WO2024081385A1 - Hpk1 inhibitors and methods of use thereof - Google Patents

Abstract

Disclosed herein are compounds that are Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors having a structure according to Formula I, and compositions containing those compounds. Methods of preparing the compounds, and methods of using the compounds for the treatment of diseases, disorders, or conditions are also described.

Description

HPK1 INHIBITORS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to US Provisional Patent Application No. 63/416,426, filed on October 14, 2022, the entire content of which is incorporated by reference herein. BACKGROUND [0002] The following discussion is provided to aid the reader in understanding the disclosure and is not admitted to describe or constitute prior art thereto. [0003] Hematopoietic Progenitor Kinase 1 (HPK1) is a serine/threonine protein kinase in the MAP4K family, and is highly expressed in hematopoietic cells and across T cells, B cells, and dendritic cells. HPK1 is a negative regulator of T cell and B cell signaling. For example, HPK1 activity has been demonstrated to restrain T cell activation through phosphorylation of SLP-76 at Serine 376, leading to T cell receptor (TCR) disassembly, thereby reducing T cell activity. [0004] Mediators generated in the tumor microenvironment (TME) such as adenosine, PGE2 and TGFβ can dampen immune cell activity and present a significant barrier to cancer therapy. HPK1 inhibition reduces TCR disassembly, and can aid in restoring T cell activity in the suppressive conditions of the TME. Accordingly, inhibition of HPK1 is a promising approach for cancer therapy. SUMMARY [0005] In one aspect, the present disclosure relates to compounds that inhibit the activity of HPK1. The compounds are represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹, X², X³, and X⁴ are each independently N or CR²; each R² is independently H, halo, -NR^2aR^2b, -C₁-C₃ alkyl, -C₁-C₃ haloalkyl, -C₁-C₃ hydroxyalkyl, -C₁-C₃ alkoxy, -S(O)₂-(C₁-C₃ alkyl), -C(O)O(C₁-C₃-alkyl), -C(O)- NR^2aR^2b, -C₁-C₃ alkylene-O-(C₁-C₃-alkyl), 5- to 6-membered heteroaryl, or 5- to 6- membered heterocycloalkyl; wherein said 5- to 6-membered heteroaryl and 5- to 6- membered heterocycloalkyl have 1-3 ring heteroatoms independently selected from N, O, and S; wherein said 5- to 6-membered heteroaryl is optionally substituted with -CN, or -C₁-C₃ alkyl; and wherein R^2a and R^2b are each independently H or -C₁-C₃ alkyl; R¹ is selected from the group consisting of: a) -L¹-R^1a; wherein: i. L¹ is -O-, -O-(C₁-C₃ alkylene)-, -NH-, or -NH-(C₁-C₃ alkylene)-, wherein the alkylene is optionally substituted with one -NH₂; and ii. R^1a is selected from the group consisting of -C₁-C₆ alkyl, -C₁-C₆ hydroxyalkyl, -C₃-C₆-cycloalkyl, 6- to 10-membered aryl, 5- to 8- membered heterocycloalkyl, and 5- to 10-membered heteroaryl; wherein said 5- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl have 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, S and O; wherein said 5- to 8-membered heterocycloalkyl and -C₃-C₆-cycloalkyl groups are optionally fused to phenyl; and wherein said - C₃-C₆-cycloalkyl and 6- to 10-membered aryl groups are optionally substituted with -OH, -C₁-C₃ hydroxyalkyl, or -NH₂; b) 5- to 10-membered heterocycloalkyl having 1-3 ring heteroatoms or ring heteroatom groups independently selected from NR^1b, N, S, and O; wherein said 5- to 10 membered heterocycloalkyl is substituted with 0-3 R^1c; wherein: i. R^1b is H, -C₁-C₃ alkyl, -C₁-C₃ hydroxyalkyl, or -(C₁-C₃ alkylene)-O-(C₁-C₃ alkyl); and ii. each R^1c is independently selected from the group consisting of -OH, - NR^1dR^1e, -C(O)-NR^1dR^1e, -C₁-C₆ alkyl, -C₁-C₆ hydroxyalkyl, -(C₁-C₃ alkylene)-NH₂, and phenyl; wherein R^1d and R^1e are independently H, -C₁- C₃ alkyl, -C₁-C₃ hydroxyalkyl, and -C(O)-(C₁-C₃ alkylene)-N(C₁-C₃ alkyl)₂; and c) -(C₁-C₃ alkylene)-NR^1fR^1g, or -C(O)-NR^1fR^1g; wherein i. R^1f and R^1g are independently H or -C₁-C₃ alkyl; or ii. R^1f and R^1g taken together with the N atom to which they are attached form a 5- to 8-membered heterocycloalkyl having 0-1 additional ring heteroatom or ring heteroatom group selected from NRº, N, O, and S; or R¹ and R² groups together with the adjacent ring atoms to which they are attached form a -C₅- C₇-cycloalkyl, or a 5- to 7-membered heterocycloalkyl having 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, O, and S; wherein said 5- to 7-membered heterocycloalkyl is optionally substituted with one oxo; and wherein said -C₅-C₇-cycloalkyl is substituted with one 5-membered heterocycloalkyl having 1- 2 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, O, and S; ring Y is

Z¹, Z², Z³, and Z⁴ are each independently CR³ or N; each R³ is independently selected from the group consisting of H, halo, -CN, -C₁-C₃ alkyl, -C₁- C₃ hydroxyalkyl, -C(O)NR^3aR^3b, and -NR^3aR^3b; wherein R^3a and R^3b are independently H, -C₁-C₃ alkyl, or –(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl); R⁴ is phenyl; 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S; or -L²-phenyl, wherein L² is -NH-, -O-(C₁-C₃ alkylene)-, or –NH- (C₁-C₃ alkylene)-; wherein R⁴ is substituted with 0-3 R^4a; or R⁴ and R³ groups together with the adjacent ring atoms to which they are attached form a 5- to 6-membered heterocycloalkyl having from 1-3 ring heteroatoms independently selected from N, O, and S; and said 5- to 6-membered heterocycloalkyl is substituted with 0-3 substituents independently selected from oxo and -C₁-C₃ alkyl; each R^4a is independently selected from the groups consisting of halo, -NH₂, -OH, -C₁-C₃ alkyl, -C₁-C₃ alkoxy, -(C₁-C₃ alkylene)-O-(C₁-C₃ alkyl), -C₁-C₃ haloalkyl, and -C₁-C₃ haloalkoxy; or two R^4a groups together with the adjacent ring atoms to which they are attached form a 5- membered heterocycloalkyl or 5-membered heteroaryl having 1-2 ring N atoms; and each Rº, when present, is independently H or C₁-C₃ alkyl. [0006] In another aspect, this disclosure is directed to methods of inhibiting HPK1 in a subject comprising administering to the subject an effective amount of a compound described herein. [0007] In yet another aspect, this disclosure provides methods for treating a disease, disorder, or condition mediated at least in part by HPK1 activity in a subject, comprising administering to the subject an effective amount of a compound described herein. Diseases, disorders, and conditions mediated by HPK1 include cancer and viral infections. Certain aspects of the present disclosure further comprise the administration of one or more additional therapeutic agents as set forth herein below. DETAILED DESCRIPTION OF THE DISCLOSURE [0008] Before the present disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Definitions [0009] Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. [0010] The term “about” as used herein has its original meaning of approximately and is used to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In general, the term “about” refers to the usual error range for the respective value readily known to the skilled person in this technical field. If the degree of approximation is not otherwise clear from the context, “about” means either within plus or minus 10% of the provided value, or rounded to the nearest significant figure, in all cases inclusive of the provided value. Where ranges are provided, they are inclusive of the boundary values. [0011] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a saturated monovalent hydrocarbon radical, having, in some embodiments, one to eight (e.g., C₁-C₈ alkyl), or one to six (e.g., C₁-C₆ alkyl), or one to three carbon atoms (e.g., C₁-C₃ alkyl), respectively. The term “alkyl” encompasses straight and branched-chain hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isopentyl, tert-pentyl, n-pentyl, isohexyl, n- hexyl, n-heptyl, 4-isopropylheptane, n-octyl, and the like. In some embodiments, the alkyl groups are C₁-C₆ alkyl groups (e.g., methyl, ethyl, isopropyl, or t-butyl). In some embodiments, the alkyl groups are C₁-C₃ alkyl groups (e.g., methyl, ethyl, n-propyl, or iso-propyl). [0012] The term “alkylene” refers to a straight or branched, saturated, hydrocarbon radical having, in some embodiments, one to six (e.g., C₁-C₆ alkylene), or one to four (e.g., C₁-C₄ alkylene), or one to three (e.g., C₁-C₃ alkylene), or one to two (e.g., C₁-C₂ alkylene) carbon atoms, and linking at least two other groups, i.e., a divalent hydrocarbon radical. When two moieties are linked to the alkylene they can be linked to the same carbon atom (i.e., geminal), or different carbon atoms of the alkylene group. For instance, a straight chain alkylene can be the bivalent radical of -(CH₂)n-, where n is 1, 2, 3, 4, 5 or 6 (i.e., a C₁-C₆ alkylene). Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secbutylene, pentylene, hexylene and the like. In some embodiments, the alkylene groups are C₁-C₂ alkylene groups (e.g., methylene or ethylene) or C₁-C₃ alkylene groups (e.g., methylene, ethylene, or propylene). [0013] As used herein, the term “alkoxy” refers to an alkyl group, as defined herein, that is attached to the remainder of the molecule via an oxygen atom (e.g., -O-C₁-C₁₂ alkyl, -O-C₁-C₈ alkyl, -O-C₁-C₆ alkyl, or -O-C₁-C₃ alkyl). Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and the like. In some embodiments, the alkoxy groups are C₁-C₃-alkoxy groups (e.g., methoxy, ethoxy, propoxy, or iso-propoxy), [0014] The term "cycloalkyl" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system having, in some embodiments, 3 to 14 carbon atoms (e.g., C₃-C₁₄ cycloalkyl), or 3 to 10 carbon atoms (e.g., C₃-C₁₀ cycloalkyl), or 3 to 8 carbon atoms (e.g., C₃-C₈ cycloalkyl), or 3 to 7 carbon atoms (e.g., C₃-C₇ cycloalkyl), or 3 to 6 carbon atoms (e.g., C₃-C₆ cycloalkyl) or 5 to 6 carbon atoms (e.g., C₅-C₆ cycloalkyl). Cycloalkyl groups can be saturated or characterized by one or more points of unsaturation (i.e., carbon-carbon double and/or triple bonds), provided that the points of unsaturation do not result in an aromatic system. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexynyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and the like. The rings of bicyclic and polycyclic cycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting examples of bicyclic, spirocyclic and polycyclic hydrocarbon groups include bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, adamantyl, indanyl, spiro[5.5]undecane, spiro[2.2]pentane, spiro[2.2]pentadiene, spiro[2.5]octane, spiro[2.2]pentadiene, and the like. In some embodiments, the cycloalkyl groups of the present disclosure are monocyclic C₃-C₇ cycloalkyl moieties (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl). In some embodiments, the cycloalkyl groups of the present disclosure are monocyclic C₃-C₅ cycloalkyl moieties (e.g., cyclopropyl, cyclobutyl, or cyclopentyl). [0015] The term "heterocycloalkyl" refers to a non-aromatic monocyclic, bicyclic or polycyclic cycloalkyl ring having, in some embodiments, 3 to 14 members (e.g., 3- to 14- membered heterocycloalkyl), or 3 to 10 members (e.g., 3- to 10-membered heterocycloalkyl), or 3 to 8 members (e.g., 3- to 8-membered heterocycloalkyl), or 3 to 7 members (e.g., 3- to 7- membered heterocycloalkyl), or 3 to 6 members (e.g., 3- to 6-membered heterocycloalkyl), or 5 to 6 members (e.g., 5- to 6-membered heterocycloalkyl), and having from one to five, one to four, one to three, one to two or one ring heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S). In some embodiments, the nitrogen and sulfur atom(s) of the heterocycloalkyl group are optionally oxidized (e.g., N-oxide (N⁺-O-), sulfoxide (S=O), or sulfone (S(=O)₂)), and the nitrogen atom(s) are optionally quaternized. Heterocycloalkyl groups are saturated or characterized by one or more points of unsaturation (e.g., one or more carbon-carbon double bonds, carbon-carbon triple bonds, carbon-nitrogen double bonds, and/or nitrogen-nitrogen double bonds), provided that the points of unsaturation do not result in an aromatic system. The rings of bicyclic and polycyclic heterocycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting examples of heterocycloalkyl groups include aziridine, oxirane, thiirane, pyrrolidine, imidazolidine, pyrazolidine, dioxolane, phthalimide, piperidine, 1,4- dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, 3,4,5,6-tetrahydropyridazine, pyran, decahydroisoquinoline, 3-pyrroline, thiopyran, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2,6-diazaspiro[3.3]heptane, 2- azaspiro[3.3]heptane, 1-oxaspiro[3.3]heptane, 6-azaspiro[3.4]octane, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon atom, or a ring heteroatom, when chemically permissible. In some embodiments, the heterocycloalkyl groups of the present disclosure are monocyclic or bicyclic 3-9 membered heterocycloalkyl moieties having one or two ring heteroatom or ring heteroatom groups selected from N, O, S, S=O and S(=O)₂ (e.g., aziridine, piperidine, piperazine, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrofuran, tetrahydropyran, isothiazolidine 1,1- dioxide, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b]pyrrole, 2,5- diazabicyclo[2.2.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 3-oxa- 6-azabicyclo[3.1.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, octahydropyrrolo[1,2- a]pyrazine, or 2,5-diazabicyclo[4.1.0]heptane). In some embodiments, the heterocycloaklyl groups of the present disclosure are monocyclic or bicyclic 5- to 10-membered heterocycloalkyl moieties having 1-3 ring heteroatoms independently selected from N, and O (e.g., pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, diazepine, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 3,8- diazabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 2- oxa-5-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[4.1.0]heptane, octahydro-1H-pyrrolo[3,4- b]pyridine, octahydropyrrolo[3,4-b]pyrrole, 2,7-diazaspiro[4.4]nonane, 1,7- diazaspiro[4.4]nonane, 2,7-diazaspiro[4.5]decane. It is to be understood that when sp³ hybridized ring N heteroatoms are present (e.g., NH or NR heteroatom groups), their valence is satisfied by a H atom, an R group as defined elsewhere herein, or via connectivity to the remainder of the molecule. [0016] The term "aryl" refers to an aromatic ring system containing one ring, or two or three rings fused together, and having, in some embodiments, six to fourteen (i.e., C_6-14 aryl), or six to ten (i.e., C_6-10 aryl), or six (i.e., C₆ aryl) carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl and anthracenyl. In some embodiments, aryl groups are phenyl. [0017] The term "heteroaryl" refers to monocyclic or fused bicyclic aromatic groups (or rings) having, in some embodiments, from 5 to 14 (i.e., 5- to 14-membered heteroaryl), or from 5 to 10 (i.e., 5- to 10-membered heteroaryl), or from 5 to 6 (i.e., 5- to 6-membered heteroaryl) members (i.e., ring vertices), and containing from one to five, one to four, one to three, one to two or one ring heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S). A heteroaryl group can be attached to the remainder of the molecule through a ring carbon atom or a ring heteroatom of the heteroaryl group, when chemically permissible. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, purinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, imidazopyridines, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. In some embodiments, the heteroaryl groups of the present disclosure are monocyclic 5- to 9-membered heteroaryl moieties (e.g., pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazole, thiazolyl, or pyrazolopyridine). In some embodiments, the heteroaryl groups of the present disclosure are monocyclic 5- to 6-membered heteroaryl moieties (e.g., pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazole, or thiazolyl). It is to be understood that when sp³ hybridized ring N heteroatoms are present (e.g., NH or NR heteroatom groups), their valence is satisfied by a H atom, an R group as defined elsewhere herein, or via connectivity to the remainder of the molecule. [0018] As used herein, a wavy line, " ", that intersects a single, double or triple bond in any chemical structure depicted herein, represents that the point of attachment of the single, double, or triple bond to the remainder of the molecule is through either one of the atoms that make up the single, double or triple bond. Additionally, a bond extending from a substituent to the center of a ring (e.g., a phenyl ring) is meant to indicate attachment of that substituent to the ring at any of the available ring vertices, i.e., such that attachment of the substituent to the ring results in a chemically stable arrangement. [0019] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," and “haloalkoxy” refer to alkyl groups or alkoxy groups, respectively, as defined herein, that are substituted with one or more halogen(s) (e.g., 1-3 halo). For example, the term "C₁-C₃ haloalkyl" is meant to include difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl, or difluoromethyl. The term “C₁-C₃ haloalkoxy” is meant to include trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 4-chlorobutyoxy, 3-bromopropoxy, and the like. In some embodiments, the haloalkoxy is trifluoromethoxy. [0020] The term “hydroxyalkyl” refers to an alkyl group, as defined herein, that is substituted with one or more hydroxyl groups (e.g., 1-3 hydroxyl groups). Exemplary hydroxyalkyl groups include methanol, ethanol, 1,2-propanediol, 1,2-hexanediol, isopropanol, glycerol, and the like. [0021] The compounds of the present disclosure can be present in their neutral form, or as a pharmaceutically acceptable salt, isomer, polymorph or solvate thereof, and may be present in a crystalline form, amorphous form or mixtures thereof. [0022] As referred to herein, "pharmaceutically acceptable salt" is meant to include salts of the compounds according to this disclosure that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N’-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. [0023] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure. [0024] This disclosure also contemplates isomers of the compounds described herein (e.g., stereoisomers and atropisomers). For example, certain compounds of the present disclosure possess asymmetric carbon atoms (chiral centers), or hindered rotation about a single bond; the racemates, diastereomers, enantiomers, and atropisomers (e.g., R_a, S_a, P and M isomers) of which are all intended to be encompassed within the scope of the present disclosure. Stereoisomeric forms may be defined, in terms of absolute stereochemistry, as (R) or (S), and/or depicted uses dashes and/or wedges. When a stereochemical depiction (e.g., using dashes,

and/or wedges,

is shown in a chemical structure, or a stereochemical assignment (e.g., using (R) and (S) notation) is made in a chemical name, it is meant to indicate that the depicted isomer is present and substantially free of one or more other isomer(s) (e.g., enantiomers and diastereomers, when present). “Substantially free of” other isomer(s) indicates at least an 70/30 ratio of the indicated isomer to the other isomer(s), more preferably 80/20, 90/10, or 95/5 or more. In some embodiments, the indicated isomer will be present in an amount of at least 99%. A chemical bond to an asymmetric carbon that is depicted as a solid line

indicates that all possible stereoisomers (e.g., enantiomers, diastereomers, racemic mixtures, etc.) at that carbon atom are included. In such instances, the compound may be present as a racemic mixture, scalemic mixture, or a mixture of diastereomers. [0025] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon- 14 (¹⁴C), or non-radioactive isotopes, such as deuterium (²H) or carbon-13 (¹³C). Such isotopic variations can provide additional utilities to those described elsewhere herein. For instance, isotopic variants of the compounds of the disclosure may find additional utility, including but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents. Additionally, isotopic variants of the compounds of the disclosure can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. In some embodiments, the compounds according to this disclosure are characterized by one or more deuterium atoms. [0026] The terms “patient” or “subject” are used interchangeably to refer to a human or a non- human animal (e.g., a mammal). [0027] The terms “treat”, “treating”, treatment” and the like refer to a course of action that eliminates, reduces, suppresses, mitigates, ameliorates, or prevents the worsening of, either temporarily or permanently, a disease, disorder or condition to which the term applies, or at least one of the symptoms associated therewith. Treatment includes alleviation of symptoms, diminishment of extent of disease, inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease, delaying or slowing of disease progression, improving the quality of life, and/or prolonging survival of a subject as compared to expected survival if not receiving treatment or as compared to a published standard of care therapy for a particular disease. [0028] The term “in need of treatment” as used herein refers to a judgment made by a physician or similar professional that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s expertise, which may include a positive diagnosis of a disease, disorder or condition. [0029] The terms “prevent”, “preventing”, “prevention”, “prophylaxis” and the like refer to a course of action initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state. Prevention also refers to a course of action initiated in a subject after the subject has been treated for a disease, disorder, condition or a symptom associated therewith in order to prevent relapse of that disease, disorder, condition or symptom. [0030] The term “in need of prevention” as used herein refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from preventative care. This judgment is made based on a variety of factors that are in the realm of a physician’s or caregiver’s expertise. [0031] “Substantially pure” indicates that a component (e.g., a compound according to this disclosure) makes up greater than about 50% of the total content of the composition, and typically greater than about 60% of the total content. More typically, “substantially pure” refers to compositions in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the component of interest will make up greater than about 90%, or greater than about 95% of the total content of the composition. [0032] Compounds that are selective may be particularly useful in the treatment of certain disorders or may offer a reduced likelihood of undesired side effects. In one embodiment, compounds of the present disclosure are selective over other MAP4K isoforms (e.g., MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAPK6, and MAPK7). In another embodiment, compounds of the present disclosure are selective over other kinases (e.g., LCK and/or ZAP70). Selectivity may be determined, for example, by comparing the inhibition of a compound as described herein against HPK1 against the inhibition of a compound as described herein against another isoform (e.g., MAP4K2, MAP4K3, MAP4K4, and/or MAP4K5), or another kinase (e.g. LCK and/or ZAP70). In one embodiment, the selective inhibition of HPK1 is at least 1000 times greater, 500 times greater, or 100 times greater, or 20 times greater than inhibition of another protein or isoform. [0033] Compounds provided herein may have advantageous pharmacokinetic profiles including, for example, e.g., potency against HPK1 in whole blood, inhibition against the human Ether-a-go-go Related Gene potassium ion channel (hERG), hepatocyte stability, clearance, and inhibition against CYP. Compounds of the Disclosure [0034] The present disclosure relates to compounds that inhibit the activity of HPK1. [0035] In one aspect, this disclosure is directed to a compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure according to Formula I:

wherein X¹, X², X³, X⁴, Z¹, Z², Z³, Z⁴, R¹, R⁴, and ring Y are defined as described herein. [0036] In another aspect, this disclosure is directed to a compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure according to Formula I:

wherein: X¹, X², X³, and X⁴ are each independently N or CR²; each R² is independently H, halo, -NR^2aR^2b, -C₁-C₃ alkyl, -C₁-C₃ haloalkyl, -C₁-C₃ hydroxyalkyl, -C₁-C₃ alkoxy, -S(O)₂-(C₁-C₃ alkyl), -C(O)O(C₁-C₃-alkyl), -C(O)- NR^2aR^2b, -C₁-C₃ alkylene-O-(C₁-C₃-alkyl), 5- to 6-membered heteroaryl, or 5- to 6- membered heterocycloalkyl; wherein said 5- to 6-membered heteroaryl and 5- to 6- membered heterocycloalkyl have 1-3 ring heteroatoms independently selected from N, O, and S; wherein said 5- to 6-membered heteroaryl is optionally substituted with -CN, or -C₁-C₃ alkyl; and wherein R^2a and R^2b are each independently H or -C₁-C₃ alkyl; R¹ is selected from the group consisting of: a) -L¹-R^1a; wherein: i. L¹ is -O-, -O-(C₁-C₃ alkylene)-, -NH-, or -NH-(C₁-C₃ alkylene)-, wherein the alkylene is optionally substituted with one -NH₂; and ii. R^1a is selected from the group consisting of -C₁-C₆ alkyl, -C₁-C₆ hydroxyalkyl, -C₃-C₆-cycloalkyl, 6- to 10-membered aryl, 5- to 8- membered heterocycloalkyl, and 5- to 10-membered heteroaryl; wherein said 5- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl have 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, S and O; wherein said 5- to 8-membered heterocycloalkyl and -C₃-C₆-cycloalkyl groups are optionally fused to phenyl; and wherein said - C₃-C₆-cycloalkyl and 6- to 10-membered aryl groups are optionally substituted with -OH, -C₁-C₃ hydroxyalkyl, or -NH₂; b) 5- to 10-membered heterocycloalkyl having 1-3 ring heteroatoms or ring heteroatom groups independently selected from NR^1b, N, S, and O; wherein said 5- to 10-membered heterocycloalkyl is substituted with 0-3 R^1c; wherein: i. R^1b is H, -C₁-C₃ alkyl, -C₁-C₃ hydroxyalkyl, or -(C₁-C₃ alkylene)-O-(C₁-C₃ alkyl); and ii. each R^1c is independently selected from the group consisting of -OH, - NR^1dR^1e, -C(O)-NR^1dR^1e, -C₁-C₆ alkyl, -C₁-C₆ hydroxyalkyl, -(C₁-C₃ alkylene)-NH₂, and phenyl; wherein R^1d and R^1e are independently H, -C₁- C₃ alkyl, -C₁-C₃ hydroxyalkyl, and -C(O)-(C₁-C₃ alkylene)-N(C₁-C₃ alkyl)₂; and c) -(C₁-C₃ alkylene)-NR^1fR^1g, or -C(O)-NR^1fR^1g; wherein i. R^1f and R^1g are independently H or -C₁-C₃ alkyl; or ii. R^1f and R^1g taken together with the N atom to which they are attached form a 5- to 8-membered heterocycloalkyl having 0-1 additional ring heteroatom or ring heteroatom group selected from NRº, N, O, and S; or R¹ and R² groups together with the adjacent ring atoms to which they are attached form a -C₅- C₇-cycloalkyl, or a 5- to 7-membered heterocycloalkyl having 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, O, and S; wherein said 5- to 7-membered heterocycloalkyl is optionally substituted with one oxo; and wherein said -C₅-C₇-cycloalkyl is substituted with one 5-membered heterocycloalkyl having 1- 2 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, O, and S; ring Y is

Z¹, Z², Z³, and Z⁴ are each independently CR³ or N; each R³ is independently selected from the group consisting of H, halo, -CN, -C₁-C₃ alkyl, -C₁- C₃ hydroxyalkyl, -C(O)NR^3aR^3b, and -NR^3aR^3b; wherein R^3a and R^3b are independently H, -C₁-C₃ alkyl, or –(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl); R⁴ is phenyl; 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S; or -L²-phenyl, wherein L² is -NH-, -O-(C₁-C₃ alkylene)-, or –NH- (C₁-C₃ alkylene)-; wherein R⁴ is substituted with 0-3 R^4a; or R⁴ and R³ groups together with the adjacent ring atoms to which they are attached form a 5- to 6-membered heterocycloalkyl having from 1-3 ring heteroatoms independently selected from N, O, and S; and said 5- to 6-membered heterocycloalkyl is substituted with 0-3 substituents independently selected from oxo and -C₁-C₃ alkyl; each R^4a is independently selected from the groups consisting of halo, -NH₂, -OH, -C₁-C₃ alkyl, -C₁-C₃ alkoxy, -(C₁-C₃ alkylene)-O-(C₁-C₃ alkyl), -C₁-C₃ haloalkyl, and -C₁-C₃ haloalkoxy; or two R^4a groups together with the adjacent ring atoms to which they are attached form a 5- membered heterocycloalkyl or 5-membered heteroaryl having 1-2 ring N atoms; and each Rº, when present, is independently H or C₁-C₃ alkyl. [0037] In some embodiments, X¹ is N, X² is CH, X³ is CH, and X⁴ is N. [0038] In some embodiments, X¹ is N, X² is CH, X³ is CR², and X⁴ is CH. [0039] In some embodiments, X¹ is N, X² is CH, X³ is CH, and X⁴ is CH. [0040] In some embodiments, X¹ is N, X² is CH, X³ is CH, and X⁴ is CR². [0041] In some embodiments, X¹ is N, X² is CR², X³ is CH, and X⁴ is CH. [0042] In some embodiments, X¹ is CH, X² is N, X³ is CH, and X⁴ is CH. [0043] In some embodiments, X¹ is N, X² is CH, X³ is N, and X⁴ is CH. [0044] In some embodiments, X¹ is N, X² is N, X³ is CH, and X⁴ is CH. [0045] In some embodiments, R¹ is H. [0046] In some embodiments, R¹ is -L¹-R^1a. In some embodiments, L¹ is -O-, -O-(C₁-C₃ alkylene)-, -NH-, or -NH-(C₁-C₃ alkylene)-, wherein the alkylene is optionally substituted with one -NH₂. In some embodiments, L¹ is -O-. In some embodiments, L¹ is -O-(C₁-C₃ alkylene)- . In some embodiments, L¹ is

, each of which is optionally substituted with -NH₂. In some embodiments, L¹ is

. In some embodiments, L¹ is -NH-. In some embodiments, L¹ is -NH-(C₁-C₃ alkylene)-. In some embodiments, L¹ is

each of which is optionally substituted with -NH₂. In some embodiments, L¹ is

[0047] In some embodiments, R^1a is selected from the group consisting of -C₁-C₆ alkyl, -C₁- C₆ hydroxyalkyl, -C₃-C₆-cycloalkyl, 6- to 10-membered aryl, 5- to 8-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; wherein said 5- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl have 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, S and O; wherein said 5- to 8- membered heterocycloalkyl and -C₃-C₆-cycloalkyl groups are optionally fused to phenyl; and wherein said -C₃-C₆-cycloalkyl and 6- to 10-membered aryl groups are optionally substituted with -OH, -C₁-C₃ hydroxyalkyl, or -NH₂. [0048] In some embodiments, R^1a is -C₁-C₆ alkyl. In some embodiments, R^1a is -C_1-C₄ alkyl. In some embodiments, R^1a is

[0049] In some embodiments R^1a is -C₁-C₆ hydroxyalkyl. In some embodiments, R^1a is -CH₂- OH. [0050] In some embodiments, R^1a is a -C₃-C₆-cycloalkyl optionally fused to phenyl, wherein said -C₃-C₆-cycloalkyl is substituted with 0-1 substituent selected from -OH, -C₁-C₃ hydroxyalkyl, and -NH₂. In some embodiments, R^1a is a C₃-C₆-cycloalkyl optionally fused to phenyl, and substituted with 0-1 -OH or-NH₂. In some embodiments, R^1a is

, ,

optionally fused to phenyl, and substituted with 0-1 -OH or -NH₂. In some embodiments, R^1a is

each of which is substituted with 0-1 -OH or -NH₂. In some embodiments, R^1a is

[0051] In some embodiments, R^1a is a 6- to 10-membered aryl substituted with 0-1 substituent selected from -OH, -C₁-C₃ hydroxyalkyl, and -NH₂. In some embodiments, R^1a is 6- to 10- membered aryl substituted with 0-1 -C₁-C₃ hydroxyalkyl. In some embodiments, R^1a is phenyl substituted with 0-1 -C₁-C₃ hydroxyalkyl. In some embodiments, R^1a is

. [0052] In some embodiments, R^1a is a 5- to 8-membered heterocycloalkyl having 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, S and O, wherein said 5- to 8-membered heterocycloalkyl is optionally fused to phenyl. In some embodiments, R^1a is a 5- to 6-membered heterocycloalkyl having 1 NRº heteroatom group, wherein said 5- to 6-membered heterocycloalkyl is optionally fused to phenyl. In some embodiments, R^1a is

each of which is optionally fused to phenyl. In some embodiments, R^1a is

In some embodiment º

s, R is H, or C₁-C₃ alkyl. In some embodiments, Rº is H. In some embodiments, Rº is C₁-C₃ alkyl. In some embodiments, Rº is methyl. [0053] In some embodiments, R^1a is 5- to 10-membered heteroaryl having 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, S and O. In some embodiments, R^1a is a 5-membered heteroaryl having 1-2 ring heteroatoms or ring heteroatom groups independently selected from NRº and N. In some embodiments, R^1a is

, or In some embodiments, Rº is H, or C -C alkyl. In so º

_{1 3} me embodiments, R is H. In some embodiments, Rº is C₁-C₃ alkyl. In some embodiments, Rº is methyl. [0054] In one or more embodiments, R¹ is

,

[0055] In one or more embodiments, R¹ is a 5- to 10-membered heterocycloalkyl having 1-3 ring heteroatoms or ring heteroatom groups independently selected from NR^1b, N, S, and O; wherein said 5- to 10 membered heterocycloalkyl is substituted with 0-3 R^1c. In some embodiments, R¹ is a 5- to 10-membered heterocycloalkyl having 1-2 ring heteroatom or ring heteroatom groups independently selected from NR^1b, and N, wherein said heterocycloalkyl is substituted with 0-3 R^1c. In some embodiments, R¹ is

each o ^1c

f which is substituted with 0-3 R . In some embodiments, R^1b is H or methyl. [0056] In one or more embodiments, R¹ is

[0057] In some embodiments, R¹ is -(C₁-C₃ alkylene)-NR^1fR^1g, or -C(O)-NR^1fR^1g, wherein R^1f and R^1g are independently H or -C₁-C₃ alkyl; or R^1f and R^1g taken together with the N atom to which they are attached form a 5- to 8-membered heterocycloalkyl having 0-1 additional ring heteroatom or ring heteroatom group selected from NRº, N, O, and S. In some embodiments, R¹ is -(C₁-C₃ alkylene)-NR^1fR^1g, wherein R^1f and R^1g are -C₁-C₃ alkyl. In some embodiments, R¹ is In some embodiments, R¹ is -C(O)- ^{1f 1g 1g}

NR R , wherein R are independently H or -C₁-C₃ alkyl; or R^1f and R^1g taken together with the N atom to which they are attached form a 5- to 8-membered heterocycloalkyl having 0-1 additional ring heteroatom or ring heteroatom group selected from NRº, N, O, and S. In some embodiments, R¹ is -C(O)-NR^1fR^1g, wherein R^1f and R^1g are H; or R^1f and R^1g taken together with the N atom to which they are attached form a 5- to 8-membered heterocycloalkyl having 0-1 additional ring NRº heteroatom group. In some embodiments, R¹ is

In some embodiments, Rº is H or methyl. In some embodiments, Rº is H. In some embodiments, Rº is methyl. [0058] In one or more embodiments, R¹ is selected from the group consisting of

. [0059] In one or more embodiments, R¹ and R² groups together with the adjacent ring atoms to which they are attached form a a -C₅-C₇-cycloalkyl substituted with one 5-membered heterocycloalkyl having 1-2 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, O, and S. In some embodiments, the moiety

. [0060] In one or more embodiments, R¹ and R² groups together with the adjacent ring atoms to which they are attached form a 5- to 7-membered heterocycloalkyl having 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, O, and S; wherein said 5- to 7-membered heterocycloalkyl is optionally substituted with one oxo. In some embodiments, R¹ and R² groups together with the adjacent ring atoms to which they are attached form a 6-membered heterocycloalkyl having 1 ring NRº heteroatom group, and said 6-membered heterocycloalkyl is optionally substituted with one oxo. In some embodiments, the moiety

In some embodiments, Rº is H or -C₁-C₃ alkyl. In one embodiment Rº is H. In another embodiment, Rº is methyl. In some embodiments, the moiety

[0061] In some embodiments, each R² is independently H, halo, -NR^2aR^2b, -C₁-C₃ alkyl, -C₁- C₃ haloalkyl, -C₁-C₃ hydroxyalkyl, -C₁-C₃ alkoxy, -S(O)₂-(C₁-C₃ alkyl), -C(O)O(C₁-C₃-alkyl), -C(O)-NR^2aR^2b, -C₁-C₃ alkylene-O-(C₁-C₃-alkyl), 5- to 6-membered heteroaryl, or 5- to 6- membered heterocycloalkyl; wherein said 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl have 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, O, and S; wherein said 5- to 6-membered heteroaryl is optionally substituted with -CN, or -C₁-C₃ alkyl; and wherein R^2a and R^2b are each independently H or -C₁-C₃ alkyl. In some embodiments, R² is H. In some embodiments, R² is halo. In some embodiments, R² is - Cl, or -F. In some embodiments, R² is -NR^2aR^2b, wherein R^2a and R^2b are each independently H or -C₁-C₃ alkyl. In some embodiments, R² is -NH₂. In some embodiments, R² is -C₁-C₃ alkyl. In some embodiments, R² is -CH₃. In some embodiments, R² is -C₁-C₃ haloalkyl. In some embodiments, R² is -CF₃. In some embodiments, R² is -C₁-C₃ hydroxyalkyl. In some embodiments, R² is -CH₂OH. In some embodiments, R² is -C₁-C₃ alkoxy. In some embodiments, R² is -OCH₃ or -OCH₂CH₃. In some embodiments, R² is -S(O)₂-(C₁-C₃ alkyl). In some embodiments, R² is -S(O)₂CH₃. In some embodiments, R² is -C(O)O(C₁-C₃-alkyl). In some embodiments, R² is -C(O)OCH₃. In some embodiments, R² is -C(O)-NR^2aR^2b, wherein R^2a and R^2b are each independently H or -C₁-C₃ alkyl. In some embodiments, R² is -C(O)- NR^2aR^2b, wherein R^2a and R^2b are H. In some embodiments, R² is -C(O)NH₂. In some embodiments, R² is -C₁-C₃ alkylene-O-(C₁-C₃-alkyl). In some embodiments R² is-CH₂OCH₃. In some embodiments, R² is 5- to 6-membered heteroaryl have 1-3 ring heteroatoms independently selected from N, O, and S, wherein said 5- to 6-membered heteroaryl is optionally substituted with -CN, or -C₁-C₃ alkyl. In some embodiments, R² is

or

, each of which is optionally substituted with -CN, or -C₁-C₃ alkyl. In some embodiments, R² is ²

In some embodiments, R is a 5- to 6- membered heterocycloalkyl having 1-3 ring heteroatoms or heteroatom groups independently selected from NRº, N, O, and S. In some embodiments, R² is a 6-membered heterocycloalkyl having 1-3 ring heteroatoms or heteroatom groups independently selected from NRº, N, and O. In some embodiments, R² is ²

In some embodiments, R is a 5- to 6-membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S. In some embodiments, R² is a 6-membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, and O. In some embodiments, R² is

[0062] In one or more embodiments, R² is selected from the group consisting of -CH₃, -CF₃, - Cl, -F, -OCH₃, -NH₂,

[0063] In some embodiments, Z¹ is CR³, Z² is CH, Z³ is N, and Z⁴ is N. [0064] In some embodiments, Z¹ is CH, Z² is CH, Z³ is N, and Z⁴ is N. [0065] In some embodiments, Z¹ is CH, Z² is CH, Z³ is CR³, and Z⁴ is N. [0066] In some embodiments, Z¹ is CH, Z² is CH, Z³ is N, and Z⁴ is CH. [0067] In some embodiments, Z¹ is CH, Z² is N, Z³ is CR³, and Z⁴ is CH. [0068] In some embodiments, Z¹ is CH, Z² is N, Z³ is CR³, and Z⁴ is N. [0069] In some embodiments, Z¹ is CH, Z² is CH, Z³ is CR³, and Z⁴ is CH. [0070] In some embodiments, each R³ is independently selected from the group consisting of H, halo, -CN, -C₁-C₃ alkyl, -C₁-C₃ hydroxyalkyl, -C(O)NR^3aR^3b, and -NR^3aR^3b; wherein R^3a and R^3b are independently H, -C₁-C₃ alkyl, or -(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl). In some embodiments, R³ is H. In some embodiments, R³ is halo. In some embodiments, R³ is -Cl, or -F. In some embodiments, R³ is -CN. In some embodiments, R³ is -C₁-C₃ alkyl. In some embodiments, R³ is methyl. In some embodiments, R³ is -C₁-C₃ hydroxyalkyl. In some embodiments, R³ is -CH₂OH. In some embodiments, R³ is -C(O)NR^3aR^3b, wherein R^3a and R^3b are independently H, -C₁-C₃ alkyl, or -(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl). In some embodiments, R³ is -C(O)NH₂. In some embodiments, R³ is -NR^3aR^3b, wherein R^3a and R^3b are independently H, -C₁-C₃ alkyl, or -(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl). In some embodiments, R³ is -NR^3aR^3b, wherein R^3a and R^3b are independently H, or -(C₁-C₃ alkylene)- (C₃-C₆ cycloalkyl). In some embodiments, R³ is -NH₂, or

[0071] In one or more embodiments, each R³ is independently selected from the group consisting of -F, -Cl, -CH₃, -CN, -NH₂,

[0072] In some embodiments, R⁴ is phenyl; 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S; or -L²-phenyl, wherein L² is -NH-, -O- (C₁-C₃ alkylene)-, or –NH-(C₁-C₃ alkylene)-; wherein R⁴ is substituted with 0-3 R^4a. In some embodiments, R⁴ is phenyl substituted with 0-3 R^4a. In some embodiments, R⁴ is phenyl substituted with 1-3 R^4a. In some embodiments, each R^4a is independently selected from the group consisting of halo, -NH₂, -OH, -C₁-C₃ alkyl, -C₁-C₃ alkoxy, -(C₁-C₃ alkylene)-O-(C₁-C₃ alkyl), -C₁-C₃ haloalkyl, and -C₁-C₃ haloalkoxy. In some embodiments, each R^4a is independently -F, -Cl, -OH, -CH₃, -NH₂, -CHF₂, -CF₃, -OCH₃, -OCF₃, or -CH₂OCH₃. In some embodiments, each R^4a is independently halo, or -C₁-C₃ alkoxy. In some embodiments, each R^4a is independently Cl, F, or -OCH₃. In some embodiments, R⁴ is

. In some embodiments, R⁴ is In some ⁴

embodiments, R is phenyl substituted with 1-3 R^4a, wherein each R^4a is independently halo, or C₁-C₃ alkoxy; or two R^4a groups together with the adjacent ring atoms to which they are attached form a 5-membered heteroaryl having 1-2 ring N heteroatoms. In some embodiments, R⁴ is phenyl substituted with 1-3 R^4a, wherein each R^4a is independently -F, or -OCH₃; or two R^4a groups together with the adjacent ring atoms to which they are attached form a 5-membered heteroaryl having 1-2 ring N heteroatoms. In some embodiments, R⁴ is

In some embodiments, R⁴ is 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, and substituted with 0-3 R^4a. In some embodiments, R⁴ is a 6- membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, and substituted with 0-3 R^4a. In some embodiments, R⁴ is pyridyl substituted with 0-2 R^4a. In some embodiments, each R^4a is independently selected from the group consisting of halo, - NH₂, -OH, -C₁-C₃ alkyl, -C₁-C₃ alkoxy, -(C₁-C₃ alkylene)-O-(C₁-C₃ alkyl), -C₁-C₃ haloalkyl, and -C₁-C₃ haloalkoxy. In some embodiments, each R^4a is independently -C₁-C₃ alkyl, -C₁-C₃ alkoxy, or -NH₂. In some embodiments, each R^4a is independently -CH₃, -NH2, or -OCH₃. In some embodiments, R⁴ is

[0073] In one or more embodiments, R⁴ is -L²-phenyl, wherein L² is -NH-, -O-, -O-(C₁-C₃ alkylene)-, or –NH-(C₁-C₃ alkylene)-, and R⁴ is substituted with 0-3 R^4a. In some embodiments, L² is -NH-, and R⁴ is substituted with 1-2 R^4a. In some embodiments, each R^4a is independently, halo, -C₁-C₃ alkyl, or -C₁-C₃ alkoxy. In some embodiments, each R^4a is independently -F, -CH₃, or -OCH₃. In some embodiments, R⁴ is

In some embodiments, L² is -O-(C₁-C₃ alkylene)-, and R⁴ is substituted with 0-3 R^4a. In some embodiments, R⁴ is substituted with 0-3 R^4a. In s ^4a

ome embodiments, each R is halo. In some embodiments, each R^4a is independently -Cl, or -F. In some embodiments, R⁴ is

. In some embodiments, L² is –NH-(C₁-C₃ alkylene)-, and R⁴ is substituted with 0-3 R^4a. In some embodiments, R⁴ is

substituted with 0-1 R^4a. In some embodiments R^4a is -OH. In some embodiments, R⁴ is

[0074] In one or more embodiments, R⁴ is

[0075] In one or more embodiments, R⁴ and R³ groups together with the adjacent ring atoms to which they are attached form a 5- to 6-membered heterocycloalkyl having from 1 to 3 ring heteroatoms selected from N, O, and S; and said 5- to 6-membered heterocycloalkyl is substituted with 0-3 substituents independently selected from oxo and -C₁-C₃ alkyl. In some embodiments, R⁴ and R³ groups together with the adjacent ring atoms to which they are attached form a 5-membered heterocycloalkyl having from 1 ring O heteroatom; and said 5- membered heterocycloalkyl is substituted with one oxo and two -C₁-C₃ alkyl. In some embodiments, the moiety

In some embodiments, the moiety

[0076] In one or more embodiments, the compound of Formula I has a structure of Formula Ia:

or pharmaceutically acceptable salt or solvate thereof. [0077] In some embodiments, ring Y is

. In some embodiments, ring Y is

. In some embodiments, ring Y is

. In some embodiments, ring Y is

. In some embodiments, ring Y is

. In some embodiments, ring Y is

[0078] In one or more embodiments, the compound of Formula I has a structure of Formula Ib:

or a pharmaceutically acceptable salt or solvate thereof. [0079] In one or more embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, according to this disclosure is selected from the compounds provided in Table 1. Therapeutic and Prophylactic Uses [0080] The present disclosure provides methods for using compounds described herein in the preparation of a medicament for inhibiting HPK1. As used herein, the terms “inhibit”, ‘inhibition” and the like refer to the ability of a compound to decrease the function or activity of a particular target, e.g., HPK1. The decrease is preferably at least 50% and may be, for example, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%. The present disclosure also encompasses the use of the compounds described herein in the preparation of a medicament for the treatment or prevention of diseases, disorders, and/or conditions that would benefit from inhibition of HPK1. As one example, the present disclosure encompasses the use of the compounds described herein in the preparation of a medicament for the treatment of cancer. As one example, the present disclosure encompasses the use of the compounds described herein in the preparation of a medicament for the treatment of an infectious disease, optionally a viral infection. In some embodiments of the aforementioned methods, the compounds described herein are used in combination with at least one additional therapy, examples of which are set forth elsewhere herein. [0081] HPK1 is a serine/threonine kinase and member of the MAP4K family. Through this activity, HPK1 functions, in one aspect, as a negative regulator of immune cell (e.g., T cell, B, cell, dendritic cell) activation. For example, activated HPK1, which is phosphorylated at residues Y381, S171, and T165, binds and phosphorylates adaptor proteins critical for T cell signaling, leading to destabilization of the T cell receptor (TCR) signaling complex and disruption of TCR signaling. In particular, activated HPK1 phosphorylates SLP76 and GADS leading to recruitment of 14-3-3 and ubiquitin mediated proteasomal degradation of intracellular signaling proteins. HPK1 is believed to negatively regulate B cell receptor signaling in an analogous way to T cells and may have a role in limiting dendritic cell activation through TLR4. [0082] As demonstrated herein, the use of compounds described herein potently inhibit HPK1 activity, resulting in increased immune cell activity and anti-tumor immune responses. Diseases, disorders, and/or conditions that would benefit from HPK1 inhibition may include those where greater immune cell (e.g., T cell, NK cell, etc.) activation is desired; where there is limited immune cell stimulation, for example, due to low antigen density, poor quality neoantigen, high PD-L1 expression, T cell exhaustion, or combinations thereof; and/or where the tumor microenvironment is characterized by extracellular immunosuppressive molecules such as adenosine, TGF-beta, PGE2, or combinations thereof. [0083] Accordingly, in some embodiments, the compounds described herein are administered to a subject in need thereof in an amount effective to inhibit HPK1 activity. HPK1 activity may be assessed using cells (e.g., T cells, B cells, dendritic cells, or precursors thereof) obtained from a peripheral blood sample or a tissue sample (e.g., a tumor sample) that was obtained from the subject. Activity may be determined, for example, by comparison to a previous sample obtained from the subject (i.e., prior to administration of the compound) or by comparison to a reference value for a control group (e.g., standard of care, a placebo, etc.). In some embodiments, a measure of HPK1 inhibition may be decreased phosphorylation of SLP76 at S376 and/or GADS in T cells. In another example, a measure of HPK1 inhibition may be increased MAP kinase pathway signaling and AP-1 transcription in T cells. In a further example, a measure of HPK1 inhibition may be decreased phosphorylation of BLNK Th-152 in B cells. [0084] Alternatively or in addition, in some embodiments, the compounds described herein are administered to a subject in need thereof in an amount effective to increase immune cell activity, as compared to a suitable control (e.g., a subject receiving standard of care, a subject receiving no treatment or a placebo treatment, etc.). Immune cell activity may be assessed using cells (e.g., T cells, B cells, dendritic cells, or precursors thereof) obtained from a peripheral blood sample or a tissue sample (e.g., a tumor sample) that was obtained from the subject. Non- limiting examples of measures of increased immune cell activity may include increased expression, production and/or secretion of chemokines, pro-inflammatory cytokines and/or cytotoxic factors, increased cytotoxic activity, and increased gene expression and/or cell surface markers related to immune cell function and immune signaling. Examples of pro- inflammatory cytokines include, but are not limited to, IL-1a, IL-1b, IL-2, IL-6, IL-13, IL-17a, interferon gamma (INF-γ or INF-g), tumor necrosis factor-alpha (TNF-α or TNF-a), TNF-beta (TNF-β or TNF-b), fibroblast growth factor (FGF) 2, granulocyte macrophage colony- stimulating factor (GM-CSF), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), vascular endothelial growth factor (VEGF), VEGF- C, VEGF-D, and placental growth factor (PLGF). Examples of cytotoxic factors include, but are not limited to, granzyme A, granzyme B, soluble Fas ligand (sFasL), and perforin. [0085] Alternatively or in addition, in some embodiments, the compounds described herein are administered to a subject in need thereof in an amount effective to increase immune cell proliferation. Immune cell numbers in tissue or blood may be quantified (absolute numbers or relative numbers) by immunophenotyping, i.e., a process of using antibodies (or other antigen- specific reagent) to detect and quantify cell-associated antigens. Lymphoid cell markers may include but are not limited to CD3, CD4, CD8, CD16, CD25, CD39, CD45, CD56, CD69, CD103, CD127, and FOXP3. CD4 and CD8 can distinguish T cell with different effector functions (e.g., CD4+ T cells and CD8+ T cells). Co-expression of different cell markers can further distinguish sub-groups. For example, co-expression of CD39 and CD103 can differentiate tumor-specific T cells (CD8+CD39+CD103+ T cells) from bystander T cells in the tumor microenvironment (TME). For dendritic cells, suitable markers may include but are not limited to CD11c, HLA-DR, CD141, and CLEC9A. For myeloid cells, suitable markers may include but are not limited to CD14, CD68, CD80, CD83, CD86, CD163, and CD206. Ki67 is a non-limiting example of a suitable marker of cell proliferation, such that an increase in Ki67 positive cells (e.g., CD8+ T cells, NK cells, etc.) as compared to a reference sample indicate cell proliferation. [0086] In some embodiments, the compounds described herein are administered to a subject in need thereof in an amount effective to increase T cell activity. In certain embodiments, the T cells are CD8+ T cells, optionally tumor infiltrating CD8+ T cells and/or antigen experienced CD8+ T cells. Measures of increased T cell activity may be increased T cell expression, production or secretion of chemokines, pro-inflammatory cytokines (e.g., IFNγ, TNF-α, IL-2, etc.) and/or cytotoxic factors (e.g. perforin, Granzyme B, etc.); increased pro-inflammatory cytokine levels in the tumor microenvironment or periphery; increased expression of T cell surface markers of activation (e.g., CD69); increased T cell receptor (TCR) signaling; increased calcium flux in a T cell, increased glucose uptake by a T cell; increased glycolysis in a T cell; and increased killing of cancer cells by T cells. [0087] In some embodiments, the compounds according to this disclosure are useful in the treatment of a viral infection. In some embodiments, the viral infection is a disease caused by hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstin-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV), or lymphocytic choriomeningitis virus (LCMV). [0088] Alternatively or in addition, in some embodiments, the compounds described herein are administered to a subject in need thereof to treat and/or prevent cancer or a cancer-related disease, disorder or condition. In some embodiments, the compounds described herein are administered to a subject in need thereof to treat cancer, optionally in combination with at least one additional therapy, examples of which are set forth elsewhere herein. [0089] Alternatively or in addition, in some embodiments, the compounds described herein are brought into contact with an immune cell or a plurality of immune cells, in vitro or ex vivo, in an amount effective to increase proliferation, activation or activity of the immune cell(s). In some embodiments, the immune cells may be T cells, B cells or dendritic cells. The immune cell(s) may be allogenic immune cell(s) collected from one or more subject, or may be autologous immune cell(s) collected from a subject in need of treatment. In certain embodiments, the cells may be “(re)programmed” allogenic immune cells produced from immune precursor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell precursor cells, stem cells, induced pluripotent stem cells, etc.). In various embodiments, the immune cells may be genetically modified to target the cells to a specific antigen and/or enhance the cells’ anti-tumor effects (e.g., engineered T cell receptor (TCR) cellular therapies, chimeric antigen receptor (CAR) cellular therapies, etc.). In some embodiments, the in vitro or ex vivo treated immune cell(s) are then administered to a subject in need thereof to treat and/or prevent cancer or a cancer-related disease, disorder or condition. In some embodiments, the in vitro or ex vivo treated immune cells are administered to a subject in need thereof to treat cancer, optionally in combination with at least one additional therapy, examples of which are set forth elsewhere herein. [0090] In one or more embodiments, the compounds described herein are useful in the treatment and/or prophylaxis of cancer (e.g., carcinomas, sarcomas, leukemias, lymphomas, myelomas, etc.). In certain embodiments, the cancer may be locally advanced and/or unresectable, metastatic, or at risk of becoming metastatic. Alternatively, or in addition, the cancer may be recurrent or no longer responding to a treatment, such as a standard of care treatment known to one of skill in the art. Exemplary types of cancer contemplated by this disclosure include cancer of the genitourinary tract (e.g., bladder, kidney, renal cell, penile, prostate, testicular, Von Hippel-Lindau disease, uterus, cerviz, ovary, etc.), breast, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestines, colon, or rectum), bone, bone marrow, skin (e.g., melanoma), head and neck, liver, gall bladder, bile ducts, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., gliomas), ganglia, central nervous system (CNS), peripheral nervous system (PNS), the hematopoietic system (i.e., hematological malignancies), and the immune system (e.g., spleen or thymus). [0091] In some embodiments, the compounds according to this disclosure are useful in the treatment and/or prophylaxis of hematological malignancies. Exemplary types of cancer affecting the hematopoietic system include leukemias, lymphomas and myelomas, including acute myeloid leukemia, adult T-cell leukemia, T-cell large granular lymphocyte leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute monocytic leukemia, Hodgkin’s and Non-Hodgkin’s lymphoma, Diffuse large B Cell lymphoma, and multiple myeloma. In a specific embodiment, the compounds according to this disclosure are useful in the treatment of Diffuse large B Cell lymphoma, optionally Diffuse large B Cell lymphoma with Richter transformation. [0092] In another embodiment, the compounds according to this disclosure are useful in the treatment and/or prophylaxis of solid tumors. The solid tumor may be, for example, ovarian cancer, endometrial cancer, breast cancer, lung cancer (small cell or non-small cell), colon cancer, prostate cancer, cervical cancer, biliary cancer, pancreatic cancer, gastric cancer, esophageal cancer, liver cancer (hepatocellular carcinoma), kidney cancer (renal cell carcinoma), head-and-neck tumors, mesothelioma, melanoma, sarcomas, central nervous system (CNS) hemangioblastomas, and brain tumors (e.g., gliomas, such as astrocytoma, oligodendroglioma and glioblastomas). [0093] In another embodiment, the compounds according to this disclosure are useful in the treatment and/or prophylaxis of breast cancer, genitourinary cancer, gastrointestinal cancer, lung cancer, skin cancer, neuroendocrine cancer, head and neck cancer, liver cancer, hematological cancer, or a combination thereof. [0094] In some embodiments, the compounds according to this disclosure are useful in the treatment of breast cancer. In further embodiments, the breast cancer is hormone receptor positive (e.g., ERα-positive breast cancer, PR-positive breast cancer, ERα-positive and PR- positive breast cancer), HER2 positive breast cancer, HER2 over-expressing breast cancer, or any combination thereof. In still further embodiments, the breast cancer is triple negative breast cancer. [0095] In some embodiments, the compounds according to this disclosure are useful in the treatment of genitourinary cancer. In further embodiments, the genitourinary cancer is gynecologic cancer. In still further embodiments, the gynecologic cancer is endometrial cancer, cervical cancer, ovarian cancer or fallopian tube carcinoma. In still further embodiments, the genitourinary cancer is urothelial cancer. In still further embodiments, the genitourinary cancer is prostate cancer, optionally castration-resistant prostate cancer. [0096] In some embodiments, the compounds according to this disclosure are useful in the treatment of kidney cancer. In further embodiments, the kidney cancer is renal cell carcinoma. In still further embodiments, the renal cell carcinoma is clear cell renal carcinoma. [0097] In some embodiments, the compounds according to this disclosure are useful in the treatment of liver cancer. In further embodiments, the liver cancer is hepatocellular carcinoma. [0098] In some embodiments, the compounds according to this disclosure are useful in the treatment of head and neck cancer. In further embodiments, the head and neck cancer is head and neck squamous cell carcinoma. [0099] In some embodiments, the compounds according to this disclosure are useful in the treatment of skin cancer. In further embodiments, the skin cancer is melanoma. [0100] In some embodiments, the compounds according to this disclosure are useful in the treatment of lung cancer. In further embodiments, the lung cancer is mesothelioma, small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In still further embodiments, the NSCLC is lung squamous cell carcinoma or lung adenocarcinoma. [0101] In some embodiments, the compounds according to this disclosure are useful in the treatment of gastrointestinal cancer. In some embodiments, the gastrointestinal cancer is upper GI cancer, such as esophageal or gastric cancer. In further embodiments, the upper GI cancer is an adenocarcinoma, a squamous cell carcinoma, or any combination thereof. In still further embodiments, the upper GI cancer is esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastroesophageal junction adenocarcinoma (GEJ), gastric adenocarcinoma (also referred to herein as “gastric cancer”) or any combination thereof. In some embodiments, the gastrointestinal cancer is lower GI cancer. In further embodiments, the lower GI cancer is colorectal cancer. [0102] In some embodiments, the compounds according to this disclosure are useful in the treatment of hematological cancer. In some embodiments, the hematological cancer is lymphoma. In some embodiments, the lymphoma is Hodgkin’s lymphoma. In some embodiments, the hematological cancer is leukemia. [0103] In some embodiments, the compounds according to this disclosure are useful in the treatment of a neuroendocrine tumor. In further embodiments, the neuroendocrine tumor is pancreatic neuroendocrine tumor, pheochromocytoma, paraganglioma, or a tumor of the adrenal gland. [0104] In some embodiments, the compounds according to this disclosure are useful in the treatment of brain cancer. In further embodiments, the brain cancer is a glioma. In still further embodiments, the glioma is an astrocytoma, an oligodendroglioma, or a glioblastoma. [0105] In some embodiments, the compounds according to this disclosure are useful in the treatment of pancreatic cancer. In further embodiments, the pancreatic cancer is pancreatic neuroendocrine tumor or pancreatic adenocarcinoma. [0106] In the aforementioned embodiments, the methods of the present disclosure may be practiced in an adjuvant setting or neoadjuvant setting, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. Alternatively or in addition, the methods described herein may be indicated as a first line treatment, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. In some embodiments, the methods described herein may be indicated as a second line, third line, or greater line of treatment, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. When indicated as a second line or greater treatment, in some embodiments an earlier line of therapy included a checkpoint inhibitor. [0107] The present disclosure also provides methods of treating or preventing other cancer- related diseases, disorders or conditions. The use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer and non-cancerous proliferative disease, and includes, e.g., angiogenesis, precancerous conditions such as dysplasia, and non-cancerous proliferative diseases disorders or conditions, such as benign proliferative breast disease and papillomas. For clarity, the term(s) cancer-related disease, disorder and condition do not include cancer per se. [0108] In general, the disclosed methods for treating or preventing cancer, or a cancer-related disease, disorder or condition, in a subject in need thereof comprise administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods for treating or preventing cancer, or a cancer-related disease, disorder or condition with a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one additional therapy, examples of which are set forth elsewhere herein. [0109] In particular embodiments of the present disclosure, the compounds are used to increase or enhance an immune response to an antigen by providing adjuvant activity. In a particular embodiment, at least one antigen or vaccine is administered to a subject in combination with at least one compound of the present disclosure to prolong an immune response to the antigen or vaccine. Therapeutic compositions are also provided which include at least one antigenic agent or vaccine component, including, but not limited to, viruses, bacteria, and fungi, or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines, in combination with at least one compound of the present disclosure. [0110] In some instances, the methods according to this disclosure may be provided in selected patients, for example subjects identified as having in a relevant tissue or sample, e.g., detectable PD-L1 expression, microsatellite instability (MSI), deficient mismatch repair, (dMMR), high tumor mutational burden, or any combination thereof. In some instances, the subject is identified as having an oncogene driven cancer that has a mutation in at least one gene associated with the cancer. [0111] In some embodiments, patients are selected by assessing the expression of relevant biomarkers, e.g., PD-L1 expression, microsatellite instability markers, T-cell inflamed gene expression profile (GEP), etc., in a relevant sample, such as a peripheral blood sample or a tumor biopsy, using immunohistochemistry, immunophenotyping, PCR-based amplification, RNA sequencing, or other clinically validated assay. In one embodiment, the disclosure provides a method of treating cancer in a patient having (i) detectable PD-L1 expression, (ii) elevated PD-L1 expression, (iii) MSI-low, (iv) MSI-high, (v) elevated GEP expression, or (vi) any combination of (i) to (v) by administering a compound as described herein. In another embodiment, the disclosure provides a method of treating cancer in a patient having (i) detectable PD-L1 expression, (ii) elevated PD-L1 expression, (iii) MSI-low, (iv) MSI-high, (v) elevated GEP expression, or (vi) any combination of (i) to (v) by administering a therapeutically effective amount of a compound as described herein. In still another embodiment, the disclosure provides a method of administering a therapeutically effective amount of a compound as described herein to an individual for the treatment of cancer based on a determination of the relative amount of PD-L1 expression. In yet another embodiment, the disclosure provides a method of administering a therapeutically effective amount of a compound described herein to an individual for the treatment of cancer, the method comprising measuring PD-L1 expression and/or microsatellite instability (e.g., MSI-low or MSI-high) in a sample obtained from an individual, for example by immunohistochemistry, immunophenotyping, PCR-based amplification, or other clinically validated test, and administering a therapeutically effective amount of the compound to the individual whose sample contained detectable PD-L1 expression and/or microsatellite instability. In various embodiments of the disclosure, detectable PD-L1 expression may be a tumor proportion (TPS) score of ≥ 50%, as measured by a clinically validated PD-L1 IHC assay or FDA-approved test. In various embodiments of the disclosure, detectable PD-L1 expression may be TPS score of < 50%, as measured by a clinically validated PD-L1 IHC assay or FDA-approved test. Routes of Administration [0112] In some embodiments, pharmaceutical compositions containing a compound according to this disclosure may be in a form suitable for oral administration. Oral administration may involve swallowing the formulation thereby allowing the compound to be absorbed into the bloodstream in the gastrointestinal tract. Alternatively, oral administration may involve buccal, lingual or sublingual administration, thereby allowing the compound to be absorbed into the blood stream through oral mucosa. [0113] In another embodiment, the pharmaceutical compositions containing a compound according to this disclosure may be in a form suitable for parenteral administration. Forms of parenteral administration include, but are not limited to, intravenous, intraarterial, intramuscular, intradermal, intraperitoneal, intrathecal, intracisternal, intracerebral, intracerebroventricular, intraventricular, and subcutaneous. Pharmaceutical compositions suitable for parenteral administration may be formulated using suitable aqueous or non- aqueous carriers. Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compounds disclosed herein over a defined period of time.

[0114] Other routes of administration are also contemplated by this disclosure, including, but not limited to, nasal, vaginal, intraocular, rectal, topical (e.g., transdermal), and inhalation.

[0115] Particular embodiments of the present disclosure contemplate oral administration or parenteral administration.

Pharmaceutical Compositions

[0116] The compounds of the present disclosure may be in the form of compositions suitable for administration to a subject. In general, such compositions are pharmaceutical compositions comprising a compound according to this disclosure or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In certain embodiments, the compound may be present in an effective amount. The pharmaceutical compositions may be used in the methods of the present disclosure; thus, for example, the pharmaceutical compositions comprising a compound according to this disclosure can be administered to a subject in order to practice the therapeutic and prophylactic methods and uses described herein.

[0117] The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration. Routes of administration may include those known in the art. Exemplary routes of administration are oral and parenteral. Furthermore, the pharmaceutical compositions may be used in combination with one or more other therapies described herein in order to treat or prevent the diseases, disorders and conditions as contemplated by the present disclosure. In one embodiment, one or more other therapeutic agents contemplated by this disclosure are included in the same pharmaceutical composition that comprises the compound according to this disclosure. In another embodiment, the one or more other therapeutical agents are in a composition that is separate from the pharmaceutical composition comprising the compound according to this disclosure.

[0118] In one aspect, the compounds described herein may be administered orally. Oral administration may be via, for example, capsule or tablets. In making the pharmaceutical compositions that include the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the tablet or capsule typically includes at least one pharmaceutically acceptable excipient. Non-limiting examples of pharmaceutically acceptable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, sterile water, syrup, and methyl cellulose. Additional pharmaceutically acceptable excipients include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates. [0119] In another aspect, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered parenterally, for example by intravenous injection. A pharmaceutical composition appropriate for parenteral administration may be formulated in solution for injection or may be reconstituted for injection in an appropriate system such as a physiological solution. Such solutions may include sterile water for injection, salts, buffers, and tonicity excipients in amounts appropriate to achieve isotonicity with the appropriate physiology. [0120] The pharmaceutical compositions described herein may be stored in an appropriate sterile container or containers. In some embodiments, the container is designed to maintain stability for the pharmaceutical composition over a given period of time. Administering [0121] In general, the disclosed methods comprise administering a compound described herein, or a composition thereof, in an effective amount to a subject in need thereof. An “effective amount” with reference to a HPK1 inhibitor of the present disclosure means an amount of the compound that is sufficient to engage the target (e.g., by inhibiting the target) at a level that is indicative of the potency of the compound. For HPK1, target engagement can be determined by one or more biochemical or cellular assays resulting in an EC50, ED50, EC90, IC50, or similar value which can be used as one assessment of the potency of the compound. Assays for determining target engagement include, but are not limited to, those described in the Examples. The effective amount may be administered as a single quantity or as multiple, smaller quantities (e.g., as one tablet with “x” amount, as two tablets each with “x/2” amount, etc.). [0122] In some embodiments, the disclosed methods comprise administering a therapeutically effective amount of a compound described herein to a subject in need thereof. As used herein, the phrase “therapeutically effective amount” with reference to compound disclosed herein means a dose regimen (i.e., amount and interval) of the compound that provides the specific pharmacological effect for which the compound is administered to a subject in need of such treatment. For prophylactic use, a therapeutically effective amount may be effective to eliminate or reduce the risk, lessen the severity, or delay the onset of the disease, including biochemical, histological and/or behavioral signs or symptoms of the disease. For treatment, a therapeutically effective amount may be effective to reduce, ameliorate, or eliminate one or more signs or symptoms associated with a disease, delay disease progression, prolong survival, decrease the dose of other medication(s) required to treat the disease, or a combination thereof. With respect to cancer specifically, a therapeutically effective amount may, for example, result in the killing of cancer cells, reduce cancer cell counts, reduce tumor burden, eliminate tumors or metastasis, or reduce metastatic spread. A therapeutically effective amount may vary based on, for example, one or more of the following: the age and weight of the subject, the subject’s overall health, the stage of the subject’s disease, the route of administration, and prior or concomitant treatments. [0123] Administration may comprise one or more (e.g., one, two, or three or more) dosing cycles. [0124] In certain embodiments, the compounds contemplated by the present disclosure may be administered (e.g., orally, parenterally, etc.) at about 0.01 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of subject’s body weight per day, one or more times a day, a week, or a month, to obtain the desired effect. In some embodiments, a suitable weight-based dose of a compound contemplated by the present disclosure is used to determine a dose that is administered independent of a subject’s body weight In certain embodiments, the compounds of the present disclosure are administered (e.g., orally, parenterally, etc.) at fixed dosage levels of about 1 mg to about 1000 mg, particularly 1, 3, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 mg, one or more times a day, a week, or a month, to obtain the desired effect. [0125] In certain embodiments, the compound is contained in a “unit dosage form”. The phrase “unit dosage form” refers to physically discrete units, each unit containing a predetermined amount of the compound, either alone or in combination with one or more additional agents, sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved.

Combination Therapy

[0126] The present disclosure contemplates the use of compounds disclosed herein alone or in combination with one or more additional therapy. Each additional therapy can be a therapeutic agent or another treatment modality. In embodiments comprising one or more additional therapeutic agents, each agent may target a different, but complementary, mechanism of action. The additional therapeutic agents can be small chemical molecules; macromolecules such as proteins, antibodies, peptibodies, peptides, DNA, RNA or fragments of such macromolecules; or cellular or gene therapies. Non-limiting examples of additional treatment modalities include surgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic therapy. The use of a compound disclosed herein in combination with one or more additional therapies may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition. In addition to or alternatively, the combination therapy may allow for a dose reduction of one or more of the therapies, thereby ameliorating, reducing or eliminating adverse effects associated with one or more of the agents.

[0127] In embodiments comprising one or more additional treatment modality, the compound can be administered before, after or during treatment with the additional treatment modality. In embodiments comprising one or more additional therapeutic agent, the therapeutic agents used in such combination therapy can be formulated as a single composition or as separate compositions. If administered separately, each therapeutic agent in the combination can be given at or around the same time, or at different times. Furthermore, the therapeutic agents are administered “in combination” even if they have different forms of administration (e.g., oral capsule and intravenous), they are given at different dosing intervals, one therapeutic agent is given at a constant dosing regimen while another is titrated up, titrated down or discontinued, or each therapeutic agent in the combination is independently titrated up, titrated down, increased or decreased in dosage, or discontinued and/or resumed during a patient’s course of therapy. If the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit. Cancer Therapies [0128] The present disclosure contemplates the use of the compounds described herein in combination with one or more additional therapies useful in the treatment of cancer. [0129] In some embodiments, one or more of the additional therapies is an additional treatment modality. Exemplary treatment modalities include but are not limited to surgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic therapy. [0130] In some embodiments, one or more of the additional therapies is a therapeutic agent. Exemplary therapeutic agents include chemotherapeutic agents, radiation therapy, hormone therapies, epigenetic modulators, ATP-adenosine axis-targeting agents, targeted therapies, signal transduction inhibitors, RAS signaling inhibitors, PI3K inhibitors, arginase inhibitors, HIF inhibitors, AXL inhibitors, PAK4 inhibitors, immunotherapeutic agents, cellular therapies, gene therapies, immune checkpoint inhibitors, and agonists of stimulatory or co-stimulatory immune checkpoints. [0131] In some embodiments, one or more of the additional therapeutic agents is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, pomalidomide, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel, nab paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6- thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin, carboplatin and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; proteasome inhibitors such as bortezomib, carfilzomib and ixazomib; topoisomerase inhibitors such as irinotecan, topotecan, etoposide, mitoxantrone, teniposide; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; anthracyclines and pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy comprises a chemotherapy regimen that includes one or more chemotherapeutic agents. In one embodiment, combination therapy comprises a chemotherapeutic regimen comprising one or more of FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), FOLFIRINOX ((folinic acid, fluorouracil, irinotecan, and oxaliplatin), a taxoid (e.g., docetaxel, paclitaxel, nab-paclitaxel,etc.), and/or gemcitabine. [0132] In some embodiments, one or more of the additional therapeutic agents is a radiation therapy. Radiation therapy includes radiopharmaceuticals which are a form of internal radiation therapy in which a source of radiation (i.e., one or more radionuclide) is put inside a subject’s body. The radiation source can be in solid or liquid form. Non-limiting examples of radiopharmaceuticals include sodium iodide I-131, radium-223 dichloride, lobenguane iodine- 131, radioiodinated vesicles (e.g., saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles), various forms of brachytherapy, and various forms of targeted radionuclides. Targeted radionuclides comprise a radionuclide associated (e.g., by covalent or ionic interactions) with a molecule (“a targeting agent”) that specifically binds to a target on a cell, typically a cancer cell or an immune cell. The targeting agent may be a small molecule, a saccharide (inclusive of oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a saccharide (inclusive of oligosaccharides and polysaccharides), a lipid, a protein, or a peptide and the target is a tumor-associated antigen (enriched but not specific to a cancer cell), a tumor- specific antigen (minimal to no expression in normal tissue), or a neo-antigen (an antigen specific to the genome of a cancer cell generated by non-synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor- associated antigen (i.e., an antigen enriched but not specific to a cancer cell), a tumor-specific antigen (i.e., an antigen with minimal to no expression in normal tissue), or a neo-antigen (i.e., an antigen specific to the genome of a cancer cell generated by non-synonymous mutations in the tumor cell genome). Non-limiting examples of targeted radionuclides include radionuclides attached to: somatostatin or peptide analogs thereof (e.g., 177Lu-Dotatate, etc.); prostate specific membrane antigen or peptide analogs thereof (e.g., 177Lu-PSMA-617, 225Ac-PSMA- 617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); a receptor’s cognate ligand, peptide derived from the ligand, or variants thereof (e.g., 188Re-labeled VEGF_125-136 or variants thereof with higher affinity to VEGF receptor, etc.); antibodies targeting tumor antigens (e.g., 131I- tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-omburtamab, etc.). [0133] In some embodiments, one or more of the additional therapeutic agents is a hormone therapy. Hormone therapies act to regulate or inhibit hormonal action on tumors. Examples of hormone therapies include, but are not limited to: selective estrogen receptor degraders such as fulvestrant, giredestrant, SAR439859, RG6171, AZD9833, rintodestrant, ZN-c5, LSZ102, D- 0502, LY3484356, SHR9549; selective estrogen receptor modulators such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, toremifene; aromatase inhibitors such as anastrozole, exemestane, letrozole and other aromatase inhibiting 4(5)-imidazoles; gonadotropin-releasing hormone agonists such as nafarelin, triptorelin, goserelin; gonadotropin-releasing hormone antagonists such as degarelix; antiandrogens such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide, leuprolide; 5α-reductase inhibitors such as finasteride, dutasteride; and the like. In certain embodiments, combination therapy comprises administration of a hormone or related hormonal agent. In one embodiment, combination therapy comprises administration of enzalutamide. [0134] In some embodiments, one or more of the additional therapeutic agents is an epigenetic modulator. An epigenetic modulator alters an epigenetic mechanism controlling gene expression, and may be, for example, an inhibitor or activator of an epigenetic enzyme. Non-limiting examples of epigenetic modulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HDAC) inhibitors. In one or more embodiments, the compounds accofrding to this disclosure are combined with DNA methyltransferase (DNMT) inhibitors or hypomethylating agents. Exemplary DNMT inhibitors include decitabine, zebularine and azacitadine. In one or more embodiments, combinations of the compounds according to this disclosure with a histone deacetylase (HDAC) inhibitor is also contemplated. Exemplary HDAC inhibitors include vorinostat, givinostat, abexinostat, panobinostat, belinostat and trichostatin A. [0135] In some embodiments, one or more of the additional therapeutic agents is an ATP- adenosine axis-targeting agent. ATP-adenosine axis-targeting agents alter signaling mediated by adenine nucleosides and nucleotides (e.g., adenosine, AMP, ADP, ATP), for example by modulating the level of adenosine or targeting adenosine receptors. Adenosine and ATP, acting at different classes of receptors, often have opposite effects on inflammation, cell proliferation and cell death. For instance, ATP and other adenine nucleotides have antitumor effects via activation of the PS2Y1 receptor subtype, while accumulation of adenosine in the tumor microenvironment has been shown to inhibit the antitumor function of various immune cells and to augment the immunosuppressive activity of myeloid and regulatory T cells by binding to cell surface adenosine receptors. In certain embodiments, an ATP-adenosine axis-targeting agent is an inhibitor of an ectonucleotidase involved in the conversion of ATP to adenosine or an antagonist of adenosine receptor. Ectonucleotidases involved in the conversion of ATP to adenosine include the ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, also known as CD39 or Cluster of Differentiation 39) and the ecto-5'-nucleotidase (NT5E or 5NT, also known as CD73 or Cluster of Differentiation 73). Exemplary small molecule CD73 inhibitors include CB-708, ORIC-533, LY3475070 and quemliclustat. Exemplary anti-CD39 and anti-CD73 antibodies include ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, oleclumab (MEDI9447), NZV930, IPH5301, GS-1423, uliledlimab (TJD5, TJ004309), AB598, and BMS-986179. In one embodiment, the present disclosure contemplates combination of the compounds described herein with a CD73 inhibitor such as those described in WO 2017/120508, WO 2018/067424, WO 2018/094148, and WO 2020/046813. In further embodiments, the CD73 inhibitor is quemliclustat (AB680). Adenosine can bind to and activate four different G-protein coupled receptors: A1R, A2_AR, A2_BR, and A₃R. A₂R antagonists include etrumadenant, inupadenant, taminadenant, caffeine citrate, NUV-1182, TT-702, DZD- 2269, INCB-106385, EVOEXS-21546, AZD-4635, imaradenant, RVU-330, ciforadenant, PBF-509, PBF-999, PBF-1129, and CS-3005. In some embodiments, the present disclosure contemplates the combination of the compounds described herein with an A2_AR antagonist, an A2_BR antagonist, or an antagonist of A2_AR and A2_BR. In some embodiments, the present disclosure contemplates the combination of the compounds described herein with the adenosine receptor antagonists described in WO 2018/136700, WO 2018/204661, WO 2018/213377, or WO 2020/023846. In one embodiment, the adenosine receptor antagonist is etrumadenant. [0136] In some embodiments, one or more of the additional therapeutic agents is a targeted therapy. In one aspect, a targeted therapy may comprise a chemotherapeutic agent, a radionuclide, a hormone therapy, or another small molecule drug attached to a targeting agent. The targeting agent may be a small molecule, a saccharide (inclusive of oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a saccharide (inclusive of oligosaccharides and polysaccharides), a lipid, a protein, or a peptide and the target is a tumor- associated antigen (enriched but not specific to a cancer cell), a tumor-specific antigen (minimal to no expression in normal tissue), or a neo-antigen (an antigen specific to the genome of a cancer cell generated by non-synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen (enriched but not specific to a cancer cell), a tumor-specific antigen (minimal to no expression in normal tissue), or a neo-antigen (an antigen specific to the genome of a cancer cell generated by non-synonymous mutations in the tumor cell genome). Specific examples include but are not limited to patritumab deruxtecan and telisotuzumab vedotin. In other aspects, a targeted therapy may inhibit or interfere with a specific protein that helps a tumor grow and/or spread. Non-limiting examples of such targeted therapies include signal transduction inhibitors, RAS signaling inhibitors, inhibitors of oncogenic transcription factors, activators of oncogenic transcription factor repressors, angiogenesis inhibitors, immunotherapeutic agents, tyrosine kinase inhibitors, ATP-adenosine axis-targeting agents, AXL inhibitors, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, HIF-2α inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists, and PD-1 antagonists. ATP-adenosine axis-targeting agents are described above, while other agents are described in further detail below. [0137] In some embodiments, one or more of the additional therapeutic agents is a signal transduction inhibitor. Signal transduction inhibitors are agents that selectively inhibit one or more steps in a signaling pathway. Signal transduction inhibitors (STIs) contemplated by the present disclosure include but are not limited to: (i) BCR-ABL kinase inhibitors (e.g., imatinib); (ii) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), including small molecule inhibitors (e.g., CLN-081, gefitinib, erlotinib, afatinib, icotinib, and osimertinib), and anti-EGFR antibodies; (iii) inhibitors of the human epidermal growth factor (HER) family of transmembrane tyrosine kinases, e.g., HER-2/neu receptor inhibitors (e.g., trastuzumab) and HER-3 receptor inhibitors; (iv) vascular endothelial growth factor receptor (VEGFR) inhibitors including small molecule inhibitors (e.g., axitinib, sunitinib and sorafenib), VEGF kinase inhibitors (e.g., lenvatinib, cabozantinib, pazopanib, tivozanib, XL092, etc.) and anti-VEGF antibodies (e.g., bevacizumab); (v) inhibitors of AKT family kinases or the AKT pathway (e.g., rapamycin); (vi) inhibitors of serine/threonine-protein kinase B-Raf (BRAF), such as, for example, vemurafenib, dabrafenib and encorafenib; (vii) inhibitors of rearranged during transfection (RET), including, for example, selpercatinib and pralsetinib; (viii) tyrosine-protein kinase Met (MET) inhibitors (e.g., tepotinib, tivantinib, cabozantinib and crizotinib); (ix) anaplastic lymphoma kinase (ALK) inhibitors (e.g., ensartinib, ceritinib, lorlatinib, crizotinib, and brigatinib); (x) inhibitors of the RAS signaling pathway (e.g., inhibitors of KRAS, HRAS, RAF, MEK, ERK) as described elsewhere herein; (xi) FLT-3 inhibitors (e.g., gilteritinib);(xii) inhibitors of Trop-2; (xiii) inhibitors of the JAK/STAT pathway, e.g., JAK inhibitors including tofacitinib and ruxolitinib, or STAT inhibitors such as napabucasin; (xiv) inhibitors of NF-kB; (xv) cell cycle kinase inhibitors (e.g., flavopiridol); (xvi) phosphatidyl inositol kinase (PI3K) inhibitors; (xix) protein kinase B (AKT) inhibitors (e.g., capivasertib, miransertib); (xx) platelet-derived growth factor receptor (PDGFR) inhibitors (e.g., imatinib, sunitinib, regorafenib, avapritinib, Lenvatinib, nintedanib, famitinib, ponatinib, axitinib, repretinib, etc.); (xxi) insulin-like growth factor receptor (IGFR) inhibitors (e.g., erlotinib, afatinib, gefitinib, Osimertinib, dacomitinib); and (xxii) inhibitors of anexelekto (AXL) as described in further detail below. In one or more embodiments, the additional therapeutic agent comprises a tyrosine kinase inhibitor that inhibits one or more of AXL, EGFR, VEGFR, PDGFR, IGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-kB, PI3K, AKT, or any combinations thereof. [0138] In some embodiments, one or more of the additional therapeutic agents is a RAS signaling inhibitor. Oncogenic mutations in the RAS family of genes, e.g., HRAS, KRAS, and NRAS, are associated with a variety of cancers. For example, mutations of G12C, G12D, G12V, G12A, G13D, Q61H, G13C and G12S, among others, in the KRAS family of genes have been observed in multiple tumor types. Direct and indirect inhibition strategies have been investigated for the inhibition of mutant RAS signaling. Indirect inhibitors target effectors other than RAS in the RAS signaling pathway, and include, but are not limited to, inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g., SOS1), mTORC1, SHP2 (PTPN11), and AKT. Non- limiting examples of indirect inhibitors under development include RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, BI1701963. Direct inhibitors of RAS mutants have also been explored, and generally target the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors under development include, but are not limited to, sotorasib (AMG510), adagrasib (MRTX849), mRNA-5671 and ARS1620. In some embodiments, the one or more RAS signaling inhibitors are selected from the group consisting of RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, SOS1 inhibitors, mTORC1 inhibitors, SHP2 inhibitors, and AKT inhibitors. In other embodiments the one or more RAS signaling inhibitors directly inhibit RAS mutants. [0139] In some embodiments one or more of the additional therapeutic agents is an inhibitor of a phosphatidylinositol 3-kinase (PI3K), particularly an inhibitor of the PI3Kγ and/or the PI3Kδ isoforms. PI3Kγ inhibitors can stimulate an anti-cancer immune response through the modulation of myeloid cells, such as by inhibiting suppressive myeloid cells, dampening immune-suppressive tumor-infiltrating macrophages or by stimulating macrophages and dendritic cells to make cytokines that contribute to effective T cell responses thereby decreasing cancer development and spread. Exemplary PI3Kγ inhibitors include copanlisib, duvelisib, AT-104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458, and pictilisib. In some embodiments, the compounds according to this disclosure are combined with one or more PI3Kγ inhibitors described in WO 2020/0247496A1. Additionally, PI3Kδ is expressed on malignant B cells, and plays a role in promoting B-cell activation, differentiation, proliferation and survival. Exemplary PI3Kδ inhibitors include duvelisib, leniolisib, parsaclisib, copanlisib, umbralisib, zandelisib, eganelisib, linperlisib, pilaralisib, and tenalisib,

[0140] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of arginase. Arginase has been shown to be either responsible for or participate in inflammation-triggered immune dysfunction, tumor immune escape, immunosuppression and immunopathology of infectious disease. Exemplary arginase compounds include CB-1158 and OAT-1746. In some embodiments, the compounds according to this disclosure are combined with one or more arginase inhibitors described in WO 2019/173188 and WO 2020/102646.

[0141] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of an oncogenic transcription factor or an activator of an oncogenic transcription factor repressor. Suitable agents may act at the expression level (e.g., RNAi, siRNA, etc.), through physical degradation, at the protein/protein level, at the protein/DNA level, or by binding in an activation/inhibition pocket. Non-limiting examples include inhibitors of one or more subunit of the MLL complex (e g., HDAC, DOT1L, BRD4, Menin, LEDGF, WDR5, KDM4C (JMJD2C) and PRMT1), inhibitors of hypoxia-inducible factor (HIF) transcription factor, and the like.

[0142] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of a hypoxia-inducible factor (HIF) transcription factor, particularly HIF-2α. Exemplary HIF- 2α inhibitors include belzutifan, ARO-HIF2, PT-2385, and those described in WO 2021113436, WO 2021188769, and WO 2023077046. In some embodiments, the compounds according to this disclosure are combined with one or more HIF-2α inhibitors described in WO 2021188769.

[0143] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of anexelekto (AXL). The AXL signaling pathway is associated with tumor growth and metastasis, and is believed to mediate resistance to a variety of cancer therapies. There are a variety of AXL inhibitors under development that also inhibit other kinases in the TAM family (i.e., TYRO3, MERTK), as well as other receptor tyrosine kinases including MET, FLT3, RON and AURORA, among others. Exemplary multikinase inhibitors include sitravatinib, rebastinib, glesatinib, gilteritinib, merestinib, cabozantinib, foretinib, BMS777607, LY2801653, S49076, and RXDX-106. AXL specific inhibitors have also been developed, e.g., small molecule inhibitors including DS-1205, SGI-7079, SLC-391, dubermatinib, bemcentinib, and DP3975; anti-AXL antibodies such as ADCT-601; and antibody drug conjugates (ADCs) such as BA3011. Another strategy to inhibit AXL signaling involves targeting AXL’s ligand, GAS6. For example, batiraxcept is under development as is a Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. In some embodiments, the compounds according to this disclosure are combined with one or more AXL inhibitors described in WO 2022246177, WO 2022246179, or PCT/US2023/069124. In one embodiment, the AXL inhibitor is AB801. [0144] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of p21-activated kinase 4 (PAK4). PAK4 overexpression has been shown across a variety of cancer types, notably including those resistant to PD-1 therapies. While no PAK4 inhibitors have been approved, some are in development, and exhibit dual PAK4/NAMPT inhibitor activity, e.g., ATG-019 and KPT-9274. In some embodiments, the compounds according to this disclosure are combined with a PAK4 selective inhibitor. In some embodiments, the compounds according to this disclosure are combined with a PAK4/NAMPT dual inhibitor, e.g., ATG-019 or KPT-9274. [0145] In some embodiments, one or more of the additional therapeutic agents is (i) an agent that inhibits the enzyme poly (ADP-ribose) polymerase (e.g., olaparib, niraparib and rucaparib, etc.); (ii) an inhibitor of the Bcl-2 family of proteins (e.g., venetoclax, navitoclax, etc.); (iii) an inhibitor of MCL-1; (iv) an inhibitor of the CD47-SIRPα pathway (e.g., an anti-CD47 antibody); (v) an isocitrate dehydrogenase (IDH) inhibitor, e.g., IDH-1 or IDH-2 inhibitor (e.g., ivosidenib, enasidenib, etc.). [0146] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent. Immunotherapeutic agents treat a disease by stimulating or suppressing the immune system. Immunotherapeutic agents useful in the treatment of cancers typically elicit or amplify an immune response to cancer cells. Non-limiting examples of suitable immunotherapeutic agents include: immunomodulators; cellular immunotherapies; vaccines; gene therapies; ATP-adenosine axis-targeting agents; immune checkpoint modulators; and certain signal transduction inhibitors. ATP-adenosine axis-targeting agents and signal transduction inhibitors are described above. Immunomodulators, cellular immunotherapies, vaccines, gene therapies, and immune checkpoint modulatorsare described further below. [0147] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a cytokine or chemokine, such as, IL-1, IL-2, IL- 12, IL-18, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, TNF, IL-15, MDC, IFNa/b, M-CSF, IL- 3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharides (LPS); an organic or inorganic adjuvant that activates antigen-presenting cells and promote the presentation of antigen epitopes on major histocompatibility complex molecules agonists including, but not limited to Toll-like receptor (TLR) agonists, antagonists of the mevalonate pathway, agonists of STING; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and immune-stimulatory oligonucleotides, as well as other T cell adjuvants. [0148] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a cellular therapy. Cellular therapies are a form of treatment in which viable cells are administered to a subject. In certain embodiments, one or more of the additional therapeutic agents is a cellular immunotherapy that activates or suppresses the immune system. Cellular immunotherapies useful in the treatment of cancers typically elicit or amplify an immune response. The cells can be autologous or allogenic immune cells (e.g., monocytes, macrophages, dendritic cells, NK cells, T cells, etc.) collected from one or more subject. Alternatively, the cells can be “(re)programmed” allogenic immune cells produced from immune precursor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell precursor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells may be an expanded subset of cells with distinct effector functions and/or maturation markers (e.g., adaptive memory NK cells, tumor infiltrating lymphocytes, immature dendritic cells, monocyte-derived dendritic cells, plasmacytoid dendritic cells, conventional dendritic cells (sometimes referred to as classical dendritic cells), M1 macrophages, M2 macrophages, etc.), may be genetically modified to target the cells to a specific antigen and/or enhance the cells’ anti-tumor effects (e.g., engineered T cell receptor (TCR) cellular therapies, chimeric antigen receptor (CAR) cellular therapies, lymph node homing of antigen-loaded dendritic cells, etc.), may be engineered to express of have increased expression of a tumor-associated antigen, or may be any combination thereof. Non-limiting types of cellular therapies include CAR-T cell therapy, CAR-NK cell therapy, TCR therapy, and dendritic cell vaccines. Exemplary cellular immunotherapies include sipuleucel-T, tisagenlecleucel, lisocabtagene maraleucel, and idecabtagene vicleucel, as well as CTX110, JCAR015, JCAR017, MB-CART19.1, MB-CART20.1, MB- CART2019.1, UniCAR02-T-CD123, BMCA-CAR-T, JNJ-68284528, BNT211, and NK- 92/5.28.z. [0149] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a gene therapy. Gene therapies comprise recombinant nucleic acids administered to a subject or to a subject’s cells ex vivo in order to modify the expression of an endogenous gene or to result in heterologous expression of a protein (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, micro RNA (miRNA) agents, viral or bacterial gene delivery, etc.), as well as gene editing therapies that may or may not comprise a nucleic acid component (e.g., meganucleases, zinc finger nucleases, TAL nucleases, CRISPR/Cas nucleases, etc.), oncolytic viruses, and the like. Non-limiting examples of gene therapies that may be useful in cancer treatment include Gendicine® (rAd-p53), Oncorine® (rAD5-H101), talimogene laherparepvec, Mx-dnG1, ARO-HIF2 (Arrowhead), quaratusugene ozeplasmid (Immunogene), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics), and CTX130 (CRISPR Therapeutics). [0150] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically an agent that modulates an immune checkpoint. Immune checkpoints are a set of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells, etc.). Immune checkpoints engage when proteins on the surface of immune cells recognize and bind to their cognate ligands. The present invention contemplates the use of compounds described herein in combination with agonists of stimulatory or co-stimulatory pathways and/or antagonists of inhibitory pathways. Agonists of stimulatory or co-stimulatory pathways and antagonists of inhibitory pathways may have utility as agents to overcome distinct immune suppressive pathways within the tumor microenvironment, inhibit T regulatory cells, reverse/prevent T cell anergy or exhaustion, trigger innate immune activation and/or inflammation at tumor sites, or combinations thereof. [0151] In some embodiments, one or more of the additional therapeutic agents is an immune checkpoint inhibitor. As used herein, the term “immune checkpoint inhibitor” refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. The terms “immune checkpoint inhibitor”, “checkpoint inhibitor” and “CPI” may be used herein interchangeably. Immune checkpoint inhibitors may antagonize an inhibitory or co-inhibitory immune checkpoint by interfering with receptor -ligand binding and/or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of cancer cells, that can be antagonized include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T-lymphocyte associated antigen 4); TIM-3 (T cell immunoglobulin and mucin domain containing protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); CD276 (B7-H3), PD-L2, Galectin 9, CEACAM-1, CD69, Galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and Killer Inhibitory Receptors, which can be divided into two classes based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Also contemplated are other less well-defined immune checkpoints that have been described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such B7-H3 (also known as CD276) and B7- H4 (also known as B7-S1, B7x and VCTN1)). [See Pardoll, (April 2012) Nature Rev. Cancer 12:252-64]. [0152] In some embodiments, an immune checkpoint inhibitor is a CTLA-4 antagonist. In further embodiments, the CTLA-4 antagonist can be an antagonistic CTLA-4 antibody. Suitable antagonistic CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab or tremelimumab, as well as bispecific antibodies such as MEDI5752 and KN046. [0153] In some embodiments, an immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonistic PD-1 antibody, small molecule or peptide. Suitable antagonistic PD-1 antibodies include, for example, monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, cemiplimab, ezabenlimab, MEDI-0680 (AMP-514; WO2012/145493), nivolumab, pembrolizumab, pidilizumab (CT-011), pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilmab, tislelizumab, toripalimab, and zimberelimab; as well as bi-specific antibodies such as LY3434172. In still further embodiments, the PD-1 antagonist can be a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl (AMP- 224). In certain embodiments, an immune checkpoint inhibitor is zimberelimab. [0154] In some embodiments, an immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist can be an antagonistic PD-L1 antibody. Suitable antagonistic PD-Ll antibodies include, for example, monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and envafolimab as well as bi-specific antibodies such as LY3434172 and KN046. [0155] In some embodiments, an immune checkpoint inhibitor is a TIGIT antagonist. In further embodiments, the TIGIT antagonist can be an antagonistic TIGIT antibody. Suitable antagonistic anti-TIGIT antibodies include monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS 986207, COM902, domvanalimab, EOS-448, etigilimab, IBI- 929, JS006, M6223, ociperlimab, SEA-TGT, tiragolumab, vibostolimab; as well as bi-specific antibodies such as AGEN1777 and AZD2936. In certain embodiments, an immune checkpoint inhibitor is an antagonistic anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In certain embodiments, an immune checkpoint inhibitor is domvanalimab or AB308. [0156] In some embodiments, an immune checkpoint inhibitor is a LAG-3 antagonist. In further embodiments, the LAG-3 antagonist can be an antagonistic LAG-3 antibody. Suitable antagonistic LAG-3 antibodies include, for example, BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO09/44273). [0157] In certain embodiments, an immune checkpoint inhibitor is a B7-H3 antagonist. In further embodiments, the B7-H3 antagonist is an antagonistic B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, enoblituzumab (WO11/109400), omburtumab, DS-7300a, ABBV-155, and SHR-A1811. [0158] In some embodiments, one or more of the additional therapeutic agents activates a stimulatory or co-stimulatory immune checkpoint. Examples of stimulatory or co-stimulatory immune checkpoints (ligands and receptors) include B7-1, B7-2, CD28, 4-1BB (CD137), 4- 1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2. [0159] In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and utomilumab (WO12/32433). In some embodiments, an agent that activates a stimulatory or co- stimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist can be an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS- 986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) and MK-4166 (WO11/028683). In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is an OX40 agonist. In further embodiments, the OX40 agonist can be an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383, MEDI- 6469, MEDI-0562, PF-04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonistic CD40 antibody. In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD27 agonist. In further embodiments, the CD27 agonist can be an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab. [0160] In some embodiments, one or more of the additional therapeutic agents is an agent that inhibits or depletes immune-suppressive immune cells. For example, to inhibit or deplete immunosuppressive macrophages or monocytes the agent may be CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264). [0161] In some embodiments, each additional therapeutic agent can independently be a chemotherapeutic agent, radiation therapy, a hormone therapy, an epigenetic modulator, a targeted agent, an immunotherapeutic agent, a cellular therapy, or a gene therapy. For example, in one embodiment, the present disclosure contemplates the use of the compounds described herein in combination with one or more chemotherapeutic agent and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently radiation therapy, a hormone therapy, a targeted agent, an immunotherapeutic agent, a cellular therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of the compounds described herein in combination with one or more chemotherapeutic agent and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeted agent, an immunotherapeutic agent, or a cellular therapy. In another embodiment, the present disclosure contemplates the use of the compounds described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently radiation therapy, a hormone therapy, a targeted agent, a chemotherapeutic agent, a cellular therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of the compounds described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, or a cellular therapy. In another embodiment, the present disclosure contemplates the use of the compounds described herein in combination with one or more immune checkpoint inhibitors and/or one or more ATP-adenosine axis-targeting agents, and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, a tyrosine kinase inhibitor, an immunotherapeutic agent, or a cellular therapy. In further embodiments of the above (a) the targeted agent can be a PI3K inhibitor, an arginase inhibitor, a HIF-2α inhibitor, an AXL inhibitor, or a PAK4 inhibitor; (b) the immunotherapeutic agent is an ATP-adenosine axis-targeting agent or an immune checkpoint inhibitor; (c) the ATP-adenosine axis-targeting agent is an A2_AR and/or A2_BR antagonist, a CD73 inhibitor, or a CD39 inhibitor; (d) the ATP-adenosine axis-targeting agent is etrumadenant, quemliclustat, or AB598; (e) the tyrosine kinase inhibitor can inhibit one or more of AXL, EGFR, VEGF, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK, and/or FGFR; (f) the tyrosine kinase inhibitor is AB801; (g) the immunotherapeutic agent is an anti- PD-1 antagonist antibody or an anti-TIGIT antagonist antibody; (h) the immunotherapeutic agent is zimberelimab, domvanalimab, or AB308; or (i) any combination thereof. In still further embodiments of the above, the present disclosure contemplates the use of the compounds described herein in combination with domvanalimab, etrumadenant, quemliclustat, zimberelimab, AB801, AB308, AB521, AB598, or any combination thereof. [0162] Selection of the additional therapeutic agent(s) may be informed by current standard of care for a particular cancer and/or mutational status of a subject’s cancer and/or stage of disease. Detailed standard of care guidelines are published, for example, by National Comprehensive Cancer Network (NCCN). See, for instance, NCCN Colon Cancer v3.2021, NCCN Hepatobiliary Cancer v5.2021, NCCN Kidney Cancer, v3.2022, NCCN NSCLC v7.2021, NCCN Pancreatic Adenocarcinoma v2.2021, NCCN Esophageal and Esophagogastric Junction Cancers v4.2021, NCCN Gastric Cancer v5.2021, Cervical Cancer v1.2022, Ovarian Cancer /Fallopian Tube Cancer /Primary Peritoneal Cancer v3.2021. EXPERIMENTAL [0163] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their invention. Additional compounds within the scope of this disclosure may be made using methods based on those illustrated in these examples, or based on other methods known in the art. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be accounted for. [0164] All reactions were performed using a Teflon-coated magnetic stir bar at the indicated temperature and were conducted under an inert atmosphere when stated. All chemicals were used as received. Reactions were monitored by TLC (silica gel 60 with fluorescence F254, visualized with a short wave/long wave UV lamp) and/or LCMS (Agilent 1100 or 1200 series LCMS with UV detection at 254 or 280 nm using a binary solvent system [0.1% formic acid in MeCN/0.1% formic acid in H₂O] using one of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm i.d. × 100 mm], Waters XSelect HSS C18 [3.5 μm, 2.1 mm i.d. × 75 mm]). Flash chromatography was conducted on silica gel using an automated system (CombiFlash RF+ manufactured by Teledyne ISCO), with detection wavelengths of 254 and 280 nm, and optionally equipped with an evaporative light scattering detector. Reverse phase preparative HPLC was conducted on an Agilent 1260 or 1290 Infinity series HPLC. Samples were eluted using a binary solvent system (MeCN/H₂O with an acid modifier as needed – for example 0.1% TFA or 0.1% formic acid) with gradient elution on a Gemini C18110 Å column (21.2 mm i.d. ×x 250 mm) with variable wavelength detection. Final compounds obtained through preparative HPLC were concentrated through lyophilization. All reported yields are isolated yields. All assayed compounds were purified to ≥95% purity as determined by ¹H NMR or LCMS (Agilent 1100 or 1200 series LCMS with UV detection at 254 or 280 nm using a binary solvent system [0.1% formic acid in MeCN/0.1% formic acid in H₂O] using one of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm i.d. × 100 mm], Waters XSelect HSS C18 [3.5 μm, 2.1 mm i.d. × 75 mm]).¹H NMR spectra were recorded on a Varian 400 MHz NMR spectrometer equipped with an Oxford AS400 magnet or a Bruker AVANCE NEO 400 MHz NMR. Chemical shifts (δ) are reported as parts per million (ppm) relative to residual undeuterated solvent as an internal reference. The abbreviations s, br s, d, t, q, dd, dt, ddd, dddt, and m stand for singlet, broad singlet, doublet, triplet, quartet, doublet of doublets, doublet of triplets, doublet of doublet of doublets, and multiplet, respectively. [0165] Unless indicated otherwise, temperature is in degrees Celsius (° C), and pressure is at or near atmospheric. Standard abbreviations are used, including the following: RT = room temperature; min = minute(s); h or hr = hour(s); mg = milligram; g = gram; ml or mL = milliliter; l or L = liter; mM = millimolar; M = molar; N = normal; mol = mole; mmol = millimole; calcd = calculated; sat. = saturated; sol. = solution; psi or psi = pounds per square inch; DCM and CH₂Cl₂ = dichloromethane; CDCl₃ = chloroform-d; THF=tetrahydrofuran; THP = tetrahydropyran; Et₂O = diethyl ether; EtOAc=ethyl acetate; ACN and CH₃CN = acetonitrile; AcOH = acetic acid; NMP = N-methyl-2-pyrrolidone; DMF = N,N- dimethylformamide; DMSO = dimethyl sulfoxide; DMSO-d₆ = dimethyl sulfoxide-d₆; EtOH = ethanol; MeOH = methanol; H₂ = hydrogen gas; N₂ = nitrogen gas; TMSN₃ = trimethylsilyl azide; InBr3 = Indium (III) bromide; MeMgBr = methylmagnesium bromide; Ti(OEt)₄ = Titanium(IV) ethoxide; AlMe3 = trimethylaluminum; Pd/C = palladium on carbon; Pd₂(dba)₃ = Tris(dibenzylideneacetone)dipalladium(0); Pd(PPh3)₄ = Tetrakis(triphenylphosphine) palladium(0); PdCl₂(dppf) = [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II); t- BuBrettPhos Pd G3 = [(2-Di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′- biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; t-BuXPhos-Pd-G3 = [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate; RuPhos Pd G4 = (SP-4-3)-[[2′,6′-Bis(1-methylethoxy)[1,1′- biphenyl]-2-yl]dicyclohexylphosphine-KP](methanesulfonato-KO)[2′-(methylamino-KN)[1,1′- biphenyl]-2-yl-KC]palladium; Pd-PEPPSI-iPent = [1,3-Bis(2,6-Di-3-pentylphenyl)imidazol-2- ylidene](3-chloropyridyl)dichloropalladium(II); PtO₂ = platinum dioxide; Na₂SO₄ = sodium sulfate; MgSO₄ = magnesium sulfate; Cs₂CO₃ = cesium carbonate; NaBH(OAc)₃ = sodium triacetoxyborohydride; NaH = sodium hydride; NaHCO₃ = sodium bicarbonate; NH4Cl = ammonium chloride; Et₃N = triethyl amine; DIPEA = N,N-diisopropylethylamine; NaOH = sodium hydroxide; NaBH4 = sodium borohydride; NaBH(OAc)₃ = Sodium triacetoxyborohydride; KOAc = potassium acetate; K₂CO₃ = potassium carbonate; TFA = trifluoroacetic acid; HCO2NH4 = ammonium formate; CuCl = copper(I) chloride; Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; Brettphos = 2- (Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl; t-BuBrettPhos = 2-(Di-tert-butylphosphino)-2′,4′,6′- triisopropyl-3,6-dimethoxy-1,1′-biphenyl; t-BuXPhos = 2- Di-tert-butylphosphino-2′,4′,6′-triisopropylbipheny; Sphos = 2-Dicyclohexylphosphino-2′,6′- dimethoxybiphenyl; N-Boc (S)-3-hydroxypiperidine = (S)-tert-Butyl 3-hydroxypiperidine-1- carboxylate; MHz = megahertz; Hz = hertz; ppm = parts per million; ESI MS = electrospray ionization mass spectrometry; NMR = nuclear magnetic resonance; LCMS = liquid chromatography-mass spectrometry; HPLC = high pressure liquid chromatography; SFC = supercritical fluid chromatography. Procedure A: Example 1. 2-(2-Fluoro-6-methoxyphenyl)-4-{1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]-1H-pyrazol-4-yl}pyrimidine

[0166] Step 1: To a mixture of 2,4-dichloropyrimidine (2.0 g, 13.4 mmol), (1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester (3.4 g, 12.1 mmol), Na₂CO₃ (2.8 g, 26.8 mmol) and Pd(PPh₃)₄ (0.76 g, 0.67 mmol) was added 50 mL degassed mixture of toluene/H₂O/EtOH in 4:2:1 ratio. The reaction mixture was heated to 70 °C and stirred for 16 h under N₂ atmosphere. The reaction mixture filtered through Celite® and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to get the desired compound (2.9 g, 92%). [0167] Step 2: To a stirred solution of chloropyrimidine derivative obtained from step 1 (2.9 g, 11.0 mmol) and 2-fluoro-6-methoxyphenylboronic acid (2.3 g, 13.4 mmol) in 4:2 degassed dioxane/H₂O (15 ml) was added XPhosPdG2 (865.5 mg, 1.1 mmol), and K₃PO₄ (2.7 g, 22 mmol). The reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 100% EtOAc in hexanes) to get the desired imine intermediate (3.4 g, 86%). [0168] Step 3: To THP intermediate obtained from step 2 (5.74 g, 16.2 mmol) was added 70 mL of 3M HCl in MeOH. The reaction mixture was stirred at RT for 1 h. Solvent was evaporated in vacuo and the crude material was resuspended in 50 mL CH₃CN. The pH was adjusted to ~8-10 using 1M NaOH and the aqueous phase was extracted twice with EtOAc. The organic layers were dried over Na₂SO₄ and concentrated in vacuo) to get the desired pyrazole intermediate-A (Int-A) (4.2 g, 97%). [0169] Step 4: A round-bottom flask was charged with intermediate obtained from step 3 (658 mg, 2.22 mmol) and commercially available 2,6-dichloropyridine 641 g (4.87 mmol). To this flask was added 5 mL of dry NMP and K₂CO₃ (1.18 g, 7.3 mmol) and heated at 100 °C for 20 h under N₂. After cooling to room temperature, the reaction mixture was poured into H₂O and the precipitate was collected by filtration. The precipitate was further washed with 20 mL H₂O and dried to obtain the chloropyridine intermediate (530 mg, 57%) [0170] Step 5: To a solution of the chloropyridine derivative obtained from step 4 (50 mg, 0.13 mmol) and N-methylpiperazine (26 mg, 0.26 mmol) in Dioxane (2 mL) was added RuPhos PdG4 (34 mg, 0.04 mmol) and Cs₂CO₃ (195 mg 0.6 mmol). After degassing for 25 min under N₂ atmosphere, the reaction mixture was heated to 100 °C and stirred for 12 h. After cooling to RT, the reaction mixture was filtered through Celite® and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% MeOH in CH₂Cl₂) to get desired compound in (29 mg, 50%).¹H NMR (400 MHz, DMSO-d₆) δ 9.30 (d, J = 0.8 Hz, 1H), 8.87 (d, J = 5.3 Hz, 1H), 8.43 (d, J = 0.7 Hz, 1H), 7.97 (d, J = 5.4 Hz, 1H), 7.80 (dd, J = 8.4, 7.7 Hz, 1H), 7.46 (td, J = 8.4, 6.9 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.95 – 6.87 (m, 2H), 4.55 (m, 2H), 3.71 (s, 3H), 3.51 (m, 2H), 3.12 (dq, J = 32.5, 11.9, 11.1 Hz, 4H), 2.83 (d, J = 3.5 Hz, 3H). ESI MS [M+H]⁺ for C₂₄H₂₄FN₇O, calcd 446.2, found 446.2. Procedure B: Example 2. 3-(6-{4-[2-(2-Fluoro-6-methoxyphenyl)pyrimidin-4-yl]-1H- 1,2,3-triazol-1-yl}pyridin-2-yl)-8-methyl-3,8-diazabicyclo[3.2.1]octane

[0171] Step 1: To a solution of 2,4-dichloropyrimidine (2.0 g, 13.4 mmol) and triisopropylacetylene (2.7 mL, 12.1 mmol) in 50 mL dry THF was added CuI (383 mg, 2.1 mmol) and PdCl₂(PPh₃)₂ (470 mg, 0.67 mmol) and Et₃N (5.6 mL, 40 mmol). The reaction mixture was degassed for 5 minutes under N₂ atmosphere, heated to 70 °C and stirred for 16 h. The reaction mixture was filtered through Celite®, washed with 1:1 mixture of brine and aqueous NH₄OH and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to get the desired compound (3.0 g, 77%). [0172] Step 2: This step was performed in a similar fashion to step 2 in procedure A. [0173] Step 3: The TIPS-acetylene intermediate obtained from step 2 (3.3 g, 8.6 mmol) was dissolved in 30 mL of dry THF. To this reaction mixture was added 0.6 mL of 1M TBAF in THF and 0.5 mL H₂O. After 30 minutes at RT, 20 mL of saturated NH₄Cl was added. The organic phase was separated and the aqueous phase was extracted twice with 20 mL EtOAc. The organic layers were dried over Na₂SO₄, concentrated in vacuo and purified by flash column chromatography (silica gel; gradient: 0% to 80% EtOAc in hexanes) to get the desired compound (1.6 g, 80%). [0174] Step 4: The acetylene intermediate obtained from step 3 (100 mg, 0.44 mmol) was dissolved in 2 mL of dry t-BuOH/H₂O (4:1). To this reaction mixture was added commercially available chloropyridylazide (102 mg, 0.66 mmol), CuSO₄•5H₂O (12.5 mg, 0.05 mmol) and sodium ascorbate (19.8 mg, 0.1 mmol). The reaction mixture was then stirred at 60 °C for 1 h. After cooling to RT, 5 mL H₂O was added to the reaction mixture and the formed precipitate was collected by filtration. The precipitate was dried and used in the next step without further purification. [0175] Step 5: This step was performed in a similar fashion to step 5 in example 1.¹H NMR (400 MHz, Chloroform-d) δ 9.09 (s, 1H), 8.96 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.38 (td, J = 8.5, 6.6 Hz, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.58 (d, J = 8.4 Hz, 1H), 4.03 (m, 2H), 3.79 (s, 3H), 3.67 (m, 2H), 3.50 (m, 3H), 2.64 (s, 3H), 2.17 (m, 2H), 1.90 (m, 2H). ESI MS [M+H]⁺ for C₂₅H₂₅FN₈O, calcd 473.2, found 473.2. Procedure C: Example 3. 3-(6-{4-[2-(2-Fluoro-6-methoxyphenyl)pyrimidin-4-yl]-1H- pyrazol-1-yl}pyridine-2-carbonyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane

[0176] Step 1: To a solution of intermediate A obtained from step 3, example 1 (270 mg, 1.0 mmol) and 6-chloropicolinic acid (172 mg, 1.0 mmol) in dioxane (5 mL) was added t- BuXPhosPd G₃ (80 g, 0.1 mmol), t-BuXPhos (85 mg, 0.2 mmol) and Cs₂CO₃ (977 mg, 3.0 mmol). After degassing for 1 min under N₂ atmosphere, the reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was quenched with water, extracted with EtOAc. The aqueous layer was acidified with 1N HCl to pH ~ 4, extracted twice with EtOAc and concentrated under reduced pressure. The residue was used in next step without purification. [0177] Step 2: To a stirred solution of compound obtained from step 1 (30 mg, 0.074 mmol), 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (22 mg, 0.11 mmol), DIPEA (0.07 mL, 0.37 mmol) in DMF (3 ml) was added HATU (56 mg, 0.15 mmol). The reaction mixture was heated to 45 °C and stirred for 2 h. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na₂SO₄ and concentrated in vacuo. Purification by reversed phase HPLC (10 to 90% gradient of CH₃CN and H₂O with 0.1% TFA) afforded the title compound.¹H NMR (400 MHz, Methanol-d4) δ 9.28 (s, 1H), 8.81 (d, J = 5.4 Hz, 1H), 8.49 (d, J = 0.7 Hz, 1H), 8.22 – 8.11 (m, 2H), 7.85 (d, J = 5.5 Hz, 1H), 7.71 (dd, J = 6.5, 2.0 Hz, 1H), 7.48 (td, J = 8.4, 6.7 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.92 – 6.82 (m, 1H), 4.71 (d, J = 14.8 Hz, 1H), 4.19 – 4.07 (m, 2H), 3.88 (s, 1H), 3.79 (s, 3H), 3.76 (m, 1H), 3.39 – 3.31 (m, 1H), 2.83 (s, 3H), 2.30 (s, 2H), 2.20 – 2.02 (m, 2H). ESI MS [M+H]⁺ for C₂₇H₂₆FN₇O₂, calcd 500.2, found 500.2. Procedure D: Example 4. (3R)-1-(6-{4-[2-(2-Fluoro-6-methoxyphenyl)pyrimidin-4-yl]- 1H-pyrazol-1-yl}pyridin-2-yl)-N,N-dimethylpyrrolidin-3-amine

[0178] Step 1: To a stirred solution of 2-bromo-6-fluoropyridine (176 mg, 1.0 mmol) in dioxane (5 mL) was added K₃PO₄ (850 mg, 4.0 mmol) and (3R)-N,N-dimethyl-3- pyrrolidinamine (114 mg, 1.0 mmol). The reaction mixture was heated to 100 °C and stirred for 24 h. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 10% MeOH in DCM) to obtain the desired compound (215 mg, 80%). [0179] Step 2: To a solution of intermediate-A obtained from step 3, example 1 (76 mg, 0.28 mmol) and compound obtained from step 1 (76 mg, 0.28 mmol) in dioxane (5 mL) was added t-BuXPhosPd G₃ (22 g, 0.028 mmol), t-BuXPhos (24 mg, 0.056 mmol) and Cs₂CO₃ (273 mg, 0.84 mmol). After degassing for 1 min under N₂ atmosphere, the reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was quenched with water, extracted with EtOAc. Purification by reversed phase HPLC (10 to 90% gradient of CH₃CN and H₂O with 0.1% TFA) afforded the title compound.¹H NMR (400 MHz, Methanol-d₄) δ 9.33 (d, J = 0.8 Hz, 1H), 8.78 (d, J = 5.5 Hz, 1H), 8.41 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 5.5 Hz, 1H), 7.71 (dd, J = 8.3, 7.8 Hz, 1H), 7.47 (td, J = 8.5, 6.7 Hz, 1H), 7.27 (dd, J = 7.8, 0.5 Hz, 1H), 6.98 (dt, J = 8.6, 0.9 Hz, 1H), 6.86 (ddd, J = 9.2, 8.5, 0.8 Hz, 1H), 6.52 (dd, J = 8.3, 0.6 Hz, 1H), 4.11 – 3.98 (m, 2H), 3.87 – 3.70 (m, 5H), 3.55 (dt, J = 10.3, 7.9 Hz, 1H), 2.98 (s, 6H), 2.70 – 2.53 (m, 1H), 2.30 (m, 1H). ESI MS [M+H]⁺ for C₂₅H₂₆FN₇O, calcd 460.3, found 460.3. Procedure E: Example 5. 2'-Fluoro-6'-methoxy-5-[1-(6-{8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl}pyridin-2-yl)-1H-pyrazol-4-yl]-[1,1'-biphenyl]-2- carboxamide

[0180] Step 1: To a stirred solution of 4-bromo-2-chlorobenzonitrile (563 mg, 2.6 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-boronic acid pinacol ester (722 mg, 2.6 mmol) in toluene/EtOH (8/2 mL) was added 2M Na₂CO₃ (4mL) and Pd(PPh₃)₄ (300 mg, 0.26 mmol). After degassing for 1 min under N₂ atmosphere, the reaction mixture was heated to 70 °C and stirred for 16 h. The reaction mixture was quenched with water, extracted with EtOAc (x2). The organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in Hexane) to obtain the desired compound as a white solid (500 mg, 67%). [0181] Step 2: To a solution of 2-fluoro-6-methoxyphenylboronic acid (178 mg, 1.04 mmol) and compound obtained from step 1 (250 mg, 0.87 mmol) in dioxane/water (6/2mL) was added XPhosPd G₃ (74 g, 0.087 mmol) and K₃PO₄ (213 mg, 1.74 mmol). After degassing for 1 min under N₂ atmosphere, the reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was quenched with water, extracted with EtOAc (x2). The organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in Hexane) to obtain the desired compound (265 mg, 80%). [0182] Step 3: To a solution of compound obtained from step 2 (265 mg, 0.70 mmol) in DCM (7mL) was added 4.0M HCl in dioxane (1mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with 1N NaOH, extracted with EtOAc (x2) and concentrated under reduced pressure. The residue was used in next step without purification. [0183] Step 4: To a solution of amine (35 mg, 0.125 mmol) and compound obtained from step 3 (32 mg, 0.125 mmol) in dioxane (5 mL) was added t-BuXPhosPd G₃ (10 g, 0.012 mmol), t- BuXPhos (11 mg, 0.025 mmol) and Cs₂CO₃ (123 mg, 0.375 mmol). After degassing for 1 min under N₂ atmosphere, the reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was quenched with water, extracted with EtOAc. Purification by reversed phase HPLC (10 to 90% gradient of CH₃CN and H₂O with 0.1% TFA) afforded the desired compound. [0184] Step 5: To a solution of compound obtained from step 4 (8 mg, 0.016 mmol) in tBuOH (2 mL) was added KOH (20 mg). After stirring at 80 °C for 16 h, the reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na₂SO₄ and concentrated in vacuo. Purification by reversed phase HPLC (10 to 90% gradient of CH₃CN and H₂O with 0.1% TFA) afforded the title compound.¹H NMR (400 MHz, Methanol- d₄) δ 8.92 (d, J = 0.9 Hz, 1H), 8.14 (d, J = 0.9 Hz, 1H), 7.79 – 7.66 (m, 3H), 7.59 (s, 1H), 7.39 – 7.28 (m, 2H), 6.86 (d, J = 8.5 Hz, 1H), 6.80 (ddd, J = 9.2, 8.3, 1.0 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 4.43 (d, J = 13.3 Hz, 2H), 4.09 (s, 1H), 3.75 (s, 3H), 3.35 – 3.25 (m, 2H), 2.89 (s, 3H), 2.35 – 2.28 (m, 2H), 2.10 (d, J = 8.7 Hz, 2H),. ESI MS [M+H]⁺ for C₂₉H₂₉FN₆O₂, calcd 513.2, found 513.3. Procedure F: Example 6. N-(2-Fluoro-6-methoxyphenyl)-4-[1-(6-{8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl}pyridin-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine

[0185] Step 1: A suspension of chloropyrimidine intermediate from step 1, example 1 (1.06 g, 4.0 mmol), aniline derivative (0.56 g, 4.0 mmol), tBuXPhosPdG₃ (0.32 g, 0.4 mmol), and KOAc (1.18 g, 12.0 mmol) in dioxane (28 mL) was degassed by bubbling with nitrogen for 10 min and heated at 100 ºC overnight under nitrogen atmosphere. The reaction was cooled to room temperature, filtered through a pad of Celite®, concentrated, and purified via column chromatography on silica gel (50-100% EtOAc/Hexane) to afford desired product (0.76 g, 52%). [0186] Step 2: The intermediate from step 2 (0.76 g, 2.0 mmol) was treated with 3M HCl solution in MeOH (6 mL) dropwise. The resulting mixture was stirred at 30 ºC for 1 h and then concentrated under reduced pressure. The residue was dissolved in 10:1 mixture of MeCN- MeOH (25 mL), then basified with 1M NaOH to pH 10 followed by extraction with EtOAc. The organic extract was washed with brine, dried over Na₂SO₄, and concentrated to afford the desired product (0.55 g, 96%). [0187] Step 3: A heterogenous mixture of intermediate from step 3 (285 mg, 1.0 mmol), 2- chloro-6-fluoropyridine (262 mg, 2.0 mmol), K₂CO₃ (276 mg, 2.0 mmol), and NMP (3 mL) was heated at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was diluted with water and then extracted with EtOAc. The organic extract was then concentrated to get crude product (411 mg), which was used for next step without further purification. [0188] Step 4: To a stirred solution of piperazine derivative (66 mg, 0.33 mmol) and crude intermediate from step 3 (119 mg, 0.30 mmol) in dioxane (3 mL) was added RuPhos Pd G₄ (25 mg, 0.03 mmol) and Cs₂CO₃ (489 mg 1.50 mmol). After degassing for 10 min under N₂ atmosphere, the reaction mixture was heated at 100 °C for 15 h. The reaction mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC to obtain the title compound (29 mg, TFA salt).¹H NMR (400 MHz, Methanol-d₄) δ 9.22 (d, J = 0.8 Hz, 1H), 8.31 (d, J = 0.8 Hz, 1H), 8.20 (d, J = 6.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.46 – 7.26 (m, 3H), 6.97 (dt, J = 8.6, 1.1 Hz, 1H), 6.88 (ddd, J = 9.6, 8.6, 1.1 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.48 – 4.37 (m, 2H), 4.18 – 4.08 (m, 2H), 3.87 (s, 3H), 3.38 – 3.30 (m, 2H), 2.92 (s, 3H), 2.42 – 2.31 (m, 2H), 2.15 – 2.05 (m, 2H). ESI MS [M+H]⁺ for C₂₆H₂₈FN₈O, calcd 487.2, found 487.1. Procedure G: Example 7. 2-[(2-Fluoro-6-methylphenyl)amino]-6-{1-[6-(4- methylpiperazin-1-yl)pyridin-2-yl]-1H-pyrazol-4-yl}pyridine-3-carboxamide

[0189] Step 1: A heterogenous mixture of N-methylpiperazine (3.0 g, 30 mmol), 2-chloro-6- fluoropyridine (7.9 g, 60 mmol), K₃PO₄ (25.5g, 120 mmol), and dioxane (90 mL) was heated at 100 °C for 24 h. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite®, concentrated, chromatographed on silica gel (0-10% MeOH/DCM) to afford desired product in quantitative yield. [0190] Step 2: A suspension of intermediate from step 1 (1.27 g, 6.0 mmol), boronate ester (1.39 g, 7.2 mmol), tBuXPhosPdG₃ (0.47 g, 0.6 mmol), tBuXPhos (0.51 g, 1.2 mmol), and Cs₂CO₃ (5.9 g, 18.0 mmol) in dioxane (24 mL) was degassed by bubbling with nitrogen for 10 min and heated at 100 ºC for 3.5 h under nitrogen atmosphere. The reaction was cooled to room temperature, filtered through a pad of Celite®, concentrated, and purified via column chromatography on silica gel (0-10% MeOH/DCM) to afford desired product (1.8 g, 82%). [0191] Step 3: To a solution of dichloronicotinamide (382 mg, 2.0 mmol) and aniline derivative (250 mg, 2.0 mmol) in THF (6 mL) was added 1M LiHMDS in THF (4 mL) dropwise at room temperature. After stirring at room temperature for 2 h, the reaction was heated at 50 °C for an additional 2 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with sat. NH4Cl, brine, and then concentrated. The residue was purified via column chromatography on silica gel (0-50% EtOAc/Hexane) to afford desired product (93 mg, 17%). [0192] Step 4: A suspension of boronate ester intermediate from step 2 (236 mg, 0.64 mmol), aminopyridine intermediate from step 3 (90 mg, 0.32 mmol), XPhosPdG₃ (33 g, 0.04 mmol), and K₃PO₄ (135 mg, 0.64 mmol) in 3:1 mixture of dioxane-H₂O (4 mL) was degassed by bubbling with nitrogen for 10 min and heated at 90 ºC overnight under nitrogen atmosphere. The reaction was cooled to room temperature, filtered through a pad of Celite®, concentrated, and purified via column chromatography on silica gel (0-10% MeOH/DCM) to afford the title compound (98 mg, 63%).¹H NMR (400 MHz, Methanol-d₄) δ 8.66 (d, J = 0.8 Hz, 1H), 8.11 – 7.94 (m, 2H), 7.61 (dd, J = 8.4, 7.7 Hz, 1H), 7.22 – 6.91 (m, 5H), 6.73 – 6.61 (m, 1H), 3.70 – 3.44 (m, 4H), 2.58 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H), 2.28 (s, 3H). ESI MS [M+H]⁺ for C₂₆H₂₈FN₈O, calcd 487.2, found 487.1. Procedure H: Example 8.4-Chloro-6-{4-[2-(2-fluoro-6-methoxyphenyl)pyrimidin-4-yl]- 1H-pyrazol-1-yl}-N-[(1H-imidazol-2-yl)methyl]pyridin-2-amine

[0193] Step 1: SNAr reaction was performed in a similar fashion to step 3, example 6 using intermediate-A in example 1. [0194] Step 2: SNAr reaction was performed by following the same protocol as step 1 and purified by reverse phase preparative HPLC to obtain the title compound (29 mg, TFA salt). ¹H NMR (400 MHz, Methanol-d₄) δ 8.88 – 8.76 (m, 2H), 8.40 (s, 1H), 7.81 – 7.77 (m, 1H), 7.55 – 7.45 (m, 1H), 7.35 – 7.31 (m, 2H), 7.27 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.91 (t, J = 9.0, 1H), 6.70 (s, 1H), 4.85 (s, 2H), 3.81 (s, 3H). ESI MS [M+H]⁺ for C₂₃H₁₉ClFN₈O, calcd 477.1, found 477.0. Procedure I: Example 9. 2-(2-Fluoro-6-methoxyphenyl)-6-(1-{6-[(1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-1H-pyrazol-4-yl)pyridin-3-amine

[0195] Step 1: A heterogenous mixture of (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (4.0 g, 14.5 mmol), 2-chloro-6-fluoropyridine (2.68 g, 20.3 mmol), K₃PO₄ (18.56 g, 87.5 mmol), and dioxane (75 mL) was heated at 100 ºC for 48 h. The reaction was cooled to room temperature and filtered through a small pad of Celite®. The solvent was evaporated under reduced pressure and the crude product was purified by flash column chromatography (silica gel; gradient: 0% to 30% MeOH in CH₂Cl₂) to afford the desired compound (2.75 g, 88%). [0196] Step 2: To a mixture of compound obtained from step 1 (1.05 g, 4.7 mmol), 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 7.21 mmol), tBuXPhos-Pd-G3 (370 mg, 0.721 mmol), tBuXPhos (400 mg, 1.44 mmol), and Cs₂CO₃ (4.6 g, 14.11 mmol) were dissolved in dioxane (20 mL). The flask containing the reaction solution was degassed (20 minutes) and the atmosphere therein was replaced by nitrogen. The reaction solution was stirred at 100 °C for 3 hours in a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel; gradient: 0% to 30% MeOH in CH₂Cl₂) to give the target compound (1.1 g, 63%). [0197] Step 3: A mixture of 2-bromo-6-chloropyridin-3-amine (1.5 g, 7.2 mmol), 2-fluoro-6- methoxyphenylboronic acid (1.23 g, 7.2 mmol), XPhos-Pd-G3 (600 mg, 0.72 mmol), K₃PO₄ (3.05 g, 14.4 mmol), dioxane (12 mL), and H₂O (3 mL) were combined and degassed by bubbling N₂ for 10 min. The mixture was stirred at 100 °C under inert atmosphere for 3 h and then cooled to room temperature. The reaction was filtered through a pad of Celite^® and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in CH₂Cl₂) to get the desired compound (0.4 g, 22%). [0198] Step 4: To a mixture of compound obtained from step 2 (0.132 g, 0.346 mmol), and step 3 (0.08 g, 0.36 mmol), was added SPhos-Pd-G3 (0.054 g, 0.07 mmol), SPhos (0.056 mg, 0.11 mmol), Na₂CO₃ (0.146 g, 1.37 mmol) and dioxane (5 mL). The flask containing the reaction solution was degassed (20 minutes) and the atmosphere therein was replaced by nitrogen. The reaction solution was stirred at 100 °C for 12 hours in a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel; gradient: 0% to 30% MeOH in CH₂Cl₂) to give the target compound (0.12 g, 73%). ¹H NMR (400 MHz, Chloroform-d) δ 8.80 (s, 1H), 8.06 (s, 1H), 7.54 – 7.46 (m, 1H), 7.43 – 7.31 (m, 2H), 7.16 (d, J = 7.7 Hz, 1H), 7.10 (dd, J = 8.3, 0.7 Hz, 1H), 6.86 – 6.80 (m, 2H), 6.18 (dd, J = 8.3, 1.0 Hz, 1H), 4.73 (s, 1H), 3.79 (s, 3H), 3.60 – 3.51 (d, J = 26.1 Hz, 4H), 3.33 (d, J = 9.7 Hz, 1H), 2.98 (d, J = 9.7 Hz, 1H), 2.63 – 2.61(m, 1H), 2.39 (s, 3H), 1.97 – 1.80 (m, 2H). ESI MS [M+H]⁺ for C₂₆H₂₆FN₇O, calcd 471.5, found 472.4. Procedure J: Example 10.2-(2-Fluoro-6-methoxyphenyl)-4-{5-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]-1H-pyrazol-3-yl}pyrimidine

[0199] Step 1: The stannane, 1-methyl-4-[6-(tributylstannyl)-2-pyridinyl]piperazine (0.800 g, 1.71 mmol) was taken in a dry screw cap vial and to this 3,5-dibromo-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazole (0.691 g, 2.2 mmol) followed by Pd(PPh₃)₄ (400 mg, 0.34 mmol) and CuI (130 mg, 0.68 mmol) were added under nitrogen. To this reaction mixture, anhydrous dioxane (10 mL) was added and degassed using nitrogen for 15 min and stirred this reaction mixture at 100 ºC for 20 h. After confirming the completion of the reaction by LCMS, the temperature of the reaction mixture was brought to room temperature and filtered through a small pad of Celite®. The solvent was evaporated under reduced pressure and the crude product was purified by flash column chromatography (silica gel; gradient: 0% to 30% MeOH in CH₂Cl₂) to afford regioisomeric mixture of pyrazole intermediate as an off white solid (530 mg, 76%). [0200] Step 2: The mixture of regioisomers obtained from step 1 (0.530 g, 1.3 mmol), bistributyltin (2.27 g, 3.9 mmol) and Pd(PPh₃)₄ (0.3 g, 0.026 mmol) were heated at 110 ºC in dry toluene for 25 h under argon. The volatiles were removed by rotary evaporation and the crude product was purified by column chromatography (silica gel; gradient: 0% to 30% MeOH in CH₂Cl₂) to provide a regioisomeric mixture of desired compound (0.24 g, 30%). [0201] Step 3: To a solution of stannane derivative obtained from step 2 (0.235 g, 0.38 mmol) and 2,4-dichloropyrimidine (0.085 g, 0.57 mmol) in dioxane (5 mL) was added Pd(PPh₃)₄ (0.09 g, 0.08 mmol) and CuI (0.03 g, 0.15 mmol). After degassing for 15 min under N₂ atmosphere, the reaction mixture was heated to 100 °C and stirred for 20 h. The reaction mixture filtered through Celite® and concentrated under pressure. To this crude intermediate was added TFA (1 mL) dropwise at room temperature. The reaction was stirred for 1 h and then concentrated under reduced pressure. The pH of the aqueous layer was adjusted to 11 using K₂CO₃ and extracted with CH₂Cl₂. The combined organic layers were dried using anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% MeOH in CH₂Cl₂) to get the desired compound (0.04 g, 29%). [0202] Step 4: Pyrazole intermediate from step 3 (0.04 g, 0.11 mmol), 2-fluoro-6- methoxyphenylboronic acid (0.028 g, .16 mmol), XPhos-Pd-G3 (0.016 mg, 0.022 mmol), K₃PO₄ (0.048 g, 0.23 mmol), dioxane (5 mL), and H₂O (1 mL) were combined and degassed by bubbling N₂ for 10 min. The mixture was stirred at 100 ºC under inert atmosphere for 3 h and then cooled to room temperature. The reaction was filtered through a pad of Celite^® and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% MeOH in CH₂Cl₂) to afford the title compound (0.02 g, 40%).¹H NMR (400 MHz, Chloroform-d) δ 8.83 (d, J = 5.3 Hz, 1H), 7.88 (d, J = 5.3 Hz, 1H), 7.49 (dd, J = 8.5, 7.4 Hz, 1H), 7.40 (s, 1H), 7.34 (td, J = 8.4, 6.6 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.84 – 6.73 (m, 2H), 6.58 (d, J = 8.5 Hz, 1H), 5.48 (s, 1H), 3.77 (s, 3H), 3.60 (t, J = 5.1 Hz, 4H), 2.50 (t, J = 5.0 Hz, 4H), 2.33 (s, 3H). ESI MS [M+H]⁺ for C₂₄H₂₄FN₇O, calcd 445.5, found 446.3. Procedure K: Example 11. 3-[(1S)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-(1-{6- [(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-1H-pyrazol-4- yl)pyridin-2-amine

[0203] Step 1: To a solution of bromo derivative (174 mg, 0.3 mmol) and boronic ester obtained in step 2 of example 9 (137 mg, 0.36 mmol) in dioxane (4 mL)/H₂O (1 mL) was added PdG2 Xanthphos (25 mg, 0.01 mmol) and K₃PO₄ (127 mg, 0.2 mmol). After degassing for 10 min with N₂, the reaction mixture was heated to 100 °C and stirred for 4 h. The reaction mixture was cooled down to RT, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to get desired product (46 mg, 62%). [0204] Step 2: To a stirred solution of Boc protected derivative from step 1 (46 mg, 0.06 mmol) in DCM (5 ml) was added TFA and stirred at RT until complete consumption of starting material. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (silica gel; gradient: 0% to 30% MeOH in CH₂Cl₂) to obtain the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (d, J = 0.9 Hz, 1H), 7.94 (d, J = 0.9 Hz, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 8.3, 7.7 Hz, 1H), 7.50 (dd, J = 9.0, 5.0 Hz, 1H), 7.41 (dd, J = 9.0, 8.4 Hz, 1H), 6.98 (dd, J = 7.7, 0.6 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.10 (q, J = 6.6 Hz, 1H), 5.79 (s, 2H), 4.75 (s, 1H), 3.89 – 3.44 (m, 2H), 3.32 (s, 1H), 2.87 (dd, J = 9.5, 2.1 Hz, 1H), 2.29 (s, 3H), 1.90 (d, J = 9.3 Hz, 1H), 1.78 (d, J = 6.7 Hz, 4H). ESI MS [M+H]⁺ for C₂₇H₂₆C_l2FN₇O, calcd 554.2, found 554.4 Procedure L: Example 12.2-(2-Fluoro-6-methoxyphenyl)-4-{1-[4-(4-methylpiperazin-1- yl)pyrimidin-2-yl]-1H-pyrazol-4-yl}pyrimidine

[0205] Step 1: A mixture of 2,4-dichloropyrimidine (0.967 g, 6.49 mmol), 1-methylpiperazine (0.65 g, 6.49 mmol), and triethylamine (6.8 mol) was dissolved in ethanol. The reaction mixture was stirred at reflux for 12 h. After complete consumption of both starting materials, the solvent was removed under reduced pressure. The crude residue was extracted with chloroform and washed with cold water. The chloroform layer was then dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; gradient: 0% to 100% EtOAc in Hexane) to obtain 2-chloro-4-(4- methylpiperazin-1-yl)pyrimidine. [0206] Step 2: To a solution of 2-chloro-4-(4-methylpiperazin-1-yl)pyrimidine. (84 mg, 0.4 mmol) and intermediate-A from example 1 (108 mg, 0.4 mmol) in dioxane was added tBuXphos PdG3 (32 mg, 0.04 mmol), tBuXphos (34 mg, 0.08 mmol) and Cs₂CO₃ (390 mg, 1.2 mmol). After degassing for 10 min with N₂, the reaction mixture was heated to 100 °C and stirred until complete consumption of starting materials. The reaction was filtered through the Celite®, and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 10% MeOH in DCM) to get title compound.¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (d, J = 0.8 Hz, 1H), 8.85 (d, J = 5.4 Hz, 1H), 8.00 (d, J = 5.3 Hz, 1H), 7.72 (dd, J = 8.4, 7.7 Hz, 1H), 7.45 (td, J = 8.5, 6.9 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.07 – 6.96 (m, 1H), 6.91 (ddd, J = 9.2, 8.4, 0.8 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H).3.72 (s, 3H), 3.53 (t, J = 5.1 Hz, 4H), 2.38 (t, J = 5.1 Hz, 4H), 2.18 (s, 3H). ESI MS [M+H]⁺ for C₂₃H₂₄FN₈O, calcd 447.2, found 447.4. Procedure M: Example 13. 2-{4-[2-(2-Fluoro-6-methoxyphenyl)pyrimidin-4-yl]-1H- pyrazol-1-yl}-6-(4-methylpiperazin-1-yl)pyridine-4-carboxamide

[0207] Step 1: A heterogenous mixture of N-methyl piperazine (300 mg, 2.7 mmol), 2,6- dichloro-4-pyridinecarboxamide (1.0 g, 5.24 mmol), K₂CO₃ (1.5 g, 21.0 mmol), and DMF (4 mL) was heated at 70 °C for 12 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic extract was concentrated, and the residue was purified by column chromatography to obtain the desired aminopyridine derivative (456 mg, 45%). [0208] Step 2: To a solution of chloro derivative (51 mg, 0.2 mmol) and pyrazole intermediate (54 mg, 0.2 mmol) in dioxane was added tBuXphos PdG3 (16 mg, 0.02 mmol), tBuXphos (17 mg, 0.04 mmol) and Cs₂CO₃ (195 mg, 0.6 mmol). After degassing for 10 min with N₂, the reaction mixture was heated to 100 °C and stirred until complete consumption of starting materials. The reaction was filtered through a pad of Celite®, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; gradient: 0% to 10% MeOH in DCM) to get the title compound.¹H NMR (400 MHz, DMSO- d₆) δ 9.28 (d, J = 0.8 Hz, 1H), 8.85 (d, J = 5.4 Hz, 1H), 8.44 (d, J = 0.7 Hz, 1H), 8.22 (s, 1H), 8.01 (d, J = 5.3 Hz, 1H), 7.64 (s, 1H), 7.55 (d, J = 0.9 Hz, 1H), 7.45 (td, J = 8.4, 6.9 Hz, 1H), 7.16 (d, J = 1.1 Hz, 1H), 6.98 (dd, J = 8.6, 0.9 Hz, 1H), 6.91 (ddd, J = 9.1, 8.5, 0.9 Hz, 1H), 3.71 (s, 3H), 3.63 (t, J = 5.0 Hz, 4H), 2.44 – 2.37 (m, 4H), 2.21 (s, 3H). ESI MS [M+H]⁺ for C₂₅H₂₆FN₈O, calcd 489.2, found 489.4. Procedure N: Example 14.2-(2-Fluoro-6-methoxyphenyl)-4-{1-[6-(1-methylpiperidin-4- yl)pyridin-2-yl]-1H-pyrazol-4-yl}pyrimidine

[0209] Step 1: To a stirred solution of chloropyridine derivative obtained from step 4, example 1 (200 mg, 0.52 mmol) and commercially available boronate-ester (117 mg, 0.52 mmol) in 4:1 degassed dioxane/H₂O (2 ml) was added XPhosPdG2 (39.3 mg, 0.05 mmol), and K₃PO₄ (220 mg, 1.0 mmol). The reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 100% EtOAc in hexanes) to get the desired olefin intermediate (116 mg, 70%). [0210] Step 2: To a stirred solution of the olefin intermediate obtained from step 1 (100 mg, 0.22 mmol) in 3 mL of 1:1 MeOH/DCM was added 10 mg of 10% Pd-C. The reaction mixture was purged with N₂ and stirred under 1 atm of H₂ at room temperature for 12 h. The reaction mixture was then filtered through a Celite® pad and the filtrate was concentrated to obtain the title compound in quantitative yield. ¹H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 0.7 Hz, 1H), 8.86 (d, J = 5.4 Hz, 1H), 8.49 (d, J = 0.8 Hz, 1H), 8.00 (d, J = 5.3 Hz, 1H), 7.97 – 7.91 (m, 1H), 7.79 (dd, J = 8.2, 0.8 Hz, 1H), 7.49 – 7.42 (m, 1H), 7.30 (dd, J = 7.7, 0.8 Hz, 1H), 6.99 (dd, J = 8.5, 0.9 Hz, 1H), 6.92 (ddd, J = 9.2, 8.4, 0.8 Hz, 1H), 3.72 (s, 3H), 3.01 (d, J = 11.3 Hz, 2H), 2.75 (tt, J = 10.6, 4.4 Hz, 1H), 2.32 (s, 3H), 2.24 (s, 2H), 1.96 – 1.82 (m, 4H). ESI MS [M+H]⁺ for C₂₅H₂₅FN₆O, calcd 445.2, found 445.2. [0211] Examples 15-174 were prepared in an analogous manner as in Procedures A-N described above from the appropriate starting materials and are shown in Table 1. Table 1.

Biological Activity Assay Examples HPK1 Biochemical Assay [0212] Dose-response assays were performed in CORNING® Low Volume 384-well assay plates containing 100 nL of 22 serial 2-fold compound dilutions. Wells containing DMSO alone were used as negative control. A kinase mixture (5 µL) containing 2 nM HPK1in assay buffer (50 mM Hepes pH 7.4, 10 mM MgCl₂, 0.01 % Brij-15, 0.01% bovine serum albumin, and 1 mM dithiothreitol) was added to the assay plates and incubated at 25 °C for 1 hour. Wells without HPK1 were used as positive control. A 5 µL mixture of 10 µM ATP and 0.2 µg/µL myelin binding protein was then added to the wells, resulting in a 10 µL total reaction volume. Following incubation of the assay plates at 25 °C for 1 hour, 10 µL of ADP-Glo reagent was added to the wells and the plates were incubated at 25 °C for a further 40 minutes. Finally, 20 µL of Kinase Detection Reagent was added, and the plates were incubated for another 30 minutes at 25 °C. An Envision plate reader was then used to detect the luminescence signals. IC₅₀ values were determined by fitting the data to a standard 4- parameter logistic equation. The results are summarized in Table 1 above. [0213] Particular embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Upon reading the foregoing, description, variations of the disclosed embodiments may become apparent to individuals working in the art, and it is expected that those skilled artisans may employ such variations as appropriate. Accordingly, it is intended that the disclosure be practiced otherwise than as specifically described herein, and that the disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS What is claimed is: 1. A compound having a structure according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹, X², X³, and X⁴ are each independently N or CR²; each R² is independently H, halo, -NR^2aR^2b, -C₁-C₃ alkyl, -C₁-C₃ haloalkyl, -C₁-C₃ hydroxyalkyl, -C₁-C₃ alkoxy, -S(O)₂-(C₁-C₃ alkyl), -C(O)O(C₁-C₃-alkyl), -C(O)- NR^2aR^2b, -C₁-C₃ alkylene-O-(C₁-C₃-alkyl), 5- to 6-membered heteroaryl, or 5- to 6- membered heterocycloalkyl; wherein said 5- to 6-membered heteroaryl and 5- to 6- membered heterocycloalkyl have 1-3 ring heteroatoms independently selected from N, O, and S; wherein said 5- to 6-membered heteroaryl is optionally substituted with -CN, or -C₁-C₃ alkyl; and wherein R^2a and R^2b are each independently H or -C₁-C₃ alkyl; R¹ is selected from the group consisting of: a) -L¹-R^1a; wherein: i. L¹ is -O-, -O-(C₁-C₃ alkylene)-, -NH-, or -NH-(C₁-C₃ alkylene)-, wherein the alkylene is optionally substituted with one -NH₂; and ii. R^1a is selected from the group consisting of -C₁-C₆ alkyl, -C₁-C₆ hydroxyalkyl, -C₃-C₆-cycloalkyl, 6- to 10-membered aryl, 5- to 8- membered heterocycloalkyl, and 5- to 10-membered heteroaryl; wherein said 5- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl have 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, S and O; wherein said 5- to 8-membered heterocycloalkyl and -C₃-C₆-cycloalkyl groups are optionally fused to phenyl; and wherein said - C₃-C₆-cycloalkyl and 6- to 10-membered aryl groups are optionally substituted with -OH, -C₁-C₃ hydroxyalkyl, or -NH₂; b) 5- to 10-membered heterocycloalkyl having 1-3 ring heteroatoms or ring heteroatom groups independently selected from NR^1b, N, S, and O; wherein said 5- to 10-membered heterocycloalkyl is substituted with 0-3 R^1c; wherein: i. R^1b is H, -C₁-C₃ alkyl, -C₁-C₃ hydroxyalkyl, or –(C₁-C₃ alkylene)-O-(C₁-C₃ alkyl); and ii. each R^1c is independently selected from the group consisting of -OH, - NR^1dR^1e, -C(O)-NR^1dR^1e, -C₁-C₆ alkyl, -C₁-C₆ hydroxyalkyl, -(C₁-C₃ alkylene)-NH₂, and phenyl; wherein R^1d and R^1e are independently H, -C₁- C₃ alkyl, -C₁-C₃ hydroxyalkyl, and -C(O)-(C₁-C₃ alkylene)-N(C₁-C₃ alkyl)₂; and c) –(C₁-C₃ alkylene)-NR^1fR^1g, or -C(O)-NR^1fR^1g; wherein i. R^1f and R^1g are independently H or -C₁-C₃ alkyl; or ii. R^1f and R^1g taken together with the N atom to which they are attached form a 5- to 8-membered heterocycloalkyl having 0-1 additional ring heteroatom or ring heteroatom group selected from NRº, N, O, and S; or R¹ and R² groups together with the adjacent ring atoms to which they are attached form a -C₅- C₇-cycloalkyl, or a 5- to 7-membered heterocycloalkyl having 1-3 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, O, and S; wherein said 5- to 7-membered heterocycloalkyl is optionally substituted with one oxo; and wherein said -C₅-C₇-cycloalkyl is substituted with one 5-membered heterocycloalkyl having 1- 2 ring heteroatoms or ring heteroatom groups independently selected from NRº, N, O, and S; ring Y is

Z¹, Z², Z³, and Z⁴ are each independently CR³ or N; each R³ is independently selected from the group consisting of H, halo, -CN, -C₁-C₃ alkyl, -C₁- C₃ hydroxyalkyl, -C(O)NR^3aR^3b, and -NR^3aR^3b; wherein R^3a and R^3b are independently H, -C₁-C₃ alkyl, or –(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl); R⁴ is phenyl; 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S; or -L²-phenyl, wherein L² is -NH-, -O-(C₁-C₃ alkylene)-, or –NH- (C₁-C₃ alkylene)-; wherein R⁴ is substituted with 0-3 R^4a; or R⁴ and R³ groups together with the adjacent ring atoms to which they are attached form a 5- to 6-membered heterocycloalkyl having from 1-3 ring heteroatoms independently selected from N, O, and S; and said 5- to 6-membered heterocycloalkyl is substituted with 0-3 substituents independently selected from oxo and -C₁-C₃ alkyl; each R^4a is independently selected from the groups consisting of halo, -NH₂, -OH, -C₁-C₃ alkyl, -C₁-C₃ alkoxy, -(C₁-C₃ alkylene)-O-(C₁-C₃ alkyl), -C₁-C₃ haloalkyl, and -C₁-C₃ haloalkoxy; or two R^4a groups together with the adjacent ring atoms to which they are attached form a 5- membered heterocycloalkyl or 5-membered heteroaryl having 1-2 ring N atoms; and each Rº, when present, is independently H or C₁-C₃ alkyl.

2. The compound of claim 1, wherein the compound of Formula I has a structure of Formula Ia:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R³ is H.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R² is H.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R⁴ is phenyl substituted with 1-3 R^4a.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein each R^4a is independently halo, or -C₁-C₃ alkoxy.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein each R^4a is independently Cl, F, or -OCH₃.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R⁴ has the structure:

.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R¹ is

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein ring Y is

11. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

12. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. A method of treating a disease, disorder, or condition, mediated at least in part by HPK1, said method comprising administering an effective amount of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, to a subject in need thereof.

15. The method according to claim 14, wherein the compound or pharmaceutical composition is administered in an effective amount to inhibit HPK1.

16. The method of claim 14 or claim 15, wherein the disease, disorder, or condition is cancer.

17. The method of claim 16, wherein the cancer is a cancer of the prostate, pancreas, cervix, endometrium, uterus, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, white blood cell (including lymphoma, leukemia, and myeloma), gastrointestinal tract (including, esophagus, oropharynx, stomach, small or large intestines, colon, or rectum) breast, muscle, connective tissue, intestine, lung (including smallcell lung carcinoma and non-small-cell lung carcinoma), adrenal gland, thyroid, kidney, or bone; or is glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including Kaposi’s sarcoma), choriocarcinoma, cutaneous basocellular carcinoma, or testicular seminoma, or any combinations thereof.

18. The method of claim 16, wherein the cancer is breast cancer, genitourinary cancer, gastrointestinal cancer, lung cancer, skin cancer, neuroendocrine cancer, head and neck cancer, liver cancer, hematological cancer, or a combination thereof.

19. The method of any one of claims 14-18, further comprising administering at least one additional therapeutic agent to the subject.

20. The method of claim 19, wherein said at least one additional therapeutic agent comprises one or more agents independently selected from the groups consisting of immune checkpoint inhibitors, agents that target the extracellular production of adenosine, inhibitors of HIF (e.g., a HIF-2α inhibitor), tyrosine kinase inhibitors, radiation therapy, and chemotherapeutic agents.

21. The method of claim 20, wherein said at least one additional therapeutic agent comprises one or more immune checkpoint inhibitors that block the activity of at least one of PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT, or CTLA-4.

22. The method of claim 21, wherein said one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

23. The method of claim 22, wherein said immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is selected from the group consisting of avelumab, atezolizumab, balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, durvalumab, emiplimab, envafolimab ezabenlimab, nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilmab, tislelizumab, toripalimab, and zimberelimab.

24. The method of claim 22, wherein said immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is zimberelimab.

25. The method of any one of claims 20-24, wherein said one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of TIGIT.

26. The method of claim 25, wherein said immune checkpoint inhibitor that blocks the activity of TIGIT is selected from AB308, domvanalimab, etigilimab, ociperlimab, tiragolumab, or vibostolimab.

27. The method of claim 25, wherein said immune checkpoint inhibitor is domvanalimab or AB308.

28. The method of any one of claims 19-27, wherein said at least one additional therapeutic agent comprises one or more agents that target the extracellular production of adenosine selected from the group consisting of an A2aR/A2bR antagonist, a CD73 inhibitor, and a CD39 inhibitor.

29. The method of claim 28, wherein the one or more agents that target the extracellular production of adenosine are selected from the group consisting of AB598, etrumadenant, inupadenant, taminadenant, caffeine citrate, imaradenant, ciforadenant, and quemliclustat.

30. The method of claim 28, wherein the one or more agents that target the extracellular production of adenosine are AB598, etrumadenant and/or quemliclustat.

31. The method of any one of claims 19-30, wherein said at least one additional therapeutic agent comprises an inhibitor of HIF-2α selected from the group consisting of belzutifan, ARO- HIF2, PT-2385, and AB521.

32. The method of claim 31, wherein said inhibitor of HIF-2α is AB521.

33. The method of any one of claims 19-32, wherein said at least one additional therapeutic agent comprises a chemotherapeutic agent.

34. The method of claim 33, wherein said chemotherapeutic agent comprises a platinum- based, taxoid-based, or anthracycline-based chemotherapeutic agent.

35. The method of claim 34, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, and paclitaxel.

36. The method of any one of claims 19-35, wherein said at least one additional therapeutic agent comprises radiation therapy.

37. A combination comprising a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

38. The combination of claim 37, wherein said at least one additional therapeutic agent comprises one or more agents independently selected from the groups consisting of immune checkpoint inhibitors, agents that target the extracellular production of adenosine, inhibitors of HIF (e.g., a HIF-2α inhibitor), tyrosine kinase inhibitors, radiation therapy, and chemotherapeutic agents.

39. The combination of claim 38, wherein said at least one additional therapeutic agent comprises one or more immune checkpoint inhibitors that block the activity of at least one of PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT, or CTLA-4.

40. The combination of claim 39, wherein said one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

41. The combination of claim 40, wherein said immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is selected from the group consisting of avelumab, atezolizumab, balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, durvalumab, emiplimab, envafolimab ezabenlimab, nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilmab, tislelizumab, toripalimab, and zimberelimab.

42. The combination of claim 40, wherein said immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is zimberelimab.

43. The combination of any one of claims 37-42, wherein said one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of TIGIT.

44. The combination of claim 43, wherein said immune checkpoint inhibitor that blocks the activity of TIGIT is selected from AB308, domvanalimab, etigilimab, ociperlimab, tiragolumab, or vibostolimab.

45. The combination of claim 43, wherein said immune checkpoint inhibitor is domvanalimab or AB308.

46. The combination of any one of claims 37-45, wherein said at least one additional therapeutic agent comprises one or more agents that target the extracellular production of adenosine selected from the group consisting of an A2aR/A2bR antagonist, a CD73 inhibitor, and a CD39 inhibitor.

47. The combination of claim 46, wherein the one or more agents that target the extracellular production of adenosine are selected from the group consisting of AB598, etrumadenant, inupadenant, taminadenant, caffeine citrate, imaradenant, ciforadenant, and quemliclustat.

48. The combination of claim 46, wherein the one or more agents that target the extracellular production of adenosine are AB598, etrumadenant and/or quemliclustat.

49. The combination of any one of claims 37-48, wherein said at least one additional therapeutic agent comprises an inhibitor of HIF-2a selected from the group consisting of belzutifan, AR0-HIF2, PT-2385, and AB521.

50. The combination of claim 49, wherein said inhibitor of HIF-2α is AB521.

51. The combination of any one of claims 37-50, wherein said at least one additional therapeutic agent comprises a chemotherapeutic agent.

52. The combination of claim 51, wherein said chemotherapeutic agent comprises a platinum-based, taxoid-based, or anthracycline-based chemotherapeutic agent.

53. The combination of claim 52, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, and paclitaxel.

54. The combination of any one of claims 37-53, wherein the at least one additional therapeutic agent comprises radiation therapy.