HEMATOPOIETIC PROGENITOR KINASE 1 INHIBITORS AND THEIR USES

Abstract

Provided herein is a compound represented by structural formula (I-0) or formula (II): or a pharmaceutically acceptable salt or a stereoisomer thereof useful for treating diseases (such as cancer) that are treatable by inhibiting HPK1 activity.

Description

BRIEF DESCRIPTION OF THE INVENTION Compounds of the formulas (1-0), (1-1), (1-2), (I), (II), (II-l), (II-2), or ( Π-2'), and the exemplary compounds (collectively referred to herein as the compounds of the invention), which inhibit HPK1 activity, and their pharmaceutically acceptable salts. In one aspect, the invention provides a compound represented by the structural formula (1-0): RR LfrZn / ZZnZ / q / YIAI or a pharmaceutically acceptable salt or a stereoisomer thereof, characterized in that X is CR2R3 or NR3; A is CR2 or N; R is 8- to 10-membered bicyclic nitrogen-containing heteroaryl or 8- to 10-membered bicyclic nitrogen-containing heterocyclyl optionally substituted with oxo, wherein the nitrogen-containing heteroaryl or nitrogen-containing heterocyclyl represented by R has 1 to 3 heteroatoms. selected from N, O and S, and is optionally substituted with one to four Ra, and wherein R is connected to the pyrimidine ring through a nitrogen ring atom or R is represented by the structure presented below : AA I ^70 / 7707 / D / YIAI Ri is H, deuterium, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O)NRuRi2, alkyl C(O)Ci-6, C(O)OCi-6 alkyl, NRuC(O)Ci-6 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, or 3-7 membered heterocyclyl , wherein the alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl represented by Ri or in the group represented by Ri is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, and NR11R12; either R and Ri, together with the carbon atoms to which they are attached, form a ring that is represented below: where the bonds connect to the pyrimidine ring; each case of R2 is independently H, deuterium, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O) NRuRi2, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRuC(O)Ci-6 alkyl, P(=O)RuRi2, S(=O)2Ru, or S(= O)2NRuRi2, wherein the alkyl, alkenyl, alkynyl or alkoxy represented by R2 or in the group represented by R2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl , C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12; R3 is H, C1-6 alkyl, C(O)Ci-6 alkyl, C3-6 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein alkyl, cycloalkyl or heterocyclyl represented by FU or in the group represented by R3 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3 cycloalkyl -6, 3- to 7-membered heterocyclyl, and NR11R12; each case of Rn and R12 is independently H or C1-6 alkyl, wherein the alkyl represented by Rn or Ri2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl , Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, or Rn and R12, together with the nitrogen atom or phosphorus atom to which they are attached, form 3 to 7 membered heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1 alkyl -4, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each case of Raes independently H, deuterium, halogen, OH, CN, NH2, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O )NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)Ci-6 alkyl, C(O)ORu, NRnC(O)Ri2, S(=O)2Rn, S (=O)2NRnRi2, NRnS(=O)2Ri2, P(=O)RuRi2, C3-6 cycloalkyl, 3- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy , cycloalkyl, heterocyclyl or heteroaryl represented by Rao in the group represented by Ra is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, Ci-4 alkyl, Ci-4 haloalkyl, Ci-alkoxy -4, Ci-4 haloalkoxy, NR11R12, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORn, NRnS(=O)2Ri2, P(= O)RuRi2, S(=O)2Rh, S(=O)2NRnRi2, and 5- to 6-membered heteroaryl; or two Ra, together with the carbon atom(s) to which they are attached, form C3-6 cycloalkyl or 3- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one to three selected substituents regardless of the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each case of Rb is independently H, deuterium, halogen, OH, CN, NH2, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C( O)NRnRi2, C(O)NRnORi2, C(O)NRuS(=O)2Ri2, C(O)Ci-6 alkyl, C(O)ORu, NRnC(O)Ri2, S(=O)2Rn, S(=O)2NRnRi2, NRuS(=O)2Ri2, P(=O)RuRi2, C3-6 cycloalkyl, 3- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl or heteroaryl represented by Rb or in the group represented by Rb is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, NR11R12, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORii, NRnS(=O)2Ri2, P(=O)RuRi2, S(=O)2Rh, RRI / 7707 / 3 / ΥΙΛΙ S(=O)2NRnRi2, and 5- to 6-membered heteroaryl; each instance of Re is independently phenyl, a 5- to 6-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N and O; 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N and O; wherein the phenyl, heterocyclyl or heteroaryl represented by Rc is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, haloalkyl C1-4, C1-4 alkoxy, C1-4 haloalkoxy, NR11R12, C(O)NRnRi2, and P(O)di-Ci-6 alkyl; Ra' is Ci-e alkyl optionally substituted with OH, CN, 5-6 membered heteroaryl, C(O)NRnRi2, C(O)NRnORi2, C(O)NRuS(=O)2Ri2, C(O)ORn , NRhS(=O)2Ri2, P(=O)RiiRi2, S(=O)2Rh, S(=O)2NRiiRi2; m is 0.1, 2, or 3; n is 0.1, 2, 3, or 4. p is 1, 2, or 3; q is 1, 2, or 3; and p + q < 4. In another aspect, the invention provides a compound represented by the structural formula (II): RRI b7n / 77n7 / d / Yl· or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Ai is CR' or N; X is -P(=O)R3'R4·; R' is H, deuterium, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NRuRn-, C(O)NRirRi2-, C alkyl (O)Ci-6, C(O)OCi-6 alkyl, NRuC(O)Ci-6 alkyl, wherein the alkyl, alkenyl, alkynyl or alkoxy represented by R' or in the group represented by R' is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11-R12'; each case of Rr is independently H, deuterium, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12', C(O)NRirRi2 -, alkyl of C(O)Ci-6, alkyl of C(O)OCi-6, NRuC(O)Ci-6 alkyl, C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocyclyl represented by Rr or in the group represented by Rr is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, Ch alkyl, C1-4 haloalkyl, Ch alkoxy, C1-4 haloalkoxy, and NR11R12' ; each case of R2' is independently H, deuterium, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12', C(O) NRirRi2·, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRn€(O)Ci-6 alkyl, phenyl, 5- to 6-membered heteroaryl, C3-7 cycloalkyl, or 3 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl represented by R2' or in the group represented by R2' is optionally substituted with one to three substituents selected independently of the group that consists of halogen, OH, CN, Cm alkyl, C1-4 haloalkyl, C1-4 alkoxy, Ci4 haloalkoxy, and NR11R12'; each Ry and R4' is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, wherein the alkyl, alkenyl or alkynyl represented by R3' or R4 is optionally substituted with one to three selected substituents regardless of the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12'; each case of Rn and R12 is independently H or C1-6 alkyl, wherein the alkyl represented by Rn or Ri2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, Ci-4 alkyl , Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, or R11 and R12, together with the nitrogen atom to which they are attached, form 3 to 7 membered heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, Ci-4 alkyl, haloalkyl Ci-4, Ci-4 alkoxy, or C1-4 haloalkoxy; m' is 0.1, or 2; and n' is 0.1, or 2. Provided herein are pharmaceutical compositions comprising an effective amount of the compounds of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also provided is a combination comprising a therapeutically effective amount of the compounds of the invention or a pharmaceutically acceptable salt thereof and one or more therapeutically active coagents. The present invention further provides a method for inhibiting HPK1 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compounds of the invention, or a pharmaceutically acceptable salt thereof. The present invention further provides a method of treating a subject with a disease or condition as described herein, such as cancer (such as breast cancer, colorectal cancer, lung cancer, ovarian cancer and pancreatic cancer), the method comprising administering to the subject a therapeutically effective amount of the compounds of the invention, or a pharmaceutically acceptable salt thereof. Certain embodiments describe a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use as a medicament, such as a medicament that acts as an HPK1 inhibitor. The present description also provides a use of the compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in any of the methods of the invention described above. In one embodiment, the compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same is provided for use in any method of the invention described herein. In another embodiment, there is provided the use of the compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the manufacture of a medicament for any of the methods of the invention described. DETAILED DESCRIPTION OF THE INVENTION.- General overview! The invention described herein provides HPK1 / MAP4K1 inhibitors, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of modulating (e.g., inhibiting) HPK1 / MAP4K1 activity using the same, said method comprising administering to a patient / subject in need thereof an HPK1 / MAP4K1 inhibitor compound of the invention or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of the invention or pharmaceutically acceptable salts thereof are useful for therapeutic administration to improve, stimulate and / or increase immunity in the treatment of cancer. For example, a method of treating a disease or disorder associated with inhibition of HPK1 interaction may include administering to a patient in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including types of cancer. 2,- Definitions As used herein the term a, an, the and similar terms used in the context of the present invention (especially in the context of the claims) will be construed to cover both the singular and plural forms, except unless otherwise indicated herein or clearly contradicted by the context. Halo as used herein means halogen and includes chlorine, fluoro, bromine and iodine. The term alkyl, used alone or as part of a larger moiety, such as alkoxy or haloalkyl and the like, means a saturated aliphatic straight chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 4 or 1 to 6 carbon atoms, that is, (C1-C4) alkyl or (Ci-Ce) alkyl. Herein, a (C1-C4) alkyl group means a radical having 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, / / -propyl, ¡so-propyl, n-butyl, secbutyl, ¡sobutyl, tere-butyl, / >pentyl, isopentyl, neopentyl, / ^hexyl, etc. The term Ci-e alkylene refers to a divalent fully saturated straight chain or branched monovalent hydrocarbon radical having 1 to 6 carbon atoms. Likewise, the terms C1-4 alkylene, C1-3 alkylene, and C1-2 alkylene should be constructed accordingly. Representative examples of C1-6 alkylene include, but are not limited to, methylene, ethylene, proplene, isopropylene, n-butylene, sec-butylene, / so-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene , and n-hexylene. The term optionally hydroxyl substituted Ci-Ce alkyl refers to CiCe alkyl as defined above that may be substituted with one or more hydroxyl. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, 2,3-dihyroxy-propyl, etc. As used herein, the term Ci-δ dialkylamino refers to a portion of the formula -N(Ra)-Raen where each Ra is a C1-6 alkyl, which may be the same or different, as has been defined above, by analogy to the term monokylamino of Ci-e which refers to a portion of the formula -N(H)-Raen where Ra is a C1-6 alkyl, as defined above. The term alkenyl means straight or branched chain monovalent hydrocarbon radical containing at least one double bond. Alkenyl may be mono- or polyunsaturated and may exist in the E or Z configuration. Unless otherwise specified, an alkenyl group typically has 2 to 6 carbon atoms, i.e. (C2-C6) alkenyl. For example, (C2-Cg)alkenyl means a radical having 2 to 6 carbon atoms in a linear or branched arrangement. The term alkynyl means a straight or branched chain monovalent hydrocarbon radical containing at least one triple bond. Unless otherwise specified, an alkynyl group typically has 2 to 6 carbon atoms, i.e. (C2-C6) alkynyl. By RRI 670 / 7707 / Σ1 / ΥΙΛΙ For example, (C2-C6) alkynyl means a radical having 2 to 6 carbon atoms in a linear or branched arrangement. The term, alkoxy means an alkyl radical linked through an oxygen bonding atom, represented by -O-alkyl. For example, Ci-Ce alkoxy refers to -O-Ci-Ce alkyl, where alkyl is defined herein above, and (C1-C4) alkoxy includes methoxy, ethoxy, propoxy, and butoxy, etc. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, te / r-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Typically, alkoxy groups have about 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. The terms haloalkyl and haloalkoxy mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl and the like. Thus, the term "C1-6 alkyl optionally substituted with halogen" refers to Ci-Ce alkyl as defined above which may be substituted with one or more halogens. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2trifluoroethyl, l-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, and l-bromomethyl-2-bromoethyl. The term cycloalkyl as used herein includes cyclic, bicyclic, tricyclic or polycyclic saturated hydrocarbon groups having 3 to 14 carbons containing the indicated number of rings and carbon atoms (for example, a C3-C14 monocyclic cycloalkyl, C4-C14 bicyclic, C5-C14 tricyclic, or C6-C14 polycyclic). In some embodiments, cycloalkyl is a monocyclic cycloalkyl. Examples of monocyclic cycloalkyl groups include cyclopentyl (C5), cyclohexyl (Ce), cyclopropyl (C3), cyclobutyl (C4), cycloheptyl (C7), and cyclooctyl (Cs). In some embodiments, cycloalkyl is a bicyclic cycloalkyl. Examples of bicyclic cycloalkyls include bicyclo[1.1.0]butane (C4), bicyclo[l.l.l]pentane (Cs), spiro[2.2] pentane (Cs), bicyclo[2.1.0]pentane (Cs), bicyclo[2.1. 1]hexane (Ce), bicyclo[3.3.3]undecane (Cu), decahydronaphthalene (Cío), bicyclo[4.3.2]undecane (Cu), spiro[5.5]undecane (Cu) and bicyclo[4.3.3]dodecane (C12). In some embodiments cycloalkyl is a tricyclic cycloalkyl. Examples of tricyclic cycloalkyls include adamantine (C12). Unless described otherwise, a cycloalkyl has three to six carbon atoms and is monocyclic. The term aryl group used alone or as part of a larger moiety as in araIkyl, aralkoxy, or aryloxyalkyl, means a carbocidic aromatic ring. The term aryl can be used interchangeably with the terms aryl ring, carbocidic aromatic ring, aryl group, and carbocidic aromatic group. Typically, aryl is a monocyclic, bicyclic, or tricyclic aryl having 6 to 20 carbon atoms, typically 6 to 14 ring carbon atoms. Furthermore, the term aryl as used herein refers to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings that are fused together. Examples include phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like. A substituted aryl group is substituted on one or more substitutable ring atoms, which is a ring carbon atom bonded to a hydrogen. A substituted aryl is typically substituted with 1-5 (such as one, two or three) substituents independently selected from the group consisting of: hydroxyl, thiol, cyano, nitro, C1-C4 alkyl, C1-C4 alkenyl, C1 alkynyl -C4, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkenyloxy, C1-C4 alkynyloxy, halogen, C1-C4 alkylcarbonyl, carboxy, C1-C4 alkoxycarbonyl, amino, C1-C4 alkylamino , di-C1-C4 alkylamino, C1-C4 alkylaminocarbonyl, di-C1-C4 alkylaminocarbonyl, C1-C4 alkylcarbonylamino, C1-C4 alkylcarboni, C1-C4 alkylamino, sulfonyl, sulfamoyl, alkylsulfamoyl, and alkylaminosulfonyl of C1-C4, wherein each of the hydrocarbon groups mentioned above (for example, alkyl, alkenyl, alkynyl, alkoxy residues) may be further substituted with one or more independently selected residues in each occurrence of halogen, hydroxyl or alkoxy groups of C1-C4. The term heterocyclyl group or heterocyclic group means a monocyclic, non-aromatic (including partially saturated) ring with preferably 3 to 10 members containing preferably 1 to 4 heteroatoms in the ring, or a polycyclic ring with ring with preferably 7 to 20 members and preferably 1 to 4 heteroatoms in the ring, wherein the polycyclic ring has one or more monocyclic non-aromatic heterocyclic rings fused with one or more aromatic rings or heteroaromatic ring. The heterocyclyl group usually has 3 to 7, 3 to 24, 4 to 16, 5 to 10, or 5 or 6 ring atoms; wherein optionally one to four, especially one or two ring atoms are a heteroatom (the remaining ring atoms are therefore carbon). Each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (eg, NO); oxygen; and sulfur, including sulfoxide and sulfone. The heterocyclic group can be attached to a heteroatom or a carbon atom. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoisdine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane , 1,3-dioxane, 1,3-dithiane, oxathane, thiomorpholine and the like. The heterocyclyl group may include fused or bridged rings, as well as spirocyclic rings. In one embodiment, the heterocyclyl group is a bicyclic ring having a monocyclic non-aromatic heterocyclic ring fused to a phenyl group. The exemplary polycyclic heterocyclic group includes tetrahydroisoquinolinyl (such as l,2,3,4-tetrahydroisoquinolin-7-yl, 2methyl-l,2,3,4-tetrahydroisoquinolin-7-yl, l,2,3,4-tetrahydroisoquinolin-6-yl and 2-methyl-l,2,3,4RRI bZn / ZZnZ / D / YIAI tetrahydroisoquinolin-6-yl), isoindolinyl (such as 2- ethylisoindolin-5-yl, 2-methylisoindolin-5-yl), indolinyl, tetrahydrobenzo[f]oxazepinyl (e.g., 2,3,4,5-tetrahydrobenzo[f][l,4]oxazepin-7-yl). The term heterocycle, heterocyclyl or heterocyclic, whether saturated or partially unsaturated, also refers to rings that are optionally substituted. A substituted heterocyclyl may be a heterocyclyl group independently substituted with 1 to 4, such as one, or two, or three or four substituents. In some embodiments, a heterocyclyl group is a 3 to 14 membered non-aromatic ring system with ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (heterocyclyl from 3 to 14 members). The term heteroaryl, heteroaromatic, heteroaryl ring, heteroaryl group, heteroaromatic ring, and heteroaromatic group, used alone or as part of a larger moiety as in heteroaralkyl or heteroarylalkoxy, refers to groups of aromatic rings having 5 to 14 atoms in the ring selected from carbon and at least one (usually 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur). Heteroaryl includes monocyclic rings and polycyclic rings (e.g., bi- or tri-cyclic) wherein a monocyclic heteroaromatic ring is fused to one or more carbocyclic aromatic or heteroaromatic rings. As such, 5-14 membered heteroaryl includes monocyclic, bicyclic or tricyclic ring systems. Examples of 5-6-membered monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., / V-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5imidazolyl), isoxazolyl (e.g. e.g. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g. 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl ( e.g. 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g. , 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g. 2-triazolyl, -triazolyl), tetrazolyl (for example, tetrazolyl), thienyl (for example, 2-thienyl, 3-thienyl), pyrimidinyl, pyridinyl and pyridazinyl. Typically, the heteroaryl is a 5-10 membered ring system (e.g., 5-6 membered monocycle or 8-10 membered bicycle) or a 5-6 membered ring system. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4 -, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4 -triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, RRI bZn / ZZnZ / D / YIAI benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl or benzisoxazolyl. Therefore, the term heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7 -, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7- , or 8-quinolyyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2 -, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- , or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9 -, or 10-phenatrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenatrolinyl, 1-, 2-, 3-, 4-, 6-, 7- , 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5- , 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3- »]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7Hpyrazino[2,3-c]carbazolyl, 2-, 3-, 5- , 6-, or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5Hpyrido[2,3-d]-o-oxaz nilo, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 5-4H-imidazo[4,5-d]thiazolyl, 3- , 5-, or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-midazo[2,1-b]-thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10-, or ll -4H-pyrido[2,3-c]carbazol¡, 2-, 3-, 8-, or 7-imidazo[l,2-b][l,2,4]triazini¡, 7-benzo[b] ]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6 -, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8 -benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or ll-lH-pyrrolo[l,2b][2]benzazapinyl. Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b] thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. As used herein, the term a pyridine or a pyridyl optionally substituted by hydroxy for example, 2-pyridyl, 3-pyridyl, or 4-pyridyl refers to a respective hydroxy-pyridine or hydroxy-pyridyl and may include its form tautomeric, such as a respective pyridone or pyridonyl. As used herein the term pyridin or pyridyl optionally substituted with oxo, for example 2-pyridyl, 3-pyridyl, or 4-pyridyl, refers to a respective pyridone or pyridonyl and may include its tautomeric form such as a hydroxy-pyridine. or respective hydroxy-pyridyl, provided that said tautomeric form can be obtained. Pyridin or pyridyl optionally substituted with oxo RRI Πζη / Ζζηζ / Σΐ / ΥΙΛΙ may also refer to a respective pyridine-N-oxide or pyridyl-N-oxide. A substituted heteroaryl group is substituted on one or more substituted ring atoms, which is a carbon or nitrogen atom in the ring bonded to a hydrogen. The term bridged bicyclic group refers to a ring system that includes two rings that share at least three adjacent ring atoms. As used herein, many moieties {e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are referred to as substituted or optionally substituted. When a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as available for substitution may be substituted, including one or more substituents. . Where if more than one substituent is present, then each substituent can be selected independently. Such means for substitution are well known in the art and / or taught by the present invention. Said optional substituents may be any of the substituents that are suitable for attaching to the moiety. Where suitable substituents are not specifically listed, exemplary substituents include but are not limited to: (C1-C5) alkyl, (C1-C5) hydroxyalkyl, (C1-C5) haloalkyl, (C1-C5) alkoxy. C5), (C1-C5) haloalkoxy, halogen, hydroxyl, cyano, amino, -CN, -NO2, -ORC1, -NRalRbl, -S(O)¡Ral, -NRalS(O)¡Rbl, -S( O)¡NRalRbl, -C(=O)ORal, -OC(=O)ORal, -C(=S)ORal, -O(C=S)Ral, -C(=O)NRalRbl, -NRalC(= O)Rbl, -C(=S)NRalRbl, -C(=O)Ral, -C(=S)Ral, NRalC(=S)Rbl, -O(C=O)NRalRbl, -NRal(C=S )ORbl, -O(C=S)NRalRbl, -NRal(C=O)NRalRbl, -NRal(C=S)N RalRbi, phenyl, or 5- to 6-membered heteroaryl. Each Raly and each Rbl is independently selected from -H and (C1-C5) alkyl, optionally substituted with hydroxyl or (C1-C3) alkoxy; RC1 is -H, (C1-C5)haloalkyl or (C1-C5)alkyl, wherein (C1-C5)alkyl is optionally substituted with hydroxyl or (C1-C3)alkoxy. The compounds described herein may exist in various tautomeric forms. The term tautomers or tautomeric refers to two or more interconvertible compounds / substituents that result from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). Exemplary tautomerizations include tautomerizations of keto to enol, amide to amide, lactam to lactime, enamine to amine, and enamine a (a different enamine). The teachings herein encompass compounds in the form of tautomers, which include forms not structurally represented. All said isomeric forms of said compounds are expressly included. If a tautomer of a compound is aromatic, this compound is aromatic. Compounds of any of the formulas described above may exhibit one or more RRI Πζη / Ζζηζ / Σΐ / ΥΙΛΙ types of isomerism (e.g. optical, geometric or tautomeric isomerism). Compounds of any of the formulas described above can also be labeled isotopically. Such variation is implied by compounds of any of the formulas described above defined as they are by reference to their structural characteristics and, therefore, within the scope of the present description. Compounds of any of the formulas described above containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. When a compound of any of the formulas described above contains an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (tautomerism) can occur. This may take the form of proton tautomerism in compounds of any of the formulas described above containing, for example, an amino, keto, or oxime group, or so-called valence tautomerism in compounds containing an aromatic moiety. It follows that a single compound can present more than one type of isomerism. Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof. The term geometric isomer refers to compounds that have at least one double bond, where the double bond(s) may exist in cis forms (also referred to as syn or entgegen (E)). or trans (also mentioned as anti or zusammen (Z)) as well as their mixtures. When a described compound is named or represented by the structure without indicating the stereochemistry, the name or structure is understood to encompass one or more of the possible stereoisomers, or geometric isomers, or a mixture of the stereoisomers, or geometric isomers. When a geometric isomer is represented by its name or structure, it should be understood that the named or represented isomer exists to a greater degree than the other isomer, that is, the geometric isomeric purity of the named or represented geometric isomer is greater than 50%, such as as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the geometric isomer mentioned or represented in the mixture by the total weight of all geometric isomers in the mixture. Racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound with a chiral center is named or represented without indicating the stereochemistry of the chiral center, the name or structure is understood to encompass both enantiomerically possible forms (e.g., both enantiomerically pure, enantiomerically enriched, or racemic) of the racemic compound. When a compound with two or more centers ΑΑίΉ7Π / 77Π7 / 3 / ΥΙΛΙ chiral is named or represented without indicating the stereochemistry of the chiral centers, the name or structure being understood to encompass all possible diasteriomeric forms {for example, diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound. Enantiomeric and diastereomeric mixtures can be resolved into their enantiomers or stereoisomers of the component by well-known methods, such as gas chromatography in the chiral phase, high-performance liquid chromatography in the chiral phase, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reactants and catalysts by well-known asymmetric synthetic methods. When a compound is designated by a name or structure indicating a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure ( also known as enantiomerically pure). Optical purity is the weight in the mixture of the named or represented enantiomer divided by the total weight in the mixture of both enantiomers. When the stereochemistry of a described compound is named or represented by the structure, and the named or represented structure encompasses more than one stereoisomer (for example, as in a diastereomeric pair), it should be understood that one of the covered stereoisomers or any mixture of Covered stereoisomers are included. It should further be understood that the stereoisomeric purity of the stereoisomers mentioned or represented is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers covered by the name or structure by the total weight in the mixture of all stereoisomers. Pharmaceutically acceptable salts of compounds of any of the formulas described above may also contain a counterion that is optically active (e.g., dlactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine). The cis / transse isomers. They can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate from a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). . Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of any of the formulas described above contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both diastereoisomers are converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art. Chiral compounds of any of the formulas described above (and their chiral precursors) can be obtained in the enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, which contains 0 to 50% by volume of isopropanol, typically 2% to 20%, and 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. The concentration of the eluate produces the enriched mixture. Chiral chromatography using sub- and supercritical fluids can be used. Methods for chiral chromatography useful in some embodiments of the present disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and the references cited herein). Columns can be obtained from Chiral Technologies, Inc, West Chester, Pa., USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan. It should be emphasized that compounds of any of the formulas described above have been drawn up herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the present description. The present disclosure also includes all pharmaceutically acceptable isotopically labeled compounds of any of the formulas described above wherein one or more atoms are replaced with atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the present description include isotopes of hydrogen, such as 2H and 3H, carbon, such as nC, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically labeled compounds of any of the formulas described above, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose due to their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. 2H, may provide certain therapeutic advantages resulting from increased metabolic stability, for example, increased half-life in vivo or reduced dosage requirements. RR I bZn / ZZnZ / D / YIAI Substitution with positron emission isotopes, such as nC,18F,15O, and 13N, may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of any of the formulas described above generally can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labeled reagent in place of the previously unlabeled reagent used. Pharmaceutically acceptable solvates according to the present disclosure include those where the crystallization solvent may be isotopically substituted, for example, D2O, de-acetone, d6-DMSO. It should be understood that when a compound is represented herein by a structural formula or is designated by a chemical name herein, all other tautomeric forms that may exist for the compound are encompassed by the structural formula. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds such as 2H. Additionally, substitution with deuterium (i.e., 2H or D) may provide certain therapeutic advantages resulting from increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or improvement in therapeutic index, if It is understood that deuterium in this context is considered a substituent of a compound of formula (1-0), (1-1) or (I2). The concentration of said heavier isotope, specifically deuterium, can be defined by the isotopic enrichment factor. The term isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is called deuterium, said compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% incorporation of deuterium into each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), by at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) , or at least 6633.3 (99.5% deuterium incorporation). The compounds of this invention may exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt form. RR LfrZn / ZZnZ / q / YIAI As used herein, the terms "salt" or "salts" refer to an acid addition or base addition salt in a compound of the invention. Salts include in particular pharmaceutically acceptable salts. The term pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are normally not biologically or otherwise undesirable, in many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar to them. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, for example, acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorotheophilionate, citrate , ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isothionate, lactate, lactobionate, laurylsuifate, maiate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate , palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygaiacturonaphe, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid. Organic acids from stem cells can be derived, including, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases, inorganic bases from which the salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table, in In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper. In certain embodiments, suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine. The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of these compounds with AA I ^70 / 7707 / D / YIAI a stoichiometric amount of the appropriate base (such as, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, PA, (1985); and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany 2002). The terms composition and formulation are used interchangeably. A subject is a mammal, preferably a human, but may also be an animal in need of veterinary treatment, for example, companion animals (for example, dogs, cats, and the like), farm animals (for example, cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). As used herein, a subject requires a treatment if said subject would benefit biologically, medically, or in quality of life from said treatment. The term administering, administering, or administration refers to methods that introduce a compound of the invention, or a composition thereof, into or on a subject. These methods include, but are not limited to, intra-articular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be employed with the agents and methods described herein are found in, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, ed. current; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pennsylvania. As used herein, the term inhibit, inhibition or inhibiting refers to the reduction or suppression of a given condition, symptom, disorder or disease, or a significant decrease in the baseline activity of a biological activity or process. The terms treatment, treating and treating refer to reversing, alleviating, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed (i.e., therapeutic treatment). In other embodiments, the treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (i.e., prophylactic treatment) (e.g., in view of a history of symptoms and / or in view of exposure to a pathogen). Treatment can also be continued after RR LfrZn / ZZnZ / q / YIAI symptoms have been resolved, for example, to delay or prevent recurrence. The terms condition, disease, and disorder are used interchangeably. In general, an effective amount of a compound described herein varies depending on various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host that is being treated, and the like, but can nevertheless be determined routinely by one skilled in the art. An effective amount of a compound of the present teachings can be readily determined by one of ordinary skill in the art by routine methods known in the art. The term an effective amount means an amount when administered to the subject that results in beneficial or desired results, including clinical results, for example, inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, an effective amount may be given in a unit dosage form (e.g., 1 mg to about 50 g per day, e.g., 1 mg to about 5 grams per day). The term a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of the activity of an enzyme or protein, or will improve symptoms, alleviate conditions, slow or delay disease progression, or prevent disease, etc. In a non-limiting embodiment, the term a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) alleviate, inhibit, prevent and / or improve at least partially a condition, disorder or disease (i) mediated by HPK1, or (i) associated with HPK1 activity, or (i¡) characterized by (normal or abnormal) HPK1 activity; or (2) reduce or inhibit HPK1 activity; or (3) reduce or inhibit HPK1 expression; or (4) modify HPK1 protein levels. In another non-limiting embodiment, the term a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective for reduce or at least partially inhibit HPK1 activity; or reduce or inhibit HPK1 expression partially or completely. All methods described herein may be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g., such as) provided herein is merely intended to better exemplify the invention and does not pose a limitation on the scope of the invention. invention otherwise claimed. RR I b7n / 77n7 / D / YIAI The general chemical terms used in the above formulas have their usual meanings. As used herein h or hr refers to hour or hours, min refers to minutes or minutes, MCL refers to mantle cell lymphoma, AML refers to acute myeloid leukemia, CML refers to chronic myeloid leukemia, Boc refers to N-tert-butoxycarbonyl, EA refers to ethyl acetate, DCM refers to dichloromethane, DMSO refers to dimethyl sulfoxide, DMA refers to dimethylacetamide, THF refers to tetrahydrofuran, MtBE refers to methyl tert-butyl ether, TEA refers to triethylamine, FBS refers to fetal bovine serum, PBS refers to phosphate-regulated saline, BSA refers to bovine serum albumin, RT refers to room temperature, mpk means milligrams per kilogram, po se refers to per os (oral), qd means once daily dosing, HPLC means high pressure liquid chromatography, q2d means a single dose every 2 days, q2dxl0 means a single dose every 2 days multiplied by 10, VSMC refers to the Vascular smooth muscle cells and XRD refers to X-ray diffraction. As used herein, the term pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, retarding agents. of absorption, salts, preservatives, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, colorants and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except to the extent that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); Therefore, the invention is intended to encompass solvated and unsolvated forms. The term solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be harmless to the recipient, for example, water, ethanol and the like. The term hydrate refers to the complex where the solvent molecule is water. The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition may be formulated for particular routes of administration such as oral administration, parenteral administration and rectal administration, etc. Furthermore, the pharmaceutical compositions of the present invention may be prepared in solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including, without limitation, solutions, suspensions or emulsions). . The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional inert diluents, lubricating agents or pH regulating agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and pH regulating agents. pH, etc. Typically, pharmaceutical compositions are gelatin tablets or capsules comprising the active ingredient together with a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets also c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) disintegrants, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavorings and sweeteners. The tablets may be film coated or enteric coated according to methods known in the art. Compositions suitable for oral administration include an effective amount of a compound of the invention in the form of tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups and elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and said compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, color agents and preservative agents. in order to provide pharmaceutically elegant and pleasant preparations. The tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for tablet manufacture. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated using techniques RR LfrZn / ZZnZ / q / YIAI known to delay disintegration and absorption in the gastrointestinal tract and thus provide long-term sustained action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient It is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Certain injectable compositions are aqueous isotonic solutions or suspensions and suppositories can advantageously be prepared from fatty emulsions or suspensions. Said compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, humectants or emulsifiers, solution promoters, salts to regulate osmotic pressure and / or pH regulators. In addition, they may also contain other therapeutically valuable substances. Such compositions are prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient. Compositions suitable for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to facilitate passage through the host's skin. For example, transdermal devices are in the form of a bandage comprising a backing element, a reservoir containing the compound optionally with carriers, optionally a rate control barrier to deliver the compound from the host's skin at a speed controlled and predetermined over an extended period of time, and means for securing the device to the skin. Compositions suitable for topical application, for example, to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or spray formulations, for example, for delivery by aerosol or the like. Such topical delivery systems will be suitable in particular for dermal application, for example, for the treatment of skin cancer, for example, for prophylactic use in sun creams, lotions, sprays and the like. Therefore, they are particularly suitable for use in topical formulations, including cosmetic ones, well known in the art. These may contain solubilizers, stabilizers, tone-enhancing agents, pH regulators and preservatives. As used herein a topical application also belongs to an inhalation or an intranasal application. They may be conveniently supplied in the form of a dry powder (either alone, as a mixture, for example, a dry mixture with lactose, or a mixed component particle, for example, with phospholipids) from a dry powder inhaler. or a presentation RRLfrZÍVZZnZ / q / YIAI aerosol sprayer from a pressurized container, pump, aerosol, atomizer or nebulizer, with or without the use of a suitable propellant. The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can facilitate the degradation of certain compounds. The anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low humidity conditions. An anhydride pharmaceutical composition can be prepared and stored in a manner that maintains its anhydride nature. Accordingly, anhydride compositions are packaged using materials known to prevent exposure to water, so that they can be included in suitable form kits. Examples of suitable containers include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. The invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate at which the compound of the present invention as an active ingredient will decompose. Such agents, which are mentioned herein as stabilizers include, but are not limited to, antioxidants such as ascorbic acid, pH regulators, or salt pH regulators, etc. 3,- Compounds RRLfrZn / ZZRZ / q / YIAI Described herein are embodiments of a compound having the general structure of Formula (1-0) or (II): In a first embodiment of the invention, there is provided a compound represented by Formula (1-0) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CR2R3 or NR3; A is CR2 or N; R is 8- to 10-membered bicyclic nitrogen-containing heteroaryl or 8- to 10-membered bicyclic nitrogen-containing heterocyclyl optionally substituted with oxo, wherein the nitrogen-containing heteroaryl or nitrogen-containing heterocyclyl represented by R has 1 to 3 heteroatoms. selected from N, O and S, and is optionally replaced with one to four Ra, and where R is connected to the pyrimidine ring through a nitrogen ring atom or R is represented by the structure presented below: Ri is H, deuterium, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O)NRuRi2, alkyl C(O)Ci-6, C(O)OCi-6 alkyl, NRuC(O)Ci-6 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, or 3-7 membered heterocyclyl , wherein the alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl represented by Ri or in the group represented by Ri is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, and NR11R12; either R and Ri, together with the carbon atoms to which they are attached, form a ring that is represented below: each case of R2 is independently H, deuterium, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O) NRuRi2, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRuC(O)Ci-6 alkyl, P(=O)RuRi2, S(=O)2Rn, or S(= O)2NRuRi2, wherein the alkyl, alkenyl, alkynyl or alkoxy represented by R2 or in the group represented by R2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl , C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12; R3 is H, C1-6 alkyl, C(O)Ci-6 alkyl, C3-6 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl represented by R3 or in the group represented by R3 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-cycloalkyl 6, 3- to 7-membered heterocyclyl, and NR11R12; each case of Ru and R12 is independently H or C1-6 alkyl, wherein the alkyl represented by Ru or Ri2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl , Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, or Rn and R12, together with the nitrogen atom or phosphorus atom to which they are attached, form 3 to 7 membered heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1 alkyl -4, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each case of Raes independently H, deuterium, halogen, OH, CN, NH2, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O )NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)Ci-e alkyl, C(O)ORu, NRhC(O)Ri2, S(=O)2Rn, S (=O)2NRnRi2, NRnS(=O)2Ri2, P(=O)RuRi2, C3-6 cycloalkyl, 3- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy , cycloalkyl, heterocyclyl or heteroaryl represented by Rao in the group represented by Ra is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1 alkoxy -4, C1-4 haloalkoxy, NR11R12, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORn, NRiiS(=O)2Ri2, P(= O)RuRi2, S(=O)2Rh, S(=O)2NRhRi2, and 5- to 6-membered heteroaryl; or two Ra, together with the carbon atom(s) to which they are attached, form C3-6 cycloalkyl or 3- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one to three selected substituents regardless of the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each case of Rb is independently H, deuterium, halogen, OH, CN, NH2, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NRuRi2, C( O)NRnRi2, C(O)NRnORi2, C(O)NRuS(=O)2Ri2, C(O)Ci-e alkyl, C(O)ORn, NRhC(O)Ri2, S(=O)2Rn, S(=O)2NRhRi2, NRuS(=O)2Ri2, P(=O)RhRi2, C3-6 cycloalkyl, 3- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl or heteroaryl represented by Rb or in the group represented by Rb is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, NR11R12, C(O)NRiiRi2, C(O)NRiiORi2, C(O)NRiiS(=O)2Ri2, C(O)ORn, NRnS(=O)2Ri2, P(=O)RnRi2, S(=O)2Rh, S(=O)2NRiiRi2, and 5- to 6-membered heteroaryl; each instance of Re is independently phenyl, a 5- to 6-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N and O; 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N and O; wherein the phenyl, heterocyclyl or heteroaryl represented by Rc is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxy, haloalkoxy of C1-4, NR11R12, C(O)NRhRi2, and P(O)di-Ci-6alkyl; RRI 67Ο / 77Ο7 / 3 / ΥΙΛΙ Ra' is Ci-6 alkyl optionally substituted with OH, CN, 5-6 membered heteroaryl, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORii , NRiiS(=O)2Ri2, P(=O)RiiRi2, S(=O)2Rii, S(=O)2NRiiRi2; m is 0.1, 2 or 3; n is 0.1, 2, 3, or 4. p is 1, 2, or 3; q is 1, 2, or 3; and p + q < 4. In a second embodiment of the invention, the compound is represented by the structural formula (1-1): ΑΑίΉ7Π / 77Π7 / 3 / ΥΙΛΙ or a pharmaceutically acceptable salt or stereoisomer thereof, and the remaining variables are as defined in the first embodiment. In a third embodiment of the invention, the compound is represented by the structural formula (1-2): or a pharmaceutically acceptable salt or stereoisomer thereof, and the remaining variables are as defined in the first and / or second embodiments. In a fourth embodiment of the invention, there is provided a compound of formula (1-0), (1-1), or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is AAI b7ñ / 77n7 / 3 / YIA link connects to the pyrimidine ring, and the remaining variables are as defined in the first, second and / or third embodiments. In a fifth embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein each case of Ra is independently H, halogen , OH, CN, C1-4 alkyl, C1-4 alkoxy, NR11R12, C(O)NRuRi2, C(O)NRnORi2, C(O)NRuS(=O)2Ri2, C(O)Ci- alkyl 4, C(O)ORu, NRnC(O)Ci-4 alkyl, NR11S(=O)2R12, S(=O)2Ru, S(=O)2NR11R12, P(=O)RuRi2, C3- cycloalkyl 6, 3- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl or heteroaryl represented by Rao in the group represented by Ra is optionally substituted with one to three substituents selected independently of the group consisting in halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, Ci-4 haloalkoxy, NR11R12, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS (=O)2Ri2, C(O)ORu, NR11S(=O)2R12, P(=O)RuRi2, S(=O)2Ru, S(=O)2NRuRi2, and 5- to 6-membered heteroaryl, and the remaining variables are as defined in the first, second, third and / or fourth modalities. In a sixth embodiment, there is provided a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ri is H, halogen, CN, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, NR11R12, C(O)NRuRi2, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRuC( O)Ci-6, wherein the alkyl, alkenyl or alkoxy represented by Ri or in the group represented by Ri is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, Ci-4 alkyl , C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, and NRuRi2 and the remaining variables are as defined in the first, second, third, fourth and / or fifth embodiments. In a seventh embodiment, there is provided a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each instance of R2 is independently H, halogen, OH, CN, NH2, NO2, C1-4 alkyl, Cu alkoxy, NR11R12, C(O)NRuRi2, C(O)Ci-4 alkyl, C(O)OCi-4 alkyl, NRuC(O)Ci-4, P(=O)RuRi2, S(=O)2Ru, or S(=O)2NRnRi2, wherein the alkyl or alkoxy represented by R2 or in the group represented by R2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12 and the remaining variables are as follows defined in the first, second, third, fourth, fifth and / or sixth modalities. In an eighth embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein R3 is H, C1-alkyl. 6, or C(O)Ci-6 alkyl, wherein the alkyl represented by R3 or in the group represented by R3 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, alkyl of C1-4, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12 and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth and / or seventh embodiments . In a ninth embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein each case of Raes independently H, halogen , OH, CN, Ci-4 alkyl, C3-6 cycloalkyl, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORii, N(Rn) S(=O)2Ri2, S(=O)2Rii, S(=O)2NRhRi2, P(O)RnRi2, or 5- to 6-membered heteroaryl, wherein the alkyl or cycloalkyl represented by Rao in the group represented by Raest optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, NR11R12, C(O) NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORn, NRuS(=O)2Ri2, P(=O)RhRi2, S(=O)2Rh, S(=O )2NRhRi2, and 5- to 6-membered heteroaryl; each case of Ru and Ri2 is independently H or C1-6 alkyl, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh and / or eighth embodiments. In a tenth embodiment, a compound of the formula (1-0), (1-1), or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, where Ri is H, halogen, CN , C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C1-4 alkoxy, or C1-4 haloalkoxy, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth and / or ninth modalities. RR LfrZn / ZZnZ / q / YIAI In an eleventh embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein R is RRLfrZO / ZZnZ / q / YIAI where the 4^^ bond connects to the pyrimidine ring, and n is 0 to 4, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth and / or tenth modalities. In a twelfth embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein R is bond connects to the pyrimidine ring, and n is 0 to 2, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth and / or tenth embodiments. In a thirteenth embodiment, a compound of formula (1-0), (1-1) or (I2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein R is bond connects to the pyrimidine ring, and n is 0 to 2, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and / or tenth embodiments. In a fourteenth embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein each case of Ra is independently H, halogen, C1-4 alkyl, -(CHRaa)kOH, 35 (CHRaa)kCN, -(CHRaa)kC(O)ORn, -(CHRaa)kC(O)NRnRi2, -(CHRaa)kC(O)NRnORi2, -(CHRaa)kS(=O)2Rn, -(CHRaa)kC(O)NRnS (=O)2Ri2, -(CHRaa)kS(=O)2NRnRi2, -(CHRaa)kNRnS(=O)2Ri2, -(CHRaa)k-5- to 6-membered heteroaryl, or -(CHRaa)kP(=O)RnRi2; Raa is independently H or C1-3 alkyl optionally substituted with halogen; Ru and R12 are independently H or C1-4 alkyl; and k is 0 or 1, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth and / or thirteenth embodiments. RRI bZn / ZZnZ / D / YIAI In a fifteenth embodiment, a compound of the formula (1-0), (1-1), or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, where Ri is H, F, Cl , CN, or CF3, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth and / or fourteenth embodiments. In a sixteenth embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein R is the bond connects with the pyrimidine ring, and n is 0 to 4, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth and / or fifteenth modalities. In a seventeenth embodiment, a compound of formula (1-0), (1-1) or (I2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein τ JO R®1' R esRai, where the bond connects with the pyrimidine ring, Raí is independently H, C1-4 alkyl, or C1-4 hydroxyalkyl; Raí' is independently -(CHRaa)kOH, -(CHRaa)kCN, -(CHRaa)kC(O)ORu, (CHRaa)kS(=O)2Rn, -(CHRaa)kC(O)NRnRi2, -(CHRaa)kC(O)NRnORi2, -(CHRaa)kC(O)NRiiS(=O)2Ri2, -(CHRaa)kS(=O)2NRnRi2, -(CHRaa)kNRuS(=O)2Ri2, -(CHRaa)k-5- to 6-membered heteroaryl, or -(CHRaa)kP(=O)RuR12; Raa is independently H or C1-3 alkyl optionally substituted with halogen; Ra is independently H, F, or Cl; Rn and R12 are independently H or C1-4 alkyl; k is 0 or 1, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth and / or tenth embodiments. In an eighteenth embodiment, a compound of formula (1-0), (1-1), or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein Raí is independently H, CH3, or CH2OH; Raí' is independently -(CHRaa)kOH, -(CHRaa)kCN, -(CHRaa)kC(O)ORn, (CHRaa)kS(=O)2Rn,-(CHRaa)kC(O)NRnRi2, -(CHRaa) kC(O)NRnORi2, -(CHRaa)kC(O)NRiiS(=O)2Ri2, -(CHRaa)kS(=O)2NRnRi2, -(CHRaa)kNRiiS(=O)2Ri2, -(CHRaa)k-tetrazol, O -(CHRaa)kP(=O)RllR12; Raa is independently H, CH3, or CF3; Ru and R12 are independently H or C1-2 alkyl; and k is 0 or 1, and the remaining variables are as defined in the seventeenth embodiment. In a nineteenth embodiment of the invention, a compound of formula (1-0), (1-1), or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein each case of Ra is independently H or F, and the remaining variables are as defined in the eighteenth embodiment. In a twentieth embodiment of the invention, there is provided a compound of the formula (ΙΟ), (1-1), or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ri is Cl, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth and / or nineteenth modes. In a twenty-first embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein R and R1, together with the atoms of carbon to which they are attached, they form a ring represented below: RRI b7n / 77n7 / D / YIAI where the bonds connect to the pyrimidine ring and the remaining variables are as defined in the first, second and / or third embodiments. In a twenty-second embodiment, there is provided a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each instance of Rb is independently H, halogen, OH, CN, NH2, COOH, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 hydroxyalkoxy, NR11R12, C( O)NRnRi2, C(O)Ci-4 alkyl, C(O)OCi-4 alkyl, C(O)NRnORi2, S(=O)2Rn, S(=O)2NR11R12, NRn(S=O) 2Ri2, C(O)NRnS(=O)2Ri2, P(=O)RnRi2, 5- to 6-membered heteroaryl, or NRuC(O)Ci-4 alkyl; and each case of Re is phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, haloC1-4 alkoxy, C1-4, C1-4 haloalkoxy, NR11R12, C(O)NRuRi2, and P(=O)di-Ci-6 alkyl, and the remaining variables are as defined in the first, second, third and / or twenty-first modalities. In a twenty-third embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein R and R1, together with the atoms of carbon to which they are attached, they form a ring represented below: where the RR LfrZn / ZZnZ / q / YIAI bonds connect to the pyrimidine ring, and the remaining variables are as defined in the first, second, third, twenty-first and / or twenty-second embodiments. In a twenty-fourth embodiment, there is provided a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each instance of Rb is independently H, halogen, CN, COOH, C1-2 alkyl, or C1-2 haloalkyl; each case of Re is phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, haloalkoxy of C1-4, NR11R12, C(O)NRuRi2, and P(=O)di-Ci-6 alkyl, and each case of Ru and R12 is independently H or C1-6 alkyl, and the remaining variables are as follows defined in the first, second, third, twenty-first, twenty-second and / or twenty-third modalities. In a twenty-fifth embodiment, there is provided a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each instance of Rb is independently H, CN, or COOH; and each case of Re is phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of C1-4 alkyl, C(O)N(CH3)2, and P(= O)(CH3)2and the remaining variables are as defined in the first, second, third, twenty-first, twenty-second, twenty-third and / or twenty-fourth embodiments. In a twenty-sixth embodiment, there is provided a compound of the formula (1-0), (1-1), or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0 or 1, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth and / or twenty-fifth modalities. In a twenty-seventh embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twentieth fourth, twenty-fifth and / or twenty-sixth modalities. In a twenty-eighth embodiment, a compound of formula (1-0), (1-1) or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein R2 is H, halogen , C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy; and R3 is H, C1-6 alkyl, C1-6 hydroxyalkyl, or COCH2NR11R12, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth and / or twenty-seventh modalities. In a twenty-ninth embodiment, there is provided a compound of the formula (1-0), (1-1), or (1-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each instance of R2 is H , F, Cl, or OCH3; and R3 is H or C1-4 alkyl, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth , sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh and / or twenty-eighth modalities. In a thirtieth embodiment of the invention, a compound represented by Formula (II) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, RR I b7ñ / 77n7 / 3 / YIA X is -P(=O)R3'Ri'; R' is H, deuterium, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NRirRu-, C(O)NRnRi2', C alkyl (O)Ci-6, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, wherein the alkyl, alkenyl, alkynyl or alkoxy represented by R' or in the group represented by R' is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12'; each case of Rr is independently H, deuterium, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12', C(O)NRnRi2 ', alkyl of C(O)Ci-6, alkyl of C(O)OCi-6, NRuC(O)Ci-6 alkyl, C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocyclyl represented by Rr or in the group represented by Rr is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, Ci-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy , and NRirRiz; each case of R2' is independently H, deuterium, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12', C(O) NRirRi2·, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, phenyl, 5- to 6-membered heteroaryl, C3-7 cycloalkyl, or heterocyclyl 3 to 7 members, wherein the alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl represented by R2- or in the group represented by R2' is optionally substituted with one to three substituents selected independently of the group consisting in halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, Ci4 haloalkoxy, and NR11R12'; each R3' and R4' is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, wherein the alkyl, alkenyl or alkynyl represented by R3' or R4' is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12; each case of Ru and R12 is independently H or C1-6 alkyl, wherein the alkyl represented by Ru or Ri2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl , Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, or Rn and R12, together with the nitrogen atom to which they are attached, form 3 to 7 membered heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, haloalkyl C1-4, C1-4 alkoxy, or C1-4 haloalkoxy; m' is 0.1, or 2; and n' is 0.1, or 2. In a thirty-first embodiment of the invention, the compound of Formula (II) is represented by the structural formula (II-l): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R' is H, halogen, NR11R12', or C1-6 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, alkyl of Ci-4, Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12' and the remaining variables are as defined in the thirtieth embodiment. In a thirty-second embodiment, the compound of formula (II) or (II-l), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3' and R4' are independently H or C1-6 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NRn-Ri2, and the remaining variables are as They are defined in the thirtieth and / or thirty-first modality. In a thirty-third embodiment, the compound of formula (II) or (II-l), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each case of Rr is independently H, halogen, C1-6 alkyl, alkenyl C2-6, C2-6 alkynyl, C3-7 cycloalkyl, or 3 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl represented by Rr is optionally substituted with one to three independently selected substituents from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12'; each case of R2' is independently H, halogen, OH, NO2, C1-6 alkyl, C1-6 alkoxy, NR11R12', C(O)NRuRi2', C(O)Ci-6 alkyl, C alkyl (O)OCi-6, NRuC(O)Ci-6 alkyl, 5- to 6-membered heteroaryl or 3- to 7-membered heterocyclyl, wherein alkyl, alkoxy, heteroaryl or heterocyclyl represented by R2· or in the group represented by R2· is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, Ci4 haloalkoxy, and NRirRi2' and the remaining variables are as defined in the thirtieth, thirty-first and / or thirty-second embodiments. In a thirty-fourth embodiment, the compound of formula (II) (II-l) is represented by the structural formula (11-2)(11-29= RR LfrZn / ZZnZ / q / YIAI X (II-2), or , thirty-second and / or thirty-third modalities. In a thirty-fifth embodiment, the compound of formula (II), (II-l), (Π-2) or (11-29, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein each case R2· is independently H, halogen, OH, Ci-4 alkyl optionally substituted with halogen or OH or NR11R12·, Ci-4 alkoxy, C(O)OCi-6 alkyl, C(O)NRnRi2', NR11R12', NRn-alkyl of C(O)Ci-6, 5-6 membered heterocyclyl, or 5-6 membered heteroaryl; and each case of Rr is independently H or C1-4 alkyl, and the remaining variables are as defined in the thirtieth , thirty-first, thirty-second, thirty-third and / or thirty-fourth modalities. In a thirty-sixth embodiment, the compound of formula (II), (II-l), (Π-2) or (11-29, ° a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Rs- and R4· are independently Ci-β alkyl; and each case of Rz is independently H, halogen, OH, C1-4 alkyl optionally substituted with halogen or OH or NR11R12', C1-4 alkoxy, C(O)OCi-alkyl 4, C(O)NRuRi2', NRirRi2', NHC(O)Ci-6 alkyl, pyrrolidinyl, pyrrolidin-2-one, oxazole, where each case of Rn- and Ri2 is independently H or C1-4 alkyl , and the remaining variables are as defined in the thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth and / or thirty-fifth embodiments. In a thirty-seventh embodiment, the compound of formula (II), (II-l), (Π-2) or (11-29, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is -P(O )(CH3)2 and each case of R2' is independently H, F, Cl, OH, CH3, NH2, or NHCOCH3, and the remaining variables are as defined in the thirtieth, thirty-first, thirty-second, thirty-third, thirtieth fourth, thirty-fifth and / or thirty-sixth modalities. .- A compound represented by the structural formula (I): or a pharmaceutically acceptable salt thereof, wherein A is CR2o Ν; R is 8- to 10-membered bicyclic nitrogen-containing heteroaryl or 8- to 10-membered bicyclic nitrogen-containing heterocyclyl optionally substituted with oxo, wherein the nitrogen-containing heteroaryl or nitrogen-containing heterocyclyl represented by R has 1 to 3 heteroatoms. selected from N, O and S, and is optionally substituted with one to four Ra; Ri is H, deuterium, halogen, OH, CN, NH2, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, NRnRi2, C(O)NRuRi2, alkyl C(O)Ci-6, C(O)OCi-6 alkyl, NRuC(O)Ci-6 alkyl, phenyl, 5- to 6-membered heteroaryl, C3-6 cycloalkyl, or 3- to 7-membered heterocyclyl , wherein the alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl represented by Ri or in the group represented by Ri is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN , C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NRuRi2; either R and Ri, together with the carbon atoms to which they are attached, form a ring that is represented below: they connect with the pyrimidine ring; R2es H, deuterium, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NRuRi2, C(O)NRuRi2, C alkyl (O)Ci-6, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, P(=O)RuRi2, S(=O)2Ru, or S(=O)2NRuRi2, in wherein the alkyl, alkenyl, alkynyl or alkoxy represented by R2o in the group represented by R2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, haloC1-4 alkyl , C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12; R3 is H, C1-6 alkyl, C(O)Ci-e alkyl, C3-6 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl represented by R3 or in the group represented by R3 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, cycloalkyl C3-6, 3- to 7-membered heterocyclyl, and NR11R12; each case of Rn and R12 is independently H or C1-6 alkyl, wherein the alkyl represented by Ru or Ri2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-alkyl 4, Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, or Rn and R12, together with the nitrogen atom or the phosphorus atom to which they are attached, form 3 to 7 membered heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, alkyl of C1-4, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each case of Raes independently H, deuterium, halogen, OH, CN, NH2, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O )NRnRi2, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, P(=O)RnRi2, -S(=O)2Rh, or - S(=O)2NRnRi2, C3-6 cycloalkyl, or 3 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl or alkoxy, cycloalkyl or heterocyclyl represented by Rao in the group represented by Ra is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12; or two Ra, together with the carbon atom to which they are attached, form C3-6 cycloalkyl or 3- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each case of Rb is independently H, deuterium, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O) NRuRi2, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, or NRuC(O)Ci-6 alkyl, wherein the alkyl, alkenyl, alkynyl or alkoxy represented by Rb or in the group represented by Rb is RRLfrZn / ZZRZ / q / YIAI 2.optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, Cu haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12; Re is phenyl, a 5- to 6-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N and O; 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N and O; wherein the phenyl, heterocyclyl or heteroaryl represented by Rc is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxy, haloalkoxy of C1-4, NR11R12, C(O)NRnRi2, and P(O)di-Ci-6 alkyl; and m is 0.1, 2 or 3. The compound of paragraph 1, or a pharmaceutically acceptable salt thereof, wherein R AAI ^70 / 7707 / D / YIAI pyrimidine, and n is 0 to 4. The compound of paragraph 1 or 2 or a pharmaceutically acceptable salt thereof, wherein each case of Ra is independently H, halogen, OH, NH2, CN, COOH, C1-4 alkyl, C1-4 haloalkyl, C1-hydroxyalkyl 4, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 hydroxyalkoxy, NR11R12, C(O)NRuRi2, C(O)Ci-4 alkyl, C(O)OCi-4 alkyl, NRhC(O)Ci-4, -P(=O)RuRi2, -S(=O)2Ru, -S(=O)2NRuRi2, C3-6 cycloalkyl, or 3- to 7-membered heterocyclyl, or two Ra, together with the carbon atom to which they are attached, they form C3-6 cycloalkyl or 3- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH , CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. 4.RRI ^70 / 7707 / 3 / Yl· The compound of any of paragraphs 1 to 3, or a pharmaceutically acceptable salt thereof, where Ri is H, halogen, C1-6 alkyl, Ci-e alkoxy, C2-6 alkenyl, 5.6.NR11R12, C(O)NRnRi2, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRuC(O)Ci-6 alkyl, wherein the alkyl, alkenyl or alkoxy represented by Ri or in the group represented by Ri is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, haloalkoxy C1-4, and NR11R12. The compound of any of paragraphs 1 to 7, or a pharmaceutically acceptable salt thereof, wherein each instance of Ra is independently H, halo, OH, C1-4 alkyl, COOH, C(O)NRnRi2, or -P (O)RuRi2, where each case of Rn and R12 is independently H or C1-6 alkyl. The compound of any of paragraphs 1 to 5, or a pharmaceutically acceptable salt thereof, where Ri is H, halogen, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C1-4 alkoxy , or C1-4 haloalkoxy. 7.The compound of any of paragraphs 1 to 6, or a pharmaceutically acceptable salt of the where the bond connects to the pyrimidine ring, and n is 0 to 2. The compound of any of paragraphs 1 to 7, or a pharmaceutically acceptable salt of the RR I bZn / ZZnZ / D / YIA with the pyrimidine ring, and n is 0 to 2. .- The compound of any of paragraphs 1 to 8, or a pharmaceutically acceptable salt thereof, wherein each case of Rais independently H, F, Cl, C1-4 alkyl, COOH, CONH2, C(O)N( CH3)2, or -P(O)(CH3)2. .- The compound of any of paragraphs 1 to 9, or a pharmaceutically acceptable salt thereof, where Ri is H, Cl, or CF3. .- The compound of paragraph 1, or a pharmaceutically acceptable salt thereof, wherein R and R1, together with the carbon atoms to which they are attached, form a ring represented below: They connect with the pyrimidine ring. .- The compound of paragraph 1 or 11 or a pharmaceutically acceptable salt thereof, wherein each instance of Rb is independently H, halogen, OH, NH2, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl , C1-4 alkoxy, C1-4 haloalkoxy, C1-4 hydroxyalkoxy, NR11R12, C(O)NRnRi2, C(O)Ci-4 alkyl, C(O)OCi-4 alkyl, or NRnC(O)Ci-4; and each case of Re is phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, haloC1-4 alkoxy C1-4, C1-4 haloalkoxy, NR11R12, C(O)NRnRi2, and -P(O)di-Ci-6 alkyl. .- The compound of any of paragraphs 1, 11 and 12, or a pharmaceutically acceptable salt thereof, wherein each case of Rb is independently H, halogen, C1-2 alkyl, C1-2 haloalkyl; and each case of Rces phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, haloalkoxy from C1-4, NR11R12, C(O)NRuRi2, and - P(O)di-Ci-6 alkyl, and > π N C 47 * c N each case of Rn and R12 is independently H or C1-6 alkyl. Yo C£ .- The compound of any of paragraphs 1 and 11 to 13, or a pharmaceutically acceptable salt thereof, wherein each instance of Rb is independently H; and each case of Rces phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of C1-4 alkyl, C(O)N(CH3)2, and -P(O )(CH3)2. .- The compound of any of paragraphs 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R2 is independently H, halogen, OH, CN, NH2, NO2, C1-4 alkyl, C1-4 alkoxy, NR11R12, C(O)NRnRi2, C(O)Ci-4 alkyl, C(O)OCi-4 alkyl, NRuC(O)Ci-4 alkyl, P(=O)RnRi2, S(=O) 2Rh, or S(=O)2NRuRi2, wherein the alkyl or alkoxy represented by R2 or in the group represented by R2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, alkyl of C1-4, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12; and m is 0 or 1. .- The compound of any of paragraphs 1 to 15, or a pharmaceutically acceptable salt .- The compound of any of paragraphs 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each case of R2 is H, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy; and R3 is H, C1-6 alkyl, hydroxy C1-6 alkyl, or COCH2NR11R12 where each instance of Rn and R12 is independently H or C1-6 alkyl. .- The compound of any of paragraphs 1 to 17, or a pharmaceutically acceptable salt thereof, wherein each case of R2 is H, Cl, or OCH3; and R3 is H, C1-4 alkyl, C1-4 hydroxyalkyl, or COCH2N(CH3)2. .- A compound represented by the structural formula (II): or a pharmaceutically acceptable salt thereof, wherein Ai is CR or N; X is -P(=O)R3R4· or -S(O)2NR5R6·; R' is H, deuterium, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12·, C(O)NRnRi2·, C alkyl (O)Ci-6, C(O)OCi-6 alkyl, NRirC(O)Ci-6 alkyl, wherein the alkyl, alkenyl, alkynyl or alkoxy represented by R' or in the group represented by R' is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12·; each case of Rr is independently H, deuterium, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12·, C(O)NRnRi2 ·, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein the alkyl , alkenyl, alkynyl, alkoxy, cycloalkyl or heterocyclyl represented by Rr or in the group represented by Rr is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, haloalkyl C1-4, C1-4 alkoxy, Ci-4 haloalkoxy, and NRirRi2·; each case of Rr is independently H, deuterium, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12', C(O)NRnRi2 ', C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, phenyl, 5- to 6-membered heteroaryl, C3-7 cycloalkyl, or 3 to 7 members, wherein the alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl represented by R2' or in the group represented by R2' is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NRnRir; each R3' and R4· is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, wherein the alkyl, alkenyl or alkynyl represented by R3' or R4- is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NRirRi2·; each Rs- and Re· is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, wherein the alkyl, alkenyl or alkynyl represented by Rs· or Re· is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NRirRi2·; either Rs and Together with the nitrogen atom to which they are attached, they form heterocyclyl of 7-membered ΑΑίΉ7Π / 77Π7 / 3 / ΥΙΛΙ optionally substituted with one to three substituents independently selected from the group consisting of halogen, - OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each case of Ru and R12 is independently H or C1-6 alkyl, wherein the alkyl represented by Ru or Ri2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-alkyl 4, Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, or Ru and R12, together with the nitrogen atom to which they are attached, form 3 to 7 membered heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, haloalkyl C1-4, C1-4 alkoxy, or C1-4 haloalkoxy; m' is 0.1, or 2; and n' is 0.1, or 2. 20.- The compound of paragraph 19, where the compound is represented by the structural formula (II-l): RR I b7n / 77n7 / D / YIAI or a pharmaceutically acceptable salt thereof, wherein Ai is CR' oN;y R' is H, halogen, NR11R12', or C1-6alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4alkyl, haloC1-4alkyl, alkoxy C1-4, C1-4 haloalkoxy, and NR11R12'. .- The compound of paragraph 19 or 20 or a pharmaceutically acceptable salt thereof, wherein X is -P(=O)R3'R4O -S(O)2NR5'R6'; each R3' and R4' is independently H or C1-6 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, haloC1-4 alkoxy, C1-4, C1-4 haloalkoxy, and NR11R12; and each Rs' and Re- are independently H or C1-6 alkyl, or Rs and Together with the nitrogen atom to which they are attached, they form 7-membered heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, C1-haloalkyl 4, C1-4 alkoxy, or C1-4 haloalkoxy. .- The compound of any of paragraphs 19 to 21, or a pharmaceutically acceptable salt thereof, wherein each case of Rr is independently H, halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C3-7 cycloalkyl, or 3 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl represented by Rr is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12'. .- The compound of any of paragraphs 19 to 22, or a pharmaceutically acceptable salt thereof, wherein each case of R2' is independently H, halogen, OH, NH2, C1-6 alkyl, C1-6 alkoxy, NR11-R12', C(O)NRnRi2', C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, 5- to 6-membered heteroaryl or heterocyclyl 3 to 7 members, wherein the alkyl, alkoxy, heteroaryl or heterocyclyl represented by R2' or in the group represented by R2' is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, CN, Ci-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12·. 24.- The compound of any of paragraphs 19 to 23, where the compound is represented by the structural formula (Π-2) or (II-2'): RR LfrZn / ZZnZ / q / YIAI X (Π-2), or X (11-29 or a pharmaceutically acceptable salt thereof, where Ai is CR' or N; and R' is H, halogen, or NH2. .- The compound of any of paragraphs 19 to 24, or a pharmaceutically acceptable salt thereof, wherein each case of R2- is independently H, halogen, OH, C1-4 alkyl optionally substituted with halogen or OH or NRirRi2· , C1-4 alkoxy, C(O)OCi-6 alkyl, C(O)NRirRi2', NR11-R12', NRir C(O)Ci-6 alkyl, 5- to 6-membered heterocyclyl (pyrrolidinyl or pyrrolidin -2-one), or heteroaryl (oxazole). .- The compound of any of paragraphs 19 to 25, or a pharmaceutically acceptable salt thereof, wherein X is -P(=O)R3'R4· or -S(O)2NR5'R6·; Rs· and R4· are independently alkyl of Ci-e; and Rs· and Re· are independently H or Ci-6 alkyl. .- The compound of any of paragraphs 19 to 26, or a pharmaceutically acceptable salt thereof, wherein each instance of Rr is independently H or C1-4 alkyl. .- The compound of any of paragraphs 19 to 27, or a pharmaceutically acceptable salt thereof, wherein each case of R2· is independently H, halogen, OH, C1-4 alkyl optionally substituted with halogen or OH or NR11R12· , C1-4 alkoxy, C(O)OCi-4 alkyl, C(O)NRuRi2·, NR11R12·, NHC(O)Ci-6 alkyl, pyrrolidinyl, pyrrolidin-2-one, oxazole, where each case of Rir and Ri2is independently Η or C1-4 alkyl. .- The compound of any of paragraphs 19 to 28, or a pharmaceutically acceptable salt thereof, wherein X is -P(O)(CH3)2 or -S(O)2NHMe. .- The compound of any of paragraphs 19 to 29, or a pharmaceutically acceptable salt thereof, wherein each case of R2' is independently H, F, Cl, OH, CH3, NH2, or NHCOCH3. .- The compound of any of paragraphs 19 to 30, or a pharmaceutically acceptable salt thereof, where X is -P(=O)(CH3)2. In one embodiment, the compound or a pharmaceutically acceptable salt thereof or stereoisomer thereof is selected from the compounds of the formula (1-0), (1-1), (1-2), (I), (II) , (II-l), (II-2) or (Π-2'), or in the Examples. In certain embodiments, the HPK1 inhibitors (the compounds of the invention) are selective against one or more kinases selected from: Lck, ZAP70, JAK3, PKC theta, TBK1, and MAP4K3. In certain embodiments, the HPK1 inhibitors of the invention are selective against one or more kinases selected from: Lck, ZAP70, and JAK3. In certain embodiments, the HPK1 inhibitors of the invention are selective against JAK3. For example, the HPK1 inhibitors in question are selective against Lck such that the IC50 against Lck is at least 2-, 3-, 5-, 10-, 20-, 40-, 50-, 75-, 100-, 150-, 200-, 300-, 400-, 500-, 600, 750 or 1000 times higher than the IC50 against HPK1. In certain embodiments, the HPK1 inhibitor is selective against ZAP70, such that the IC50 against ZAP70 is at least 2-, 3-, 5-, 10-, 20-, 40-, 50-, 75-, 100- , 150-, 200-, 300-, 400-, 500-, 600-, 750- or 1000 times higher than the IC50 against HPK1. In certain embodiments, the HPK1 inhibitor is selective against JAK3, such that the IC50 against JAK3 is at least 2-, 3-, 5-, 10-, 20-, 40-, 50-, 75-, 100- , 150-, 200-, 300-, 400-, 500-, 600-, 750- or 1000 times higher than the IC50 against HPK1. In certain embodiments, the HPK1 inhibitor is selective against PKC theta, such that the IC50 against PKC theta is at least 2-, 3-, 5-, 10-, 20-, 40-, 50-, 75- , 100-, 150-, 200-, 300-, RRI / D / YIAI 400-, 500-, 600-, 750- or 1000 times higher than the IC50 against HPK1. In certain embodiments, the HPK1 inhibitor is selective against TBK1, such that the IC50 against TBK1 is at least 2-, 3-, 5-, 10-, 20-, 40-, 50-, 75-, 100- , 150-, 200-, 300-, 400-, 500-, 600-, 750- or 1000 times higher than the IC50 against HPK1. In certain embodiments, the HPK1 inhibitor is selective against MAP4K3, such that the IC50 against MAP4K3 is at least 2-, 3-, 5-, 10-, 20-, 40-, 50-, 75-, 100- , 150-, 200-, 300-, 400-, 500-, 600-, 750- or 1000 times higher than the IC50 against HPK1. Activity against HPK1, Lck, ZAP70, PKC theta, JAK3, TBK1 and MAP4K3 can be measured (e.g., measured by IC50 values) using any method recognized in the art, such as exemplary protocols described in the biology examples, such as Biology Examples 1-7 (all incorporated herein by reference). 4- Treatable diseases The HPK1 inhibitors, their pharmaceutically acceptable salts, their pharmaceutical compositions, can be used in methods to modulate (i.e., inhibit) the activity of HPK1, said method comprising administering to a patient / subject in need thereof an HPK1 inhibitor compound of the invention, or a pharmaceutically acceptable salt thereof, as described herein. In particular, the present invention contemplates the use of the compounds of the invention or stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, for use in the treatment or prophylaxis of diseases, in particular cancer (particularly hematopoietic and solid tumors) or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling. The pharmaceutical activity of the compounds according to the invention can be explained at least partially by their activity as MAP4K1 inhibitors. In certain embodiments, the compounds of the invention or pharmaceutically acceptable salts thereof are useful for therapeutic administration to a subject in need thereof to treat a disease or indication, including, but not limited to, benign hyperplasia, atherosclerotic disorder, sepsis, autoimmune disorder, vascular disorder, viral infection, neurodegenerative disorder, inflammatory disorder and male fertility control disorder. In certain embodiments, the compounds of the invention or pharmaceutically acceptable salts thereof are useful for therapeutic administration to improve, stimulate and / or increase immunity in the treatment of cancer. The HPK1 inhibitor compounds of the invention can be used alone, or in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including types of cancer. In certain embodiments, the methods of the invention can be used to treat cancers including, but not limited to, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, breast cancer. uterus, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of vagina, vulvar carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid gland cancer, parathyroid gland cancer, adrenal gland cancer, soft tissue sarcoma, breast cancer urethra, penile cancer, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, carcinoma of the renal pelvis, central nervous system (CNS) neoplasia, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, squamous cell cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers, including those induced by asbestos, and combinations of the above cancers. In some embodiments, types of cancer treatable with the compounds of the invention include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., refractory prostate adenocarcinoma). to hormones), breast cancer, triple negative breast cancer, colon cancer and lung cancer (for example, non-small cell lung cancer and small cell lung cancer). Furthermore, refractory or recurrent malignancies whose growth can be inhibited using the compounds of the invention are also treatable. In some embodiments, types of cancer that are treatable using the compounds of the invention include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, respiratory tract cancer, brain cancer, eye cancer, thyroid and parathyroid cancer, skin cancer, breast cancer head and neck, cancer of the reproductive organs, cancer of the digestive tract, cancer of the urinary tract, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (for example, lymphoma, leukemia such as acute lymphoblastic leukemia (AIL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and RR I ^70 / 7707 / 3 / ΥΙΛΙ follicular), Hodgkin lymphoma or multiple myeloma), sarcoma and distant metastasis thereof. In some embodiments, diseases and indications that are treatable using the compounds of the invention include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers. , cancers of the nervous system, gynecological cancers and skin cancers. Examples of hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse cell lymphoma large B cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory and recurrent follicular NHL), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom macroglubulinemia, hairy cell lymphoma, chronic myelogenous lymphoma, and Burkitt lymphoma. Exemplary sarcomas include chondrosarcoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma and teratoma. Exemplary lung cancer types include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma. , bronchial adenoma, chondromatous hamartoma and mesothelioma. Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) and colorectal cancer. Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testes (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma). Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma. RRLfrZÍVZZnZ / q / YIAI Exemplary bone cancer types include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronoma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors. Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) and spinal cord tumors (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease. Exemplary gynecologic cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pretumoral cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), g cell tumors). ra nu slab-theca I, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma) and fallopian tubes (carcinoma). Exemplary cancer types include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer, moles, dysplastic nevi, lipoma, angioma, dermatofibroma and keloids. In some embodiments, diseases and indications that are treatable using the compounds of the invention include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple negative breast cancer (TNBC), syndromes myelodysplastic, testicular cancer, bile duct cancer, esophageal cancer and urothelial carcinoma. Exemplary head and neck cancers include glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas, adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancers, and thyroid and parathyroid cancers. In some embodiments, the subject HPK1 inhibitors can be used to treat tumors producing PGE2 (e.g., tumors that overexpress Cox-2) and / or adenosine (tumors that overexpress CD73 and CD39). Overexpression of Cox-2 has been detected in a number of tumors, such as colorectal, breast, pancreatic and lung cancer, where it is correlated with a poor prognosis. Overexpression of COX-2 has been reported in hematological cancer models such as RAJI (Burkitt's lymphoma) and U937 (acute promonocyte leukemia). AA I ^70 / 7707 / D / YIAI as well as in the patient's blast cells. CD73 is upregulated in several human carcinomas, including those of the colon, lung, pancreas, and ovary. Higher expression levels of CD73 have been associated with tumor neovascularization, invasiveness and metastasis, and with shorter patient survival time in breast cancer. Examples of treatable breast cancer types include, but are not limited to, triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of types of airway cancer include, but are not limited to, small cell and non-small cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastema. Examples of treatable brain cancer types include, but are not limited to, brainstem and hypophthalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor. Treatable tumors of the male reproductive organs include, but are not limited to, prostate and testicular cancer. Treatable tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal and vulvar cancer, as well as sarcoma of the uterus. Treatable ovarian cancer includes, but is not limited to, serous tumor, endometrioid tumor, mucinous cystadenocarcinoma, granulosa cell tumor, Sertoli-Leydig cell tumor, and arrhenoblastoma. Treatable cervical cancer includes, but is not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, vitreous cell carcinoma, and viloglandular adenocarcinoma. Treatable tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small intestine, and salivary gland cancers. Treatable esophageal cancer includes, but is not limited to, esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lantern. Treatable gastric cancer includes, but is not limited to, intestinal-type and diffuse-type gastric adenocarcinoma. Treatable pancreatic cancer includes, but is not limited to, ductal adenocarcinoma, adenosquamous carcinomas, and pancreatic endocrine tumors. Treatable urinary tract tumors include, but are not limited to, cancers of the bladder, penis, kidney, renal pelvis, ureter, urethra, and human papillary kidney. AAI Π7Π / 77η7 / =1 / ΥΙΛΙ Treatable kidney cancer includes, but is not limited to, renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear cell sarcoma of the kidney, mesoblastic nephroma and Wilms tumor. Treatable bladder cancer includes, but is not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma. Treatable eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma. Treatable types of liver cancer include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without mellar fibrola variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Treatable skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Treatable head and neck cancers include, but are not limited to, squamous cell cancer of the head and neck, cancer of the larynx, cancer of the hypopharynx, nasopharynx, oropharynx, salivary gland cancer, cancer of the lip and oral cavity and squamous cell cancer. Treatable lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin disease, and central nervous system lymphoma. Treatable sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Treatable leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. In certain embodiments, the compounds of the invention can be used to treat a variety of other disorders where MAP4K1 is involved, such as cardiovascular and pulmonary diseases. In certain embodiments, the compounds of the invention can be used in medicaments for the treatment and / or prophylaxis of cardiovascular, inflammatory and fibrotic disorders, renal disorders, in particular acute and chronic renal failure, as well as acute and chronic renal failure. Herein, the term renal failure encompasses both the acute and chronic manifestations of renal failure, and also underlying or related renal disorders, RR I b7n / 77n7 / D / YIAI such as diabetic and non-diabetic nephropathies, hypertensive nephropathies, ischemic renal disorders, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, renal stenosis, glomerulopathies, glomerulonephritis (such as, for example, primary glomerulonephritis; minimal changes (lipoidnephrosis); membranous glomerulonephritis; focal segmental glomerulonephritis (FSGS); proliferative membrane glomerulonephritis; crescentic glomerulonephritis; iterative ngioprol table glomerulonephritis (IgA nephritis, Berger's disease); postinfectious glomerulonephritis; secondary glomerulonephritis; ), diabetes mellitus, lupus erythematosus, amyloidosis, Goodpasture syndrome, Wegener's granulomatosis, Henoch-Schonlein purpura, microscopic polyangiitis, acute glomerulonephritis, pyelonephritis (for example as a result of: urolithiasis, benign prosthetic hyperplasia, diabetes, malformations, analgesic abuse, Crohn's disease) , glomerulosclerosis, arteriolonecrosis of the kidney, tubulointerstitial diseases, nephropathic disorders such as primary and congenital or acquired renal disorder, Alport syndrome, nephritis, immunological disorders of the kidney such as kidney transplant rejection and immune complex-induced renal disorders, substance-induced nephropathy toxicities, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome that may be characterized at diagnosis, for example, by abnormally reduced excretion of creatinine and / or water, blood concentrations abnormally high levels of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes, for example glutamyl synthetase, altered urine osmolarity or volume, elevated microalbuminuria, macroalbuminuria, lesions in glomeruli and arterioles, tubular dilation, hyperphosphatemia and / or need of dialysis. In certain embodiments, the compounds of the invention can be used for the treatment and / or prophylaxis of sequelae of renal failure, for example, pulmonary edema, heart failure, uremia, anemia, electrolyte alterations (for example, hyperkalemia, hyponatremia) and alterations in bone and carbohydrate metabolism. In certain embodiments, the compounds of the invention can be used for the treatment / or prevention of sequelae of renal failure, for example, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (for example, hyperkalemia, hyponatremia) and alterations of the bone and carbohydrate metabolism. In certain embodiments, the compounds of the invention are further suitable for the treatment and / or prevention of polycystic kidney disease (PCKD) and syndrome of inappropriate ADH secretion (SIADH). In certain embodiments, the compounds of the invention are also suitable for the treatment and / or prophylaxis of metabolic syndrome, hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, RR LfrZn / ZZnZ / q / YIAI peripheral and cardiac vascular disorders, arrhythmias, atrial and ventricular arrhythmias and conduction disturbance, for example, atrioventricular blocks grades l-lll (AB block l-lll), supraventricular tachyarrhythmia, atrial fibrillation, flutter atrial fibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV junctional extrasystoles, sick sinus syndrome, syncope, AV node disease - inlet tachycardia, Wolff-Parkinson syndrome White, acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), shock such as cardiogenic shock, septic shock and anaphylactic shock, aneurysms, boxer's cardiomyopathy (premature ventricular contraction (PVC)), for the treatment and / or prophylaxis of thromboembolic and ischemic disorders such as myocardial ischemia, myocardial infarction, cerebrovascular accident, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, edema formation, for example, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, myocardial insufficiency, endothelial dysfunction, to prevent restenosis, for example after thrombolysis therapies, angioplasty percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplants and bypass operations, as well as micro- and macrovascular damage (vasculitis), elevated fibrinogen and low-density lipoprotein (LDL) levels, and elevated plasma inhibitor concentrations. plasminogen activator 1 (PAI-1), and also for the treatment and / or prophylaxis of erectile dysfunction and female sexual dysfunction. In certain embodiments, the compounds of the invention are also suitable for the treatment and / or prophylaxis of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH) including left heart disease, HIV, sickle cell anemia , thromboembolism (CTEPH), sarcoidosis, COPD or pulmonary hypertension associated with pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-l-antitrypsin deficiency (AATD) ), pulmonary fibrosis, pulmonary emphysema (e.g., cigarette smoke-induced pulmonary emphysema), and cystic fibrosis (CF). In certain embodiments, the compounds of the invention are also effective for the control of central nervous system disorders that are characterized by alterations of the NO / cGMP system. They are particularly suitable for improving perception, concentration, learning or memory after cognitive impairments such as those that occur in particular in association with situations / diseases / syndromes, such as mild cognitive impairment, learning and memory problems associated with age, age-related memory losses, vascular dementia, rr i bzn / zznz / zi / Yl· traumatic brain injury, stroke, dementia that occurs after a stroke (post-stroke dementia), post-traumatic traumatic brain injury, general impairments concentration, concentration deficits in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies, dementia with frontal lobe degeneration, including Pick syndrome, Parkinson's disease, progressive dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff psychosis. In certain embodiments, the compounds of the invention are also suitable for the treatment and / or prophylaxis of disorders of the central nervous system such as states of anxiety, tension and depression, sexual dysfunctions related to the CNS and sleep disturbances, and for the control of pathological alterations in the intake of food, stimulants and addictive substances. In certain embodiments, the compounds of the invention are furthermore also suitable for the control of cerebral blood flow and thus represent effective agents for the control of migraines. In certain embodiments, the compounds of the invention are also suitable for the prophylaxis and control of the sequelae of cerebral infarction (cerebral stroke) such as stroke, cerebral ischemia and traumatic brain injury. The compounds according to the invention can also be used to control pain and tinnitus conditions. In certain embodiments, the compounds of the invention have anti-inflammatory action and, therefore, can be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney , chronic intestinal inflammations (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory eye disorders. In certain embodiments, the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases. In certain embodiments, the compounds of the invention are also suitable for the treatment and / or prophylaxis of fibrotic disorders of internal organs, for example, the lung, heart, kidney, bone marrow and, in particular, the liver. , as well as dermatological fibrosis and fibrotic eye disorders. As used, the term fibrotic disorders includes in particular the following: liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also RR LfrZn / ZZnZ / q / YIAI after surgical procedures), nevi, diabetic retinopathy, proliferative vitroretinopathy, and connective tissue disorders (e.g., sarcoidosis). In certain embodiments, the compounds of the invention are also suitable for controlling postoperative scars, for example, as a result of glaucoma operations. In certain embodiments, the compounds of the invention can also be used cosmetically for aging and keratinized skin. In certain embodiments, the compounds of the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasia, osteoporosis, glaucoma and gastroparesis. In certain embodiments, the compounds of the invention are suitable for the treatment and / or prophylaxis of viral infections (e.g., HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (for example, colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; skin diseases (for example, psoriasis); hyperplasia-based diseases that are characterized by an increase in the number of cells (for example, fibroblasts, hepatocytes, bone and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (for example, endometrial hyperplasia)); bone diseases and cardiovascular diseases (for example, restenosis and hypertrophy). In another embodiment, the compounds of the invention can also be used to treat or prevent uterine fibroids (uterine leiomyoma or uterine myoma) in women. Uterine fibroids are benign tumors of the myometrium, the smooth muscle layer of the uterus. Uterine fibroids grow slowly throughout a woman's life and their growth depends on the female sex hormones estradiol and progesterone. Therefore, the highest prevalence of uterine fibroids at approximately 70% and >80% in white and African American women, respectively, is found from age 35 until menopause, when they shrink due to reduced hormonal levels. . Approximately 30% and 45% of white and African American women, respectively, show clinically relevant symptoms due to their fibroids, which are heavy menstrual bleeding and pain, which is related to the menstrual cycle (David et al, Eur J Obstet Gynecol Reprod Bio!. 199:137-140, 2016). Heavy menstrual bleeding in this regard is defined as a blood loss of more than 80 mL in one period of menstrual bleeding. The submucosal position of uterine fibroids, for example those located directly under the endometrium, appears to have an even more serious effect on uterine bleeding, which can lead to anemia in affected women. Furthermore, uterine fibroids, due to their symptoms, do seriously affect the quality of life of affected women. In certain embodiments, the compounds of the invention are useful for the treatment and / or prophylaxis of chronic kidney disorders, acute and chronic kidney failure, diabetic nephropathies, RRLfrZn / ZZRZ / q / YIAI inflammatory or hypertensive, fibrotic disorders, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prosthetic hyperplasia, associated dysuria to benign prostatic hyperplasia, Huntington's, dementia, Alzheimer's and Creutzfeld-Jakob. The present invention provides a method for the treatment and / or prophylaxis of chronic kidney disorders, acute and chronic renal failure, diabetic, inflammatory or hypertensive nephropathies, fibrotic disorders, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders , thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, dysuria associated with benign prostatic hyperplasia, Huntington's, dementia, Alzheimer's and CreutzfeldJakob. The present invention further provides the use of the compounds according to the invention for the treatment and / or prophylaxis of disorders, especially the disorders mentioned above. The present invention further provides a method for the treatment and / or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention. Therefore, the compounds of the present invention can be used to inhibit, block, reduce or diminish the activation of MAP4K1 by exogenous and / or endogenous ligands for the reduction of tumor growth and the modulation of dysregulated immune responses, for example, to blocking immunosuppression and increasing the activation and infiltration of immune cells in the context of cancer and cancer immunotherapy This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a of its pharmaceutically acceptable salts, isomers, polymorphs, metabolites, hydrates, solvates or esters; which is effective in treating the disorder. The present invention also provides methods for treating a variety of other disorders where MAP4K1 is involved such as, but not limited to, disorders with dysregulated immune responses, inflammation, vaccination against infections and cancer, viral infections, obesity and diet-induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administration of pharmaceutical compositions of the present invention. 5- Combination therapy The compounds of the invention can be used in combination therapy with one or more RR LfrZn / ZZnZ / q / YIAI additional / secondary therapeutic agents suitable for treating a disease or indication treatable by the compounds in question. Thus, in certain embodiments, for example, the methods of the invention using the compounds of the invention may comprise administering to the subject in need thereof an additional therapeutic agent. The additional therapeutic agent may be: (i) an immunomodulatory agent that blocks or inhibits a checkpoint of the immune system, which checkpoint may or may not be a component of the NF-κΒ pathway; and / or (i) an agent that directly stimulates an immune effector response, such as a cytokine, or a population of adoptively transferred T cells specific to a tumor, or an antibody specific for a protein expressed by a tumor cell; and / or (ii) a composition comprising a tumor antigen or an immunogenic fragment thereof; and / or (iv) a chemotherapeutic agent. In certain embodiments, the second therapeutic agent comprises an inhibitor of the PI3K-AKT-mTOR pathway, an inhibitor of the Raf-MAPK pathway, an inhibitor of the JAK-STAT pathway, an inhibitor of the beta catenin pathway, an inhibitor of the notch pathway, an inhibitor of the hedgehog pathway, an inhibitor of Pim kinases, and / or an inhibitor of chaperone proteins and cell cycle progression. In certain embodiments, the combination therapy of the invention reduces the likelihood of drug resistance arising in a cell population and / or reduces the toxicity of the treatment. In certain embodiments, the HPK1 inhibitor compounds of the invention can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Aktl, Akt2, Akt3, TGF-βΡν, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFaR, PDGF8R, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK -4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphAI, EphA2, EphA3, EphB2, EphB4, Tie2, Src , Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. In certain embodiments, the HPK1 inhibitor compounds of the invention can be combined with one or more of the following inhibitors for the treatment of cancer, including an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., AZD4547, BAY 1187982 , ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, 1 1-42756493, Debiol347, INCB54828, INCB62079, and INCB63904), a JAK inhibitor (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib or itacitinib (INCB39110)), an IDO inhibitor (e.g., epacadostat and NLG919), an LSD1 inhibitor (e.g., GSK2979552, INCB59872, and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a PI3K-gamma inhibitor such as a selective PI3K-gamma inhibitor, a CSFIR inhibitor (e.g., PLX3397 and LY3022855), a TAM tyrosine kinase receptor (Tyro-3, Axl, and Mer), a aryl hydrocarbon receptor modulator RRI b7ñ / 77Γ>7 / 3 / ΥΙΛΙ (AhR) (as laquinimod, aminoflavone, CB7993113, CH223191, 6, 2',4'-trimethoxyflavone (TMF), GNF351 (N-(2-(lH-indol-3 - ¡l)et¡l)-9-¡soprop¡l-2-(5-met¡lp¡ridin-3-¡l)-9H-pur¡n-6-amine), aminoflavone, NKI150460, indole -3-carbinol, β-naphthoflavone and dimer thereof, diindolylmethane (DIM), 4hydroxytamoxifen, leflunomide, raloxifene, tranilast, flutamide, mexiletine, nimodifine, omeprazole, sulindac, tranilast and TCDD (2,3,7,8-tetrachlorodibenzo- p-dioxin)), an angiogenesis inhibitor, an interleukin receptor inhibitor, inhibitors of extra-terminal family members and bromine (for example, bromodomain inhibitors or BET inhibitors such as OTX015, CPI-0610, INCB54329 and INCB57643) , and an adenosine receptor antagonist or combinations thereof In certain embodiments, the HPK1 inhibitor compounds of the invention can be combined with HDAC inhibitors, such as panobinostat and vorinostat. In certain embodiments, the HPK1 inhibitor compounds of the invention can be combined with c-Met inhibitors, such as onartumzumab, tivantnib, and capmatinib (INC-280). In certain embodiments, the HPK1 inhibitor compounds of the invention can be combined with BTK inhibitors, such as ibrutinib. In certain embodiments, the HPK1 inhibitor compounds of the invention can be combined with mTOR inhibitors, for example, rapamycin, sirolimus, temsirolimus, and everolimus. In certain embodiments, the HPK1 inhibitor compounds of the invention can be combined with MEK inhibitors, such as trametinib, selumetinib and GDC-0973. In certain embodiments, the HPK1 inhibitor compounds of the invention can be combined with inhibitors of Hsp90 (e.g., tanespimycin), cyclin-dependent kinases (e.g., palbociclib), PARP (e.g., olaparib), and Pim kinases (LGH447, INCB053914, and SGI-1776). In certain embodiments, the HPK1 inhibitor compounds of the invention can be combined with a DNA sensor agonist (c-GAS) and / or its downstream adapter protein STING. The cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway is a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, trigger the expression of inflammatory genes that can lead to senescence or the activation of defense mechanisms. Localization of DNA from the usual nuclear location to the cytosol is associated with tumorigenesis or viral infection. cGAS is located in the cytosol, and by binding directly to cytosolic DNA, cGAS forms dimers to catalyze the production of 2'3'-cGAMP from ATP and GTP. The resulting cGAMP then acts as a second messenger to bind to STING and trigger activation of the transcription factor IRF3. Activated IRF3 leads to the transcription of type 1 IFN-β and a series of downstream target genes to initiate a diverse series of biological responses, such as viral response, tumor surveillance, autoimmunity, and cellular senescence. In many tumor cells, the constitutively active DNA damage response leads to cytoplasmic DNA accumulation and activation of the cGAS / STING pathway. It has been shown in lymphoma cells that the NKG2D ligand, Rael, was upregulated in a STING / IRF3-dependent manner, to aid in NK-mediated tumor clearance. Activation of the c-GAS-STING pathway in antigen-presenting cells, such as dendritic cells, has been shown to improve their function and increase anti-tumor immunity. In certain embodiments, the HPK1 inhibitor compounds of the invention can be combined with one or more immune checkpoint inhibitors. Activation of effector T cells is normally triggered by the TCR that recognizes the antigenic peptide presented by the MHC complex. The type and level of activation achieved is then determined by the balance between the signals that stimulate and the signals that inhibit the effector T cell response. The immune system checkpoint is used herein to refer to any molecular interaction that alters the balance in favor of inhibiting the effector T cell response. That is, a molecular interaction that, when it occurs, negatively regulates the activation of an effector T cell. Such an interaction may be direct, such as the interaction between a ligand and a cell surface receptor that transmits an inhibitory signal to an effector T cell. Or it may be indirect, such as blocking or inhibiting an interaction between a ligand and a cell surface receptor that might otherwise transmit an activating signal to the effector T cell or an interaction that promotes upregulation of a molecule. inhibitory cell or cell, or the depletion by an enzyme of a metabolite required by the effector T cell, or any combination thereof. Examples of immune system checkpoints include: a) The interaction between indoleamine 2,3-dioxygenase (IDO1) and its substrate; b) The interaction between PD1 and PD-L1 and / or PD1 and PD-L2; c) The interaction between CTLA-4 and CD86 and / or CTLA-4 and CD80; d) The interaction between B7-H3 and / or B7-H4 and their respective ligands; e) The interaction between HVEM and BTLA; f) The interaction between GAL9 and TIM3; g) The interaction between MHC class I or II and LAG 3; and h) The interaction between MHC class I or II and KIR; i) The interaction between 0X40 (CD134) and OX40L (CD252); j) The interaction between CD40 and CD40L (CD154); k) The interaction between 4-1 BB (CD137) and ligands including 4-1 BBL; I) The interaction between GITR and ligands including GITRL. Therefore, examples of immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD20, CD27, CD28, CD39, CD40, CD 122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK , PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, RR I Π7Π / 77Π7 / 3 / ΥΙΛΙ ΤΙΜ3, VISTA, PD-1, PD-L1, and PD-L2. A representative checkpoint for the purposes of the present invention is checkpoint (b), primarily the interaction between PD1 and any of its ligands PD-L1 and PD-L2. PD1 is expressed on effector T cells. Docking with any ligand results in a signal that downregulates activation. The ligands are expressed by some tumors. PD-L1 in particular is expressed by many solid tumors, including melanoma. Therefore, these tumors downregulate immune-mediated antitumor effects through activation of inhibitory PD-1 receptors on T cells. By blocking the interaction between PD1 and one or both of its ligands, a immune response checkpoint can be eliminated, leading to increased anti-tumor T cell responses. Therefore, PD1 and its ligands are examples of components of an immune system checkpoint that can be targeted in the method of the invention. Another checkpoint for the purposes of the present invention is checkpoint (c), primarily the interaction between the T cell receptor CTLA-4 and its ligands, the B7 proteins (B7-1 and B7-2). CTLA-4 is normally upregulated on the surface of T cells after initial activation, and ligand binding results in a signal that inhibits further / continued activation. CTLA-4 competes for binding to B7 proteins with the CD28 receptor, which is also expressed on the surface of T cells but upregulates activation. Thus, by blocking the interaction of CTLA-4 with B7 proteins, but not the interaction of CD28 with B7 proteins, one of the normal checkpoints of the immune response can be eliminated, leading to cell responses. Increased anti-tumor T. Therefore, CTLA-4 and its ligands are examples of components of an immune system checkpoint that can be targeted in the method of the invention. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule that is selected from CD27, CD28, CD40, ICOS, 0X40, GUR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, HM3 , andVIEW. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors. . In some embodiments, the compounds provided herein can be used in combination with immune checkpoint inhibitors that are small molecule inhibitors (SMI), which are typically small organic molecules. For example, in certain RRI bZn / ZZnZ / D / YIAI modalities, IDO1 inhibitors include Epacadostat (INCB24360), Indoximod, GDC-0919 (NLG919), and F001287. Other IDO1 inhibitors include 1-methyltryptophan (1MT). In some embodiments, the inhibitor of an immune checkpoint molecule is also known as an immunomodulatory agent, which includes any agent that, when administered to a subject, blocks or inhibits the action of an immune system checkpoint, giving resulting in the upregulation of an immune effector response in the subject, typically a T cell effector response, which may comprise an anti-tumor T cell effector response. The immunomodulatory agent used in the method of the present invention can block or inhibit any of the immune system checkpoints described above. The agent may be an antibody or any other suitable agent that results in said blocking or inhibition. The agent thus can be generally mentioned as an inhibitor of said checkpoint. An antibody as used herein includes complete antibodies and any antigen-binding fragments (i.e., antigen-binding portion) or individual chains thereof. An antibody may be a polyclonal antibody or monoclonal antibody and may be produced by any suitable method. Examples of binding fragments encompassed within the term antigen-binding fragment of the antibody include a Fab fragment, an F(ab')2 fragment, a Fab' fragment, an Fd fragment, an Fv fragment, a dAb fragment and a determining region. of isolated complementarity (CDR). Single chain antibodies such as scFv and heavy chain antibodies such as VHH and camel antibodies are also intended to be included in the term antigen-binding portion of an antibody. In certain embodiments, the immunomodulatory agent used with the HPK1 inhibitor of the invention is an anti-PD1 antibody, anti-PD-LI antibody, or anti-CTLA-4 antibody. In some embodiments, the inhibitor of an immune checkpoint molecule is a PD-1 inhibitor, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab (MDX-1106), pembrolizumab (Merck 3475 or Lambrolizumab), pidilizumab (CT-011), Tislelizumab (BGB-A317), Camrelizumab (SHR-1210), spartalizumab (PDR001), or AMP-514 (MEDI0680). In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PDl antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is Camrelizumab (SHR1210). In certain embodiments, the PD-1 inhibitor is AMP-224 (PD-L2 Fc fusion protein that binds to PD-1) or AuNP-12 (anti-PD-1 peptide). In some embodiments, the inhibitor of an immune checkpoint molecule is a PD-L1 inhibitor, for example, an anti-PD-LI monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, BMS-936559 (MDX-1105), MEDI-4736 (durvalumab), MPDL3280A (also known as RG7446), YW243.55. S70 (HPAB-0381-WJ), or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is MPDL3280A or MEDI-4736. In certain embodiments, anti-PD-Ll antibodies include atezolizumab, avelumab, durvalumab or MEDI-4736, and MPDL3280A. In some embodiments, the inhibitor of an immune checkpoint molecule is a CTLA-4 inhibitor, for example, an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, or any of the antibodies described WO2014 / 207063 (incorporated herein by reference). Other molecules include soluble mutant CD86 polypeptides or polypeptides. In certain embodiments, the antibody is Ipilumumab. In certain embodiments, the inhibitor of an immune checkpoint molecule is a combination of two or more of the modulators described herein, such as a combination that targets two or more different targets (e.g., PD-1, PD -L1 and PD-L2). Exemplary combinations include: a-PD-1 and a-PD-Ll; a-CTLA-4, a-PD-Ll, and a-CD20; etc In some embodiments, the inhibitor of an immune checkpoint molecule is an antibody that blocks or inhibits the interaction between 4-1 BB and its ligand, including utomilumab. In some embodiments, the inhibitor of an immune checkpoint molecule is a CSFIR inhibitor, for example, an anti-CSFIR antibody. In some embodiments, the anti-CSFIR antibody is IMC-CS4 or RG7155. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, for example, an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, IMP321 or GSK2831781. In some embodiments, the inhibitor of an immune checkpoint molecule is a GITR inhibitor, for example, an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, MK1248, BMS-986156, MEDI1873, or GWN323. In some embodiments, the inhibitor of an immune checkpoint molecule is an 0X40 inhibitor, for example, an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MEDI6469, MOXR0916, PF-04518600, or GSK3174998. In some embodiments, the OX40L fusion protein is MEDI6383. In some embodiments, the inhibitor of an immune checkpoint molecule is a TIM3 inhibitor, for example, an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is MBG-453. In some embodiments, the inhibitor of an immune checkpoint molecule is a CD20 inhibitor, for example, an anti-CD20 antibody. In some embodiments, the antibody RRI ^70 / 7707 / 3 / ΥΙΛΙ anti-CD20 is obinutuzumab or rituximab. In some embodiments, the compounds of the invention can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an IDO I, TDO, or arginase inhibitor. Examples of IDO1 inhibitors include epacadostat and NGL919. An example of an arginase inhibitor is CB-1158. In some embodiments, the compounds of the invention can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets the PD-1, PD-L1, CTLA-4, GITR, 0X40, TIM3, LAG3, CD137, ICOS, CD3 or TGFp receptor. In some embodiments, the compounds of the invention can be used in combination with one or more agents for the treatment of diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include bendamustine, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes, uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan , carmustine, lomustine, streptozocin, dacarbazine and temozolomide. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). The compounds of the present disclosure can further be used in combination with other methods to treat types of cancer, for example, by chemotherapy, radiotherapy, tumor-directed therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, adoptive T cell transfer, eneolytic virotherapy, and molecular small immunomodulators, including thalidomide or JAK1 / 2 inhibitor and the like. The compounds of the invention can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutic. Examples of chemotherapeutics include any of: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparlisib, intravenous busulfan, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactin mycin , daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin. RRI ^70 / 7707 / D / YIAI dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fluda rabbi , fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovo rina , leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone fenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin, ponatinib, prednisone, procarbazine, quinacrine, rasburicase, regorafenib, reloxafin, rituximab, ruxolitinib, sorafenib , streptozocin, sunitinib , sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vinorelbine, vorinostat and zoledronate . Other anticancer agents include antibody therapies such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies against PD-1 and PD-L1, or antibodies against cytokines. (IL-10, TGF-β, etc.). Examples of antibodies against PD-1 and / or PD-L1 that can be combined with compounds of the present disclosure for the treatment of cancer or infections such as viral, bacterial, fungal and parasitic infections include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736, and SHR-1210. Other anticancer agents include kinase-associated cell proliferative disorder inhibitors. These kinases include, but are not limited to Aurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk , Itk, Bmx, GSK3, JNK, ΡΑΚΙ, PAK2, PAK3, PAK4, PDKI, PKA, PKC, Rsk, and SGK. Other anticancer agents also include those that block immune cell migration, such as antagonists of chemokine receptors, including CCR2 and CCR4. The compounds of the present disclosure may further be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants or therapeutic antibodies. In some embodiments, the compounds of the invention can be used in combination with an additional therapeutic agent that directly stimulates an immune effector response, such as a cytokine, or a population of adoptively transferred T cells specific to a tumor, or an antibody specific for a protein expressed by a tumor cell. ΑΑίΉ7Π / 77η7 / 3 / ΥΙΛΙ As used herein, an agent that directly stimulates an immune effector response means any suitable agent, but typically refers to a cytokine or chemokine (or an agent that stimulates the production of either), a population of T cells transferred adoptively specific for a tumor, or an antibody specific for a protein expressed by a tumor cell. The cytokine may be an interferon selected from IFNa, ΙΡΝβ, IFNy and IFNA, or an interleukin, such as IL-2. The chemokine may be an inflammatory mediator, for example, selected from CXCL9, 10 and 11, which attracts CXCR3-expressing T cells. The agent that stimulates the production of a cytokine or chemokine may be a suitable adjuvant for administration to humans. An example is Bacille Calmette-Guerin (BCG), which is typically administered intravesically (i.e., urethral catheter) for the treatment of bladder cancer. A typical BCG dosing regimen for bladder cancer is once a week for six weeks, but given its long safety history it is also given indefinitely as maintenance. BCG has been shown to stimulate immune responses to bladder cancer. BCG has also been used as an adjuvant in combination with compositions comprising tumor antigens (i.e. with cancer vaccines), particularly for colon cancer when typically administered intradermally. Such uses of BCG are also contemplated in the present invention. The adoptively transferred tumor-specific T cell population directly increases the size of the tumor-specific T cell population in an individual, and can be generated by any suitable means. However, typically the process involves isolating tumor-specific T cells from a tumor sample taken from a patient, and selectively culturing these cells before returning the expanded population of tumor-specific T cells to the patient. Alternatively, a population of tumor-specific T cells can be produced by genetic engineering of the T cell receptor locus, followed by expansion of the altered cell. Antibodies specific for proteins expressed by a tumor cell typically stimulate immune activity by binding to the tumor cell and promoting cell destruction through antibody-dependent cell-mediated cytotoxicity (ADCC). Examples of antibodies of this type include anti-CD20 antibodies such as ofatumumab or rituximab, and anti-CD52 antibodies such as alemtuzumab. Thus, in certain exemplary embodiments, the compounds of the invention can be used in combination with a calcineurin inhibitor, for example, cyclosporin A or FK 506; an mTOR inhibitor, for example, rapamycin, 40-0-(2-hydroxyethyl)-rapacin, biolimus-7 or biolimus-9; an ascomycin having immunosuppressive properties, for example, ABT-281, ASM981; a corticosteroid; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; acid RRI b7n / 77n7 / D / YIAI mycophenolic or salt; mycophenolate mofetil; IL-Ιβ inhibitor. In another embodiment, the compounds of the invention are combined with a co-agent that are PI3 kinase inhibitors. In another embodiment, the compounds of the invention are combined with a co-agent that influences BTK (Bruton's tyrosine kinase). For the treatment of oncological diseases, the compounds of the invention can be used in combination with B cell modulating agents, for example, Rituximab, BTK or Syk inhibitors, PKC inhibitors, PI3, PDK, PIM, JAK and mTOR kinases and BH3 mimetics. In some embodiments, the compounds of the invention, including salts thereof, can be combined with another immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules), cells and cells transfected with genes that They encode immunostimulatory cytokines. Non-limiting examples of tumor vaccines that can be used include melanoma antigen peptides, such as gplOO peptides, MAGE, Trp-2, MARTI and / or tyrosinase antigens, or tumor cells transfected to express the cytokine GM-CSF. In some embodiments, the compounds of the invention, or salts thereof can also be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancers, such as human papillomaviruses (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the compounds of the present disclosure can be used in combination with a tumor-specific antigen such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the compounds of the invention, or salts thereof can be combined with dendritic cell immunization to activate potent antitumor responses. In some embodiments, the compounds of the invention can be used in combination with bispecific macrocyclic peptides that target effector cells that express the Fe receptor or Feγ receptor to tumor cells. The compounds of the invention can also be combined with macrocyclic peptides that activate the immune response capacity of the host. In some embodiments, the compounds of the invention can be used in combination with bone marrow transplantation for the treatment of a variety of tumors of hematopoietic origin. Suitable antiviral agents contemplated for use in combination with the compounds of the invention may comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), RR I bZn / ZZnZ / D / YIAI protease inhibitors and other antiviral drugs. Exemplary suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and called beta-L-2',3'-dicleoxy-5-fluorocytidene); DAPD ((-)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA). Suitable typical NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (l-(ethoxl·methyl)-5-(l-methyllet¡l)-6-(phen¡lmethyl)-(2,4(lH,3H)pyrimidinedione); and ( +)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG1343); amprenavir (141W94 ); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607. It will be appreciated that many of the additional therapeutic agents used in the methods of the invention may be biological products requiring intravenous, intraperitoneal or depot administration. In another embodiment, the compound of the invention is administered orally and the additional therapeutic agent is administered parenterally, for example, intravenously, intraperitoneally or as a depot. In any of the combination therapies described herein, when more than one pharmaceutical agent is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents). In one embodiment, the invention provides a product comprising a compound of the invention, such as a subject compound or any subgroup thereof, and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. Products provided as a combination preparation include a composition comprising the compound of the invention or any subgroup thereof and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound in question or any subgroup thereof and the other therapeutic agent(s) separately, for example, in the form of a kit. In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a subject compound and the other contains a second therapeutic agent discussed herein. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle or divided aluminum package. An example of such a kit is a blister pack, as is normally used to package tablets, capsules and the like. The kit of the invention can be used to administer different dosage forms, for example, oral and parenteral, RR LfrZn / ZZnZ / q / YIAI to administer the separate compositions at different dosage intervals, or to titrate the separate compositions from each other. To aid compliance, the kit of the invention typically comprises instructions for administration. 6. - Compound testing / detection methods The compounds of the invention inhibit the kinase activity of HPK1, which kinase activity can be assayed directly using numerous biochemical assays, such as the assay described in Example 1. The IC50 values ​​of any of the compounds can be determined accordingly on a scale of inhibitor concentrations. Furthermore, the inhibitory effect of the compounds can also be evaluated by a biological assay, to determine the effect of the compounds on the secretion of cytokines by T cells after stimulation with TCR and CD28. For example, Example 5 describes such a functional assay to determine the effect of an HPK1 inhibitor on the release of IL-2 and IFN-γ upon stimulation of Pan T cells. Secreted IL2 and IFN-γ can be measured / quantified by a standard ELISA assay. Briefly, pan T cells can be isolated from peripheral blood (PB) mononuclear cells (MNC), or PBMC, using commercially available kits, such as the Pan T MACS Isolation Kit (Miltenyl Biotec) (Cat. No. 130-096 -535). Primary human pan-T cells include CD4 and CD8 T cells, as well as some gamma / delta T cell subsets. Pan-T cells can be isolated using the negative immunomagnetic separation technique without the use of columns. Isolated pan-T cells can be dispensed into 96-well plates at 100,000 cells / well and stimulated with immobilized anti-CD3 antibody and soluble anti-CD28 antibody, or PMA / ionomycin as a positive control (or culture media as a negative control). . Different concentrations of test compounds can be added to cells to evaluate the effect of the compound on cytokine secretion after TCR stimulation / CD28 costimulation. The stimulated cells are incubated for a further 2 days, before collecting the supernatant (containing cytokines secreted by pan-T cells) from each well for ELISA assay and quantification of IL-2 and IFN-y. Additional assays can also be used to evaluate the ability of any HPK1 inhibitor to inhibit HPK1, or to select compounds that possess HPK1 inhibitory activity. For example, in one assay, inhibition of HPK1 kinase activity can be analyzed using a Treg assay (the regulatory T cell proliferation assay) described below. Specifically, primary CD47CD25' T cells and CD4+ / CD25+ regulatory T cells are isolated from peripheral blood mononuclear cells (PBMCs) donated by humans, using a suitable kit, such as one from Thermo Fisher Scientific (Cat. No. 11363D). . T cells AAI ^70 / 7707 / D / YIAI CD4+ / CD25‘ are labeled with CFSE (Thermo Fisher Scientific, C34554) after the protocol provided by the supplier. CFSE-labeled T cells and CD4+ / CD25+ regulatory T cells are resuspended at a concentration of 1 χ 106 cells / mL in RPMI-1640 medium. 100 pL of CFSE-labeled T cells are mixed with or without 50 pL of CD4+ / CD25+ regulatory T cells, treated with 5 pL of anti-CD3 / CD28 beads (Thermo Fisher Scientific, 11132D) and various concentrations of compounds diluted in 50 pL of RPMI-1640 medium. The mixed populations of cells are cultured for 5 days (37°C, 5% CO2), and the proliferation of CFSE-labeled T cells is analyzed by BD LSRFortessa X-20 using the FITC channel at 5t0day. Inhibition of HPK1 by the subject compounds is expected to improve Treg function and inhibit the proliferation of CFSE-labeled primary CD4+ / CD25' T cells. In another example, inhibition of HPK1 kinase activity can be assayed using the p-SLP-76 S376 HTRF assay (Cisbio) described below. This HTRF cell-based assay allows rapid quantitative detection of SLP-76 phosphorylated at Serine 376 by HPK1. PhosphoSLP-76 creates a scaffold on which key signaling complexes are built and is a marker of T cell activation. According to the manufacturer, the Phospho-SLP-76 (Ser376) assay uses two labeled antibodies: one with a donor fluorophore, the other with an accept. The first antibody is specific for binding to the phosphorylated S376 motif in SLP-76, and the second for its ability to recognize SLP-76 regardless of its phosphorylation state. Phosphorylation of the protein allows an immune complex formation involving both labeled antibodies and bringing the donor fluorophore into close proximity to the acceptor, thereby generating a FRET signal. Its intensity is directly proportional to the concentration of phosphorylated protein present in the sample and provides a means to assess the phosphorylation status of the protein under a wash-free assay format. Briefly, Jurkat cells (cultured in RPMI1640 medium with 10% FBS) were harvested and subjected to cetrifugation, followed by resuspension in appropriate medium at 3 x 106 cells / mL. Jurkat cells (35 pL) are then dispensed into each well of a 384-well plate. Test compounds are diluted with cell culture medium for a 40-fold dilution (adding 39 pL of cell culture media in 1 pL of compound). Jurkat cells in the well plate are treated with the test compounds at various concentrations (by adding 5 pL of the compound diluted in 35 pL of Jurkat cells, and starting from 3 pM with 1:3 dilution) for 1 hour at 37° C, 5% CO2), followed by treatment with anti-CD3 (5 pg / ml, OKT3 clone) for 30 min to activate TCR and HPK1. A 1:25 dilution of xlOO blocking reagent (from the p-SLP76 ser376HTRF kit) with lysis buffer (LB) x4 is prepared, and 15 pL of LB buffer x4 with blocking reagent is added to each well and They are incubated at room temperature for 45 minutes with gentle shaking. The cell lysate (16 pL) is added to a white Greiner plate, treated ΑΑίΉ7Π / 77Π7 / 3 / ΥΙΛΙ with p-SLP76 Ser376 HTRF reagents (2 pL donor, 2 pL acceptor) and incubated at 4 °C overnight. Homogeneous time-resolved fluorescence (HTRF) is measured on a PHERAstar plate reader the next day. Determination of IC50 is performed by curve fitting the percent inhibition against the log inhibitor concentration using GraphPad Prism 5.0 software. Any of the assays described above can be scaled up for large-scale or high-throughput screening (HTS). By using any of the assays described above, the IC50 values ​​of the compounds in question can be determined. 7,- Pharmaceutical compositions The invention provides pharmaceutical compositions comprising any of the compounds described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable excipient and pharmaceutically acceptable carrier refer to a substance that assists in the formulation and / or administration of an active agent and / or absorption by a subject and can be included in the compositions of the present description without causing a significant adverse toxicological effect. in the subject. Non-limiting examples of pharmaceutically acceptable carriers and excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, saline solutions (such as Ringer), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, esters of fatty acids, hydroxymethylcellulose, polyvinylpyrrolidine, and colors, and the like. Said preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to influence the osmotic pressure, pH regulators, coloring and / or aromatic substances and the like. They do not react detrimentally with or interfere with the activity of the compounds provided herein. One skilled in the art will recognize that other pharmaceutical carriers and excipients are suitable for use with the described compounds. These compositions optionally further comprise one or more additional therapeutic agents. Alternatively, a compound of the invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic regimens (e.g., Gleevec or other kinase inhibitors, interferon, bone marrow transplant, farnesyl transferase, bisphosphonates, thalidomide, cancer vaccines, hormone therapy, antibodies, radiation, etc.). For example, additional therapeutic agents for coadministration or inclusion in a pharmaceutical composition with a compound of this invention may be one or more anticancer agents. As described herein, the compositions of the present invention comprise RR I Πζη / Ζζηζ / Σΐ / ΥΙΛΙ a compound of the invention together with a pharmaceutically acceptable carrier which, as used herein, includes any and all solvents, diluents, or other vehicles, dispersing or suspending aids, agents surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) describes various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except to the extent that any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effects or otherwise interacting detrimentally with any other component(s) of the pharmaceutical composition, it is contemplated that its use is within the scope of this invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; sunflower seed oil; sesame oil, olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; pH regulating agents such as magnesium hydroxide and aluminum hydroxide; alginic acid, pyrogen-free water; osotonic saline solution; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring and perfuming agents, preservatives and antioxidants, They may also be present in the composition. 8. - Formulations The invention also encompasses a class of compositions comprising the active compounds of this invention in association with one or more pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as carrier materials) and, if desired, other active ingredients. In certain embodiments, the invention provides a pharmaceutical formulation for treating cancer, particularly the types of cancer described herein, comprising a compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. In certain embodiments, the invention provides a pharmaceutical formulation for treating a cancer selected from the group consisting of breast cancer, colorectal cancer, breast cancer. RR LfrZn / ZZnZ / q / YIAI lung, ovarian cancer and pancreatic cancer, comprising a compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. The compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to said route, and in a dose effective for the intended treatment. The compounds and compositions of the present invention may, for example, be administered orally, mucosal, topically, rectally, pulmonary, such as by aerosol inhalation, or parenterally, including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular. , transdermal, intraorbital, intrathecal, intraventricular, intratumoral, intranasal, intrasternal, by implantation, by inhalation, and by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. Typically, pharmaceutical compositions are gelatin tablets or capsules comprising the active ingredient together with a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets also c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) disintegrants, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavorings and sweeteners. The tablets may be film coated or enteric coated according to methods known in the art. Compositions suitable for oral administration include an effective amount of a compound of the invention in the form of tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups and elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and said compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, color agents and preservative agents. in order to provide pharmaceutically elegant and pleasant preparations. The tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for tablet manufacture. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated using techniques RRLfrZn / ZZRZ / q / YIAI known to delay disintegration and absorption in the gastrointestinal tract and thus provide long-term sustained action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient It is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Certain injectable compositions are aqueous isotonic solutions or suspensions and suppositories can advantageously be prepared from fatty emulsions or suspensions. Said compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, humectants or emulsifiers, solution promoters, salts to regulate osmotic pressure and / or pH regulators. In addition, they may also contain other therapeutically valuable substances. Such compositions are prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient. Compositions suitable for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to facilitate passage through the host's skin. For example, transdermal devices are in the form of a bandage comprising a backing element, a reservoir containing the compound optionally with carriers, optionally a rate control barrier to deliver the compound from the host's skin at a speed controlled and predetermined over an extended period of time, and means for securing the device to the skin. Compositions suitable for topical application, for example, to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or spray formulations, for example, for delivery by aerosol or the like. Such topical delivery systems will be suitable in particular for dermal application, for example, for the treatment of skin cancer, for example, for prophylactic use in sun creams, lotions, sprays and the like. Therefore, they are particularly suitable for use in topical formulations, including cosmetic ones, well known in the art. These may contain solubilizers, stabilizers, tone-enhancing agents, pH regulators and preservatives. As used herein a topical application also belongs to an inhalation or an intranasal application. They may be conveniently supplied in the form of a dry powder (either alone, as a mixture, for example, a dry mixture with lactose, or a mixed component particle, for example, with phospholipids) from a dry powder inhaler. or a presentation RR LfrZn / ZZnZ / q / YIAI of aerosol sprayer from a pressurized container, pump, aerosol, atomizer or nebulizer, with or without the use of a suitable propellant. The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can facilitate the degradation of certain compounds. The anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low humidity conditions. An anhydride pharmaceutical composition can be prepared and stored in a manner that maintains its anhydride nature. Accordingly, anhydride compositions are packaged using materials known to prevent exposure to water, so that they can be included in suitable form kits. Examples of suitable containers include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. The invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate at which the compound of the present invention as an active ingredient will decompose. Such agents, which are mentioned herein as stabilizers include, but are not limited to, antioxidants such as ascorbic acid, pH regulators, or salt pH regulators, etc. The pharmaceutically active compounds of this invention can be processed according to conventional pharmacy methods to produce medicinal agents for administration to patients, including humans and other mammals. The amount of compounds that are administered and the dosage regimen to treat a disease condition with the compounds and / or compositions of this invention depend on a variety of factors, including age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound used. Thus, the dosage regimen can vary widely, but can be determined routinely using standard methods. As previously mentioned, the daily dose may be given in one administration or may be divided among 2, 3, 4, or more administrations. For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants, excipients or carriers appropriate for the indicated route of administration. If administered orally, the compounds may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, alkyl esters of cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium salts and calcium from phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation which may be provided in a dispersion of the active compound in hydroxypropylmethylcellulose. In the case of skin conditions, it may be preferable to apply a topical preparation of the compounds of this invention to the affected area two to four times a day. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (for example, liniments, lotions, ointments, creams or pastes) and drops suitable for administration into the eyes, ears or nose. For topical administration, the active ingredient may comprise 0.001% to 10% w / w, for example, 1% to 2% by weight of the formulation, although it may comprise as much as 10% w / w, but preferably not more than 5% w / w, and more preferably 0.1% to 1% of the formulation. The compounds of this invention can also be administered by means of a transdermal device. Transdermal administration will be achieved using a patch of either the porous membrane and reservoir type or a solid matrix variety. In any case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane in the adhesive permeable to the active agent, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent can also function as the membrane. The oil phase of the emulsions of this invention can be made up of known ingredients in a known manner. While the phase may simply comprise an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) form the so-called emulsifying wax, and the wax together with oil and fat form the so-called emulsifying ointment base that forms the dispersed oil phase of the formulations. cream. Emulsifiers and emulsifier stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other well materials. known in the art. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining, washable product of adequate consistency to prevent leaks from tubes or other containers. Straight or branched chain mono- or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a Branched chain ester mixtures can be used. These can be used alone or in combination depending on the properties required. Alternatively, high melting point lipids can be used, such as white soft paraffin and / or liquid paraffin or other mineral oils. Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredients. The active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w / w. Formulations for parenteral administration may be in the form of sterile isotonic aqueous and non-aqueous solutions or suspensions for injection. These solutions and suspensions can be prepared from sterile powders or granules using one or more of the mentioned carriers or diluents for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, gum tragacanth and / or various pH regulators. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin {i.e., Captisol), cosolvent solubilization (i.e., propylene glycol), or micellar solubilization (i.e., Tween 80). The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any mild fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids like oleic acid find use in the preparation of injectables. For pulmonary administration, the pharmaceutical composition can be administered in aerosol form or with an inhaler that includes a dry powder aerosol. Suppositories for rectal administration of the drug can be prepared by mixing the RR LfrZn / ZZnZ / q / YIAI drug with a suitable non-irritant excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures, but liquid at rectal temperature and will therefore melt in the rectum and release the drug. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, pH regulators, etc. Tablets and pills can also be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring and perfuming agents. The pharmaceutical compositions of this invention comprise a compound of the formulas described herein or a pharmaceutically acceptable salt thereof; an additional agent selected from a kinase inhibitor agent (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic or a vascular antihyperproliferation compound ; and any pharmaceutically acceptable carrier, adjuvant or vehicle. Alternative compositions of this invention comprise a compound of the formulas described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle. Such compositions may optionally comprise one or more additional therapeutic agents including, for example, kinase inhibitory agents (small molecule, polypeptide, antibody, etc.), immunosuppressants, anticancer agents, antiviral agents, anti-inflammatory agents, antifungal agents, antibiotics or antihyperproliferation compounds. vascular. The term pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that can be administered to a patient, together with a compound of this invention and that does not destroy the pharmacological activity thereof and is non-toxic when administered in doses sufficient to provide a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of this invention include but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as succinate. d-atocopherol polyethylene glycol 1000, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, pH-regulating substances, such as phosphates, glycine, sorbic acid, potassium sorbate , mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, RR I Π7Π / 77Π7 / 3 / ΥΙΛΙ polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool grease. Cyclodextrins such as u-, P- and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be used advantageously to improve the delivery of compounds of the formulas described in the present. The pharmaceutical compositions may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and suspensions, dispersions and aqueous solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oil phase combined with emulsifying and / or suspending agents. If desired, certain sweeteners, flavorings and / or colorings can be added. Pharmaceutical compositions may comprise formulations using microencapsulation or liposome techniques, several examples of which are known in the art. The pharmaceutical compositions can be administered by nasal spray or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or others. solubilizing or dispersing agents, examples of which are also well known in the art. 9. - Treatment kits One aspect of the present invention relates to a kit for conveniently and effectively carrying out the methods or uses according to the present invention. In general, the pharmaceutical package or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially adapted for the delivery of oral and solid forms such as tablets or capsules. Said kit preferably includes a number of unit dosages and may also include a card that has the dosages oriented in the order of their intended use. If desired, a memory aid may be provided, for example, in the form of numbers, letters or other markings or with a calendar insert, which designates the days in the treatment schedule on which doses can be administered. Optionally associated with such container(s) may be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects the agency's approval of the manufacture, use or sale for administration in humans. The following representative examples contain additional important exemplification information and guides that may be adapted to the practice of this invention in its various embodiments and their equivalents. These examples are intended to help illustrate the invention, and are not intended, nor should they be construed, to limit its scope. In fact, several modifications of the invention and many additional embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art upon review of this document, including the following examples and references to the scientific publications and patent literature cited herein. The contents of the cited references are incorporated herein by reference to help illustrate the state of the art. Furthermore, for the purposes of this invention, the chemical elements are identified according to the periodic table of the elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and Organic Chemistry, Morrison & Boyd (3d Ed), the complete contents of both are incorporated herein by reference. 10. - Synthesis schemes The compounds of the invention can be prepared by one skilled in the art following techniques and procedures recognized in the art. More specifically, the compounds of the invention can be prepared as set forth in the schemes, methods and examples set forth below. One skilled in the art will recognize that the individual steps in the following schemes can be varied to provide the compounds of the invention. Reagents and starting materials are readily available to one skilled in the art. All substituents, unless otherwise specified, are as previously defined. RRI bZn / ZZnZ / D / YIAI EXAMPLES The following are the abbreviations used and their meaning in the specification: EtOAc: Ethyl acetate 5 DCM: Dichloromethane ACN: Acetonitrile THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide MeOH: Methanol 10 EtOH: Ethanol DMF: N,N-Dimethylformamide DMA: N,N-Dimethylacetam¡de DMF DMA: Ν,Ν- Dimethylformamide dimethylacetal NCS: N-Chlorosuccinimide 15 NBS: N-Bromosuccinimide NIS: N-Iodosuccinimide Pd-C: Palladium on carbon LDA: Lithium diisopropylamide TFA: Trifluoroacetic acid 20 PTSA: p-Toluene sulfonic acid DIBAL-H: Diisobutylaluminum hydride LAH: Lithium aluminum hydride Py: Pyridine DPPA: Diphenylphosphoryl azide 25 GDI: 1,1-Carbonyl diimidazole TEA: Triethylamine DIPEA: Ν,Ν-Diisopropylethylamine DMAP: 4-(Dimethylamino)pyridine EDCI: N-(3-dimet¡lam¡noprop¡l)-N-ethylcarbod¡mide hydrochloride 30 HATU: (l-[Bis(dimet¡lam¡no)met¡len]-lH-l, 2,3-tnazolo[4,5-b]pyridínium hexafluorophosphate HOBT: 1- Hydroxybenzo triazole TfOH: Trifluoromethane sulfonic acid dppf: 1,1 Ferrocenedi¡l-bas(diphenylphosphine) 3-oxide 35 DAST: (diethylamine)sulfur trifluoride Pd2(dba)3: Tris(dibenzylideneacetone) dipalladium(0) Boc: tert-Butoxycarbonyl Ac: Acetyl TMSI: trimethylsilyl iodide TBAI: Tetrabutylammonium iodide PPh3: Triphenyl phosphine dba: Dibenzylideneacetone BINAP: 2,2'-Bis(diphenyl phosphino)-l,l'-bi-naphthyl MsCI: Methanesulfonyl chloride 10 TsCI: Toluenesulfonyl chloride DMAP: 4-Dimethyl aminopyridine LiHMDS: Lithium bis(trimethylsilyl)amide NaHMDS: Bis(trimethylsil) sodium l)amide DMS: dimethyl sulfide 15 DME: dimethoxyethane DCE: Dichloroethane NMR: Nuclear Magnetic Resonance LC-MS: Liquid Chromatography-Mass Spectrometry ESI-MS: Electrospray Ionization Mass Spectrometry 20 GCMS: Gas Chromatography Mass Spectrometry TLC: Thin Layer Chromatography TCR: T cell receptor BCR: B cell receptor CARD: Caspase activation and recruitment domain 25 mM: millimolar μΜ: micromolar mL: microliter ng: nanogram nM: nanomolar 30 nm: nanometer IC5o: average maximum inhibitory concentration OD: Optical density A. Biological examples Biology Example 1 HPK1 Biochemical Assay This example used the ADP-Glo™ kinase assay to measure the effect of the compounds RR Lfrzn / Zznz / D / YIAI potential HPK1 inhibitors on HPK1 kinase activity. The ADP-Glo™ Kinase Assay (Promega Corp., Madison, WI) measures ADP formed from a kinase reaction. According to manufacturing, ADP formed in a kinase assay is first converted to ATP, which is then used to generate light in a 5-luciferase reaction. The luminescence generated correlates with the kinase activity. An exemplary experimental setting is described below, although minor adjustments may be made to individual trials. rr i πζη / ζζηζ / ζι / γΐΛΐ Materials and equipment 1.- Reagents: Reagents Supplier Supplier Catalog HPK-1 Signal Chem M23-11G-10 MBP Signal Chem M42-51N ATP From ADP-Glo ​​Kinase Kit - ADPGLO™ Kinase Kit Promega V9102 10% BSA Stock Solution Miltenyi 130-091-376 DTT Sigma D0632 MgCb Sigma 208337 Trizma base Sigma T1503 2.- Equipment and Supplies: Equipment Source #Cat Greiner 96V Bottom Well Plate 651201 Greiner 384-Well Plates 6007290 Labcyte LP0200 Bravo LDV Plate Agilent - Envision PerkinElmer - Water System Millipore Milli-Q Reference System - 10 pL Bravo Tips Axygen VT-384 - lOuL-R 30 μL Bravo Tips Axygen VT-384-31UL-R RAININ Manual Single-Channel Pipette - Thermo / RAININ Electronic Multi-Channel Pipette - 3.- Plate configuration 3-fold serial dilution of compounds from 10 μΜ (higher concentration) to 0.508 nM (lower concentration). The positive control is 10 μΜ Reference + enzyme + substrate. The negative control is 1% DMSO + enzyme + substrate. 4.- Procedures 1. - Preparation of! Tris pH buffer pH7.5; 20 mM MgCb, 0.1 mg / ml BSA, 50 μΜ DTT pH regulator reserve 1M Tris, PH7.5, 121.14 g / molar Add 6.057 g to 50 mL of H2O, adjust the PH to 7.5 ________1M MgCb, 95.21 g / molar____________________ Add 4.7605 g to 50 mL of H2O Add 20 mL of 1M Tris and 10 mL of 1M MgCb to 470 mL of ddH2O to obtain the buffer stock, and store at RT. 2. - Preparation of 1*fresh assay pH regulator AA I ^70 / 7707 / D / YIAI Reagent [Reserve] [Final] Times Add (mL) DTT (mM) 10 0.05 200 0.015 BSA (mg / mL) 100 0.1 1000 0.003 pH regulator reserve 3 3. - Preparation of the compounds 1) The compounds were diluted to 1 mM, by mixing 10 pL of stocks of the respective compound at 10 mM with 90 pL of DMSO. 2) Compounds were then diluted 3-fold for 10 doses (5 pL to 10 pL dilution) by BRAVO. The concentration of the main compound was 1 mM (lOOx), the concentration of DMSO was 100%. 3) Transfer 100 nL of each diluted compound sample to a 384-well plate (Corning-4512) by ECHO. 4) Centrifuge the plate at 1,500 rpm for 1 minute. . - Preparation of the 2x A TP-MBP mixture: pM ATP, 0.2 pg / pL MBP in kinase buffer (final concentration: 10 pM ATP, 0.1 pg / pL MBP) Reagent [Reserve] [Work] [Final] Times Add (PL) Assay pH regulator (pL) Total (PL) ATP (pM) 10,000 20 10 500 0.2 79.8 100 MBP (pg / pL) 1 0.2 0.1 5 20.00 .- Preparation of 2χ HPK1 working solution with test pH regulator. The final concentration of HPK1 was 0.6 ng / pL. For compounds with high potency, the lowest concentration of HPK1 was used (0.26 ng / pL-0.065 ng / pL). .- Add 5 pL / well of 2χ HPK1 working solution, centrifuge at 1,500 rpm for 1 minute. .- Add 5 pL / well of 2x ATP-Substrate, Centrifuge at 1,500 rpm for 1 minute. .- Incubate at 25°C for 1 hour (or 6 hours for compounds with high potency). .- Add 5 pL / well of ADP-GLO™ reagent to stop the kinase reaction and deplete the unconsumed ATP. Centrifuge at 1,500 rpm for 1 minute. Incubate at 25°C for 40 min. .- Add 10 pL of kinase detection reagent to convert ADP to ATP. Centrifuge at 1,500 rpm for 1 minute. Incubate at 25°C for 40 min. .- Record the luminescence signal in an Envision plate reader (384-CTG). 5.- Data Analysis The percentage (%) of inhibition at each concentration of the compound is calculated based on and in relation to the signal in the high and low control wells contained in each assay plate. High control wells served as 0% inhibition, and low control wells containing no compound but DMSO (final concentration = 0.5%) served as 100% inhibition. Concentrations and % inhibition values ​​for the tested compounds are plotted, and the compound concentration required for 50% inhibition (IC50) is determined with a three-parameter logistic dose response equation. The endpoint value (IC50) for the reference peptide / compound was evaluated in each experiment as a quality control measure. If the endpoint value was within 3 times the expected value, then the experiment was considered acceptable. Biology Example 2 PKC-theta Biochemical Assay This example used the ADP-Glo™ kinase assay to measure the effect of potential HPK1 inhibitor compounds on PKC-theta kinase activity. An exemplary experimental setting is described below, although minor adjustments may be made to individual trials. RRI b7n / 77O7 / 3 / YIAI Materials and equipment 1.- Reagents: Description Supplier Catalog PKC theta Signal Chem P74-10G-10 PKCtide Signal Chem P15-58-1MG ATP From ADP-Glo ​​Kinase Kit - PKC Lipid Activator (10x, 500 Signal Chem L51-39-500 mL) ADP-GLO™ Kinase Kit Promega V9102 10% BSA Stock Solution Miltenyi 130-091-376 DTT Sigma D0632 MgCb Sigma 208337 Trizma Base Sigma T1503 2.- Equipment and Supplies: RR I b7n / 77n7 / D / YIAI Equipment Source #Cat Greiner 96V Bottom Well Plate 651201 Corning 4512 384-Well Plates Labcyte LP0200 Bravo LDV Plate Agilent - Envision PerkinElmer - Water System Millipore Milli-Q Reference System - 10 μί Bravo Tips Axygen VT-384- 10uL-R 30 μL Bravo Tips Axygen VT-384-31uL-R RAININ Manual Single-Channel Pipette - Thermo / RAININ Electronic Multi-Channel Pipette - 3.- Plate configuration 3-fold serial dilution of compounds from 10 μΜ (higher concentration) to 0.508 nM (lower concentration). The positive control is 10 μΜ Reference + enzyme + substrate. Negative control 5 is 1% DMSO + enzyme + substrate. .- Procedures 1. - Preparation of! Tris pH buffer pH7.5; 20 mM MgCb, 0.1 mg / ml BSA, 50 μΜ DTT pH regulator reserve 1M Tris, PH7.5, 121.14 g / molar Add 6.057 g to 50 mL of H2O, adjust the PH to 7.5 ________1M MgCb, 95.21 g / molar___________________________ _______Add 4.7605 g to 50 mL of H2O______________________ Add 20 mL of 1M Tris and 10 mL of 1M MgCb to 470 mL of ddH2Ü to obtain the pH regulator reserve, and store at RT. 2. - Preparation of 1*fresh assay pH regulator Reagent [Reserve] [Final] Times Add (mL) DTT (mM) 10 0.05 200 0.015 BSA (mg / ml) 100 0.1 1000 0.003 Lipid activator PKC 10 1 10 0.3 buffer reserve 3 3. - Preparation of the compounds 1) The compounds were diluted to 1 mM, by mixing 10 pL of stocks of the respective compound at 10 mM with 90 pL of DMSO. 2) Compounds were then diluted 3-fold for 10 doses (5 pL to 10 pL dilution) by BRAVO. The concentration of the main compound was 1 mM (100x), the concentration of DMSO was 100%. 3) Transfer 50 nL of each diluted compound sample to a 384-well plate (Corning-4512) by ECHO. 4) Centrifuge the plate at 1,500 rpm for 1 minute. 4. - Preparation of 2* enzyme working solution in kinase pH regulator: Enzyme [Reserve] [Work] [Final] Times Add (ML) Assay pH regulator (pL) Total (mL) PKC theta (ng / pL) 100 0.25 0.125 400.0 1.0 399.0 400 5. - Preparation of mixture A TP-sub 2x: Enzyme [Reserve ] [Work] [Final] Times Add (ML) Assay pH regulator (pL) Total (ML) ATP(pM) 10,000 60 30 167 2.40 237.6 400 PKC tide (pg / pL) 1 0.4 0.2 2.50 160.00 6.- Add 2.5 pL / well of 2x enzyme working solution, centrifuge at 1,500 rpm for 1 minute. .- Add 2.5 pL / well of 2x ATP-Substrate, Centrifuge at 1,500 rpm for 1 minute. .- Incubate at 25°C for 60 min. .- Add 5 pL / well of ADP-GLO™ reagent to stop the kinase reaction and deplete the unconsumed ATP after 1 hour. Centrifuge at 1,500 rpm for 1 minute. Incubate at 25°C for 40 min. .- Add 10 pL of kinase detection reagent to convert ADP to ATP. Centrifuge at 1,500 rpm for 1 minute. Incubate at 25°C for 40 min. .- Record the luminescence signal in an Envision license plate reader (384-USL). .- Analysis of data The percentage (%) of inhibition at each concentration of the compound is calculated based on and in relation to the signal in the high and low control wells contained in each assay plate. High control wells served as 0% inhibition, and low control wells containing no compound but DMSO (final concentration = 0.5%) served as 100% inhibition. Concentrations and % inhibition values ​​for the tested compounds are plotted and the compound concentration required for 50% inhibition 5 (IC50) is determined with a three-parameter logistic dose response equation. The end point value (IC50) for the reference peptide / compound was evaluated in each experiment as a quality control measure. If the endpoint value was within 3 times the expected value, then the experiment was considered acceptable. Biology Example 3 TBK1 Biochemical Assay This example used the ADP-Glo™ Kinase Assay to measure the effect of potential HPK1 inhibitor compounds on TBK1 kinase activity. An exemplary experimental setting is described below, although minor adjustments may be made to individual trials. Materials and equipment aa Lfrzn / zznz / q / viAi 1.- Reagents: Description Supplier Catalog TBK1 Signal Chem T02-10G-10 MBP Signal Chem M42-51N ATP From ADP-Glo ​​Kinase Kit - ADP-GLO™ Kinase Kit Promega V9102 10% BSA Stock Solution Miltenyi 130-091-376 DTT Sigma D0632 MgCI2 Sigma 208337 Trizma base Sigma T1503 .- Equipment and Supplies: Equipment Source #Cat Greiner 96V Bottom Well Plate 651201 Corning 4512 384 Well Plate LDV Labcyte Plate LP0200 Bravo Agilent - Envision PerkinElmer - Water System Millipore Milli-Q Reference System - 10 pL Bravo Tips Axygen VT-384- 10uL-R 30 μL Bravo Tips Axygen VT-384-31uL-R RAININ Manual Single-Channel Pipette - Thermo / RAININ Electronic Multi-Channel Pipette - 3.- Plate configuration See above. .- Procedures 1. - Preparation of! Tris pH buffer pH7.5; 20 mM MgCb, 0.1 mg / ml BSA, 50 μΜ DTT pH regulator reserve 1M Tris, PH7.5, 121.14 g / molar Add 6.057 g to 50 mL of H2O, adjust the PH to 7.5 ________1M MgCb, 95.21 g / molar_____________________________ _______Add 4.7605 g to 50 mL of H2O_______________________ Add 20 mL of 1M Tris and 10 mL of 1M MgCb to 470 mL of ddH2O to obtain the buffer stock, and store at RT (room temperature). RR LfrZn / ZZnZ / q / YIAI 2. - Preparation of 1*fresh assay pH regulator Reagent [Reserve] [Final] Times Add (mL) DTT (mM) 10 0.05 200 0.015 BSA (mg / ml) 100 0.1 1000 0.003 PH regulator reserve 3 3. - Preparation of the compounds 1) The compounds were diluted to 1 mM, by mixing 10 pL of stocks of the respective compound at 10 mM with 90 pL of DMSO. 2) Compounds were then diluted 3-fold for 10 doses (5 pL to 10 pL dilution) by BRAVO. The concentration of the main compound was 1 mM (100x), the concentration of DMSO was 100%. 3) Transfer 50 nL of each diluted compound sample to a 384-well plate (Corning-4512) by ECHO. 4) Centrifuge the plate at 1,500 rpm for 1 minute. 4. - Preparation of 2x enzyme working solution in kinase pH regulator: Enzyme [Reserve ] [Work] [Final] Times Add (PL) Assay pH regulator (PL) Total (PL) TBK1 (ng / pL) 100 1.6 0.8 62.5 6.4000 393.6 400 5. - Preparation of mixture A TP-sub 2x: Reagent [Reserve] [Work] [Final] Times Add (PL) Assay pH regulator (pL) Total (PL) ATP (pM) 10,000 50 25 200 2.00 318.0 400 MBP (pg / pL) 1 0.2 0.1 5 80.00 6.- Add 2.5 pL / well of 2x enzyme working solution, centrifuge RRL^zn / zznz / q / YiAi 1,500 rpm for 1 minute. .- Add 2.5 pL / well of 2x ATP-Substrate, Centrifuge at 1,500 rpm for 1 minute. .- Incubate at 25°C for 60 min. .- Add 5 pL / well of ADP-GLO™ reagent to stop the kinase reaction and deplete the unconsumed ATP after 1 hour. Centrifuge at 1,500 rpm for 1 minute. Incubate at 25°C for 40 min. .- Add 10 pL of kinase detection reagent to convert ADP into ATP. Centrifuge at 1,500 rpm for 1 minute. Incubate at 25°C for 40 min. .- Record the luminescence signal in an Envision license plate reader (384-USL). 5.- Data Analysis The percentage (%) of inhibition at each concentration of the compound is calculated based on and in relation to the signal in the high and low control wells contained in each assay plate. High control wells served as 0% inhibition, and low control wells containing no compound but DMSO (final concentration = 0.5%) served as 100% inhibition. Concentrations and % inhibition values ​​for the tested compounds are plotted, and the compound concentration required for 50% inhibition (IC50) is determined with a three-parameter logistic dose response equation. The endpoint value (IC50) for the reference peptide / compound was evaluated in each experiment as a quality control measure. If the endpoint value was within 3 times the expected value, then the experiment was considered acceptable. Biology Example 4 JAK3 Biochemical Essay This example used the ADP-Glo™ Kinase Assay to measure the effect of potential HPK1 inhibitor compounds on JAK3 kinase activity. An exemplary experimental setting is described below, although minor adjustments may be made to individual trials. Materials and equipment 1.- Reagents: Description Supplier Catalog JAK3 Thermo fisher PV3855 POÜ(E4Y1) Signal Chem P61-58 Ultra-pure ATP Promega Del ADP-GLO™ Kinase Kit Promega ADP-GLO™ Kinase Kit V9102 10% BSA Stock Solution Miltenyi 130-091-376 DTT Sigma 03 / 12 / 3483 MgCb Sigma M1028 Tris-base Sigma T1503 2.- Equipment and Supplies: RR LfrZn / ZZnZ / q / YIAI Equipment Source #Cat 384-Well Low Dead Volume Microplate Echo Qualified Perkinelmer LP0200 Assay Plate, Corning® 384-Well Microplate, Low Volume Corning C4512 MICROPLATE, 96 WELL, PP, V-BOTTOM Greiner 651201 10 pL Bravo Tips Axygen 301 -78-401 Axygen 30 pL Bravo Tips 301-78-301 ECHO Perkinelmer - Envision PerkinElmer - BRAVO - - Water System Millipore Milli-Q Reference System - Cimo SPX-60BSH-II Incubator ElclipTip Multichannel Electronic Pipette (1-30 pL) Thermo Fisher 4671030BT 3.- Procedures 1. - Prepare JAK3 kinase pH regulator Freshly add DTT and BSA in pH regulator (Final conc.: 40 mM Tris pH7.5; 20 mM MgCb, 0.1 mg / ml BSA, 50 μΜ DTT). Reagent [Stock]) [Final] Times Add(pL) DTT (mM) 10 0.05 200 15 BSA (mg / ml) 100 0.1 1,000 3 lx Kinase pH regulator lx lx 1 2,982 Total 3,000 2. - Preparation of the compounds For compounds tested: Compounds were diluted to 1 mM by mixing 5 pL of 10 mM compound stocks to 45 pL of DMSO. The compound solutions were then diluted 3-fold for 10 doses. The concentration of the main compound was 1 mM (100x), the concentration of DMSO was 100%. nL of each 10 doses of the diluted compound were added to the 384-well assay plate (Corning #4512) by ECHO. For positive control, 50 nL of lmM reference compound was added to the 384-well assay plate (Corning #4512) by ECHO. For negative control: 50 nL of DMSO was transferred to the 384-well assay plate as a negative control. The test plate was centrifuged at 1,500 rpm for 1 minute. 3. - Compounds were transferred by ECHO following the design below: Reference and test compounds 1-15: 3-fold serial dilution from 10 μΜ to 0.508 nM (10 doses); the negative control is 0.78 ng JAK3, 4 μΜ ATP and 0.2 pg / pL poly, 1% DMSO; the positive control is the maximum dose of the reference compound, 0.78 ng JAK3, 0.2 pg / pL Poly(E4Yl), 4 p MATP, 1% DMSO. .- Add 2.5 pL / well of 2χ JAK3 working solution using a pipette (Thermo, 30 pL multi-channel), centrifuge at 1,500 rpm for 1 minute. .- Add 2.5 pL / well of a 2x ATP-Poly(E4Yl) working mixture using a pipette (Thermo, 30 pL multi-channel), centrifuge at 1,500 rpm for 1 minute. .- Incubate the test plate at 25°C for 60 min. - Add 5 pL / well of ADP-GLO™ reagent per BRAVO to stop the kinase reaction and deplete unconsumed ATP after 1 hour. Centrifuge at 1,500 rpm for 1 minute. Incubate at 25°C for 40 min. .- Add 10 pL of BRAVO kinase detection reagent to convert ADP to ATP. Centrifuge at 1,500 rpm for 1 minute. Incubate at 25°C for 40 min. .- Record the luminescence signal in an Envision license plate reader (384-USL). .- Process the data using XL-fit. % inhibition = [l-(test well - negative control) / (positive control - negative control)]*100%. 5.- Data Analysis The percentage (%) of inhibition at each concentration of the compound is calculated based on and in relation to the signal in the negative and positive control wells contained in each assay plate. Negative control wells served as 0% inhibition, and positive control wells served as 100% inhibition. The concentrations and the RR I ^70 / 7707 / D / YIAI % inhibition values ​​for the compounds tested and the compound concentration required for 50% inhibition (IC50) is determined with a three-parameter logistic dose response equation. The end point (IC50) for the reference peptide / compound was evaluated in each experiment as a quality control measure. If the value of endpoint 5 was within 3 times the expected value then the experiment was considered acceptable. Biology Example 5 ZAP70 Biochemical Assay Protocol This example used the ADP-Glo™ Kinase Assay to measure the effect of potential HPK1 inhibitor compounds on ZAP70 kinase activity. An exemplary experimental setting is described below, although minor adjustments may be made to individual trials. Materials and equipment rr i bzn / zznz / D / YiAi 1.- Reagents: Description Supplier Catalog ZAP70 Sigma Chem Z02-10G Pol¡(E4Yl) Sigma Chem P61-58 Ultra-pure ATP Promega ADP-Glo ​​Kinase Kit Promega ADP-GLO™ Kinase Kit V9102 10% BSA Stock Solution Miltenyi 130- 091-376 DTT Sigma 03 / 12 / 3483 DMSO Sigma D5879 MnCL Sigma M5505 MgCL Sigma M1028 Tris base Sigma TI 503 2.- Equipment and Supplies: Equipment Source #Cat 384-Well Low Dead Volume Microplate Echo Qualified Perkinelmer LP0200 Assay Plate, Corning® 384-Well Microplate, Low Volume Corning C4512 MICROPLATE, 96 WELL, PP, V-BOTTOM Greiner 651201 10 pL Axygen 301 Bravo Tips -78-401 Axygen 30 pL Bravo Tips 301-78-301 ECHO Perkinelmer - Envision PerkinElmer - BRAVO - - Water System Millipore Reference System Milli-Q - Cimo SPX-60BSH-II Incubator El-clipTip Multichannel Pipette (1- 30 pL) Thermo Fisher 4671030BT 3.- Procedures.- Preparation of the ZAP70 pH regulator: Freshly add DTT and BSA in pH regulator (Final conc.: 40 mM Tris pH7.5; 20 mM MgCl2, 0.1 mg / ml BSA, 50 μΜ DTT, 2 mM MnCl2). RRLfrZÍVZZnZ / q / YIAI Reagent [Reserve] [Final]( mM: Times Add(pL) DTT (mM) 10 0.05 200 15 BSA (mg / ml) 100 0.1 1000 3 MnCb 500 mM 2 250 12 lx Kinase pH regulator lx lx 1 2970 Total 3000 2.- Preparation of the compound: For compounds tested, compounds were first diluted to 1 mM by mixing 5 pL of the 10 mM compound stock to 45 pL of DMSO. These compounds were then diluted 3-fold for 10 doses. The concentration of the main compound was 1 mM (100x), the concentration of DMSO was 100%. nL of the compound solutions were transferred to a 384-well assay plate (Corning #4512) by ECHO. For positive control: 50 nL of 1 mM staurosporine was transferred to a 384-well assay plate as a positive control. For negative control: 50 nL of DMSO was transferred to the 384-well assay plate as a negative control. Spin the test plate at 1,500 rpm for 1 minute. .- Compounds were transferred by ECHO following the design below: Staurosporine and test compounds 1-15: 3-fold serial dilution from 10 pM to 0.508 nM (10 doses); the negative control is 6.25 ng ZAP70, 10 pM ATP and 0.4 pg / pL poly, 1% DMSO; the positive control is 10 pM of staurosporine, 6.25 ng of ZAP70, 10 pM of ATP and 0.4 pg / pL of poly, 1% DMSO. .- Prepare the mixture of 2x ATP-Poly(E4Yl): 20 pM ATP, 0.8 pg / pL poly(E4Yl) in kinase pH regulator (final concentration: 10 pM ATP, 0.4 pg / pL poly(E4Yl). E4Yl). .- Prepare 2χ ZAP70 working solution: (2.5 ng / pL) in kinase pH regulator (Final Conc. was 1.25 ng / pL). .- Add 2.5 pL / well of 2χ ZAP70 working solution using a pipette (Thermo, 30 pL multi-channel), centrifuge at 1,500 rpm for 1 minute. .- Add 2.5 pL / well of a 2x ATP-Poly(E4Yl) working mixture using a pipette (Thermo, 30 pL multi-channel), centrifuge at 1,500 rpm for 1 minute. 100.- Incubate the test plate at 25°C for 60 min. .- Add 5 pL / well of ADP-GLO™ reagent per BRAVO to stop the kinase reaction and deplete unconsumed ATP after 1 hour. Centrifuge at 1,500 rpm for 1 minute. Incubate at 25°C for 40 min. .- Add 10 pL of BRAVO kinase detection reagent to convert ADP to ATP. Centrifuge at 1,500 rpm for 1 minute. Incubate at 25°C for 40 min. .- Record the luminescence signal in an Envision license plate reader (384-USL). .- Process the data using XL-fit. % inhibition = [l-(test well - negative control) / (positive control - negative control)]*100%. 5.- Data Analysis The percentage (%) of inhibition at each concentration of the compound is calculated based on and in relation to the signal in the negative and positive control wells contained in each assay plate. Negative control wells served as 0% inhibition, and positive control wells served as 100% inhibition. Concentrations and % inhibition values ​​for the tested compounds are plotted and the compound concentration required for 50% inhibition (IC50) is determined with a three-parameter logistic dose response equation. The endpoint value (IC50) for the reference peptide / compound was evaluated in each experiment as a quality control measure. If the endpoint value was within 3 times the expected value then the experiment was considered acceptable. Biology Example 6 LCK Biochemical Assay Protocol This example used the ADP-Glo™ Kinase Assay to measure the effect of potential HPK1 inhibitor compounds on Lck kinase activity. An exemplary experimental setting is described below, although minor adjustments may be made to individual trials. Materials and equipment 1.- Reagents: Description Seller LCK Catalog Sigma Chem Z03-10G Pol¡(E4Yl) Sigma Chem P61-58 Ultra-pure ATP Promega ADP-Glo ​​Kinase Kit Promega ADP-GLO™ Kinase Kit V9102 10% BSA Stock Solution Miltynyl Biotec 130 -091-376 DTT Sigma 03 / 12 / 3483 DMSO Sigma D5879 MnCb Sigma M5505 MgCI2 Sigma M1028 Tris base Sigma TI 503 101 RR LfrZn / ZZnZ / q / YIAI 2.- Equipment and Supplies: Equipment Source #Cat 384-Well Low Dead Volume Microplate Echo Qualified Perkinelmer LP0200 Assay Plate, Corning® 384-Well Microplate, Low Volume Corning C4512 MICROPLATE, 96 WELL, PP, V-BOTTOM Greiner 651201 10 pL Bravo Tips Axygen 301 -78-401 Axygen 30 pL Bravo Tips 301-78-301 ECHO Perkinelmer - Envision PerkinElmer - BRAVO - - Water System Millipore Reference System Milli-Q - Cimo SPX-60BSHII Incubator ElclipTip Multichannel Electronic Pipette (1-30 pL) Thermo Fisher 4671030BT 3.- Procedures.- Preparation of the LCK kinase pH regulator: Freshly add DTT and BSA in pH regulator (Final conc.: 40 mM Tris pH7.5; 20 mM MgCb, 0.1 mg / ml BSA, 50 μΜ DTT, 2mM MnCb). Reagent [Reserve] [Final]( mM: Times Add(pL) DTT (mM) 10 0.05 200 15 BSA (mg / ml) 100 0.1 1000 3 MnCb 500 mM 2 250 12 lx Kinase pH regulator lx lx 1 2970 Total 3000 2.- Preparation of the compound: For compounds tested, compounds were first diluted to 1 mM by mixing 5 pL of the 10 mM compound stock to 45 pL of DMSO. The compound solutions were then diluted 3-fold for 10 doses. The concentration of the main compound was 1 mM (100x), the concentration of DMSO was 100%. For positive control: Staurosporine was diluted to 300 pM by mixing 3 pL of 10 mM stock with 97 pL of DMSO. nL of the compound and 300 pM staurosporine solutions were transferred to a 384-well assay plate (Corning #4512) by BRAVO. For negative control: 50 nL of DMSO was transferred to the 384-well assay plate as a negative control. Centrifuge the test plate 102 1,500 rpm for 1 minute. .- Compounds were transferred by ECHO following the design below: Staurosporine and test compounds 1-15: 3-fold serial dilution from 10 μΜ to 0.508 nM (10 doses); the negative control is 7 ng of LCK, 20 μΜ of ATP and 0.4 pg / pL of poly, 1% DMSO; the positive control is 3 μΜ of staurosporine, 7 ng of LCK, 20 μΜ of ATP and 0.4 pg / pL of poly, 1% DMSO. .- Prepare the 2x ATP-Poly(E4Yl) mixture: 40 μΜ of ATP, 0.8 pg / pL of poly(E4Yl) in kinase pH regulator (final concentration: 20 μΜ of ATP, 0.4 pg / pL of poly(E4Yl). E4Yl). .- Prepare 2x LCK working solution: (2.8 ng / pL) in kinase pH regulator (Final Conc. was 1.4 ng / pL). .- Add 2.5 pL / well of 2x LCK working solution using a pipette (Thermo, 30 pL multi-channel), centrifuge at 1,000 rpm for 1 minute. .- Add 2.5 pL / well of a 2x ATP-Poly(E4Yl) working mixture using a pipette (Thermo, 30 pL multi-channel), centrifuge at 1,000 rpm for 1 minute. .- Incubate the test plate at 25°C for 60 min. .- Add 5 wells of ADP-GLO™ reagent per BRAVO to stop the kinase reaction and deplete unconsumed ATP after 1 hour. Centrifuge at 1,000 rpm for 1 minute. Incubate at 25°C for 40 min. .- Add 10 pL of BRAVO kinase detection reagent to convert ADP to ATP. Centrifuge at 1,000 rpm for 1 minute. Incubate at 25°C for 30 min. .- Record the luminescence signal in an Envision license plate reader (384-USL). .- Process the data using XL-fit. % inhibition = (Positive control - test well) / (Negative control-positive control) xl00%. 4.- Data Analysis The percentage (%) of inhibition at each concentration of the compound is calculated based on and in relation to the signal in the negative and positive control wells contained in each assay plate. Negative control wells served as 0% inhibition, and positive control wells served as 100% inhibition. Concentrations and % inhibition values ​​for the tested compounds are plotted, and the compound concentration required for 50% inhibition (IC50) is determined with a three-parameter logistic dose response equation. The endpoint value (IC50) for the reference peptide / compound was evaluated in each experiment as a quality control measure. If the value of the end point RR I Π7Π / 77Π7 / 3 / ΥΙΛΙ 103 was within 3 times the expected value so the experiment was considered acceptable. Biology Example 7 MAP4K3 Protein Kinase Assay This example provides an assay protocol for measuring phosphorylation of a peptide substrate by the MAP4K3 protein kinase. Briefly, MAP4K3, its substrate, and cofactors (ATP and Mg2+) were combined in one well of a microtiter plate and incubated for 5 hours at 25°C. At the end of the incubation, the reaction was quenched by the addition of an EDTA-containing buffer. Substrate and product are separated and quantified electrophoretically using Caliper Life Sciences' microfluidic-based LabChip 3000 drug discovery system. For this assay, the MAP4K3 substrate is FAM-GAGRLGRDKYKTLRQIRQ-NH2 (FAM is carboxyfluorescein). The peptide substrate is preferably >98% pure by Capillary Electrophoresis. A typical test configuration and condition is provided below. .- To one well of a 384-well plate, add 5 pL of 2 x enzymatic pH regulator (or control). .- Add 100 nL of 100x compound. The enzyme and compound can be preincubated at this time if desired. .- Add 5 pL of 2x substrate pH regulator. .- Incubate the plate at 25°C for 5 hours. .- Terminate the reaction by adding 40 pL of 1.25 x stop pH regulator. .- Create a job on a Caliper LabChip® 3000 drug discovery system using the values ​​in the following table. RR I bZn / ZZnZ / D / YIAI Separation Conditions for a 12 Sipper Chip Initial delay sip time 50 sec Post-sample buffer sip time 40 sec Post-dye buffer sip time 40 sec Sample sip time 0.2 sec Final delay sip time 120 sec Time colorant sip rate 0.2 sec Pressure -13789.5 Pasca les (-2 psi) Downstream voltage -3000 volts Upstream voltage -800 volts .- Load the plate and begin electrophoresis using blue laser (480 nm) to 104 excitation and green CCD (520 nm) for detection (CCD2). The above test is run under the following reaction condition: 5 hours in total; at 25°C, in the presence of 20 mM 100% EDTA inhibitor The final assay reaction mixture is: 100 mM HEPES, pH 7.5; 0.1% BSA; 0.01% Triton X-100; 1 mM DTT; 5 mM MgCl, 10 μΜ sodium orthovanadate, 10 μΜ beta-glycerophosphate, 20 μΜ ATP; 1% DMSO (of the compound); 0.5 μΜ of FAM-GAGRLGRDKYKTLRQIRQ-NH2; 0.5 nM of the MAP4K3 enzyme. It should be noted that the specific activity of MAP4K3 varies from batch to batch, and the enzyme concentration may need to be adjusted to produce ~10-20% conversion of substrate to product. The product and substrate peptides present in each sample are separated electrophoretically using the LabChip 3000 capillary electrophoresis instrument. As the product and substrate peptides are separated, two fluorescence peaks are observed. The change in the relative fluorescence intensity of the substrate and product peaks is the measured parameter, which reflects the enzyme activity. Capillary electrophoregrams (RDA acquisition files) are analyzed using HTS Well Analyzer software (Caliper Life Sciences). The kinase activity in each sample is determined as the product-sum ratio (PSR): P / (S+P), where P is the peak height of the product peptide and S is the peak height of the peptide. of the substrate. For each compound, the enzyme activity is measured at various concentrations (12 concentrations of the compound separated by 3 x dilution intervals). Negative control samples (0% inhibition in the absence of inhibitor) and positive control samples (100% inhibition, in the presence of 20 mM EDTA) are assembled in replicates of four and used to calculate % values. of inhibition for each compound at each concentration. Percent inhibition (Pmh) is determined using the following equation: P¡nh= (PSRo% - PSR¡nh) / (PSRo%- PSRwo%)*lOO, where PSR¡nh is the ratio of the sum of the product in the presence of the inhibitor, PSRo% is the ratio of the sum of the average product in the absence of the inhibitor, and PSRioo% in the ratio of the sum of the average product in the 100% inhibition control samples. The IC50 values ​​of the inhibitors are determined by fitting the inhibition curves (Pinhversus inhibitor concentration) using a 4-parameter sigmoidal dose-response model using XLfit 4 software (IBDS). Certain materials and pH regulators used in the test are listed below for reference value. ITEM SUPPLIER PART NUMBER Enzyme 105 MAP4K3 Invitrogen Invitrogen-PV63491763523 Substrate FAM-GAGRLGRDKYKTLRQIRQ-NH2 Nanosyn Custom synthesis Control inhibitor «Staurosporine» «LKT» «S7600» pH regulator components HEPES, free acid Calbiochem 391338 HEPES, sodium salt Calbiochem 391333 Triton X-1 00 Sigma T8787 BSA Sigma A3059 Magnesium Chloride Fluka 63020 ATP Disodium Salt Sigma A7699 DTT (Cleland's Reagent) Calbiochem 233153 Sodium Orthovanadate Sigma S6508 Beta-Glyocerophosphate Calbiochem 35675 EDTA, Disodium Salt, Dihydrate VWR VW1474-01 DMSO VWR BJ081-4 Coating Reagent 3 Cali per Life Sci. 760050 Sodium hydroxide, 50% VWR VW3246-1 Hydrochloric acid, concentrated JT Baker 9530-33 Sodium carbonate Mallinckrodt 7521 Sodium bicarbonate Sigma S-6297 Biology Example 8 Efficacy study of compounds on IL2 and IFN-γ released by human Pan T cells This example is an assay method that can be used to determine the effects of the compound on the release of IL2 and IFN-γ using pan T cells and the ELISA assay format. Materials and equipment 1.- Reagents: Name Source #Cat RPMI 1640 ATCC 30-2001 FBS Gibco 10099141 DMSO Sigma D8418 Pen / Strep (100x) Gibco 15140122 No Essential Amino Acid Assay Solution Gibco 11140050 Human IL-2 ELISA Set A (containing anti-human monoclonal antibody (mAb) -Human IL-2, biotinylated anti-human IL-2 mAb, streptavidin-horseradish peroxidase (Sav-HRP) conjugate, recombinant human IL-2) BD ELISA Set B (containing buffer buffer, diluent assay, substrate reagents A and B, stop solution and 20X wash buffer) BD 550534 Human IFN-γ ELISA Set A (containing anti-human IFN-γ mAb, anti-human IFN-γ mAb biotinylated, streptavidin-horseradish peroxidase conjugate (Sav-HRP), recombinant human IFN-γ) BD 555142 106 Beta- Mercaptoethanol Gibco 21985023 PMA Sigma P8139-lmg lonomycin Sigma 4079511MG CD3 anti-human BioXcell BE0001-2 CD28 anti-human BioXcell BE0291 Pan T isolation kit MACS 130-096- 535 LS separation columns MACS 130-042- 401 Solution auto rinse MACS® MACS 130-091- 222 BSA Sigma B2064 0.5M EDTA ThermoFisher 15575020 PBS GE Healthcare Life Sciences SH30256.01 PE anti-CD3 BD 555333 FITC anti-CD4 BD 555346 BV421 anti-CD8 BD 562428 human PBMC Allcells PB 007-3 PB006-C RR I Π7Π / 77η7 / 3 / ΥΙΛΙ 2.- Equipment and Supplies: Name Source #Cat MICROPLATE, 96 WELL, PP, ΕΝ V BOTTOM Greiner 651201 Greiner 96-Well Cell Plates 655180 Flat Bottom 96-Well Plate (High Junction Plate) Greiner 655061 Corning 3599 96-Well Supernatant Dilution Plate 384 Microplate CTG Assay PerkinElmer 6007290 PerkinElmer Envision Plate Reader - Thermo Fisher Cell Incubator - Count star-IC-1000 Automated Cell Counter - Ex-50 Plate Washer BioTek ELx50 / 8 Centrifuge Thermo Centrifuge ST 40R - Water System Millipore Reference System Milli-Q - 3.- Procedures Procedures for the isolation of Pan and preparation of reagents (Day 0): 1.- Cell growth medium: RPMI1640: ATCC, Cat # 30-2001 10% FBS: Gibco, Cat # 10099141 1% Pen-Strep: Gibco, Cat # 15140122 1% non-essential amino: Gibco, Cat #11140050 Beta-Mercaptoethanol: Gibco, Cat#21985023 2.- Preparation of the Pan T isolation pH regulator: 107 Prepare a solution containing phosphate-regulated saline (PBS, pH 7.2, 0.5% bovine serum albumin (BSA), and 2 mM EDTA by diluting the MACS® BSA stock solution (#130-091-376) 20 times with the autoMACS® rinse. Keep the pH regulator at 4°C. Degas the pH regulator before use, as air bubbles could block the column. AAI ^70 / 7707 / D / YIAI Contents [Reserve] [Conc. final] Times Vol. (mL) BSA 10% 0.5% 20 5 mL EDTA 0.5 M 2 mM 250 0.4 mL PBS, pH7.2 lx lx 1 94.6 mL Total 100 mL 3.- Thawing frozen PBMC 1) Preheat the medium in a water bath to 37°C. 2) Quickly thaw the cells in a 37°C water bath. 3) Add the previously warmed medium to a 15 mL tube. Transfer the cells to the tube. 4) Centrifuge 300 x g for 8 min. (centrifuge increment 0, decrement 0). 5) Wash the PBMC using the pH regulator rinse. 6) Centrifuge the PBMC at 300 x g for 8 min, wash twice (centrifuge increment 9, decrement 1). 7) Resuspend the cells with buffered Pan T cell isolation and count the number of cells. 4.- Isolation of pan T cells: Cell staining with microsphere cocktail 1) Prepare the cells and determine the number of cells. Filter the cells with a 70 pm cell filter. 2) Resuspend the cell pellet in 40 pL of pH regulator for 107 cells in total. 3) Add 10 pL of Pan T cell biotin antibody cocktail per 107 cells in total. 4) Mix well and incubate for 10 minutes in the refrigerator (ice). 5) Add 30 pL of pH regulator for 107 cells in total. 6) Add 20 pL of Pan T cell microsphere cocktail for 107 cells in total. 7) Mix well and incubate for 15 minutes in the refrigerator (ice). 8) Proceed to the subsequent separation of magnetic cells. Note: a. Work quickly, keep cells cold and use pre-chilled solutions (2-8°C). B. Volumes provided for magnetic labeling are for 108 a maximum of 107 cells in total. When working with fewer cells, use the same volumes as indicated, c. When working with higher cell numbers, scale up all reagent volumes and total volumes accordingly, d. For optimal performance, it is important to obtain a single-cell suspension before magnetic labeling. Subsequent manual cell separation: 1) Place the LS column in the magnetic field of a suitable MACS separator. For details, refer to the respective MACS column data sheet. 2) Prepare the column by rinsing with 3 mL of pH regulator. 3) Apply the cell suspension to the column. Collect the continuous stream, which represents enriched T cells. 4) Wash the column with 5 mL of pH regulator. Collect the unlabeled cells that pass through, which represent the enriched T cells. Warning: Always wait until the column reservoir is empty before proceeding to the next step. 5.- FACS of pan T cells: 1) Take 50 pL of PBMC and Pan T cells to FACS tubes respectively. 2) Incubate the cells with anti-human CD3 / CD4 / CD8 antibodies (1 pL / l pL / Ι pL / tube) for 20 min at 4 °C. For unstained control, incubate cells with buffered FACS staining. 3) Wash 2 times with cold stain pH regulator (PBS with 0.2% BSA and ImM EDTA). 4) Run FACS. Regulate the CD3+, CD3+CD4+, and CD3+CD8+ population for percentage analysis. 5) If the purity of Pan T cells is greater than 90%, dilute the cell suspension to 1 million cells / mL with the appropriate volume of cell culture medium. 6) Supply the cell suspension in a disposable and sterile reservoir for future use. Procedures for the preparation of compounds and anti-human CD3 / CD28 (Day 0): .- Preparation of the compound Serial dilution of compound (1OOOx source plate) The compounds are solubilized in 100% DMSO at a concentration of 10 mM. They were then diluted 3-fold serially to 8-point doses. RR I b7n / 77O7 / 3 / YIAI 109 4x Composite dose preparation (between plate: Corning-3599): Prepare 4x compound solution in culture medium. Pipette aspirating and expelling. To control ZPE, prepare 0.4% DMSO (4x) in culture medium. For HPE control, prepare 0.4 μΜ of RGT003-026 (4x) in culture medium. .- Anti-human CD3 (reserve conc. 6.76 mg / ml): which is stored at 4°C. 1) Dilute the anti-human CD3 with PBS to the final concentration of 0.5 pg / mL 2) Add 50 pL / well of CD3 to each well, except for the positive and negative control wells. Positive and negative control wells have no CD3 / CD28 stimulation. 3) Incubate at 37°C in a 5% CO2 incubator for 2 hours. 4) Remove 50 pL of the antibody solution from the cell culture plate. Rinse each well twice with 200 pL of sterile PBS each time. .- Preparation of anti-human CD28 (4x) The antibody was diluted with culture medium from the stock concentration of 11.07 mg / mL to 2 pg / mL (4x). .- Preparation of PMA / Inomycin (4x) 1) Dilute PMA to 400 ng / mL (8x) in medium. 2) Dilute Inomycin to 8 pM (8x) in medium. 3) Mix an equal volume of PMA with lonomycin to obtain a mixture 4x. Procedures to stimulate the cell (Day 0).- Transfer 1 x 105 cells / well (100 pUwell) of the cell suspension to a 96-well plate (cell plate: greiner-655180). .- Add 50 pL / well of anti-human CD28 to the cpds and ZPE / HPE controls tested. For positive or negative control, add 50 pL / well of 4x PMA / inomycin solution or culture medium, respectively. .- Add 50 pL / well of the compounds to the cell plate according to the plate map shown below. For ZPE / HPE controls, add 50 pL / well of 0.4% DMSO solution or 0.4 pM RGT003-026 (4x), respectively. For positive or negative control, add 50 pL / well of culture medium. .- Incubate the plate for 48 hours. Procedures for ELISA of IL-2 and IFN-y: Day 1: Cover plates: RRI Π7Π / 77η7 / 3 / ΥΙΛΙ 110 1) Coat microplates with 100 pL per well of IL-2 and IFN-γ capture antibody diluted in coating buffer. For the recommended dilution of the antibody coating, refer to the lot-specific Instruction / Analysis Certificate. Seal the plate and incubate overnight at 4°C. Day 2: Sample collection: 1) After incubation in an incubator at 37°C, 5% CO2 for 48 hours, centrifuge the cell plates at 1,000 rpm for 10 min. Collect 100 pL / well of supernatant and then perform an IL-2 and IFN-γ ELISA assay. The supernatant can be stored at -80°C and the IL-2 and IFN-γ ELISA assay can be performed the next day. The supernatant may need to be diluted 30- to 40-fold to ensure that the assay does not exceed the linear range of the IL-2 and IFN-y standard curve. 2) Add new medium (containing anti-CD28, P / I and the compounds) to the plate, 100 pL / well. 3) Plate map: Day 3-4: IL-2 and IFN-γ ELISA: 1) Aspirate the wells and wash 3 times with > 300 pL / well of wash pH regulator. After the final wash, invert the plate and dry on absorbent paper to remove any residual buffer. 2) Block the plates with > 200 ptywell of assay diluent. Incubate at RT for 1 hour. 3) Vacuum / wash as in step 2. 4) Prepare standards in the assay diluent. Preparation of IL-2 standard stock: Add 1 mL of deionized water to the vial (235 ng / vial), the stock concentration is 235 ng / mL. Reserve standard aliquot at 10 pL / flask, freeze at -80°C. Preparation of standard stock of IFN-γ: Add 1 mL of deionized water to the vial (145 ng / vial), the stock concentration is 145 ng / mL. Stock standard aliquot at 10 pL / flask, freeze at -80 C. Preparation of the standard curve for IL-2 / IFNy: Dilute the standard sample to the maximum concentration of 500 pg / mL. Then run a 2-fold serial dilution to 10-point doses (including blank control). Transfer different concentrations of standards to the ELISA plate, 100 pL / well. 1) Pipette 100 pL of each standard, sample and control into the appropriate wells. Seal the plate and incubate for 2 hours at RT. 2) Vacuum / wash as in step 2, but with a total of 5 washes. RR LfrZn / ZZnZ / q / YIAI 111 3) Add 100 pL of working detector (detection antibody + SAv-HRP reagent) to each well. Seal the plate and incubate for 1 hour at RT. 4) Vacuum / wash as in step 2, but with a total of 7 washes. NOTE: In this final wash step, immerse the wells in the wash buffer for 30 seconds to 1 minute per wash. 5) Add 100 pL of the substrate solution to each well. Incubate the plate (without plate sealer) for 30 minutes at room temperature in the dark. 6) Add 50 pL of stop solution to each well. 7) Read the absorbance at 450 nm within 30 minutes of stopping the reaction. It became normalized OD450nm to OD value at 570nm. 4. - Data analysis: For biochemical assays, the percentage (%) of inhibition at each compound concentration is calculated based on and relative to the signal in the HPE and ZPE wells contained within each assay plate. The HPE wells were considered 100% effective, and the ZPE wells did not contain any compounds but rather DMSO (final concentration = 0.1%) was considered 0% effective. For the cellular assay, the response of IL-2 or IFN-γ (data not shown) over the DMSO control at each compound concentration is calculated. See Table 2. EC2x presents the concentration of the compound that gives a 200% (2-fold) response, and EC50 was calculated using GraphPad Prism. The biochemical and cellular data obtained for the exemplary compounds are listed in Tables 1 and 2 below. 112 TABLE 1 IC50 ratio of JAKs / HPK1 * >558 642 601 >2457 571 * CÚ LO 00 CM 00 o in m 00 i—l 1—1 Λ co CM A IC50 of JAK3 (nM) Relative * + + + + + + + * ω + + + + + + IC50 of HPK1 (nM) Relative * + + + + + + + + + + + + + + + + + + + + * ω + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Structure of the compound Oxide of (l-(5-Chlorine-2-(( 6-methoxy-2-methyl-l, 2,3,4tetrahydro¡soquinolín-7-¡l)amino)p¡nmid¡n-4-¡l)-l / - / indole -3-yl)dimethylphosphina <4i X o tu E = É οι ra E o o.'5 σ = o ' ω । O fS y (D |g o Π (J V LO P E ¿ ra ? e oí ra c c E o o. '5 σ = o oí Ξ 2 2 s o 3 ro c <υ 4-» +¡J X A r= 1 t—1 1—1 O Ό (D •S E at όι i—i . _L 4 § E rxj i £ 2 ή ψ Zl LO p E AA(5-chloro-4-(3,4-dih¡dro¡soquinol¡n-2(l / 7)-¡l)p¡r¡m¡d¡n2-¡ l)-6-methoxy-2-methyl¡l-l,2,3,4-tetrahydro¡soquinolín-7amine / ^(5-chloro-4-(3,4-dihydroquinol¡n-l( 25)-¡l)pyr¡m¡d¡n-2yl)-6-methoxy-2-methyl-l,2,3,4-tetrahydro¡soquinolin-7- amine AL(5- chloro-4-(2,3-dihydro-4 / Ti-benzo[Z7][l,4]oxaz¡n-4¡l)pyrimidin-2-¡l)-6-methoxy¡-2-methyl -l, 2,3,4tetrahydroisoquinolin-7-amine l-(5-Chloro-2-((6-methoxy-2-methyl-l, 2,3,4tetrahydro¡soquinolin-7-¡ l)amino)p¡r¡m¡d¡n-4-¡l)- / V, / Vdimethyl-lMindol-S-carboxamide 1 c oí ro S c E^ c £-5 2 σ δ o ü m 2 O T 2 ro S m E oT δ -C> OI ό ra Φ E 01 ra ¿ E o σ o 0 tu .“2 E 2 2 2 0 = 2 M— 4c <u 4-» -m ·>*_✓ 1 LO A 1"1 i—l O -p (ü .E E ϊί V (ü E ' ro LO C ¿'E íü CX! C । i 0 V <Λ T 'o 0 δ T—1 + J ό δ m — H ro _¡_ T c ό y δ 'τ1 9 « in 2 V <u E íü c . 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E S s । ω = O ΓΜ O Ό H <l>Q. And ¿ CM Ip <—« (U = E rxi rx! ¿ ¿ s 2 E O) iΣ ñ ό "G 2-(2-((6-Methoxy-2-met¡l-l,2,3,4- tetrahydroisoquinolin7-¡l)amino)-7 / 7Lpyrrolo[2,3-í / ]pyr¡m¡din-7-¡l)- / V, / V- dimethylbenzamide Oxide (2-(2-((6-Methoxy-2-methyl-l, 2,3,4- tetrahydro¡soquinolín-7-¡l)amino)-7 / 7Lpyrrolo[2, 3¿ / ]pyr¡mid¡n-7-¡l)phen¡l)dimet¡lphosph¡na íü c ή. ra P ¿ t O o. E S 8 i ω = o m o ií= <υ o . Y ¿ ΓΜ i i—1 Ip * (U = E rxi rxi ¿ ¿ s 2 2 <D ΪΣ Σ ñ ώ Έ co CM σι CM i—1 CO (N m co in 't' co in co LO in in CO m m O RR Lfrzn / Zznz / D / YIAI 115 O i—1 A >10 101 o CM CM A >179 163 i—1 LO o CÑ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 6-Methoxy-2 -methyl- / V-(7-(2-methylpyridin-3-yl)-7 / 7pyrrolo[2,3-o]pyrimidin-2-¡l)-l,2,3,4tetrahydroisoquinolin-7-amine 6- Methoxy-2-methyl- / V-(9-phenyl-9 / - / -purin-2-yl)-l,2,3,4tetrahydroisoquinolin-7-amine 2-(2-((6-Methoxy-2- methyl-l,2,3,4-tetrahydro¡soquinol¡n7-¡l)amino)-9 / 7Lpur¡n-9-¡l)- / V,ALdimethylbenzamide (2-(2-((6-Methoxy-2-methyl-l, 2,3,4- tetrahydro¡soquinolín-7-¡l)amino)-9 / 7£-purín oxide -9yl)phenyl)dimethylphosphinane rxj c ¿ Ό ΰ .E S = o o (Λ p ¡=; 2 LA 4-J 1—J <υ o Y Ό ^E in (N o. Y — lo Id ¿ ¿P o co 4—» ·* CD >> E = ω ώ ra Oxide of (2-(2- ((6-Methoxy-2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl)amino)-6 / 7-pyrimido[5,4¿>]ri,4]oxaz¡n-8(7 / 7H)phen¡l)dimet¡lphosphina § QJ E lo ro i CZ = E ΓΜ Π5 e ΐγ c E o o. '5 o σ r o Ϊ2 11 ó™ o P (J 13 ¿ E C\1 CM o a> E <¿ c .i P: σ = o i (Λ T O - S O 4= c ro σ' 4 + ó <_> T LO E (5-(3-Ethyl-l / 7£-p¡rrolo[ 2,3-Z?]pyridín-5-íl)-2methylpheniOdimethylphosphine (5-(3-Ethyl-l / t7£-pyrrolo[2,3-Z>]pyridin-5-yl) oxide -2fluorophenyl)dimethylphosphine (2-Chloro-5-(3-ethyl-l / 7Lpyrrolo[2,3- / 7]pyridin-5yl)phenyl)dimethylphosphine oxide (3-(3-Ethyl-l / 7í-pyrrolo[2,3- / 2]pyridín-5yl)phenyl)dimethylphosphina (5-(3-) oxide Ethyl-l / - / -pyrrolo[2,3-Z7]pyridin-5-¡l)-2methoxyphenyl)d i methylphosphine Oxide (5-(3-Ethyl-lALpyrrolo[2,3- / j] p¡r¡d¡n-5-¡l)-2hydroxy¡phen¡l)dimethylphosphíne Oxide of (3-(3-Ethyl-lMpyrrOlo[2,3-#]pindin-5-¡l) -5methylphenyl)dimethylphosphinae i—1 ΓΩ LO LO Pt cp O LO i—1 LO CM in ΓΩ m un un un LO un RR LfrZn / ZZnZ / q / YIAI 116 CX] LO 22.6 C\J CM LO CM LO i—l LO O i-I >10 CO O i—l OJ O i—l 1—1 LO + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + r¡din-5yl)phenyl)dimethylphosphine AL(2-(dimethylphosphoryl)-4-(3-ethyl-l / 7í-pyrrolo[2,3- / 2]pyr¡d ¡n5-¡l)phenyl)acetamide LO C Ό cl co O o. ab i—1 qj 4· E ό 13 £ O íu jd = (2-Am¡no-3-(3-et¡l-l / 7Lp¡nOlo[2,3-£]p¡r¡d¡n oxide -5yl)-6-fluorophenyl)dimethylphosphine l)phenyl)dimethylphosphine (3-(3-Ethyl-l / 7£-pyrrolo[2,3-Z2]pyridin-5-yl)-2fluoro-6-methylphen¡l)dimet oxide Phosphine (5-(3-Ethyl-l / 7-pyrrolo[2,3- / 2]pyridin-5-l)-2(oxazol-2-l)phenyl)dimethylphosphine oxide na Oxide of (6-(3-Ethyl-l A / -pyrrolo[2,3-Z?]p¡r¡d¡n-5-¡l)-3met¡lp¡r¡d¡n- 2-(l)dimethylphosphine (2-((Dimethylamino)methyl)-5-(3-ethyl-l / 7L pyrrolo[2,3- / 7]pyridin-5) oxide -¡l)phenyl)dimet¡lphosphine c Q. co C\F o o £ i-I 'P <p CO Π3 T ? τΞ' CM O ¿ ω ίο 4—» t e a Ó Έ v ¿y OJ ι-l LO 2-(Dimethylphosphonl)-4-(3-ethyl¡l-l / / -pyrrolo[2,3-d]p¡ r¡d¡n-5yl)benzamide c o. co rxT 03 o Q_ ab 1—1 'P <p co LO íü P ω Ξ .p ro S Φ <u y E 5 33 C V ,<υ m LO Oxide of (2-Amino-5-(2-chloro-3 -ethyl-l / 7Lpyrrolo[2,3¿>]pyridin-5-yl)phenyl)dimethylphosphine (2-Amino-5-(3-ethyl-l / 7-pyrrolo[2,3-Z7]) oxide pyridin-5-¡l)phenyl)dimethylphosphine Oxide of (5-(3-Ethyl-lf7Lpyrrolo[2,3-Z?]pyridin-5-¡l)-2(methyl lam i no)phen i 1 ) d i methyl Ifosfi na Methyl 2-(dimethylphosphor¡l)-4-(3-ethyl-l / 7Lpyrrolo[2,3- / ?]pyridin-5-yl)benzoate (5- (3-Ethyl-lMpyrrolo[2,3-¿»]pyridin-5-yl)-2(hydroxyl-methyl)phenyl)dimethylphosphine LO CO LO LO O LO 1—1 LO CM LO CO LO LO LO LO LO LO LO 00 LO σι LO O i—1 CO RR LfrZn / ZZnZ / q / YIAI 117 o i—l O LO Φ O m i—1 A >1172 444 O o 00 232 250 178 (o 275 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + (5-(3-Ethyl-l / 7-pyrrolo[2,3-Z2]pyridin-5-yl)-2- (fluoromethyl)phenyl)dimethylphosphine (3-Amino-6-(3-ethyl-l / 7Lpyrrolo) oxide [2.3- / 7]pyr¡d¡n-5- ¡l)pyr¡din-2-¡l)dimethylphosphina (5-(3-Et¡l) oxide -lrií-pyrrolo[2,3-Z?]pyr¡din-5-¡l)-2- (oxetan-3-ylamino)phen¡l)dimethylphosphíne Oxide (2-Am¡no-5-(3-¡soprop¡l-l / 7Lp¡rrolo[2,3é]pyr¡din-5-¡l)phen¡l)dimet¡lphosphíne Oxide of ( 5-(3-Ethyl-lA / -pyrrolo[2,3-¿']pyridín-5-yl)-2(trifluoromethyl)phenyl)dimethylphosphinae c T5 E '5. z—x. i—l O Ό C át i—l Z—X Έ ¡2 in 'P <υ E CO 4- O O o lo 2-¡l)-6-methoxy-2-met ¡l-l,2,3,4-tetrahydro¡soqunol¡n-7-amine | Cxl C p E o. z—> i—1 c o Ό z—X Έ ¡2 3 in 'P (U E co 4p o o LT) £ il)-6-methoxy¡-2-met¡l-l,2,3,4-tetrahydro¡ soquinol¡n-7-amine | i—l O Ό C 1—1 oí E z—X c ,p 5 in 'P (U £ CO 4p O o LT) £ co CxT i-H ai E A § ai E ό z—> rxl c T3 E Q. Z —> tetrahydroisoquinolin-7-amine l-(5-Chloro-2-((6-methoxy-2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-l / 7- indole-3-sulfonamide t—1 i——1 .C o 4 T rxj ño t-7 i—1 4—» C 0J fü P Q. Y o rxl a. 8 ° O1 1 O O. JL 4ό c δ V £ LT> tetrahydroisoquinolin-7-amine íü c ώ E Λχ φ ¿ c — s g E '5 c σ H i íc ΙΛ fu 4—» 'ϊ1 4£ co C ΤΗ ° é E a> 2 E ? Ai LO .J. ^E (l-(5-Chloro-2-((6-methoxy-2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)indolin- 5-oxide ¡l)dimethylphosphine ro CM i—l a; E CM Έ oí E ό Ai 2 o u LO •x—«< i—l •x—«< tetrah¡dro¡soquínol¡n-7-¡l)am¡no)p¡r¡m¡d¡ n-4-yl)¡ndol¡n- 3-¡l)methanol LO O 1^ 00 o 00 i—l 00 cxj co CO 00 00 LO 00 O 00 00 AA LfrZn / ZZnZ / q / YIAI 118 CxJ O Os O rxj co LO co Q σ o o 00 o I-1 i—1 I-1 σ LO o o o o A Φ Λ CO φ i-I 00 00 LO 1—1 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Ύ *Y to c ro Γ\Ι , Γ\Ι , rxj , to c to c c ™ o C C C i i to q *XL o o 1-1 Ό Ό C Ό C l c i—i Ό i-ι Ό Ό _ I | E or E or E or / —X <—S / —X. / —x 0) = rxj Ύ i— i— c P - — — cu = 0) = — 7= — Ξ 4 ¿ .£ Q. = CL 13 Q. = J t Φ t Φ i | / —> CT / —«s o- <-> cr 1 1 1 1 | | | ΓΜ C ó o E el j- σ 8 A 2 = o ' in । O c »- V O ' in « O C i- toS toS to E tos uipiw Z-!xo: OI c δ E toE ,3,4midin 1 UipiUJ (D E Á ω = o = O O Έ Έ 2 = T3 O Έ 2 = T3 or 2 ra ¢^: met )pirii (L) E Q; rxj tH 'cl -S £ -1,2. )pirii o o V 1=3 E o E o ό O LO o 75 O = O ra Ξ O C to E C -C 2 a5 4- = -t-» 1 (U ιγ (V aJ 4- Y c T E Y c TE ra UILU )j-z c to E (ü .E E E mei min box mei min 1 fü o o §to §to x A o = x ra S oPE ro-: il)a i ro O O to Λό .1 — c rxj S .1 = o T § o rl Ψ ¿ LO = V ° m -7- O ,< (J । LO ~ V o metox olin-7rboxan metox olin-7olin-3- metox olin-7- Λ .E 2 3 C ó E Ó to E V.E ¿ rxj Z5 íd V c ω cxJ ^ m )-iuin A> '5 eO E V, LJ ó-E-o co Y Y n o .o to $y 2 o Yes P o <u — o="5" to । too s de rois etilf 1 h o cxj ó § ό g δ .a 2 p e xílic en 2^ c £ p é>ro-i rois nitri TJ 2 O 1 o 0) or <U O <u in ό a o o s τί .e 3 ra s v 8 to 2 t ¡f>ó - 2 t ra toó - 2 E ra toó - to te Λ 2 o ó ra o S 2 ra o 2 ra O J= s LO 2 ¿i 5-C rahi ethylí o d -2 ó 2 ra o S to v <u E ^a e < — ΓΌ ^A e < — Γϋ YA E < — ΓΌ Y+J Ό to £ o 5 S S £Sto £Sto ·γ> AJ (D Λ £ E i-( teti (e i-( teti 3 -c co σι O 1—1 rxj co LO LO 00 O co 00 O σ σ in σ O in σ RR LfrZn / ZZnZ / q / YIAI 119 200 373 >2603 540 45 140 1—1 1—1 2200 LO 00 00 269 477 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 1 I y y y y y y y y I1'·*. rn rn rn en rn co C rn c c rxj rxj rxj rxi rxi CM or B O Si V1 Ln ’T1 or T1 LO ’T1 or i-ι Ό 1 C i-ι Ό i c | 9- = <—x oJ = oJ = aí ~ a; = ai = 4-» a; v ai = O θ y y y E xf- ÍZ ·ψ E ·Φ E Tt- ίζ 'Φ iz ·φ ÍZ Xf- 1 c | c | c ΓΧ| c rxj c rxj c CN c rxj c rxj c rxl c | O ^f- Ό T3 π Ό •A Ό Ό p n. e E ro IWI X Ί= a ε X Ί= 5 ε X Ώ E χ Ώ £ L· a» 1"^ ι-l Q. τΗ Cl E 1-1 Q. E Q- E E Q- E Q- E E Q- E Q- = 2 = o έ ° x = o ό o ό o ό o ό o ό o t¿ o ό o C C C C C 0^8 <xi n ό-θ rxl £ ό^θ rxl £ _ ό-θ o-2-( l)am¡ o-2-( l)ami y t—। 'σ ° N 'σ O rt 'x O N 8 Ψ ¿8 ¡T c ó A o 0> N P 2 । (6-me uinoli 3-car (6-me uinoli ilindole (6-me uinoli 3-car l-(5 uinoli 3-cart l-(5 uinoli 3-cart l-(5 uinoli 3-car l-(5 uinoli 3-car l-(5 uinoli 3-car 1-(5-1 uinoli l-(5uinoli Y CT ¿ V C tn V ¿ Oí' CT ' / <3· ¿ r- ¿ c c SU £ rxl O ·— Ai o 92 rxl O ·— O c o <z o - o - o - o o o o -L H rxj QJ A - o P O Ό A - E 2 o i ¿I 2 o ό ω — δ -2 oís lolii .9) O O Ό .Yes} O O T3 .92 o O T3 oís ílic ois ílic £ É o -O :- οΐΎ ° Ό - i- T0 T0 C S- T0 T0 C S- c Ό -σ .9 i- c Ό ;— σ o 8 6 V Ur x ιλ 2 2 U E X lA 2 2 CJ íc X lA 2 2 82? 82? 8 2 | 8 O 8 O 8 s S 8 2 § T y t < C\J ΓΟ i-( tet hid i-( tet hid i-( tet me 3 si 3 si < S Ξ Γ-. 4_> <U < 2 Ξ < 2 Ξ ^2<X ^2 <x o 1—1 rxj rn φ ln 00 σι o i—l 1-1 rri b7n 77n7 =l yiai 120>236 >3309 293 >118 1275 890 LD O co O i—l 120 O LO + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + r(5-Chloro-2-((6-isopropoxy) acid -2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)indoline- 3-carboxylic Methyl l-(5-(difluoromethyl)-2-((6- methoxy-2-methyl-l,2,3,4tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)indoline- 3-carboxylate Acid l-(5-Chloro-2-((6-methoxy-2 -methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-l / 7indazole-3-carboxylic Methyl l-(5-chloro-2-((6-methoxy-2 -methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-l / 7indole-3-carboxylate Methyl l-(5-chloro-2-((6-methoxy-2 -methyl-l, 2,3,4- tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)indoline- 3-carboxylate Methyl l-(5-chloro-2-((6-methoxy-2- methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-3methylindoline-3-carboxylate Acid l-(5-Chloro-2-((6-methoxy-2-methyl- l, 2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-3methylindoline-3-carboxylic acid ( / ?)-l-(5-chloro-2-((6-methoxy-2 -methyl-l, 2,3,4tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-3methylindoline-3-carboxylic acid (5)-l-(5-chloro-2-((6-methoxy-2 -methyl-l, 2,3,4- tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-3methylindoline-3-carboxylic l-(5-Chloro-2-((6-methoxy-2-methyl- l, 2,3,4tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-3methylindoline-3-carboxamide l-(5-Chloro-2-((6-methoxy-2-met ¡l-l, 2,3,4tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-3-methylindolin-3-carbonitrile 111 112 113 114 115 116 117 118 119 120 121 RRI b70 / 7707 / 3 / ΥΙΛΙ 121 100 09 20 LO O 280 640 >243 >82 >426 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + in in in in co c in in co in ch CM CM CM CM T or Y' | i-ι Ό < co । in 1 LO 1 LO । in i i-1 i i-1 i i-1 l i-1 | z—\ X / -> X_> z—> 0) - α> τ <u t o — α>τ (U T 0) .- CU T 0) .- E xf- E v E v CU V E v E V E V E xf- E xf- 1 £Z 4 .= cxj c cxj c CXJ C E¿ ΓΜ ¿ Λ c rxj ¿ CXJ c cxi V O m 3 •R ? ¿ 3 5< 3 O Ό 3 3 3 3 3 3 3 3 3 to E CxT .2 o 2 p 2 p 2 V 2 5 2 S 2 S 2 5 2 5 2 l-Γ ex V O. (U E ex o <υ .½ E ex o 7 o U (U .½ E ex o 1 <-> u Cxj J= o -me )pir -me )pir -me )pir -me )pir -me )pir -. o <¿ o ~ CO O = o o o o L0 O có o o LO o có o <y c C Yz c χ c χ tY c c c x—* C c c E E s £ E CxJ (U V e o to £ £ Τ' c Ó ΓΧ1 £ -O ru i— Τ' c ó ΓΧ1 £ -O ru i— Ψ E Λ ro rx! £ ro 1 fü rx! 1 ÍU rxj I ÍU ro T E o ra 0^2 0^2 1 o o o o o o J_ — <J J_ — CJ i— · — i— — i— — i— ·— i— — x ,< x o i o qj C -Q P c Ψΐί -Cío n-71-3- A >< -Cío n-7- -Cío n-7- !-Cl0 n-7- ¡-cío n-7- ¡-cío n-7- E — <υ LO — — LO — ·— LO — — LO — LO — LO ” LO ~ LO ” Fon ' ° E ' O o ν' o o O r> o £ O O Y'' O O Y^ O 1 c Y SSÓ O c Λ c -§ 3 c Λ .s ό O C 1uin indi E ro = Y ι-l — (1uin ¡co -( 1· uin ato -duin ato -(1· uin ato Y r rxi O — <1 oto C O 7= CT = o CT 7= O Ή SY ΓΜ g o-'g o R ™ o 3 ™ o R A ω o 2 o -σ o .E o 2 o g? ω <y 2 £ rois -me ω c 2 o o O o s— ·η 1— " ¡1 rois il)ac til rois il)ac )B(|| SIOJ O -o O i Ü3 ώ 2 £ 9 ~ g ¡n ro = 3 x o^2 Ό 2ΐ O ΓΟ o £ ό ό 2 £ do rahid iro-3 O Ό s H ia=e( piqej op do rahid ol-3- iprop rahid ol -3- ztilbu rahid ol-3- rahid ol-3- 4-1 t 1 _|_> 0) Γ-. -|_> <U •n O +J Ό U-I -|_I T3 •í-. LQ Λ £ =6 E < ^ £ < P ¿ < P ti < £ E < 2 m < .E ti £ .E Λ £ .E iTi £ .E C\J co LO Ό co σι O 1—1 rxj C\J CM CXJ cxj Cxl CXI ΓΜ (N co CO co 1—1 i—1 i—1 i—l 1—1 1—1 1-1 1—1 1—1 1—1 1—1 RR LfrZn / ZZnZ / q / YIAI 122 or 00 243 269 438 1304 382 520 783 541 117 433 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 2-(1-( 5-Chloro-2-((6-methoxy-2-methyl-l, 2,3,4tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-l / 7- indol-3-yl)acetamide 2-(1-( 5-Chloro-2-((6-methoxy-2- methyl-l, 2,3,4tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-l / 7- indole-3-íl)acetonítrile / V-(4-(3-(( 2 / 7ctetrazol-5-¡l)methyl¡l)-l / 7í-¡ndol-l-¡l)-5chlorop¡r¡midin-2-yl)-6-methoxy¡-2-methyl¡l-l , 2,3,4tetrahydroisoquinolin-7-amine 2-(1-( 5-Chloro-2-((6-methoxy-2-methyl-l, 2,3,4tetrahydroisoquinolin-7-yl)amino)pyrimidin-4- il)-l / 7- indol-3-yl)- / V-methyllacetamide 2-(1-( 5-Chloro-2-((6-methoxy-2-methyl-l, 2,3 ,4tetrahydroisoquinolin-7-yl)amino)pyrimídin-4-yl)-l / 7índole-3-íl)- / Wcyanomethyl)acetamída Acid 2-(l-(5-Chlorine-2 -((6-methoxy-2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-5fluoro-l / ¥-índol-3-¡Dacetic Acid 2-(l-(5-Chloro-2-((6-methoxy-2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-6fluoro-l / / -indol-3-l)acetic acid 2-(l-(5-Chloro-2-((6-methoxy-2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl)amino )pyrimidin-4-yl)-5,6difluoro-l / Z-indol-S-iDacetic acid 2-(l-(5-Chloro-2-((6-methoxy-2-methyl-l, 2,3, 4- tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-íl)-l / yndazol-3-yl)acetic acid 2-(l-(5-Chloro-2-((6- methoxy-2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-l)-l / yándol-3-yl)propanoic acid l-(l-(5-Chloro-2-((6-methoxy-2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidein-4- ¡l)-l / y¡ndol-3-yl)cyclopropan-l-carboxylic acid 133 134 135 136 137 138 139 140 141 142 143 RR LfrZn / ZZnZ / q / YIAI 123 250 476 06 132 209 >944 171 187 253 358 430 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + in in in in in in in in in in CM -J CM CM CM CM CM CM CM CM CM ™ «A w w w w w w w w 1 1 1 1 1 1 1 1 1 —* i-1 1 °? । in . EITHER . EITHER . EITHER . ΜΙ i LO Lp i Ό । LO O = ti = 1P íZ? <υ = eti ¡I)· eti -ii)· eti -ii)· eti ¡1)· eti -ii)· eti -ii)· oí = eti -ii)· Ξ 4 E 4- E ·Φ E · Φ E Ί- E ·Φ E ·Φ E -Φ E 'Φ E ·Φ E ·Φ i | i | 1 1 1 1 1 1 1 1 1 1 | | cm c CM C CM C CM C CM C CM C CM C CM C CM C CM C CM C •Λ Ό •¿ Ό A Ό •¿ Ό •¿ Ό A Ό A Ό ¿ Ό •Λ Ό ¿ Ό ¿ Ό x — X — X — X — X — X — X — X — X — X — H (U .½ E o- (U .L· E CL (D E cl me pir me pir (D .L· E o- <ü E CL me pir <D .L· E o- <u .L· e ^s 1 < > O o c <¿ o ό o ό o ό o MO O <¿ o 8 <¿ o' 8 <¿ o' 8 ό o' 8 c ÍÜ C c c C C c π c ” C ” C fc. <<l E O । c -<υ cm £ u । c -<υ cm £ υ । c -<υ cm £ υ । c -<υ cm £ υ i 05 1 05 1 05 1 05 1 05 1 05 i 05 (ü i 05 (ü i fO (ü i 05 — o p o o o o o O o o o O^i °N fe o rl 2 P rL 8 P rL 2 O ¿ Q o rt 2 P Λ Λ P rL Λ P rL Λ P r< o < 1 φ ¿ § o 2 ' c V (J 1 05 ιό = OJ O y Λ c (l-(5-C uinolin-yl)acet¡( -(l-(5-c uinolin-yl)acet¡< -(l-(5-c uinolin-yl)acet¡( -(l-(5-c uinolin-yl)aceta -(l-(5-C uinolin¡ndolin-; (l-(5-C uinolin¡ndolin- í -(l-(5-c uinolintilindolin- υ । । ιό^ P Y O o d - (1-( 5-C uinolintilindolir O^ N σπη ΓΜ S T cm σ m । O « cm ü m । O । cm and in O i o P cm cr — । O Ή CM O- = 1 o -JH ™ fe £ ω en p ω c 2 O ω c 2 o p — 2o P — 2o rois olin rois -me rois -me (5) rois -me — P. rois -3-n T5 A σ o Ό O σ ό σ o σ o o m Ό m Ό ÍO q m Ό O - en Ό 2 O 7= íü = sis sis sis rahi tilín o -S 2 P 2 fe o -S 2 P 2 fe O -s 2 P 2 fe o P 9 P 2 fe o O Ό 2 = Me tet me Aci tet me Aci tet me Aci tet me .—; 4-» ÍU ÜJ 2 E .½ .½ Aci tet difl LO LO 00 in O i—l CM CQ Φ Φ in LO in LO m 1—1 i—1 i—1 i—l 1—1 1—1 1 -1 1—1 1—1 1—1 1—1 RR LfrZn / ZZnZ / q / YIAI 124 >111 O CM 176 192 i—1 O 510 415 456 306 421 N.D. + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Acid 2-(l-(5-Chloro-2-((2-methoxy-6-methyl-5,6 ,7,8- tetrahydro-l,6-naphthyridin-3-yl)amino)pyrimidin-4-yl)-3- methylindolin-3-yl)acetic acid 2-(l-( 5-Chloro-2-((6-fluoro-2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-3-methylindolín-3-íl) acetic acid 2-(l-(5-Chloro-2-((2-ethyl-6-methoxy-l,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-3 - methylindolyn-3-l)acetic acid 2-(l-(5-Chloro-2-((2-isopropyl-6-methoxyl,2,3,4-tetrahydroisoquinolin-7-yl) )amino)pyrimidin-4-yl)-3-methylindolín-3-¡l)acetic acid 2-(l-(5-Chloro-2-((6-methoxy-2-methylíso¡ndolin) -5yl)amino)pyrimidin-4-yl)-3-methylindolin-3-yl)acetic acid 2-(l-(5-Chloro-2-((6- methoxy-l,2,3,4) methanesulfonic acid -tetrahydro¡soquinolín-7-yl)amino)pyrimidin-4-yl)-3-methylindolin-3-yl)acetic acid 2-(3-(5-Chloro-2-((6- methoxy-2-methyl-l,2,3,4- tetrahydro¡soquinolín-7-¡l)amino)p¡nm¡d¡n-4-¡l)-l / 7 - indol-l-yl)acetic acid 1 2-(3-(5-Chloro-2-((6-methoxy-2-methyl-l,2,3,4- tetrahydro¡soquinolín) acid -7-¡l)am¡no)pyrám¡din-4-¡l)-l / 7- indazol-l-yl)acetic acid l-(2-((6-Methoxy-2-methyl -l,2,3,4- tetrahydro¡soquinol¡n-7-¡l)amino)p¡r¡m¡din-4-yl)¡ndol¡n- 3-carboxylic 2- ((6-Methoxy-2-methyl-l,2,3,4-tetrahydroisoquinolin-7- Ó c E δ. co CM cj* o o. 'E ,(D 3 C E ÍU carbonitrile | Acid 2-((6-Methoxy-2-methyl-l,2,3,4- CO CM O O Q. Έ ,(U 3 c E tu c o c 'o CT o ω o le 2 4—» £ d\ p¡ r¡ m id i n-6-ca rboxyl ¡co 2-((6-Methoxy-2-methyl-l,2,3,4-tetrah¡droisoquino¡no¡ n-7- tD C O co c Q. i co o le Έ .QJ cp oí E 31 c E ro 155 156 157 158 159 160 161 162 163 164 165 166 RRI b70 / 7707 / 3 / ΥΙΛΙ 125 995 737 1482 121 + + + + + + + + + + + + + + + + + + + + + + + + + + Acid 2-(5-Chloro-2-((6-methoxy-2-methyl -l, 2,3,4- tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)-2azaspiro[4.5]decane-4-carboxylic acid 2-(5-Chloro-2-((6-methoxy-2 -methyl-l, 2,3,4- tetrahydro¡soquinolin-7-¡l)am¡no)p¡r¡m¡d¡n-4-¡l)-8-oxa-2- azaspiro[4.5]decane-4-carboxylic acid 2-(5-Chloro-2-((6-methoxy-2-met¡ 1-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4 -yl)-2azaspiro[4.4]nonan-4-carboxylic / V-(5-chloro-4-(2-oxa-6-azaspiro[3.4]octan-6yl)p¡rmádin-2-yl) -6-methoxy-2-met¡l-l, 2,3,4tetrahydroisoquinolin-7-amine c ~ fü O c c O £5 O 00 ω o Ύ o .S S E 4—» T 'T o <u E £ íi δ o °? o SE 03 C\1 7= (2-((6-Methoxy-2-methyl-l, 2,3,4-tetrahydro¡soquinol¡n-7-¡l)amino)qu¡ oxide nazolin-7yl)dimethylphosphine 167 168 169 170 171 172 EC50 (nM) VN VN + + + + + + EC2x (nM) N.A. NA + + + + + Maximum fold response of IL-2 <2 ΓΜ V CM A CM Λ Compound structure (l-(5-Chloro-2-((6-methoxy-2-methyl-l,2, 3,4-tetrahydro¡soquinol¡n-7- ¡)amino)p¡r¡m¡d¡n-4-¡l)-l / / -¡ndol-3-yl) dimethylphosphina / V-(5-chloro-4-(l / / -índol-l-íl)pyrídín-2-íl)-6-methoxy¡-2 -methyl-l,2,3,4-tetrah¡dro¡soqu¡nol¡n-7amine Buiiue-z-uiiouinbosiojpiqejio) -t''£'Z'T-|!PUJ-2-!XO)9UJ-9 -(|!-z-U!P!UJ!J!d(|R9UJOJon|j!J4)-g-(|!--[-|opu!- / yT)-b)-!v / V-(5 -Chlorine-4-(¡ndol¡n-l-¡l)p¡r¡m¡d¡n-2-¡l)-6-methox¡-2-met¡l-l,2,3,4-tetrahldro¡soqu ¡nol¡n-7amine Example t—1 CSI co AA Lfrzn / Zznz / D / YIAI IT 126 VN + + + VN VN + N.A. | + + + + + + + + + + + + + + + + + + + + + + + + + + + N.A. + + N.A. NA NA <r + N.A. NA + + + + + + + + + + + N.A. NA + + + + N.A. CM V >2 CM V CM V CX1 V CXJ V CXJ Λ CM V CM V CM Λ CM Λ C\l A Λ CM V rxi V ΓΧΙ Λ rxi Λ rxi V l-(5-Chlorine-2-((6- methoxy¡-2-methyl¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-yl)amino)prim¡din-4-¡l)- / V, / V- dimethyl-lAHndol-3-carboxamide / V-(4-(l / / -benzo[ü]imídazol-l-yl)-5-chloropyrímidín-2-íl)-6- methoxy-2-methyl-l, 2,3,4tetrahydroisoquinolin-7-amine / V-(4-(l / 7-indol-l-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-6-methoxy -2-methyl-l, 2,3,4tetrahydroisoquinolin-7-amine euiwe-z-uiiouinbosiojpiqe-qs} -F'£'Z>l!13W-Z-|xcqsw-9-(|!-z-U!P! W!J!d(|!-T-|opu!TyT-OJOny-£)-^^ / W5-chloro-4-(5-chloro¡ndol¡n-l-¡l)p¡r¡m¡d¡ n-2-¡l)-6-methoxy¡-2-met¡ 1-1,2,3,4tetrahydroisoquinolin-7-amine AL(5-Chloro-4-(indolin-l-yl)pyrimidin -2-yl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-7-amine 6-Chloro- / W5-chloro-4-(¡ndol¡n-l-¡l)pyr¡m¡d ¡n-2-¡l)-2-methyl¡l-l,2,3,4-tetrahydro¡soquinolín-7amine '-M (U E rxi δ tí E Z—«X ΓΧΙ c E q. Z—X . i—1 c '5. Λ Γλ rü o\E o bro cl rl V o O C o — o Ό & rn £ cí 5 'í- 2 o LO / V-(5-chloro-4-(6-chloro ¡ndol¡n-l-¡l)pyr¡m¡d¡n-2-yl)-6-methoxy¡-2-met¡ 1-1,2,3,4tetrahydroisoquinolin-7-amine / V-(5 -chloro-4-(indol¡n-l-¡l)pyr¡m¡din-2-yl)-2-methoxy¡-6-methyl-5,6,7,8-tetrahydro -l,6-naphthyridin-3amine V(5-chloro-4-(5-fluoroindolin-l-yl)pyrimidin-2-yl)-6-methoxy-2- methyl-l, 2,3,4tetrahydroisoquinolin-7-amine / ^(5-chloro-4-(6-fluoro¡ndolin-l-¡l)p¡r¡m¡din-2-¡l)-6- methoxy¡-2-methyl¡l-l, 2,3,4tetrahydroisoquinolin-7-amine A / -(5-chloro-4-(¡ndol¡n-l-¡l)p¡rm¡din-2-¡l) -2-¡soprop¡l-6-methoxy¡-l,2,3,4-tetrahydro¡soquinolín-7amine ÍU c E rp c O c σ' o ω 'o i— o le 2 - 1—» O) 4—» rn i—l X o ti E ό z*—s CXJ c E o. Z—X. i—l c o Ό tc x^-z o o o LO 1 C O σ o σι 0 p 1c Π3 S rn r\F 1—I l OJ E rxi § tí E ό z—X. rxj c E o. 0 1—i 0 N (U Ό C 1—1 'ψ ό O ru O .Ξ LO E A45-Chlorine-4-(3,3-dimet¡ndol¡n-l-¡l)p¡r m¡d¡n-2-¡l)-6-methoxy¡-2-methyl¡l-l,2,3,4tetrahydroisoquinolin-7-amine 2-(7-((5-Chloro-4-(¡ndol) n-l-¡l)p¡r¡m¡din-2-¡l)amino)-6-methoxy¡-3,4-d¡hydro¡soqunol¡n-2(l / 7) il)ethan-l-ol / ^(5-Chloro-4-(2,3-d¡hídro-l / Ap¡rrolo[3,2- / 2]p¡r¡d¡n-l-¡l )p¡r¡m¡d¡n-2-¡l)-2-methoxy¡-6-met¡l5,6,7,8-tetrah¡dro-l,6-naphthyr¡din-3- amine co en 10 i—1 i—1 ΓΟ 1—1 1 H 1 LO i—1 kO i—1 18 03 i—l 20 1—1 CM 22 LO ΓΌ d ro m 24 25 27 29 RR Lfrzn / Zznz / D / YIAI 127 + + + VN VN + + VN +++ + + + + + + + + + + + + + + + + N.A. VN N.A. + + + + + + N.A. NA + N.A. < + + + N.A. NA + N.A. NA NA NA NA NA + + + CM Λ <2 CM V CM A ΓΜ V rxi V CM Λ rxi V CM V rxi Λ CXI V CM V C\l V rxi V r\J V CM V CM Λ Acid l-(5-Chlorine-2-( (6-methox¡-2-met¡l-l / 2,3,4-tetrah¡drO¡soquinol¡n-7-¡l)amino)p¡r¡m¡d¡n-4- ¡l) indoline-3-carboxylic l-(5-Chloro-2-((6-methoxy¡-2-met¡l-l;2,3,4-tetrah¡drO¡soqunol¡n-7-¡l)am¡ no)pyr¡m¡din-4- ¡l)indolín-3-carboxamide l-(5-Chloro-2-((6-methoxy¡-2-methyl¡l-l,2,3,4- tetrahydro¡soquinol¡n-7-¡l)amino)pyr¡m¡d¡n-4-¡l)-l / 7L indole-3-carboxamide l-(5-Chlorine) acid -2-((6-methoxy¡-2-met¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)amino)pyr¡m¡d¡n -4-yl)-l / / -indole-3-carboxylic 6-Methoxy-2-methyl- / K7-pheníl-7Mpírrolo[2,3-í / ]pyrmád ¡n-2-¡l)-l,2,3,4-tetrahydro¡soquinolín-7amine 6-Methoxy¡-2-methyl- / V-(7-(pyrídin- 2-¡l)-7Aí-pyrrolo[2,3-o]pyrim¡din-2-¡l)-l,2,3,4tetrahydroisoquinolin-7-amine / ^(5-chloro-4- (3-(met¡lsulfon¡l)¡ndol¡n-l-¡l)p¡r¡m¡d¡n-2-¡l)-6-methoxy¡-2-met¡l-l, 2,3,4tetrahydroisoquinolin -7-amine l-(5-Chloro-2-((6-methoxy¡-2-met¡l-l,2,3,4-tetrahydro¡soquino¡nol¡n-7-¡l)amino )p¡r¡m¡d¡n-4-¡l)-l / 7L indole-3-sulfonamide / V-(5-chloro-4-(spiro[cyclopropan-l,3'-indolin]-l' -yl)pyrimidin-2-yl)-6-methoxy-2-methyl-l, 2,3,4tetrahydroisoquinolin-7-amine (l-(5-Chloro-2-((6-methoxy-2) oxide -met¡l-l,2,3,4-tetrah¡droisoquinol¡n-7- ¡l)amino)p¡r¡m¡d¡n-4-yl)¡ndol¡n-5-¡ l)dimethylphosphina (l-(5-Chloro-2-((6-methoxy¡-2-methyl-l,2,3,4-tetrahydro¡soquinol¡n-7- ¡l)amino)pyr¡m¡d¡n-4yl)indolín-3-¡l)methanol Oxide of (l-(5-Chloro-2-((6-methoxy¡-2-met¡ l-l,2,3,4-tetrahydro¡soquinol¡n-7- ¡l)amino)pyrmid¡n-4-¡l)¡ndol¡n-3-¡l)d¡ methylphosphine / ^(5-chloro-4-(5-(difluoromethyl)indol-l-l)pyrm-dn-2-l)-6- methoxy¡-2-methyl¡l-l, 2,3,4tetrahydroisoquinolin-7-amine AL(5-chloro-4-(6-(difluoromethyl)indol¡n-l-yl)pyrimidín-2-¡l) -6-methoxy-2-methyl-l,2,3,4tetrahydroisoquinolin-7-amine / ^(5-chloro-4-(4-(difluoromethyl)¡ndol¡n-l-¡l)p¡nm ¡d¡n-2-yl)-6-methoxy¡-2-methyl¡l-l,2,3,4tetrahydroisoquinolin-7-amine 3-(l-(5-Chloro-2-((6-methoxy¡-2 -met¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)am¡no)p¡r¡m¡d¡n-4-¡l)lAHndol-S-iDoxetan -S-ol Acid ( / ?)-l-(5-chloro-2-((6-methoxy¡-2-methyl-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l )amino)p¡r¡m¡din- 4-¡l)indolín-3-carboxylic 32 33 34 35 36 fn i—1 00 83 84 86 87 00 00 06 91 92 93 96 RRI ^70 / 7707 / =1 / ΥΙΛΙ 128 + + + VN VN + VN N.A. VN + + + + + + + N.A. + + + + N.A. NA + + + + + + + + N.A. NA + N.A. NA NA + + + + + + N.A. NA + + N.A. NA NA + + + + + CM Λ <2 CM V CM A ΓΜ V rxi V CM V rxi Λ CM Λ rxi V CXI V CM Λ C\l V rxi V r\J V CM Λ CM Λ l-(5-Chlorine-2 -((6-methoxy¡-2-methyl¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-yl)amino)p¡nmid¡n-4-¡l)- / V· methylindolin-3-carboxamide l-(5-Chloro-2-((6-methoxy¡-2-methyl-l;2,3,4-tetrahydro¡soquinolin-7-yl)amino)pyrim¡ d¡n-4-yl)-AA (methylsulfonyl)indolin-3-carboxamide l-(5-Chloro-2-((6-methoxy¡-2-methyll-l,2,3,4 -tetrah¡dro¡soquínol¡n-7-¡l)am¡no)p¡r¡m¡d¡n-4- ¡l)indol¡n-3-carbon¡trilo euiwe-z- uiiouinbosiojpiqe-iis} -FTT'l-lliaw-^-ixopw-g-Oi-^-uipiwiJidOJOp-g-Oi-t-uiiopuiOi-g-iozejpi- / ^)-^^^ l-(5-Chlorine-2 -((6-methoxy¡-2-methyl¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-yl)amino)pyrimid¡n-4-l )-AA hydroxyindoline-3-carboxamide l-(5-Chloro-2-((6-methoxy-2-methyl-l,2,3,4-tetrahydroisoquinolin-7-l)amino) pyrimídin-4-íl)- / V· hydroxy- / V-methyndolin-3-carboxamide l-(5-Chloro-2-((6-methox¡ -2-met¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)amino)pyrimid¡n-4-¡l)-AA methoxyindolin-3 -carboxamide Acid l-(5-Chloro-2-((6-methoxy¡-2-methyl-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)amino) p¡r¡m¡din-4- ¡l)-5-fluoroindole¡n-3-carboxylic acid l-(5-Chloro-2-((6-methoxy-2-methyl-l / 2.3 ,4-tetrahydroisoquinol¡n-7-yl)amino)pyrimidín-4- ¡l)-6-fluoroindolín-3-carboxylic acid l-(5-Chloro-2-((6-methoxl· 2-met¡l-l / 2,3,4-tetrah¡dιΌ¡soquinol¡n-7-¡l)amino)prim¡d¡n-4yl)-6-methoxy¡ i ndol i η -3-ca rboxylic acid l-(5-Chloro-2-((6-methoxy¡-2-met¡l-l,2,3,4-tetrah¡dro¡soquinolin-7-¡l)am¡ no)p¡r¡m¡d¡n-4yl)-4-methoxy¡ i indol i η-3-ca rboxylic acid l-(5-Fluoro-2-((6-methoxy¡-2-met¡ l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)am¡no)p¡r¡m¡d¡n-4- ¡l)indoline-3-carboxylic Acid l-(5-C¡ano-2-((6-methoxy¡-2-methyl¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)amino)p ¡r¡m¡din-4-yl)indoline-3-carboxylic Methyl l-(5-(difluoromethyl)-2-((6-methoxy-2-methyll-l,2,3,4- tetrahydro¡soquinol¡n-7- l)amino)pyr¡m¡din-4-l)¡ndole¡n-3-carboxylate Acid l-(5-Chloro-2- ((6-methoxy¡-2-methyl¡l-l,2,3,4-tetrahydro¡soquinolín-7-¡l)amino)p¡nm¡d¡n-4- ¡D-l / Aindazole -S-ca rboxyl ico Methyl l-(5-chloro-2-((6-methoxy¡-2-methyl¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l) amino)pyrimidin-4-yl)indoline-3-carboxylate Methyl l-(5-chloro-2-((6-methoxy¡-2-methyl-l,2,3,4- tetrahydro¡soquinolin-7-¡l)amino)pyrimidín-4-yl)- 3-methyl¡ndole¡n-3-carboxylate 97 98 66 100 101 102 103 104 105 107 108 O or Ί—1 110 112 113 115 116 RRI 670 / 7707 / 3 / ΥΙΛΙ 129 + + + + + VN VN VN +++ + + + + + + + + + + + + + + VN + + + + + + + + + + N.A. + + + + N.A. NA NA < + + + + + + + + + + + + + + N.A. NA NA NA NA NA + + + CM V (N Λ CM V CM V ΓΜ V rxi V CM A rxi Λ CM Λ rxi Λ CXI V CM V C\l V rxi V r\J V CM V CM Λ Acid ( / ?)-l-(5 -chloro-2-((6-methoxy¡-2-met¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)amino)pyrámidín - 4-l)-3-methylhndoline-3-carboxylic acid (5)-l-(5-chloro-2-((6-methoxyl-2-methyll-l,2,3,4 -tetrahydro¡soquinol¡n-7-¡l)amino)pyr¡m¡d¡n- 4-¡l)-3-methyl¡ndole¡n-3-carboxylic ¡l-( 5-Chloro-2-((6-methoxy¡-2-met¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)amino)p¡r¡m¡ d¡n-4-¡l)-3methylindoline-3-carboxamide l-(5-Chloro-2-((6-methoxy¡-2-methyl-l,2,3,4-tetrahydro¡soquinol) ¡n-7-¡l)am¡no)pyrámidín-4-¡l)-3methylindoline-3-carbonitrile l-(5-Chloro-2-((6-methoxy¡-2-met ¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)amino)p¡r¡m¡d¡n-4-¡l)- / V,3dimethylindoline-3 -carboxamide (l-(5-Chloro-2-((6-methoxy-2-methyl-l,2,3,4-tetrahydro¡soquinol¡n-7-yl)amino)pyrimidín- 4-¡l)-3methylindolín-3-¡l)methanol l-(5-Chloro-2-((6-methoxy¡-2-methyl-l,2,3,4-tetrahydro¡soqu) acid ¡nol¡n-7-¡l)am¡no)pyr¡m¡d¡n-4yl)-5-fluoro-3-methyl¡ndolin-3-carboxylic acid l-(5- Chlorine-2-((6-methox¡-2-met¡l-l,2,3,4-tetrah¡dro¡soquinol¡n-7-¡l)amino)pyr¡m¡d¡ n-4yl)-6-fluoro-3-methylindoline-3-carboxylic acid 2-(l-(5-Chloro-2-((6-methoxy-2-methyl-l,2,3 ,4-tetrahydroisoquinolin-7-yl)amino)pyrim¡din- 4-¡l)indolín-3-¡l)acetic acid 2-(l-(5-Chloro-2-((6-methox ¡-2-met¡l-l,2,3,4-tetrah¡dro¡soquinolín-7-¡l)am¡no)prim¡d¡n- 4-yl)-l / -Aindol -3-yl)acetic Isopropyl 2-(l-(5-chloro-2-((6-methoxy-2-methyl-l,2,3,4-tetrahydroisoquinolin-7- l) am¡no)p¡r¡m¡d¡n-4-yl)-l / / -¡ndole-3-¡l)acetate 2-(l-(5-Chloro-2-((6-methoxy¡ -2-met¡l-l,2,3,4-tetrah¡dro¡soquinol¡n-7-¡l)am¡no)p¡r¡m¡d¡n-4-¡l)l / Findol -S-iDacetamide 2-(l-(5-Chloro-2-((6-methoxy¡-2-methyl-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l) am¡no)p¡r¡m¡d¡n-4-¡l)l / - / -indol-3-yl)acetonitrile 'P E Λ 8 O> E ό r\i c p E o. o o o LO S i—1 o Ό ru SI E C? o — c lo o o N (Λ 2 O ti Ό r\i .h 4-» d*· i™ 2-(l-(5-Chloro-2-((6-methoxy-2-methyl-l,2 ,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)lMandol-3-yl)- / V-methylacetamida 2-(l-(5-Chloro-2-((6- methoxy¡-2-methyl¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)am¡no)p¡r¡m¡d¡n-4-¡l)l / 7'-indole-3-¡l)- / V-(cyanomethyl)acetamide Acid 2-(l-(5-Chloro-2-((6-methoxy¡-2-methyl-l,2 ,3,4-tetrahydro¡soquinolin-7-¡l)amino)pyr¡m¡din- 4-¡l)-5-fluoro-l / 7L¡ndol-3-yl)acetic acid 118 σι τ—1 t—1 120 121 122 CM i—1 125 126 128 129 130 133 134 135 136 137 138 RR LfrZn / ZZnZ / q / YIAI 130 RR LfrZn / ZZnZ / q / YIAI 131 + + + + + VN + + + + + + + + + + + + N.A. + N.A. + + + + + CM Λ C\J A CM V CM Λ r\i V CM Λ CM A 3-¡l)acetic acid methanesulfonic acid 2-(l-(5-Chloro-2-((6-methoxy- l,2,3,4-tetrahydro¡soquinol¡n-7¡l)amino)pyrimidin-4-¡l)-3-met¡ndol¡n-3-yl) acetic acid 2-(3-(5-Chloro-2-((6-methoxy¡-2-methyl-l,2,3,4-tetrah¡diO¡soquinol¡n-7-¡l) am¡no)p¡r¡m¡d¡n- 4-¡l)-l / TL¡ndol-l-¡l)acetic acid 2-(3-(5-Chlorine-2-((6 -methoxy¡-2-met¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)amino)p¡r¡m¡d¡n- 4-¡l)-lH -indazol-l-¡l)acetic acid l-(2-((6-Methox¡-2-methyl¡l-l,2,3,4-tetrahydro¡soquinol¡n-7-¡l)am ¡no)pyr¡m¡d¡n-4-¡l)¡ndol¡n- 3-carboxylic 2-((6-Methoxy¡-2-methyl-l,2,3,4-tetrahydro) ¡soqu¡nol¡n-7-¡l)am¡no)-7-fen¡l-7 / / -p¡rrolo[2,3¿ / ]p¡r¡m¡d¡n-6-carbon Trilo Acid 2-(5-Chloro-2-((6-methoxy¡-2-methyl-l / 2,3,4-tetrah¡diO¡soquinol¡n-7-yl)amino )pyr¡m¡din-4- ¡l)-2-azaspiro[4.5]decane-4-carboxylic acid 2-(5-Chloro-2-((6-methoxy¡-2-methyl¡l-l ,2,3,4-tetrahydro¡soquinolín-7-¡l)amino)p¡r¡m¡d¡n-4- ¡l)-2-azaspiro[4.4]nonan- 4-carboxylic 160 161 162 163 164 167 169 RR LfrZn / ZZnZ / q / YIAI 132 In Tables 1 and 2, the values ​​of IC50, EC2x and EC50 are indicated as ++++, for values ​​less than or equal to 100 nM; +++, for values ​​greater than ++++ but less than or equal to 500 nM; ++, for values ​​greater than +++ but less than or equal to 1 μΜ; and +, for more than 1 μΜ, respectively. B. Synthetic Examples Equipment Description NMR spectra were measured with a Varian Mercury spectrometer operating at 400 MHz (1H), 376 MHz (19F), or 75 MHz (13C). The solvents used for the samples are specified in the experimental procedures for each compound. Chemical changes are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). The division patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad). The following system was used for LCMS: Agilent 6120 (Binary Gradient Module Pump), XBridge Cie analytical column, 5 pm, 4.6 x 50 mm, 25 °C, 5 pL injection volume, 2 mL / min, with a gradient of acetonitrile in 0.1% aqueous ammonium acetate according to the following times: RR I Π7Π / 77η7 / =1 / ΥΙΛΙ Time (min) Acetonitrile (%) 0.1% aqueous ammonium acetate (%) 0.50 5 95 4.50 95 5 6.00 95 5 Experimental Procedures: All reactions were carried out in a dry nitrogen atmosphere unless otherwise specified. TLC plates were visualized with UV light. Flash chromatography refers to column chromatography on silica gel (40-60 pm) using glass columns. Alternatively, automated chromatography was performed using the Biotage SP1 or Biotage Isolera systems with u.v. detection. at 220 or 254 nm and when using Biotage normal phase or reverse phase silica cartridges. Additional details can be found in the relevant experimental procedure. General methods and preparations Compounds, including those of the general formula (1-0), (1-1), (1-2), (I), (II), (II-l), (Π-2), or (II -2'), intermediates and specific examples are prepared through the synthetic methods described herein. In experimental procedures, modifications of the reaction conditions, such as temperature, concentration of solutions, volume of solvents, application of microwave conditions, duration of the reaction or combinations of the 133 same, are contemplated as part of the present invention, and in addition to the acids, bases, reagents, coupling reagents, solvents, etc., specifically mentioned, acids, bases, reagents, coupling reagents, solvents, etc. Suitable alternatives may be used and are included within the scope of the present invention. All possible geometric isomers, stereoisomers, salt forms are contemplated within the scope of this invention. General scheme and synthetic procedures of pyrimidine compounds: AAI ^70 / 7707 / D / YIAI Condition Al: To a solution of Int. E (or commercially available reagent) (1.0 eq.) in DMF was added sodium hydroxide (60% dispersion in mineral oil, 1.2 eq.) at 0 °C and the mixture was stirred at 0 °C for 30 minutes. 5-Ri substituted 2,4-dichloropyrimidine (1.0-1.3 eq.) was added to the above reaction mixture at 0 °C, and the resulting mixture was then stirred at room temperature for 1 hour, cooled to 0 °C , and was quenched with ice-H2O. The crude product was purified to provide 4-R and 5-Ri substituted 2-CI-pyrimidine. Condition A2: To a solution of 5-Ri substituted 2,4-dichloropyrimidine (1.0-1.5 eq.) in DMF were added potassium carbonate (2.0 eq.) and Int. E (or commercially available reagent) (1.0 eq. ). The mixture was stirred at 80 °C overnight, cooled to room temperature, diluted with H2O, and extracted with EA. The crude product was purified to provide 4-R and 5-Ri substituted 2-CI-pyrimidine. Condition A3: To a solution of Int. eq.) later. The reaction mixture was stirred at 100 °C for 18 hours, diluted with water, and extracted with EA. The crude product was purified to provide 4-R and 5-Ri substituted 2-CI-pyrimidine. Condition Bl: To a solution of Int. W (1.0-1.4 eq.) in 2-methoxyethanol were added 2-CIpyrimidine substituted with 4-R and 5-Ri (1.0 eq.) and HCl in EtOH solution (3.0 eq. ). The resulting mixture was stirred at 120 °C for 20 hours and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and / or preparative HPLC. Condition B2: To a solution of 2-CI-pyrimidine substituted with 4-R and 5-Ri (1.0 eq.) and Int. W (1-1.3 eq.) in isopropanol was added trifluoroacetic acid (1.0-3.0 eq.) . The mixture was stirred under N2 at 100 °C for 20 hours, cooled to room temperature, basified with saturated aqueous NaHCOs solution at pH ~8, extracted with DCM. The organic phases were washed with brine, dried over anhydrous Na2SÜ4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified 134 by means of flash column chromatography on silica gel and / or preparative HPLC. Condition B3: To a solution of 2-CI-pyrimidine substituted with 4-R and 5-Ri (1.0 eq.) and Int. W (1-1.3 eq.) in isopropanol was added TSOH H2O (1.0-1.2 eq.) . The mixture was stirred at 100°C overnight, cooled to room temperature, basified with saturated aqueous NaHCO3a pH ~8, extracted with DCM. The organic phases were washed with brine, dried over anhydrous NazSO and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash silica gel column chromatography and / or preparative HPLC. Condition B4: To a solution of 2-CI-pyrimidine substituted with 4-R and 5-Ri (1.0 eq.) in dioxane were added Int. W (1.0-1.2 eq.), Pd2(dba)3 (0.2 eq. ), Xantphos (0.2 eq.), and potassium carbonate (2.0 eq.). The mixture was stirred at 100 °C under N2 for 12 hours, cooled to room temperature and filtered. The residue was purified by silica gel flash column chromatography and / or preparative HPLC. There were additional conversions of 4-R and 5-R1 substituted 2-CI-pyrimidine between Condition A and B, and additional conversions after Condition B, depending on the specific examples. Intermediaries Int. W1 YYj 6-Methoxy-2-methyl-l,2,3,4-tetrahydroisoquinolin-7-amine 1) here HCHO, here. HCl (1 N), 60 °C íf^T^NNAAj con.Hcl- \oA^k^NH22)aq.NaOH(50%) UUv ¡-PrOH 1) here HCHO, MeOH2Fe / NH4CI____, / ^7^7-7^((7 2) NaBH„, 3 h ”\qAJ\Z with. HZSO4, 0 °C * \ ΑΑΆ EA / EtOH / H2O / 60 °C,’ \ During the night θ Step T. An aqueous solution of formaldehyde (37% by weight, 41.64 g, 529.08 mmol). The mixture was stirred at 60 °C for 1 hour, cooled to 0 °C, and basified by dropwise addition of 50% NaOH aqueous solution (17.44 g, 218 mmol) at 0 °C. The resulting mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated to give bis(6-methoxy¡-3,4-dihydro¡soquinolin-2(l / / )yl)methane as a white solid (23 g, 100% yield). Step 2. To a suspension of b¡s(6-methoxy¡-3,4-dihydro¡soquinolín-2(l / / )-¡l)methane (28 g, 82.73 mmol) in ¡ -PrOH (200 mL) concentrated HCl (15.20 g, 182.01 mmol, 15.3 mL) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 18 hours. MTBE (70 mL) was added to the above mixture and the suspension was stirred at room temperature for 4 hours. RRI b7n / 77O7 / 3 / YIAI 135 additional. After filtration, the cake was washed with a mixture of MTBE / i-PrOH (100 mL, 1 / 1 v / v) and dried to provide 6-methoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride as a white solid, which was suspended in DCM (300 mL). A saturated aqueous NaHCOs solution (500 mL) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. After separation, the aqueous layer was extracted with DCM (50 mL x 4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to provide 6-methoxy-1,2,3,4tetrahydroisoquinoline as a yellow oil (10 g, 75% yield). LC-MS (ESI) m / z: 164 [M+H]+. Step 3. To a solution of 6-methoxy-l,2,3,4-tetrahydro¡soquinolíne (1.63 g, 9.99 mmol) in MeOH (30 mL) was added aqueous formaldehyde (37% w / w , 4.8 g, 59.92 mmol, 1.67 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes and cooled to 0 °C, to which NaBH4 (1.13 g, 29.96 mmol) was added in portions. The mixture was stirred at room temperature for 3 hours, quenched with ice-water (10 mL) and extracted with DCM (20 mL x 5). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash column chromatography on silica gel (DCM / MeOH = 10 / 1 v / v) to provide 6-methoxy-2-methyl-1,2,3,4-tetrahydro¡soquinoline as yellow oil (1.7 g, 96% yield). LC-MS (ESI) m / z: 178 [M+H]+. Step 4: To a pre-cooled (0 °C) solution of concentrated sulfuric acid (4 mL), 6-methoxy-2-methyl-l,2,3,4-tetrahydro¡soquinoline (2 g) was subsequently added. , 11.28 mmol), and guanidine nitrate (1.17 g, 9.59 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes, quenched with ice-water (20 mL), basified to pH 10-11 with aqueous NaOH solution (4 N) and extracted with DCM (50 mL x 4 ). The combined organic layers were dried over anhydrous Na2SÜ4, filtered and concentrated. The residue was purified with flash column chromatography on silica gel (PE 100% v / v, PE / EA = 1 / 1 v / v, EA 100% v / v, and then DCM / MeOH = 20 / 1, v / v) to provide 6-methoxy-2-methyl-7-nitro-l,2,3,4-tetrahydro¡soquinoline as a yellow solid (0.9 g, 36% yield). LC-MS (ESI) m / z: 223 [M+H]+. Step 5: To a solution of 6-methoxy-2-methyl-7-nitro-l,2,3,4-tetrohydroisoquinoline (4.2 g, 14.40 mmol) in EA (32 mL), H2O (16 mL), and EtOH (144 mL), Fe powder (5.5 g, 93.99 mmol) and ammonia chloride (793.96 mg, 13.08 mmol) were added. The mixture was stirred at 60°C for 48 hours, cooled to room temperature, and filtered. The cake was washed with methanol (30 mL x 3), and the filtrate was concentrated. The residue was purified with flash column chromatography on silica gel (DCM / MeOH = 20 / 1 to 10 / 1 v / v) to provide 6-methoxy-2-methyl,2,3,4-tetrahydroisoquinol hydrochloride. ¡n-7-amine as a yellow solid (4.5 g, 100% yield). LC-MS (ESI) m / z: 193 [M+H]+. Alternative synthetic method. RR LfrZn / ZZnZ / q / YIAI 136 2-chloropyridine, O í| η Boc2O, TEA, DMAP ί Ί Tf2O, BF3-Et2O DCM,0-rt, 16h jf jT JH O h2so4, hno3o2ni) bh3 / thf,ebb, 16 h °zNnh -20°C, 3h || ] I 2) Warm MeOH 2) NaBH4.3 h 3) 2M HCl reflux, 3 h ° °zN^%^N^Fe / NH4CI \ A^L j EA / EtOH / H2O / 60 °C overnight step added BOC2O (15.88 g, 72.75 mmol, 16.70 mL) slowly at 0 °C. The mixture was then stirred at room temperature for 16 hours, diluted with ice-cold water (200 mL), and extracted with EtOAc (3 x 200 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous NazSO, filtered and concentrated in vacuo. The residue was purified with flash chromatography (SIO2, petroleum ether / ethyl acetate = 10 / 1) to provide te / v-butyl (3methoxyphenethyl)carbamate (14.6 g, 79.06% yield, 90% purity) as colorless liquid. LCMS (ESI) m / z: 196 [M+H-56]+. Step 2·. A solution of Tf2Ü (8.64 g, 30.64 mmol, 5.15 mL) in CH2CI2 (5 mL) at -78 °C. 20 minutes later, BH3-Et2O (19.77 g, 139.26 mmol) was added dropwise to the above solution. The reaction mixture was then warmed to room temperature, stirred for 2 hours, and carefully quenched with saturated NaHCOs solution. The resulting mixture was extracted with CH2CI2 (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO, filtered and concentrated in vacuo. The residue was purified with flash chromatography (SIO2, petroleum ether / ethyl acetate / methanol = 5 / 1 / 0 to 10 / 10 / 1) to provide 6-methoxy-3,4dihydroisoquinolin-1(2 / / ) -one (3.4 g, 68.89% yield) as an off-white solid. LC-MS (ESI) m / z: 178 [M+H]+. Step 3\ To a solution of 6-methoxy-3,4-dihydroisoquinolin-1(2 / / )-one (3.8 g, 21.44 mmol, 9.62 mL) in concentrated H2SO4 (50 mL) was added HNO3 (2.16 g , 22.29 mmol, 65% purity) drop by drop at -20°C. The mixture was stirred at -20 °C ~ -25 °C for 3 hours and poured into ice-cold water (300 mL). The aqueous layer was extracted with dichloromethane (3 x 200 mL). The combined organic layers were concentrated in vacuo, and the residue was purified with flash column chromatography (SIO2, Petroleum ether / ethyl acetate / methanol = 10 / l / 0~10 / 10 / l) to provide 6-methox ¡-7-nitro-3,4-dihydro¡soquinolin-l(2 / 7)-one (2.02 g, 40.78% yield). L.C. 137 MS (ESI) m / z: 223 [M+H]+. Step 4: To a solution of 6-methoxy-7-nitro-3,4-dihydro¡soquinolin-l(2 / 7)-one (2.02 g, 9.09 mmol) in THF (200 mL) 1M BH3 / THF (45.46 mmol, 45.5 mL) was added. The mixture was stirred at reflux for 20 hours and carefully quenched with methanol (30 mL). The resulting solution was concentrated in vacuo. The residue was heated in 2N HCl (50 mL) at 80 °C for 3 hours, cooled, basified with aqueous ammonium hydroxide, and extracted with dichloromethane (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to provide 6-methoxy-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.89 g, 100.00% yield). ). LCMS (ESI) m / z: 209 [M+H]+. Step 5·. Formaldehyde (1.64 g, 54.46 mmol, 1.51 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes and cooled to 0 °C. Then, NaBH4 (1.03 g, 27.23 mmol) was added to the above mixture in portions. The resulting mixture was stirred at room temperature for 3 hours, quenched with ice-cold water (10 mL), and extracted with DCM (20 mL x 5). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (DCM / MeOH = 10 / 1, v / v) to provide 6-methoxy¡-2methyl-7-nítro-1,2,3,4-tetrah Drisoquinoline (1.4 g, 69.40% yield) as a yellow oil. LC-MS (ESI) m / z: 223 [M+H]+. Step 6: To a solution of 6-methoxy-2-methyl-7-nitro-l,2,3,4-tetrahydro¡soquinoline (1.3 g, 5.85 mmol) in EtOAc (2 mL ), H2O (1 mL), and EtOH (10 mL) Fe (2.19 g, 39.19 mmol) and ammonia chloride (284.74 mg, 5.32 mmol) were added. The mixture was stirred at 60°C for 16 hours, cooled to room temperature, and filtered. The cake was washed with methanol (30 mL x 3), and the filtrate was concentrated. The residue was purified with flash column chromatography on silica gel (DCM / MeOH = 20 / 1 to 10 / 1 v / v) to provide 6-methoxy-2-methyl-l,2,3,4tetrahydroisoquinolin-7 hydrochloride. -amine as a yellow solid (0.85 g, 75.6% yield). LC-MS (ESI) m / z: 193 [M+H]+. Int. W2 2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-amine 138 Formalin NaBH(OAc)3, DCE AA I ^70 / 7707 / D / YIAI Step T. To an ice-water solution of 1,2,3,4-tetrahydroisoquinoline (4.8 g, 36.04 mmol) in concentrated sulfuric acid (20 mL) was added potassium nitrate (4.01 g, 47.21 mmol) in small portions, keeping the temperature below 5 °C. The reaction mixture was stirred at room temperature overnight, poured onto ice (100 g), adjusted to pH ~9 with ΝΗ3Ή2Ο, and extracted with CH2Cl2 (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was crystallized from methanol to give 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride as a yellow solid (4.2 g, 54% yield). LC-MS (ESI) m / : 179 [M+H]+. Step 2. To a stirred mixture of 7-nitro-1,2,3,4-tetrahydro¡soquino¡line hydrochloride (5.0 g, 23.29 mmol) in dry 1,2-dichloroethane (200 mL) formalin was added. (37% aqueous formaldehyde, 2.0 mL, 25.86 mmol), followed by triacetoxyborohydride (19.81 g, 104.82 mmol). The reaction mixture was stirred vigorously at room temperature for 4 hours, and concentrated. The residue was diluted with EtOAc (400 mL), slowly quenched with saturated aqueous NaHCOs solution (400 mL), and stirred for 30 minutes. The mixture was extracted with EA (100 mL x 4). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to provide 2methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline as a brown solid (3.8 g, yield to 85%). LC-MS (ESI) m / : 193 [M+H]+. Step 3\ A suspension of 2-methyl-7-nitro-l,2,3,4-tetrahydroisoquinoline (3.8 g, 19.77 mmol), Fe (5.52 g, 98.85 mmol), NFUCI ( 15.86 g, 296.54 mmol) in EA (10 mL), EtOH (100 mL), and H2O (20 mL) was stirred vigorously at 70 °C for 24 hours. After filtration, the cake was washed with a mixed solvent of EA / EtOH (100 mL, 10 / 1, v / v) and the filtrate was concentrated. The residue was purified with flash column chromatography on silica gel (MeOH in DCM, 0% to 25% v / v) to provide 2-methyl-1,2,3,4-tetrahydro¡soquinolin-7- amine as a yellow solid (1.84 g, 57% yield). LC-MS (ESI) m / z: 163 [M+H]+. Int. W3 6-Chloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-7-amine 139 RRI b7n / 77O7 / 3 / YIA Fe, NH4CIH2NN EA / EtOH / H2O, 60 °C wl Step 1\ To a solution of 6-chloroisoquinoline (2.0 g, 12.22 mmol) in MeCN (15 mL) was added Mel (5.21 g, 36.67 mmol) at room temperature. The mixture was stirred at 50 °C in a se...

Claims

1. - A compound represented by the structural formula (1-0): or a pharmaceutically acceptable salt or a stereoisomer thereof, characterized in that X is CR2R3 or NR3; A is CR2 or N; R is an 8- to 10-membered bicyclic nitrogen-containing heteroaryl or an 8- to 10-membered bicyclic nitrogen-containing heterocyclyl optionally substituted with oxo, wherein the nitrogen-containing heteroaryl or nitrogen-containing heterocyclyl represented by R has 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with one to four Ra, and wherein R is connected to the pyrimidine ring through a nitrogen ring atom or R is represented by the structure shown below: Ri is H, deuterium, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O)NRnRi2, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, alkyl of NRnC(O)Ci6, phenyl, 5- to 6-membered heteroaryl,C3-6 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl represented by Ri or in the group represented by Ri is optionally substituted with one to three substituents selected independently from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, and NR11R12; or R and Ri, together with the carbon atoms to which they are attached, form a ring represented below: 272 RR LfrZn / ZZnZ / q / YIA R AJ c , wherein the J bonds are connected to the pyrimidine ring; each case of R2 is independently H, deuterium, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O)NRuRi2, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, P(=O)RuRi2, S(=O)2Ru, or S(=O)2NRnRi2, wherein the alkyl, alkenyl,alkynyl or alkoxy represented by R2 or in the group represented by R2 is optionally substituted with one to three substituents selected independently from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C4 haloalkoxy, and NR11R12; R3 is H, C1-6 alkyl, C(O)Ci-6 alkyl, C3-6 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl represented by R3 or in the group represented by R3 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C3-6 haloalkoxy, C3-6 cycloalkyl, 3- to 7-membered heterocyclyl, and NR11R12; each instance of Rn and R12 being independently H or C1-6 alkyl,wherein the alkyl represented by Rn or Ri2 is optionally substituted with one to three substituents selected independently from the group consisting of halogen, OH, CN, Ci-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, or Rn and R12, together with the nitrogen atom or phosphorus atom to which they are attached, form a 3- to 7-membered heterocyclyl optionally substituted with one to three substituents selected independently from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each case of Ra is independently H, deuterium, halogen, OH, CN, NH2, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)Ci-6 alkyl, C(O)ORn, NRnC(O)Ri2, S(=O)2Rn, S(=O)2NRnRi2, NRnS(=O)2Ri2, P(=O)RuRi2, C3-6 cycloalkyl,3- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl or heteroaryl represented by Ra or in the group represented by Ra is optionally substituted with one to three substituents selected independently from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, NR11R12, C(O)NRnRi2, C(O)NRnORi2, C(O)NRiiS(=O)2Ri2, C(O)ORii, NRhS(=O)2Ri2, P(=O)RnRi2, S(=O)2Rh, S(=O)2NRhRi2, and 5- to 6-membered heteroaryl; or two Ra, together with the carbon atom(s) to which they are attached, form a C3-6 cycloalkyl or 3- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one to three substituents selected independently from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each instance of Rb is independently H,deuterium, halogen, OH, CN, NH2, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12, C(O)NRnRi2, C(O)NRnORi2, C(O)NRiiS(=O)2Ri2, C(O)Ci-6 alkyl, C(O)ORn, NRnC(O)Ri2, S(=O)2Rn, S(=O)2NR11R12, NR11S(=O)2R12, P(=O)RnRi2, C3-6 cycloalkyl, 3- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl or heteroaryl is represented by Rb or in the group represented by Rb is optionally substituted with one to three substituents selected independently from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, NR11R12, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORn, NRnS(=O)2Ri2, P(=O)RiiRi2, S(=O)2Rh, S(=O)2NRnRi2, and 5- to 6-membered heteroaryl; each instance of Rc is independently phenyl,5- to 6-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N and O; 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N and O; wherein the phenyl, heterocyclyl or heteroaryl represented by Rc is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, NR11R12, C(O)NRnRi2, and P(O)di-Ci-6 alkyl; Ra' is optionally substituted OH, CN, 5- to 6-membered heteroaryl of Ci6, C(O)NRuRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORn, NRnS(=O)2Ri2, P(=O)RnRi2, S(=O)2Rn, S(=O)2NRiiRi2; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1, 2 or 3; q is 1, 2 or 3; and p + q < 4. 2,- The compound according to claim 1, further characterized in that the compound is represented by the structural formula (1-1): RRI b7n / 77n7 / D / YIAI or a pharmaceutically acceptable salt or a stereoisomer thereof.

3. The compound according to claim 1 or 2, further characterized in that the compound is represented by the structural formula (1-2): 274 RRLfrzn / zznz / q / YL or a pharmaceutically acceptable salt or a stereoisomer thereof.

4. The compound according to any of claims 1 to 3, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that the bond is connected to the pyrimidine ring.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that each instance of Ra is independently H, halogen, OH, CN, C1-4 alkyl, C1-4 alkoxy, NR11R12, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)Ci-4 alkyl, C(O)ORu, NRuC(O)Ci-4 alkyl, NRnS(=O)2Ri2, S(=O)2Ru, S(=O)2NRnRi2, P(=O)RuRi2, C3-6 cycloalkyl, 3- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, 275 cycloalkyl, heterocyclyl or heteroaryl represented by Ra or in the group represented by Ra is optionally substituted with one to three substituents selected independently from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, NR11R12, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORu, NRhS(=O)2Ri2, P(=O)RuRi2, S(=O)2Rh, S(=O)2NRhRi2, and 5- to 6-membered heteroaryl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that Ri is H, halogen, CN, Ci-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, NR11R12, C(O)NRnRi2, C(O)Ci-e alkyl, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, wherein the alkyl, alkenyl or alkoxy represented by Ri or in the group represented by Ri is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, and NR11R12.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that each instance of R2 is independently H, halogen, OH, CN, NH2, NO2, C1-4 alkyl, C1-4 alkoxy, NR11R12, C(O)NRuRi2, C(O)Ci-4 alkyl, C(O)OCi-4 alkyl, NRnC(O)Ci-4 alkyl, P(=O)RnRi2, S(=O)2Rh, or S(=O)2NR11R12, wherein the alkyl or alkoxy represented by R2 or in the group represented by R2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, Ci-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that R3 is H, C1-6 alkyl, or C(O)Ci-6 alkyl, wherein the alkyl represented by R3 or in the group represented by R3 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, further characterized in that each instance of Ra is independently H, halogen, OH, CN, C1-4 alkyl, C3-6 cycloalkyl, C(O)NRnRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORn, N(Rn)S(=O)2Ri2, S(=O)2Rh, S(=O)2NRuRi2, P(O)RuRi2, or a 5- to 6-membered heteroaryl, wherein the alkyl or cycloalkyl represented by Ra or in the group represented by Ra is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, alkoxy C1-4, C1-4 haloalkoxy, NR11R12, C(O)NRuRi2, C(O)NRnORi2, C(O)NRnS(=O)2Ri2, C(O)ORii, NRnS(=O)2Ri2, P(=O)RhRi2, S(=O)2Rh, 276 S(=O)2NRuRi2, and heteroaryl 5 to 6 members; each case of Ru and R12 is independently H or C1-6 alkyl.

10. The compound according to any of claims 1 to 9, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that Ri is H, halogen, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C1-4 alkoxy, or C1-4 haloalkoxy.

11. The compound according to any of claims 1 to 10, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized where the linkage connects to the pyrimidine ring, and n is 0 to 4. 12.- The compound according to any of claims 1 to 10, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized by the bond connecting to the pyrimidine ring, and n is 0 to 2. 13.- The compound according to any of claims 1 to 10, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized where the bond connects to the pyrimidine ring, and n is 0 to 2.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that each instance of Ra is independently H, halogen, C1-4 alkyl, -(CHRaa)kOH, -(CHRaa)kCN, -(CHRaa)kC(O)OR11, -(CHRaa)kC(O)NR12R12, -(CHRaa)kC(O)NR12R12, -(CHRaa)kC(O)NR12R12, -(CHRaa)kC(O)NR12R12, -(CHRaa)kC(O)NR12R12R13, -(CHRaa)kC(O)NR12R13R14R12, -(CHRaa)kC(O)NR12R13R14R14R15R16R16R16R16R17R17R18R17R18R18R18R19 ... Raa is independently H or C1-3 alkyl optionally substituted with halogen; Ru and R12 are independently H or C1-4 alkyl; yk is 0 or 1.

15. The compound according to any of claims 1 to 14, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that Ri is H, F, Cl, CN, or CF3.

16. The compound according to any of claims 1 to 15, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized RRI 670 / 7707 / 3 / YILI 17.- The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that R is Ra1, wherein the bond is connected to the pyrimidine ring, Ra1 is independently C1-4 alkyl, or C1-4 hydroxyalkyl; Raí' is independently -(CHRaa)kOH, -(CHRaa)kCN, -(CHRaa)kC(O)ORll, -(CHRaa)kC(O)NRnR12, -(CHRaa)kC(O)NRllOR12, -(CHRaa)kC(O)NRnS(=O)2Ri2, -(CHRaa)kS(=O)2Ru, -(CHRaa)kS(=O)2NRuRi2, -(CHRaa)kNRnS(=O)2Ri2, -(CHRaa)k-5- to 6-membered heteroaryl, or -(CHRaa)kP(=O)RuRi2; Raa is independently H or C1-3 alkyl optionally substituted with halogen; Ra is independently H, F, or Cl; Ru and R12 are independently H or C1-4 alkyl; k is 0 or 1. 18.- The compound according to claim 17, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that Raí is independently H, CH3, or CH2OH; Raí' is independently -(CHRaa)kOH, -(CHRaa)kCN, -(CHRaa)kC(O)ORn, -(CHRaa)kC(O)NRuRi2, -(CHRaa)kC(O)NRnORi2, -(CHRaa)kC(O)NRiiS(=O)2Ri2, -(CHRaa)kS(=O)2Rn, -(CHRaa)kS(=O)2NRuRi2, -(CHRaa)kNRuS(=O)2Ri2, -(CHRaa)k-tetrazol, or -(CHRaa)kP(=O)RuRi2; Raa is independently H, CH3, or CF3; Ru and R12 are independently H or C1-2 alkyl; yk is 0 or 1. 278 19. The compound according to claim 18, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that each instance of Ra is independently H or F.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that Ri is Cl. RRI ^70 / 7707 / 3 / YILI 21. The compound according to any of claims 1 to 3, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that R and R1, together with the carbon atoms to which they are attached, form a ring represented below: wherein the bonds are connected to the pyrimidine ring.

22. The compound according to any one of claims 1 to 3 and 21, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that each instance of Rb is independently H, halogen, OH, CN, NH2, COOH, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxyalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-4 hydroxyalkoxy, NR11R12, C(O)NRiiRi2, C(O)Ci-4 alkyl, C(O)OCi-4 alkyl, C(O)NRhORi2, S(=O)2Rn, S(=O)2NR11R12, NR11(S=O)2R12, C(O)NRuS(=O)2Ri2, P(=O)RuRi2, 5- to 6 members, or NRnC(O)Ci-4 alkyl; and each instance of Re is either phenyl or pyridinyl, each of which is optionally substituted with one or two substituents selected independently from the group consisting of halogen, OH, CN, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, NR11R12, C(O)NRuRi2, and P(=O)di-Ci-6 alkyl.

23. The compound according to any of claims 1 to 3, 21, and 22, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that R and R1, together with the carbon atoms to which they are attached, form a ring represented below: 279 connect to the pyrimidine ring.

24. The compound according to any one of claims 1 to 3 and 21 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, further characterized in that each instance of Rb is independently H, halogen, CN, COOH, C1-2 alkyl, or C1-2 haloalkyl; each instance of Rc is phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, NR11R12, C(O)NRnRi2, and P(=O)di-Ci-6 alkyl, and each instance of Rn and R12 is independently H or C1-6 alkyl.

25. The compound according to any one of claims 1 to 3 and 21 to 24, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that each instance of Rb is independently H, CN, or COOH; and each instance of Rc is phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of C1-4 alkyl, C(O)N(CH3)2, and P(=O)(CH3)2.

26. The compound according to any of claims 1 to 25, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that m is 0 or 1.

27. The compound according to any of claims 1 to 26, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized 28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that each instance of R2 is H, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy; and R3 is H, C1-6 alkyl, C1-6 hydroxyalkyl, or COCH2NR11R12.

29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that each instance of R2 is H, F, Cl, or OCH3; and R3 is H or Cl-4 alkyl. 30.- A compound represented by the structural formula (II): 280 RR LfrZn / ZZnZ / q / YIA or a pharmaceutically acceptable salt or a stereoisomer thereof, characterized in that Ai is CR' or N; X is -P(=O)R3'R4·; R' is H, deuterium, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e alkoxy, NR11R12', C(O)NRnRi2', C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRuC(O)Ci-6 alkyl, wherein the alkyl, alkenyl, alkynyl or alkoxy represented by R' or in the group represented by R' is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11-R12;each instance of Rr is independently H, deuterium, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12·, C(O)NRn Ri2', C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, or heterocyclyl represented by Rr or in the group represented by Rr is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, Cm haloalkoxy, and NRnRiz;each instance of R2· is independently H, deuterium, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR11R12', C(O)NRnRi2', C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRnC(O)Ci-6 alkyl, phenyl, 5- to 6-membered heteroaryl, C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl, or heterocyclyl represented by R2' or in the group represented by R2' is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, alkyl of C1-4, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11-R12-;each R3' and R4· is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, wherein the alkyl, alkenyl or alkynyl represented by R3' or R4' is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NRnRu·;each instance of Ru and R12 is independently H or C1-6 alkyl, wherein the alkyl represented by Ru or Ri2 is optionally substituted with one to three substituents selected independently from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, or Ru and R12, together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclyl optionally substituted with one to three substituents selected independently from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; m' is 0, 1, or 2; yn' is 0, 1, or 2.; 31. The compound according to claim 30, further characterized in that the compound is represented by the structural formula (II-l): AAI bZn / ZZnZ / D / YIAI or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R' is H, halogen, NR11R12', or C1-e alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12'.

32. The compound according to claim 30 or 31, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that R3' and R4' are independently H or C1-6 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and NR11-R12'.

33. The compound according to any one of claims 30 to 32, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that each instance of Rr is independently H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl represented by Rr is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12·;each instance of R2· is independently H, halogen, OH, NO2, C1-6 alkyl, C1-6 alkoxy, NR11-R127 C(O)NRn Ri2·, C(O)Ci-6 alkyl, C(O)OCi-6 alkyl, NRuC(O)Ci-6 alkyl, 5- to 6-membered heteroaryl or 3- to 7-membered heterocyclyl, wherein the alkyl, alkoxy, heteroaryl or heterocyclyl represented by R2' or in the group represented by R2' is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and NR11R12'.

34. The compound according to any of claims 30 to 33, further characterized in that the compound is represented by the structural formula (II-2) or (II2'): RR I ^70 / 7707 / D / YIA X ​​(Π-2), or X (II-2') or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R' is H, halogen, or NH2.

35. The compound according to any one of claims 30 to 34, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that each instance of R2- is independently H, halogen, OH, C1-4 alkyl optionally substituted with halogen or OH or NRn Ri2·, C1-4 alkoxy, C(O)OCi-6 alkyl, C(O)NRuRi2', NRnRir, NRir C(O)Ci-6 alkyl, 5- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl; and each instance of Rr is independently H or C1-4 alkyl.

36. The compound according to any one of claims 30 to 35, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that Rs· and R4' are independently C1-4 alkyl; and each instance of R2- is independently H, halogen, OH, C1-4 alkyl optionally substituted with halogen or OH or NRnRir, C1-4 alkoxy, C(O)OCi-4 alkyl, C(O)NRnRi2', NRu-Ri2·, NHC(O)Ci-6 alkyl, pyrrolidinyl, pyrrolidin-2-one, oxazole, wherein each instance of Rir and Rizes independently H or C1-4 alkyl. 37.- The compound according to any one of claims 30 to 36, or a pharmaceutically acceptable salt or a stereoisomer thereof, further characterized in that X is -P(O)(CH3)2 and each instance of R2- is independently H, F, Cl, OH, CH3, NH2, or NHCOCH3. 38.- A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any of claims 1 to 37, or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

39. A combination comprising a therapeutically effective amount of the compound according to any of claims 1 to 37, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more therapeutically active co-agents.

40. A method for treating a subject with cancer, comprising: administering to the subject an effective amount of a compound of any of claims 1 to 37, or a pharmaceutically acceptable salt or stereoisomer thereof.

41. The method according to claim 40, further characterized in that the cancer is selected from breast cancer, colorectal cancer, lung cancer, ovarian cancer, and pancreatic cancer.

42. A method for inhibiting HPK1 activity in a subject in need thereof, said method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or stereoisomer thereof.

43. The method according to claim 42, further characterized in that the subject has cancer and wherein the cancer is treated.

44. The method according to claim 43, further characterized in that the cancer is selected from breast cancer, colorectal cancer, lung cancer, ovarian cancer, and pancreatic cancer.

45. A compound of any of claims 1 to 37, or a pharmaceutically acceptable salt or stereoisomer thereof, for use as a medicament, such as a medicament acting as an HPK1 inhibitor.

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