Combination therapy including an SHP2 inhibitor and a PD-1 inhibitor

Abstract

Provided herein is a combination comprising an SHP2 inhibitor and a PD-1 inhibitor, and a method for treating cancer. The SHP2 inhibitor is a pyrazine derivative. The combination may comprise a first pharmaceutical composition comprising an SHP2 inhibitor and a second pharmaceutical composition comprising a PD-1 inhibitor, which are packaged together as a kit, and the kit may further comprise instructions.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 184,685, filed May 5, 2021, and U.S. Provisional Patent Application No. 63 / 320,997, filed March 17, 2022, the contents of which are incorporated by reference in their entireties herein.

[0002] The present disclosure relates to combinations comprising SHP2 and PD-1 inhibitors, and the use of such combinations in the treatment of cancer. [Background technology]

[0003] Cancer is a leading cause of morbidity and mortality worldwide. Although the standard of care for many different cancer types has improved significantly over the years, the current standard of care still does not meet the need for effective therapies to improve cancer treatment. Protein tyrosine phosphatase 2 (SHP2) belongs to the protein tyrosine phosphatase family, which is involved in regulating cell proliferation, survival, differentiation, migration and apoptosis. In recent years, SHP2 has been shown to play an important role in tumor inhibition, and the role of SHP2 in tumors in particular is becoming increasingly evident. Thus, inhibition of SHP2 represents a viable antitumor strategy.

[0004] In the protein tyrosine phosphatase superfamily, SHP2 is the first identified true proto-oncogene and plays a key role in various signaling pathways such as metabolism, differentiation, proliferation, migration and survival. SHP2 can regulate Ras mitogen-activated protein kinase, Janus kinase-signal transduction and activator of transcription (JAK-STAT) or phosphoinositide 3-kinase-AKT and nuclear factor kappa B (NF-kappa B) as well as other signaling pathways. SHP2 is also a master regulator of programmed cell death protein-1 (PD-1) and B and T lymphocyte attenuator (BTLA) immune checkpoint signaling pathways, which may be related to tumor immune suppression. Moreover, SHP2 mutations occur rarely in tumors.

[0005] The clinical use of cancer immunotherapeutic agents targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death receptor-1 (PD-1) and its ligand PD-L1 has provided improvements over standard therapies in the treatment of many cancer types. Although these checkpoint inhibitors have provided improved clinical responses in certain such cancers, durable clinical responses occur in only approximately 10-45% of patients. In addition, a significant number of tumors either exhibit resistance or become refractory. Thus, new therapies, including, for example, combination therapies for the treatment of cancer, are needed. Combinations and methods of treating cancer are provided herein. Summary of the Invention

[0006] Provided herein, inter alia, is a combination comprising an SHP2 inhibitor and a PD-1 inhibitor.

[0007] In one embodiment, the compound of formula (Ia)

[0008] [ka] or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor.

[0009] In some embodiments, the combination comprises about 5 mg to about 100 mg of a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the combination comprises about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg of a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof.

[0010] In some embodiments, the PD-1 inhibitor is a small molecule compound, a nucleic acid, a peptide, a protein, an antibody, a peptibody, a diabody, a minibody, a single chain variable fragment (ScFv), or a fragment or variant thereof. In some embodiments, the PD-1 inhibitor is an antibody. In some embodiments, the PD-1 antibody is selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR001, SHR-1210, or MEDI0680.

[0011] In another aspect, provided herein is a pharmaceutical composition comprising a combination described herein and a pharma- ceutically acceptable excipient.

[0012] In another aspect, provided herein is a method for preventing and / or treating a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition. In some embodiments, a method for treating cancer in a subject in need thereof comprises administering a therapeutically effective amount of a compound of formula (Ia)

[0013] [ka] or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically acceptable amount of a PD-1 inhibitor.

[0014] In some embodiments, the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, is administered to the patient in need thereof at about 5 mg / kg to about 25 mg / kg. In some embodiments, the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, is administered to the patient in need thereof at about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg.

[0015] In another embodiment, the PD-1 inhibitor is a small molecule compound, a nucleic acid, a peptide, a protein, an antibody, a peptibody, a diabody, a minibody, a single chain variable fragment (ScFv), or a variant thereof. In some embodiments, the PD-1 inhibitor is a PD-1 inhibitor antibody. In some embodiments, the PD-1 antibody is nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR001, SHR-1210, or MEDI0680.

[0016] In some embodiments, the method comprises administering a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor simultaneously or sequentially. In some embodiments, the method comprises administering a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor to a patient as a regimen. In some embodiments, the method comprises administering a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor to a patient orally or as an intraperitoneal injection. In some embodiments, the administration is by intravenous injection (IV). In some embodiments, the method comprises administering a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor to a patient daily. In some embodiments, the methods comprise administering a compound of Formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor once daily (QD), twice daily (BID), once weekly (QW), twice weekly (BID), three times weekly (TIW), or once monthly (QM).

[0017] In some embodiments, the patient is treatment naive. In some embodiments, the method comprises administering to the patient a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor as a first line therapy. In some embodiments, the method comprises administering to the patient a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor as a second line, third line, fourth line, fifth line, or sixth line of treatment. In some embodiments, the method comprises administering to the patient a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor after treatment with at least one anti-cancer therapy, the anti-cancer therapy being chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination thereof. In some embodiments, the method comprises administering to the patient a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor after failure of at least one PD-1 therapy. In some embodiments, the cancer is resistant to at least one anti-cancer agent.

[0018] In some embodiments, the cancer is squamous cell carcinoma, non-squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial carcinoma, breast cancer, prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor (MPNST).

[0019] In some embodiments, the method includes inhibiting metastasis of a cancer in a patient in need of treatment. In some embodiments, the method of treating cancer extends the patient's time to disease progression of the cancer. In some embodiments, the method of treating cancer extends the patient's survival. In some embodiments, the method of treating cancer increases the patient's progression-free survival. In some embodiments, the method of treating cancer reduces a tumor or tumor burden in a patient. In some embodiments, the method reduces or prevents metastasis of a primary tumor in a patient in need of such reduction or prevention.

[0020] In another aspect, provided herein is a method of modulating one or more biomarkers (cytokines) selected from TNF-α, INF-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, and KC / GRO (CXCL1). In some embodiments, one or more biomarkers are increased or decreased above baseline levels. In some embodiments, one or more biomarkers are decreased or increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 100%, or at least 150%. In some embodiments, one or more biomarkers are decreased or increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold.

[0021] Other objects, features and advantages of the combinations and methods described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0022] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0023] Various aspects of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings, in which:

[0024] [Figure 1A] FIG. 1 shows the results of an efficacy study in mice after dosing with various combinations, including those described herein. [Figure 1B] FIG. 1 shows the results of an efficacy study in mice after dosing with various combinations, including those described herein. [Figure 2A] FIG. 1 shows expression levels of keratinocyte chemoattractant (KC) / human growth-regulating oncogene (GRO) in tumors (MC38) after various combination treatments. [Figure 2B] FIG. 1 shows the expression levels of TNF-α in tumors (MC38) after various combination treatments. [Figure 2C] FIG. 1 shows expression levels of IFN-γ and IL-6 in tumors (MC38) after various combination treatments. [Figure 3A] FIG. 1 shows expression levels of M1 in MC38 tumors. [Figure 3B] FIG. 1 shows the expression levels of M2 in MC38 tumors. [Figure 3C] FIG. 1 shows expression levels of CD8 in MC38 tumors. [Figure 4A] FIG. 1 shows the results of tumor immune profiling. [Figure 4B] FIG. 1 shows the results of blood immune profiling. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] combination In one aspect, combinations (e.g., combination therapies, e.g., treatment methods and uses, kits, and compositions) for treating cancer are described herein. In some embodiments, the combinations described herein include an SHP2 inhibitor and a PD-1 inhibitor. In some embodiments, the SHP2 inhibitor is a pyrazine derivative. In some embodiments, the combinations may include a first pharmaceutical composition and a second pharmaceutical composition. In some embodiments, the first pharmaceutical composition includes an SHP2 inhibitor and the second pharmaceutical composition includes a PD-1 inhibitor. In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are co-packaged as a kit, which may further include instructions for co-administration of the first and second pharmaceutical compositions. In some embodiments, the first and second compositions may be packaged separately for combination in a clinical setting by administering them to a patient within a time frame in which the patient will simultaneously receive clinical benefit from the first and second pharmaceutical compositions. In some embodiments, the combinations may include a pharmaceutical composition including an SHP2 inhibitor and a PD-1 inhibitor. In some embodiments, the combinations include a unit dosage form of a pharmaceutical composition including an SHP2 inhibitor and a PD-1 inhibitor. In some embodiments, the combination comprises a first pharmaceutical composition comprising an SHP2 inhibitor for use in treating cancer, in combination with a second pharmaceutical composition comprising a PD-1 inhibitor. In some embodiments, the combination comprises use of an SHP2 inhibitor to prepare a first pharmaceutical composition for use in treating cancer, in combination with a second pharmaceutical composition comprising a PD-1 inhibitor.

[0026] In some embodiments, (i) Formula (I)

[0027] [ka] or a pharma- ceutical acceptable salt or solvate thereof, During the ceremony, R 1 and R 2 are the same or different, R 1and R 2 are each independently H, D, halogen, -CN, -C(O)OH, -CHO, -OH, -NO2, and the following substituted or unsubstituted groups: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 aryl group, 5- to 10-membered heteroaryl group, or R 1 and R 2 form a 3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group, optionally the 3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group being optionally selected from 1 to 3 of -OH, -NH2, -CN, NO2, halogen, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl; R 3 is selected from H, D or -NH2; X is selected from a bond, -NH- or -C(O)NH-; Y is N or CR 13 where R 13 H, D, -OH, -CN, halogens, C1-C 10 Alkyl groups, C1-C 10 Alkoxy, C3-C 12 Cycloalkaneamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, 3-8 membered heterocyclic groups, halogenated C1-C 10 Alkylamino or C6-C 10 aryl or 5-10 membered heteroaryl groups, the heterocyclic or heteroaryl groups optionally containing 1-4 heteroatoms, the heteroatoms being selected from S, O, N or NH; Each R 4are the same or different and independently represent H, D, halogen, -CN, -C(O)OH, -CHO, -OH, -NO2, -C(O)NHR 14 or -NHC(O)R 15 selected from the following groups: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl, or 5-10 membered heteroaryl, substituted or unsubstituted, where R 14 and R 15 are each independently C1 to C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, the substitution being selected from C1-C 10 Alkyl, halogen atom, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, C1~C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group substituted with one or more substituents, the substituents being selected from C1-C 10 Alkyl, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, C1~C 10 Alkoxy, C1-C 10 Alkylamino or C3-C 12 Optionally substituted with 1 to 3 substituents selected from cycloalkyl;

[0028] [ka] is C6~C 10 Aryl, 5-10 membered heteroaryl, C4-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 14 Bridged or spiro ring groups, or C6-C14 A bridged heterocyclic group or a spiro heterocyclic group is selected from a 5-10 membered heteroaryl, a 3-12 membered heterocyclic group, a C6-C 14 The bridged or spiroheterocyclic group contains 1 to 3 heteroatoms or groups selected from N, -NH-, O, S, C(O), or S(O); Each R 5 are the same or different and independently represent H, D, halogen, -CN, -C(O)OH, -CHO, -OH, -NO2, aminoacyl, substituted or unsubstituted groups of the following: C1 to C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3~C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl group, the substitution being selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, hydroxy-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaromatic group, C6-C 10 An aryl group or a 3- to 12-membered heterocyclic group substituted with one or more substituents, or any two adjacent R 5 form a 3-6 membered saturated or unsaturated ring, optionally the 3-6 membered saturated or unsaturated ring is optionally 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 substituted with aryl or 5-10 membered heteroaryl; R 6 , R 7 , R 8, R 9 , R 10 , R 11 , R 12 , and R 13 are each independently selected from H, D, halogen, -CN, -C(O)OH, -CHO, -OH, -NO2, -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy group, 3-12 membered heterocyclic group, C6-C 10 aryl, and 5- to 10-membered heteroaryl, substituted or unsubstituted, 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, hydroxy-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaryl or C6-C 10 aryl; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1 or 2; a therapeutically effective amount of an SHP2 inhibitor having a structure of formula (I), or a pharma- ceutically acceptable salt or solvate thereof; (ii) a therapeutically effective amount of a PD-1 inhibitor; and Combinations including are described herein.

[0029] In some embodiments, the compound of formula (I) is represented by formula (II):

[0030] [ka] or a pharma- ceutical acceptable salt or solvate thereof, During the ceremony, X is selected from a chemical bond, -NH-, -CONH-; R 4 are H, D, halogen atoms, -CN, -C(O)OH, -CHO, -OH, -NO2, -C(O)NHR 14 or -NHC(O)R 15 -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl, or 5-10 membered heteroaryl, substituted or unsubstituted, where R 14 and R 15 are each independently C1 to C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl groups, the substituents being C1-C 10 Alkyl, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, C1~C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclic group, and the substituents are C1-C 10 Alkyl, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, C1~C 10 Alkoxy, C1-C 10 Alkylamino or C3-C 12 Optionally substituted cycloalkyl;

[0031] [ka] is C6~C 10 Aryl, 5-10 membered heteroaryl, C4-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 14Bridged or spiro ring groups, or C6-C 14 A bridged heterocyclic group or a spiro heterocyclic group is selected from a 5- to 10-membered heteroaryl group, a 3- to 12-membered heterocyclic group, a C6-C 14 The bridged or spiroheterocyclic group contains 1 to 3 heteroatoms or groups selected from N, -NH-, O, S, C(O), or S(O); Each R 5 are the same or different and are independently selected from H, D, a halogen atom, -CN, -C(O)OH, -CHO, -OH, -NO2, or aminoacyl, and are C1 to C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3~C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl groups, the substituents being C1 to C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen, -NH2, -CN, -C(O)OH, -CHO, -OH, -NO2, hydroxy-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaromatic group, C6-C substituted with one or more substituents 10 Aryl or 3- to 12-membered heterocyclic group, or any two adjacent R 5 form a 3-6 membered saturated or unsaturated ring, optionally the 3-6 membered saturated or unsaturated ring is optionally 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 aryl or 5-10 membered heteroaryl; n is 0, 1, 2 or 3; The compound has a therapeutically effective amount of an SHP2 inhibitor having a structure of formula (II), or a pharma- ceutically acceptable salt or solvate thereof.

[0032] In some embodiments, R 4 is H, D, halogen, -CN, unsubstituted or halogen-substituted C1-C 10 is selected from alkyl.

[0033] In some embodiments,

[0034] [ka] is selected from phenyl, naphthyl, a 5- to 10-membered heteroaryl group, or a 3- to 12-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the 3- to 12-membered heterocyclic group containing 1 to 3 heteroatoms or groups optionally selected from N, NH, O, S, or C(O).

[0035] In some embodiments, the 5- to 10-membered heteroaromatic ring is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indole[1,2-a]pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazo-pyrimidinyl, oxazolopyrimidinyl, isoxazopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, or furan. In some embodiments, any one of pyrazinyl, thienopyrazinyl, pyridopyrimidinone, benzoxazolyl, and benzothiazolyl, the 3-12 membered heterocyclic group is aziridinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxythiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactone, caprolactone, succinimide, or

[0036] [ka] is selected from.

[0037] In some embodiments, the 3- to 12-membered heterocyclic group is butyrolactamyl, pyrrolidinyl, succinimide, or

[0038] [ka] is selected from.

[0039] In some embodiments, each R 5are the same or different and are independently selected from H, D, halogen, -CN, -C(O)OH, -CHO, -OH, -NO2, aminoacyl, C1 to C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2 substituted or unsubstituted, the substitution being C1-C 10 alkyl, halogen, -NH, -CN, -OH, -NO2 substituted with one or more substituents, or any two adjacent R 5 form a 3-6 membered saturated or unsaturated ring, optionally the 3-6 membered saturated or unsaturated ring is optionally 10 Alkyl and C1-C 10 It is substituted with alkoxy.

[0040] In some embodiments, the compound of formula (I) has the formula (Ia):

[0041] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0042] In some embodiments, the compound of formula (I) or (Ia) is N-(3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof.

[0043] In some embodiments, the compound of formula (I), (Ia) or (II), or a pharma- ceutically acceptable salt thereof, is an SHP2 inhibitor. The compounds of formula (I), (Ia) and (II) are substantially as described in International Patent Application No. PCT / CN2020 / 077391, filed March 2, 2020, which is incorporated herein by reference in its entirety.

[0044] In some embodiments, (i) Formula (III)

[0045] [ka] or a pharma- ceutical acceptable salt or solvate thereof, During the ceremony, X 1 is N or CH, X 2 is N or CH, X 3 is N or CH, X 1 , X 2 , or X 3 At least one of is N, Y 1 is S or a direct bond, A is selected from the group consisting of 5-12 membered monocyclic or polycyclic cycloalkyl, monocyclic or polycyclic heterocycloalkyl, monocyclic or polycyclic aryl, or polycyclic heteroaryl; R 20 is independently, at each occurrence, -H, -D, -C1-C6 alkyl, -C2-C6 alkenyl, -C4-C8 cycloalkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -OH, -OR 25 , halogen, -NO2, -CN, -NR 24 R 25 , -SR 24 , -S(O)NR 24 R 25 , -S(O)2R 24 , -NR 24S(O)2NR 24 R 25 , -NR 24 S(O)2R 25 , -S(O)NR 24 R 25 , -S(O)R 24 , -NR 24 S(O)NR 24 R 25 , -NR 24 S(O)R 25 , -C(O)R 24 , -CO2R 24 , -C(O)NR 24 R 25 , -NR 24 CO)R 25 or a 3- to 12-membered monocyclic or polycyclic heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is selected from the group consisting of -OH, halogen, -NO2, oxo, -CN, -R 24 ,-OR 24 , -NR 24 R 25 , -SR 24 , -S(O)NR 24 R 25 , -S(O)2R 24 , -NR 24 S(O)2NR 24 R 25 , -NR 24 S(O)2R 25 , -S(O)NR 24 R 25 , -S(O)R 2 , -NR 24 S(O)NR 24 R 25 , -NR 24 S(O)R 25 , optionally substituted with heterocycle, aryl, or heteroaryl; R 21 and R 22 are independently -H, -D, -OH, -C1-C6 alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiro heterocycle, a C3-C8 cycloalkyl, -(CH2) q -R 28 , or -(CH2) q C(O)NR24 R 25 wherein each alkyl, heterocycle or cycloalkyl is selected from the group consisting of one or more of -C1-C6 alkyl, -OH, -NH2, -OR 28 , -NHR 28 , -(CH2) q optionally substituted with OH, heterocyclyl, or spiroheterocyclyl; or R 22 is R 21 and may combine with each other to form a 3- to 12-membered monocyclic or polycyclic heterocycle, or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle may be selected from the group consisting of one or more of -C1-C6 alkyl, halogen, -OH, -OR, -NHR 28 , optionally substituted heteroaryl, optionally substituted heterocyclyl, -(CH2) q NH2, -(CH2) q OH, -COOR 28 , -CONHR 28 , -CONH(CH2) q COOR 28 , -NHCOOR 28 , -OC(O)-NR 24 R 25 , -CF3, -CHF2, -CH2F, or =O, where heteroaryl and heterocyclyl are optionally substituted with -CN; R 23 is -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl, -CF2OH, -CHFOH, -NH-NHR 24 , -NH-OR 24 , -O-NR 24 R 25 , -NHR 24 , -OR 24 , -NHC(O)R 24 , -NHC(O)NHR 24 , -NHS(O)2R 24 , -NHS(O)2NHR 24 , -S(O)2OH, -C(O)OR 24 , -NH(CH2) n OH, -C(O)NH(CH2)n OH, -C(O)NH(CH2) q R 28 , -C(O)R 28 , -NH2, -OH, -CN, -C(O)NR 24 R 25 , -S(O)NR 24 R 25 , a C3-C8 cycloalkyl, an aryl, a heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or a heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more -OH, -NH2, -OR, halogen, or oxo, and each aryl or heteroaryl is optionally substituted with one or more -OH, -NH2, or halogen; R 24 and R 25 are each independently, at each occurrence, -H, -D, -C1-C6 alkyl, -C2-C6 alkenyl, -C3-C8 cycloalkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, -OR 26 , -SR 26 , halogen, -NR 26 R 27 , -NO2, and -CN; R 26 and R 27 is independently, for each occurrence, -H, -D, -C1-C6 alkyl, -C2-C6 alkenyl, -C4-C8 cycloalkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, or a monocyclic or polycyclic 3-12 membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; R 28 are independently -H, -D, -C1-C6 alkyl, -C1-C6 cycloalkyl, -C2-C6 alkenyl, -(CH2) q-aryl, heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, or O, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or -(CH2) q -Aryl is one or more of -OH, halogen, -NO2, oxo, -CN, -R 24 , -OR 24 , -NR 24 R 25 , -SR 24 , -S(O)NR 24 R 25 , -S(0)2R 25 , -NR 24 S(O)2NR 24 R 25 , -NR 24 S(O)2R 25 , -S(O)NR 24 R 25 , -S(O)R 24 , -NR 24 S(O)NR 24 R 25 , -NR 24 S(O)R 25 , -C(O)NR 24 R 25 -, -NR 24 R 25 C(O)-, heterocycle, aryl, heteroaryl, -(CH2) q optionally substituted with OH, -C1-C6 alkyl, CF3, CHF2, or CH2F; q is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; a therapeutically effective amount of an SHP2 inhibitor having a structure of formula (III), or a pharma- ceutically acceptable salt or solvate thereof; (ii) a therapeutically effective amount of a PD-1 inhibitor; and Combinations including are described herein.

[0046] In some embodiments, the formula (IIIa)

[0047] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0048] In some embodiments, the compound of formula (IIIa) is RMC-4550 or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the SHP2 inhibitor is a compound described in PCT / US2018 / 055502, filed October 11, 2018, which is incorporated herein by reference in its entirety.

[0049] In some embodiments, (i) Formula (IV)

[0050] [ka] or a pharma- ceutical acceptable salt or solvate thereof, During the ceremony, c is selected from 0 and 1; d is selected from 0 and 1; Y 4 is selected from CH and N; Y 5 CR 35 and N, R 30 -X 5 R 30a where: R 30a is C 6~10 Aryl, C 3~8 Cycloalkyl, C 3~8 cycloalkenyl and 5-9 membered heteroaryl groups containing 1-4 heteroatoms or groups independently selected from N, C(O), O and S, where R 30a The aryl or heteroaryl may be halo, amino, hydroxy, N3, C 1~4 Alkyl, dimethylamino, hydroxy substituted C 1~4 Alkyl, halo substituted C 1~4Alkyl, amino substituted C 1~4 Alkyl, -C(O)OR 40 and -NHC(O)R 40 1 to 5 R independently selected from 38 is substituted with a group, X 5 is a bond, S(O) m1 , O, C(O), COR 40 , C.R. 39a R 39b , N.R. 40 where: m1 is selected from 0, 1 and 2; Each R 39a and R 39b Halo and C 1~4 independently selected from alkyl, R 40 is hydrogen and C 1~4 alkyl, R 31 and R 31a are independently hydrogen, C 1~4 Alkyl, C 1~4 Alkoxy, amino, hydroxy, C 3~8 Cycloalkyl and C 1~4 alkyl-amino; R 32 and R 32a are independently halo, carbonyl, C 1~4 Alkyl, C 1~4 Alkoxy, amino, hydroxy, C 3~8 Cycloalkyl and C 1~4 alkyl-amino; R 33 and R 33a are independently hydrogen, halo, carbonyl, C 1~4 Alkyl, Ci ~4 Alkoxy, amino, hydroxy, C 3~8 Cycloalkyl and C 1~4 alkyl-amino; R 34 and R 34a are independently hydrogen, carbonyl, C 1~4 Alkyl, C 1~4Alkoxy, amino, hydroxy, C 3~8 Cycloalkyl and C 1~4 alkyl-amino; Here, R 31 , R 31a , R 32 , R 32a , R 33 , R 33a , R 34 , R 34a and R 36 Any two groups selected from the group consisting of: can form a 5- to 6-membered unsaturated or partially saturated ring; R 35 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, amino-carbonyl, halo-substituted C 1~4 Alkyl, halo substituted C 1~4 Alkoxy, hydroxy substituted C 1~4 Alkyl, amino substituted C 1~4 Alkyl, -S(O) 1~2 R 35a , -C(S)R 35b , -C(O)NR 35a R 35b , and -NR 35a C(O)R 35b where -R 35a and R 35b are independently hydrogen and C 1~4 alkyl, R 36 and R 37 together with the carbon atom to which they are both attached: N, C(O), O, and S(O). m1 wherein m1 is selected from 0, 1 and 2; R 36 and R 37 the saturated ring formed by may be unsubstituted or substituted with 1 to 3 groups independently selected from amino, hydroxy, methoxy, halo, methyl, methyl-amino and isobutyloxy; a therapeutically effective amount of an SHP2 inhibitor having a structure of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof; (ii) a therapeutically effective amount of a PD-1 inhibitor; and Combinations including are described herein.

[0051] In some embodiments, the structure of formula (IVa), or a pharma- ceutically acceptable salt or solvate thereof, is

[0052] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0053] In some embodiments, the compound of formula (IVa) is TNO-155 or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the SHP2 inhibitor is any of the compounds disclosed in PCT / IB2015 / 050345, filed Jan. 16, 2015, which is incorporated herein by reference in its entirety.

[0054] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, such groups and substituents are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0055] In some embodiments, the combination comprises a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof (e.g., Formula (Ia)), present in an amount greater than about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. In some embodiments, the compound disclosed herein is present in an amount greater than about 5 mg or about 10 mg. In some embodiments, the composition comprises a compound disclosed herein in an amount of about 1 mg to about 500 mg. In some embodiments, the composition comprises a compound disclosed herein in an amount of about 1 mg to about 10 mg, about 1 mg to about 25 mg, about 1 mg to about 50 mg, about 5 mg to about 10 mg, about 5 mg to about 25 mg, about 5 mg to about 50 mg, about 10 mg to about 25 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, or about 200 mg to about 500 mg.

[0056] In some embodiments, the combination comprises at least about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg of a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof (e.g., a compound of formula (Ia)). In some embodiments, the combination comprises at least about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of a compound disclosed herein. In some embodiments, the compound disclosed herein is present in the composition in an amount of at least about 5 mg, or about 10 mg. In some embodiments, the combination includes at least about 1 mg to about 10 mg, about 1 mg to about 25 mg, about 1 mg to about 50 mg, about 5 mg to about 10 mg, about 5 mg to about 25 mg, about 5 mg to about 50 mg, about 10 mg to about 25 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, or about 100 mg to about 200 mg of a compound disclosed herein.

[0057] In some embodiments, the combination comprises about 5 mg to about 500 mg, or about 5 mg to about 100 mg of a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof (e.g., a compound of Formula (Ia)). In some embodiments, the combination comprises about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg of a compound disclosed herein.

[0058] In some embodiments, the combination includes a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof (e.g., Formula (Ia)), in an amount relative to the patient's body weight (i.e., mg / kg). In some examples, the compound disclosed herein is administered at a dose of about 0.0001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 200 mg / kg, about 0.01 mg / kg to about 200 mg / kg, about 0.01 mg / kg to about 150 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 25 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.01 mg / kg to about 5 mg / kg, about 0.05 mg / kg to about 200 mg / kg, about 0.05 mg / kg to about 150 mg / kg. g, about 0.05 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, about 0.05 mg / kg to about 25 mg / kg, about 0.05 mg / kg to about 10 mg / kg, or about 0.05 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 200 mg / kg, about 0.5 mg / kg to about 150 mg / kg, about 0.5 mg / kg to about 100 mg / kg, about 0.5 mg / kg to about 50 mg / kg, about 0.5 mg / kg to about 25 mg / kg, about 0.5 mg / kg to about 10 mg / kg, or about 0.5 mg / kg to about 5 mg / kg. In other examples, the compounds disclosed herein are present in an amount equivalent to about 1 mg / kg to about 200 mg / kg, about 1 mg / kg to about 150 mg / kg, about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 5 mg / kg.

[0059] In some embodiments, the combination comprises about 5 mg / kg to about 25 mg / kg of a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof (e.g., a compound of Formula (Ia)) per patient's body weight. In some embodiments, the combination comprises about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg of a compound disclosed herein per patient's body weight.

[0060] In some embodiments, the combination includes a PD-1 inhibitor. PD-1 inhibitors useful in the combinations described herein include any molecule capable of inhibiting, blocking, suppressing, or interfering with the activity or expression of PD-1. In some embodiments, the PD-1 inhibitor can be a small molecule compound, a nucleic acid, a polypeptide, an antibody, a peptibody, a diabody, a minibody, a single chain variable fragment (ScFv), or a functional fragment or variant thereof. In some embodiments, the PD-1 inhibitor is a small molecule compound (e.g., a compound having a molecular weight of less than about 1000 Da). In some examples, the PD-1 inhibitors useful in the combinations described herein include nucleic acids and polypeptides. In some embodiments, the PD-1 inhibitor is a polypeptide (e.g., a macrocyclic polypeptide). In some embodiments, the PD-1 inhibitor is an antibody, a peptibody, a diabody, a minibody, a ScFv, or a functional fragment thereof.

[0061] In some embodiments, the PD-1 inhibitor is AMP-224 (GSK). AMP-224 is a recombinant fusion protein that includes the extracellular domain of PD-1 ligand programmed cell death ligand 2 (PD-L2) and the Fc region of human IgG. Certain cancers can evade and suppress the immune system, in part, and without being bound to any particular theory, through the interaction between PD-1 and B7-H1. AMP-224 is believed to block this interaction, and thus overcomes immune suppression.

[0062] In some embodiments, the PD-1 inhibitor is a PD-1 antibody. In some embodiments, the PD-1 antibody is a monoclonal antibody or a polyclonal antibody. In certain embodiments, the PD-1 inhibitor antibody is a monoclonal antibody.

[0063] PD-1 antibodies include all known types of antibodies and functional fragments thereof, including, but not limited to, those exemplified herein, such as, for example, human antibodies, murine antibodies, chimeric antibodies, humanized antibodies, or chimeric human antibodies.

[0064] In some embodiments, the PD-1 antibody is a human antibody. In another embodiment, the PD-1 antibody is a murine antibody. In some embodiments, the PD-1 antibody is a chimeric antibody. In some embodiments, the PD-1 antibody is a humanized antibody. In some embodiments, the PD-1 antibody is a chimeric humanized antibody. The PD-1 antibody is a human antibody or a humanized antibody. In some embodiments, the PD-1 antibody is nivolumab, pembrolizumab, pidilizumab, EGN2810, PDR001, or MEDI0680. In some embodiments, two or more PD-1 antibodies are administered in combination with a compound of Formula I described herein.

[0065] In some embodiments, the PD-1 antibody is nivolumab. Nivolumab (marketed as OPDIVO®) is a fully human monoclonal antibody against PD-1 with immune enhancing activity. Without being bound by theory, nivolumab binds to PD-1 through its cognate ligand and blocks the activation of PD-1, resulting in the activation of T cells and cell-mediated immune responses against tumor cells or pathogens.

[0066] In some embodiments, the PD-1 antibody is pembrolizumab. Pembrolizumab (MK-3475, commercially available as KEYTRUDA®) is a humanized monoclonal IgG4 antibody against the human cell surface receptor PD-1, which potentially has immune enhancing activity. Without being bound by any particular theory, pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks binding to and activation of PD-1 by its cognate ligand. Blocking binding and activity results in activation of T cell-mediated immune responses against tumor cells.

[0067] In some embodiments, the PD-1 antibody is pidilizumab. Pidilizumab (CT-011) is a humanized monoclonal antibody against human PD-1 with immunomodulatory and antitumor activity. Without being bound by any particular theory, pidilizumab blocks the interaction between the receptor PD-1 and its ligand, resulting in the attenuation of the apoptotic process in lymphocytes, mainly effector / memory T cells, and the enhancement of the antitumor activity of NK cells.

[0068] In some embodiments, the PD-1 antibody is REGN2810 (also known as cemiplimab). REGN2810 is a human monoclonal antibody against PD-1, which potentially has immune checkpoint inhibitory activity and antitumor activity. Without being bound by any particular theory, REGN2810 binds to PD-1, inhibits its binding to its cognate ligand, and prevents the activation of its downstream signaling pathway. This restores immune function through the activation of cytotoxic T cells.

[0069] In some embodiments, the PD-1 antibody is PDR001 (also known as spartalizumab). PDR001 is a fully humanized monoclonal antibody against PD-1 with immune checkpoint inhibitory and antitumor activity. Without being bound to a particular theory, PDR001 binds to PD-1 expressed on activated T cells and blocks interaction with its cognate ligand. Inhibition of ligand binding prevents PD-1-mediated signal transduction, resulting in both T cell activation and induction of T cell-mediated immune responses against tumor cells.

[0070] In some embodiments, the PD-1 antibody is MEDI0680 (also known as durvalumab and commercially available as IMFINZI®). MEDI0680 is a monoclonal antibody against PD-1 with potential immunomodulatory and anti-tumor activity. Without wishing to be bound by theory, MEDI 0680 inhibits activation of PD-1 and its downstream signaling pathways. This inhibition can restore immune function through activation of both T cell and cell-mediated immune responses against PD-1-overexpressing tumor cells.

[0071] In some embodiments, the PD-1 antibody is of any antibody isotype. The term isotype refers to the antibody class encoded by the heavy chain constant region genes. The heavy chain of a given antibody or functional fragment determines the class of the antibody or functional fragment: IgM, IgG, IgA, IgD, or IgE. Each class may have either a kappa or a lambda light chain. The term subclass refers to the slight differences in the amino acid sequence of the heavy chain that distinguish the subclass. In humans, there are two subclasses of IgA (subclasses IgA1 and IgA2) and four subclasses of IgG (subclasses IgG1, IgG2, IgG3, and IgG4). Such classes and subclasses are well known in the art.

[0072] Useful PD-1 antibodies bind to PD-1 with sufficient strength to inhibit the activity of PD-1. The term binding, as used herein, refers to the interaction between molecules forming a complex. The interaction can be non-covalent, including, for example, hydrogen bonds, ionic bonds, hydrophobic interactions and / or van der Waals interactions. A complex also includes the association of two or more molecules that are held together by covalent or non-covalent bonds, interactions or forces. Binding of an antibody or functional fragment thereof can be detected, for example, using an enzyme-linked immunosorbent assay or any one of many methods well known to those of skill in the art.

[0073] The PD-1 antibody can be present in an amount that is a measure of the body weight of a patient in need of the PD-1 antibody. For example, the PD-1 antibody can be present in an amount of about 0.1 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 7.5 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 2.5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. In some embodiments, the PD-1 antibody is present in an amount of about 0.5 mg / kg to about 30 mg / kg, about 0.5 mg / kg to about 25 mg / kg, about 0.5 mg / kg to about 20 mg / kg, about 0.5 mg / kg to about 15 mg / kg, about 0.5 mg / kg to about 10 mg / kg, about 0.5 mg / kg to about 7.5 mg / kg, about 0.5 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 2.5 mg / kg, or about 0.5 mg / kg to about 1 mg / kg. In some embodiments, the PD-1 antibody is present in an amount of about 0.5 mg / kg to about 5 mg / kg or about 0.1 mg / kg to about 10 mg / kg. In some embodiments, the PD-1 antibody is present in an amount of about 0.5 mg / kg to about 15 mg / kg or about 0.1 mg / kg to about 20 mg / kg.

[0074] In some aspects, the PD-1 antibody is present in an amount of about 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, or 30 mg / kg. In some embodiments, the PD-1 antibody is present in an amount of about 1 mg / kg, 2 mg / kg, 3 mg / kg, or 5 mg / kg.

[0075] In some embodiments, the PD-1 antibody is present in the combination in an amount of about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg. In some embodiments, the PD-1 antibody is present in the combination in an amount of about 1 mg to about 10 mg, about 10 mg to about 20 mg, about 25 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 50 mg to about 100 mg, about 75 mg to about 150 mg, about 100 mg to about 200 mg, about 200 mg to about 500 mg, about 500 mg to about 1000 mg, about 1000 mg to about 1200 mg, about 1000 mg to about 1500 mg, about 1200 mg to about 1500 mg, or about 1500 mg to about 2000 mg.

[0076] In some embodiments, the PD-1 antibody may be present in the combination in an amount of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL, 400 mg / mL or 500 mg / mL. In some embodiments, the PD-1 antibody is present in the combination in an amount of about 1 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 15 mg / mL, about 10 mg / mL to about 25 mg / mL, about 20 mg / mL to about 30 mg / mL, about 25 mg / mL to about 50 mg / mL, or about 50 mg / mL to about 100 mg / mL.

[0077] In certain embodiments, the therapeutically effective amount of the PD-1 antibody is determined as the amount provided on a package insert provided with the PD-1 antibody. The term package insert refers to instructions customarily included in commercial packaging of pharmaceutical products approved by the FDA or similar regulatory agency in countries other than the USA, which contain, for example, information about the use, dosage, administration, contraindications and / or warnings concerning the use of such pharmaceutical products.

[0078] In some embodiments, a compound as described herein may be provided in an amount that is synergistic with the amount of a PD-1 inhibitor. The term synergistic refers to a combination described herein (e.g., a compound of Formula (Ia) and a PD-1 inhibitor (including co-administration with another active agent, such as an anti-cancer agent described herein)) or a combination of regimens that is more effective than the additive effect of each individual treatment or regimen.

[0079] The synergistic effect of the combinations described herein may allow the use of lower dosages of one or more components of the combination (e.g., a compound of formula (Ia) or a PD-1 inhibitor). The synergistic effect may allow for less frequent administration of at least one of the administered therapeutic agents (e.g., a compound of formula (Ia) or a PD-1 inhibitor) to a subject having a disease, disorder, or condition described herein. Such lower dosages and reduced frequency of administration may reduce the toxicity associated with administration of at least one of the therapeutic agents to a subject without reducing the efficacy of the treatment. The synergistic effect avoids or reduces adverse undesirable side effects associated with the use of any treatment.

[0080] Further forms of the compound In some embodiments, the compounds disclosed herein have one or more stereocenters, and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, and appropriate mixtures thereof. The compounds and methods provided herein include all cis-, trans-, syn-, anti-, entgegen (E), and zusammen (Z) isomers, and appropriate mixtures thereof. In certain embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, the resolution of the enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is accomplished by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis.

[0081] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be administered more easily than the parent drug. For example, a prodrug may be bioavailable for oral administration, whereas the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester ("prodrug") to facilitate crossing cell membranes where water solubility is disadvantageous for mobility, but is metabolically hydrolyzed to the active entity, a carboxylic acid, once inside a cell where water solubility is beneficial. A further example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, which is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharma- ceutical, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharma- ceutical or therapeutically active form of the compound.

[0082] In one aspect, prodrugs are designed to alter the metabolic stability or transport properties of a drug, mask side effects or toxicity, improve the taste of a drug, or alter other properties or characteristics of a drug. Once a pharmacokinetic, pharmacodynamic process, and drug metabolism in vivo, knowledge allows the design of a prodrug of that compound once a pharmacologic active compound is known. (For example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho, "Recent Advances in Oral Prodrug Discovery", Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series).

[0083] In some embodiments, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0084] In some embodiments, the aromatic ring moiety of the compounds described herein is susceptible to various metabolic reactions, and the incorporation of suitable substituents on the aromatic ring structure reduces, minimizes, or eliminates this metabolic pathway. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogens, or alkyl groups.

[0085] In another embodiment, the compounds described herein are isotopically labeled (e.g., radioisotopes) or labeled by means including, but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0086] The compounds disclosed herein include isotopically labeled compounds that are identical to the compounds listed herein except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, and 125 In one embodiment, certain isotopically labeled compounds, such as 3 H and 14 Compounds having radioactive isotopes incorporated therein, such as C, are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0087] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism that needs to produce metabolic products that are used to provide a desired effect, including a desired therapeutic effect.

[0088] As used herein, "pharmaceutical acceptable" refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, that is, the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0089] The term "pharmaceutical acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, a pharmaceutical acceptable salt is obtained by reacting a compound disclosed herein with an acid. A pharmaceutical acceptable salt is also obtained by reacting a compound disclosed herein with a base to form a salt.

[0090] The compounds described herein can be formed as and / or used as pharma- ceutically acceptable salts. Types of pharma-ceutically acceptable salts include, but are not limited to, the following: (1) The free base form of the compound can be dissolved in an aqueous solution of an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, tert-butyl ether ... and the like. (2) Salts formed by reaction of the parent compound with a pharma- ceutically acceptable inorganic or organic acid, such as phenylenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, t-butyl acetate, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, etc. (3) Salts formed by replacement of an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), alkaline earth ion (e.g., magnesium, calcium), or aluminum ion. In some cases, the compounds described herein may be coordinated with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexyl-amine, tris(hydroxymethyl)methylamine.In other cases, the compounds described herein may form salts with amino acids, such as, but not limited to, arginine and lysine.Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0091] Pharmaceutically acceptable salts include solvent addition forms, particularly solvates.Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and can be formed during the process of crystallization with pharma-ceutically acceptable solvents such as water and ethanol. When the solvent is water, hydrates are formed, and when the solvent is alcohol, alcoholates are formed.Solvates of the compounds described herein can be conveniently prepared or formed during the process described herein.In addition, the compounds provided herein can exist in unsolvated and solvated forms.In general, solvated forms are considered equivalent to unsolvated forms in the compounds and methods provided herein.

[0092] Pharmaceutical Compositions In one aspect, the compound described herein is formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharma- ceutical preparations. Appropriate formulations depend on the route of administration selected. Summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), and such disclosures are incorporated by reference.

[0093] As used herein, a pharmaceutical composition refers to a mixture of a compound disclosed herein with other chemical components (i.e., pharma- ceutically acceptable inactive components), such as carriers, pharmaceutical excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, permeation enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. A pharmaceutical composition facilitates administration of a compound to an organism.

[0094] The pharmaceutical formulations described herein can be administered to a subject in a variety of ways by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intracerebroventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical, or transdermal routes of administration.The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0095] In some embodiments, the compounds disclosed herein are administered orally.

[0096] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation of the compounds disclosed herein is in the form of a capsule.

[0097] In one embodiment, the liquid pharmaceutical dosage form for oral administration is in the form of an aqueous suspension or solution selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0098] For administration by inhalation, the compounds disclosed herein will be formulated for use as an aerosol, mist, or powder.

[0099] For buccal or sublingual administration, the compositions can take the form of tablets, lozenges, or gels formulated in conventional manner.

[0100] In some embodiments, the compounds disclosed herein are formulated as transdermal dosage forms.

[0101] In one aspect, the compounds disclosed herein are formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection.

[0102] In some embodiments, the compounds disclosed herein are administered topically and can be formulated into a variety of topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments.

[0103] In some embodiments, the compounds disclosed herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.

[0104] The pharmaceutical compositions and dosage forms described herein typically contain one or more pharmaceutical additives.Suitable pharmaceutical additives are well known to those skilled in the art of pharmacy.Whether a particular pharmaceutical additive is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors, such as the intended route of administration to a patient.The pharmaceutical compositions described herein can contain other agents, such as stabilizers, lubricants, buffers and disintegrants, which can reduce the rate at which active ingredients may decompose in a particular formulation.

[0105] The pharmaceutical compositions described herein may, in certain instances, include additional active agents other than the active agents in the combinations described herein (e.g., anti-cancer agents as described herein) in the amounts provided herein.

[0106] In some embodiments, the compounds disclosed herein are provided in an oral dosage form, such as a tablet or capsule. In some embodiments, the compounds disclosed herein are supplied as a powder (e.g., a lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration.

[0107] The PD-1 inhibitors described herein may be provided in a form that is convenient for administration to a patient or that facilitates administration to a patient. For example, when the PD-1 inhibitor is a PD-1 antibody described herein, the PD-1 inhibitor can be formulated as a ready-to-use solution for parenteral administration. In another example, the PD-1 inhibitor, including, for example, a PD-1 antibody, can be formulated as a powder (e.g., lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration. In one embodiment, the combination includes a PD-1 antibody formulated for intravenous administration. In yet another embodiment, the combination includes a compound of formula I formulated as an oral dosage form (e.g., tablet or capsule) and a PD-1 inhibitor formulated for intravenous administration.

[0108] The combinations described herein can be provided as controlled release pharmaceuticals, with the goal of improving drug therapy over that obtained by non-controlled counterparts.Controlled release formulations can extend the activity of drugs, reduce the frequency of dosing, and increase the compliance of subjects.In addition, controlled release formulations can be used to affect other characteristics such as the onset of action or blood levels of drugs, thereby affecting the occurrence of side (e.g., adverse) effects.

[0109] Treatment Method The combinations and pharmaceutical compositions described herein are useful for treating diseases, disorders, such as cancer, or reducing or eliminating symptoms of diseases and disorders.

[0110] In one aspect, described herein is a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a combination comprising a SHP2 inhibitor compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof (e.g., a compound of Formula (Ia)), and a PD-1 inhibitor.

[0111] In some embodiments, the cancer is in the form of a tumor. In some embodiments, the cancer is selected from squamous cell carcinoma, non-squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial carcinoma, breast cancer, prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is squamous cell carcinoma. In some embodiments, the cancer is non-squamous cell carcinoma. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is urothelial carcinoma. In some embodiments, the cancer is breast cancer (e.g., HER2-negative or HER2-positive breast cancer). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is leiomyosarcoma. In some embodiments, the cancer is malignant peripheral nephrotic tumor (MPNST).

[0112] In some embodiments, the tumor is a solid tumor. In some embodiments, the method of treating cancer reduces tumor volume or tumor burden in a patient. In some embodiments, the tumor is reduced in volume by 5% to 95% or 5% to 50% or any value therein. In some embodiments, the tumor is reduced in volume by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, the tumor volume is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, the tumor is reduced by about 10% to about 99%. In some embodiments, the tumor is about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 99%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 99%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, reduced by about 30% to about 90%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99%. In some embodiments, the tumor is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 99%. In some embodiments, the tumor is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.In some embodiments, the tumor is reduced by up to about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 99%.

[0113] In some embodiments, the method of treating cancer results in a reduction in tumor growth over a treatment regimen. In some embodiments, the treatment regimen is from about 1 week to about 12 weeks. In some embodiments, the treatment regimen is from about 1 week to about 2 weeks, from about 1 week to about 3 weeks, from about 1 week to about 4 weeks, from about 1 week to about 5 weeks, from about 1 week to about 6 weeks, from about 1 week to about 7 weeks, from about 1 week to about 8 weeks, from about 1 week to about 9 weeks, from about 1 week to about 10 weeks, from about 1 week to about 11 weeks, from about 1 week to about 12 weeks, from about 2 weeks to about 3 weeks, from about 2 weeks to about 4 weeks, from about 2 weeks to about 5 weeks, from about 2 weeks to about 6 weeks, from about 2 weeks to about 7 weeks. 2 weeks to 8 weeks, 2 weeks to 9 weeks, 2 weeks to 10 weeks, 2 weeks to 11 weeks, 2 weeks to 12 weeks, 3 weeks to 4 weeks, 3 weeks to 5 weeks, 3 weeks to 6 weeks, 3 weeks to 7 weeks, 3 weeks to 8 weeks, 3 weeks to 9 weeks, 3 weeks to 10 weeks, 3 weeks to 11 weeks, 3 weeks to 12 weeks, 4 weeks to 5 weeks, 4 weeks to 6 weeks, 4 weeks to 7 weeks, 4 weeks to about 8 weeks, about 4 weeks to about 9 weeks, about 4 weeks to about 10 weeks, about 4 weeks to about 11 weeks, about 4 weeks to about 12 weeks, about 5 weeks to about 6 weeks, about 5 weeks to about 7 weeks, about 5 weeks to about 8 weeks, about 5 weeks to about 9 weeks, about 5 weeks to about 10 weeks, about 5 weeks to about 11 weeks, about 5 weeks to about 12 weeks, about 6 weeks to about 7 weeks, about 6 weeks to about 8 weeks, about 6 weeks to about 9 weeks, about 6 weeks to about 10 weeks, about 6 weeks to about 11 weeks, about 6 weeks to about 6 weeks weeks to about 12 weeks, about 7 weeks to about 8 weeks, about 7 weeks to about 9 weeks, about 7 weeks to about 10 weeks, about 7 weeks to about 11 weeks, about 7 weeks to about 12 weeks, about 8 weeks to about 9 weeks, about 8 weeks to about 10 weeks, about 8 weeks to about 11 weeks, about 8 weeks to about 12 weeks, about 9 weeks to about 10 weeks, about 9 weeks to about 11 weeks, about 9 weeks to about 12 weeks, about 10 weeks to about 11 weeks, about 10 weeks to about 12 weeks, or about 11 weeks to about 12 weeks. In some embodiments, the treatment regimen is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. In some embodiments, the treatment regimen is at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, or about 11 weeks. In some embodiments, the treatment regimen is at most about 2 weeks, about 3 weeks, about 4 weeks,about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. In some embodiments, the tumor grows about 50% over the duration of the treatment plan, about 600% over the duration of the treatment plan. In some embodiments, the tumor grows from about 50% over the duration of the treatment plan to about 100% over the duration of the treatment plan, from about 50% over the duration of the treatment plan to about 150% over the duration of the treatment plan, from about 50% over the duration of the treatment plan to about 200% over the duration of the treatment plan, from about 50% over the duration of the treatment plan to about 250% over the duration of the treatment plan, from about 50% over the duration of the treatment plan to about 300% over the duration of the treatment plan, from about 50% over the duration of the treatment plan to about 600% over the duration of the treatment plan. about 350%, about 50% over the duration of the treatment plan to about 400% over the duration of the treatment plan, about 50% over the duration of the treatment plan to about 450% over the duration of the treatment plan, about 50% over the duration of the treatment plan to about 500% over the duration of the treatment plan, about 50% over the duration of the treatment plan to about 550% over the duration of the treatment plan, about 50% over the duration of the treatment plan to about 600% over the duration of the treatment plan, about 100% over the duration of the treatment plan to about 100% over the duration of the treatment plan about 150% over the duration of the treatment plan, about 100% over the duration of the treatment plan to about 200% over the duration of the treatment plan, about 100% over the duration of the treatment plan to about 250% over the duration of the treatment plan, about 100% over the duration of the treatment plan to about 300% over the duration of the treatment plan, about 100% over the duration of the treatment plan to about 350% over the duration of the treatment plan, about 100% over the duration of the treatment plan to about 400% over the duration of the treatment plan, about 100% over the duration of the treatment plan to about 450%, from about 100% over the duration of the treatment plan to about 500% over the duration of the treatment plan, from about 100% over the duration of the treatment plan to about 550% over the duration of the treatment plan, from about 100% over the duration of the treatment plan to about 600% over the duration of the treatment plan, from about 150% over the duration of the treatment plan to about 200% over the duration of the treatment plan, from about 150% over the duration of the treatment plan to about 250% over the duration of the treatment plan, from about 150% over the duration of the treatment plan to about 300% over the duration of the treatment plan,about 150% over the duration of the treatment plan to about 350% over the duration of the treatment plan, about 150% over the duration of the treatment plan to about 400% over the duration of the treatment plan, about 150% over the duration of the treatment plan to about 450% over the duration of the treatment plan, about 150% over the duration of the treatment plan to about 500% over the duration of the treatment plan, about 150% over the duration of the treatment plan to about 550% over the duration of the treatment plan, about 150% over the duration of the treatment plan to about 600% over the duration of the treatment plan, about 200% over the duration of the treatment plan to about about 250% over the duration of the treatment plan, about 200% over the duration of the treatment plan to about 300% over the duration of the treatment plan, about 200% over the duration of the treatment plan to about 350% over the duration of the treatment plan, about 200% over the duration of the treatment plan to about 400% over the duration of the treatment plan, about 200% over the duration of the treatment plan to about 450% over the duration of the treatment plan, about 200% over the duration of the treatment plan to about 500% over the duration of the treatment plan, about 200% over the duration of the treatment plan to about 550% over the duration of the treatment plan, about 200% over the duration of the treatment plan ~about 600% over the treatment plan period, about 250% over the treatment plan period to about 300% over the treatment plan period, about 250% over the treatment plan period to about 350% over the treatment plan period, about 250% over the treatment plan period to about 400% over the treatment plan period, about 250% over the treatment plan period to about 450% over the treatment plan period, about 250% over the treatment plan period to about 500% over the treatment plan period, about 250% over the treatment plan period to about 550% over the treatment plan period, from about 250% to about 600% over the duration of the treatment plan, from about 300% over the duration of the treatment plan to about 350% over the duration of the treatment plan, from about 300% over the duration of the treatment plan to about 400% over the duration of the treatment plan, from about 300% over the duration of the treatment plan to about 450% over the duration of the treatment plan, from about 300% over the duration of the treatment plan to about 500% over the duration of the treatment plan, from about 300% over the duration of the treatment plan to about 550% over the duration of the treatment plan, from about 300% over the duration of the treatment plan to about 600% over the duration of the treatment plan,about 350% over the duration of the treatment plan to about 400% over the duration of the treatment plan, about 350% over the duration of the treatment plan to about 450% over the duration of the treatment plan, about 350% over the duration of the treatment plan to about 500% over the duration of the treatment plan, about 350% over the duration of the treatment plan to about 550% over the duration of the treatment plan, about 350% over the duration of the treatment plan to about 600% over the duration of the treatment plan, about 400% over the duration of the treatment plan to about 450% over the duration of the treatment plan, about 400% over the duration of the treatment plan to about 500% over the duration of the treatment plan, about 400% over the duration of the treatment plan to about 500% over the duration of the treatment plan grow from about 550% over the duration of the treatment plan, from about 400% over the duration of the treatment plan to about 600% over the duration of the treatment plan, from about 450% over the duration of the treatment plan to about 500% over the duration of the treatment plan, from about 450% over the duration of the treatment plan to about 550% over the duration of the treatment plan, from about 450% over the duration of the treatment plan to about 600% over the duration of the treatment plan, from about 500% over the duration of the treatment plan to about 550% over the duration of the treatment plan, from about 500% over the duration of the treatment plan to about 600% over the duration of the treatment plan, or from about 550% over the duration of the treatment plan to about 600% over the duration of the treatment plan. In some embodiments, the tumor grows about 50% over the duration of the treatment plan, about 100% over the duration of the treatment plan, about 150% over the duration of the treatment plan, about 200% over the duration of the treatment plan, about 250% over the duration of the treatment plan, about 300% over the duration of the treatment plan, about 350% over the duration of the treatment plan, about 400% over the duration of the treatment plan, about 450% over the duration of the treatment plan, about 500% over the duration of the treatment plan, or about 550% over the duration of the treatment plan, about 600% over the duration of the treatment plan. In some embodiments, the tumor expands by about 50% over the duration of the treatment plan to about 100% over the duration of the treatment plan, about 150% over the duration of the treatment plan to about 200% over the duration of the treatment plan, about 250% over the duration of the treatment plan to about 300% over the duration of the treatment plan, about 350% over the duration of the treatment plan to about 400% over the duration of the treatment plan, about 450% over the duration of the treatment plan, or about 500% over the duration of the treatment plan,The tumor grows about 550% over the duration of the treatment plan. In some embodiments, the tumor grows about 100% over the duration of the treatment plan, about 150% over the duration of the treatment plan, about 200% over the duration of the treatment plan, about 250% over the duration of the treatment plan, about 300% over the duration of the treatment plan, about 350% over the duration of the treatment plan, about 400% over the duration of the treatment plan, about 450% over the duration of the treatment plan, about 500% over the duration of the treatment plan, about 550% over the duration of the treatment plan, or about 600% over the duration of the treatment plan.

[0114] In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a hematological cancer selected from lymphoma, non-Hodgkin's lymphoma (myeloid leukemia (NHL), Reed-Sternberg disease, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL) or chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is Hodgkin's lymphoma or Reed-Sternberg disease.

[0115] In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is non-Hodgkin's lymphoma (NHL). In some embodiments, the NHL is low-grade NHL (e.g., follicular lymphoma (FL), lymphoplasmacytic lymphoma (LL), marginal zone lymphoma (MZL) or primary cutaneous anaplastic large cell lymphoma) or aggressive NHL (e.g., diffuse large B-cell lymphoma (DLBCL), follicular large cell lymphoma stage III, anaplastic large cell lymphoma, extranodal NK / T-cell lymphoma, lymphomatoid granulomatosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, intravascular large B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, adult T-cell leukemia / lymphoma, or mantle cell lymphoma). In some embodiments, the cancer is Hodgkin's lymphoma (e.g., classical or nodular lymphocyte predominant). In some embodiments, the Hodgkin's lymphoma contains Reed-Sternberg cells and can cause Reed-Sternberg disease. In some embodiments, the cancer is multiple myeloma (MM). In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is chronic myelogenous leukemia (CML). In some embodiments, the cancer is chronic lymphocytic leukemia (CLL) (e.g., Binet stage A cancer or Binet stage B cancer). In some embodiments, the cancer is acute lymphocytic leukemia (ALL) (e.g., T-cell or B-cell lymphoblastic leukemia).

[0116] In some embodiments, the cancer is stage I, stage II, stage III, or stage IV cancer. In some embodiments, the cancer is stage I cancer (e.g., stage IA, IB, or IC). In some embodiments, the cancer is stage II cancer (e.g., stage IIA or IIB). In some embodiments, the cancer is stage III cancer (e.g., stage IIIA, IIIB, or IIIC). In some embodiments, the cancer is stage IV cancer (e.g., stage IVA or IVB).

[0117] The combinations described herein can be administered to cancer patients at any time after diagnosis. For example, the cancer patient can be treatment-naive (e.g., never received cancer treatment for the cancer diagnosed). The cancer patient can be treatment-naive for a cancer or diagnosed with one or more other cancers, for example caused by metastasis or malignancy. The cancer patient can be immune checkpoint naive for one or more cancers. The cancer patient can have refractory cancer. In certain examples, the combinations described herein are administered to patients in need of administration as first-line therapy (e.g., first-line therapy administered to cancer patients who have not been treated).

[0118] In some embodiments, the methods of treating cancer inhibit metastasis of the cancer in a patient, hi some embodiments, metastasis is inhibited by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0119] In some embodiments, the methods of treating cancer reduce existing tumor metastases in a patient, hi some embodiments, existing tumor metastases are reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0120] In some embodiments, the methods of treating cancer extend or increase the time to disease progression (including progression between advanced stages, e.g., progression from stage III to stage IV cancer) of the patient's cancer. In some embodiments, the increase is a comparison of the time to disease progression with treatment to the time to disease progression without treatment. In some embodiments, the methods described herein extend the time to disease progression by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year or more, including values ​​therein.

[0121] In some embodiments, the method of treating cancer extends the survival of the patient. In some embodiments, the method of treating cancer increases the progression-free survival of the patient. In some embodiments, the method of treating cancer extends the time to disease progression of the cancer in the patient. In some embodiments, the method of treating cancer extends the survival of the patient. In some embodiments, the method of treating cancer extends the progression-free survival of the patient. In some embodiments, the survival is extended for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years or more, inclusive.

[0122] In some embodiments, the patient is treatment naive.

[0123] In some embodiments, the method comprises administering to the patient a combination as described herein as a first line therapy. In some embodiments, the method comprises administering to the patient a combination as described herein as a second line, third line, fourth line, fifth line, or sixth line of treatment. In some embodiments, the method comprises administering to the patient a combination as described herein as a second line of treatment. In some embodiments, the method comprises administering to the patient a combination as described herein as a third line of treatment.

[0124] In some embodiments, the method comprises administering to the patient the combination described herein after treatment with at least one anti-cancer therapy. In some embodiments, the anti-cancer therapy comprises chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy or a combination thereof. In some embodiments, the anti-cancer therapy is chemotherapy. In some embodiments, the anti-cancer therapy is radiation therapy. In some embodiments, the anti-cancer therapy is cancer surgery. In some embodiments, the anti-cancer therapy is tumor resection or excision. In some embodiments, the anti-cancer therapy is immunotherapy.

[0125] In some embodiments, the methods comprise administering a combination described herein to a patient who has failed at least one PD-1 therapy.

[0126] In some embodiments, the cancer is resistant to at least one anti-cancer agent.

[0127] Methods of Dosing and Treatment Regimen In another aspect, the combinations described herein are used in the preparation of a medicament for treating a disease or condition described herein.

[0128] In certain embodiments, the combination disclosed herein is administered for preventive and / or therapeutic treatment. In therapeutic applications, the combination is administered to a patient who already suffers from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. The amount effective for such use may vary depending on the severity and course of the disease or condition, previous treatment, the patient's health condition, weight and response to drugs, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0129] In prophylactic applications, the combinations described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.

[0130] In some embodiments, the method includes administering a combination described herein to a patient by oral or intraperitoneal methods (ip), or a combination thereof. In some embodiments, the combination is administered orally. In some embodiments, the combination is administered orally. In some embodiments, the combination is administered by ip methods. In some embodiments, the combination is administered intravenously (IV).

[0131] Doses employed in adult human treatment typically range from 0.01 mg to 5000 mg per day, or from about 0.01 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently provided in a single dose or in divided doses.

[0132] In certain embodiments, the dose of the administered drug may be temporarily reduced or temporarily suspended for a period of time (ie, a "drug holiday").

[0133] In some embodiments, the method comprises administering to a patient a combination described herein daily, weekly, or monthly. In some embodiments, the combination is administered daily. In some embodiments, the combination is administered weekly. In some embodiments, the combination is administered every other week. In some embodiments, the combination is administered monthly. In some embodiments, the combination is administered every other month.

[0134] The combinations described herein may be administered, for example, once daily (QD), twice daily (BID), once weekly (QW), twice weekly (BID), three times weekly (TIW) or once monthly (QM). In some embodiments, the method includes administering the combinations described herein QD, BID or TID. In some embodiments, the combination is administered QD. In some embodiments, the combination is administered BID. In some embodiments, the combination is administered TID. In certain examples, the compound of formula I is administered 2-3 times per week. In another embodiment, the compound of formula I is administered QD. The compound may be administered once daily for about 1 day to about 7 days, 1 day to about 14 days, 1 day to about 21 days, 1 day to about 28 days, or daily until disease progression or unacceptable toxicity occurs. Administration of the compound of formula I may depend in part on the patient's tolerance, where greater tolerance may allow for more or more frequent administration.

[0135] The term "administered simultaneously" as used herein is not specifically limited and means that a compound of the present disclosure and an additional active agent are administered at substantially the same time, for example as a mixture or in immediate succession order.

[0136] The term "administered sequentially" as used herein is not specifically limited and means that the compound of the present disclosure and the additional active agent are not administered simultaneously, but are administered alternately or in groups with a specific time interval between administrations. The time interval may be the same or different between each administration of the compound of the present disclosure and the additional active agent, and may be selected, for example, from the range of 2 minutes to 96 hours, 1 to 7 days, or 1, 2, or 3 weeks. In general, the time interval between administrations may range from a few minutes to a few hours, such as from 2 minutes to 72 hours, 30 minutes to 24 hours, or 1 to 12 hours. Further examples include time intervals in the ranges of 24 to 96 hours, 12 to 36 hours, 8 to 24 hours, and 6 to 12 hours.

[0137] In some embodiments, the SHP2 inhibitor of Formula (I), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor are administered simultaneously or sequentially. In some embodiments, the SHP2 inhibitor compound described herein and the PD-1 inhibitor are administered sequentially. In some embodiments, the SHP2 inhibitor compound described herein, or a pharma- ceutically acceptable salt or solvate thereof (e.g., a compound of Formula (Ia)), is administered QD, BID, or TID, and the PD-1 inhibitor is administered QD, BID, or TID.

[0138] The combinations described herein can include administration of each treatment (e.g., a compound of Formula (Ia) and a PD-1 inhibitor), where administration occurs simultaneously or sequentially (in either order). In some embodiments, a SHP2 inhibitor compound described herein and a PD-1 inhibitor are administered simultaneously (e.g., within at least 1-5 minutes of each other). In other embodiments, a compound described herein and a PD-1 inhibitor are administered sequentially (e.g., within at least 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 10 hours, 12 hours, 1 day, 2 days, 5 days, 7 days, 14 days, or 21 days of each other).

[0139] In some embodiments, a SHP2 inhibitor compound described herein is administered simultaneously with a PD-1 inhibitor. In some embodiments, a compound described herein is administered before the PD-1 inhibitor. In some embodiments, a compound described herein is administered after the PD-1 inhibitor.

[0140] The combinations described herein may be administered in a regimen. The regimen may be configured to provide a therapeutically effective amount of the SHP2 inhibitor compound and the PD-1 inhibitor described herein over a predetermined period (e.g., administration time). The regimen may be configured to limit or prevent side effects or undesirable complications from each of the components of the combinations described herein. The regimen may be configured in a manner that results in an increased effect (e.g., synergistic effect) of both therapies of the combination. A regimen useful for treating cancer may include any number of administration days that may be repeated as necessary. The administration period may be interrupted by a rest period that does not include any administration of at least one of the therapies. For example, the regimen may include an administration period that includes 2 days, 3 days, 5 days, 7 days, 10 days, 15 days, 21 days, 28 days, or more. These periods may be repeated. For example, a regimen may include a series of days as described above where the regimen is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more times.

[0141] The regimen may include a drug holiday of at least 1 day, 2 days, 3 days, 5 days, 7 days, 10 days or more, when at least one treatment is not administered to the patient any more.The drug holiday may be determined, for example, by monitoring the patient's response to the drug or by measuring the effectiveness of the treatment.The drug holiday may be applied to a single treatment, so that only one treatment of the combination described herein is interrupted during the drug holiday, while the other treatment is still administered.The drug holiday may be applied to all of the treatments administered to the subject, so that the subject is not administered the treatment during the course of the drug holiday.

[0142] The regimens described herein for treating cancer using the combinations described herein may be continued until disease progression or unacceptable toxicity occurs.

[0143] Biomarkers In another aspect, provided herein is a method of modulating one or more biomarkers above pre-treatment baseline levels in a patient in need of treatment, comprising administering to the patient a combination of a SHP2 inhibitor compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor (e.g., a compound of Formula (Ia)).

[0144] In some embodiments, the one or more biomarkers include pro-inflammatory cytokines or chemokines that are important in inflammatory responses and immune system regulation. In some embodiments, the one or more biomarkers include, but are not limited to, INF-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, KC / GRO (CXCL1), and M1 / M2 macrophage expression.

[0145] In some embodiments, one or more biomarkers are increased or decreased above pre-treatment baseline levels. In some embodiments, one or more biomarkers are increased above baseline levels. In some embodiments, one or more biomarkers are decreased above baseline levels.

[0146] In some embodiments, one or more biomarkers are increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 100%, or at least 150%. In some embodiments, one or more biomarkers are increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold. In some embodiments, one or more biomarkers are decreased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 100%, or at least 150%. In some embodiments, one or more biomarkers are decreased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold.

[0147] In some embodiments, administration of the combinations described herein results in at least a 5%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, at least a 40%, at least a 50%, at least a 100%, or at least a 150% decrease in KC / GRO. In some embodiments, one or more biomarkers are decreased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold. In some embodiments, administration of the combinations described herein results in about a 5% to about a 90% decrease in KC / GRO. In some embodiments, administration of the combinations described herein provides about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 45%, about 5% to about 50%, about 5% to about 75%, about 5% to about 90%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 10% to about 75%, about 10% to about 90%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 15% to about 75%, about 15% to about 90%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 20% to about 75%, about 20% to about 90%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% to about 75%, about 25% to about 90%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about a reduction of 75%, about 30% to about 90%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 75%, about 35% to about 90%, about 40% to about 45%, about 40% to about 50%, about 40% to about 75%, about 40% to about 90%, about 45% to about 50%, about 45% to about 75%, about 45% to about 90%, about 50% to about 75%, about 50% to about 90%, or about 75% to about 90%.In some embodiments, administration of the combinations described herein results in about a 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 90% reduction in KC / GRO. In some embodiments, administration of the combinations described herein results in at least about a 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or about 75% reduction in KC / GRO. In some embodiments, administration of the combinations described herein results in up to about a 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 90% reduction in KC / GRO.

[0148] In some embodiments, administration of the combinations described herein results in at least a 5%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, at least a 40%, at least a 50%, at least a 100%, or at least a 150% reduction in TNF-α. In some embodiments, one or more biomarkers are reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold. In some embodiments, administration of the combinations described herein results in about a 5% to about a 90% reduction in TNF-α. In some embodiments, administration of the combinations described herein provides about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 45%, about 5% to about 50%, about 5% to about 75%, about 5% to about 90%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35 ... 0%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 10% to about 75%, about 10% to about 90%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 15% to about 75%, about 15% to about 90%, about 20% to about 25%, about 20% to about 30%, about 0% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 20% to about 75%, about 20% to about 90%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% to about 75%, about 25% to about 90%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about a reduction of 75%, about 30% to about 90%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 75%, about 35% to about 90%, about 40% to about 45%, about 40% to about 50%, about 40% to about 75%, about 40% to about 90%, about 45% to about 50%, about 45% to about 75%, about 45% to about 90%, about 50% to about 75%, about 50% to about 90%, or about 75% to about 90%.In some embodiments, administration of the combinations described herein results in about a 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 90% reduction in TNF-α. In some embodiments, administration of the combinations described herein results in at least about a 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or about 75% reduction in TNF-α. In some embodiments, administration of the combinations described herein results in up to about a 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 90% reduction in TNF-α.

[0149] In some embodiments, administration of the combinations described herein results in an M1 / M2 macrophage ratio in the tumor indicative of inhibition of tumor progression. In some embodiments, administration of the combinations described herein results in an M1 / M2 macrophage ratio of about 0.1 to about 1.2. In some embodiments, administration of the combinations described herein results in an M1 / M2 macrophage ratio of about 0.1 to about 0.2, about 0.1 to about 0.3, about 0.1 to about 0.4, about 0.1 to about 0.5, about 0.1 to about 0.6, about 0.1 to about 0.7, about 0.1 to about 0.8, about 0.1 to about 0.9, about 0.1 to about 1, about 0.1 to about 1.1, about 0.1 to about 1.2, about 0.2 to about 0.3, about 0.2 to about 0.4, about 0.2 to about 0.5, about 0. 2 to about 0.6, about 0.2 to about 0.7, about 0.2 to about 0.8, about 0.2 to about 0.9, about 0.2 to about 1, about 0.2 to about 1.1, about 0.2 to about 1.2, about 0.3 to about 0.4, about 0.3 to about 0.5, about 0.3 to about 0.6, about 0.3 to about 0.7, about 0.3 to about 0.8, about 0.3 to about 0.9, about 0.3 to about 1, about 0.3 to about 1.1, about 0.3 to about 1.2, about 0.4 to about 0.5, about 0.4 to about 0.6, about 0.4 to about 0.7, about 0.4 to about 0.8, about 0.4 to about 0.9, about 0.4 to about 1, about 0.4 to about 1.1, about 0.4 to about 1.2, about 0.5 to about 0.6, about 0.5 to about 0.7, about 0.5 to about 0.8, about 0.5 to about 0.9, about 0.5 to about 1, about 0.5 to about 1.1, about 0.5 to about 1.2, about 0.6 to about 0.7, about 0.6 to about 0.8, about 0.6 to about 0.9, about 0.6 to about 1, about 0.6 to about 1.1 , about 0.6 to about 1.2, about 0.7 to about 0.8, about 0.7 to about 0.9, about 0.7 to about 1, about 0.7 to about 1.1, about 0.7 to about 1.2, about 0.8 to about 0.9, about 0.8 to about 1, about 0.8 to about 1.1, about 0.8 to about 1.2, about 0.9 to about 1, about 0.9 to about 1.1, about 0.9 to about 1.2, about 1 to about 1.1, about 1 to about 1.2, or about 1.1 to about 1.2. In some embodiments, administration of the combinations described herein results in an M1 / M2 macrophage ratio of about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, or about 1.2.In some embodiments, administration of the combinations described herein results in an M1 / M2 macrophage ratio of at least about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, or about 1.1. In some embodiments, administration of the combinations described herein results in an M1 / M2 macrophage ratio of up to about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, or about 1.2.

[0150] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Also, it should be noted that the term "or" is generally used in its sense including "and / or" unless the content clearly dictates otherwise. Moreover, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0151] As used herein, the following terms have the following meanings unless otherwise indicated.

[0152] "Oxo" refers to the =O substituent.

[0153] "Alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing up to 10 carbon atoms is any of the C1 to C 10 Similarly, for example, an alkyl group containing up to 6 carbon atoms is a C1-C6 alkyl group. Alkyl groups containing other numbers of carbon atoms (and other moieties defined herein) are similarly represented. Alkyl groups include C1-C 10Exemplary alkyl groups include, but are not limited to, alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. Preferably, the alkyl is C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. 10 Alkyl is any one of methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Unless otherwise specifically stated in the specification, alkyl groups may be optionally substituted as described below.

[0154] "Alkylene" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a radical group. In some embodiments, alkylene is -CH-, -CHCH-, or -CHCHCH-. In some embodiments, alkylene is -CH-. In some embodiments, alkylene is -CHCH-. In some embodiments, alkylene is -CHCHCH-. In some embodiments, alkylene is -CHCHCH-.

[0155] "Alkoxy" refers to a radical of the formula -OR, where R is an alkyl radical as defined. Unless otherwise specifically stated in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy. In some embodiments, an alkoxy is methoxy. In some embodiments, an alkoxy is ethoxy. "C1-C 10 The term "alkoxy", alone or in combination, refers to the groups C1-C 10 It means alkyl-O-, and is defined as C1-C10 "Alkyl" means as defined above, including, but not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy (-OCH2CH2CH3), iso-propoxy (-OCH(CH3)2), n-butoxy (-OCH2CH2CH2CH3), sec-butoxy (-OCH(CH3)CH2CH3), iso-butoxy (-OCH2CH(CH3)2), tert-butoxy (-OC(CH3)3), and the like.

[0156] "Heteroalkyl" refers to an alkyl radical as described above in which one or more carbon atoms of the alkyl are replaced with an O, N (i.e., NH, N-alkyl), or S atom. "Heteroalkylene" refers to a straight or branched divalent heteroalkyl chain linking the remainder of the molecule to a radical group. Unless specifically stated otherwise in the specification, a heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCH2CH2OMe, or -OCH2CH2OCH2CH2NH2. Representative heteroalkylene groups include, but are not limited to, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0157] "Alkylamino" refers to a radical of the formula -NHR or -NRR, where each R is independently an alkyl radical as defined above. Unless otherwise specifically stated in the specification, an alkylamino group may be optionally substituted as described below.

[0158] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. An aromatic may be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0159] "Aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is a phenyl. Depending on the structure, an aryl group may be a monoradical or a diradical (i.e., an arylene group). Unless specifically stated otherwise in the specification, "aryl" or the prefix "ar-" (e.g., "aralkyl") is meant to include aryl radicals that are optionally substituted.

[0160] "Carboxy" refers to -CO2H. In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties as a carboxylic acid group. A compound having a carboxylic acid moiety can replace the carboxylic acid moiety with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to a carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere ionizes at physiological pH to about the same extent as a carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to, the following:

[0161] [ka] And so on.

[0162] "Cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. Cycloalkyls can be saturated or partially unsaturated. Cycloalkyls can be fused to an aromatic ring (in which case the cycloalkyl is attached via a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3-10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3-10 carbon atoms, 3-8 carbon atoms, 3-6 carbon atoms, or 3-5 carbon atoms. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, bicyclic, or polycyclic. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, decalinyl, and adamantyl. In some embodiments, the cycloalkyl is monocyclic. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, a cycloalkyl is bicyclic. Bicyclic cycloalkyl groups include fused bicyclic cycloalkyl groups, spiro bicyclic cycloalkyl groups, and bridged bicyclic cycloalkyl groups.In some embodiments, the cycloalkyl group is selected from among spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, 3,4-dihydronaphthalene-1(2H)-one, and decalinyl. In some embodiments, the cycloalkyl is polycyclic. Polycyclic radicals include, for example, adamantyl and. In some embodiments, the polycyclic cycloalkyl is adamantyl. Unless specifically stated otherwise in the specification, the cycloalkyl group may be optionally substituted.

[0163] "Fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, a carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring may be replaced with a nitrogen atom.

[0164] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

[0165] "Haloalkyl" refers to an alkyl radical, as defined above, substituted with one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specifically stated in the specification, a haloalkyl group may be optionally substituted.

[0166] "Haloalkoxy" refers to an alkoxy radical, as defined above, substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless specifically stated otherwise in the specification, a haloalkoxy group can be optionally substituted.

[0167] "Heterocycloalkyl" or "heterocyclyl" or "heterocyclic ring" refers to a stable 3-14 membered non-aromatic ring radical containing 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless specifically stated otherwise in the specification, a heterocycloalkyl radical can be monocyclic, bicyclic (which can include fused bicyclic heterocycloalkyls (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), bridged heterocycloalkyls, or spiroheterocycloalkyls) or polycyclic. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic. In some embodiments, a heterocycloalkyl is bicyclic. The nitrogen, carbon, or sulfur atoms in a heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocyclyl radical is partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2-10 carbons in the ring. In some embodiments, heterocycloalkyls have 2-8 carbons in the ring. In some embodiments, heterocycloalkyls have 2-8 carbons and 1 or 2 N atoms in the ring.In some embodiments, a heterocycloalkyl has 2-10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heterocycloalkyl has 2-10 carbons, 1-2 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless otherwise specifically indicated in the specification, a heterocycloalkyl group may be optionally substituted. In some embodiments, the term "3- to 12-membered heterocyclic group" refers to a saturated or partially unsaturated monocyclic ring or polycyclic heterocyclic group containing 3 to 12, particularly 5 to 12, more particularly 5 to 7 carbon atoms and a heteroatom or heteroatomic group, wherein the heteroatom or heteroatomic group is N, NH, O, C(O), or S(O). m (wherein m is 0, 1, or 2). In some embodiments, the 3- to 12-membered heterocyclic group includes aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholine, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamyl, valerolactam, caprolactam, butyrolactone, valerolactone, or caprolactone.

[0168] "Heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Heteroaryl is monocyclic or bicyclic. Specific examples of monocyclic heteroaryl include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine and pteridine. Specific examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Specific examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, the heteroaryl contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl.In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0169] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6 alkylalkyne, halogen, acyl, acyloxy, -CO2H, -CO2alkyl, nitro, and amino (e.g., -NH2, -NHR, -NR2), and protected derivatives thereof. In some embodiments, the optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH2, -NH(CH3)2, -N(CH3)2, -OH, -CO2H, and -CO2alkyl. In some embodiments, optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0170] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom with the switching of a single bond and an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric interconversions include the following:

[0171] [ka]

[0172] Terms such as "co-administration," as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which agents are administered by the same or different routes of administration or at the same or different times.

[0173] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound administered that relieves to some extent one or more of the symptoms of the disease or condition being treated. This result may be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in a disease symptom. The appropriate "effective amount" in any individual case may be determined using techniques such as dose escalation studies. An "effective amount" is an amount sufficient for the compound to achieve the stated purpose (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signal transduction pathway, or reduce one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount." "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) refers to a decrease in the severity or frequency of one or more symptoms, or the elimination of one or more symptoms. A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, has an intended prophylactic effect, e.g., prevents or delays the onset (or recurrence) of an injury, disease, condition or symptom, or reduces the likelihood of the onset (or recurrence) of an injury, disease, condition or symptom, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of one dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. As used herein, a "function-disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein compared to the absence of the antagonist.The exact amount will depend on the purpose of the treatment, and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Ieberman, 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).

[0174] As used herein, the term "pharmaceutical combination" refers to a product resulting from mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, e.g., a compound of formula (I) and an auxiliary agent, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound of formula (I) and an auxiliary agent, are administered to a patient simultaneously, in parallel or sequentially as separate entities without any specific time limit, and such administration provides an effective level of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients.

[0175] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.

[0176] The terms "treat", "treating" or "treatment" as used herein include alleviating, attenuating or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating symptoms caused by a disease or condition, or prophylactically and / or therapeutically arresting a symptom of a disease or condition.

[0177] The term "cancer" refers to any physiological condition in a mammal characterized by unregulated cell growth. Cancers as described herein include solid tumors and hematological (blood) cancers. "Hematologic cancer" refers to any blood-borne cancer, including, for example, myeloma, lymphoma, and leukemia. "Solid tumor" or "tumor" refers to lesions and all cancerous cells and cancerous cells and tissues resulting from neoplastic cell growth and proliferation, whether malignant or benign, and abnormal tissue growth. As used herein, "neoplastic" refers to any type of dysregulated or uncontrolled cell growth resulting from abnormal tissue growth, whether malignant or benign.

[0178] The term "enhance" refers to an increase or improvement in the function or activity of a protein or cell after administration of or contacting with a combination described herein compared to the protein or cell prior to administration or contacting.

[0179] The term "anti-cancer agent" is used according to its plain and ordinary meaning to refer to a composition having anti-tumor properties or the ability to inhibit cell growth or proliferation. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the anti-cancer agent is an agent disclosed herein to have utility in methods of treating cancer. In some embodiments, the anti-cancer agent is an agent approved by the FDA or similar regulatory agency in a country other than the USA to treat cancer.

[0180] The terms "chemotherapeutic agent" or "chemotherapeutic drug" are used according to their plain and ordinary meaning to refer to a chemical composition or compound having anti-tumor properties or the ability to inhibit cell growth or proliferation. "Chemotherapy" refers to a treatment or regimen that includes the administration of a chemotherapeutic agent or anti-cancer agent as described herein.

[0181] The term "PD-1 inhibitor" refers to a moiety (e.g., compound, nucleic acid, polypeptide, antibody) that reduces, inhibits, blocks, suppresses or interferes with the activity of PD-1 or its expression, including variants, isoforms, species homologs of human PD-1 (e.g., murine) and analogs having at least one epitope in common with PD-1. As used herein, a PD-1 inhibitor refers to any moiety that antagonizes PD-1 activity or expression. The efficacy of a PD-1 inhibitor can be measured, for example, by the 50% inhibitor concentration (half maximal inhibitory concentration or IC 50 ) can be measured.

[0182] "Polypeptide" and "protein" are used interchangeably herein to refer to any molecule that contains at least two or more amino acids.

[0183] The term "regimen" refers to a protocol for the dosing and timing of administration of one or more therapies (e.g., a combination described herein or another active agent, such as an anti-cancer agent described herein) to treat a disease, disorder, or condition described herein. A regimen can include effective dosing periods and drug holiday periods, as known in the art.

[0184] The antibodies described herein may be polyclonal or monoclonal, including xenogeneic, allogeneic or syngeneic types and modified versions thereof (e.g., humanized or chimeric). "Antibody" is intended to mean a polypeptide product of B cells of the immunoglobulin class capable of binding to a specific molecular antigen and composed of two identical pairs of polypeptide chains, each pair of polypeptide chains having one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), each amino-terminal portion of each chain containing a variable region of about 100 to about 130 or more amino acids, and each carboxy-terminal portion of each chain containing a constant region (see Borrebaeck (ed.) (1995) Antibody Engineering, Second Edition, Oxford University Press.: Kuby (1997) Immunology, Third Edition, W.H. Freeman and Company, New York). Specific molecular antigens to which the antibodies described herein can bind include PD-1 and epitopes thereof.

[0185] The term "monoclonal antibody" refers to a population of antibody molecules that contain one species of antigen-binding site capable of immunoreacting with a particular epitope of an antigen, while the term "polyclonal antibody" refers to a population of antibody molecules that contain more than one species of antigen-binding site capable of interacting with a particular antigen. A monoclonal antibody typically exhibits a single binding affinity for the particular antigen with which it immunoreacts. For example, the monoclonal antibodies used in accordance with the present invention can be produced using, for example, hybridoma techniques (e.g., Kohler and Milstein., Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA techniques (see, e.g., U.S. Pat. No. 4,816,567), phage display techniques (e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al., J. Immunol. 1999: 111-113 (1999)). Mol.Biol.222:581-597(1992);Sidhu et al. / .Mol.Biol.338(2):299-310(2004);Lee et al.,J.Mal.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Set.USA 101(34):12467-12472(2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004)), as well as techniques for producing human or human-like antibodies in animals that have some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (e.g., WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 10741; Jakobovits et al., Proc. Natl.Acad. Set. USA 90:2551 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425 and 5,661,016; Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-813 (1994); Fishwild et al., Nature Biotechnol. 14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13:65-93 (1995)).

[0186] The monoclonal antibodies of the present specification also include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequences of antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of one or more chains is identical or homologous to the corresponding sequences of antibodies derived from another species or belonging to another antibody class or subclass, and fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; Morrison et al., Proc. Natl. Acad. Set. USA, pp. 6851-6855 (1984)). "One or more humanized antibodies" may be considered a subset of the chimeric antibodies described herein.

[0187] The term "human" when used in reference to an antibody or functional fragment thereof (e.g., "one or more humanized antibodies") refers to an antibody or functional fragment having a human variable region or a portion thereof that corresponds to human germline immunoglobulin sequences. Such human germline immunoglobulin sequences are described in Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242. In the context of this specification, a human antibody can include an antibody that binds to PD-1 or a variant thereof as described herein. In certain examples, a human antibody is an antibody having an amino acid sequence that corresponds to the amino acid sequence of an antibody produced in a human and / or an antibody made using any of the techniques for making human antibodies disclosed herein. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries. Hoogenboom and Winter, Mol. Biol., 227:381 (1991); Marks et al. Mol. Biol., 222:581 (1991). The methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boemer et al., Immunol., 147(1):86-95 (1991) can also be used to prepare human monoclonal antibodies. See also Van Dijk and van de Winkel, Curr. Opin. Pharmacol., 2:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals (e.g., immunized xenoMouse) that have been modified to produce such antibodies in response to antigenic change, but whose endogenous gene loci have been disabled (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding xenoMouse technology).See also, e.g., Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies produced via human B cell hybridoma technology.

[0188] "Humanized antibody" refers to an antibody made by a non-human cell with a variable region or a variable region and a constant region that have been modified to closely resemble an antibody made by a human cell, for example, by modifying a non-human antibody amino acid sequence to incorporate amino acids found in human germline immunoglobulin sequences. The humanized antibody of the present invention can include, for example, in the CDRs, amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). Humanized antibodies can also include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0189] Humanized forms of non-human (e.g., murine) antibodies are antibodies that have minimal sequence derived from non-human immunoglobulin. In some embodiments, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and / or capacity. In some instances, framework ("FR") residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or the donor antibody. These modifications may be made to further improve antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR regions are those of a human immunoglobulin sequence, although the FR regions may comprise one or more individual FR residue substitutions which improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of amino acid substitutions in these FRs will typically be no more than six in the H chain and no more than three in the L chain. The humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc), which may optionally be a human immunoglobulin. Exemplary methods and humanized antibodies include those described in Jones et al. Nature 321:522-525 (1986); Riechmann et al. Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992); Vaswani and Hamilton, Ann. Allergy. Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Burle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0190] The term "functional fragment" when used in reference to an antibody refers to a portion of an antibody, including a heavy or light chain polypeptide, that retains some or all of the binding activity of the antibody from which the fragment is derived. Such functional fragments can include, for example, Fd, Fv, Fab, F(ab'), F(ab)2, F(ab')2, single chain Fv (ScFv), diabodies, triabodies, tetrabodies, and minibodies. Other functional fragments include, for example, heavy or light chain polypeptides, variable region polypeptides, or CDR polypeptides or portions thereof, so long as such functional fragments retain binding activity. For example, such antibody-binding fragments can be found in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York (1989); Myers (ed.), Molec. Biology and Biotechnology: A Comprehensive Desk Reference, New York: VCH Publisher, Inc.; Huston et al., Cell Biophysics, 22: 189-224 (1993); Pluckthun and Skerra, Meth. EnzymoL., 178: 497-515 (1989) and Day, ED, Advanced Immunochemistry, Second Ed., Wiley-Liss, Inc., New York, NY (1990). Antibody Engineering, Second Edition, Oxford University Press, 1995.

[0191] The term "heavy chain" when used in reference to an antibody refers to a polypeptide chain of about 50-70 kDa, with an amino terminal portion containing a variable region of about 120-130 or more amino acids, and a carboxy terminal portion containing a constant region. The constant region can be one of five different types, designated alpha (a), delta (δ), epsilon (ε), gamma (γ) and mu (μ), based on the amino acid sequence of the heavy chain constant region. Different heavy chains vary in size; α, δ and γ contain approximately 450 amino acids, while μ and ε contain approximately 550 amino acids. When combined with light chains, these different types of heavy chains give rise to the five well-known classes of antibodies, IgA, IgD, IgE, IgG and IgM (four subclasses of IgG: IgG1, IgG2, IgG3 and IgG4), respectively. The heavy chain can be a human heavy chain.

[0192] The term "light chain" when used in reference to an antibody refers to a polypeptide chain of about 25 kDa, the amino terminal portion containing a variable region of about 100 to about 110 or more amino acids, and the carboxy terminal portion containing the constant region. The approximate length of a light chain is 211 to 217 amino acids. Based on the amino acid sequence of the constant domain, two different types exist, designated lambda (λ) and kappa (κ). Light chain amino acid sequences are well known in the art. The light chain may be a human light chain.

[0193] The term "variable domain" or "variable region" refers to a portion of an antibody light or heavy chain, generally located at the amino terminus of the light or heavy chain, having a length of about 120-130 amino acids in the heavy chain and about 100-110 amino acids in the light chain, which is used in the binding and specificity of each particular antibody for its particular antigen. Variable domains can vary extensively in sequence between different antibodies. The sequence variability is concentrated in the CDRs, while the less variable portions of the variable domains are called framework regions (FRs). The CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with the antigen. The numbering of amino acid positions used herein is based on Kabat et al. (1991) Sequences of proteins of immunological interest (USDepartment of Health and Human Services, Washington, DC) 5 th The variable regions may be human variable regions.

[0194] CDR refers to one of the three hypervariable regions (H1, H2 or H3) in the non-framework region of the immunoglobulin (Ig or antibody) VH β-sheet framework, or the three hypervariable regions (L1, L2 or L3) in the non-framework region of the antibody VL β-sheet framework. Thus, CDR is a variable region sequence distributed in the framework region sequence. CDR regions are well known to those skilled in the art, and are defined by Kabat, for example, as the most hypervariable region in the antibody variable (V) domain (Kabat et al., Biol. Chem. 252:6609-6616 (1977); Kabat, Adv. Prot. Chem. 32:1-75 (1978)). CDR region sequences have also been structurally defined by Chothia as those residues that are not part of the conserved β-sheet framework and therefore can adapt to different conformations (Chothia and Lesk, Mol. Biol. 196:901-917 (1987)). Both terms are recognized in the art. The positions of CDRs within canonical antibody variable domains have been determined by comparing multiple structures (Al-Lazikani et al., Mol. Biol. 273:927-948 (1997); Morea et al., Methods 20:267-279 (2000)). Because the number of residues within the hypervariable regions differs in various antibodies, additional residues relative to the canonical position are conventionally numbered a, b, c, etc. next to the residue number in the standard variable domain numbering scheme (Al-Lazikani et al., supra (1997)). Such nomenclature is likewise well known to those of skill in the art. EXAMPLES

[0195] It will be understood that the following examples are intended to illustrate the present disclosure, but are not intended to limit the present disclosure.Various other examples and modifications of the above description and examples will be apparent to those skilled in the art after reading this disclosure without departing from the spirit and scope of the present disclosure, and all such examples or modifications are intended to be included within the scope of the appended claims.All publications and patents referred to in this specification are incorporated herein by reference in their entirety.

[0196] Example 1: Synthesis of compounds of formula (Ia) Compounds of formula (I), (Ia) and (II) can be synthesized by the methods provided in PCT / CN2020 / 07791, which is incorporated herein by reference in its entirety. In some embodiments, synthesis of the compounds described herein is accomplished using means described in the chemical literature, using methods described herein, or by a combination thereof.

[0197] Example 2: Tumor Volume GH21001 (TNO-155), GH21005 (compound of formula Ia) were supplied by HUYA Biosciences (USA), and RMC-4550 was supplied by MCE (China). Osimertinib was purchased from Selleck, China. Cisplatin was purchased from Qilu Pharma (China). Anti-PD-1 (RMP 1-14) and rat IgG2a antibody were purchased from BioXCell (China).

[0198] Procedures involving the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Crown Biosciences prior to implementation. Throughout the study, the care and use of animals was performed in accordance with the International Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC) regulations. Animals (6–8 weeks) were obtained from Shanghai Lingchang Biotechnology Co., Ltd (Shanghai, China) and allowed to acclimate prior to tumor cell inoculation.

[0199] All cell lines were maintained in culture and cells in the exponential growth phase were harvested and quantified by cell counter prior to tumor inoculation. MC38 tumor cells (1 × 10 6 ) was inoculated into the right anterior flank of female C57 / Bl animals (mean tumor size at the start of treatment was approximately 112 mm 3 ).

[0200] The date of randomization and treatment initiation was designated as day 0. Tumor volumes were measured twice weekly in two dimensions using calipers, and volumes were expressed in mm3 using the formula: V = (L x W x W) / 2, where V is tumor volume, L is tumor length (longest tumor dimension), and W is tumor width (longest tumor dimension perpendicular to L). Dosage was 10 mL / kg / day. GH21001 and GH21005 were dissolved in HP-β-CD and dissolved in 200 ml of 50 mM sodium citrate (pH = 4.2). Anti-PD-1 and rat IgG2a were diluted in PBS. RMC-4550 was diluted in 1% Capitsol in 50 mM sodium citrate (pH = 5.0), and a 0.5% dosing solution of osmertinib was diluted in 2% DMSO / 30% PEG300. The results of this study are shown in Figure 1A and Figure 1B.

[0201] Example 3: FACS and cytokine analysis At termination, tumors were harvested. A portion of the tumor was minced and immediately flash frozen for protein isolation or tumor tissue was dissociated for FACs analysis. Another portion of the tumor was fixed in 10% neutral buffered formalin and then processed into paraffin blocks.

[0202] Tumor dissociation: 12 hours after the last dose, tumors and blood of MC38 tumor-bearing animals were harvested. Tumors were enzymatically and mechanically dissociated using The Tumor Dissociation Kit (130-096-730) Miltenyi Biotec MACS Technology. Mononuclear blood cells (PBMCs) were isolated from whole blood using Histopaque-1077 (Sigma).

[0203] Cytokine detection assay: The V-Plex Proinflammatory Panel 1 Mouse Kit (Mesoscale Discovery) was used to determine cytokine levels in plasma isolated from tumor-bearing animals 2 hours after the last dose. Plasma from tumor-bearing animals was analyzed as described in the manufacturer's guidelines. Briefly, diluted plasma is introduced to MSD plates pre-coated with capture antibodies against the following cytokines: IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, KC / GRO, IL-10, IL-12p70, and TNF-α. After incubation, samples are washed and incubated with a secondary detection antibody (MSD SULFO-TAG™). Electrochemiluminescence detection from the assay is analyzed on the Meso Scale Discovery platform and cytokine levels are calculated according to the manufacturer's control samples. The results of this study are shown in Figure 2A, Figure 2B, and Figure 2C. As seen in Figure 2A and Figure 2B, anti-PD1 monotherapy in MC38 tumors results in an increase in both KC / GRO and TNF-α. Treatment with the compound of formula (Ia) resulted in a slight decrease in KC / GRO and TNF-α. However, combined treatment with both anti-PD-1 and the compound of formula (Ia) resulted in a significant increase in both KC / GRO and TNF-α, proving the synergistic effect between anti-PD-1 and the compound of formula (Ia). This synergistic effect confirmed the results of the tumor volume assay shown in Figure 1B. Figures 2A and 2B also showed the same synergistic relationship between RMC-4550 and anti-PD-1 as GH21001 (TNO-155) and anti-PD-1, proving that the compounds of formula (I) and formula (II) show synergistic effects with anti-PD-1 when administered to tumors.

[0204] Example 4: M1 / M2 macrophage expression All tumors treated with the treatment groups utilized in Examples 2-3 (MC38 tumors from Examples 2-3) were further examined for M1 / M2 macrophage and CD8 expression, see Figures 3A, 3B, and 3C.

[0205] Taken together, Figures 3A and 3B show that combined treatment with anti-PD-1 and compound of Formula (Ia) results in the greatest M1 / M2 ratio among all treatment groups. These findings are further supported in IHC assays (Figures 3A and 3B, bottom panels).

[0206] Immunohistochemistry: Freshly collected tumor tissues were placed in 10% NBF and fixed at room temperature for 24 hours. Tumor tissues were trimmed and rinsed with running water. Specimens were transferred to a vacuum tissue processor (VP1-JC, SAKURA) for dehydration and then embedded in FFPE blocks using a tissue embedding center (TEC 5-EM JC-2, SAKURA). FFPE blocks were sectioned on a manual rotary microtome (HistoCore MULTICUT, Leica) at a thickness of 4 μm / section. Reagents for IHC and antigen retrieval, including Bond™ Epitope Retrieval Solution 1 (Bond ER1), Bond™ Epitope Retrieval Solution 2 (Bond ER2), Bond™ Dewax Solution, and Bond™ Wash, were purchased from Leica. Primary antibody F4 / 80 [SP115] Abcam ab111101 was used at 1:1000. iNOS (D6B6S) CST 13120 and Arginase-1 (D4E3M) CST 93668S were both used at 1:500 dilution. Anti-rabbit poly-HRP-IgG (<25 μg / mL) containing 10% (v / v) animal serum in Tris-buffered saline / 0.09% ProClin™ 950 (ready-to-use) Leica DS9800 was used for secondary detection. For IF signal, TSA 520 and TSA 670 were purchased from YX Biology (China).

[0207] All stained sections were scanned using a Pannoramic Digital Slide Scanner (3DHISTECH, Pannoramic SCAN). High-resolution pictures of all sections were generated and further analyzed. All images were analyzed on the HALO™ platform. IHC scoring method: M1 = (iNOS and F4 / 80) macrophage density = number of double positive cells / total tumor area x 100%. M2 = (Arg-1 / F4 / 80) macrophage density = number of double positive cells / total tumor area x 100%. The results of this study are shown in Figure 3A and Figure 3B (lower panel). These results further demonstrate the improved efficacy of the combination of anti-PD-1 and compound of formula (Ia) in the treatment of cancer.

[0208] Example 5: Tumor and Blood Immunotyping Tumor dissociation: 12 hours after the last dose, tumors and blood of MC38 tumor-bearing animals were harvested. Tumors were enzymatically and mechanically dissociated using The Tumor Dissociation Kit (130-096-730) Miltenyi Biotec MACS Technology. Mononuclear blood cells (PBMCs) were isolated from whole blood using Histopaque-1077 (Sigma). Tumor cell suspensions, whole lysed blood or isolated PBMCs were resuspended and blocked with staining buffer containing 1 μg / ml Fc-Block (mouse BD Fc Block™ Cat. No. 553141). All antibodies were diluted in Fc-blocking buffer, except for FoxP3, which was diluted in permeabilization buffer. Antibodies were diluted according to Crown Bioscineces optimization. Cell surface markers CD45, CD4, CD335, CD11b, Gr-1, F4 / 80 were purchased from Biolegend. CD3 was purchased from BD Biosciences. CD8, FoxP3 and L / D BD were purchased from eBiosciences. Data was collected on a BD FACS cytometer and analyzed using Kaluza Analysis Software. See Figure 4A and Figure 4B.

[0209] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art should be included within the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

Claims

1. Formula (Ia) 【Chemistry 1】 or a pharma- ceutically acceptable salt or solvate thereof; PD-1 inhibitors and Combinations including:

2. The combination of claim 1, wherein said combination comprises from about 5 mg to about 100 mg of said compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof.

3. 2. The combination of claim 1, wherein the combination comprises about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg of the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof.

4. The combination according to any one of claims 1 to 3, wherein the PD-1 inhibitor is a small molecule compound, a nucleic acid, a peptide, a protein, an antibody, a peptibody, a diabody, a minibody, a single chain variable fragment (ScFv), or a variant thereof.

5. The combination according to any one of claims 1 to 3, wherein the PD-1 inhibitor is a PD-1 inhibitor antibody.

6. 4. The combination of any one of claims 1 to 3, wherein the PD-1 inhibitor is nivolumab, pembrolizumab, pidilizumab, REGN2810 (SAR-439684), PDR 001, SHR-1210, or MEDI 0680.

7. A therapeutic agent for treating cancer in a patient in need of such treatment, said therapeutic agent comprising a therapeutically effective amount of a compound of formula (Ia) 【Chemistry 2】 or a pharma- ceutically acceptable salt or solvate thereof; PD-1 inhibitors and administering to said patient a combination comprising

8. The method of claim 7, wherein the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, is administered at about 5 mg / kg to about 25 mg / kg to a patient in need of treatment for said cancer.

9. 8. The method of claim 7, wherein the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, is administered at about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg to a patient in need of treatment for the cancer.

10. The therapeutic agent of any one of claims 7 to 9, wherein the PD-1 inhibitor is a small molecule compound, a nucleic acid, a peptide, a protein, an antibody, a peptibody, a diabody, a minibody, a single chain variable fragment (ScFv), or a variant thereof.

11. The combination according to any one of claims 7 to 9, wherein the PD-1 inhibitor is a PD-1 inhibitor antibody.

12. 10. The combination of any one of claims 7 to 9, wherein the PD-1 inhibitor is nivolumab, pembrolizumab, pidilizumab, REGN2810 (SAR-439684), PDR 001, SHR-1210, or MEDI 0680.

13. The therapeutic agent according to any one of claims 7 to 9, wherein the therapeutic agent is administered simultaneously or sequentially with the compound or formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor.

14. The therapeutic agent according to any one of claims 7 to 9, wherein the cancer is squamous cell carcinoma, non-squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial carcinoma, breast cancer, prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor (MPNST).

15. The therapeutic agent of any one of claims 7 to 9, wherein the patient is treatment-naive.

16. The method according to any one of claims 7 to 9, wherein the compound of formula (Ia), or a pharma- ceutically acceptable salt of a solvate thereof, and the PD-1 inhibitor are administered to the patient as a first-line therapy.

17. The therapeutic agent of any one of claims 7 to 9, wherein the therapeutic agent is administered to a patient the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor as a second, third, fourth, fifth or sixth line of treatment.

18. The therapeutic agent of any one of claims 7 to 9, wherein the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and a PD-1 inhibitor are administered to the patient after treatment with at least one anti-cancer therapy, wherein the anti-cancer therapy is chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination thereof.

19. The method of any one of claims 7 to 9, wherein the therapeutic agent is administered the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor to the patient who has failed another PD-1 therapy.

20. The therapeutic agent according to any one of claims 7 to 9, wherein the cancer is resistant to at least one anticancer agent.

21. The method according to any one of claims 7 to 9, wherein the therapeutic agent is administered to the patient as a regimen of the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor.

22. The therapeutic agent according to any one of claims 7 to 9, wherein the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor are administered to the patient orally or by intraperitoneal injection.

23. The method of any one of claims 7 to 9, wherein the compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor are administered to the patient daily.

24. The method of claim 22, wherein the therapeutic agent is a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor administered QD, BID, or TID.

25. The therapeutic agent for treating cancer according to any one of claims 7 to 9, wherein the therapeutic agent inhibits metastasis of the cancer in the patient.

26. The method of any one of claims 7 to 9, wherein the therapeutic agent for treating cancer extends the time to disease progression of the cancer in the patient.

27. The therapeutic agent for treating cancer according to any one of claims 7 to 9, wherein the therapeutic agent prolongs survival of the patient.

28. The method of any one of claims 7 to 9, wherein the therapeutic agent for treating cancer increases progression-free survival of the patient.

29. The therapeutic agent for treating cancer according to any one of claims 7 to 9, wherein the therapeutic agent reduces the tumor or tumor burden in the patient.

30. It is a combination, (i) a compound of formula (I) 【Chemistry 3】 or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R １ and R ２ are the same or different, and the R １ and the R ２ each independently represents H, D, halogen, —CN, —C(O)OH, —CHO, —OH, or —NO ２ and the following substituted or unsubstituted groups: -NH ２ , C １ ~C １０ Alkyl, C １ ~C １０ Alkylamino, C １ ~C １０ Alkoxy, C ３ ~C １２ Cycloalkyl, C ３ ~C １２ cycloalkyloxy, 3- to 12-membered heterocyclic group, C ６ ~C １０ aryl group, 5- to 10-membered heteroaryl group, or １ and the R ２ form a 3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group, optionally the 3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group containing 1-3 -OH, -NH ２ , -CN, NO ２ , halogen, C １ ~C １０ Alkyl, C １ ~C １０ Alkanoxy, C １ ~C １０ Alkylamino, C ３ ~C １２ Cycloalkyl, C ６ ~C １０ aryl or 5-10 membered heteroaryl; R ３ is H, D or -NH ２ is selected from X is selected from a bond, —NH—, or —C(O)NH—; Y is N or CR １３ where R １３ is H, D, -OH, -CN, halogen, C １ ~C １０ Alkyl group, C １ ~C １０ Alkoxy, C ３ ~C １２ Cycloalkaneamino, C １ ~C １０ Alkylamino, C ３ ~C １２ Cycloalkyl, 3- to 8-membered heterocyclic group, halogenated C １ ~C １０ Alkylamino, or C ６ ~C １０ aryl or 5-10 membered heteroaryl groups, said heterocyclic or heteroaryl groups optionally containing 1 to 4 heteroatoms, said heteroatoms being selected from S, O, N or NH; Each R ４ are the same or different and independently represent H, D, halogen, —CN, —C(O)OH, —CHO, —OH, —NO ２ , -C(O)NHR １４ or -NHC(O)R １５ and is selected from the following groups: ２ , C １ ~C １０ Alkyl, C １ ~C １０ Alkylamino, C １ ~C １０ Alkoxy, C ３ ~C １２ Cycloalkyl, 3- to 12-membered heterocyclic group, C ６ ~C １０ aryl, or 5- to 10-membered heteroaryl, substituted or unsubstituted, where R １４ and R １５ are each independently １ ~C １０ Alkylamino, C ３ ~C １２ Cycloalkyl, C ６ ~C １０ aryl or 5-10 membered heteroaryl, the substitutions being selected from C １ ~C １０ Alkyl, halogen atom, -NH ２ , -CN, -C(O)OH, -CHO, -OH, -NO ２ , C １ ~C １０ Alkoxy, C １ ~C １０ Alkylamino, C ３ ~C １２ Cycloalkyl, C ６ ~C １０ aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclic group substituted with one or more substituents, said substituents being selected from C １ ~C １０ Alkyl, halogen, -NH ２ , -CN, -C(O)OH, -CHO, -OH, -NO ２ , C １ ~C １０ Alkoxy, C １ ~C １０ Alkylamino or C ３ ~C １２ Optionally substituted with 1 to 3 substituents selected from cycloalkyl; 【Chemistry 4】 is C ６ ~C １０ Aryl, 5-10 membered heteroaryl, C ４ ~C １２ Cycloalkyl, 3- to 12-membered heterocyclic group, C ６ ~C １４ a bridged or spirocyclic group, or C ６ ~C １４ a bridged heterocyclic group or a spiro heterocyclic group, ６ ~C １４ The bridged or spiroheterocyclic group contains 1 to 3 heteroatoms or groups selected from N, NH, O, S, C(O), or S(O); Each R ５ are the same or different and independently represent H, D, halogen, —CN, —C(O)OH, —CHO, —OH, —NO ２ , aminoacyl, substituted or unsubstituted groups as follows: C １ ~C １０ Alkyl, C １ ~C １０ Alkylamino, C １ ~C １０ Alkoxy, -NH ２ , C ３ ~C １２ Cycloalkyl, 3- to 12-membered heterocyclic group, C ６ ~C １０ aryl or 5-10 membered heteroaryl groups, said substitutions being selected from C １ ~C １０ Alkyl, C ３ ~C １２ Cycloalkyl, 3- to 12-membered heterocyclic group, halogen, -NH ２ , -CN, -C(O)OH, -CHO, -OH, -NO ２ , hydroxy-C １ ~C １０ Alkyl, C １ ~C １０ Alkoxy, C １ ~C １０ alkylamino, 5- to 10-membered heteroaromatic group, C ６ ~C １０ An aryl group or a 3- to 12-membered heterocyclic group is selected from those substituted with one or more substituents, or any two adjacent R ５ form a 3-6 membered saturated or unsaturated ring, optionally the 3-6 membered saturated or unsaturated ring being ２ , -CN, halogen, C １ ~C １０ Alkyl, C １ ~C １０ Alkoxy, C ３ ~C １２ Cycloalkylamino, C １ ~C １０ Alkylamino, C ３ ~C １２ Cycloalkyl, halogenated C １ ~C １０ Alkylamino, C ６ ~C １０ substituted with aryl or 5-10 membered heteroaryl; R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , and R １３ each independently represents H, D, halogen, —CN, —C(O)OH, —CHO, —OH, or —NO ２ is selected from: ２ , C １ ~C １０ Alkyl, C １ ~C １０ Alkylamino, C １ ~C １０ Alkoxy, C ３ ~C １２ Cycloalkyl, C ３ ~C １２ Cycloalkyloxy group, 3- to 12-membered heterocyclic group, C ６ ~C １０ aryl, and 5- to 10-membered heteroaryl, substituted or unsubstituted groups selected from C １ ~C １０ Alkyl, C ３ ~C １２ Cycloalkyl, 3- to 12-membered heterocyclic group, halogen, -NH ２ , -CN, -C(O)OH, -CHO, -OH, -NO ２ , hydroxy-C １ ~C １０ Alkyl, C １ ~C １０ Alkoxy, C １ ~C １０ alkylamino, 5- to 10-membered heteroaryl or C ６ ~C １０ aryl; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1 or 2; a therapeutically effective amount of an SHP2 inhibitor having a structure of formula (I), or a pharma- ceutically acceptable salt or solvate thereof; (ii) a therapeutically effective amount of a PD-1 inhibitor; Combinations including:

31. The combination according to claim 30, wherein the combination comprises from about 5 mg to about 100 mg of the compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof.

32. 32. The combination according to claim 30 or 31, wherein the combination comprises about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg or about 50 mg of the compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof.

33. 32. The combination of claim 30 or 31, wherein the PD-1 inhibitor is a small molecule compound, a nucleic acid, a peptide, a protein, an antibody, a peptibody, a diabody, a minibody, a single chain variable fragment (ScFv), or a variant thereof.

34. 32. The combination of claim 30 or 31, wherein the PD-1 inhibitor is a PD-1 inhibitor antibody.

35. 32. The combination of claim 30 or 31, wherein the PD-1 inhibitor is nivolumab, pembrolizumab, pidilizumab, REGN2810 (SAR-439684), PDR 001, SHR-1210, or MEDI 0680.

36. A therapeutic agent for treating cancer in a patient in need of such treatment, the therapeutic agent comprising a therapeutically effective amount of a compound of formula (II) 【Chemistry 5】 or a pharma- ceutically acceptable salt or solvate thereof; PD-1 inhibitors and administering to said patient a combination comprising

37. The method of claim 36, wherein the compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof, is administered at about 5 mg / kg to about 25 mg / kg to a patient in need of said treatment.

38. 38. The method of claim 36 or 37, wherein the compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof, is administered at about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg to a patient in need of said treatment.

39. The therapeutic agent of claim 36 or 37, wherein the PD-1 inhibitor is a small molecule compound, a nucleic acid, a peptide, a protein, an antibody, a peptibody, a diabody, a minibody, a single chain variable fragment (ScFv), or a variant thereof.

40. 38. The combination of claim 36 or 37, wherein the PD-1 inhibitor is a PD-1 inhibitor antibody.

41. 38. The combination of claim 36 or 37, wherein the PD-1 inhibitor is nivolumab, pembrolizumab, pidilizumab, REGN2810 (SAR-439684), PDR 001, SHR-1210, or MEDI 0680.

42. The method of claim 36 or 37, wherein the therapeutic agent is administered simultaneously or sequentially with the compound or formula (II), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor.

43. The therapeutic agent of claim 36 or 37, wherein the cancer is squamous cell carcinoma, non-squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial carcinoma, breast cancer, prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor (MPNST).

44. The method of claim 36 or 37, wherein the patient is treatment-naive.

45. The method of claim 36 or 37, wherein the compound of formula (II), or a pharma- ceutically acceptable salt of a solvate thereof, and the PD-1 inhibitor are administered to the patient as a first-line therapy.

46. 38. The method of claim 36 or 37, wherein the compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor are administered to the patient as a second, third, fourth, fifth or sixth line of treatment.

47. 38. The method of claim 36 or 37, wherein the compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor are administered to the patient after treatment with at least one anti-cancer therapy, wherein the anti-cancer therapy is chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination thereof.

48. The method of claim 36 or 37, wherein the therapeutic agent is administered the compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor to the patient who has failed another PD-1 therapy.

49. The method of claim 36 or 37, wherein the cancer is resistant to at least one anti-cancer agent.

50. The method of claim 36 or 37, wherein the therapeutic agent is administered to the patient as a regimen of the compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor.

51. The method of claim 36 or 37, wherein the compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor are administered orally or by intraperitoneal injection to the patient.

52. The method of claim 36 or 37, wherein the therapeutic agent administers the compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor to the patient daily.

53. The therapeutic agent of claim 36 or 37, wherein the compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof, and the PD-1 inhibitor are administered QD, BID, or TID.

54. The method of claim 36 or 37, wherein the therapeutic agent for treating cancer inhibits metastasis of the cancer in the patient.

55. 38. The method of claim 36 or 37, wherein the therapeutic agent for treating cancer extends the time to disease progression of the cancer in the patient.

56. 38. The method of claim 36 or 37, wherein the therapeutic agent for treating cancer extends survival of the patient.

57. 38. The method of claim 36 or 37, wherein the therapeutic agent for treating cancer increases progression-free survival of the patient.

58. 38. The method of claim 36 or 37, wherein the therapeutic agent for treating cancer reduces the tumor or tumor burden in the patient.

Images