (10 mg/kg), a delay in progression to tumor burden was observed in the combination arm treated with formula (10b) and ANTIBODY A (FIG.4 and FIG.6). In FIG.4: Tumor burden endpoint was defined as the tumor burden endpoint where a subject was recorded with a tumor volume >1,500 mm³. Study Day 1 was defined as the first day of dosing. [0496] As shown in Table 1, the median increased increased by nine days following administration of the combination formula (10b) plus ANTIBODY A compared to either agent alone or was increased by thirteen days when compared to the vehicle plus isotype control. Table 1: Summary of Median Progression-Free to Tumor Burden Endpoint in CT-26 Bearing Balb/c Mice with KRAS D12C KI Following Administration of Vehicle plus Isotype Control, or Formula (10b) and ANTIBODY A Alone or in Combination

Abbreviations: Balb/c = Bagg Albino; KRAS = Kirsten rat sarcoma viral oncogene homolog; D12C = aspartic acid to cysteine at amino acid codon number twelve; KI = Knock-In; n=number. Note: Tumor burden endpoint was defined where a subject was recorded with a tumor volume >1,500 mm³. Study Day 1 was defined as the first day of dosing. [0497] As shown in FIG. 5, a statistically significant delay in progression to tumor burden endpoint was observed, p = 0.0309, when evaluating the benefit of adding the SHP2 inhibitor, formula (10b), to mice receiving the mouse surrogate for anti-PD-1 therapy, ANTIBODY A, from the two progression-free curves using the Log-rank (Mantel-Cox) test. In FIG. 5, Abbreviations: *, p < 0.05. Comparison of progression-free curve ANTIBODY A versus combination with Formula (10b) performed with the Log-rank (Mantel-Cox) test. Tumor burden endpoint was defined as the tumor burden endpoint where a subject was recorded with a tumor volume >1,500 mm³. Study Day 1 was defined as the first day of dosing. [0498] In addition, Mantel-Haenszel hazard ratios were determined on each permutation between pairs of progression-free to tumor burden endpoint curves. In all comparisons, a reduced hazard ratio incidence rate was found in subjects receiving formula (10b) and ANTIBODY A in combination compared to those receiving either treatment alone, or to subjects receiving the vehicle plus isotype control (Table 2). Table 2: Summary of the Hazard Ratio in CT-26 Bearing Balb/c Mice with KRAS D12C KI Following Administration of Vehicle plus Isotype Control, Formula (10b) and ANTIBODY A Alone or in Combination

Abbreviations: Balb/c = Bagg Albino; KRAS = Kirsten rat sarcoma viral oncogene homolog; D12C = aspartic acid to cysteine at amino acid codon number twelve; KI = Knock-In; n=number; n/a = not applicable. Note: Hazard Ratio determined using the Mantel-Haenszel test based on progression-free to tumor burden endpoint curves. Tumor burden endpoint was defined where a subject was recorded with a tumor volume >1,500 mm³. Study Day 1 was defined as the first day of dosing. D. CONCLUSIONS [0499] The result from this in vivo study demonstrates that the addition of SHP2 inhibitor, formula (10b), combined with a mouse surrogate for nivolumab, i.e., a murine anti-PD-1 antibody ANTIBODY A, showed a significant delay to tumor burden compared to anti-PD-1 treatment alone in the engineered KRAS D12C knock-in colorectal carcinoma CT-26 syngeneic model. The in-vivo study supports the clinical evaluation of the combination SHP2 inhibitor plus anti-PD-1 therapy, such as nivolumab, and shows that SHP2 inhibition by formula (10b) may potentiate the response of the anti-PD-1 antibody. [0500] Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

WHAT IS CLAIMED IS: 1. A method of treating cancer in a subject, comprising administering to the subject: a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PTPN11 inhibitor is represent by formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein: subscript a is 0 or 1; subscript b is 0 or 1; Y₁ is a direct bond or CR₁₇R₁₈; Y₂ is selected from the group consisting of C_1-4alkyl, amino, C_1-4alkylC(O)O-, C_1-4alkylamino and C_1-4aminoalkyl; R₁ is selected from the group consisting of C_6-10aryl, C_3-8cycloalkyl, C_3-8cycloalkenyl, and a 5-10 membered heteroaryl group having 1 to 4 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S; said aryl or heteroaryl of R₁ is unsubstituted or substituted with 1 to 5 R₁₂ groups independently selected from the group consisting of halo, hydroxy, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4haloalkyl, C_1-4aminoalkyl, C_3-8cycloalkyl, C_3-8cycloalkenyl, NR₁₅C(O)R₁₄, NR₁₅C(O)OR₁₄, NR₁₄C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₄, NR₁₅S(O)2R₁₄, C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)2NR₁₅R₁₆, C(O)R₁₄, C(O)OR₁₄, OR₁₄, SR₁₄, S(O)R₁₄, and S(O)2R₁₄; R2, R₃, R10, and R11 are each independently selected from the group consisting of hydrogen, C_1-4alkyl, and C_3-8cycloalkyl; R4, R5, R8, and R9 are each independently selected from the group consisting of hydrogen, cyano, C_1-4alkyl, C_1-4alkoxy, amino, hydroxy, C_3-8cycloalkyl, halo, and C_1-4alkylamino; R₆ is selected from the group consisting of amino, C_1-4aminoalkyl, and C_1-4alkylamino; R₇ is selected from the group consisting of hydrogen, amido, cyano, halo, and hydroxy, or is selected from the group consisting of C_1-4alkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, phenyl, and 5- or 6- membered heteroaryl, any of which is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino, and C_1-4aminoalkyl; or R₆ and R₇ together with the carbon atom to which they are both attached form a 3- to 7- membered saturated or unsaturated ring, having 0 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O)m; subscript m is 0, 1, or 2; and said saturated or unsaturated ring formed by R₆ and R₇ is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; any two groups of R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₁ can form a 5 to 6 membered ring, having 0 to 2 heteroatoms as ring vertices elected from N, O and S; any two groups of R₂, R₄, R₆, R₈ and R₁₀ can form a direct bond, or a 1 or 2 atom carbon bridge; R₁₃ is selected from the group consisting of hydrogen, halo, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6 dihydroxyalkyl, -NH-NHR₁₉, -NHR₁₉, -OR₁₉, -NHC(O)R₁₉, -NHC(O)NHR₁₉, -NHS(O)2NHR₁₉, -NHS(O)2R₁₉, -C(O)OR₁₉, -C(O)NR₁₉R₂₀, -C(O)NH(CH₂)qOH, -C(O)NH(CH₂)qR₂₁, -C(O)R₂₁, -NH₂, -OH, -S(O)₂NR₁₉R₂₀, C_3-8cycloalkyl, aryl, heterocyclyl having 1-5 heteroatoms as ring vertices selected from N, O, S and P, and heteroaryl having 1-5 heteroatoms as ring vertices selected from N, O, S and P; subscript q is an integer of from 0 to 6; and each of aryl, heteroaryl, heterocyclyl and cycloalkyl of R₁₃ is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of C_1-4alkyl, –OH, -NH₂, -OR₂₁, halo, cyano, and oxo; R₁₄, R₁₅ and R₁₆ are each independently selected from the group consisting of hydrogen, C_1-4alkyl, C_3-8cycloalkyl, C_6-10aryl and 5-10 membered heteroaryl, any of which is unsubstituted or substituted with one or more groups independently selected from the group consisting of amido, amino, halo, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkylamino and C_1-4aminoalkyl; R17 and R18 are each independently selected from the group consisting of hydrogen, C_1-4alkyl, and CF₃; R₁₉ and R₂₀ are each independently selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl and C_3-6cycloalkyl; and each R₂₁ is independently selected from the group consisting of hydrogen, -OH, C_1-6 alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl and C_3-6cycloalkyl.

2. The method of claim 1, wherein the PTPN11 inhibitor is selected from the group consisting of:

,

. 3. The method of claim 1 or 2, wherein the PTPN11 inhibitor is represented by formula (2b):

having the name of 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(R_a)-(2,

3- dichlorophenyl)-2-methyl-4(3H)-pyrimidinone.

4. The method of claim 1 or 2, wherein the PTPN11 inhibitor is represented by formula (10b):

having the name of 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(R_a)-(2,3- dichlorophenyl)-2,5-dimethyl-4(3H)-pyrimidinone.

5. The method of claim 4, wherein the PD-1/PD-L1 inhibitor is other than nivolumab.

6. The method of any one of claims 1 to 4, wherein the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, or tebotelimab, provided that, when the PTPN11 inhibitor is represented by formula (10b), the PD-1/PD-L1 inhibitor is other than nivolumab.

7. The method of any one of claims 1 to 6, wherein the cancer expresses PD- L1, the cancer displays a high level of microsatellite instability (MSI-H), a deficient mismatch repair (dMMR), or a high level of tumor mutational burden (TMB-H), or the cancer is a KRAS- positive cancer.

8. The method of any one of claims 1 to 7, wherein the cancer comprises a solid tumor and/or a liquid tumor.

9. The method of any one of claims 1 to 8, wherein the cancer is anal cancer, biliary tract cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer (CRC), endometrial cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), merkel cell carcinoma, melanoma, mesothelioma, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, renal cell carcinoma (RCC), small cell lung cancer (SCLC), squamous cell carcinoma (SCC), triple negative breast cancer (TNBC), or a combination thereof.

10. The method of claim 9, wherein the cancer is colorectal cancer (CRC) or non-small cell lung cancer (NSCLC).

11. The method of any one of claims 1 to 10, wherein the cancer is resistant to a PD-1/PD-L1 inhibitor; and/or the cancer is characterized by intrinsic and/or acquired resistance to a PD-1/PD-L1 inhibitor.

12. The method of any one of claims 1 to 11, wherein the cancer is a PD-L1- positive cancer resistant to pembrolizumab or nivolumab; and/or the cancer is a KRAS-positive cancer resistant to pembrolizumab or nivolumab.

13. The method of any one of claims 1 to 12, wherein the cancer is characterized by a KRAS G12C mutation.

14. The method of any one of claims 1 to 13, wherein the cancer has progressed or recurred on or after at least one prior line of a systemic therapy comprising a platinum-based doublet chemotherapy and/or an anti-PD-1/PD-L1 therapy, each of which is given in monotherapy or both of which are given in combination therapy.

15. The method of any one of claims 1 to 14, wherein the cancer has progressed or recurred during a treatment of an anti-PD-1/PD-L1 therapy or within about 90 days after discontinuing an anti-PD-1/PD-L1 therapy.

16. The method of any one of claims 1 to 15, wherein the subject does not have one or more additional activating mutations in BRAF V600X, PTPN11 (SHP2), or KRAS Q61X.

17. The method of any one of claims 1 to 16, wherein the subject is not previously treated with a PTPN inhibitor, provided that the PTPN inhibitor is other than the compound of Formula (I) or formula (10b).

18. The method of any one of claims 1 to 17, wherein the subject is human.

19. The method of any one of claims 1 to 18, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are administered concomitantly.

20. The method of any one of claims 1 to 18, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are administered sequentially.

21. The method of claim 20, wherein the PTPN11 inhibitor is administered prior to the administration of the PD-1/PD-L1 inhibitor; or the PTPN11 inhibitor is administered after the administration of the PD-1/PD-L1 inhibitor.

22. The method of any one of claims 1 to 21, wherein the PTPN11 inhibitor is administered orally; and the PD-1/PD-L1 inhibitor is administered intravenously.

23. The method of any one of claims 1 to 22, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are provided in jointly therapeutically effective amounts.

24. The method of any one of claims 1 to 22, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are provided in synergistically effective amounts.

25. The method of any one of claims 1 to 22, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are each used at a dose less than when each is used alone.

26. The method of any one of claims 4 to 25, wherein the therapeutically effective amount of the compound of formula (10b) is a total daily dosage of from about 10 mg to about 2000 mg, from about 50 mg to about 2000 mg, from about 80 mg to about 2000 mg, from about 80 mg to about 1000 mg, from about 80 mg to about 700 mg, from about 80 mg to about 550 mg, from about 80 mg to about 400 mg, from about 80 mg to about 250 mg, or from about 80 mg to about 150 mg, on a salt-free and anhydrous basis.

27. The method of claim 26, wherein the therapeutically effective amount of the compound of formula (10b) is is a total daily dosage of about 80 mg, about 150 mg, about 250 mg, about 400 mg, about 550 mg, or about 700 mg, on a salt-free and anhydrous basis.

28. The method of any one of claims 1 to 27, wherein the PTPN11 inhibitor is administered once, twice, three times, or four times daily.

29. The method of claim 28, wherein the PTPN11 inhibitor is administered once daily; and the PD-1/PD-L1 inhibitor is administered once every 1, 2, 3, 4, 5, or 6 weeks.

30. The method of any one of claims 1 to 29, wherein the treating with the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor reduces a volume of the cancer or a solid tumor at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.

31. The method of any one of claims 1 to 29, wherein treating with the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor stabilizes the cancer or a solid tumor.

32. A kit for treating cancer in a subject, comprising: a) a therapeutically effective amount of a PTPN11 inhibitor according to any one of claims 1 to 4; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, together with instruction for effective administration.

33. The kit of claim 32, wherein the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, retifanlimab, BMS-986213, or tebotelimab, provided that, when the PTPN11 inhibitor is represented by formula (10b), the PD-1/PD-L1 inhibitor is other than nivolumab.

34. The kit of claim 32 or 33, wherein the PTPN11 inhibitor and the PD-1/PD- L1 inhibitor are formulated for concomitant administration.

35. The kit of claim 32 or 33, wherein the PTPN11 inhibitor and the PD-1/PD- L1 inhibitor are formulated for sequential administration.