HPK1 antagonists and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using them for inhibiting HPK1 and treating HPK1-mediated disorders.It has now been found that the compounds of the present invention and their pharmaceutically acceptable compositions are effective as HPK1 antagonists.In certain embodiments, the present invention provides compounds of the formulas described herein.The compounds of the present invention and their pharmaceutically acceptable compositions are useful for treating various diseases, disorders or conditions associated with the regulation of signal transduction pathways involving HPK1 kinase.Such diseases, disorders or conditions include those described herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 62 / 900,152, filed September 13, 2019, and Provisional Patent Application No. 63 / 032,070, filed May 29, 2020, the entire contents of each of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to compounds and methods useful for antagonizing hematopoietic progenitor kinase 1 (HPK1). The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, as well as methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] Background of the Invention Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1), is a hematopoietic cell-restricted member of the Ste20 serine / threonine kinase superfamily. The MAP4K family includes MAP4K1 / HPK1, MAP4K2 / GCK, MAP4K3 / GLK, MAP4K4 / HGK, MAP4K5 / KHS, and MAP4K6 / MINK. HPK1 is a tissue-specific upstream activator of the MEKK / JNK / SAPK signaling pathway.

[0004] HPK1 is of particular interest because it is expressed primarily in hematopoietic cells such as T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells (Hu, MC, et al., Genes Dev, 1996. 10(18): pp. 2251-64; Kiefer, F., et al., EMBO J, 1996. 15(24): pp. 7013-25). HPK1 kinase activity was found to be involved in the regulation of T cell receptor (TCR) (Liou, J., et al., Immunity, 2000. 12(4): pp. 399-408), B cell receptor (BCR) (Liou, J., et al., Immunity, 2000. 12(4): pp. 399-408), transforming growth factor receptor (TGF-PR) (Wang, W., et al., J Biol Chem, 1997. 272(36): pp. 22771-5; Zhou, G., et al., J Biol Chem, 1999. 274(19): pp. 13133-8), or Gs-linked PGE2 receptors (EP2 and EP4) (Ikegami, R., et al., J Immunol, 2001. 166(7): p. HPK1 has been shown to be induced upon activation of the IL-1 receptor agonist (IL-1), IL-1 receptor agonist (IL-1), and IL-2 receptor agonist (IL-2). Thus, HPK1 regulates diverse functions of various immune cells. HPK1 is also an example of a negative regulator of dendritic cell activation and T cell and B cell responses that can be targeted to enhance antitumor immunity. HPK1 is primarily expressed by hematopoietic cells, including early precursors. In T cells, HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, which is thought to recruit 14-3-3 proteins that bind phosphorylated SLP76 and Gads, resulting in the release of SLP76-Gads-14-3-3 complexes from LAT-containing microclusters (Lasserre et al. (2011) J Cell Biol 195(5):839-853).HPK1 can also become activated in response to prostaglandin E2, which is often secreted by tumors, and this contributes to tumor cell evasion from the immune system.

[0005] HPK1 is important for regulating the functions of various immune cells and is associated with autoimmune diseases and antitumor immunity (Shui, JW, et al., Nat Immunol, 2007. 8(1): p. 84-91; Wang, X., et al., J Biol Chem, 2012. 287(14): p. 11037-48). Summary of the Invention [Means for solving the problem]

[0006] SUMMARY OF THE INVENTION It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as antagonists of HPK1. In certain embodiments, the present invention provides compounds of the formulae depicted herein:

[0007] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions associated with the regulation of signal transduction pathways involving HPK1 kinase, including those described herein.

[0008] The compounds provided by the present invention are also useful for the study of the HPK1 enzyme in biological and pathological phenomena; the study of intracellular signaling pathways occurring in body tissues; and the in vitro or in vivo comparative evaluation of new HPK1 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels. In an embodiment of the present invention, for example, the following items are provided. (Item 1) A compound of formula I: [ka] or a pharmaceutically acceptable salt thereof (wherein, Z is CR or N, X is a covalent bond, -O-, -S-, -NR-, -S(O) 2 -, -S(O) 2 NR-, -S(O)-, -S(O)NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(O)N(R)O-, -OC(O)-, -OC(O)NR-, -N(R)C(O)O-, -N(R)C(O)-, -N(R)S(O) 2 -, or X is a divalent saturated or unsaturated straight-chain or branched hydrocarbon chain of C 1~4 , wherein one or two methylene units of said chain are optionally and independently -C(R) 2 -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 -; R 1 is C 1~6 aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, each of which is substituted by q examples of R C ; R 2 is a 6- to 11-membered saturated, partially unsaturated or unsaturated, fused, bridged or spiro bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, each of which is substituted by q examples of R C ; R 3 each example of is independently hydrogen or an optionally substituted C 1~6 aliphatic group; R C each example of is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -N=S(O)R 2 、-S(NR)(O)R、-N(R)S(O)R、-N(R)CN、-P(O)(R)NR 2 , -P(O)(R)OR or -P(O)R 2 or R C Each instance of 1~6 aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and sulfur; a 6- to 11-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is represented by the r instances of R and the s instances of R. D is replaced by R D Each example is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -N=S(O)R 2 、-S(NR)(O)R、-N(R)S(O)R、-N(R)CN、-P(O)(R)NR 2 , -P(O)(R)OR or -P(O)R 2 and Each R is independently hydrogen, -CN, halogen, or C 1~6 Aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is a optionally substituted group, or two R groups on the same nitrogen together with said nitrogen form a optionally substituted 4- to 7-membered monocyclic saturated ring, partially unsaturated ring or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to said nitrogen; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, m is 0, 1 or 2, each q is independently 0, 1, 2, 3 or 4, each r is independently 0, 1, 2, 3 or 4, each s is independently 0, 1, 2, 3 or 4). (Item 2) Formula II:

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[0009] Detailed Description of Specific Embodiments 1. General Description of Certain Embodiments of the Invention: In certain embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula I, X, Z, R 1 , R 2 , R 3 and m, both alone and in combination, are as defined below and described in embodiments herein.

[0010] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0011] In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder, or condition, comprising administering to a patient in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0012] 2. Compounds and definitions: The compounds of the present invention include those generally described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise specified, the following definitions shall apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Edition, eds. Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0013] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), having one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, saturated or unsaturated, alkyl, alkenyl, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0014] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system (i.e., carbocyclic or heterocyclic) that is saturated or partially unsaturated and has at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or a single atom, or a valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (other than hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents, such as those described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic rings include: [ka] [ka] Examples include:

[0015] The term "lower alkyl" refers to C 1~4 Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0016] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1~4 The term "alkyl" refers to a straight or branched chain alkyl group.

[0017] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring (e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0018] The term "unsaturated," as used herein, means a moiety having one or more units of unsaturation.

[0019] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated, straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0020] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogens are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0021] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0022] The term "halogen" means F, Cl, Br, or I.

[0023] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may bear one or more substituents. As used herein, and included within its scope, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0024] The terms "heteroaryl" and "heteroara-," used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroara-," as used herein, also encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and the radical or point of attachment, unless otherwise specified, is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0025] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having zero to three heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl) or NH (as in pyrrolidinyl). + It may also be NR (as in N-substituted pyrrolidinyl).

[0026] A heterocyclic ring can be attached to its parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0027] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0028] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0029] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH) 0~4 R ○ ;-(CH2) 0~4 OR ○ ;-O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 SR ○ ;-(CH2) 0~4 Ph (which is R ○ -(CH2) 0~4 O(CH2) 0~1 Ph (which is R ○ -CH=CHPh (which may be substituted with R ○ -(CH2) 0~4 O(CH2) 0~1 -pyridyl (which is R ○which can be replaced); -NO2; -CN; -N3; -(CH2) 0~4 N(R ○ )2; -(CH2) 0~4 N(R ○ )C(O)R ○ ; -N(R ○ )C(S)R ○ ; -(CH2) 0~4 N(R ○ )C(O)NR ○ 2; -N(R ○ )C(S)NR ○ 2; -(CH2) 0~4 N(R ○ )C(O)OR ○ ; -N(R ○ )N(R ○ )C(O)R ○ ; -N(R ○ )N(R ○ )C(O)NR ○ 2; -N(R ○ )N(R ○ )C(O)OR ○ ; -N(R ○ )C(NR ○ )N(R ○ )2; -(CH2) 0~4 C(O)R ○ ; -C(S)R ○ ; -(CH2) 0~4 C(O)OR ○ ; -(CH2) 0~4 C(O)SR ○ ; -(CH2) 0~4 C(O)OSiR ○ 3; -(CH2) 0~4 OC(O)R ○ ; -OC(O)(CH2) 0~4 SR ○ ; -SC(S)SR ○ ; -(CH2) 0~4 SC(O)R ○ ; -(CH2) 0~4 C(O)NR ○ 2; -C(S)NR ○ 2; -C(S)SR ○ ; -SC(S)SR ○ , -(CH2) 0~4 OC(O)NR ○ 2; -C(O)N(OR○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C(NOR ○ )R ○ ;-(CH2) 0~4 SSR ○ ;-(CH2) 0~4 S(O)2R ○ ;-(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH2) 0~4 S(O)R ○ ;-N(R ○ )S(O)NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;-SiR ○ 3;-(C 1~4 straight or branched chain alkylene)ON(R ○ )2; or -(C 1~4 straight or branched chain alkylene)C(O)ON(R ○ )2, where each R ○ may be substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R ○two independent occurrences of together with the atom(s) between them form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0030] R ○ (R ○ Suitable monovalent substituents on the ring formed by two independent occurrences of (a ring formed by two independent occurrences of together with the atom between them) are independently halogen, -(CH2) 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0031] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2~3 S-. Here R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 and an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatom independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 It is selected from an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] As used herein, the term "pharmaceutically acceptable salts" refers to those salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of the salts include phonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0036] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N+ (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0037] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures of the invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by methyl ... 13 C or 14 Compounds having the invention in which C is replaced with an enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools according to the invention, as probes in biological assays, or as therapeutic agents. In certain embodiments, the warhead moiety R of a given compound is 1 contains one or more deuterium atoms. In certain embodiments, ring B of provided compounds can be substituted with one or more deuterium atoms.

[0038] Structures depicted represent relative configuration unless indicated as absolute configuration. The present invention contemplates individual enantiomers as well as racemic mixtures.

[0039] As used herein, an "HPK1 antagonist" or "HPK1 inhibitor" refers to a molecule that reduces, inhibits, or otherwise attenuates one or more of HPK1's biological activities (e.g., serine / threonine kinase activity, recruitment to the TCR complex upon TCR activation, interaction with protein binding partners such as SLP76). Antagonism using an HPK1 antagonist does not necessarily indicate total elimination of HPK1 activity. Instead, activity may be reduced by a statistically significant amount, including, for example, at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% reduction in HPK1 activity compared to an appropriate control. In some embodiments, the HPK1 antagonist reduces, inhibits, or otherwise attenuates the serine / threonine kinase activity of HPK1. In some of these embodiments, the HPK1 antagonist reduces, inhibits, or otherwise attenuates HPK1-mediated phosphorylation of SLP76 and / or Gads. The presently disclosed compounds directly bind to HPK1 and inhibit its kinase activity.

[0040] A "specific antagonist" is intended to be an agent that reduces, inhibits, or otherwise weakens the activity of a specified target to a greater extent than the activity of an unrelated target. For example, an HPK1-specific antagonist reduces at least one biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other serine / threonine kinase). In some embodiments, the IC of the antagonist against the target 50 is the IC of the antagonist against the non-target 50The presently disclosed compounds may or may not be specific HPK1 antagonists. A specific HPK1 antagonist reduces the biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., another serine / threonine kinase). In certain embodiments, the HPK1 antagonist specifically inhibits the serine / threonine kinase activity of HPK1. In some of these embodiments, the IC of the HPK1 antagonist for HPK1 is 50 indicates the IC of HPK1 antagonists against other serine / threonine kinases or other types of kinases (e.g., tyrosine kinases). 50 or less than about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the

[0041] The compounds of the present invention can be tethered to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that a detectable moiety can be attached to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently linked to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate, amino, thiol, or hydroxyl moieties, to name a few. It is understood that such moieties can be attached directly to a provided compound or via a tethering group such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0042] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), primary labels, such as mass tags and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0043] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a secondary intermediate to generate a detectable signal. For biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. For antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radioactive fluorescence resonance energy transfer (FRET), and the second group generates the signal that is detected.

[0044] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, BODIPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, BODIPY581 / 591, BODIPY630 / 650, BODIPY650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydrochloride Examples of suitable dyes include, but are not limited to, roxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0045] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection technology.Examples of mass tag include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives.The synthesis and usefulness of these mass tags are described in U.S. Patent No. 4,650,750, U.S. Patent No. 4,709,016, U.S. Patent No. 5,360,8191, U.S. Patent No. 5,516,931, U.S. Patent No. 5,602,273, U.S. Patent No. 5,604,104, U.S. Patent No. 5,610,020 and U.S. Patent No. 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides of various lengths and base compositions, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, in the appropriate mass range (100-2000 daltons) may be used as mass tags.

[0046] The terms "measurable affinity" and "measurably inhibit," as used herein, refer to a measurable change in HPK1 protein kinase activity between a sample containing a compound of the present invention or a composition thereof and HPK1 protein kinase and an equivalent sample containing HPK1 protein kinase in the absence of the compound or composition thereof. 3. Description of Exemplary Embodiments:

[0047] As noted above, in certain embodiments, the present disclosure provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is CR or N; X is a covalent bond, -O-, -S-, -NR-, -S(O)2-, -S(O)2NR-, -S(O)-, -S(O)NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(O)N(R)O-, -OC(O)-, -OC(O)NR-, -N(R)C(O)O-, -N(R)C(O)-, -N(R)S(O)2-, or X is C 1~4 wherein one or two methylene units of said chain are optionally and independently replaced by -C(R)-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-; R 1 is C 1~6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from q instances of R C is replaced by R 2 is a 6- to 11-membered saturated, partially unsaturated, or unsaturated, fused, bridged, or spiro bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from q instances of R C is replaced by R 3 Each instance of is independently hydrogen or an optionally substituted C 1~6 is an aliphatic group, R CEach instance of is independently selected from oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C (O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2, or R C Each instance of 1~6 aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and sulfur; a 6- to 11-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is represented by the r instances of R and the s instances of R. D is replaced by R DEach instance of is independently selected from oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R )C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; Each R is independently hydrogen, -CN, halogen, or C 1~6 aliphatic; phenyl; naphthalenyl; 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; two R groups on the same nitrogen, taken together with said nitrogen, form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to said nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1 or 2; each q is independently 0, 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; each s is independently 0, 1, 2, 3, or 4).

[0048] Z is CR or N, as generally defined above.

[0049] In some embodiments, Z is CR. In some embodiments, Z is N.

[0050] In some embodiments, Z is CH. In some embodiments, Z is CCl. In some embodiments, Z is CF. In some embodiments, Z is CCH.

[0051] In some embodiments, Z is selected from those depicted in Table 1 below.

[0052] As generally defined above, X is a covalent bond, -O-, -S-, -NR-, -S(O)2-, -S(O)2NR-, -S(O)-, -S(O)NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(O)N(R)O-, -OC(O)-, -OC(O)NR-, -N(R)C(O)O-, -N(R)C(O)-, -N(R)S(O)2-, or X is C 1~4wherein one or two methylene units of said chain are optionally and independently replaced by -C(R)-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-.

[0053] In certain embodiments, X is —O—, —S—, —NR—, —S(O)—, —S(O)NR—, —S(O)—, —S(O)NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(O)N(R)O—, —OC(O)—, —OC(O)NR—, —N(R)C(O)O—, —N(R)C(O)—, —N(R)C(O)NR—, —N(R)C(NR)NR—, —N(R)NR—, —N(R)S(O)NR—, or —N(R)S(O)—.

[0054] In some embodiments, X is C 1~4 wherein one or two methylene units of said chain are optionally and independently replaced by -C(R)-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-.

[0055] In certain embodiments, X is -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(O)N(R)O-, -OC(O)-, -OC(O)NR-, -N(R)C(O)O-, -N(R)C(O)-, -N(R)C(O)NR-, -N(R)C(NR)NR-, or -N(R)NR-.

[0056] In certain embodiments, X is -NR-. In certain embodiments, X is -NH-.

[0057] In some embodiments, X is selected from those depicted in Table 1 below.

[0058] As generally defined above, R 1 is C 1~6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from q instances of R C has been replaced by

[0059] In some embodiments, R 1 is the number of q examples in R C C replaced by 1~6 Aliphatic; q examples of R C phenyl substituted by q instances of R C a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring substituted by q examples of R C a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted by: C a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted by C and n is 0 or 1. The heterocyclic ring is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted by:

[0060] In some embodiments, R 1 is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from q instances of R Chas been replaced by

[0061] In certain embodiments, R 1is phenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydro Furan, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxetanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4 thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl or xanthenyl, each of which is selected from q instances of R; C has been replaced by

[0062] In certain embodiments, R 1is phenyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxetanyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazo lysinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl or xanthenyl, each of which is selected from the group consisting of q instances of R C has been replaced by

[0063] In certain embodiments, R 1 is furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxetanyl, pyrimidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl or 1,2,5-triazolyl, 1,3,4-triazolyl, each of which is selected from the q instances of R C has been replaced by

[0064] In certain embodiments, R 1 is phenyl, pyrazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each of which is selected from the group consisting of q instances of R C has been replaced by

[0065] In certain embodiments, R 1 is pyrazolyl or pyridinyl, which are respectively the q instances of R C has been replaced by

[0066] In certain embodiments, R 1 is pyrazolyl or pyridinyl, which are respectively the q instances of R C is replaced by R C are each independently halogen, —CN, —OR, —S(O)R, —C(O)NR, or R c Each instance of 1~6 an optionally substituted group selected from aliphatic; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-12 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur, or two R C groups, taken together with the atoms to which they are each attached, form a 5- to 6-membered bridged, fused, or spiroaryl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur, and R c Each instance of is independently R and R D are substituted as necessary by

[0067] In certain embodiments, R 1 teeth [ka] is.

[0068] In certain embodiments, R 1 teeth [ka] is.

[0069] In certain embodiments, R 1 teeth [ka] (wherein R C are independently a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are respectively represented by the r instances of R and the s instances of R. D is replaced by ).

[0070] In certain embodiments, R 1 teeth [ka] (wherein R C Each example is independently -Me, -Et, -CN, -F, -OMe, -S(O)Me [ka] [ka] (It is).

[0071] In certain embodiments, R 1 That R C Together with the substituents, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0072] In certain embodiments, R 1 That R C Together with the substituents, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0073] In certain embodiments, R 1 That R C Together with the substituents, [ka] [ka] is.

[0074] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0075] As generally defined above, R 2 is a 6- to 11-membered saturated, partially unsaturated, or unsaturated, fused, bridged, or spiro bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from q instances of R C has been replaced by

[0076] In some embodiments, R 2 is a 6-11 membered saturated, partially unsaturated or unsaturated, fused, bridged or spiro bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which are represented by the q instances of R C has been replaced by

[0077] In certain embodiments, R 2is a 7- to 10-membered fused bicyclic ring having 1 to 3 nitrogen atoms, each of which is selected from q instances of R C has been replaced by

[0078] In certain embodiments, R 2 is a 9-membered fused bicyclic ring having 1 to 3 nitrogen atoms, which is represented by each of q instances of R C is replaced by R C are each independently halogen, —CN, —OR, —C(O)NR, —NR, or R c Each instance of 1~6 an optionally substituted group selected from aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; and a 6- to 11-membered saturated or partially unsaturated fused, bridged, or spiro bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; c Each instance of is independently a R of r instances and a R of s instances. D are substituted as necessary by

[0079] In certain embodiments, R 2 teeth [ka] [ka] [ka] is.

[0080] In certain embodiments, R 2 teeth [ka] is.

[0081] In certain embodiments, R 2 teeth [ka] is.

[0082] In certain embodiments, R 2 That R C Together with the substituents, [ka] [ka] [ka] [ka] is.

[0083] In certain embodiments, R 2 That R C Together with the substituents, [ka] is.

[0084] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0085] As generally defined above, R 3 Each instance of is independently hydrogen or an optionally substituted C 1~6 It is an aliphatic group.

[0086] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is replaced by C 1~6 It is an aliphatic group.

[0087] In some embodiments, R 3 is methyl. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0088] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0089] As generally defined above, R C Each instance of is independently selected from oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C (O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2, or R C Each instance of 1~6aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is represented by the r instances of R and the s instances of R. D has been replaced by

[0090] In some embodiments, R C Each instance of is independently selected from oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C (O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2, or R C Each instance of 1~6aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from an aryl ring; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0091] In some embodiments, R C Examples of each of the following are oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C (O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2.

[0092] In some embodiments, R C Each example of C 1~6aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from an aryl ring; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0093] In some embodiments, R C is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is represented by r instances of R and s instances of R D is replaced by

[0094] In some embodiments, R C is a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is represented by r instances of R and s instances of R D is replaced by

[0095] In some embodiments, R C is methyl, oxo, fluoro or methoxy.

[0096] In some embodiments, R C teeth, [ka] [ka] [ka] [ka] is.

[0097] In some embodiments, R C is -CHF2 or chloro.

[0098] In some embodiments, R C teeth, [ka] [ka] [ka] [ka] [ka] [ka] is.

[0099] In some embodiments, R C teeth, [ka] is.

[0100] In some embodiments, R C Each example is selected from those illustrated in Table 1 below.

[0101] As generally defined above, R DEach instance of is independently selected from oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R )C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2.

[0102] In some embodiments, R D means oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O )R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2.

[0103] In some embodiments, R D is hydroxy, fluoro or methoxy.

[0104] In some embodiments, R D teeth, [ka] is.

[0105] In some embodiments, R D is oxo.

[0106] In some embodiments, R D teeth, [ka] [ka] is.

[0107] In some embodiments, R D is selected from those illustrated in Table 1 below.

[0108] Each R is independently hydrogen, or C, as generally defined above. 1~6 aliphatic; phenyl; naphthalenyl; 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Two R groups on the same nitrogen, together with the nitrogen, form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0109] In some embodiments, R is methyl. In some embodiments, R is [ka] is.

[0110] In some embodiments, R is ethyl.

[0111] In some embodiments, R is [ka] [ka] is.

[0112] In some embodiments, R is selected from those depicted in Table 1 below.

[0113] As generally defined above, each hydrogen bonded to a carbon can be optionally and independently replaced by deuterium.

[0114] In some embodiments, a hydrogen bonded to a carbon is replaced by deuterium.

[0115] As generally defined above, m is 0, 1 or 2.

[0116] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0117] In some embodiments, m is selected from those depicted in Table 1 below.

[0118] As generally defined above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0119] In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2.

[0120] In some embodiments, q is selected from those depicted in Table 1 below.

[0121] As generally defined above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

[0122] In some embodiments, r is 1 or 2. In some embodiments, r is 2 or 3. In some embodiments, r is 2, 3, or 4.

[0123] In some embodiments, r is selected from those depicted in Table 1 below.

[0124] As generally defined above, s is 0, 1, 2, 3, or 4. In some embodiments, s is 0. In some embodiments, s is 1, 2, 3, or 4. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4.

[0125] In some embodiments, s is 1 or 2. In some embodiments, s is 2 or 3. In some embodiments, s is 2, 3, or 4.

[0126] In some embodiments, s is selected from those depicted in Table 1 below.

[0127] In some embodiments, the present invention provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 and R 2 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0128] In some embodiments, the present invention provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 and R 2 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0129] In some embodiments, the present invention provides a compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof (wherein R 2 and R Care each as defined above, both alone and in combination, and as described in embodiments herein.

[0130] In some embodiments, the present invention provides a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 and X are each as defined above, both alone and in combination, and as described in embodiments herein.

[0131] In some embodiments, the present invention provides a compound of formula VI: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 and R 2 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0132] In some embodiments, the present invention provides a compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof (wherein R 2 and R C are each as defined above, both alone and in combination, and as described in embodiments herein.

[0133] In some embodiments, the present invention provides a compound of formula XI-a or XI-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C, X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0134] In some embodiments, the present invention provides a compound of formula XII-a or XII-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0135] In some embodiments, the present invention provides a compound of formula XIII-a or XIII-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R C and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0136] In some embodiments, the present invention provides a compound of formula XIV-a or XIV-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0137] In some embodiments, the present invention provides a compound of formula XV-a or XV-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1, R C and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0138] In some embodiments, the present invention provides a compound of formula XVI-a or XVI-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R C and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0139] In some embodiments, the present invention provides a compound of formula XVII-a or XVII-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0140] In some embodiments, the present invention provides a compound of formula XVIII-a or XVIII-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0141] In some embodiments, the present invention provides a compound of formula XIX-a or XIX-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R C and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0142] In some embodiments, the present invention provides a compound of formula XX-a or XX-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0143] In some embodiments, the present invention provides a compound of formula XXI-a or XXI-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0144] In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0145] In some embodiments, the present invention provides a compound of formula XXIII-a or XXIII-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0146] In some embodiments, the present invention provides a compound of formula XXIV-a or XXIV-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0147] In some embodiments, the present invention provides a compound of formula XXV-a or XXV-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0148] In some embodiments, the present invention provides a compound of formula XXVI-a or XXVI-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0149] In some embodiments, the present invention provides a compound of formula XXVII-a or XXVII-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0150] In some embodiments, the present invention provides a compound of formula XXVIII-a or XXVIII-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0151] In some embodiments, the present invention provides a compound of formula XXIX-a or XXIX-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0152] In some embodiments, the present invention provides a compound of formula XXX-a or XXX-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0153] In some embodiments, the present invention provides a compound of formula XXXI-a or XXXI-b: [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R C , X and q are each as defined above, both alone and in combination, and as described in embodiments herein.

[0154] Exemplary compounds of the present invention are set forth in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66

Table 1-67

Table 1-69

Table 1-90

Table 1-97

Table 1-110

[0155] In some embodiments, the present invention provides a compound described above in Table 1. In some embodiments, the present invention provides a compound described above in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described above in Table 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0156] In some embodiments, the present invention provides a compound of formula I as defined above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I as defined above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use in a pharmaceutical.

[0157] In some embodiments, the present invention also provides a compound of formula I as described herein or a pharmaceutical composition as described herein for use in the methods of inhibiting HPK1 as described herein, for use in the methods of enhancing an immune response in a subject in need thereof as described herein, and / or for use in the methods of treating an HPK1-dependent disorder as described herein.

[0158] In some embodiments, the present invention also provides a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, for use in a method of inhibiting HPK1, as described herein.

[0159] In some embodiments, the present invention also provides a compound of formula I as described herein or a pharmaceutical composition as described herein for use in a method of enhancing an immune response in a subject in need thereof, as described herein.

[0160] In some embodiments, the present invention also provides a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, for use in a method of treating an HPK1-dependent disorder, as described herein.

[0161] In some embodiments, the present invention also provides the use of a compound of Formula I, as described herein, or a pharmaceutical composition, as described herein, for the manufacture of a medicament for inhibiting HPK1, enhancing an immune response in a subject in need thereof, and / or treating an HPK1-dependent disorder.

[0162] In some embodiments, the present invention also provides the use of a compound of Formula I, as described herein, or a pharmaceutical composition, as described herein, for the manufacture of a medicament for inhibiting HPK1.

[0163] In some embodiments, the present invention also provides the use of a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, for the manufacture of a medicament for enhancing an immune response in a subject in need thereof.

[0164] In some embodiments, the present invention also provides the use of a compound of Formula I, as described herein, or a pharmaceutical composition, as described herein, for the manufacture of a medicament for treating an HPK1-dependent disorder.

[0165] In some embodiments, the present invention also provides for the use of a compound of formula I as described herein or a pharmaceutical composition as described herein in a method for inhibiting HPK1 as described herein, in a method for enhancing an immune response in a subject in need thereof as described herein, and / or in a method for treating an HPK1-dependent disorder as described herein.

[0166] In some embodiments, the present invention also provides the use of a compound of Formula I, as described herein, or a pharmaceutical composition, as described herein, in a method of inhibiting HPK1, as described herein.

[0167] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein in a method of enhancing an immune response in a subject in need thereof, as described herein.

[0168] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein in a method of treating an HPK1-dependent disorder as described herein. 4. General Methods of Providing the Compounds

[0169] The compounds of the invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods described in detail in the Examples herein. 5. Use, Prescription and Administration Pharmaceutically Acceptable Compositions

[0170] According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is an amount effective to measurably inhibit HPK1 or a mutant thereof in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective to measurably inhibit HPK1 or a mutant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0171] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0172] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, electrolytes such as salts or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0173] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, directly or indirectly, the compound of this invention or an inhibitory active metabolite or residue thereof.

[0174] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of HPK1 or a mutant thereof.

[0175] The subject matter disclosed herein includes prodrugs, metabolites, derivatives and pharmaceutically acceptable salts of the compounds of the present invention.Metabolites include compounds produced by a process comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce the metabolite.When the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, etc. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treating the free acid with an inorganic base or an organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include, but are not limited to, inorganic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0176] The compounds of the present invention can be in the form of a "prodrug," which includes compounds having a moiety that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free acid form or a hydroxyl with a suitable esterifying agent. A hydroxyl group can be converted to an ester by treating with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate ester), lower alkenyl ester, lower dialkyl-amino lower alkyl ester (e.g., dimethylaminoethyl ester), acylamino lower alkyl ester (e.g., acetyloxymethyl ester), acyloxy lower alkyl ester (e.g., pivaloyloxymethyl ester), aryl ester (phenyl ester), aryl-lower alkyl ester (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl ester, amide, lower alkyl amide, lower dialkyl amide, and hydroxyamide. Prodrugs that are converted to active forms in vivo by other mechanisms are also included. In an embodiment, the compounds of the present invention are prodrugs of any of the formulas herein.

[0177] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0178] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides.Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated form, are useful for preparing injectable substances, as are natural pharmaceutically acceptable oils such as olive oil or castor oil.These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions.Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0179] The pharmaceutically acceptable composition of this invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants 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 are required for oral use, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavoring agents or coloring agents can also be added.

[0180] Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0181] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0182] Topical application for the lower intestinal tract may be in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0183] For topical application, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0184] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated into an ointment such as petrolatum.

[0185] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol 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 enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0186] Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

[0187] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg of body weight per day of the inhibitor can be administered to a patient receiving these compositions.

[0188] It should also be understood that the specific dosage and treatment regimen for any particular patient will vary depending on a variety of factors, including the activity of the specific compounds employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also vary depending on the particular compound in the composition.

[0189] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods of the invention is HPK1.

[0190] The presently disclosed compounds are used to inhibit the activity of the HPK1 enzyme. HPK1 is a member of the germinal center kinase subfamily of Ste20-related serine / threonine kinases. HPK1 functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKK1, MLK3, and TAK1, leading to activation of the MAPK Jnk.

[0191] In one embodiment, the presently disclosed subject matter is directed to a method of inhibiting HPK1, comprising contacting HPK1 with an effective amount of a compound of the invention or a pharmaceutical composition described herein.

[0192] In certain embodiments, the presently disclosed subject matter is directed to a method of enhancing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention or a pharmaceutical composition described herein. In certain aspects of this embodiment, T cells in the subject have at least one of enhanced priming, enhanced activation, enhanced migration, enhanced proliferation, enhanced survival, and enhanced cytolytic activity compared to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, T cell activation is characterized by an increased frequency of γ-IFN+ CD8 T cells or an increased level of IL-2 or granzyme B production by T cells compared to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the number of T cells is increased compared to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the T cells are antigen-specific CD8 T cells. In certain aspects of this embodiment, antigen-presenting cells in the subject have enhanced maturation and activation compared to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the antigen-presenting cells are dendritic cells. In certain aspects of this embodiment, maturation of antigen-presenting cells is characterized by an increased frequency of CD83+ dendritic cells. In certain aspects of this embodiment, activation of antigen-presenting cells is characterized by increased expression of CD80 and CD86 on dendritic cells.

[0193] The presently disclosed compounds directly bind to HPK1 and inhibit its kinase activity. In some embodiments, the presently disclosed compounds reduce, inhibit, or otherwise attenuate HPK1-mediated phosphorylation of SLP76 and / or Gads.

[0194] The presently disclosed compounds may or may not be specific HPK1 antagonists. A specific HPK1 antagonist reduces the biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other serine / threonine kinase). In certain embodiments, the presently disclosed compounds specifically inhibit the serine / threonine kinase activity of HPK1. In some of these embodiments, the IC of the HPK1 antagonist for HPK1 is 50 indicates the IC of HPK1 antagonists against other serine / threonine kinases or other types of kinases (e.g., tyrosine kinases). 50 or less than about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the

[0195] The presently disclosed compounds can be used in methods for inhibiting HPK1. Such methods include contacting HPK1 with an effective amount of a presently disclosed compound. By "contacting," it is intended to mean bringing the compound within sufficiently close proximity of an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., a T cell, a B cell, or a dendritic cell) so that the compound can bind to HPK1 and inhibit its activity. The compound can be contacted with HPK1 in vitro or in vivo by administering the compound to a subject.

[0196] Any method known in the art for measuring the kinase activity of HPK1 can be used to determine whether HPK1 is inhibited, including in vitro kinase assays, immunoblots using antibodies specific for phosphorylated targets of HPK1 such as SLP76 and Gads, or measuring downstream biological effects of HPK1 kinase activity such as recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of SLP76-Gads-14-3-3 complexes from LAT-containing microclusters, or T cell or B cell activation.

[0197] The presently disclosed compounds can be used to treat HPK1-dependent disorders. As used herein, "HPK1-dependent disorders" refers to pathological conditions in which HPK1 activity is required for the development or maintenance of the pathological condition. In some embodiments, the HPK1-dependent disorder is cancer.

[0198] The presently disclosed compounds are also used to enhance immune responses in a subject in need thereof. Such methods comprise administering an effective amount of a compound of the invention.

[0199] As used herein, "enhanced immune response" refers to any improvement in immunogenic response to an antigen. Non-limiting examples of improvements in immunogenic response to an antigen include enhanced maturation or migration of dendritic cells, enhanced activation of T cells (e.g., CD4 T cells, CD8 T cells), enhanced proliferation of T cells (e.g., CD4 T cells, CD8 T cells), enhanced B cell proliferation, enhanced survival of T cells and / or B cells, improved antigen presentation by antigen-presenting cells (e.g., dendritic cells), improved antigen clearance, increased production of cytokines (e.g., interleukin-2) by T cells, increased resistance to prostaglandin E2-induced immune control, and enhanced priming and / or cytolytic activity of CD8 T cells.

[0200] In some embodiments, CD8 T cells in a subject have enhanced priming, activation, proliferation, and / or cytolytic activity compared to before administration of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, CD8 T cell priming is characterized by increased CD44 expression and / or enhanced cytolytic activity on CD8 T cells. In some embodiments, CD8 T cell activation is characterized by increased expression of γ-IFN. + The invention is characterized by an increased frequency of CD8 T cells. In some embodiments, the CD8 T cells are antigen-specific T cells.

[0201] In some embodiments, the antigen-presenting cells in the subject are more mature and activated than before administration of the compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the antigen-presenting cells are dendritic cells. In some embodiments, the maturation of the antigen-presenting cells is enhanced by CD83 + In some embodiments, the activation of antigen-presenting cells is characterized by increased expression of CD80 and CD86 on dendritic cells.

[0202] In some embodiments, the serum levels of the cytokine IL-10 and / or the chemokine IL-8, which are human homologs of mouse KC, in the subject are reduced compared to before administration of the compound of Formula I or Ia, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

[0203] TCR engagement leads to the activation of HPK1, which functions as a negative regulator of the TCR-induced AP-1 response pathway. HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254. This is thought to recruit 14-3-3 proteins that bind to phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, leading to T cell dysfunction, including anergy and exhaustion (Lasserre et al. (2011) J Cell Biol 195(5):839-853).

[0204] In some embodiments, administering a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof, to a subject results in enhanced T cell function.

[0205] Therefore, the presently disclosed compounds of the present invention, or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof, are useful for treating T cell dysfunction. "T cell dysfunction" refers to a T cell disorder or condition characterized by reduced responsiveness to antigenic stimulation. In certain embodiments, T cell dysfunction refers to a disorder specifically associated with increased kinase activity of HPK1. In another embodiment, T cell dysfunction refers to a disorder in which T cells are anergic or have a reduced ability to secrete cytokines, proliferate, or achieve cytolytic activity. In certain aspects, reduced responsiveness results in ineffective control of pathogens or tumors expressing immunogens. Examples of T cell dysfunctions characterized by abnormal T cell function include unresolved acute infections, chronic infections, and tumor immunity.

[0206] Thus, the presently disclosed compounds can be used in the treatment of conditions where enhanced immunogenicity is desirable, such as increasing tumor immunogenicity for the treatment of cancer.

[0207] The term "dysfunction" in the context of immune dysfunction refers to a state of decreased immune responsiveness to antigenic stimulation. This term includes the common elements of both exhaustion and / or anergy, in which antigen recognition may occur but mounting an immune response is ineffective in controlling infection or tumor growth.

[0208] As used herein, the term "dysfunctional" also includes refractory or unresponsive to antigen recognition, specifically, impaired ability to translate antigen recognition into downstream T cell effector functions, such as proliferation, cytokine production (e.g., IL-2, γ-IFN) and / or target cell killing.

[0209] The term "anergy" refers to a state of unresponsiveness to antigenic stimulation resulting from defective or insufficient signals delivered by the T cell receptor (e.g., intracellular Ca in the absence of ras activation). +2T cell anergy can also occur upon stimulation with an antigen in the absence of costimulation, rendering the cells refractory to subsequent activation by antigen, even in the context of costimulation. The unresponsive state can often be abrogated by the presence of interleukin-2. Anergic T cells do not undergo clonal expansion and / or acquire effector function.

[0210] The term "exhaustion" refers to T cell exhaustion, a state of T cell dysfunction resulting from persistent TCR signaling, which occurs during many chronic infections and cancers. Exhaustion is distinct from anergy in that it results from persistent signaling rather than incomplete or insufficient signaling. Exhaustion is defined by poor effector function, persistent expression of inhibitory receptors, and a transcriptional state that differs from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunomodulatory cytokines) and cell-intrinsic negative regulatory (costimulatory) pathways (e.g., PD-1, B7-H3, B7-H4).

[0211] "Immunogenicity" refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic, and increasing the immunogenicity of tumors aids in the clearance of tumor cells by the immune response.

[0212] "Enhancing T cell function" refers to inducing, causing, or stimulating T cells to have sustained or amplified biological function, or renewing or reactivating exhausted or inactive T cells. Examples of enhancing T cell function include increased secretion of cytokines (e.g., gamma-interferon, IL-2, IL-12, and TNFα), improved proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance), and increased production of granule effectors, such as granzyme B, by CD8 T cells compared to such levels before the intervention. In one embodiment, the level of enhancement is at least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, or 200%. Methods for measuring this enhancement are known to those skilled in the art.

[0213] "Tumor immunity" refers to the process by which tumors evade immune recognition and clearance. Therefore, as a therapeutic concept, tumor immunity is "treated" when such evasion is weakened and when tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.

[0214] The present disclosure provides a method of modulating (e.g., inhibiting) HPK1 activity, comprising administering to a patient a compound provided herein or a pharmaceutically acceptable salt thereof.

[0215] In one aspect, provided is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

[0216] In the methods described herein, a compound of the present invention or a pharmaceutical composition thereof is administered to a subject with cancer.

[0217] In certain embodiments, the presently disclosed subject matter is directed to a method for treating an HPK1-dependent disorder, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutical composition described herein. In certain aspects of this embodiment, the HPK1-dependent disorder is cancer. In certain aspects of this embodiment, the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma. In certain aspects of this embodiment, the cancer has an increased level of T cell infiltration. In certain aspects of this embodiment, the cancer cells in the subject have selectively increased expression of MHC class I antigens compared to before administration of the compound or composition.

[0218] In some embodiments, the subject matter disclosed herein is directed to the method for treating chronic viral infection.In some embodiments, the subject matter disclosed herein is directed to the use of HPK1 inhibitor as adjuvant therapy to increase the effectiveness of vaccination.

[0219] In some embodiments, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0220] In certain aspects, the present invention provides methods for treating cell proliferative disorders including cancer, benign papillomatosis, gestational trophoblastic disease, and benign neoplastic diseases such as cutaneous papillomas (warts) and genital papillomas.

[0221] In one aspect, the invention provides a method of treating a cell proliferation disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0222] In certain embodiments, the cell proliferative disorder is cancer.

[0223] Examples of cancers that can be treated using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal gland cancer, sarcoma of soft tissue, cancer of the urethra, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), solid tumors of childhood, lymphocytic lymphoma, bladder cancer, cancer of the kidney or urethra, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, tumors), brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinomas, squamous cell carcinomas, T-cell lymphomas, environmentally induced cancers including those induced by asbestos, and combinations of the above cancers.

[0224] In some embodiments, cancers treatable using the compounds of the present disclosure 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, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, etc.), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of the foregoing cancers.

[0225] In certain embodiments, the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer, or sarcoma. In other embodiments, the cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, supratentorial primitive neuroectodermal tumor, acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, melanoma, breast, prostate, thyroid, colon, lung, intraosseous chondrosarcoma, enchondroma and periosteal cartilage tumor, fibrosarcoma, and cholangiocarcinoma.

[0226] In certain embodiments, the cancer is selected from brain and spinal cord cancer, head and neck cancer, leukemia and blood cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, liver and bile duct cancer, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancer, and cancer of unknown primary (cancer in which metastatic cancer is discovered but the site of origin is unknown). In certain embodiments, the cancer is in an adult patient. In additional embodiments, the cancer is in a pediatric patient. In certain embodiments, the cancer is AIDS-related.

[0227] In further embodiments, the cancer is selected from cancers of the brain and spinal cord. In certain embodiments, the cancer is selected from the group consisting of anaplastic astrocytoma, glioblastoma, astrocytoma, and nasal neuroblastoma (olfactory neuroblastoma). In certain embodiments, the brain cancer is selected from the group consisting of astrocytic tumors (e.g., pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumors (e.g., oligodendroglioma and anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., glioma, glioma, glioma) and glioma. For example, the brain cancer is selected from the group consisting of oligoastrocytoma and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma and anaplastic ependymoma), medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, optic nerve and hypothalamic glioma, and primary central nervous system lymphoma. In particular examples of these embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and supratentorial primitive neuroectodermal tumor (sPNET).

[0228] In certain embodiments, the cancer is selected from nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, hypopharyngeal cancer, oral cancer (e.g., squamous cell carcinoma, lymphoma, and sarcoma), lip cancer, oropharyngeal cancer, salivary gland tumors, laryngeal cancer (e.g., pharyngeal squamous cell carcinoma, rhabdomyosarcoma), and head and neck cancer, including eye or ocular cancer. In certain embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.

[0229] In certain embodiments, the cancer is selected from leukemia and blood cancer. In certain embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasm, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML, post-MDS AML, high-risk MDS or AML with del(5q), blast phase chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasm (including plasmacytoma and multiple myeloma). The leukemia referred to herein may be acute or chronic.

[0230] In certain embodiments, the cancer is selected from skin cancer, hi certain embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell carcinoma, and basal cell carcinoma.

[0231] In certain embodiments, the cancer is selected from cancers of the reproductive system. In certain embodiments, the cancer is selected from the group consisting of breast cancer, cervical cancer, vaginal cancer, ovarian cancer, prostate cancer, penile cancer, and testicular cancer. In certain examples of these embodiments, the cancer is breast cancer selected from the group consisting of ductal carcinoma and phyllodes tumor. In certain examples of these embodiments, the breast cancer may be male breast cancer or female breast cancer. In certain examples of these embodiments, the cancer is cervical cancer selected from the group consisting of squamous cell carcinoma and adenocarcinoma. In certain examples of these embodiments, the cancer is ovarian cancer selected from the group consisting of epithelial cancer.

[0232] In certain embodiments, the cancer is selected from cancers of the gastrointestinal system. In certain embodiments, the cancer is selected from the group consisting of esophageal cancer, gastric cancer (also known as stomach cancer), gastrointestinal carcinoid tumor, pancreatic cancer, gallbladder cancer, colorectal cancer, and anal cancer. In exemplary of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastric lymphoma, gastrointestinal lymphoma, solid pseudopapillary tumor of the pancreas, pancreatoblastoma, pancreatic islet cell tumor, pancreatic carcinoma (including acinar cell carcinoma and ductal adenocarcinoma), gallbladder adenocarcinoma, colorectal adenocarcinoma, and anal squamous cell carcinoma.

[0233] In certain embodiments, the cancer is selected from liver and cholangiocarcinoma. In certain embodiments, the cancer is liver cancer (hepatocellular carcinoma). In certain embodiments, the cancer is cholangiocarcinoma (cholangiocarcinoma). In exemplary of these embodiments, the cholangiocarcinoma is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

[0234] In certain embodiments, the cancer is selected from kidney and bladder cancer. In certain embodiments, the cancer is kidney cancer selected from the group consisting of renal cell carcinoma, Wilms' tumor, and transitional cell carcinoma. In certain embodiments, the cancer is bladder cancer selected from the group consisting of urinary tract cancer (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

[0235] In certain embodiments, the cancer is selected from bone cancer, hi certain embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing's sarcoma, and chordoma.

[0236] In certain embodiments, the cancer is selected from lung cancer. In certain embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, bronchial tumor, and pleuropulmonary blastoma.

[0237] In certain embodiments, the cancer is selected from the group consisting of malignant mesothelioma, hi certain embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoid.

[0238] In certain embodiments, the cancer is selected from a sarcoma, hi certain embodiments, the sarcoma is selected from the group consisting of intraosseous chondrosarcoma, entosoal and periosteal chondroma, fibrosarcoma, clear cell sarcoma of the tendon sheath, and Kaposi's sarcoma.

[0239] In certain embodiments, the cancer is selected from lymphoma. In certain embodiments, the cancer is selected from the group consisting of Hodgkin's lymphoma (e.g., Reed-Sternberg cell), non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sézary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphoma, and primary central nervous system lymphoma.

[0240] In certain embodiments, the cancer is selected from an adenocarcinoma, hi certain embodiments, the cancer is selected from the group consisting of an adrenocortical carcinoma, a pheochromocytoma, a paraganglioma, a pituitary tumor, a thymoma, and a thymic carcinoma.

[0241] In certain embodiments, the cancer is selected from thyroid cancer, hi certain embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid cancer, papillary thyroid cancer, and follicular thyroid cancer.

[0242] In certain embodiments, the cancer is selected from a germ cell tumor. In certain embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In certain examples of these embodiments, the malignant extragonadal germ cell tumors are selected from the group consisting of non-seminomas and seminomas.

[0243] In certain embodiments, the cancer is selected from a cardiac tumor, hi certain embodiments, the cardiac tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0244] In certain embodiments, the cell proliferative disorder is selected from benign papillomatosis, benign neoplastic disease, and gestational trophoblastic disease. In certain embodiments, the benign neoplastic disease is selected from cutaneous papillomas (warts) and genital papillomas. In certain embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform mole and gestational trophoblastic neoplasia (e.g., invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor).

[0245] In some embodiments, the subject has melanoma. The melanoma may be at an early stage or at a later stage. In some embodiments, the subject has colorectal cancer. The colorectal cancer may be at an early stage or at a later stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer may be at an early stage or at a later stage. In some embodiments, the subject has pancreatic cancer. The pancreatic cancer may be at an early stage or at a later stage. In some embodiments, the subject has a hematological malignancy. The hematological malignancy may be at an early stage or at a later stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer may be at an early stage or at a later stage. In some embodiments, the subject has breast cancer. The breast cancer may be at an early stage or at a later stage. In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma may be at an early stage or at a later stage. In some embodiments, the cancer has an elevated level of T-cell infiltration.

[0246] In some embodiments, cancers treatable with the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer, triple-negative breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer and small cell lung cancer). Additionally, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0247] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0248] Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0249] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0250] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma.

[0251] Exemplary gastrointestinal cancers include cancer of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0252] Exemplary genitourinary tract cancers include cancer of the kidney (adenocarcinoma, Wilms' tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma).

[0253] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0254] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0255] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Dacros disease.

[0256] Exemplary gynecological cancers include cancer of the uterus (endometrial carcinoma), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonic rhabdomyosarcoma)), and fallopian tube (carcinoma).

[0257] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, lentigineous dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids. In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[0258] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cavity cancer, laryngeal cancer, nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, and thyroid and parathyroid cancer.

[0259] In some embodiments, HPK1 inhibitors may be used to treat tumors that produce PGE2 (e.g., Cox-2-overexpressing tumors) and / or adenosine (CD73 and CD39-overexpressing tumors). Cox-2 overexpression has been detected in some tumors, such as colorectal, breast, pancreatic, and lung cancer, where overexpression correlates with poor prognosis. COX-2 overexpression has been reported in hematological cancer models, such as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia), and in patient blast cells. CD73 is upregulated in various human carcinomas, including colon, lung, pancreatic, and ovarian carcinomas. Importantly, higher CD73 expression levels are associated with tumor angiogenesis, invasiveness, and metastasis, as well as shorter patient survival, in breast cancer.

[0260] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases mentioned herein, for example, preventing or reducing the risk of developing a disease, condition or disorder in individuals who may be predisposed to the disease, condition or disorder but who have not yet experienced or exhibited the pathology or symptoms of the disease.

[0261] The presently disclosed compounds may be administered by any suitable method known in the art, hi some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof, are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implant, by inhalation, intrathecally, intracerebroventricularly, intratumorally, or intranasally.

[0262] In some embodiments, the HPK1 antagonist is administered continuously. In other embodiments, the HPK1 antagonist is administered intermittently. Moreover, treatment of a subject with an effective amount of an HPK1 antagonist can include a single treatment or can include a series of treatments.

[0263] It will be understood that the appropriate dose of the active compound will depend on several factors within the knowledge of an ordinarily skilled physician or veterinarian, and will vary depending, for example, on the age, weight, general health, sex, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any combined drugs.

[0264] It will also be understood that the effective dosage of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof, used for treatment may increase or decrease over the course of a particular treatment. Variations in dosage may result and become evident from the results of diagnostic assays.

[0265] In some embodiments, the HPK1 antagonist is administered to a subject at a dose of between about 0.001 μg / kg and about 1000 mg / kg, including but not limited to, about 0.001 μg / kg, 0.01 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 100 μg / kg, 250 μg / kg, 500 μg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 200 mg / kg.

[0266] In the methods described herein, the method can further comprise administering a chemotherapeutic agent to the subject. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject simultaneously with the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject prior to administration of the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject after administration of the compound or composition.

[0267] As used herein, the terms "treatment," "treat," and "treating," as described herein, refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of symptom history and / or genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0268] The term "administration" or "administering" includes the route of introducing the compound into a subject so that it can perform its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0269] The term "effective amount" includes an amount effective at the dosage and duration necessary to achieve the desired result. The effective amount of a compound may vary depending on factors such as the disease state, age, and weight of the subject, and the ability of the compound to exert a desired response in the subject. The dosage regimen may be adjusted to achieve the optimal therapeutic response.

[0270] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" refer to the administration of a compound, drug, or other substance such that the compound, drug, or other substance enters the patient's system and, thus, is subject to metabolic and other similar processes.

[0271] The phrase "therapeutically effective amount" refers to an amount of a compound of the present invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down and preferably stop, to some extent) the infiltration of cancer cells into peripheral organs; inhibit (i.e., slow down and preferably stop, to some extent) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent. To the extent that the drug prevents growth and / or kills existing cancer cells, it may be cytostatic and / or cytotoxic. With respect to cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or by determining the response rate (RR).

[0272] The term "subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0273] Combination therapy Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, can be administered in combination with the compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0274] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0275] Examples of drugs with which the combinations of this invention may be combined include, but are not limited to: drugs for treating Alzheimer's disease, such as Aricept® and Excelon®; drugs for treating HIV, such as ritonavir; drugs for treating Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; drugs for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; drugs for treating asthma, such as albuterol and Singulair®; drugs for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory drugs, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents agents); agents for treating cardiovascular disease, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antivirals; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immune deficiency disorders, such as gamma globulins.

[0276] In certain embodiments, the combination therapy of the invention, or a pharmaceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

[0277] These additional agents may be administered separately from the combination therapy provided, as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. When administered as part of a multiple dose regimen, the two active agents may be given simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0278] As used herein, the terms "combination," "in combination," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, a combination of the invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0279] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0280] In one embodiment, the present invention provides a composition comprising a compound of Formula I and one or more additional therapeutic agents. The therapeutic agents can be administered together with the compound of Formula I, or before or after the administration of the compound of Formula I. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of Formula I can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of formula I can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0281] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), probenecid, allopurinol, febuxostat, etc. (febuxostat) (Uloric®), sulfasalazine (Azulfidine®), antimalarials (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®) )), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Gibberish®), fluconazole (Fenix ​​... Mabs (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), canakinumab (Ilaris®), anti-Jak inhibitors (e.g., tofacitinib), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g.,Abatacept (Orencia®), “anti-IL-6” agents (e.g., tocilizumab (Actemra®)), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies (e.g., tanezumab), anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)), antidiarrheal drugs (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders (e.g., cholestyramine), alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives (e.g., milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®)), Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids (e.g., beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®)), Afviar®, Symbicort®, Dulera®,Cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), IgE antibodies (e.g., omalizumab (Xolair®)), nucleoside reverse transcriptase inhibitors (e.g., zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine (Epzicom®)), abacavir / lamivudine (Epzicom® ... vacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), (R)) and etravirine (Intelence®)), nucleotide reverse transcriptase inhibitors (e.g., tenofovir (Viread®)), protease inhibitors (e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracep®), t®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®)), entry inhibitors (e.g., enfuvirtide (Fuzeon®) and maraviroc (Selzentry®)), integrase inhibitors (e.g., raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®),Bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination(s) thereof.

[0282] In another embodiment, the present invention provides a method of treating rheumatoid arthritis by administering to a patient in need thereof a compound of Formula I and nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), sulfasalazine (Azulfidine®), antimalarials (e.g., benzodiazepines), benzocaine (benzocaine), benzodiazepines (e.g., benzocaine), benzocaine ( ... For example, hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imura®), n®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and “anti-TNF” agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and adalimumab and administering one or more additional therapeutic agents selected from rituximab (Humira®), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g., abatacept (Orencia®)), and "anti-IL-6" agents (e.g., tocilizumab (Actemra®)).

[0283] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies (e.g., tanezumab).

[0284] In some embodiments, the present invention provides a method of treating cutaneous lupus erythematosus or systemic lupus erythematosus, comprising administering to a patient in need thereof a compound of Formula I and a combination of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), antimalarials (e.g., hydroxychloroquine, and administering one or more additional therapeutic agents selected from fluticasone (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)).

[0285] In some embodiments, the present invention provides a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease by administering to a patient in need thereof a compound of Formula I and mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal drugs (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine, alosetron (Lotronex®), lubiprostone (Amit®), or other antidiarrheal drugs. and administering one or more additional therapeutic agents selected from an anticholinergic or antispasmodic drug (e.g., dicyclomine (Bentyl®)), an anti-TNF therapeutic agent, a steroid, and an antibiotic (e.g., Flagyl or ciprofloxacin).

[0286] In some embodiments, the present invention provides a method of treating asthma by administering to a patient in need thereof a compound of Formula I and one or more of Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate), or steroids (e.g., benzodiazepine, benzocaine ... and administering one or more additional therapeutic agents selected from fluticasone (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®), cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), and IgE antibodies (e.g., omalizumab (Xolair®)).

[0287] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a compound of Formula I and a beta-2 agonist (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), an anticholinergic (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), a methylxanthine (e.g., theophylline (Theophylline)), or a steroid (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)). and aminophylline), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®).

[0288] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0289] In another embodiment, the present invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0290] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al., "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma," Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0291] In another embodiment, the invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0292] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, in combination with lenalidomide (Revlimid®).

[0293] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a BTK inhibitor, wherein the disease is selected from the group consisting of inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, and inflammatory bowel disease. thyroiditis), Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated cerebrospinal meningitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia , Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerular nephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, house dust mites, or cockroach calyx) calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitisMyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Walde's lymphoma M. Lundstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mastocytoma) alveolar sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including but not limited to rheumatoid arthritis, seronegative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass, restenosis after aortocoronary artery bypass, stroke, transient ischemia, peripheral arterial occlusive disorder , pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis (cholocystitis), agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease) (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, The method further comprises treating a subject with a condition selected from arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0294] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0295] In another embodiment, the invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid gland, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon cancer or colorectal adenoma or head and neck tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, intraepithelial neoplasia, character), adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dudos disease Diseases including Banayan-Zonana syndrome or diseases in which the PI3K / PKB pathway is abnormally activated, asthma of any type or onset, including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, chronic obstructive airway disease or chronic obstructive lung diseasedisease (COPD, COAD or COLD) (including associated chronic bronchitis or dyspnea), emphysema, and exacerbations of airway overactivity as a result of other medications (especially other inhaled medications), bronchitis of any type or occurrence (including but not limited to acute, arachidic, catarrhal, croupus, chronic or tuberculous bronchitis), pneumoconiosis of any type or occurrence (an inflammatory, generally occupational, lung disease, whether chronic or acute, frequently associated with airway obstruction and caused by repeated inhalation of dust) (including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tabacosis and byssinosis), Loffler's syndromesyndrome), eosinophilic, pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophil-related disorders affecting the airways caused by eosinophilic granulomas and drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous Diseases affecting the nose, including pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, allergic rhinitis, and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, multiple myeloma, ulcerative colitis, ulcerative colitis, urticaria ... Osteitis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis The present invention provides methods for treating a neurodegenerative disease selected from the group consisting of nephritis (with or without nephrotic syndrome (including, for example, idiopathic nephrotic syndrome or minimal change nephropathy)), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, as well as neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0296] In some embodiments, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0297] In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the JH2-binding compound is a compound of Formula I. Other suitable JH2 domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain-binding compounds include those described in WO2015131080A1, each of which is incorporated herein by reference in its entirety.

[0298] According to the method of the present invention, the compounds and compositions can be administered in any amount and by any route of administration effective for treating or reducing the severity of autoimmune, inflammatory, proliferative, endocrine, neurological, or transplant-related disorders. The exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific drug, its mode of administration, etc. The compounds of the present invention are preferably formulated into unit dosage forms for ease of administration and uniformity of dosage. The term "unit dosage form" as used herein refers to a physically separate unit of drug appropriate for the patient to be treated. However, it is understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The effective dose level specific to any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used, and similar factors well known in the medical field. The term "patient", as used herein, means an animal, preferably a mammal, most preferably a human.

[0299] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg to about 50 mg per kg of subject body weight per day, preferably about 1 mg to about 25 mg per kg, one or more times daily to achieve the desired therapeutic effect.

[0300] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, as well as sweeteners, flavoring agents and fragrances.

[0301] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be injectable sterile solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0302] Injectable preparations can be sterilized prior to use, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other injectable sterile medium.

[0303] To prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The compound release rate can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0304] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of this invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0305] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0306] Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be composed so that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc.

[0307] The active compound may be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms may contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0308] Dosage forms for topical or transdermal administration of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0309] According to one embodiment, the present invention relates to a method of inhibiting protein kinase activity in a biological sample, comprising the step of contacting said biological sample with a compound of this invention or a composition comprising said compound.

[0310] According to another embodiment, the present invention relates to a method for inhibiting the activity of HPK1 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of this invention or a composition comprising said compound. In a specific embodiment, the present invention relates to a method for irreversibly inhibiting the activity of HPK1 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of this invention or a composition comprising said compound.

[0311] The term "biological sample," as used herein, includes, but is not limited to, a cell culture or extract thereof; a biopsy or extract thereof obtained from a mammal; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0312] Inhibition of the activity of HPK1 (or a mutant thereof) in a biological sample is useful for a variety of purposes known to those skilled in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0313] Another embodiment of the invention relates to a method of inhibiting protein kinase activity in a patient, comprising administering to said patient a compound of the present invention, or a composition comprising said compound.

[0314] According to another embodiment, the present invention provides a method for inhibiting the activity of HPK1 or a mutant thereof in a patient, comprising administering to the patient a compound of the present invention or a composition comprising said compound. According to certain embodiments, the present invention provides a method for reversibly or irreversibly inhibiting the activity of HPK1 or one or more mutants thereof in a patient, comprising administering to the patient a compound of the present invention or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by HPK1 or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0315] Depending upon the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0316] The compounds of the present invention can also be advantageously used in combination with other therapeutic compounds.In some embodiments, the other therapeutic compounds are antiproliferative compounds.Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platin compounds; compounds that target / reduce protein kinase activity or lipid kinase activity and further antiangiogenic compounds; compounds that target, reduce or inhibit the activity of protein phosphatases or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptides. putidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease, or inhibit the activity of Flt-3; Hsp90 inhibitors (e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors (e.g., SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx)); MEK inhibitors (e.g., ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer) and leucovorin).The term "aromatase inhibitor" as used herein refers to a compound that inhibits estrogen production, for example, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, particularly atamestane, exemestane, and formestane, and nonsteroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Lentaron™. Fadrozole is commercially available under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is commercially available under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. Combinations of the present invention which include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.

[0317] The term "antiestrogen" as used herein refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is commercially available under the trade name Nolvadex™. Raloxifene hydrochloride is commercially available under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combination of the present invention, which includes a chemotherapeutic agent that is an antiestrogen, is particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0318] The term "antiandrogen" as used herein relates to any substance capable of inhibiting the biological effects of androgens, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0319] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form as it is marketed, for example, under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0320] The term "topoisomerase II inhibitors", as used herein, includes, but is not limited to, anthracyclines (e.g., doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM 26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin™ or Adriamycin™. Epirubicin is commercially available under the trade name Farmorubicin™. Idarubicin is commercially available under the trade name Zavedos™. Mitoxantrone is commercially available under the trade name Novantron.

[0321] The term "microtubule active agent" refers to microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubule polymerization inhibitors, including, but not limited to, taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; colchicine and epothilone, and their derivatives. Paclitaxel is commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin RP™. Vincristine sulfate is commercially available under the trade name Farmistin™.

[0322] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

[0323] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0324] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folate antagonists (e.g., pemetrexed). Capecitabine is commercially available under the trade name Xeloda™. Gemcitabine is commercially available under the trade name Gemzar™.

[0325] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0326] The term "compounds which target / reduce the activity of protein kinases or lipid kinases; or compounds which target / reduce the activity of protein phosphatases or lipid phosphatases; or further anti-angiogenic compounds", as used herein, includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors, or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFRs) (e.g., compounds which target, reduce or inhibit the activity of PDGFRs, in particular compounds which inhibit PDGF receptors, such as N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib, SU101, SU6668 and GFB-111); b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFRs); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR) (e.g., For example, compounds that target, reduce or inhibit the activity of IGF-IR, in particular compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factors; d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, for example imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family (for example compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, for example imatinib);i) Compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants (e.g., compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (ParkeDavis); or dasatinib (BMS-354825); j) compounds (including staurosporine derivatives, e.g., midostaurin) that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK); further exemplary compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, for example, compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors such as imatinib mesylate (Gleevec™) or tyrphostins (e.g., tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44 (+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957) and adaphostine (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); l) compounds that target, decrease or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and mutants thereof, for example, compounds that target, decrease or inhibit the activity of the epidermal growth factor receptor family are in particular compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, e.g., EGF receptor, ErbB2, ErbB3 and ErbB4, or that bind to EGF or EGF-related ligands (e.g., CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives); m) compounds that target, decrease or inhibit the activity of the c-Met receptor, for example, compounds that target, decrease or inhibit the activity of c-Met, particularly compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) one or more JAK family members (JAK1 / J o) compounds that target, decrease, or inhibit the kinase activity of PI3 kinase (PI AK2 / JAK3 / TYK2 and / or pan-JAK) (including but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib); Compounds that target, decrease or inhibit the kinase activity of 3K (including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib);and q) compounds that target, decrease, or inhibit the signaling effects of the Hedgehog (Hh) or Smoothened receptor (SMO) pathways (including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib));

[0327] The term "PI3K inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family (including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87). Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0328] The term "BTK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0329] The term "SYK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0330] The term "Bcl-2 inhibitor", as used herein, refers to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), the TW series of compounds (Univ. of In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0331] Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2008039218 and WO2011090760, which are incorporated herein by reference in their entireties.

[0332] Further examples of SYK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, which are incorporated herein by reference in their entireties.

[0333] Further examples of PI3K inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, which are incorporated herein by reference in their entireties.

[0334] Further examples of JAK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, which are incorporated by reference in their entireties.

[0335] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, for example, a mechanism unrelated to protein kinase inhibition or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0336] Examples of useful proteasome inhibitors for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0337] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are eg inhibitors of phosphatase 1, inhibitors of phosphatase 2A or inhibitors of CDC25 (eg okadaic acid or a derivative thereof).

[0338] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ- or δ-tocopherol, or α-, γ- or δ-tocotrienol.

[0339] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid, lumiracoxib.

[0340] The term "bisphosphonate," as used herein, includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is commercially available under the trade name Didronel™. Clodronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0341] The term "heparanase inhibitor," as used herein, refers to a compound that targets, decreases, or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological response modifier," as used herein, refers to lymphokines or interferons.

[0342] The term "inhibitor of Ras oncogenic isoforms" (e.g., H-Ras, K-Ras, or N-Ras) as used herein refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors" such as L-744832, DK8G557, or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to compounds that target, reduce, or inhibit the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are particularly compounds that inhibit the telomerase receptor, such as telomestatin.

[0343] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. Compounds that target, decreases or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0344] The term "proteasome inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of the proteasome. Compounds that target, reduces or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN 341.

[0345] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors), as used herein, includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives (e.g., the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996).

[0346] The term "compounds used in the treatment of hematological malignancies," as used herein, includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0347] Compounds that target, decrease or inhibit the activity of FLT-3R are, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0348] The term "HSP90 inhibitor," as used herein, includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol, and HDAC inhibitors.

[0349] The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. Antibody refers to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

[0350] For the treatment of acute myeloid leukemia (AML), the compound of the present invention can be used in combination with standard leukemia therapy, particularly in combination with the therapy used for the treatment of AML.In particular, the compound of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum and PKC412.In some embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutation, comprising administering the compound of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), staurosporine derivatives (e.g., midostaurin or lestaurtinib), sorafenib, tanzutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0351] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogue of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (previously FR901228), trichostatin A, and the compounds disclosed in US6,552,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt, particularly lactate.Somatostatin receptor antagonists as used herein refer to compounds that target, treat or inhibit somatostatin receptors, such as octreotide and SOM230.Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, eds., Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

[0352] Also included are EDG binders and ribonucleotide reductase inhibitors.The term "EDG binder" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720.The term "ribonucleotide reductase inhibitor" refers to pyrimidine nucleoside analogs or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL) and / or pentostatin.The ribonucleotide reductase inhibitor is particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivative.

[0353] Also included are VEGF compounds, proteins or monoclonal antibodies, such as, in particular, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies (e.g., rhuMAb and RHUFab), VEGF aptamers (e.g., Macugon); FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610), and bevacizumab (Avastin™).

[0354] Photodynamic therapy, as used herein, refers to the use of certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0355] Antiangiogenic steroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0356] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[0357] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0358] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilator, or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airway diseases such as those mentioned hereinabove, e.g., as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. The compounds of the present invention may be mixed with other drug substances in a given pharmaceutical composition, or may be administered separately from, before, simultaneously with, or after the other drug substances. Thus, the present invention includes combinations of the compounds of the present invention as described hereinabove with anti-inflammatory, bronchodilator, antihistamine, or antitussive drug substances, wherein the compounds of the present invention and the drug substances are in the same or different pharmaceutical compositions.

[0359] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids (e.g., budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate); non-steroidal glucocorticoid receptor agonists; LTB4 antagonists (e.g., LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247); LTD4 antagonists (e.g., montelukast and zafirlukast); PDE4 inhibitors (e.g., cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo)); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists (e.g., albuterol (salbutamol), metaproterenol, terbutaline, salmeterol Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0360] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine.

[0361] Other useful combinations of the compounds of the invention with anti-inflammatory drugs are with antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0362] The structures of active compounds identified by code number, generic name or trade name can be obtained from the current edition of the standard compendium "The Merck Index" or from databases such as Patents International (e.g. IMS World Publications). Exemplary Immuno-Oncology Agents

[0363] In some embodiments, one or more other therapeutic agents are immuno-oncology agents.As used herein, the term " immuno-oncology agent" refers to an agent that is effective for enhancing, stimulating and / or upregulating the immune response in subject.In some embodiments, the administration of the compound of the present invention and the immuno-oncology agent in the treatment of cancer has a synergistic effect.

[0364] The immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biological agent or small molecule. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is humanized or human.

[0365] In some embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal to T cells, either of which results in amplification of the antigen-specific T cell response.

[0366] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3 , EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0367] In some embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0368] In some embodiments, the combination of the compound of the present invention and an immuno-oncology agent can stimulate a T cell response. In some embodiments, the immuno-oncology agent is (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor) (such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin-9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4); or (ii) an agonist of a protein that stimulates T cell activation (such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H).

[0369] In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells. In some embodiments, the immuno-oncology agent is a KIR antagonist, such as lirilumab.

[0370] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including a CSF-1R antagonist such as a CSF-1R antagonist antibody, including but not limited to RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0371] In some embodiments, the immuno-oncology agent is selected from agonist agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome distinct immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor ligation (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell energetics or exhaustion), and agents that induce innate immune activation and / or inflammation at the tumor site.

[0372] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0373] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012 / 145493). In some embodiments, the immuno-oncology agent can be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein called AMP-224 (B7-DC), consisting of the extracellular domain of PD-L2 fused to the Fc portion of IgG1.

[0374] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), or MSB0010718C (WO2013 / 79174).

[0375] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG-3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0376] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0377] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116) or MK-4166 (WO11 / 028683).

[0378] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0379] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0380] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0381] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0382] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0383] In some embodiments, the immuno-oncology agent is MGA271 (directed against B7H3) (WO11 / 109400).

[0384] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolizumab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, integravir, cefotaxime ... intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0385] In some embodiments, the immuno-oncology agent is an immunostimulatory agent. For example, clinical trials have shown that antibodies that block the PD-1 and PD-L1 inhibitory axis can liberate activated tumor-reactive T cells and induce durable anti-tumor responses in an increasing number of tumor histologies, including some tumor types not traditionally considered susceptible to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (OPDIVO®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in patients with RCC who have experienced disease progression during or after prior antiangiogenic therapy.

[0386] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®, LEO Pharma).

[0387] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (PROVENGE®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex / Amgen, formerly known as T-VEC), a genetically engineered oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodular lesions in melanoma.In some embodiments, the immuno-oncology agent is an oncolytic virotherapy (such as PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics) which is a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF) for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); Biotech) (a mutant of respiratory enterovirus (reovirus) that does not replicate in cells that are not activated by RAS) in multiple cancers, including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), squamous cell carcinoma of the head and neck (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT00861627); enadenotsilibe (NG-348, PsiOxus, formerly known as ColoAd1) (ovarian cancer (NCT02028117), colorectal cancer, bladder cancer) Adenoviruses engineered to express full-length CD80 and antibody fragments specific for the T-cell receptor CD3 protein in metastatic or advanced epithelial tumors, such as bladder cancer, squamous cell carcinoma of the head and neck, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos) (an adenovirus engineered to express GM-CSF in melanoma (NCT03003676), and peritoneal, colorectal, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux) GmbH) (vaccinia viruses engineered to express beta-galactosidase (beta-gal) / beta-glucuronidase or beta-gal / human sodium iodide symporter (hNIS), which have been investigated in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer; ovarian cancer (NCT02759588), respectively); or CG0070 (Cold Genesys) (adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818)).

[0388] In some embodiments, the immuno-oncology agents include JX-929 (SillaJen / formerly Jennerex Biotherapeutics) (a TK-deficient and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil); TG01 and TG02 (Targovax / formerly Oncos) (peptide-based immunotherapeutics targeting refractory RAS mutations); and TILT-123 (TILT Biotherapeutics) (an engineered adenovirus designated Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20); and VSV-GP (ViraTherapeutics) (an engineered adenovirus engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) and expressing antigen-specific CD8 + The virus is selected from vesicular stomatitis virus (VSV), which can be further engineered to express antigens designed to generate a T cell response.

[0389] In some embodiments, the immuno-oncology agent is a T cell that has been engineered to express a chimeric antigen receptor, i.e., a CAR. Such T cells that have been engineered to express a chimeric antigen receptor are called CAR-T cells.

[0390] CARs have been constructed that consist of a binding domain, which can be derived from a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, which is a natural ligand, fused to an endodomain that is the functional end of the T cell receptor (TCR), such as the CD3-zeta signaling domain from the TCR, which can generate an activation signal in T lymphocytes. Upon antigen binding, such CARs link to endogenous signaling pathways in effector cells, resulting in activating signals similar to those initiated by the TCR complex.

[0391] For example, in some embodiments, the CAR-T cells are one of those described in U.S. Pat. No. 8,906,682 (June et al.; incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to include an extracellular domain having an antigen-binding domain (e.g., a domain that binds to CD19) fused to the intracellular signaling domain of the T cell antigen receptor complex zeta chain (e.g., CD3 zeta). When expressed on T cells, CARs can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, this antigen is expressed on malignant B cells. Over 200 clinical trials using CAR-T cells in a wide range of indications are currently underway. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1]

[0392] In some embodiments, the immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of IL-17 expressing innate immune cell subsets, such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials to treat solid tumors (NCT02929862).

[0393] In some embodiments, the immunostimulatory agent is a toll-like receptor (TLR) agonist or activator. Suitable TLR activators include TLR9 agonists or activators, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG currently being investigated for follicular B-cell and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is currently being investigated for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0394] Other immuno-oncology agents that can be used herein include urelumab (BMS-663513, Bristol-Myers Squibb) (anti-CD137 monoclonal antibody); varlilumab (CDX-1127, Celldex Therapeutics) (anti-CD27 monoclonal antibody); BMS-986178 (Bristol-Myers Squibb) (anti-OX40 monoclonal antibody); lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb) (anti-KIR monoclonal antibody); monalizumab (IPH2201, Innate Pharma, AstraZeneca) (anti-NKG2A monoclonal antibody); andecaliximab (GS-5745, Gilead Sciences) (anti-MMP9 antibody); MK-4166 (Merck & Co.) (anti-GITR monoclonal antibody).

[0395] In some embodiments, the immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORγt.

[0396] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin-15 (rhIL-15). rhIL-15 is being tested in the clinic as a treatment for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888), and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex consisting of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which is being tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724 or NCT02542124.

[0397] In some embodiments, the immuno-oncology agent is selected from those described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology," Cancer Therapy 2015, Vol. 14, pages 603-622, the entire contents of which are incorporated herein by reference. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule that targets an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.

[0398] In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the entire contents of which are incorporated herein by reference. In some embodiments, the immuno-oncology agent is an agent that targets a pathway described in Peter L. Toogood.

[0399] In some embodiments, the immuno-oncology agent is selected from those described in Sandra L. Ross et al., "Bispecific T cell engager (BITE®) antibody constructs can mediate bystander tumor cell killing," PLoS ONE 12(8): e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a bispecific T cell engaging (BITE®) antibody construct. In some embodiments, the bispecific T cell engaging (BITE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engaging (BITE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engaging (BITE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engaging (BITE®) antibody construct activates T cells, releasing cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, the bispecific T cell engaging (BITE®) antibody construct activates T cells, inducing lysis of bystander cells. In some embodiments, the bystander cells are present in a solid tumor. In some embodiments, lysis of bystander cells occurs in the vicinity of the BITE®-activated T cells. In some embodiments, the bystander cells comprise tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the immuno-oncology agent is ex vivo expanded tumor-infiltrating T cells. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptor (CAR) that directly links T cells to tumor-associated surface antigens (TAA). Exemplary Immune Checkpoint Inhibitors

[0400] In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor described herein.

[0401] The term " checkpoint inhibitor " as used herein refers to the drug that is useful for preventing cancer cells from evading the immune system of patients.One of the main mechanisms of anti-tumor immune destruction is known as " T cell exhaustion ", which is caused by long-term exposure to antigen, which leads to the upregulation of inhibitory receptors.These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune response.

[0402] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuator (BTLA; CD272), T-cell immunoglobulin and mucin domain-3 (Tim-3), and lymphocyte activation gene-3 (Lag-3; CD223) are often referred to as checkpoint regulators. They act as "gatekeeper" molecules, allowing extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0403] In some embodiments, the immune checkpoint inhibitor is an antibody against PD-1, which binds to the programmed death 1 receptor (PD-1) and prevents the receptor from binding to the inhibitory ligand PDL-1, thus abolishing the tumor's ability to suppress the host's anti-tumor immune response.

[0404] In some embodiments, the checkpoint inhibitor is a biotherapeutic agent or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a ligand of the B-7 family, or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

[0405] Checkpoint inhibitors include any agent that statistically significantly blocks or inhibits an inhibitory pathway of the immune system. Such inhibitors can include small molecule inhibitors, or can include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary checkpoint molecules that can be targeted for blockage or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (a member of the CD2 family of molecules, which inhibits NK, gamma delta, and memory CD8+ (expressed on all αβ T cells), CD160 (also called BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Exemplary immune checkpoint inhibitors include, but are not limited to, tremelimumab (a CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (a PD-1 blocker), nivolumab (an anti-PD1 antibody), CT-011 (an anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (an anti-PDL1 antibody), BMS-936559 (an anti-PDL1 antibody), MPLDL3280A (an anti-PDL1 antibody), MSB0010718C (an anti-PDL1 antibody), and ipilimumab (an anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0406] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, TECENTRIQ®, Genentech).

[0407] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab.

[0408] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron) (an anti-PD-1 antibody being studied in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376)); pidilizumab (CureTech) (an antibody that binds to PD-1, also known as CT-011, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma); avelumab (BAVENCIO®, Pfizer / Merck KGaA) (also known as MSB0010718C, a fully human IgG1 anti-PD-L1 antibody in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer); or PDR001 (Novartis) (an inhibitory antibody that binds to PD-1 in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors). Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that is being investigated in clinical trials for several indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody currently being investigated in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0409] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin mucin-containing protein-3 (TIM-3). TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody currently being investigated in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody currently being investigated in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody currently being investigated in advanced malignancies (NCT02608268).

[0410] In some embodiments, the checkpoint inhibitor is an inhibitor of TIGIT, which is a T cell immunoreceptor having Ig and ITIM domains or an immunoreceptor on certain T cells and NK cells.TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0411] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is currently being investigated in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), also an anti-LAG-3 antibody, is currently being investigated in malignant tumors (NCT03005782). IMP321 (Immutep SA), a LAG-3-Ig fusion protein, is currently being investigated in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0412] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists currently being investigated in clinical trials include PF-04518600 / PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in a Phase 1 cancer trial (NCT02528357); and agonistic anti-OX40 antibody in advanced solid tumors (NCT02318394 and NCT02705482). These include MEDI0562 (Medimmune / AstraZeneca), an agonistic anti-OX40 antibody, in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475).

[0413] Checkpoint inhibitors that can be used in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists currently being investigated in clinical trials include utomilumab (PF-05082566, Pfizer), an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti-CD137 antibody, in metastatic or locally advanced malignancies (NCT03881488).

[0414] The checkpoint inhibitor that can be used in the present invention includes CD27 agonist.The CD27 agonist that is currently being investigated in clinical trials includes varlilumab (CDX-1127, Celldex Therapeutics), which is an agonistic anti-CD27 antibody in head and neck squamous cell carcinoma, ovarian cancer, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918); lymphoma (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0415] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists currently being investigated in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody in melanoma and other malignant solid tumors (NCT01239134 and NCT02628574), GWN323 (Novartis), an agonistic anti-GITR antibody in solid tumors and lymphomas (NCT02740270), INCAGN01876 (Incyte / Agenus), an agonistic anti-GITR antibody in advanced cancers (NCT02697591 and NCT03126110), MK-4166 (Merck), an agonistic anti-GITR antibody in solid tumors (NCT02132754), and human IgG1 (NCT02583165). This includes MEDI1873 (Medimmune / AstraZeneca), an agonistic hexameric GITR ligand molecule with an Fc domain.

[0416] Checkpoint inhibitors that can be used in the present invention include inducible T-cell costimulator (ICOS, also known as CD278) agonists. ICOS agonists currently being investigated in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody in lymphoma (NCT02520791), GSK3359609 (Merck), an agonistic anti-ICOS antibody in Phase 1 (NCT02723955), and JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody in Phase 1 (NCT02904226).

[0417] Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors currently being investigated in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma), in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to the three domains in the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

[0418] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors currently under investigation in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and blocks CD47 / SIRPa-mediated signaling, in Phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein generated by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgG1, which binds to human CD47 and blocks its "do not eat me" signal. These include: CC-90002 (Celgene), an anti-CD47 antibody that works by blocking the delivery of "eat" signals to macrophages and is in Phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.) in colorectal neoplasia and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0419] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors currently being investigated in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody in solid tumors (NCT02754141).

[0420] Checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes protein (STING, also known as transmembrane protein 173 or TMEM173). STING agonists currently being investigated in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonistic synthetic cyclic dinucleotide in Phase 1 (NCT02675439 and NCT03172936).

[0421] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors currently being investigated in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710), melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT02452424); and pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor in pancreatic cancer (NCT03153410), melanoma (NCT03101254). ) and solid tumors (NCT02718911); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody; and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).

[0422] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors currently being investigated in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0423] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0424] The compounds of the present invention can also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0425] The compound of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combined therapy can be in the form of a fixed combination, or the compound of the present invention and one or more other therapeutic compounds are administered alternately or independently, or in the form of a fixed combination administered in combination with one or more other therapeutic compounds.Otherwise or in addition, the compound of the present invention can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor treatment.As described above, in the context of other treatment strategies, long-term treatment is possible, as well as adjuvant treatment.Other possible treatments are treatments to maintain the patient's condition after tumor regression, or even chemopreventive treatment, for example, in patients at risk.

[0426] These additional agents can be administered separately from the compound-containing compositions of this invention, as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compound of this invention in a single composition. When administered as part of a multiple dose regimen, the two active agents may be given simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0427] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0428] The amounts of both the compounds of the present invention and additional therapeutic agents (in compositions containing such additional therapeutic agents) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of this invention should be formulated so that a dosage of between 0.01-100 mg / kg of body weight per day of the compound of the present invention can be administered.

[0429] In these compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Therefore, the amount of the additional therapeutic agent in such compositions is less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent can be administered at a dosage of between 0.01 and 1,000 μg per kg of body weight per day.

[0430] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0431] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents are used to overcome restenosis (re-narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of blood clot formation or platelet activation. These unwanted effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with the compounds of this invention is another embodiment of the present invention. [Example]

[0432] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. While the general methods illustrate the synthesis of certain specific compounds of the invention, it will be recognized that the following general methods, and other methods known to those of skill in the art, are applicable to all compounds, as described herein, and to each subclass and species of these compounds. Additional compounds of the invention were prepared by methods substantially similar to those described herein in the Examples and methods known to those skilled in the art. Synthesis of intermediates Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1). [ka] Step-1 Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1-1)

[0433] To a solution of 5-bromo-2-nitropyridine (3.0 g, 14.76 mmol, 1.0 equiv.) and tert-butyl piperazine-1-carboxylate (4.2 g, 22.58 mmol, 1.5 equiv.) in dry DMSO (10.0 mL) was added triethylamine (2.25 g, 22.27 mmol, 1.5 equiv.) and lithium chloride (0.63 g, 14.76 mmol, 1.0 equiv.) at room temperature. The reaction mixture was heated at 70° C. for 20 hours. After the reaction was completed, the reaction mixture was poured into ice water, and the solid product was collected by filtration. Trituration of the solid with n-pentane gave intermediate AA1-1 (3.0 g, 65.84%). MS (ES) m / z 309.33 (M+H). + . Step-2 Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1). Under a nitrogen atmosphere, a solution of intermediate AA1-1 (4.0 g, 12.98 mmol) in methanol (10 mL) was added to a suspension of 10% Pd / C (2.2 g) in methanol (50 mL). H2 (gas) was bubbled through the reaction mixture for 3 hours. After the reaction was complete, the reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure to give intermediate AA1 (2.4 g, 55.39%). MS (ES): m / z 279.24 [M+H] + . Synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine (Intermediate AA2). [ka] Step-1 Synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine (Intermediate AA2)

[0434] 5-(4-Methylpiperazin-1-yl)pyridin-2-amine (Intermediate AA2) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and 1-methylpiperazine in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (1.0 g, 70.84%) MS (ES) m / z 193.2 (M+H). + . Synthesis of 5-morpholinopyridin-2-amine (intermediate AA3). [ka] Step-1 Synthesis of 5-morpholinopyridin-2-amine (intermediate AA3).

[0435] 5-Morpholinopyridin-2-amine (Intermediate AA3) was prepared from 5-bromo-2-nitropyridine (Intermediate AA3-1) and morpholine in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (1.0 g, 64.84%) MS (ES) m / z 180.33 (M+H). + . Synthesis of tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (intermediate AA6). [ka] Step-1 Synthesis of tert-butyl 3-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate AA6-1).

[0436] To a solution of 5-bromo-2-nitropyridine (Intermediate AA1-1) (1.0 g, 4.9 mmol, 1.0 equiv.) in 1,4-dioxane (13.0 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.05 g, 4.9 mmol, 1.0 equiv.) and potassium phosphate tripotassium (2.03 g, 14.7 mmol, 3.0 equiv.) at room temperature. After degassing with argon for 20 minutes, Pd2dba3 (0.45 g, 0.49 mmol, 0.1 equiv.) and Xantphos (0.57 g, 0.98 mmol, 0.2 equiv.) were added. The reaction mixture was heated at 120 °C for 3 hours, poured into water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with brine solution (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography (gradient elution: 0-40% EtOAc in hexanes) to give the title compound (Intermediate AA6-1) (0.500 g, 30.35%). MS (ES): m / z 334.3 (M+H). + . Step-2 Synthesis of tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (intermediate AA6).

[0437] tert-Butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was prepared in a manner similar to that described for (Intermediate AA6) tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in General Process). (0.430 g, 94.4%). MS (ES): m / z 304 (M+H). + . Synthesis of 1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol (intermediate AA7). [ka] Step-1 Synthesis of 1-(5-methoxy-6-nitropyridin-3-yl)piperidin-4-ol (Intermediate AA7-2)

[0438] To a solution of 5-bromo-3-methoxy-2-nitropyridine (Intermediate AA7-1) (0.5 g, 2.1 mmol, 1.0 equiv.) in dry DMSO (6 mL) was added piperidin-4-ol (0.35 g, 2.6 mmol, 1.2 equiv.), potassium carbonate (1.7 g, 12.0 mmol, 6.0 equiv.), and tetrabutylammonium iodide (0.22 g, 0.6 mmol, 0.3 equiv.) at room temperature. The reaction mixture was heated at 90 °C for 2 h, then poured into water (100 mL) and extracted with ethyl acetate (100 × 3). The organic layer was washed with brine solution (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography (gradient elution: 0–40% EtOAc in hexane) to give the title compound (Intermediate AA7-1) (0.3 g, 56.24%). MS(ES): m / z 254.2 (M+H) + . Step-2 Synthesis of 1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol (Intermediate AA7)

[0439] 1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol (Intermediate AA7) was prepared in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (0.2 g, 74.73%). MS (ES): m / z 224.2 (M+H). + . Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)-4-methylpiperidine-1-carboxylate (Intermediate AA9) [ka] Step-1 Synthesis of ethyl (E)-3-(6-chloropyridin-3-yl)-2-cyanobut-2-enoate (intermediate AA9-2).

[0440] To a solution of 1-(6-chloropyridin-3-yl)ethan-1-one (10.0 g, 64.51 mmol, 1.0 equiv.) and ethyl 2-cyanoacetate (7.2 g, 64.51 mmol, 1.0 equiv.) in toluene (35 mL) was added ammonium acetate (1.0 g, 12.90 mmol, 0.2 equiv.) and acetic acid (4 mL). The reaction mixture was stirred in a Dean-Stark apparatus at 140 °C for 6 hours, then diluted with sodium bicarbonate solution (150 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material. This material was used in the next step without purification. Intermediate AA9-2 (15.0g, 96.09%), MS(ES)m / z251.05(M+H) + Step-2 Synthesis of 4-(6-chloropyridin-3-yl)-4-methyl-2,6-dioxopiperidine-3,5-dicarbonitrile (intermediate AA9-3).

[0441] To a solution of intermediate AA9-2 (14.9 g, 59.6 mmol) and 2-cyanoacetamide (6.0 g, 71.52 mmol, 1.2 equiv.) in ethanol (130 mL) was added sodium hydroxide (2.86 g, 71.52 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1 M potassium hydrogen sulfate solution was added to the reaction mixture. After stirring at 10 °C, a solid precipitated from the solution. The solid was filtered and dried under high vacuum to give intermediate AA9-3, which was used in the next step without purification. (20.0 g, 98.12%). MS (ES): m / z 289.04 [M+H] + Step-3 Synthesis of 4-(6-chloropyridin-3-yl)-4-methylpiperidine-2,6-dione (intermediate AA9-4).

[0442] To a solution of intermediate AA9-3 (20.0 g, 69.44 mmol) in water (12 mL) was added dropwise sulfuric acid (12 mL) at 10 °C. After stirring at 110 °C for 7 h, solid sodium hydroxide was added at 0 °C. The reaction mixture was filtered and washed with 10% methanol in DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a liquid material. Urea (40 g) was added to this crude material and stirred at 140 °C for 2 h. The reaction mixture was diluted with ethyl acetate (1 L) and saturated sodium bicarbonate solution (500 mL). The organic layers were collected, washed with brine solution (300 mL), dried over sodium sulfate, and concentrated under reduced pressure to give intermediate AA9-4, which was used in the next step without purification. (2.2 g, 13.31%). MS (ES): m / z 239.05 [M+H] + Step-4 Synthesis of 1-benzyl-4-(6-chloropyridin-3-yl)-4-methylpiperidine-2,6-dione (intermediate AA9-5).

[0443] To a solution of intermediate AA9-4 (1.2 g, 5.02 mmol) in acetone (50 mL), potassium carbonate (1.38 g, 10.04 mmol, 2.0 equiv.) was added and stirred at 0 °C. Benzyl bromide (0.94 g, 5.52 mmol, 1.1 equiv.) was added to the reaction mixture, which was then stirred at 70 °C for 2 h. After the reaction was completed, the reaction mixture was distilled to remove acetone. The residue was diluted with water (150 mL) and extracted with ethyl acetate (70 mL × 3). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. The residue was purified by column chromatography eluting with 25% ethyl acetate in hexane to give intermediate AA9-5 (1.5 g, 90.74%). MS (ES): m / z 329.10 [M+H] + Step-5 Synthesis of 5-(1-benzyl-4-methylpiperidin-4-yl)-2-chloropyridine (intermediate AA9-6).

[0444] To a solution of intermediate AA9-5 (1.2 g, 3.65 mmol) in dry THF (20 mL) was added lithium aluminum hydride (1.0 M in THF) (14 mL, 14.06 mmol, 4.0 equiv.) at −5° C. The reaction mixture was stirred at 70° C. for 1 hour and then concentrated. The residue was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This material was purified by column chromatography eluting with 1.2% ethyl acetate in hexane to give intermediate AA9-6 (0.4 g, 36.43%). MS (ES): m / z 301.2 [M+H] + Step-6 Synthesis of N-(5-(1-benzyl-4-methylpiperidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide (Intermediate AA9-7).

[0445] A solution of intermediate AA9-6 (1.6 g, 5.33 mmol), cyclopropanecarboxamide (0.679 g, 7.99 mmol, 1.5 equiv.), and cesium carbonate (5.1 g, 15.99 mmol, 3.0 equiv.) in 1,4-dioxane (20 mL) was degassed under a stream of N. After 15 min, Xantphos (0.308 g, 0.53 mmol, 0.1 equiv.) and Pd(dba) (0.487 g, 0.53 mmol, 0.1 equiv.) were added. The reaction mixture was stirred at 120 °C for 16 h, then cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 2.5% methanol in DCM to give intermediate AA9-7 (1.6 g, 69.94%) as a brown solid. MS (ES): m / z = 350.2 [M+H] + Step-7 Synthesis of N-(5-(4-methylpiperidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide (Intermediate AA9-8).

[0446] To a solution of intermediate AA9-7 (0.5 g, 1.43 mmol) in methanol (10 mL), 10% Pd / C (0.250 g) was added and the mixture was hydrogenated at room temperature for 6 hours at atmospheric pressure. After the reaction was completed, the reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to give the crude material, which was used in the next step without further purification. Intermediate AA9-8 (0.450 g, 94.32%). MS (ES): m / z 260.1 [M+H] + Step-8 Synthesis of tert-butyl 4-(6-(cyclopropanecarboxamido)pyridin-3-yl)-4-methylpiperidine-1-carboxylate (intermediate AA9-9).

[0447] To a solution of intermediate AA9-8 (0.450 g, 1.73 mmol) in DCM (20 mL) were added trimethylamine (0.524, 5.19 mmol, 3.0 equiv) and DMAP (0.021 g, 0.173 mmol, 0.1 equiv). Di-tert-butyl dicarbonate (0.754, 3.46 mmol, 2.0 equiv) was then added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, then concentrated, diluted with water (50 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. The residue was purified by column chromatography eluting with 2.5% methanol in DCM to give intermediate AA9-9 (0.450 g, 72.15%). MS(ES): m / z 360.2 [M+H] + Step-9 Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)-4-methylpiperidine-1-carboxylate (Intermediate-AA9).

[0448] To a solution of intermediate AA9-9 (0.450 g, 1.25 mmol) in methanol (10 mL) was added sodium hydroxide (0.5 g, 12.5 mmol, 10.0 equiv). The reaction mixture was stirred at 50 °C for 16 hours, then poured into water (70 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. The residue was purified by column chromatography eluting with 4.0% methanol in DCM to give intermediate-AA9 (0.210 g, 57.57%). MS (ES): m / z 292.2 [M+H] + Synthesis of 2-(1-(6-aminopyridin-3-yl)piperidin-3-yl)propan-2-ol (intermediate AA13). [ka] Step-1 Synthesis of ethyl 1-(6-nitropyridin-3-yl)piperidine-3-carboxylate (intermediate AA13-2)

[0449] Ethyl 1-(6-nitropyridin-3-yl)piperidine-3-carboxylate (Intermediate AA13-2) was prepared from 5-bromo-2-nitropyridine (Intermediate AA2-1) and 1-ethylpiperidine-3-carboxylate in a manner similar to that described for tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (1.5 g, 36.34%) MS (ES): m / z 280.14 [M+H] + Step-2 Synthesis of ethyl 1-(6-aminopyridin-3-yl)piperidine-3-carboxylate (intermediate AA13-3).

[0450] Ethyl 1-(6-aminopyridin-3-yl)piperidine-3-carboxylate (Intermediate AA13-3) was prepared from ethyl 1-(6-nitropyridin-3-yl)piperidine-3-carboxylate (Intermediate AA13-2) in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (1.2 g, 89.62%). MS (ES): m / z 250.15 [M+H] + Step-3 Synthesis of 2-(1-(6-aminopyridin-3-yl)piperidin-3-yl)propan-2-ol (Intermediate AA13).

[0451] To a solution of ethyl 1-(6-aminopyridin-3-yl)piperidine-3-carboxylate (Intermediate AA13-3) (2.0 g, 8.03 mmol) in THF (15 mL) was added dropwise a solution of 3N methylmagnesium bromide (3N in THF) (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, then quenched with ice-cold water (100 mL) and filtered through a bed of celite. The filtrate was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. The crude compound was purified by column chromatography (gradient elution: 0-80% EtOAc in hexane) to give the title compound (Intermediate AA13) (0.200 g, 10.60%). MS (ES): m / z 236.17 [M+H] + Synthesis of 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2-amine (intermediate AA14). [ka] Step-1 Synthesis of 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2-amine (intermediate AA14).

[0452] 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2-amine (Intermediate AA14) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane in a manner similar to that described for tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (0.330 g, quantitative yield). MS (ES): m / z 192.5 [M+H] + . Synthesis of 1-(6-bromopyridin-3-yl)-4-(morpholinomethyl)piperidin-4-ol (intermediate AA15). [ka] Step-1 Synthesis of 1-(6-bromopyridin-3-yl)-4-(morpholinomethyl)piperidin-4-ol (intermediate AA15).

[0453] To a solution of 2-bromo-5-iodopyridine (0.6 g, 2.0 mmol) in 1,4-dioxane (6 mL), 4-(morpholinomethyl)piperidin-4-ol (0.64 g, 3.0 mmol, 1.5 equiv.) and cesium carbonate (2.1, 6.0 mmol, 3.0 equiv.) were added. After degassing with nitrogen gas for 10 minutes, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.125 g, 0.02 mmol, 0.1 equiv.) and tris(dibenzylideneacetone)dipalladium (0.2 g, 0.2 mmol, 0.1 equiv.) were added under a nitrogen atmosphere. The reaction mixture was heated to 120 °C for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude material, which was purified using combi-flash silica eluted with 4% methanol / DCM to give intermediate AA15 (0.2 g, 26.56%). MS (ES): m / z 357.26 [M+H] + Synthesis of 1-(6-chloro-4-methoxypyridin-3-yl)piperidin-4-ol (intermediate AA18). [ka] Step-1 Synthesis of 6-chloro-4-methoxypyridin-3-amine (intermediate AA18-2).

[0454] To a solution of 2-chloro-4-methoxy-5-nitropyridine (intermediate AA18-1) (2.0 g, 10.6 mmol) in ethanol (8 mL) was added SnCl2.2HO (9.6 g, 63.8 mmol, 6.0 equiv). The reaction mixture was stirred at 90 °C for 30 min, then quenched with 3 M NaOH solution (100 mL) and extracted with DCM (100 mL). The combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. The residue was purified by column chromatography eluting with 15-20% ethyl acetate in hexane to give intermediate AA18-2. LCMS purity 100%, MS (ES): m / z 159.03 [M+H] + Step-2 Synthesis of 1-(6-chloro-4-methoxypyridin-3-yl)piperidin-4-one (Intermediate AA18-3)

[0455] To a refluxing slurry of sodium carbonate (1.51 g, 14 mmol, 1.5 equiv) in MeOH (8 mL) was added a solution of intermediate AA18-2 (1.5 g, 9.5 mmol) in MeOH (2 mL) and 1,5-dichloropentan-3-one (1.6 g, 9.5 mmol, 1.0 equiv). The reaction mixture was stirred at 50 °C for 16 h and then concentrated in vacuo to give the crude material, which was purified by column chromatography eluting with 20–25% ethyl acetate in hexane to give intermediate AA18-3 (1.2 g, 80.01%). MS (ES): 241.07 m / z [M+H]. + . Step-3 Synthesis of 1-(6-chloro-4-methoxypyridin-3-yl)piperidin-4-ol (Intermediate AA18)

[0456] To a solution of intermediate AA18-3 (1.2 g, 5 mmol) in MeOH (12 mL) was added NaBH4 (0.228 g, 6 mmol, 1.2 equiv). The reaction mixture was stirred for 30 min, then diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude material, which was purified using combi-flash silica eluted with 15-20% ethyl acetate in hexanes to give intermediate AA18. MS (ES): 243 m / z [M+H]+. Synthesis of 2-(6-aminopyridin-3-yl)-2-azaspiro[3.3]heptan-6-ol (intermediate AA19). [ka] Step-1 Synthesis of 2-(6-aminopyridin-3-yl)-2-azaspiro[3.3]heptan-6-ol (Intermediate AA19)

[0457] 2-(6-aminopyridin-3-yl)-2-azaspiro[3.3]heptan-6-ol (Intermediate AA19) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and 2-azaspiro[3.3]heptan-6-ol in a manner similar to that described for tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (0.600 g, 98.23%). MS (ES): m / z 206.12 [M+H] + Synthesis of 1-(6-aminopyridin-3-yl)-4-(methoxymethyl)piperidin-4-ol (intermediate AA20). [ka] Step-1 Synthesis of 1-(6-aminopyridin-3-yl)-4-(methoxymethyl)piperidin-4-ol (Intermediate AA20).

[0458] 1-(6-aminopyridin-3-yl)-4-(methoxymethyl)piperidin-4-ol (Intermediate AA20) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and 4-(methoxymethyl)piperidin-4-ol in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (0.600 g, 96.54%). MS (ES): m / z 238.12 [M+H] + Synthesis of 5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-amine (intermediate AA21). [ka]

[0459] 5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-amine (Intermediate AA21) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and 2-oxa-7-azaspiro[3.5]nonane in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (0.3 g, 75.76%). MS (ES): m / z 220.2 (M+H). + . Synthesis of 5-(1,4-oxazepan-4-yl)pyridin-2-amine (intermediate AA22). [ka]

[0460] 5-(1,4-Oxazepan-4-yl)pyridin-2-amine (Intermediate AA22) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and 1,4-oxazepane in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (0.300 g, 57.76%). MS (ES): m / z 194.15 [M+H]+ Synthesis of (1R,3r,5S)-8-(6-aminopyridin-3-yl)-8-azabicyclo[3.2.1]octan-3-ol (intermediate AA23). [ka]

[0461] (1R,3r,5S)-8-(6-aminopyridin-3-yl)-8-azabicyclo[3.2.1]octan-3-ol (Intermediate AA23) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and (1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-ol in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the general process). (1.8 g, 94.7%). MS (ES): m / z 219.2 (M+H). + . Synthesis of 5-(azetidin-1-ylsulfonyl)-2-chloropyridine (intermediate AA25). [ka] Step 1: Synthesis of intermediate AA25-2

[0462] Prepared as described in WO2020 / 89026. Step-2 Synthesis of 5-(azetidin-1-ylsulfonyl)-2-chloropyridine (intermediate AA25).

[0463] A solution of 5-(azetidin-1-ylsulfonyl)-2-chloropyridine (Intermediate AA25-2) (400 mg, 1.51 mol) in ammonia solution in water (3000 mL) was stirred at 80 °C for 16 hours. After completion of the reaction, the reaction mass was concentrated in vacuo to give the title compound (Intermediate AA25) as a white solid (200 mg, 78.74%). MS (ES): m / z 214.59 [M+H] + Synthesis of 5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine (intermediate AA30). [ka] Step-1: Synthesis of (3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (intermediate AA30-2).

[0464] To a solution of 5-fluoro(fluro)-2-nitropyridine (1.0 g, 7.04 mmol, 1.0 equiv.) in dimethyl sulfoxide (13.0 mL) was added (3aR, 6aS)-rel-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (1.05 g, 7.04 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (10 equiv., 70.4 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 1 hour, then poured into water and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with brine solution (100 mL × 3). The combined organic layer was concentrated under reduced pressure at 45 °C to give intermediate AA30-2 (2 g, 172.5%). MS (ES): m / z 236.33 (M+H). + . Step-2 Synthesis of 5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine (Intermediate AA30).

[0465] The synthesis of 5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine (Intermediate AA30) was prepared from (3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30-2) in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1 in the General Process). (0.600 g, 96.54%). MS (ES): m / z 238.12 [M+H] + Synthesis of 5-((cyclobutylmethyl)sulfonyl)pyridin-2-amine (intermediate AA32). [ka] Step-1 Synthesis of 2-chloro-5-((cyclobutylmethyl)sulfonyl)pyridine (intermediate AA32-2).

[0466] To a solution of 6-chloropyridine-3-sulfonyl chloride (2.0 g, 9.43 mmol) in water (40 mL) were added sodium bicarbonate (1.73 g, 9.43 mmol) and sodium sulfite (1.18 g, 9.43 mmol). The reaction mixture was stirred at 40° C. for 1 hour and then concentrated under high vacuum to give a solid. To a solution of this solid in N′N-DMF (20 mL) was added (bromomethyl)cyclobutane (1.68 g, 11.3 mmol, 1.2 equiv.) and pyridine (0.679 g, 11.3 mmol). The reaction mixture was stirred at room temperature for 16 hours, then concentrated, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material, which was purified using column chromatography eluting with 15% ethyl acetate / hexane to give intermediate AA32-2 (0.900 g, 27.29%). MS (ES): m / z 246.03 [M+H] + Step-2 Synthesis of 5-((cyclobutylmethyl)sulfonyl)pyridin-2-amine (Intermediate AA32).

[0467] To a solution of methanolic ammonia (5 mL) was added 2-chloro-5-((cyclobutylmethyl)sulfonyl)pyridine (0.900 g, 3.65 mmol). The reaction mixture was stirred at room temperature for 16 hours, then diluted in water and extracted with ethyl acetate. The combined organic solution was concentrated under reduced pressure to give the crude material. The residue was purified by column chromatography eluting with 30% ethyl acetate in hexane to give intermediate AA32 (0.100 g, 12.06%). MS (ES): m / z 227.12 [M+H] + . Synthesis of 1-(2-aminopyridin-4-yl)piperidin-4-ol (intermediate AA34). [ka]

[0468] 1-(2-aminopyridin-4-yl)piperidin-4-ol (Intermediate AA34) was prepared from 4-chloro-2-nitropyridine (Intermediate AA34-1) and piperidin-4-ol in a manner similar to that described for 1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol (Intermediate AA7 in the general process). (1.37 g, 83.29%). MS (ES): m / z 194.12 [M+H] + Synthesis of 1-(6-aminopyridin-3-yl)azepan-4-ol (intermediate AA37). [ka]

[0469] 1-(6-aminopyridin-3-yl)azepan-4-ol (Intermediate AA37) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and azepan-4-ol in a manner similar to that described for 5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine (Intermediate AA30 in General Process) (0.500 g, 81.76%). MS (ES): m / z 208.14 [M+H] + Synthesis of 5-(2-(methoxymethyl)morpholino)pyridin-2-amine (intermediate AA39). [ka]

[0470] 5-(2-(Methoxymethyl)morpholino)pyridin-2-amine (Intermediate AA37) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 2-(methoxymethyl)morpholine in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.700 g, 79.4%). MS (ES): m / z 224.14 [M+H] + Synthesis of 4-(6-aminopyridin-3-yl)-1,4-oxazepan-6-ol (intermediate AA43). [ka]

[0471] 4-(6-aminopyridin-3-yl)-1,4-oxazepan-6-ol (Intermediate AA43) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 1,4-oxazepan-6-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.7 g, 61.56%). MS (ES): m / z 210.26 [M+H] + Synthesis of (S)-2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-ol (intermediate AA48) [ka]

[0472] (S)-2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-ol (Intermediate AA43) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and (S)-2-(morpholin-2-yl)propan-2-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.7 g, 61.56%). (4 g, 75%). MS (ES): m / z 237.15 [M+H] + Synthesis of (3R,4R)-1-(6-aminopyridin-3-yl)-4-fluoropiperidin-3-ol (Intermediate AA49) [ka]

[0473] (3R,4R)-1-(6-aminopyridin-3-yl)-4-fluoropiperidin-3-ol (Intermediate AA49) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and (3R,4R)-4-fluoropiperidin-3-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in General Process). (0.500 g, 63.44%). MS (ES): m / z 212.11 [M+H] + Synthesis of 1-(6-aminopyridin-3-yl)-2-methylpiperidin-4-ol (Intermediate AA50) [ka]

[0474] 1-(6-aminopyridin-3-yl)-2-methylpiperidin-4-ol (Intermediate AA50) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 2-methylpiperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.900 gm, 93.75%) MS (ES): m / z 207 [M+H] + Synthesis of (1R,2S)-2-((6-aminopyridin-2-yl)oxy)cyclopentan-1-ol (Intermediate AA51) [ka] Step-1 Synthesis of (1R,2S)-2-((6-nitropyridin-2-yl)oxy)cyclopentan-1-ol (Intermediate AA51-2)

[0475] To a solution of 2-chloro-6-nitropyridine (3.0 g, 18.98 mmol, 1.0 equiv.) and (1R,2S)-cyclopentane-1,2-diol (2.3 g, 22.77 mmol, 1.2 equiv.) in dry DMF (36 mL) was added potassium carbonate (7.8 g, 56.94 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred at 120 °C for 16 h, then poured into ice water and extracted with ethyl acetate (2 × 120 mL). The combined organic extracts were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material. The residue was purified by column chromatography eluting with a gradient of 3.0% ethyl acetate in hexane to give intermediate AA51-2 (0.330 g, 8.0%). MS (ES) m / z 225.08 (M+H). + . Step-2 Synthesis of (1R,2S)-2-((6-aminopyridin-2-yl)oxy)cyclopentan-1-ol (Intermediate AA51)

[0476] To a suspension of intermediate AA51-2 (0.3 g, 1.33 mmol) in methanol (10 mL), 10% Pd / C (0.250 g) was added and the mixture was hydrogenated at room temperature for 6 hours at atmospheric pressure. After the reaction was completed, the reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to give the crude material, which was used in the next step without purification. Intermediate AA51 (0.268 g, 98.12%). MS (ES): m / z 195.1 [M+H] + Synthesis of 1-(1-(6-aminopyridin-3-yl)piperidin-3-yl)ethan-1-ol (Intermediate AA52) [ka]

[0477] 1-(1-(6-aminopyridin-3-yl)piperidin-3-yl)ethan-1-ol (Intermediate AA52) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 2-methylpiperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in General Process). (1.1 gm, 78.6%) MS (ES): m / z 222.1 [M+H] + Synthesis of (3R,4S)-1-(6-aminopyridin-3-yl)-4-fluoropiperidin-3-ol (intermediate AA54) [ka]

[0478] (3R,4S)-1-(6-aminopyridin-3-yl)-4-fluoropiperidin-3-ol (Intermediate AA54) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and (3R,4S)-4-fluoropiperidin-3-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in General Process). (1.0 g, 76.13%). MS (ES): m / z 212.11 [M+H] + Synthesis of 1-(6-aminopyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)piperidin-4-ol (Intermediate AA55) [ka]

[0479] 1-(6-aminopyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)piperidin-4-ol (Intermediate AA55) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-((4-methylpiperazin-1-yl)methyl)piperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.8 g, 87.75%). MS (ES): m / z 306.2 [M+H] + Synthesis of 1-(6-aminopyridin-3-yl)-4-((dimethylamino)methyl)piperidin-4-ol (Intermediate AA56) [ka]

[0480] 1-(6-aminopyridin-3-yl)-4-((dimethylamino)methyl)piperidin-4-ol (Intermediate AA56) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-((dimethylamino)methyl)piperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.85 g, 86.53%). MS (ES): m / z 251.4 [M+H] + Synthesis of 1-(6-aminopyridin-3-yl)-4-morpholinopiperidin-4-ol (intermediate AA58) [ka]

[0481] 1-(6-aminopyridin-3-yl)-4-morpholinopiperidin-4-ol (Intermediate AA58) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-morpholinopiperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.40 g, 44.34%). MS (ES): m / z 277.4 [M+H] + Synthesis of 5-((oxetan-3-ylmethyl)sulfonyl)pyridin-2-amine (intermediate AA59) [ka]

[0482] 5-((Oxetan-3-ylmethyl)sulfonyl)pyridin-2-amine (Intermediate AA59) was prepared from 6-chloropyridine-3-sulfonyl chloride (Intermediate AA32-1) and 3-(bromomethyl)oxetane in a manner similar to that described for 5-((cyclobutylmethyl)sulfonyl)pyridin-2-amine (Intermediate AA32 in General Process). (0.19 g, 89.94%). MS (ES): m / z 277.4 [M+H] + Synthesis of 5-(2-((dimethylamino)methyl)morpholino)pyridin-2-amine (Intermediate AA63) [ka]

[0483] 5-(2-((dimethylamino)methyl)morpholino)pyridin-2-amine (Intermediate AA63) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and N,N-dimethyl-1-(morpholin-2-yl)methanamine in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.60 g, 74.34%). MS (ES): m / z 237.4 [M+H] + Synthesis of 1-(6-aminopyridin-3-yl)-3-((dimethylamino)methyl)piperidin-3-ol (Intermediate AA64) [ka]

[0484] 1-(6-aminopyridin-3-yl)-3-((dimethylamino)methyl)piperidin-3-ol (Intermediate AA64) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 3-((dimethylamino)methyl)piperidin-3-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.60 g, 78%). MS (ES): m / z 251.4 [M+H] + Synthesis of 4-(6-aminopyridin-3-yl)-1-(2-(dimethylamino)ethyl)piperidin-2-one (Intermediate AA65) [ka] Step-1 Synthesis of 4-bromo-1-(2-(dimethylamino)ethyl)pyridin-2(1H)-one (Intermediate AA65-1)

[0485] Prepared as described in WO2009 / 74812A1. Steps 2, 3, and 4: Synthesis of 4-(6-aminopyridin-3-yl)-1-(2-(dimethylamino)ethyl)piperidin-2-one (Intermediate AA65)

[0486] 4-(6-aminopyridin-3-yl)-1-(2-(dimethylamino)ethyl)piperidin-2-one (Intermediate AA65) was prepared from 4-bromo-1-(2-(dimethylamino)ethyl)pyridin-2(1H)-one (Intermediate AA65-1) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in a manner similar to that described for 4-(6-aminopyridin-3-yl)-1-methylpiperidin-2-one (Intermediate AA8) (1 g, 65.65%). MS (ES): m / z 266.4 [M+H] + Synthesis of 1-(6-aminopyridin-3-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-ol (intermediate AA66). [ka]

[0487] 1-(6-aminopyridin-3-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-ol (Intermediate AA66) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1), 4-(pyrrolidin-1-ylmethyl)piperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (1.5 gm, 90.90%) MS (ES): m / z 277.3 [M+H] + Synthesis of 1-(6-aminopyridin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)piperidin-3-ol (intermediate AA67). [ka]

[0488] 1-(6-aminopyridin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)piperidin-3-ol (Intermediate AA67) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 3-((4-methylpiperazin-1-yl)methyl)piperidin-3-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in General Process). (0.80 g, 79%). MS (ES): m / z 306.4 [M+H] + Synthesis of 1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperidin-3-ol (intermediate AA69) [ka]

[0489] 1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperidin-3-ol (Intermediate AA69) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 3-(methoxymethyl)piperidin-3-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.9 g, 84%). MS (ES): m / z 238.4 [M+H] + Synthesis of 4-(6-aminopyridin-3-yl)-4-azaspiro[2.5]octan-6-ol (intermediate AA70) [ka]

[0490] 4-(6-aminopyridin-3-yl)-4-azaspiro[2.5]octan-6-ol (Intermediate AA70) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-azaspiro[2.5]octan-6-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.17 g, 94%). MS (ES): m / z 220.4 [M+H] + Synthesis of (3S,4S)-1-(6-aminopyridin-3-yl)-3-fluoropiperidin-4-ol (intermediate AA72) [ka]

[0491] (3S,4S)-1-(6-aminopyridin-3-yl)-3-fluoropiperidin-4-ol (Intermediate AA72) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and (3S,4S)-3-fluoropiperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (2.5 g, 52%). MS (ES): m / z 212.2 [M+H] + Synthesis of (1R,5S)-3-(6-aminopyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-ol (Intermediate AA73) [ka]

[0492] (1R,5S)-3-(6-aminopyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-ol (Intermediate AA73) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and (1R,5S)-3-azabicyclo[3.2.1]octan-8-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30 in the General Process). (0.9 g, 93%). MS (ES): m / z 220.2 [M+H] + Synthesis of 4-(6-aminopyridin-2-yl)-1-methylpiperidin-4-ol (intermediate AA74) [ka] Step-1 Synthesis of 4-(6-bromopyridin-2-yl)-1-methylpiperidin-4-ol (intermediate AA74-2).

[0493] To intermediate AA74-1 (7.5 g, 31.77 mmol) dissolved in THF (25 mL) was added a solution of n-butyllithium (19 mL, 1.59 mmol, 1.5 equiv) in diethyl ether (35 mL) at −78° C. After stirring for 30 min at −78° C., 1-methylpiperidin-4-one (3.6 g, 31.77 mmol) was added. The reaction mixture was stirred for 45 min at −78° C., then diluted with sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to give intermediate AA74-2 (3 g, 34.91%). MS (ES) m / z 272.2 (M+H). + Step-2 Synthesis of N-(6-(4-hydroxy-1-methylpiperidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide (Intermediate AA74-3).

[0494] To a solution of intermediate AA74-2 (1.7 g, 6.29 mmol) in 1,4-dioxane (20 mL) was added cyclopropanecarboxamide (0.641 g, 7.54 mmol, 1.2 equiv.) and CS2CO3 (6.1 g, 18.87 mmol, 3.0 equiv.). After degassing under a stream of N2 for 15 min, Xantphos (0.363 g, 0.62 mmol, 0.1 equiv.) and Pd2(dba)3 (0.567 g, 0.62 mmol, 0.1 equiv.) were added. The reaction mixture was stirred at 110 °C for 2 h, cooled to room temperature, diluted with water (90 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 2.0% methanol in DCM to give intermediate AA74-3 (1.7 g, 98.48%). MS (ES): m / z = 276.2 (M+H). + Step-3 Synthesis of 4-(6-aminopyridin-2-yl)-1-methylpiperidin-4-ol (Intermediate AA74).

[0495] To a solution of intermediate AA74-3 (1.7 g, 6.18 mmol) in methanol:water (30 mL:5 mL) was added sodium hydroxide (2.47 g, 61.8 mmol, 10 equiv). The reaction mixture was stirred at 80 °C for 16 h and then concentrated under reduced pressure. The residue was diluted with water (30 mL) at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to approximately 6-6.5. The solution was extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material, which was used in the next step without purification. Intermediate AA74 (0.750 g, 58.61%) MS (ES): m / z = 208.2 (M+H). + Synthesis of 1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperidin-4-ol (Intermediate AA77) [ka] Step-1 Synthesis of 3-(hydroxymethyl)-1-(6-nitropyridin-3-yl)piperidin-4-ol (Intermediate AA77-1)

[0496] 3-(Hydroxymethyl)-1-(6-nitropyridin-3-yl)piperidin-4-ol (Intermediate AA77-1) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 3-(hydroxymethyl)piperidin-4-ol in a manner similar to that described for (3aR,6aS)-5-(6-nitro...

Claims

1. Compounds of Formula I: 【Chemical 364】 or a pharmaceutically acceptable salt thereof, Z is CH or N; X is a covalent bond or —NH—; R １ is pyrazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each of which is Ｃ where R Ｃ are each independently a halogen, —CN, —OR, or —S(O) ２ R, —C(O)NR ２ or R Ｃ Each instance of is independently １～６ an optionally substituted group selected from aliphatic; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-12 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur, or two R Ｃ groups together with the atom to which each is attached form a 3- to 7-membered partially unsaturated monocyclic carbocyclic ring; or a 3- to 7-membered partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur, or R １ When R is pyrazolyl or pyridinyl, two R Ｃ groups together with the atoms to which they are each attached form a bridged, fused, or spiro 5- to 6-membered aryl ring, where R Ｃ Each instance of is independently r R and s R Ｄ and R ２ are 9-membered fused bicyclic rings having 1 to 3 nitrogen atoms, each of which is Ｃ and R Ｃ are each independently a halogen, —CN, —OR, or —C(O)NR ２ , -NR 2 or R Ｃ Each instance of is independently １～６ an optionally substituted group selected from aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; and a 6-11 membered saturated or partially unsaturated fused, bridged, or spiro bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R independently has r R and s R Ｄ and R Ｄ Each instance of is independently oxo, halogen, —CN, —NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -S(O)NR ２ , -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)NR ２ , -N(R)S(O) ２ NR ２ , -N(R)S(O) ２ R, -N=S(O)R ２ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR ２ , -P(O)(R)OR or -P(O)R ２ and Each R is independently hydrogen, —CN, halogen, or C １～６ aliphatic; phenyl; naphthyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen together with said nitrogen form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to said nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, each q is independently 0, 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each s is independently 0, 1, 2, 3, or 4.

2. Formula II: 【Chemical 365】 2. The compound of claim 1, wherein:

3. Formula V: 【Chemical 366】 2. The compound of claim 1, wherein:

4. Formula IV: 【Chemical 367】 3. The compound of claim 2, wherein:

5. Formula VII: 【Chemical 368】 4. The compound of claim 3, wherein:

6. Formula XI-a or XI-b: 【Chemical 369】 2. The compound of claim 1, wherein the compound is any one of:

7. Formula XIV-a or XIV-b: 【Chemistry 370】 2. The compound of claim 1, wherein the compound is any one of:

8. Formula XVII-a or XVII-b: 【Chemistry 371】 2. The compound of claim 1, wherein the compound is any one of:

9. Formula XX-a or XX-b: 【Chemistry 372】 2. The compound of claim 1, wherein the compound is any one of:

10. Formula XXIII-a or XXIII-b: 【Chemistry 373】 2. The compound of claim 1, wherein the compound is any one of:

11. Formula XXVI-a or XXVI-b: 【Chemistry 374】 2. The compound of claim 1, wherein the compound is any one of:

12. Formula XXIX-a or XXIX-b: 【Chemistry 375】 2. The compound of claim 1, wherein the compound is any one of:

13. R １ but, 【Transformation 376】 The compound according to any one of claims 1 to 3 or 6 to 12,

14. R １ but, 【Chemical 377】 【Chemistry 378】 【Chemistry 379】 【Chemical 380】 【Chemistry 381】 【Chemistry 382】 【Chemistry 383】 【Chemical 384】 【Chem.385】 【Chemical 386】 【Chemistry 387】 【Chemical 388】 【Chem.389】 【Chemical 390】 【Chemistry 391】 【Chemistry 392】 【Chemistry 393】 【Chem. 394】 【Chemical 395】 【Chemistry 396】 【Chemistry 397】 【Chem.398】 【Chem.399】 The compound according to any one of claims 1 to 3 or 6 to 12,

15. R ２ but 【Chemical 400】 【Chemical 401】 The compound according to any one of claims 1 to 5.

16. R ２ but, 【Chemical 403】 【Chemical 404】 The compound according to any one of claims 1 to 5,

17. R ２ but, 【Chemical 406】 【Chemical 407】 【Chemical 408】 【Chemical 409】 【Chemical Engineering 409-1】 The compound according to any one of claims 1 to 5,

18. The compound is 【Chemistry 1-1】 【Chemistry 1-2】 [Chemistry 1-3] [Chemistry 1-4] [Chemistry 1-5] [Chemistry 1-6] [Chemistry 1-7] [Chemistry 1-8] [Chemistry 1-9] 【Chemistry 1-10】 【Chemistry 1-11】 【Chemistry 1-12】 【Chemistry 1-13】 [Chemistry 1-14] 【Chemistry 1-15】 【Chemistry 1-16】 【Chemistry 1-17】 【Chemistry 1-18】 【Chemistry 1-19】 【Chemistry 1-20】 【Chemistry 1-21】 【Chemistry 1-22】 [Chemistry 1-23] [Chemistry 1-24] [Chemistry 1-25] [Chemistry 1-26] [Chemistry 1-27] [Chemistry 1-28] [Chemistry 1-29] 【Chemistry 1-30】 【Chemistry 1-31】 【Chemistry 1-32】 【Chemistry 1-33】 [Chemistry 1-34] 【Chemistry 1-35】 [Chemistry 1-36] 【Chemistry 1-37】 [Chemistry 1-38] [Chemistry 1-39] 【Chemistry 1-40】 【Chemistry 1-41】 【Chemistry 1-42】 [Chemistry 1-43] [Chemistry 1-44] [Chemistry 1-45] [Chemistry 1-46] [Chemistry 1-47] [Chemistry 1-48] [Chemistry 1-49] 【Chemistry 1-50】 【Chemistry 1-51】 【Chemistry 1-52】 [Chemistry 1-53] [Chemistry 1-54] 【Chemistry 1-55】 [Chemistry 1-56] 【Chemistry 1-57】 [Chemistry 1-58] [Chemistry 1-59] 【Chemistry 1-60】 【Chemistry 1-61】 【Chemistry 1-62】 [Chemistry 1-63] [Chemistry 1-64] 【Chemistry 1-65】 【Chemistry 1-66】 【Chemistry 1-67】 【Chemistry 1-68】 【Chemistry 1-69】 【Chemistry 1-70】 【Chemistry 1-71】 【Chemistry 1-72】 【Chemistry 1-73】 [Chemistry 1-74] 【Chemistry 1-75】 【Chemistry 1-76】 【Chemistry 1-77】 【Chemistry 1-78】 【Chemistry 1-79】 【Chemistry 1-80】 【Chemistry 1-81】 【Chemistry 1-82】 【Chemistry 1-83】 [Chemistry 1-84] 【Chemistry 1-85】 【Chemistry 1-86】 【Chemistry 1-87】 【Chemistry 1-88】 【Chemistry 1-89】 【Chemistry 1-90】 【Chemistry 1-91】 【Chemistry 1-92】 【Chemistry 1-93】 [Chemistry 1-94] 【Chemistry 1-95】 【Chemistry 1-96】 【Chemistry 1-97】 【Chemistry 1-98】 【Chemistry 1-99】 【Chemistry 1-100】 【Chemistry 1-101】 【Chemistry 1-102】 【Chemistry 1-103】 【Chemistry 1-104】 【Chemistry 1-105】 【Chemistry 1-106】 【Chemistry 1-107】 【Chemistry 1-108】 【Chemistry 1-109】 【Chemistry 1-110】 【Chemistry 1-111】 【Chemistry 1-112】 【Chemistry 1-113】 【Chemistry 1-114】 【Chemistry 1-115】 【Chemistry 1-116】 【Chemistry 1-117】 【Chemistry 1-118】 【Chemistry 1-119】 【Chemistry 1-120】 【Chemistry 1-121】 【Chemistry 1-122】 【Chemistry 1-123】 【Chemistry 1-124】 【Chemistry 1-125】 【Chemistry 1-126】 【Chemistry 1-127】 【Chemistry 1-128】 【Chemistry 1-129】 【Chemistry 1-130】 【Chemistry 1-131】 【Chemistry 1-132】 【Chemistry 1-133】 [Chemistry 1-134] 【Chemistry 1-135】 【Chemistry 1-136】 【Chemistry 1-137】 【Chemistry 1-138】 【Chemistry 1-139】 【Chemistry 1-140】 【Chemistry 1-141】 【Chemistry 1-142】 【Chemistry 1-143】 【Chemistry 1-144】 【Chemistry 1-145】 [Chemistry 1-146] 【Chemistry 1-147】 【Chemistry 1-148】 [Chemistry 1-149] 【Chemistry 1-150】 【Chemistry 1-151】 【Chemistry 1-152】 【Chemistry 1-153】 【Chemistry 1-154】 【Chemistry 1-155】 【Chemistry 1-156】 【Chemistry 1-157】 【Chemistry 1-158】 【Chemistry 1-159】 【Chemistry 1-160】 【Chemistry 1-161】 【Chemistry 1-162】 【Chemistry 1-163】 [Chemistry 1-164] 【Chemistry 1-165】 【Chemistry 1-166】 【Chemistry 1-167】 [Chemistry 1-168] 【Chemistry 1-169】 【Chemistry 1-170】 【Chemistry 1-171】 【Chemistry 1-172】 【Chemistry 1-173】 [Chemistry 1-174] 【Chemistry 1-175】 【Chemistry 1-176】 【Chemistry 1-177】 【Chemistry 1-178】 【Chemistry 1-179】 【Chemistry 1-180】 【Chemistry 1-181】 【Chemistry 1-182】 【Chemistry 1-183】 [Chemistry 1-184] 【Chemistry 1-185】 【Chemistry 1-186】 【Chemistry 1-187】 【Chemistry 1-188】 【Chemistry 1-189】 【Chemistry 1-190】 【Chemistry 1-191】 【Chemistry 1-192】 【Chemistry 1-193】 【Chemistry 1-194】 【Chemistry 1-195】 【Chemistry 1-196】 【Chemistry 1-197】 【Chemistry 1-198】 【Chemistry 1-199】 【Chemistry 1-200】 【Chemistry 1-201】 【Chemistry 1-202】 【Chemistry 1-203】 【Chemistry 1-204】 【Chemistry 1-205】 【Chemistry 1-206】 【Chemistry 1-207】 【Chemistry 1-208】 【Chemistry 1-209】 【Chemistry 1-210】 【Chemistry 1-211】 【Chemistry 1-212】 【Chemistry 1-213】 【Chemistry 1-214】 【Chemistry 1-215】 【Chemistry 1-216】 【Chemistry 1-217】 【Chemistry 1-218】 【Chemistry 1-219】 【Chemistry 1-220】 【Chemistry 1-221】 【Chemistry 1-222】 【Chemistry 1-223】 【Chemistry 1-224】 【Chemistry 1-225】 【Chemistry 1-226】 【Chemistry 1-227】 【Chemistry 1-228】 【Chemistry 1-229】 【Chemistry 1-230】 【Chemistry 1-231】 【Chemistry 1-232】 【Chemistry 1-233】 【Chemistry 1-234】 【Chemistry 1-235】 【Chemistry 1-236】 【Chemistry 1-237】 【Chemistry 1-238】 【Chemistry 1-239】 【Chemistry 1-240】 【Chemistry 1-241】 【Chemistry 1-242】 【Chemistry 1-243】 【Chemistry 1-244】 【Chemistry 1-245】 【Chemistry 1-246】 【Chemistry 1-247】 【Chemistry 1-248】 【Chemistry 1-249】 【Chemistry 1-250】 【Chemistry 1-251】 【Chemistry 1-252】 【Chemistry 1-253】 【Chemistry 1-254】 【Chemistry 1-255】 【Chemistry 1-256】 【Chemistry 1-257】 【Chemistry 1-258】 【Chemistry 1-259】 【Chemistry 1-260】 【Chemistry 1-261】 【Chemistry 1-262】 【Chemistry 1-263】 [Chemistry 1-264] 【Chemistry 1-265】 【Chemistry 1-266】 【Chemistry 1-267】 【Chemistry 1-268】 【Chemistry 1-269】 【Chemistry 1-270】 【Chemistry 1-271】 【Chemistry 1-272】 【Chemistry 1-273】 【Chemistry 1-274】 【Chemistry 1-275】 【Chemistry 1-276】 【Chemistry 1-277】 【Chemistry 1-278】 【Chemistry 1-279】 【Chemistry 1-280】 【Chemistry 1-281】 【Chemistry 1-282】 【Chemistry 1-283】 【Chemistry 1-284】 【Chemistry 1-285】 【Chemistry 1-286】 【Chemistry 1-287】 【Chemistry 1-288】 2. The compound of claim 1, selected from: 【Request Item 19】 【Chemistry 410】 4. The compound of claim 1 or 3, wherein: 【Request Item 20】 【Chemistry 411】 20. The compound of any one of claims 1, 3 and 19, wherein:

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

22. A composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 for use as a medicament.

23. A method for inhibiting HPK1 in a biological sample, comprising contacting the sample with a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21.

24. A composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for treating an HPK1-mediated disorder, disease or condition in a patient.

25. 25. The composition of claim 24, wherein the disorder is a proliferative disorder.

26. 26. The composition of claim 25, wherein the proliferative disorder is cancer.

27. 26. The composition of claim 25, wherein the proliferative disorder is associated with one or more activating mutations in HPK1.

28. 25. The composition of claim 24, wherein the disease is a chronic viral infection.

29. A composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for increasing the efficacy of vaccination in a patient, characterized in that said composition is administered as an adjuvant.

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