HPK1 antagonists and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of their use for the inhibition of HPK1 and the treatment of HPK1-mediated disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 148,857, filed February 12, 2021, the contents of which are incorporated herein by reference.

[0002] 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, and methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] 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 has been shown to be induced upon activation of the 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-coupled PGE2 receptors (EP2 and EP4) (Ikegami, R., et al., J Immunol, 2001.166(7):pp.4689-96). Thus, HPK1 regulates various 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 progenitor cells. In T cells, HPK1 is thought to negatively regulate T cell activation by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, thereby reducing the persistence of signaling microclusters, leading to the recruitment of 14-3-3 proteins that bind to phosphorylated SLP76 and Gads, resulting in the release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters (Lasserre et al. (2011) J Cell Biol 195(5):839-853). HPK1 is also activated in response to prostaglandin E2, which is often secreted by tumors, and may contribute to the escape of tumor cells from the immune system. It is important to regulate the function of HPKl and immune cells, and is closely related to autoimmune diseases and anti-tumor 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). [Preliminary Technology Documents] [Non-licensed literature]

[0005] [Non-licensed Document 1] Hu,MC,et al.,Genes Dev,1996.10(18):p.2251-64 [Non-licensed Document 2] Kiefer,F.,et al.,EMBO J,1996.15(24):p.7013-25 [Non-licensed Document 3] Liou,J.,et al.,Immunity,2000.12(4):p.399-408 [Non-licensed Document 4] Wang,W.,et al.,J Biol Chem,1997.272(36):p.22771-5 [Non-licensed Document 5] Zhou,G.,et al.,J Biol Chem,1999.274(19):p.13133-8 [Non-licensed Document 6] Ikegami,R.,et al.,J Immunol,2001.166(7):p.4689-96 [Non-licensed Document 7] Di Bartolo et al.(2007)JEM 204:681-691 [Non-licensed Document 8] Lasserre et al.(2011)J Cell Biol 195(5):839-853 [Non-licensed Document 9] Shui,JW,et al.,Nat Immunol,2007.8(1):p.84-91 [Non-licensed Document 10] Wang, X., et al., J Biol Chem, 2012.287(14):p.11037-48 Summary of the Invention [Means for solving the problem]

[0006] 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 presented 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 modulation of signal transduction pathways involving HPK1 kinase, including those described herein.

[0008] The compounds provided by the present invention are also useful for studying the HPK1 enzyme in biological and pathological phenomena, for studying intracellular signaling pathways occurring in body tissues, and for the comparative evaluation of new HPK1 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo. DETAILED DESCRIPTION OF THE INVENTION

[0009] 1. General Description of Certain Embodiments of the Invention: In certain aspects, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, A, L, R 1 , R 2 , R 3 , R 4 , m, and n, both alone and in combination, are as defined below and described in the embodiments herein.

[0010] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0011] In some embodiments, the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition, the method comprising administering to a patient in need thereof a compound provided herein, or a pharmaceutically acceptable salt thereof.

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

[0013] The terms "aliphatic" or "aliphatic group," as used herein, mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, having a single point of attachment to the rest of the molecule; or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl"). 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 yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet 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, having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0014] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or a valence bond connecting two bridgehead positions, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding 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 shown below, in which each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents as shown for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic groups include: [ka]

[0015] The term "lower alkyl" refers to C 1-4 It refers to a straight-chain or branched alkyl group. 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 It 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, for example, N (such as 3,4-dihydro-2H-pyrrolyl), NH (such as pyrrolidinyl), or NR + (including N-substituted pyrrolidinyl, etc.)

[0018] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0019] As used herein, "divalent C 1-8 (or C 1-6 The term "saturated or unsaturated, straight or branched, hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0020] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is preferably a positive integer of 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 hydrogen atoms have been 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 methylene hydrogen atoms are replaced with a substituent. 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 such as "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 of the system is aromatic and each ring of 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 present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as used herein, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl.

[0024] The terms "heteroaryl" and "heteroa-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, and having 6, 10, or 14 pi electrons shared in a cyclic array, 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. As used herein, the terms "heteroaryl" and "heteroa" also include groups in which a heterocyclic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and unless otherwise specified, the radical or point of attachment is on the heterocyclic ring or on one of the rings to which the heterocyclic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazole, benzthiazolyl, 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 "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, wherein 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 that, in addition to carbon atoms, has one or more, preferably 1 to 4, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (e.g., 3,4-dihydro-2H-pyrrolyl), NH (e.g., pyrrolidinyl), or + It can be NR (such as N-substituted pyrrolidinyl).

[0026] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, 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 include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein 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 are 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 if 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 the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that remains substantially unchanged when subjected to conditions that allow for its production, detection, and, in certain embodiments, its 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 , -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR゜)2;-(CH2) 0-4 -(CH2) which may be substituted with SR°;R° 0-4 Ph; R° may be substituted with -(CH2) 0-4 O(CH2) 0-1 Ph; -CH=CHPh, which may be substituted with R°; -(CH2), which may be substituted with R° 0-4 O(CH2) 0-1-pyridyl; -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)2NR゜2;-N(R゜)S(O)2R゜;-N(OR゜)R゜;-C(NH)N R゜2;-P(O)2R゜;-P(O)R゜2;-OP(O)R゜2;-OP(O)(OR゜)2;-SiR゜3;-(C 1-4 Linear or branched alkylene)ON(R°)2, or -(C 1-4 linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2)0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independent occurrences of R° taken together with their intervening atoms form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0030] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms) 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 Linear or branched alkylene)C(O)OR ● , or -SSR ● and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R include =0 and =S.

[0031] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =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 Contains S-, R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below 1-6 and optionally substituted groups are selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR * 2) 2-3 O-, wherein R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 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, wherein each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 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 † wherein each R † are independently hydrogen, C which may be substituted as defined below 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, R † two independent occurrences of together with their intervening atoms form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 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 only with one or more halogens, and independently represents C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.

[0036] Pharmaceutically acceptable salts of the compounds of the present 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 using 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, and 2-hydroxy-ethanesulfonate. , 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, valerate, and the like.

[0037] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0038] Unless otherwise stated, structures depicted herein are also meant to include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational) forms) of the structure, for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomers of the present compounds are within the scope of the invention. Additionally, 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, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure including the replacement of a carbon with a C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, the warhead moiety R of provided compounds 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.

[0039] As used herein, an "HPK1 antagonist" or "HPK1 inhibitor" is a molecule that reduces, inhibits, or otherwise decreases 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 complete 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 decreases the serine / threonine kinase activity of HPK1. In some of these embodiments, the HPK1 antagonist reduces, inhibits, or otherwise decreases HPK1-mediated phosphorylation of SLP76 and / or Gads. Compounds of the present disclosure directly bind to HPK1 and inhibit its kinase activity.

[0040] By "specific antagonist" is intended an agent that reduces, inhibits, or otherwise decreases the activity of a defined 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., another 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 IC50 of the HPK1 antagonist is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001%, or less. Compounds of the present disclosure 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 HPK1 antagonist specifically inhibits the serine / threonine kinase activity of HPK1. In some of these embodiments, the IC50 of the HPK1 antagonist for HPK1 is 50 The IC50 of HPK1 antagonists against other serine / threonine kinases or other types of kinases (e.g., tyrosine kinases) 50 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less.

[0041] The compounds of the present invention may be linked to a detectable moiety. It will be understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that the detectable moiety can be attached to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety capable of covalently binding to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name a few. It will be understood that such moieties can be attached to a provided compound directly or via a linking group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties may 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 is capable of being detected, such as primary labels and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 Primary labels, mass tags, and fluorescent labels such as C) are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and fluorescent 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 second intermediate for the generation of 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-radiative fluorescence resonance energy transfer (FRET), and the second group generates the detected signal.

[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, but are not limited to, 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 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, hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lisa Rhodamine B, Marine 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, 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 techniques. Examples of mass tags include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and derivatives thereof. The synthesis and utility of these mass tags are described in U.S. Patent Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of various lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) in the appropriate mass range (100-2000 daltons), can also be used as mass tags.

[0046] As used herein, the terms "measurable affinity" and "measurably inhibit" 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.

[0047] 3. Description of Exemplary Embodiments: As described above, in certain embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: X is N or CR 3 and Y is N or CR 2 and Z is N or CR 2 and A is N or CR 2 and L 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 L is C 1-4 a divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the 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 H;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; and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from q R C has been replaced by the example Each R 2 are independent, H;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; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 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 selected from r RD or R 2 is halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)(NR)R, —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)R, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, —N(R)S(O)2R, or —P(O)R2; Each R 3 are independent, H;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; and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from s R E or R 3 is halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)(NR)R, —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)R, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, —N(R)S(O)2R, or —P(O)R2; R 4 is H or C 1-6 aliphatic, which means that tR F has been replaced by the example R C , R D , R E , and R FEach example independently represents 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 , R D , R E , and R F Each example of C 1-6 Aliphatic; phenyl; naphthalenyl; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; 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; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is substituted with u instances of R; Each R is independently hydrogen, —CN, halogen, or C 1-6Aliphatic; phenyl; naphthalenyl; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted group selected from: 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 unsaturated bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; two R groups on the same nitrogen, taken 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; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 1, 2, or 3; n is 0, 1, or 2; each of q, r, s, and t is independently 0, 1, 2, 3, or 4; u is 0, 1, 2, 3, or 4.

[0048] In one embodiment, X is CR 3 and Y is N or CR 2 and Z is N or CR 2 and A is N or CR 2 is.

[0049] In certain embodiments, X is CR 3 and Y is CR 2 and Z is N and A is CR 2 is.

[0050] In certain embodiments, X is CR 3 and Y is N and Z is CR 2 and A is CR 2 is.

[0051] In certain embodiments, X is CR 3 and Y is CR 2 and Z is CR 2 and A is CR 2 is.

[0052] In certain embodiments, X is CR 3 and Y is CR 2 and Z is CR 2 and A is N.

[0053] In certain embodiments, X is CR 3 and Y is N and Z is CR 2 and A is N.

[0054] In another embodiment, X is N and Y is N or CR 2 and Z is N or CR 2 and A is N or CR 2 is.

[0055] In certain embodiments, X is N and Y is CR 2 and Z is N and A is CR 2 is.

[0056] In certain embodiments, X is N and Y is NCR 2 and A is CR 2 is.

[0057] In certain embodiments, X is N and Y is CR 2 and Z is CR 2 and A is CR 2 is.

[0058] In certain embodiments, X is N and Y is CR 2 and Z is CR 2 and A is N.

[0059] In certain embodiments, X is N, Y is N, and Z is CR 2 and A is N.

[0060] In certain embodiments, L is a covalent bond, —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)—.

[0061] In some embodiments, L is a covalent bond.

[0062] In certain embodiments, L 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)-.

[0063] In certain embodiments, L 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-.

[0064] In certain embodiments, L is -NR-. In certain embodiments, L is -NH-.

[0065] In some embodiments, L is selected from those shown in Table 1 below.

[0066] In some embodiments, R 1 is H.

[0067] In some embodiments, R 1 Let q be the number of R C Example of C being substituted 1-6 Aliphatic; q R C Examples of phenyl substituted with q R C q R C a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with, for example, q R C and 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 with, for example,

[0068] 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 R C has been replaced with the example.

[0069] In certain embodiments, R 1is -H, -Et, -i-Pr, s-Bu, straight-chain or branched pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazole, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1, 5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, 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 thiadiazinyl, 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 q R; C has been replaced by the example

[0070] In certain embodiments, R 1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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 yl, pyranyl, pyrazinyl, pyrazolidinyl, 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 R C has been replaced by the example

[0071] In certain embodiments, R 1 is phenyl, 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 q R C has been replaced by the example

[0072] In certain embodiments, R 1 is phenyl, pyrazolyl, or pyridinyl, each of which is q R Chas been replaced by the example

[0073] In certain embodiments, R 1 is phenyl, pyrazolyl, or pyridinyl, each of which is q R C are replaced by examples, and each R C are independently halogen, —CN, —OR, —S(O)R, —C(O)NR, or R C Each example of C 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; 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 atoms to which each is attached, form a bridged, fused, or spiro 5- to 6-membered aryl 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, or R C Each instance of is independently R and R D is optionally replaced by

[0074] In certain embodiments, R 1 teeth, [ka] is.

[0075] In certain embodiments, R 1 teeth, [ka] and In the formula, R CEach example is independently halogen, -CN, -OR, -S(O)R, -S(O)NR, -C(O)NR, C 1-6 an optionally substituted group selected from aliphatic; 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; 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 heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from r instances of R and s instances of R. D has been replaced with the example.

[0076] In certain embodiments, R 1 teeth, [ka] and In the formula, R C Each example is independently -Me, -Et, -CH2N(CH3) 2、 -CN, -CH2CN, -F, -OMe, -S(O)2Me, -CH2S(O)2Me, [ka] [ka] is.

[0077] In certain embodiments, R 1 teeth, [ka] [ka] [ka] [ka] is.

[0078] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0079] In some embodiments, each R 2 are independently H.

[0080] In some embodiments, each R 2 independently, C 1-6 R is selected from 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; and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and each of them is rR D has been replaced with the example.

[0081] In some embodiments, each R 2 independently, C 2-6 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; and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from r R D has been replaced with the example.

[0082] In some embodiments, each R 2 are independently r R D Example of C substituted in 2-6 It is aliphatic.

[0083] In some embodiments, each R 2 are independently r RD An example is phenyl substituted with phenyl.

[0084] In some embodiments, each R 2 are independently r R D Examples of the substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring include:

[0085] In some embodiments, each R 2 are independently a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and r R D has been replaced with the example.

[0086] In some embodiments, each R 2 are independently 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 r R D has been replaced with the example.

[0087] In certain embodiments, each R 2are independently -H, -Et, -i-Pr, s-Bu, straight-chain or branched pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazole, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- 1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, 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 thiadiazinyl, 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 r R; D has been replaced by the example

[0088] In certain embodiments, each R 2are independently -H, -Et, -i-Pr, s-Bu, straight-chain or branched pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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, oxadiazolyl ... cetyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, 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; R D Each example independently represents 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 D Each example of C 1-6an optionally substituted group selected from aliphatic; phenyl; naphthalenyl; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 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 heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R D groups, each taken together with the atoms to which it is attached, form a bridged, fused, or spiro 5- to 6-membered aryl 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 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R D is optionally replaced by u instances of R.

[0089] In certain embodiments, each R 2 are independently -H, -Et, -i-Pr, s-Bu, straight-chain or branched pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, azetidinyl, each of which is selected from the group consisting of r R D has been replaced by the example

[0090] In certain embodiments, each R 2are independently -H, -Et, -i-Pr, s-Bu, straight-chain or branched pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, and azetidinyl, each of which is r and R D and each R D are independently oxo, halogen, —CN, —OR, —C(O)R, —C(O)OR, —C(O)NR, —N(R)C(O)R, or R D Each example of C 1-6 an optionally substituted group selected from aliphatic; 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 a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R D groups, each taken together with the atoms to which it is attached, form a bridged, fused, or spiro 5- to 6-membered aryl 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 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R D is optionally replaced by u instances of R.

[0091] In some embodiments, each R 2 are independently 6-11 membered saturated, partially unsaturated, or unsaturated, fused, bridged, or spiro bicyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is substituted by r R D has been replaced with the example.

[0092] In certain embodiments, each R 2are independently 7-10 membered fused bicyclic rings having 1-3 nitrogen atoms, each of which is selected from r R D is replaced by each of the examples of

[0093] In certain embodiments, each R 2 are independently 9-membered fused bicyclic rings having 1 to 3 nitrogen atoms, each of which is selected from r R D Each R is substituted by each of the examples of D are independently halogen, —CN, —OR, —C(O)NR, —NR, or R D Each example of C 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; D is optionally replaced by u instances of R.

[0094] In certain embodiments, each R 2 are independently -H, [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0095] In certain embodiments, each R 2 is independent, [ka] [ka] [ka] is.

[0096] In certain embodiments, each R 2 is independent, [ka] is.

[0097] In certain embodiments, each R 2 is independent, [ka] is.

[0098] In certain embodiments, each R 2 is that R D Independently together with the substituents, [ka] [ka] [ka] [ka] is.

[0099] In certain embodiments, each R 2 is that R D Independently together with the substituents, [ka] is.

[0100] In some embodiments, each R 2 are independently selected from those shown in Table 1 below.

[0101] In certain embodiments, each R 3 are independently -H.

[0102] In certain embodiments, each R 3 are independent, -C 1-6 aliphatic, or -phenyl, each of which is s R E or each R 3 are independently -CN, halogen, -OR, -SR, -NR, -S(O)R, -S(O)(NR), -S(O)NR, -S(O)R, -S(O)NR, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, or -N(R)S(O)R.

[0103] In certain embodiments, each R 3 are independently -H, -C 1-6 aliphatic, or -phenyl, each of which is s R E or each R 3 are independently -CN, halogen, -OR, -SR, -NR, -S(O)R, -S(O)(NR), -S(O)NR, -S(O)R, -S(O)NR, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, or -N(R)S(O)R.

[0104] In certain embodiments, each R 3 are independently -H, C 1-6 aliphatic, or -phenyl, each of which is s R E or each R 3 are independently -CN, halogen, -OR, -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)R, -N(R)C(O)OR, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)NR2, or -N(R)S(O)R.

[0105] In certain embodiments, each R 3 are independently -H, C 1-6 aliphatic, or -phenyl, each of which is s R E or each R 3 are independently -CN, halogen, -OR, -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)R, -N(R)C(O)OR, -N(R)C(O)NR2, or -N(R)C(NR)NR2.

[0106] In certain embodiments, each R 3 are independently -H, C 1-6 aliphatic, or -phenyl, each of which is s R E or each R 3 are independently —CN, halogen, —C(O)R, —C(O)OR, —C(O)NR, or —C(O)N(R)OR.

[0107] In certain embodiments, each R 3 are independently -H, -Me, -Et, or -phenyl, each of which is selected from s R E or each R 3 are independently —CN, halogen, or —C(O)OR.

[0108] In some embodiments, each R 3 are independently -H, -Me, -Et, -CN, -Br, [ka] is.

[0109] In some embodiments, each R 3 are independently selected from those shown in Table 1 below.

[0110] In some embodiments, R 4 is H.

[0111] In some embodiments, R 4 t R F Example of C being substituted 1-6 It is aliphatic.

[0112] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0113] In some embodiments, R C , R D , R E , and R F Each example independently represents 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 , R D , R E , and R F Each example of C 1-6an optionally substituted group selected from 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; 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 heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0114] In some embodiments, R C , R D , R E , and R F 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.

[0115] In some embodiments, R C , R D , R E , and R F 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; 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 a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms; 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 unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0116] In some embodiments, R C , R D , R E , and R F Each example is selected from those shown in Table 1 below.

[0117] As generally defined above, each R is independently hydrogen or C 1-6Aliphatic; phenyl; naphthalenyl; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0-10 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having from 1 to 3 heteroatoms; a 6- to 11-membered saturated or unsaturated bicyclic heterocyclic ring having from 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen, taken together with the nitrogen, form an optionally substituted 4- to 7-membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0118] In some embodiments, R is selected from those shown in Table 1 below.

[0119] As generally defined above, m is 1, 2, or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

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

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

[0122] In some embodiments, n is selected from those shown in Table 1 below.

[0123] 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.

[0124] In some embodiments, q is selected from those shown in Table 1 below.

[0125] 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.

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

[0127] 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.

[0128] In some embodiments, s is selected from those shown in Table 1 below.

[0129] As generally defined above, t is 0, 1, 2, 3, or 4. In some embodiments, t is 0. In some embodiments, t is 1, 2, 3, or 4. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4.

[0130] In some embodiments, t is selected from those shown in Table 1 below.

[0131] As generally defined above, u is 0, 1, 2, 3, or 4. In some embodiments, u is 0. In some embodiments, u is 1, 2, 3, or 4. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4.

[0132] In some embodiments, u is selected from those shown in Table 1 below.

[0133] In some embodiments, the present invention provides a compound of formula II, III, IV, V, VI, VII, VIII, IX, X, or XI: [Table 1] or a pharmaceutically acceptable salt thereof, wherein L, R 1 , R 2 , R 3 , R 4 , m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0134] In some embodiments, the present invention provides a compound of formula II-a, III-a, IV-a, Va, VI-a, VII-a, VIII-a, IX-a, Xa, or XI-a: [Table 2] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0135] In some embodiments, the present invention provides a compound of formula II-b, III-b, IV-b, Vb, VI-b, VII-b, VIII-b, IX-b, Xb, or XI-b: [Table 3]

[0136] or a pharmaceutically acceptable salt thereof, wherein L, R 1 , R 2 , R 3 , R 4 Each of, and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0137] In some embodiments, the present invention provides a compound of formula II-c, III-c, IV-c, Vc, VI-c, VII-c, VIII-c, IX-c, Xc, or XI-c, [Table 4] or a pharmaceutically acceptable salt thereof, wherein L, R 1 , R 2 , R 3 , R 4 Each of, and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0138] Exemplary compounds of the present invention are shown in Table 1 below. [Table 5-1] [Table 5-2] Table 5-3 Table 5-4 Table 5-5 Table 5-6 Table 5-7 Table 5-8 Table 5-9 Table 5-10 Table 5-11 Table 5-12 Table 5-13 Table 5-14 Table 5-15 Table 5-16 Table 5-17 Table 5-18 Table 5-19 Table 5-20 Table 5-21 Table 5-22 Table 5-23 Table 5-24 Table 5-25 Table 5-26 Table 5-27 Table 5-28 Table 5-29 Table 5-30 Table 5-31 Table 5-32 Table 5-33 Table 5-34 Table 5-35 Table 5-36 [Table 5-37] [Table 5-38] [Table 5-39] [Table 5-40] [Table 5-41] [Table 5-42] [Table 5-43]

[0139] In some embodiments, the present invention provides a compound shown in Table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound shown in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound shown in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0140] 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 as a medicament.

[0141] 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, in a method for enhancing an immune response as described herein in a subject in need thereof, and / or in a method for treating an HPK1-dependent disorder as described herein.

[0142] 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 for inhibiting HPK1, as described herein.

[0143] 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 for enhancing an immune response in a subject in need thereof, as described herein.

[0144] 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 for treating an HPK1-dependent disorder, as described herein.

[0145] 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.

[0146] In some embodiments, the present invention also provides the use of a compound of Formula I described herein or a pharmaceutical composition described herein for the manufacture of a medicament for inhibiting HPK1.

[0147] 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.

[0148] In some embodiments, the present invention also provides the use of a compound of formula I described herein or a pharmaceutical composition described herein for the manufacture of a medicament for treating an HPK1-dependent disorder.

[0149] 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 as described herein in a subject in need thereof, and / or in a method for treating an HPK1-dependent disorder as described herein.

[0150] 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 for inhibiting HPK1, as described herein.

[0151] 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 for enhancing an immune response in a subject in need thereof.

[0152] 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 for treating an HPK1-dependent disorder, as described herein.

[0153] As generally defined above, each hydrogen bonded to a carbon can be optionally and independently replaced by deuterium.

[0154] In some embodiments, a hydrogen bonded to a carbon is replaced by deuterium.

[0155] 4. General Methods of Providing Compounds of the Invention 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, and by methods detailed in the Examples herein.

[0156] 5. Use, Formulation, and Administration Pharmaceutically acceptable compositions 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 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 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.

[0157] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0158] 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 in which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present 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, salts or electrolytes such as 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.

[0159] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of this invention that is capable of providing, either directly or indirectly, a compound of this invention or an inhibitory active metabolite or residue thereof, upon administration to a recipient.

[0160] 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.

[0161] 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 its metabolic product. 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 acid 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, a pyranosidyl acid such as glucuronic acid or galacturonic acid, an alpha hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, or a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid. If the compound of the present invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, tertiary), alkali metal hydroxide, or alkaline earth metal hydroxide. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary amines, secondary amines, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0162] The compounds of the present invention may be in the form of a "prodrug," including 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 via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate esters), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl esters), acylamino lower alkyl esters (e.g., acetyloxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl esters), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Prodrugs that are converted to active forms in vivo through other mechanisms are also included. In an embodiment, the compounds of the present invention are prodrugs of any of the formulas herein.

[0163] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "oral" 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 the present 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 non-toxic parenterally acceptable diluents or solvents, for example, as solutions 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.

[0164] 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 versions, are useful for preparing injectables, 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 commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens®, Spans®, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0165] The pharmaceutically acceptable composition of the present 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, active ingredients are combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavorings or coloring agents can also be added.

[0166] Alternatively, the pharmaceutically acceptable compositions of the present invention may 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.

[0167] 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 gastrointestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0168] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0169] For topical application, the provided pharmaceutically acceptable compositions can be formulated in 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 petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated in 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.

[0170] 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, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment, such as petrolatum.

[0171] 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.

[0172] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0173] 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 on the host being treated and the particular mode of administration. Preferably, the provided compositions should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0174] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, excretion rate, 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 depend on the particular compound in the composition.

[0175] 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.

[0176] The compounds of the present disclosure find use in inhibiting the activity of the enzyme HPK1. 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.

[0177] In one embodiment, the presently disclosed subject matter is directed to a method of inhibiting HPK1, the method comprising contacting HPK1 with an effective amount of a compound of the invention or a pharmaceutical composition described herein.

[0178] In certain embodiments, the presently disclosed subject matter is directed to a method for enhancing an immune response in a subject in need thereof, the method 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 relative to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, T cell activation is characterized by an elevated frequency of γ-IFN+ CD8 T cells or enhanced levels of IL-2 or granzyme B production by the T cells relative to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the number of T cells is increased relative 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 relative 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, antigen-presenting cell maturation is characterized by an increased frequency of CD83+ dendritic cells. In certain aspects of this embodiment, antigen-presenting cell activation is characterized by elevated expression of CD80 and CD86 on dendritic cells.

[0179] Compounds of the present disclosure directly bind to and inhibit the kinase activity of HPK1, hi some embodiments, compounds of the present disclosure reduce, inhibit, or otherwise decrease HPK1-mediated phosphorylation of SLP76 and / or Gads.

[0180] The compounds of the present disclosure 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 compounds of the present disclosure specifically inhibit the serine / threonine kinase activity of HPK1. In some of these embodiments, the IC of the HPK1 antagonist for HPK1 50 The IC50 of HPK1 antagonists against other serine / threonine kinases or other types of kinases (e.g., tyrosine kinases) 50 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less.

[0181] The compounds of the present disclosure can be used in methods for inhibiting HPK1. Such methods include contacting HPK1 with an effective amount of a compound of the present disclosure. By "contacting" is intended bringing the compound within sufficient proximity of an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., a T cell, a B cell, a dendritic cell) so that the compound can bind to and inhibit the activity of HPK1. The compound can be contacted with HPK1 in vitro or in vivo via administration of the compound to a subject.

[0182] Any method known in the art for measuring the kinase activity of HPK1 may be used to determine whether HPK1 is inhibited, including in vitro kinase assays, immunoblots with antibodies specific for phosphorylated targets of HPK1 such as SLP76 and Gads, or measurement of 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 activation of T cells or B cells.

[0183] The compounds of the present disclosure can be used to treat HPK1-dependent disorders. As used herein, an "HPK1-dependent disorder" is a pathological condition in which HPK1 activity is required for the development or maintenance of the pathological condition. In some embodiments, the HPK1-dependent disorder is cancer.

[0184] The compounds of the present disclosure also find use in enhancing an immune response in a subject in need thereof. Such a method comprises administering an effective amount of a compound of the present invention.

[0185] As used herein, "enhancing an immune response" refers to any improvement in an immunogenic response to an antigen. Non-limiting examples of improved immunogenic responses 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 T cell (e.g., CD4 T cells, CD8 T cell) proliferation, enhanced B cell proliferation, increased survival of T cells and / or B cells, improved antigen presentation by antigen-presenting cells (e.g., dendritic cells), improved antigen clearance, increased cytokine production by T cells (e.g., interleukin-2), increased resistance to prostaglandin E2-induced immunosuppression, and / or increased priming and / or cytolytic activity of CD8 T cells.

[0186] In some embodiments, CD8 T cells in a subject have enhanced priming, activation, proliferation, and / or cytolytic activity relative to prior 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 elevated CD44 expression and / or enhanced cytolytic activity in CD8 T cells. In some embodiments, CD8 T cell activation is characterized by increased γ-IFN expression and / or increased cytolytic activity in CD8 T cells. + In some embodiments, the CD8 T cells are antigen-specific T cells.

[0187] In some embodiments, antigen-presenting cells in a subject have enhanced maturation and activation relative to before administration of a 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, maturation of antigen-presenting cells is enhanced by CD83 + In some embodiments, activation of antigen-presenting cells is characterized by increased frequency of dendritic cells. In some embodiments, activation of antigen-presenting cells is characterized by increased expression of CD80 and CD86 on dendritic cells.

[0188] In some embodiments, 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 relative to before administration of the compound of Formula I or Ia, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

[0189] TCR engagement leads to activation of HPK1, which functions as a negative regulator of the TCR-induced AP-1 response pathway. HPK1 is thought to negatively regulate T cell activation by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, thereby reducing the persistence of signaling microclusters. This leads to the recruitment of 14-3-3 proteins that bind to phosphorylated SLP76 and Gads, resulting in the release of 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).

[0190] In some embodiments, administration of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof, to a subject results in enhanced T cell function.

[0191] Thus, the disclosed compounds of the present invention or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof are useful in treating T cell dysfunction disorders. A "T cell dysfunction disorder" is a disorder or condition of T cells characterized by reduced responsiveness to antigenic stimulation. In certain embodiments, the T cell dysfunction disorder is a disorder specifically associated with increased kinase activity of HPK1. In another embodiment, the T cell dysfunction disorder is one in which T cells are anergic or have a reduced ability to secrete cytokines, proliferate, or achieve cytolytic activity. In certain aspects, the reduced responsiveness results in ineffective control of pathogens or tumors expressing immunogens. Examples of T cell dysfunction disorders characterized by T cell dysfunction include unresolved acute infections, chronic infections, and tumor immunity.

[0192] Thus, the compounds of the present disclosure can be used in the treatment of conditions where enhanced immunogenicity is desirable, such as increasing tumor immunogenicity for the treatment of cancer.

[0193] The term "dysfunction" in the context of immune dysfunction refers to a state of reduced immune responsiveness to antigenic stimulation. This term includes the general components of both exhaustion and / or anergy, in which antigen recognition can occur, but the subsequent immune response is ineffective in controlling infection or tumor growth.

[0194] As used herein, the term "dysfunctional" also refers to refractoriness or non-responsiveness to antigen recognition, specifically including 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.

[0195] The term "anergy" refers to the incomplete or insufficient signal delivered via the T cell receptor (e.g., intracellular Ca in the absence of ras activation). +2T cell anergy refers to a state of non-responsiveness to antigenic stimulation resulting from stimulation with 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 reversed by the presence of interleukin-2. Anergic T cells do not undergo clonal expansion and / or acquire effector function.

[0196] 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. It is distinguished from anergy in that it results from persistent signaling rather than incomplete or defective signaling. It is defined by insufficient effector function, persistent expression of inhibitory receptors, and a transcriptional state that differs from 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 endogenous negative regulatory (costimulatory) pathways (PD-1, B7-H3, B7-H4, etc.).

[0197] "Immunogenicity" refers to the ability of a particular substance to induce an immune response. Tumors are immunogenic, and enhancing tumor immunogenicity aids in the clearance of tumor cells by the immune response.

[0198] "Enhancing T cell function" means inducing, causing, or stimulating T cells to have sustained or amplified biological function, or to regenerate or reactivate exhausted or inactive T cells. Examples of enhancing T cell function include increased cytokine secretion (e.g., gamma-interferon, IL-2, IL-12, and TNFα), increased proliferation, increased antigen responsiveness to such levels prior to the intervention (e.g., viral, pathogen, or tumor clearance), and increased production of effector granules by CD8 T cells, such as granzyme B. 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.

[0199] "Tumor immunity" refers to the process by which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated and the tumor is recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.

[0200] The present disclosure provides methods for modulating (eg, inhibiting) HPKl activity, the methods comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0201] In one aspect, provided herein is a method for 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.

[0202] In the methods described herein, a compound of the present invention or a pharmaceutical composition thereof is administered to a subject with cancer.

[0203] In certain embodiments, the presently disclosed subject matter is directed to a method for treating an HPK1-dependent disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutical composition described herein. In certain aspects of these embodiments, the HPK1-dependent disorder is cancer. In certain aspects of these embodiments, 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 these embodiments, the cancer has an elevated level of T cell infiltration. In certain aspects of these embodiments, the cancer cells in the subject have elevated expression of MHC class I antigens, selectively relative to before administration of the compound or composition.

[0204] 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.

[0205] In certain aspects, the present invention provides methods for treating cell proliferative disorders, including cancer, benign papillomas, gestational trophoblastic disease, and benign neoplastic diseases such as cutaneous papillomas (warts) and genital papillomas.

[0206] In one aspect, the invention provides a method of treating a cell proliferative disorder in a subject, 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.

[0207] In certain embodiments, the cell proliferative disorder is cancer.

[0208] Examples of cancers that can be treated using the compounds of the present disclosure include 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, cancer of the fallopian tubes, cancer of the lining of the uterus, endometrial cancer, cancer of the cervix, cancer of the vagina, cancer of the vulva, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, acute myeloid leukemia, These include, but are not limited to, chronic or acute leukemias, including chronic myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia; solid tumors of childhood; lymphocytic lymphoma; cancer of the bladder; cancer of the kidney or urethra; cancer of the renal pelvis; neoplasms of the central nervous system (CNS); primary CNS lymphoma; tumor angiogenesis; spinal axis tumors; brain stem glioma; pituitary adenoma; Kaposi's sarcoma; epidermoid carcinoma; squamous cell carcinoma; T-cell lymphoma; environmentally induced cancers, including asbestos-induced cancers; and combinations of such cancers.

[0209] In some embodiments, cancers treatable using 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, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., leukemias such as lymphoma, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of such cancers.

[0210] 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, central chondrosarcoma, central and periosteal chondroma tumor, fibrosarcoma, and cholangiocarcinoma.

[0211] 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, digestive 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 duct carcinoma, and cancer of unknown primary origin (cancer in which metastases are found but the site of original cancer is unknown). In certain embodiments, the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient. In certain embodiments, the cancer is AIDS-related.

[0212] In further embodiments, the cancer is selected from brain cancer and spinal cord cancer. 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 ... In certain embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and supratentorial primitive neuroectodermal tumor (sPNET).

[0213] In certain embodiments, the cancer is selected from nasopharyngeal cancer, cancer of the nasal cavity and paranasal sinuses, hypopharyngeal cancer, oral cancer (e.g., squamous cell carcinoma, lymphoma, and sarcoma), lip cancer, oropharyngeal cancer, salivary gland tumors, cancer of the larynx (e.g., laryngeal squamous cell carcinoma, rhabdomyosarcoma), and cancer of the head and neck, including eye cancer. In certain embodiments, the eye cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.

[0214] In certain embodiments, the cancer is selected from leukemia and hematological cancer. In certain embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high-risk MDS or AML, blastic phase chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphocytic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms, including plasmacytoma and multiple myeloma. Leukemias referred to herein can be acute or chronic.

[0215] 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.

[0216] 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 can 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 cancers.

[0217] In certain embodiments, the cancer is selected from a cancer of the digestive 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 cancer including acinar cell carcinoma and ductal adenocarcinoma, gallbladder adenocarcinoma, colorectal adenocarcinoma, and anal squamous cell carcinoma.

[0218] In certain embodiments, the cancer is selected from liver cancer and cholangiocarcinoma. In certain embodiments, the cancer is liver cancer (hepatocellular carcinoma). In certain embodiments, the cancer is bile duct cancer (cholangiocarcinoma), and in exemplary of these embodiments, the cholangiocarcinoma is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

[0219] In certain embodiments, the cancer is selected from kidney cancer 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 urothelial carcinoma (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

[0220] 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.

[0221] 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.

[0222] In certain embodiments, the cancer is selected from the group consisting of malignant mesothelioma, epithelioid mesothelioma, and sarcomatoid.

[0223] In certain embodiments, the cancer is selected from a sarcoma, hi certain embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of the tendon sheath, and Kaposi's sarcoma.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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 tumor and malignant extragonadal germ cell tumor. In certain examples of these embodiments, the malignant extragonadal germ cell tumor is selected from the group consisting of nonseminoma and seminoma.

[0228] 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, rhabdomyoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0229] In certain embodiments, the cell proliferative disorder is selected from benign papilloma, benign neoplastic disease, and gestational trophoblastic disease. In certain embodiments, the benign neoplastic disease is selected from cutaneous papilloma (warts) and genital papilloma. In certain embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform mole and gestational trophoblastic neoplasms (e.g., invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor).

[0230] In some embodiments, the subject has melanoma. The melanoma can be at an early or late stage. In some embodiments, the subject has colon cancer. The colon cancer can be at an early or late stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer can be at an early or late stage. In some embodiments, the subject has pancreatic cancer. The pancreatic cancer can be at an early or late stage. In some embodiments, the subject has a hematological malignancy. The hematological malignancy can be at an early or late stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer can be at an early or late stage. In some embodiments, the subject has breast cancer. The breast cancer can be at an early or late stage. In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma can be at an early or late stage. In some embodiments, the cancer has elevated levels of T cell infiltration.

[0231] In some embodiments, cancers treatable with the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), kidney 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 resistant or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0232] In some embodiments, diseases and indications treatable using compounds of the present disclosure include hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0233] 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 syndromes (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.

[0234] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0235] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma.

[0236] Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0237] Exemplary genitourinary 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 tumor, fibroma, fibroadenoma, adenomatous tumor, lipoma).

[0238] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0239] 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 (cartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0240] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), cancers of the meninges (meningioma, meningeal sarcoma, gliomatosis), cancers of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and cancers of the spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Dacros disease.

[0241] Exemplary gynecological cancers include cancer of the uterus (endometrial carcinoma), cancer of the cervix (cervical carcinoma, preneoplastic cervical dysplasia), cancer of the ovaries (ovarian carcinoma (serous cystadenoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosathecocytoma, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), cancer of the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), cancer of the vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), and cancer of the fallopian tubes (carcinoma).

[0242] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, 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 cancer.

[0243] 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, thyroid cancer, and parathyroid cancer.

[0244] In some embodiments, HPK1 inhibitors can 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 several tumors, such as colon cancer, breast cancer, pancreatic cancer, and lung cancer, where it 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), as well as in blast cells from patients. CD73 is upregulated in various human carcinomas, including colon, lung, pancreatic, and ovarian carcinomas. Importantly, high CD73 expression levels are associated with tumor neovascularization, invasiveness, and metastasis, and shorter patient survival in breast cancer.

[0245] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases referenced herein, for example, for 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.

[0246] The compounds of the present disclosure can be administered in any suitable manner 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 implantation, by inhalation, intrathecally, intracerebroventricularly, intratumorally, or intranasally.

[0247] 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.

[0248] It will be understood that the appropriate dose of the active compound will depend on several factors within the knowledge of a physician or veterinarian of ordinary skill in the art. The dose of the active compound will vary depending on, for example, 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 drug combinations.

[0249] 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. Modifications in dosage may arise and become apparent from the results of diagnostic assays.

[0250] In some embodiments, the HPK1 antagonist is administered to a subject at a dose of about 0.001 μg / kg to 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.

[0251] In the methods described herein, the methods can further include administering a chemotherapeutic agent to the subject. In certain aspects of these embodiments, the chemotherapeutic agent is administered to the subject simultaneously with the compound or composition. In certain aspects of these embodiments, the chemotherapeutic agent is administered to the subject prior to administration of the compound or composition. In certain aspects of these embodiments, the chemotherapeutic agent is administered to the subject after administration of the compound or composition.

[0252] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, 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 a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay recurrence.

[0253] The term "administration" or "administering" includes routes of introducing a compound into a subject to perform its intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0254] The term "effective amount" includes an amount effective, at dosages and for periods of time 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 elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimal therapeutic response.

[0255] 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 so that it enters the patient's system and is therefore subject to metabolic and other similar processes.

[0256] 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, ameliorate, 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 may reduce the number of cancer cells, reduce tumor size, inhibit (i.e., slow to some extent, and preferably stop) cancer cell invasion into peripheral organs, inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with cancer. To the extent that the agent can prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0257] 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.

[0258] Combination therapy Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may 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."

[0259] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0260] Examples of drugs that may also be combined with the agents of the invention include, but are not limited to, treatments for Alzheimer's disease such as Aricept® and Excelon®; treatments for HIV such as ritonavir; treatments for Parkinson's disease such as L-DOPA / carbidopa, entacapone, lopinrol, pramipexole, bromocriptine, pergolide, trihexefendil, and amantadine; drugs for treating multiple sclerosis (MS) such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; drugs for treating schizophrenia such as Zyprexa, Risperdal, Seroquel, and haloperidol; corticosteroids, TNF blockers, IL-1 Anti-inflammatory drugs such as RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, antispasmodics, ion channel blockers, riluzole, and antiparkinsonian drugs; beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers drugs for treating cardiovascular disease, such as drugs and statins; drugs for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antivirals; drugs for treating blood disorders, such as corticosteroids, anti-leukemia drugs, and growth factors; drugs that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir); and drugs for treating immune deficiency disorders, such as gamma globulins.

[0261] 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.

[0262] These additional agents can be administered separately from the combination therapy provided as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compound of the present invention in a single composition. When administered as part of a multiple dose regimen, the two active agents can be administered simultaneously, sequentially, or within a certain period of each other, usually within 5 hours of each other.

[0263] As used herein, the terms "combination," "in combination," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a combination of the present invention may be administered with another therapeutic agent, either simultaneously or sequentially, in separate unit dosage forms or together in a single unit dosage form.

[0264] The amount of additional therapeutic agent present in the compositions of the invention is 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 ranges 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.

[0265] 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 may be administered together with the compound of Formula I, or may be administered 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 may 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 may 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.

[0266] 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, for example, nonsteroidal anti-inflammatory drugs (NSAIDS) such as acetaminophen, aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib; colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone; probenecid; allopurinol; febuxostat (Uloric®); Antimalarials such as sulfasalazine (Azulfidine®), hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), ®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), as well as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and adalimumab. "Anti-TNF" agents such as rilonacept (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), anti-Jak inhibitors such as canakinumab (Ilaris®) and tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), "anti-IL-6" agents such as tocilizumab (Actemra®), diclofenac, cortisone,Hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheal drugs such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), magnesium Shea milk, polyethylene glycol (MiraLax®), laxatives such as Dulcolax®, Correctol®, and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), beta-2 agonists such as terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), inhaled corticosteroids such as mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), methylxanthines such as Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline,IgE antibodies such as omalizumab (Xolair®), zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), )), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), amprenavir (Agenerase®), atazanavir (Azadafenib), and rivaroxaban (Renavir®). protease inhibitors such as fluprenavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), enfuvir entry inhibitors such as rivaroxaban (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination thereof.

[0267] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, the method comprising administering to a patient in need thereof a compound of Formula I and nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib; corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone; antimalarials such as sulfasalazine (Azulfidine®), hydroxychloroquine (Plaquenil®), and chloroquine (Aralen®); gold salts such as methotrexate (Rheumatrex®), gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®); D-penicillamine (Depen®) or Cuprimine®. Other drugs that are being used include: azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), as well as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pego (Petroleum®), and fluconazole (Ventilator®). and one or more additional therapeutic agents selected from "anti-TNF" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), "anti-T-cell" agents such as abatacept (Orencia®), and "anti-IL-6" agents such as tocilizumab (Actemra®).

[0268] In some embodiments, the present invention provides a method of treating osteoarthritis, the method comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, aspirin, ibuprofen, naproxen, etodolac (Lodine®), and nonsteroidal anti-inflammatory drugs (NSAIDS) such as celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® and Hyalgan®), and monoclonal antibodies such as tanezumab.

[0269] In some embodiments, the present invention provides methods of treating cutaneous lupus erythematosus or systemic lupus erythematosus, the methods comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDS) such as acetaminophen, aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib; corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone; antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®); cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0270] In some embodiments, the present invention provides methods of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, the methods comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from antidiarrheal agents such as mesalamine (Asacol®), sulfasalazine (Azulfidine®), diphenoxylate (Lomotil®), and loperamide (Imodium®), bile acid binding agents such as cholestyramine, laxatives such as alosetron (Lotronex®), lubiprostone (Amitiza®), milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®, and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapy, steroids, and antibiotics such as flagyl or ciprofloxacin.

[0271] In some embodiments, the present invention provides a method of treating asthma, the method comprising administering to a patient in need thereof a compound of Formula I and a beta-2 agonist such as Singulair®, albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Arpent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic agent such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), prednisone, prednisolone, beclomethasone dipropionate (Beclov®), or a steroid agent such as benzodiazepine (Benthiazol-3, benzodiazepine). and one or more additional therapeutic agents selected from inhaled corticosteroids such as ent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, methylxanthines such as cromolyn sodium (Intal®), theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0272] In some embodiments, the present invention provides methods of treating COPD, comprising administering to a patient in need thereof a compound of Formula I and a beta-2 agonist such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Arpent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), theophylline (Theo-Dur (R), Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and methylxanthines such as aminophylline; prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0273] In another embodiment, the invention provides a method of treating a hematological malignancy, the method comprising administering to a patient in need thereof the 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.

[0274] In another embodiment, the invention provides a method of treating a solid tumor, the method 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.

[0275] In another embodiment, the invention provides a method of treating a hematological malignancy, the method 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).

[0276] In another embodiment, the invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), the method comprising administering to a patient in need thereof the 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.

[0277] In another embodiment, the invention provides a method of treating multiple myeloma, the method comprising administering to a patient in need thereof the compound of formula I and one or more additional therapeutic agents selected from 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 bortezomib (Velcade®), and lenalidomide (Revlimid®).

[0278] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, the method 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 disease (chronic thyroiditis), Ord's thyroiditis (Ord's thyroiditis), and inflammatory bowel disease (inflammatory bowel disease). thyroiditis), Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, 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, dysautonomia, membranous glomerulonephritis, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV) ), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, dust mites, or cockroach umbrellas), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplants Unilateral rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, gastroenteritis, epicondylitis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, 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 such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasma cell myeloma, Cancers that may be present include, but are not limited to, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behcet's disease, rheumatoid arthritis ... Bone and joint diseases including Egren'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 surgery, restenosis after aortocoronary artery bypass surgery, stroke, transient cerebral ischemia, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis), pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies , Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's syndrome, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyendocrine disease (also known as autoimmune polyendocrine 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,Selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's disease (chronic thyroiditis), atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0279] In another embodiment, the invention provides a method of treating or lessening the severity of a disease, the method 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.

[0280] In another embodiment, the invention provides a method of treating or lessening the severity of a disease, the method 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, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, or gastrointestinal cancer, particularly colon cancer or colorectal adenoma or head Diseases including cervical tumors, epidermal hyperproliferation, psoriasis, benign prostatic hyperplasia, neoplasia, neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (Hodgkin's lymphoma, or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dacros disease, and Banayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is abnormally activated, intrinsic (non-allergic) asthma, and extrinsic Asthma of any type or genesis, including acute, arachidonic, catarrhal, croupy, chronic, or allergic (allergic) asthma, both mild asthma, moderate asthma, severe asthma, bronchial 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, airway or lung disease (COPD, COAD, or COLD), including chronic bronchitis or related dyspnea, emphysema, and exacerbations of airway hyperresponsiveness as a result of other medications, especially other inhaled medications. Bronchitis of any kind or genesis, including but not limited to tuberculous bronchitis, pneumoconiosis of any kind or genesis (an inflammatory, generally occupational, lung disease, whether acute or chronic, often complicated by airway obstruction and caused by repeated dust inhalation) (including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tobacco disease, and byssinosis), Loeffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis,Polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, and drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, eosinophil-related disorders affecting the airways caused by conjunctivitis, keratoconjunctivitis sicca, and vernal keratoconjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases in which an autoimmune response is involved or has an autoimmune component or etiology (autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia) keratoconjunctivitis, cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, 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 (pre- and post-operative), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and glomerulonephritis (with or without nephrotic syndrome (e.g., idiopathic nephrotic syndrome or minimal change nephropathy)). The therapeutic agent is selected from neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia, including cerebrovascular disease (including cerebrovascular accidents), 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, and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.

[0281] In some embodiments, the invention provides a method of treating or reducing the severity of a disease, the method 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 lymphoma, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0282] In some embodiments, the invention provides methods of treating or reducing the severity of a disease, the methods comprising administering to a patient in need thereof an HPK1 binding compound. 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 HPK1 binding compound is a compound of Formula I.

[0283] The compounds and compositions according to the methods of the present invention may be administered in any amount and using any route of administration effective to treat or reduce the severity of an autoimmune, inflammatory, proliferative, endocrine, neurological, or transplant-related disorder. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, the severity of the infection, the particular drug, its mode of administration, and the like. The compounds of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete pharmaceutical unit appropriate for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder and severity of the disorder being treated, the activity of the particular compound employed, the particular composition employed, the patient's age, weight, general health, sex, and diet, the time, route of administration, and excretion rate of the particular compound employed, the duration of treatment, drugs used in combination with or concurrently with the particular compound employed, and similar factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0284] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intravesically, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally, one or more times daily, at dosage levels of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg, of the subject's body weight per day to achieve the desired therapeutic effect.

[0285] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, 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 / or 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, sweeteners, flavoring agents, and fragrances.

[0286] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can 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 can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0287] Injectable preparations can be sterilized, 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 sterile injectable medium before use.

[0288] In order 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 rate of dissolution, which may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. 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.

[0289] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the 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.

[0290] 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 retardants 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 forms may also comprise buffering agents.

[0291] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. 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 formulation art. They may optionally contain opacifying agents and can be of a composition that releases the active ingredient 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 in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0292] The active compound may also be in microencapsulated form with one or more excipients, as 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. Such dosage forms may also contain, as is common practice, 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 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.

[0293] Dosage forms for topical or transdermal administration of the compounds of the present 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, if required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present 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 dispensing 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.

[0294] According to one embodiment, the present invention relates to a method of inhibiting protein kinase activity in a biological sample, the method comprising the step of contacting said biological sample with a compound of the present invention, or a composition comprising said compound.

[0295] 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, the method comprising contacting the biological sample with a compound of the present invention, or a composition comprising the compound. In certain embodiments, the present invention relates to a method for irreversibly inhibiting HPK1 or a mutant thereof, activity in a biological sample comprising contacting the biological sample with a compound of the present invention, or a composition comprising the compound.

[0296] In another embodiment, the present invention provides a method for selectively inhibiting HPK1 over one or more kinases.

[0297] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies obtained from mammals or extracts thereof, as well as blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0298] Inhibition of HPK1 (or variants thereof) activity in a biological sample is useful for a variety of purposes known to those of skill in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0299] 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 invention or a composition comprising said compound.

[0300] According to another embodiment, the present invention relates to a method for inhibiting the activity of HPK1 or a mutant thereof in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising the compound. According to certain embodiments, the present invention relates to a method for reversibly or irreversibly inhibiting HPK1 or one or more mutants thereof in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising the 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, the method 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.

[0301] Depending on 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."

[0302] The compounds of the invention may also be used to advantage in combination with other therapeutic compounds, hi some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include 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; antineoplastic antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and further antiangiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptidase 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, reduce or inhibit the activity of Flt-3; Conforma Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Therapeutics; kinesin spindle protein inhibitors such as temozolomide (Temodal®); SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and leucovorin. The term "aromatase inhibitor", as used herein, relates to compounds which inhibit estrogen production, eg the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.The 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 sold under the trade name Aromasin™. Formestane is sold under the trade name Lentaron™. Fadrozole is sold under the trade name Afema™. Anastrozole is sold under the trade name Arimidex™. Letrozole is sold under the trade name Femara™ or Femar™. Aminoglutethimide is sold under the trade name Orimeten™. Combinations of the present invention containing a chemotherapeutic agent that is an aromatase inhibitor are particularly useful in the treatment of hormone receptor-positive tumors, such as breast tumors.

[0303] As used herein, the term "anti-estrogen" 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 sold under the trade name Nolvadex™. Raloxifene hydrochloride is sold 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 anti-estrogen, is particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0304] As used herein, the term "antiandrogen" refers to any substance capable of inhibiting the biological effects of androgen hormones, including, but not limited to, bicalutamide (Casodex™). As used herein, the term "gonadorelin agonist" includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0305] As used herein, the term "topoisomerase I inhibitor" 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 in the form as it is marketed, for example, under the trademark Camptosar™. Topotecan is sold under the trade name Hycamptin™.

[0306] As used herein, the term "topoisomerase II inhibitors" includes, but is not limited to, doxorubicin (including liposomal formulations such as Caelyx™), anthracyclines such as daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraponones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name Etopophos™. Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name Acriblastin™ or Adriamycin™. Epirubicin is sold under the trade name Farmorubicin™. Idarubicin is sold under the trade name Zavedos™. Mitoxantrone is sold under the trade name Novantron.

[0307] The term "microtubule active agent" refers to microtubule stabilizing, 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 epothilones and their derivatives. Paclitaxel is sold under the trade name Taxol™. Docetaxel is sold under the trade name Taxotere™. Vinblastine sulfate is sold under the trade name Vinblastin RP™. Vincristine sulfate is sold under the trade name Farmistin™.

[0308] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosoureas (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin™. Ifosfamide is sold under the trade name Holoxan™.

[0309] 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).

[0310] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, DNA demethylating compounds such as capecitabine, gemcitabine, 5-azacytidine, and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is sold under the trade name Xeloda™. Gemcitabine is sold under the trade name Gemzar™.

[0311] As used herein, the term "platinum compounds" includes, but is not limited to, carboplatin, cis-platin, cisplatinum, and oxaliplatin. Carboplatin can be administered in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0312] The term "compounds which target / reduce protein or lipid kinase activity, or protein or lipid phosphatase activity; or further anti-angiogenic compounds" refers to a) compounds which target, reduce or inhibit the activity of PDGFR, in particular compounds which inhibit PDGF receptors, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib, SU101, SU6668, and GFB-111, which target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFR), b) compounds which target, reduce or inhibit the activity of PDGFR, in particular compounds which inhibit PDGF receptors, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib, SU101, SU6668, and GFB-111, c) compounds which target, reduce or inhibit the activity of PDGFR, such as fibroblast growth factor receptors (GFAP), c) compounds that target, reduce or inhibit the activity of IGF-IR, in particular compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor 1 (IGF-IR), such as 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 which target, decrease or inhibit the activity of the AxI receptor tyrosine kinase family, f) compounds which target, decrease or inhibit the activity of the Ret receptor tyrosine kinase, g) compounds which target, decrease or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, e.g., imatinib, h) compounds which target, decrease or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, e.g., compounds which target the activity of the c-Kit receptor tyrosine kinase family. 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, for example compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, for example N-phenyl-2-pyrimidine-amine derivatives, for example imatinib or nilotinib (AMN107); PD180970;AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825), j) compounds that target, decrease, or inhibit the activity of members of the protein kinase C (PKC) and Raf family 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) (including staurosporine derivatives such as midostaurin) (further examples of compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; irmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors)), k) compounds which target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, for example protein tyrosine kinase inhibitors (imatinib mesylate (Gleevec™) or tyrphostins, for example 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;l) compounds which target, decrease or inhibit the activity of epidermal growth factor family receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and variants thereof, for example, compounds which inhibit members of the EGF receptor tyrosine kinase family, such as, in particular, EGF receptor, ErbB2, ErbB3, and ErbB4, or EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180;compounds that target, decrease, or inhibit the activity of the epidermal growth factor receptor family, such as 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 compounds, proteins, or antibodies that bind to 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, decrease, or inhibit the activity of the epidermal growth factor receptor family, such as 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; n) one of the following compounds: a compound that targets, decreases, or inhibits the activity of the c-Met receptor, in particular a compound that inhibits the kinase activity of the c-Met receptor, or an antibody that targets the extracellular domain of c-Met or binds to HGF; n) one of the following compounds: PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds that target, decrease, or inhibit the kinase activity of the above JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK); o) compounds that target, decrease, or inhibit the kinase activity of PI3 kinase (PI3K) kinases, 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; q) protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as compounds that target, decrease or inhibit the activity of phosphodiesterases, 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 (salidegib);

[0313] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to, PI3K α, PI3K γ, PI3K δ, PI3K β, 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 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.

[0314] As used herein, the term "BTK inhibitor" 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.

[0315] As used herein, the term "SYK inhibitor" 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.

[0316] As used herein, the term "Bcl-2 inhibitor" includes but is not limited to ABT-199, ABT-731, ABT-737, apogossypol, the pan-Bcl-2 inhibitors of Ascenta, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof, see WO2008 / 118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004 / 106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Examples of compounds that have inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to, cefotaxime (C271), ...

[0317] Further examples of BTK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2008 / 039218 and WO2011 / 090760, which are incorporated herein by reference in their entireties.

[0318] Further examples of SYK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2003 / 063794, WO2005 / 007623, and WO2006 / 078846, which are incorporated herein by reference in their entireties.

[0319] Further examples of PI3K inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2004 / 019973, WO2004 / 089925, WO2007 / 016176, US8138347, WO2002 / 088112, WO2007 / 084786, WO2007 / 129161, WO2006 / 122806, WO2005 / 113554, and WO2007 / 044729, which are incorporated herein by reference in their entireties.

[0320] Further examples of JAK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2009 / 114512, WO2008 / 109943, WO2007 / 053452, WO2000 / 142246, and WO2007 / 070514, which are incorporated herein by reference in their entireties.

[0321] Additional anti-angiogenic compounds include, for example, compounds that have another mechanism for their activity not related to protein or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0322] Examples of proteasome inhibitors useful 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.

[0323] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are eg inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0324] 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.

[0325] As used herein, the term cyclooxygenase inhibitors 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.

[0326] As used herein, the term "bisphosphonate" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridronic acid is sold under the trade name Didronel™. Clodronic acid is sold under the trade name Bonefos™. Tiludronic acid is sold under the trade name Skelid™. Pamidronic acid is sold under the trade name Aredia™. Alendronic acid is sold under the trade name Fosamax™. Ibandronic acid is sold under the trade name Bondranat™. Risedronic acid is sold under the trade name Actonel™. Zoledronic acid is sold 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.

[0327] As used herein, the term "heparanase inhibitor" refers to a compound that targets, decreases, or inhibits heparin sulfate degradation. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or interferon.

[0328] As used herein, the term "inhibitors of Ras oncogenic isoforms," ​​such as H-Ras, K-Ras, or N-Ras, refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras, e.g., "farnesyltransferase inhibitors," such as L-744832, DK8G557, or R115777 (Zarnestra™). As used herein, the term "telomerase inhibitors" refers to compounds that target, reduce, or inhibit the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are, in particular, compounds that inhibit the telomerase receptor, such as telomestatin.

[0329] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. Compounds that target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[0330] As used herein, the term "proteasome inhibitor" refers to a compound that targets, decreases, or inhibits the activity of the proteasome. Compounds that target, decrease, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN 341.

[0331] As used herein, the term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as 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.

[0332] As used herein, the term "compounds used in the treatment of hematological malignancies" 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-arabinofuranosylcytosine (ara-c), and bisulfan; ALK inhibitors, which are compounds that target, decrease, or inhibit anaplastic lymphoma kinase; and Bcl-2 inhibitors.

[0333] Compounds that target, decrease or inhibit the activity of the FLT-3R-like tyrosine kinase receptor 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.

[0334] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90, such as degrading, targeting, reducing, or inhibiting 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.

[0335] As used herein, the term "antiproliferative antibody" 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.

[0336] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapy, particularly in combination with therapy used to treat AML. In particular, the compounds of the present invention can be administered in combination with farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, and PKC412. In some embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutation, the method comprising administering a compound of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), a staurosporine derivative (e.g., midostaurin or lestaurtinib), sorafenib, tandutinib, 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, lestaurin, sorafenib, and sunitinib.

[0337] Other anti-leukemic compounds include, for example, deoxycytidine 2’These include Ara-C, a pyrimidine analogue that is an alpha-hydroxyribose (arabinoside) derivative. Also included are purine analogues of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, decrease 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 (formerly FR901228), trichostatin A, and compounds disclosed in US Pat. No. 6,552,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxy){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly the lactate salt. As used herein, somatostatin receptor antagonists refer to compounds that target, treat, or inhibit somatostatin receptors and SOM230, such as octreotide. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and below means ionizing radiation that occurs either as electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy and is known in the art. Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).

[0338] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to a pyrimidine or purine nucleoside analog, 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. Ribonucleotide reductase inhibitors are, in particular, hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0339] Also included are, inter alia, those compounds, proteins, or monoclonal antibodies of VEGF, such as 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, such as rhuMAb and RHUFab, VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610), and bevacizumab (Avastin™).

[0340] As used herein, photodynamic therapy refers to therapy that uses 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.

[0341] As used herein, angiogenic antisteroids 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.

[0342] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[0343] 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.

[0344] 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, bronchodilatory, or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airway diseases such as those described above, for example, as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosing or potential side effects of such drugs. The compounds of the present invention can be mixed with the other drug substances in a fixed pharmaceutical composition, or they can 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 described above with anti-inflammatory, bronchodilatory, antihistamine, or antitussive drug substances, wherein the compounds of the present invention and the drug substances are in the same or different pharmaceutical compositions.

[0345] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate; nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allofilin (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 ardenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and, in particular, formoterol and its pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts, and CHF 4226 (Chiesi), and glycopyrrolate.

[0346] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and tefenadine.

[0347] Another useful combination of compounds of the invention with anti-inflammatory agents is with antagonists of chemokine receptors, e.g., 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, particularly CCR-5 antagonists such as the 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).

[0348] The structures of active compounds identified by code number, generic name or trade name can be obtained from the actual edition or database of the standard compendium "The Merck Index", for example from Patents International (e.g. IMS World Publications).

[0349] The compounds of the present invention may 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.

[0350] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy takes the form of a fixed combination, or the administration of the compounds of the present invention and one or more other therapeutic compounds that are given alternately or independently, or the combined administration of a fixed combination and one or more other therapeutic compounds.The compounds of the present invention can also be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor therapy, or in addition.Long-term therapy is possible in the context of other treatment strategies, as described above, as well as adjuvant therapy.Other possible treatments are therapy to maintain the patient's condition after tumor regression, or further, for example, chemoprevention therapy in at-risk patients.

[0351] These additional agents can be administered separately from the composition containing the compound of the present 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 the present invention in a single composition. When administered as part of a multiple dose regimen, the two active agents can be administered simultaneously, sequentially, or within a certain period of each other, usually within 5 hours of each other.

[0352] As used herein, the terms "combination," "in combination," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the invention. For example, a compound of the invention may be administered with another therapeutic agent, either simultaneously or sequentially, in separate unit dosage forms or together in a single unit dosage form. Thus, the invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0353] The amounts of both the compounds of the present invention and additional therapeutic agents (in compositions containing additional therapeutic agents described above) 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 the present invention should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the compounds of the present invention can be administered.

[0354] In compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Thus, the amount of additional therapeutic agent in such compositions will be less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of 0.01 to 1,000 μg / kg body weight / day of the additional therapeutic agent can be administered.

[0355] The amount of additional therapeutic agent present in the compositions of the invention is 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 ranges 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.

[0356] The compounds of the present invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, artificial blood vessels, stents, and catheters. For example, vascular stents have been 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 thrombus formation or platelet activation. These undesirable 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 the present invention is another embodiment of the present invention. [Example]

[0357] Example 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, the following general methods, and other methods known to those of skill in the art, can be applied to all compounds as described herein and to each subclass and species of these compounds. Additional compounds of the invention have been prepared by methods substantially similar to those described herein in the examples and methods known to those of skill in the art.

[0358] Preparation of intermediates Method CA1 - Preparation of 2-(6-aminopyridin-3-yl)-N-ethyl-2-methylpropanamide (CA1) [ka] Step 1: Ethyl 2-methyl-2-(6-nitropyridin-3-yl)propanoate (CA1.1) A solution of ethyl 2-(6-nitropyridin-3-yl)acetate (CA1.0) (980 mg, 4.6 mmol) in DMF (20 mL) at 0 °C was treated with sodium hydride (60% dispersion in mineral oil, 196 mg, 4.8 mmol). The mixture was stirred for 5 minutes, and then iodomethane (0.316 mL, 5.0 mmol) was added dropwise. After an additional 2 hours, an additional portion of sodium hydride (60% dispersion in mineral oil, 196 mg, 4.8 mmol) was added, followed by iodomethane (0.316 mL, 5.0 mmol) 5 minutes later. The mixture was stirred at room temperature for 18 hours, quenched with water (30 mL), and extracted into EtOAc (2 × 30 mL). The combined extracts were washed with brine (30 mL), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (0-50% gradient elution, EtOAc in cyclohexane) to afford the title compound (CA1.1) (758 mg, 68%) as a yellow oil. 1H NMR(400MHz,CDCl3):δ 8.63(s,1H),8.22(d,J=8.4Hz,1H),7.99(d,J=8.2Hz,1H),4.16(q,J=7.2Hz,2H),1.67(s,6H),1.20(t,J=7.2Hz,3H)

[0359] Step 2: 2-Methyl-2-(6-nitropyridin-3-yl)propanoic acid (CA1.2) A solution of ethyl 2-methyl-2-(6-nitropyridin-3-yl)propanoate (CA1.1) (750 mg, 3.1 mmol) in methanol-water (14 mL, 1:1) was treated with lithium hydroxide monohydrate (198 mg, 4.7 mmol), and the mixture was stirred at room temperature overnight. The pH was adjusted to approximately 5 using 1 M aqueous HCl, and the mixture was extracted with 9:1 DCM-MeOH (3 × 25 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated in vacuo to give the title compound (CA1.2) (423 mg, 63%) as a crude off-white solid. 1 H NMR (400MHz, DMSO): δ 12.87(s,1H),8.67(d,J=1.8Hz,1H),8.28(d,J=8.6Hz,1H),8.19(dd,J=2.4,8.5Hz,1H),1.59(s,6H).

[0360] Step 3: N-Ethyl-2-methyl-2-(6-nitropyridin-3-yl)propenamide (CA1.3) To a suspension of 2-methyl-2-(6-nitropyridin-3-yl)propanoic acid (CA1.2) (430 mg, 2.0 mmol) in THF (5 mL) was added 1-hydroxybenzotriazole (359 mg, 2.6 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (510 mg, 2.6 mmol). The mixture was stirred at room temperature for 10 minutes. DIPEA (1.069 mL, 6.1 mmol) and ethylamine (2 M solution in THF, 2.04 mL, 4.0 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction was diluted with EtOAc (20 mL), and the organic phase was washed with water (15 mL) and brine (15 mL). The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by column chromatography (0-100% gradient elution, EtOAc in cyclohexane) to afford the title compound (CA1.3) (375 mg, 77%) as a pale yellow oil. 1 H NMR(400MHz,DMSO):δ 8.58(d,J=2.0Hz,1H),8.27(d,J=7.8Hz,1H),8.10(dd,J=2.4,8.5Hz,1H),7.60(d d,J=6.2,6.2Hz,1H),3.11-3.03(m,2H),1.53(s,6H),0.97(dd,J=7.2,7.2Hz,3H).

[0361] Step 4: 2-(6-aminopyridin-3-yl)-N-ethyl-2-methylpropanamide (CA1) To N-ethyl-2-methyl-2-(6-nitropyridin-3-yl)propenamide (CA1.3) (375 mg, 1.5 mmol) dissolved in methanol (5 mL) was added 10% palladium on carbon (35 mg). After hydrogenation under a hydrogen atmosphere overnight, the mixture was filtered through Celite and the solvent was removed in vacuo to give the title compound (CA1) (320 mg, 96%) as a pale yellow oil, which was used without further purification. 1H NMR(400MHz,DMSO):δ 7.83(d,J=2.0Hz,1H),7.26(dd,J=2.5,8.6Hz,2H),6.38(d,J=8.1Hz,1H),5.74(s,2H),3.05-3.01(m,2H),1.36(s,6H),0.93(t,J=7.0Hz,3H).

[0362] Method CA2 - Preparation of 2-(6-aminopyridin-3-yl)-N-ethyl-N,2-dimethylpropanamide (CA2) [ka] Intermediate CA2 was synthesized according to Method CA1 but using N-methylethanamine in step 3. The crude product was used without further purification or characterization.

[0363] Method CA3 - Preparation of 5-(3-(2-methoxyethoxy)azetidin-1-yl)pyridin-2-amine (CA3) [ka] Intermediate CA3 was prepared according to the method described in WO2015 / 131080, but using 3-(2-methoxyethoxy)azetidine. 1 H NMR (400 MHz, CDCl) d 7.40 (d, J = 2.3 Hz, 1H), 6.74 (dd, J = 3.0, 8.6 Hz, 1H), 6.47-6.43 (m, 1H), 4.50-4.42 (m, 1H), 4.11-4.01 (m, 2H), 3.65 (t, J = 6.3 Hz, 2H), 3.60-3.54 (m, 4H), 3.40-3.38 (m, 3H). No exchangeable protons were observed at 2H.

[0364] Method PA1 - Preparation of 1-(6-aminopyridin-3-yl)piperidin-4-ol (PA1) [ka] Step 1. 5-(3,4-Dihydro-2H-pyran-5-yl)-2-nitropyridine (PA1.1) To a stirred solution of 3,4-dihydro-2H-pyran-5-ylboronic acid, pinacol ester (0.217 g, 1.06 mmol, 1.0 equiv.) in THF (4.5 mL) and water (0.5 mL), 5-bromo-2-nitropyridine (0.336 g, 1.60 mmol, 1.5 equiv.), S-phos (0.043 g, 0.106 mmol, 0.1 equiv.), and potassium phosphate (0.680 g, 3.206 mmol, 3.0 equiv.) were added. After degassing under an argon atmosphere for 5 minutes, palladium acetate (0.011 g, 0.053 mmol, 0.05 equiv.) was added, and the reaction mixture was degassed again under an argon atmosphere for 10 minutes. After stirring at 60 °C for 1 hour, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine solution (25 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 19% ethyl acetate in n-hexane to give pure PA1.1 (0.140 g, 63.51%). MS (ES): m / z 206.20 [M+H] + .

[0365] Step 2. 1-(6-aminopyridin-3-yl)piperidin-4-ol (PA1) To a suspension of palladium hydroxide (0.03 g) in methanol (3 mL) was added a solution of 5-(3,4-dihydro-2H-pyran-5-yl)-2-nitropyridine (PA1.1) (0.140 g, 0.678 mmol, 1.0 equiv.) in methanol (3 mL) under a nitrogen atmosphere. Hydrogen gas was bubbled through the reaction mixture for 1 hour. After completion of the reaction, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure to give pure PA1 (0.095 g, 78.45%). MS (ES): m / z 178.24 [M+H] +,1H NMR(400MHz,DMSO-d6)δ 7.77(s,1H),7.28-7.25(dd,J=2Hz,8.4Hz,1H),6.37(d,J=8.4,1H),5.72(s,2H),3.94(s,2H) ),3.84(d,12.4Hz,1H),3.72(d,J=8.4Hz,1H),3.2(t,J=11.4,1H),1.82(s,1H),1.62(s,3H).

[0366] Method PA2 - Preparation of 5-(2-methyltetrahydro-2H-pyran-2-yl)pyridin-2-amine (PA2) [ka] Step 1. 2-(6-chloropyridin-3-yl)pent-4-en-2-ol (PA2.1) To a stirred solution of 1-(6-chloropyridin-3-yl)ethan-1-one PA2.0 (1.2 g, 7.71 mmol, 1.0 equiv.) dissolved in THF (12 mL) and cooled to -78 °C, allylmagnesium bromide (in ether) (11.56 mL, 11.56 mmol, 1.5 equiv.) was added. After stirring at -78 °C for 30 min, the reaction mixture was quenched with water (50 mL) and ammonium chloride solution (10 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. The residue was purified by column chromatography eluting with 15% ethyl acetate in n-hexane to give pure PA2.1 (1.31 g, 85.93%). MS (ES): m / z 197.66 [M+H]+.

[0367] Step 2. 5-(2-(allyloxy)pent-4-en-2-yl)-2-chloropyridine (PA2.2) To a stirred solution of 2-(6-chloropyridin-3-yl)pent-4-en-2-ol PA2.1 (1.31 g, 6.6 mmol, 1.0 equiv.) dissolved in THF (5 mL) at 0 °C, sodium hydride (0.792 g, 19.8 mmol, 3.0 equiv.) was added. After stirring at 0 °C for 10 minutes, allyl bromide (2.0 g, 16.5 mmol, 2.5 equiv.) was slowly added to the reaction mixture. After stirring at 0 °C for 15 minutes, the reaction mixture was heated to reflux for 6 hours. After completion of the reaction, the reaction mixture was quenched with cold 0.5 N hydrochloric acid solution (100 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. The residue was purified by column chromatography eluting with 8% ethyl acetate in n-hexane to give pure PA2.2 (1.05 g, 66.64%). MS (ES): m / z 237.73 [M+H] + .

[0368] Step 3. 2-Chloro-5-(2-methyl-3,6-dihydro-2H-pyran-2-yl)pyridine (PA2.3) To a stirred solution of 5-(2-(allyloxy)pent-4-en-2-yl)-2-chloropyridine PA2.2 (0.5 g, 2.1 mmol, 1.0 equiv.) in DCM (5 mL) was added Grubbs' catalyst (0.021 g, 0.025 mmol, 0.012 equiv.). After stirring at room temperature for 45 min, the solvent was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 15% ethyl acetate in n-hexane to give pure PA2.3 (0.4 g, 90.70%). MS (ES): m / z 209.67 [M+H] + .

[0369] Step 4. 2-Chloro-5-(2-methyl-3,6-dihydro-2H-pyran-2-yl)pyridine (PA2.4) To a stirred solution of 2-chloro-5-(2-methyl-3,6-dihydro-2H-pyran-2-yl)pyridine (0.4 g, 1.9 mmol, 1.0 equiv.), tris(dibenzylideneaceto)dipalladium(0) (0.174 g, 0.19 mmol, 0.1 equiv.), and (2-biphenyl)dicyclohexylphosphine (0.134 g, 0.38 mmol, 0.2 equiv.) in 1,4-dioxane (5 mL) that had been degassed with argon for 30 minutes, lithium hexamethyldisilazide (5.7 mL, 5.7 mmol, 3.0 equiv.) was added. After heating at 70 °C for 3 hours, the reaction mixture was poured into 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. The residue was purified by column chromatography eluting with 2.5% methanol in DCM to give pure PA2.4 (0.255 g, 70.26%). MS (ES): m / z 190.25 [M+H] + .

[0370] Step 5. 5-(2-Methyltetrahydro-2H-pyran-2-yl)pyridin-2-amine (PA2) To a suspension of 10% Pd / C (0.050 g) in methanol (3 mL) was added a solution of 2-chloro-5-(2-methyl-3,6-dihydro-2H-pyran-2-yl)pyridine PA2.4 (0.250 g, 1.3 mmol, 1.0 equiv.) in methanol (3 mL). H2 (gas) was bubbled through the reaction mixture for 1 h. After completion of the reaction, the reaction mixture was filtered through Celite and washed with methanol (30 ml). The filtrate was concentrated under reduced pressure to give pure PA2 (0.220 g, 54.42%). MS (ES): m / z 192.26 [M+H] + , LCMS purity: 97.40%, HPLC purity: 96.52%.

[0371] Method PA4 - Preparation of tert-butyl 3-(6-aminopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (PA4) [ka] Step 1. tert-Butyl 3-(6-nitropyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (PA4.1) To a solution of 5-bromo-2-nitropyridine (1.1 g, 5.42 mmol, 1.0 equiv.) in 1,4-dioxane (10 mL), degassed with nitrogen for 10 min, tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.18 g, 5.96 mmol, 1.1 equiv.) and potassium carbonate (2.24 g, 16.26 mmol, 3.0 equiv.) were added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.62 g, 1.08 mmol, 0.2 equiv.) and tris(dibenzylideneaceto)dipalladium (0.49 g, 0.542 mmol, 0.1 equiv.). After stirring at 120 °C for 5 h, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine solution (50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified using combi-flash silica eluting with 7% methanol / DCM to give the material as tert-butyl 3-(6-nitropyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate PA4.1 (1 g, 57.03% yield). MS (ES): m / z 321.35 [M+H]+ .

[0372] Step 2. tert-Butyl 3-(6-aminopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (PA4) To a suspension of 10% Pd / C (0.050 g) in methanol (3 mL) was added a solution of tert-butyl 3-(6-nitropyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (0.850 g, 2.65 mmol, 1.0 equiv.) in methanol (3 mL). After bubbling hydrogen gas through the solution for 1 h, the reaction mixture was filtered through Celite, which was washed with MeOH. The filtrate was concentrated under reduced pressure to give crude PA4 (0.900 g, 55.16%). MS (ES): m / z 291.37 [M+H]+.

[0373] Method PA9 - Preparation of tert-butyl 3-(6-aminopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (PA9) [ka] Step 1. 6-Fluoro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (PA9.1) To a solution of 6-fluoro-3,4-dihydroisoquinolin-1(2H)-one PA9.0 (2.5 g, 15.13 mmol, 1.0 equiv.) in dry THF (130 mL) at 0 °C was added sodium hydride (60% in mineral oil) (1.2 g, 30.27 mmol, 2.0 equiv.). After stirring for 30 minutes, methyl iodide (4.3 g, 30.27 mmol, 2.0 equiv.) was added. After stirring at room temperature for 1 hour, the reaction mixture was diluted with saturated sodium bicarbonate solution (100 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 PA9.1 (3.07 g, quantitative yield). MS (ES): m / z 180.2 [M+H] +

[0374] Step 2. 6-Fluoro-2-methyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (PA9.2) To a solution of 6-fluoro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one PA9.1 (2.9 g, 16.201 mmol, 1.0 equiv.) dissolved in concentrated sulfuric acid (25 mL) at room temperature was added potassium nitrate (1.44 g, 17.821 mmol, 1.1 equiv.). After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water and stirred for 10 minutes. The solid was filtered, washed with water, and dried under high vacuum to give PA9.2 (3.1 g, 85.44%). MS (ES): m / z 225 [M+H] +

[0375] Step 3. 6-Fluoro-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (PA9.3) To a solution of 6-fluoro-2-methyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one PA9.2 (3.0 g, 13.392 mmol, 1.0 equiv.) in dry THF (80 mL) at 0 °C, borane-THF complex (0.9 mol) (22 mL, 20.089 mmol, 1.5 equiv.) was added. After stirring at 80 °C for 2 h, the reaction mixture was cooled to room temperature and diluted with water (100 mL). The aqueous layer was 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. The residue was purified using combi-flash silica eluting with 5% methanol / DCM to give PA9.3 (0.8 g, 28.44%). MS (ES): m / z 211.2 [M+H] +

[0376] Step 4. 6-Fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (PA9) To a suspension of 10% Pd / C (158 mg, 0.2% w / w q) in methanol (3 mL) was added a solution of 6-fluoro-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline PA9.3 (0.79 g, 3.761 mmol, 1.0 equiv.) in methanol (30 mL). After purging hydrogen gas through the solution for 1 hour, the reaction mixture was filtered through Celite, which was washed with MeOH. The filtrate was concentrated under reduced pressure to give crude PA9 (0.56 g, 82.68%). MS (ES): m / z 181.3 [M+H] +

[0377] Method PA28 - Preparation of 3-(6-aminopyridin-3-yl)-1-methylpyrrolidin-2-one (PA28) [ka] Step 1. 6-Fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (PA28.1) To a solution of 2-(6-chloropyridin-3-yl)acetonitrile PA28.0 (8 g, 52.4 mmol, 1.0 equiv.) in ethanol (40 ml) at 0 °C, sulfuric acid (15 ml) was added dropwise. After stirring at 100 °C for 3 hours, the reaction mixture was poured into ice-cold water (300 ml) and extracted with ethyl acetate (50 ml × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude material PA28.1, which was used directly in the next step without further purification (8 g, 76.4%). MS (ES): m / z 200.30 [M+H]+.

[0378] Step 2. 3-(6-Chloropyridin-3-yl)-1-methylpyrrolidin-2-one (PA28.2) To a solution of 6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine PA28.1 (1.0 g, 5.025 mmol, 1.0 equiv.) dissolved in DMSO (10 mL) at 10 °C, sodium hydride (0.603 g, 25.12 mmol, 3.0 equiv.) was added. After stirring at the same temperature for 20 minutes, 2-bromo-N-methylethan-1-amine (1.3 g, 6.030 mmol, 1.2 equiv.) was added. After stirring at room temperature for 1 hour, the reaction mixture was poured into ice-cold water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude PA28.2 (0.258 g, 24.48%). MS (ES): m / z 211.30 [M+H]+.

[0379] Step 3. N-(5-(1-methyl-2-oxopyrrolidin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (PA28.3) The reaction of Step 3 was carried out following the representative procedure described in Method PA4 (Step 1) using 3-(6-chloropyridin-3-yl)-1-methylpyrrolidin-2-one PA28.2 and cyclopropanecarboxamide to afford PA28.3 (0.80 g, 64.99% yield). MS (ES): m / z 260.61 [M+H]+

[0380] Step 4. 3-(6-aminopyridin-3-yl)-1-methylpyrrolidin-2-one (PA28) To a solution of N-(5-(1-methyl-2-oxopyrrolidin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (0.500 g, 1.93 mmol, 1.0 equiv.) in MeOH (7 mL) was added a solution of 5 N sodium hydroxide (2.31 ml, 56.0 mmol, 6 equiv.). After stirring at 60 °C for 16 h, the reaction mixture was poured into ice-cold water (100 ml) and extracted with 10% chloroform / isopropyl alcohol (100 ml × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was further purified by diethyl ether trituration (20 ml × 2) to give pure PA28 (0.250 g, 67.80%). MS (ES): m / z 192.51 [M+H]+

[0381] Methods PA29 and PA30 - Preparation of (S)-5-(3-(dimethylamino)piperidin-1-yl)pyridin-2-amine (PA29) and (R)-5-(3-(dimethylamino)piperidin-1-yl)pyridin-2-amine (PA30) [ka] Step 1 and Step 2. 5-(3-(dimethylamino)piperidin-1-yl)pyridin-2-amine (PA29.2) The reaction was carried out following the representative procedure outlined in Method PA4 to give PA29.2 (0.980 g, 45.15%). MS (ES): m / z 221.35 [M+H].

[0382] Step 3. (S)-5-(3-(dimethylamino)piperidin-1-yl)pyridin-2-amine (PA29) and (R)-5-(3-(dimethylamino)piperidin-1-yl)pyridin-2-amine (PA30) Compound 29.2 (980 mg racemic) was separated by Chiral SFC on a Shimadzu LC-20AP equipped with a CHIRALPAK IC (250 × 21.0) mm, 5 micron column and UV detector at a flow rate of 20 mL / min using mobile phases (A) 0.1% DEA in n-hexane and (B) 0.1% DEA in propan-2-ol:acetonitrile (70:30) to give pure compounds PA29 (350 mg) and PA30 (351 mg). Arbitrary assignment of stereochemistry.

[0383] Method PA31 - Preparation of 5-(oxetan-3-yl)pyridin-2-amine (PA31) [ka] Step 1. 2-Bromo-5-(oxetan-3-yl)pyridine (PA32.1) To a solution of (6-bromopyridin-3-yl)boronic acid (1.10 g, 5.44 mmol, 1 equiv.), nickel iodide (51 mg, 0.16 mmol, 0.2 equiv.), and trans-2-aminocyclohexanol hydrochloride (24.73 mg, 0.16 mmol, 0.1 equiv.) in 2-propanol (5 mL) was added sodium bis(trimethylsilyl)amide (1.0 g, 5.44 mmol, 1 equiv.). After stirring under nitrogen for 10 minutes, a solution of 3-iodooxetane (0.5 g, 2.7 mmol) in 2-propanol (2 mL) was added. After stirring in a sealed vial at 80 °C for 16 hours, the reaction was filtered through Celite, which was washed with ethanol. The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (10 to 100% ethyl acetate in hexanes) to give the title compound PA32.1 (0.28 g, 26%). MS (ES) m / z 215.87 [M+2+H]+

[0384] Step 2 and Step 3. 5-(Oxetan-3-yl)pyridin-2-amine (PA31) The reaction of steps 2 and 3 was carried out using 2-bromo-5-(oxetan-3-yl)pyridine (PA32.1) and cyclopropanecarboxamide following the representative procedure described in Method PA28 (steps 3 and 4) to give PA31 (0.15 g, 76.36% yield). MS (ES): m / z 151.2 [M+H]+

[0385] Method PA32 - Preparation of 3-(6-aminopyridin-3-yl)-1-methylpyrrolidin-2-one (PA32) [ka] Step 1. 6-Fluoro-1'-methyl-[3,4'-bipyridin]-2'(1'H)-one (PA32.1) To a solution of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine (2.0 g, 0.0089 mol, 1.0 equiv.) and 4-bromo-1-methylpyridin-2(1H)-one (1.3 g, 0.0074 mol, 0.8 equiv.) in 1,2-dimethoxyethane (10 mL) and water (2 mL) was added NaCO (2.8 g, 0.0267 mol, 3.0 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst (0.36 g, 0.0004 mol, 0.05 equiv.). After stirring in a microwave oven at 120 °C for 30 minutes, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified using Combi-Flash silica eluting with 3% methanol in DCM to give PA32.1 (1.4 g, 76.46%). MS (ES): m / z 205.3 [M+H] +

[0386] Step 2. 4-(6-Fluoropyridin-3-yl)-1-methylpiperidin-2-one (PA32.2) To a suspension of 10% Pd / C (558 mg, 0.5% w / w q) in methanol (3 mL) was added a solution of 6-fluoro-1'-methyl-[3,4'-bipyridin]-2'(1'H)-one PA32.1 (1.0 g, 0.0049 mol, 1.0 equiv.) in methanol (30 mL). After bubbling hydrogen gas through the solution for 1 hour, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give crude PA32.2 (1.0 g, 98.06%). MS (ES): m / z 209.2 [M+H] +

[0387] Step 3. 4-(6-aminopyridin-3-yl)-1-methylpiperidin-2-one (PA32) A solution of 4-(6-fluoropyridin-3-yl)-1-methylpiperidin-2-one PA32.2 (0.850 g, 0.00048 mol, 1.0 equiv.) in aqueous ammonia (40 mL) in a steel bomb (40% headspace remaining) was heated at 150 °C (100 psi) for 20 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified using combi-flash silica eluting with 6.2% methanol in DCM to give PA32 (0.220 g, 26.26%). MS (ES): m / z 206.3 [M+H] +

[0388] Method PA35 - Preparation of 5-cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (Intermediate PA35) [ka] Step 1. Methyl 6-amino-3-bromopicolinate (PA35.1): To a solution of PA35.0 (500 g, 3289.4 mmol, 1.0 equiv.) in acetonitrile (12.5 L) was added N-bromosuccinamide (644 g, 3618.4 mmol, 1.1 equiv.) in portions over 30 minutes at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was quenched with 10% NaSO solution in water (3.0 L) and concentrated to remove acetonitrile. The residue was diluted with 10% NaSO solution in water (20 L) and extracted with 50% ethyl acetate in hexane (10 L x 5). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude material was triturated with 25% ethyl acetate in hexane to give pure PA35.1 (methyl 6-amino-3-bromopicolinate) (57.07% yield). MS (ES): m / z 231-233 [M+2] + , 1 H NMR (400 MHz, CDCL): δ 7.66 (d, 1H), 6.53 (d, 1H), 4.68 (s, 2H), 3.98 (s, 3H). Note: The other regioisomer (methyl 6-amino-5-bromopicolinate) also forms and can be separated via silica purification. The required regioisomer was confirmed by H NMR and NOE analysis.

[0389] Step 2. Methyl 3-bromo-6-(bis(tert-butoxycarbonyl)amino)picolinate (PA35.2) To a solution of PA35.1 (1100 g, 4782.6 mmol, 1.0 equiv.) in THF (20 L) was added dimethylaminopyridine (116.7 g, 956.5 mmol, 0.2 equiv.) and Boc anhydride (2502 g, 11478.2 mmol, 2.4 equiv.). After stirring at 75 °C for 1.5 h, the solvent was evaporated, and the residue was diluted with brine solution and extracted with ethyl acetate (2 x 10 L). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with 5% ethyl acetate in hexane. The isolated material was triturated with hexane (4 L) to give PA35.2 (1700 g, 82.79%) as a white solid. MS (ES): m / z 431-433 [M+2] + . 1H NMR (400MHz, DMSO): δ 8.32(d,1H),7.61(d,1H),3.90(s,3H),1.40(s,18H).

[0390] Step 3. Methyl 6-(bis(tert-butoxycarbonyl)amino)-3-(furan-3-yl)picolinate (PA35.3) To a solution of PA35.2 (730 g, 1693.7 mmol, 1.0 equiv.), furan boronic acid (379 g, 3387.4 mmol, 2 equiv.), and potassium phosphate tribasic (Sigma, 1078.3 g, 5086.2 mmol, 3.0 equiv.) suspended in 1,4-dioxane (5.85 L) and water (1.46 L) and degassed with a stream of nitrogen for 20 minutes, Dikis (59.5 g, 84.8 mmol, 0.05 equiv.) was added. After stirring at 120 °C for 15 minutes, the reaction was cooled to room temperature. The organic layer was collected, filtered through a Celite bed, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 6.0% to 10% ethyl acetate / hexane. The isolated material was triturated with n-pentane to give PA35.3 (84% yield) as a cream-colored solid. MS(ES): m / z 418[M+1] +1 H NMR(400MHz,DMSO):δ 8.12(d,1H),8.00(d,1H),7.81(s,1H),7.61(s,1H),6.70(s,1H),3.83(S,3H),1.41(s,18H)

[0391] Step 4. Methyl 6-(bis(tert-butoxycarbonyl)amino)-3-(furan-3-yl)picolinate (PA35.4) To a solution of PA35.4 (191 g, 456.9 mmol, 1.0 equiv.) in methanol (1140 mL) and THF (955 mL) was added ammonium formate (115.1 g, 182.5 mmol, 4.0 equiv.), acetic acid (133.7 mL, 0.7 V), and 20% wet palladium hydroxide on carbon (133.7 g, 1:0.7 w / w). After stirring for 24 hours at room temperature under an atmosphere of hydrogen gas, the reaction mixture was combined with six other batches of the same scale prepared by the same method. The combined reaction mixture was then filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was neutralized with saturated NaHCO3 (10 L) solution and extracted with DCM (10 L x 3) to give PA35.4 (1251 g, 92.6%). MS (ES): m / z 423 [M+1] +1 H NMR (400MHz, DMSO): δ 8.01(d,1H),7.58(d,1H),3.99(t,2H),3.87(s,3H),3.71(m,2H),3.60(m,1H),2.31(m,1H)1.91(d,1H),1.4(S,18H).

[0392] Step 5. tert-Butyl (6-(hydroxymethyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (PA35.5) To a solution of PA35.4 (250 g, 592.4 mmol, 1.0 equiv) in ethanol (2500 mL) was added sodium borohydride (135 g, 355.4 mmol, 6 equiv) in portions. After stirring at 60 °C for 2 h, the reaction was concentrated under reduced pressure, diluted with water (10 L), and extracted with DCM (4 × 10 L). The combined organic layers were washed with brine (10 L), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was combined with four other batches of the same scale prepared by the same method to give PA35.5 (640 g, 73.49%) as a colorless gummy liquid that became a white solid at room temperature after 2 days. MS (ES): m / z 295.0 [M+1] +1H NMR(400MHz,DMSO):δ 7.81(d,1H),7.67(d,1H),7.2(d,1H),5.22(d,1H),4.55(t,1H),3.99( s,3H),3.77(m,3H),3.55(m,2H),2.28(d,2H),1.87(d,1H),1.41(s,9H)

[0393] Steps 6 and 7. tert-Butyl (6-((dimethylamino)methyl)-5-(THF-3-yl)pyridin-2-yl)carbamate (PA35.6) To a solution of PA35.5 (440 g, 149.6 mmol, 1.0 equiv) in DCM (6.5 L) was added diisopropylethylamine (581.4 g, 448.9 mmol, 3.0 equiv) dropwise at 0 °C. After stirring for 20 min, mesyl chloride (257.04 g, 2244 mmol, 1.5 equiv) was added at 0 °C. After stirring at 0 °C to room temperature for 2 h, the reaction mixture was quenched with DM water (1 L) and extracted with DCM (3 × 2 L). The combined organic layers were washed with brine (10 L), passed through a NaSO frit, and concentrated under reduced pressure to give the mesylated intermediate. This mesylated intermediate was combined with one other batch (200 g scale) prepared by the same method. 700 g (crude, 86.44%) was obtained as a pale yellow liquid. MS(ES): m / z 373.35[M+1] + .

[0394] To a solution of the mesylated intermediate (350 g, 940.0 mmol, 1.0 equiv.) in MeCN (3.5 L) at room temperature, diisopropylethylamine (529.23 g, 423.0 mmol, 4.5 equiv.) was added dropwise, followed by dimethylamine hydrochloride (152.41 g, 1880.0 mmol, 2.0 equiv.). After stirring at 90 °C for 3 h, the reaction mixture was concentrated to remove acetonitrile, quenched in DM water (1500 mL), and extracted with DCM (3 × 3 L). The combined organic layers were washed with brine (10 L), dried over NaSO, and concentrated under reduced pressure to give PA35.6. The product was combined with one other batch on the same scale prepared by the same method. As a brown semi-solid (700 g, quantitative yield). MS (ES): m / z 322.39 [M+1] + , 1 H NMR(400MHz,DMSO):δ 9.61(s,1H),7.67(s,2H),3.96-3.94(t,2H,J=7.6),3.78-3.77(d,2H,J=4HZ),3 .57(S,1H),3.54(s,1H),2.26-2.25(t,1H),2.1(s,6H),1.86(s,1H),1.45(s,9H)

[0395] Step 8. 5-Cyclopentyl-6-((dimethylamino)methyl)pyridin-2-amine (PA35) To a solution of PA35.6 (700 g, 2180.7 mmol, 1.0 equiv) in DCM (5.0 L) was added trifluoroacetic acid (2.1 L, 3v) at 0 °C. After stirring at 70 °C for 2 h, the reaction mixture was concentrated, diluted in DM water (2 L), and washed with heptane. The collected aqueous layer was neutralized with 10% NaOH solution and then extracted with 15% MeOH in DCM (4 × 3.0 L). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with 20% ethyl acetate in hexanes followed by diethyl ether to give pure PA35 as a light brown solid (330 g, 68.47%). MS (ES): m / z 222.30 [M+1] +,1H NMR(400MHz,DMSO-d6)δ 7.33(d,J=8.4Hz,1H),6.36(d,J=8.5Hz,1H),5.71(s,1H),3.96-3.85(m,1H),3.72(dq,J=31.0,7.7Hz,1H),3.46-3.3 4(m,1H),3.35(s,1H),3.30(d,J=11.9Hz,0H),2.19(td,J=7.8,4.2Hz,0H),2.14(s,3H),1.79(dq,J=12.2,8.0Hz,1H).

[0396] Method PA37 - Preparation of 6-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (PA37) [ka] Step 1. tert-Butyl (5-bromo-6-(hydroxymethyl)pyridin-2-yl)carbamate (PA37.1) To a solution of PA35.2 (50 g, 116.27 mmol, 1.0 equiv) in ethanol (200 mL) was added sodium borohydride (26.3 g, 697.6 mmol, 6 equiv) in portions. After stirring at 70 °C for 2 h, the reaction was concentrated under reduced pressure, carefully diluted with water (200 mL), and extracted into DCM (3 x 150 mL). The combined organic layers were washed with brine (100 mL), passed through a hydrophobic filter, and concentrated under reduced pressure to give PA37.1 (27 g, 79%) as a white solid. MS (ES): m / z 395 [M+1] +1 H NMR(400MHz,DMSO):δ 7.81(d,1H),7.67(d,1H),7.2(d,1H),5.22(d,1H),4.55(t,1H),3.99(s ,3H),3.77(m,3H),3.55(m,2H),2.28(d,2H),1.87(d,1H),1.41(s,19H)

[0397] Step 2, 3. tert-Butyl (5-bromo-6-((dimethylamino)methyl)pyridin-2-yl)carbamate (PA37.2) To a solution of PA37.1 (22.2 g, 73.2 mmol, 1.0 equiv) and N-N-diisopropylethylamine (33.3 g, 256.3 mmol, 3.5 equiv) in DCM (200 mL) at 0° C. was added methanesulfonyl chloride (12.5 g, 109.8 mmol, 1.5 equiv). After stirring for 30 minutes, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine, passed through a hydrophobic filter, and concentrated under reduced pressure.

[0398] To the mesylate intermediate dissolved in acetonitrile (200 mL) was added dimethylamine (15 g, 183.0 mmol, 2.5 equiv) and N-N-diisopropylethylamine (33.3 g, 256.3 mmol, 3.5 equiv). After stirring at 70 °C for 1 h, the reaction was quenched with water (100 mL) and extracted into ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, passed through a hydrophobic filter, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50% ethyl acetate / hexane to give PA37.2 (17.0 g, 94.3%). MS (ES): m / z 330 [M+H] +

[0399] Step 3. tert-Butyl (5-(3,6-dihydro-2H-pyran-4-yl)-6-((dimethylamino)methyl)pyridin-2-yl)carbamate (PA37.3) To a solution of PA37.2 (50 g, 151.5 mmol, 1.0 equiv.) in 1,4-dioxane:water (400 mL:100 mL) containing 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (47.7 g, 227.2 mmol, 1.5 equiv.) and potassium phosphate tribasic (96.3 g, 454.5 mmol, 3.0 equiv.) that had been degassed with N for 15 min, X-phosPdG (11.9 g, 15.1 mmol, 0.1 equiv.) was added. After stirring at 140 °C for 4 h, the reaction mixture was cooled to room temperature, diluted with water (1 L), and extracted with ethyl acetate (2 × 2 L). The combined organic extracts were washed with brine (1 L), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 2% methanol in DCM to give PA37.3 (40 g, 79%). MS (ES): m / z 334.2 [M+H] +

[0400] Step 4. tert-Butyl (6-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)carbamate (PA37.4) To a suspension of palladium hydroxide (130 g) in methanol (600 ml) and THF (40 ml) was added intermediate PA37.3 (130 g, 1.0 equivalent). Hydrogen gas was purged through the reaction mixture at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered through a bed of celite, which was washed with methanol. The filtrate was concentrated under reduced pressure to give PA37.4 (120 g, 91.75%). MS (ES): m / z 336.2 [M+H] +

[0401] Step 5. 6-((Dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (PA37) To a solution of intermediate PA37.4 (120 g, 356.9 mmol, 1.0 equiv) in DCM (1.2 L) was added trifluoroacetic acid (360 mL) dropwise. After stirring at 55 °C for 2 h, the reaction mixture was neutralized with saturated sodium hydroxide solution and extracted with 10% methanol in DCM (4 x 10 L). The combined organic layers were concentrated under reduced pressure to give PA37 (66 g, 78.40%). MS (ES): m / z 236.1 [M+H] +

[0402] Method PA39 - Preparation of 2-(1-(6-aminopyridin-3-yl)piperidin-3-yl)propan-2-ol (PA39) [ka] Step 1 and Step 2. Ethyl 1-(6-aminopyridin-3-yl)piperidine-3-carboxylate (PA39.2). Ethyl 1-(6-aminopyridin-3-yl)piperidine-3-carboxylate (PA39.2) was prepared in a similar manner as described in Method PA4 (1.2 g, 89.62%). MS (ES): m / z 250.15 [M+H]

[0403] Step 3. 2-(1-(6-aminopyridin-3-yl)piperidin-3-yl)propan-2-ol (PA39). To a solution of ethyl 1-(6-aminopyridin-3-yl)piperidine-3-carboxylate (PA39.2) (2.0 g, 8.03 mmol, 1.0 equiv.) in THF (15 mL) was added dropwise a solution of methylmagnesium bromide (3N in THF, 20 mL) at 0 °C. After stirring at room temperature for 1 h, the reaction mixture was quenched with ice-cold water (100 mL) and filtered through a bed of Celite. The filtrate was extracted with ethyl acetate (100 mL × 3), and the combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (0–80% gradient elution, EtOAc in hexanes) to give PA39 (0.200 g, 10.60%). MS (ES): m / z 236.17 [M+H] +

[0404] Method PA40 - Preparation of 1-(6-amino-2-((dimethylamino)methyl)pyridin-3-yl)piperidin-4-ol (PA40) [ka] Step 1. 6-Chloro-3-(4-hydroxypiperidin-1-yl)picolinaldehyde (PA40.1) To a solution of PA40.0 (1.0 g, 6.28 mmol, 1.0 equiv.) and piperidin-4-ol (1.0 g, 10.04 mmol, 1.6 equiv.) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.6 g, 18.84 mmol, 3.0 equiv.). After stirring at 100° C. for 1 hour, the reaction mixture was cooled to room temperature, diluted with ice-cold water (100 mL), and extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine (80 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30% ethyl acetate in hexane to give PA40.1 (1.2 g, 79.54%). MS (ES): m / z 241.07 [M+H] +

[0405] Step 2. 1-(6-chloro-2-((dimethylamino)methyl)pyridin-3-yl)piperidin-4-ol (PA40.2) To a cooled solution of PA40.1 (1.2 g, 5.00 mmol, 1.0 equiv) in 1,2-dichloroethane (20 ml) was added acetic acid (2.4 ml) at 0° C. Dimethylamine gas was bubbled through the reaction for 30 minutes, after which sodium triacetoxyborohydride (7.4 g, 35 mmol, 7.0 equiv) was added portionwise. After stirring at room temperature for 16 hours, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with DCM (4×40 mL). The combined organic extracts were washed with brine (90 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a 3.0% gradient of methanol in DCM to give PA40.2 (0.450 g, 33.46%). MS (ES): m / z 270.2 [M+H] +

[0406] Step 3 and Step 4. 5-(Oxetan-3-yl)pyridin-2-amine (PA40) The reaction of steps 3 and 4 was carried out using PA40.2 and cyclopropanecarboxamide following the representative procedure described in Method PA28 (steps 3 and 4) to give PA40 (0.3 g, 64%). MS (ES): m / z 251.35 [M+H]+

[0407] The following aniline intermediates were prepared according to any of the intermediate methods PA1-PA40 described above. [Table 6-1] [Table 6-2]

[0408] Method CB1 - Preparation of 5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)(piperidin-1-yl)methanone (CB1) [ka] Step 1. 5-Fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzoic acid (CB1.1) To a solution of methyl 5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzoate (CB1.0) (2.0 g, 6.45 mmol) in THF (60 mL) was added LiOH (2 M, 7.1 mL, 14.2 mmol). After stirring at room temperature for 16 h, the organic solvent was removed under reduced pressure, and the residual material was neutralized with 2 M aqueous HCl (20 mL), diluted with brine (10 mL), and then extracted into ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (40 mL), passed through a hydrophobic frit, and concentrated under reduced pressure to give the product (CB1.1) (1.66 g, 87%) as a white solid, which was used without further purification. m / z = 297.1 [M+H] + , 1 H NMR (400MHz, CDCl3): δ 10.83(brs,1H),7.85(d,J=8.7Hz,1H),7.38(d,J=4.0Hz,1H),4.13(s,3H),1.40(s,2H).

[0409] Step 2. 5-Fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)(piperidin-1-yl)methanone (CB1) To a solution of (CB1.1) (1.66 g, 5.61 mmol) in THF (25 mL) was added hydroxybenzotriazole (0.98 g, 7.29 mmol) and EDC hydrochloride (1.40 g, 7.29 mmol). After stirring at room temperature for 1 h, N,N-diisopropylethylamine (2.9 mL, 16.8 mmol) and piperidine (0.66 mL, 6.73 mmol) were added sequentially. After stirring at room temperature for 22 h, the organic solvent was evaporated under reduced pressure, diluted with water (40 mL), and extracted with DCM (2 × 40 mL). The combined organic layers were passed through a hydrophobic frit and concentrated under reduced pressure. The resulting foam was dissolved in DCM (10 mL), and the product was precipitated by the addition of diethyl ether. The solvent was removed under reduced pressure to give crude (CB1) (2.07 g, quantitative) as an off-white solid, which was used without further purification. m / z = 364.2 [M+H] + , 1 H NMR(400MHz,CDCl3):δ 7.18(d,J=4.2Hz,1H),6.92(d,J=8.1Hz,1H),3.85(s,3H),3.82-3.64(m,4H),1.56-1.41(m,4H),1.36(s,12H),1.33-1.25(m,2H).

[0410] Method CB2 - Preparation of N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)-N-methylcyclopropanecarboxamide (CB2) [ka] Step 1. N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)cyclopropanecarboxamide (CB2.1) To a solution of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)aniline (CB2.0) (600 mg, 2.53 mmol) in dry DCM (12.0 mL) was added cyclopropanecarbonyl chloride (0.24 mL, 2.66 mmol) and N,N-diisopropylethylamine (0.88 mL, 5.06 mmol). After stirring at room temperature for 2 h, the reaction was quenched with 2 M HCl (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), passed through a hydrophobic frit, and concentrated under reduced pressure to give the crude product (CB2.1) (650 mg, 85%) as a white solid, which was used without further purification. m / z = 306.1 [M+H] + . 1 H NMR(400MHz,CDCl3):δ 7.61-7.55(m,1H),7.47(d,J=1.6Hz,1H,)7.25(s,1H),7.18(d,J=1.6Hz,1H), 1.54-1.50(m,1H),1.38-1.30(m,12H),1.88-1.83(m,2H),0.75-0.69(m,2H).

[0411] Step 2. N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)-N-methylcyclopropanecarboxamide (CB2) To a solution of N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)cyclopropanecarboxamide (CB2.1) (650 mg, 2.13 mmol) and methyl iodide (0.65 mL, 3.62 mmol) in dry THF (6.0 mL) was added sodium hydride (60% in mineral oil, 145 mg, 3.62 mmol) in portions. After stirring at room temperature for 4 h, the reaction was [carefully!] quenched with dropwise addition of water (1.0 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 0–100% EtOAc in iso-hexane) to afford the title compound (CB2) (390 mg, 57%) as an off-white solid. m / z=320.2[M+H] + , 1 H NMR(400MHz,CDCl3):δ 8.75(s,1H),8.08(d,J=1.6Hz,1H,)8.02(d,J=1.6Hz,1H),3.28(s,3H), 2.54(s,1H),1.68-1.60(m,12H),0.88-0.83(m,2H),0.75-0.69(m,2H).

[0412] Method CB3 - Preparation of 2-(2-fluoro-4-methoxy-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (CB3) [ka] To a mixture of 1-bromo-2-fluoro-4-methoxy-5-methylbenzene (CB3.0) (500 mg, 2.28 mmol), bis(pinacolato)diboron (696 mg, 2.74 mmol), and potassium acetate (560 mg, 5.71 mmol) in 1,4-dioxane (10 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (186 mg, 0.23 mmol). After degassing with nitrogen, the mixture was heated at 100 °C for 6 h. The cooled mixture was diluted with EtOAc. The organic solution was collected, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (0–50% EtOAc in isohexane gradient) to afford the title compound (CB3) (539 mg, 89%) as a light brown solid.

[0413] Method CB4 - Preparation of 5-fluoro-N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-2,3-dihydro-1H-inden-1-amine (CB4) [ka] Step 1: 6-Bromo-5-fluoro-2,3-dihydro-1H-inden-1-ol (CB4.1) To a solution of 6-bromo-5-fluoro-2,3-dihydro-1H-inden-1-one (CB4.0) (300 mg, 1.3 mmol) in methanol (3.0 mL) was added sodium borohydride (141 mg, 3.9 mmol). After stirring at room temperature for 30 min, the mixture was diluted with DCM (20 mL) and washed with saturated aqueous NaHCO3 (15 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure to give the desired product (CB4.1) (307 mg, quantitative) as an off-white solid, which was used in the next step without further purification. m / z = 231.9 [M+H] + , 1H NMR(400MHz,CDCl3):δ 7.56(d,J=6.3Hz,1H),7.02-6.97(m,1H),5.25-5.16(m,1H),3.06-2.96(m,1H), 2.83-2.72(m,1H),2.58-2.47(m,1H),2.04-1.94(m,1H),1.78(d,J=6.8Hz,1H).

[0414] Step 2: 6-Bromo-5-fluoro-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine (CB4.2) To a solution of 6-bromo-5-fluoro-2,3-dihydro-1H-inden-1-ol (CB4.1) (307 mg, 3.9 mmol) in THF (12 mL) and triethylamine (0.94 mL, 5.1 mmol) at −15° C., methanesulfonyl chloride (200 μL, 2.6 mmol) was added dropwise. After stirring at −15° C. for 3 h, a dimethylamine solution (2 M in THF, 7.8 mL, 15.5 mmol) was added. After warming to room temperature and stirring overnight, the reaction mixture was filtered and the solvent evaporated under reduced pressure. The crude product was passed through an SCX cartridge (loaded with DCM, washed with 10% MeOH in DCM, and eluted with 10% 7N methanolic ammonia in DCM). The solvent was evaporated under reduced pressure to give the desired product (CB4.2) (310 mg, 92%) as a reddish-brown oil, which was used in the next step without further purification. m / z=259.1[M+H] + , 1 H NMR (400MHz, CDCl3): δ 7.51(d,J=6.7Hz,1H),6.97-6.94(m,1H),4.26(t,J=6.8Hz,1H),2.93-2.72(m,2H),2.23(s,6H),2.12-2.03(m,2H).

[0415] Step 3: 5-Fluoro-N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-2,3-dihydro-1H-inden-1-amine (CB4) A large carousel tube was charged with 6-bromo-5-fluoro-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine (CB4.2) (310 mg, 1.2 mmol), bis(pinacolato)diboron (475 mg, 1.8 mmol), and potassium acetate (354 mg, 3.6 mmol) in dioxane (10 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (44 mg, 0.06 mmol) was added. The tube was sealed and heated with stirring at 110 °C for 3 h. The reaction mixture was allowed to cool to room temperature, and compound (CB4) was carried on to the next step without further purification. m / z = 306.2 [M+H] + .

[0416] Method CB5 - 4-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenoxy)methyl)pyridine (CB5) [ka] Step 1: 4-((4-bromo-3-fluorophenoxy)methyl)pyridine (CB5.1) To a solution of 4-bromo-3-fluorophenol (CB5.0) (1.00 g, 5.24 mmol) in DMF (8 mL) was added 4-(bromomethyl)pyridine (1.59 g, 6.28 mmol) and potassium carbonate (1.81 g, 13.1 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-100% EtOAc in DCM to give the desired product (CB5.1) (162 mg, 11%) as a white solid. m / z = 283.9 [M+H]+, 1 H NMR(400MHz,CDCl3):δ 8.63(d,J=6.1Hz,2H),7.45-7.38(m,1H),7.32(d,J=5.8Hz,2H),6.73(dd,J=2.4,8.4Hz,1H),6.67(dd,J=2.3,11.0Hz,1H),5.09(s,2H).

[0417] Step 2: 4-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenoxy)methyl)pyridine (CB5) A mixture of 4-((4-bromo-3-fluorophenoxy)methyl)pyridine (CB5.1) (155 mg, 0.55 mmol), bis(pinacolato)diboron (167 mg, 0.66 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (45 mg, 0.05 mmol), and potassium acetate (135 mg, 1.37 mmol) in 1,4-dioxane (10 mL) was degassed and purged with nitrogen. After heating to 100 °C for 6 h, the reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0 to 100% EtOAc in DCM to afford CB5 (179 mg, 99%) as an orange-brown residue. m / z=330.0[M+H]+, 1 H NMR(400MHz,CDCl3):δ 8.62(d,J=6.1Hz,2H),7.70-7.65(m,1H),7.34(d,J=5.8Hz,2H),6.74(dd,J=2 .4,8.4Hz,1H),6.63(dd,J=2.3,11.0Hz,1H),5.10(s,2H),1.35-1.24(m,12H).

[0418] Method CB6 - 2-(5-cyclobutyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (CB6) [ka] Step 1: 2-Bromo-4-cyclobutyl-1-fluorobenzene (CB6.1) A solution of 2-bromo-1-fluoro-4-iodobenzene (CB6.0) (600 mg, 1.99 mmol), Xantphos palladacycle 3rd generation (95 mg, 0.10 mmol), and Xantphos (58 mg, 0.10 mmol) in THF (10 mL) was degassed and purged with nitrogen. After the addition of cyclobutylzinc bromide (0.5 M, 5.2 mL, 2.59 mmol), the reaction was heated at 50 °C for 7 h. After 3 days at room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0–20% EtOAc in iso-hexane to afford CB6.1 (385 mg, 84%) as a colorless oil. 1 H NMR(400MHz,CDCl3):δ 7.37(dd,J=1.8,6.6Hz,1H),7.12-7.06(m,1H),7.02(dd,J=8.5,8.5Hz,1H),3.54-3.43(m,1H),2.39-2.30(m,2H),2.15-1.96(m,4H).

[0419] Step 2: 2-(5-cyclobutyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (CB6) A mixture of 2-bromo-4-cyclobutyl-1-fluorobenzene (CB6.1) (378 mg, 1.65 mmol), bis(pinacolato)diboron (503 mg, 1.98 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (135 mg, 0.17 mmol), and potassium acetate (405 mg, 4.12 mmol) in 1,4-dioxane (10 mL) was degassed and purged with nitrogen. After heating at 100 °C for 6 h, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0–40% EtOAc in isohexane to afford CB6 (286 mg, 63%) as a pale yellow oil. 1H NMR(400MHz,CDCl3):δ 7.53(dd,J=2.4,5.6Hz,1H),6.95(dd,J=8.8,8.8Hz,1H),3.57-3.46(m,1H ),2.37-2.28(m,2H),2.18-1.95(m,3H),1.89-1.83(m,1H),1.36(s,12H).

[0420] Method CB7 - 2-(2-fluoro-5-(1-methylcyclopropyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (CB7) [ka] Step 1: 2-Bromo-1-fluoro-4-(prop-1-en-2-yl)benzene (CB7.1) A suspension of methyltriphenylphosphonium bromide (1.73 g, 4.84 mmol) in THF (10 mL) was cooled to 0 °C and then treated portionwise with potassium tert-butoxide (0.57 g, 5.07 mmol). After stirring at 0 °C for 2 h, the reaction was treated portionwise with a solution of 1-(3-bromo-4-fluorophenyl)ethan-1-one (CB7.0) (1.00 g, 4.61 mmol) in THF (5 mL). After warming to room temperature and stirring overnight at room temperature, the reaction mixture was quenched with 1 M aqueous HCl and extracted into EtOAc (2 x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0-20% EtOAc in iso-hexane to afford CB7.1 (352 mg, 36%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ 7.63(dd,J=2.4,6.7Hz,1H),7.38-7.34(m,1H),7.06(dd,J=8.5,8.5Hz,1H),5.31(s,1H),5.10(s,1H),2.11(s,3H).

[0421] Step 2: 2-Bromo-1-fluoro-4-(1-methylcyclopropyl)benzene (CB7.2) A solution of diethylzinc (1.0 M in hexanes, 1.95 mL, 1.95 mmol) in DCM (5 mL) was placed under an atmosphere of nitrogen and cooled to −15° C. The solution was treated with a solution of dibutyl phosphate (0.39 mL, 1.95 mmol) in DCM (4 mL) added portionwise. After stirring at −15° C. for 15 minutes, the reaction was then treated with diiodomethane (0.16 mL, 1.95 mmol). After stirring at −15° C. for 30 minutes, a solution of 2-bromo-1-fluoro-4-(prop-1-en-2-yl)benzene (CB7.1) (350 mg, 1.63 mmol) in DCM (4 mL) was added. After warming to room temperature and stirring for 18 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted into EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0-30% EtOAc in iso-hexane to afford CB7.2 (311 mg, 67%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ 7.36(ddd,J=2.2,4.7,8.5Hz,1H),7.17-7.10(m,2H),2.11(s,3H),0.84-0.78(m,4H).

[0422] Step 3: 2-(2-fluoro-5-(1-methylcyclopropyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (CB7) A mixture of 2-bromo-1-fluoro-4-(1-methylcyclopropyl)benzene (CB7.2) (310 mg, 1.35 mmol), bis(pinacolato)diboron (412 mg, 1.62 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (111 mg, 0.14 mmol), and potassium acetate (332 mg, 3.38 mmol) in 1,4-dioxane (10 mL) was degassed and purged with nitrogen. After heating at 100 °C for 5 h, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0 to 50% EtOAc in isohexane to give CB7 (357 mg) as an orange residue, which was used in the subsequent step without further purification.

[0423] Method CB8 - 1,1,1-trifluoro-2-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)propan-2-ol (CB8) [ka] Step 1: 2-(3-bromo-4-fluorophenyl)-1,1,1-trifluoropropan-2-ol (CB8.1) A solution of 1-(3-bromo-4-fluorophenyl)ethan-1-one (CB8.0) (1.00 g, 4.61 mmol) and trimethyl(trifluoromethyl)silane (1.4 mL, 9.22 mmol) in THF (15 mL) was treated with the dropwise addition of tetrabutylammonium fluoride (1.0 M, 6.9 mL, 6.91 mmol). After stirring overnight at room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted into EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0–50% EtOAc in iso-hexane to afford CB8.1 (1.39 g, quantitative) as a pale yellow oil. 1H NMR(400MHz,DMSO):δ 12.42(s,1H),8.69(s,1H),8.05(dd,J=1.9,7.5Hz,1H),7.99(d,J=2.8Hz,1H),7. 65-7.58(m,1H),7.40(dd,J=2.9,9.0Hz,1H),7.35(d,J=7.6Hz,2H),2.43(s,6H).

[0424] Step 2: 1,1,1-trifluoro-2-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)propan-2-ol (CB8) A mixture of 2-(3-bromo-4-fluorophenyl)-1,1,1-trifluoropropan-2-ol (CB8.1) (521 mg, 1.82 mmol), bis(pinacolato)diboron (553 mg, 2.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (148 mg, 0.18 mmol), and potassium acetate (445 mg, 4.54 mmol) in 1,4-dioxane (10 mL) was degassed and purged with nitrogen. After heating to 100 °C for 5 h, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0-10% MeOH in DCM to give CB8 (348 mg) as an orange residue, which was used in the subsequent step without analysis.

[0425] Method CB9 -(2-Ethoxy-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)(piperidin-1-yl)methanone (CB9) [ka] Step 1: (4-Bromo-5-fluoro-2-methoxyphenyl)(piperidin-1-yl)methanone (CB9.1) A solution of 4-bromo-5-fluoro-2-methoxybenzoic acid (CB9.0) (215 mg, 0.82 mmol) in THF (5 mL) was treated with HOBt (144 mg, 1.06 mmol) and EDC hydrochloride (204 mg, 1.06 mmol). After stirring at room temperature for 1 h, the reaction mixture was treated with DIPEA (0.43 mL, 2.45 mmol) and piperidine (0.10 mL, 0.98 mmol). After stirring at room temperature for 3 days, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and diluted with DCM. The organic layer was separated, passed through a hydrophobic frit, and concentrated under reduced pressure to give CB9.1 (250 mg, 93%). m / z = 318.0 [M+H]+, 1 H NMR (400MHz, CDCl3): δ 7.07-7.00(m,2H),3.81(s,3H),3.78-3.61(m,4H),3.21-3.14(m,2H),1.53-1.41(m,4H).

[0426] Step 2: (4-Bromo-5-fluoro-2-hydroxyphenyl)(piperidin-1-yl)methanone (CB9.2) A solution of (4-bromo-5-fluoro-2-methoxyphenyl)(piperidin-1-yl)methanone (CB9.1) (500 mg, 1.58 mmol) in DCM (30 mL) was cooled to −78° C. and treated with boron tribromide (1.0 M in DCM, 4.7 mL, 4.74 mmol). After stirring at −78° C. for 2 h, the reaction was quenched with water and neutralized with saturated aqueous sodium bicarbonate. The organic layer was separated, passed through a hydrophobic frit, and concentrated under reduced pressure to afford CB9.2 (450 mg, 94%) as a tan solid. m / z=304.0 [M+H]+, 1 H NMR (400MHz, CDCl3): δ 7.37(d,J=5.8Hz,1H),6.97(d,J=8.1Hz,1H),3.58(dd,J=5.2,5.2Hz,4H),3.21-3.14(m,2H),1.53-1.41(m,4H).

[0427] Step 3: (4-Bromo-2-ethoxy-5-fluorophenyl)(piperidin-1-yl)methanone (CB9.3) To a solution of (4-bromo-5-fluoro-2-hydroxyphenyl)(piperidin-1-yl)methanone (CB9.2) (220 mg, 0.73 mmol) in DMF (5 mL) was added potassium carbonate (1.00 g, 7.28 mmol) and bromoethane (0.12 mL, 1.60 mmol). After stirring at 60 °C for 3 h, the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give crude CB9.3 (250 mg), which was used in the subsequent step without further purification. m / z = 332.0 [M+H]+, 1 H NMR (400MHz, CDCl3): δ 7.06-7.00(m,2H),4.08-3.96(m,2H),3.75-3.62(m,3H),3.23-3.09(m,4H),1.89(s,2H),1.45-1.35(m,4H).

[0428] Step 4: (2-ethoxy-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)(piperidin-1-yl)methanone (CB9) A mixture of (4-bromo-2-ethoxy-5-fluorophenyl)(piperidin-1-yl)methanone (CB9.3) (250 mg, 0.76 mmol), bis(pinacolato)diboron (211 mg, 0.83 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (28 mg, 0.04 mmol), and potassium acetate (223 mg, 2.27 mmol) in 1,4-dioxane (10 mL) was degassed and purged with nitrogen. After stirring overnight at 110 °C, the reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and filtered. The filtrate was extracted with DCM, and the organic layer was passed through a hydrophobic frit and concentrated under reduced pressure to give crude CB9, which was used in the subsequent step without further purification. m / z = 378.3 [M+H]+.

[0429] Method CB10 - (2,3-Difluoro-5-methoxy-4-(piperidine-1-carbonyl)phenyl)boronic acid (CB10) [ka] A solution of (2,3-difluoro-6-methoxyphenyl)(piperidin-1-yl)methanone (CB10.0) (2.30 g, 9.01 mmol) in THF (40 mL) was degassed, purged with nitrogen, cooled to −78° C., and then treated with n-butyllithium (2.50 M in hexanes, 3.6 mL, 9.01 mmol) added dropwise. After stirring at −78° C. for 30 minutes, trimethyl borate (1.2 mL, 10.8 mmol) was added dropwise. After warming to room temperature and stirring for 16 hours, the reaction was quenched with 1 M aqueous HCl (40 mL) and extracted into EtOAc (3×50 mL). The combined organic layers were washed with brine (40 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give CB10 (2.76 g, quantitative) as an off-white solid. m / z=299.9[M+H]+, 1 H NMR(400MHz,CDCl3):δ 7.04(s,1H),5.13-5.05(m,2H),3.84(s,3H),3.82-3.76(m,1H),3.71-3.67(m,1H),3.21(q,J=5.1Hz,2H),1.67-1.63(m,4H),1.25(s,2H).

[0430] Method CB11 - 1-(2-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)pyrrolidin-1-yl)ethan-1-one (CB11) [ka] Step 1: tert-Butyl (4-(3-bromo-4-fluorophenyl)-4-oxobutyl)carbamate (CB11.1) A solution of 2-bromo-1-fluoro-4-iodobenzene (CB11.0) (3.00 g, 9.97 mmol) in THF (75 mL) was cooled to −40° C. and treated with the dropwise addition of isopropylmagnesium chloride (2.0 M, 5.0 mL, 9.97 mmol). After stirring at −40° C. for 1 h and then cooling to −78° C., tert-butyl 2-oxopyrrolidine-1-carboxylate (1.85 g, 9.97 mmol) was added. After warming to room temperature over 90 min, the reaction was quenched with saturated aqueous ammonium chloride and extracted into EtOAc. The organic layer was washed with brine, passed through a hydrophobic frit, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0–60% EtOAc in cyclohexane to afford CB11.1 (1.50 g, 42%) as a tan oil that solidified upon standing. m / z=362.2[M+H]+, 1 H NMR(400MHz,CDCl3):δ 8.18(dd,J=1.8,6.6Hz,1H),7.94-7.89(m,1H),7.19(dd,J=8.3,8.3Hz,1H),4.70-4.59(m, 1H),3.26-3.22(m,2H),2.98(dd,J=7.1,7.1Hz,2H),1.99-1.88(m,2H),1.27-1.14(m,9H).

[0431] Step 2: 2-(3-bromo-4-fluorophenyl)pyrrolidine (CB11.2) To a solution of tert-butyl (4-(3-bromo-4-fluorophenyl)-4-oxobutyl)carbamate (CB11.1) (1.50 g, 4.16 mmol) in DCM (15 mL) was added trifluoroacetic acid (15 mL, 196 mmol). After stirring at room temperature for 30 min, the solvent was removed under reduced pressure. The crude residue was taken up in THF (30 mL) and treated with trimethylamine (0.70 mL, 5.00 mmol), followed by sodium triacetoxyborohydride (2.65 g, 12.5 mmol). After 2 h, sodium cyanoborohydride (392 mg, 6.24 mmol) was added. After stirring for 30 min, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted into EtOAc. The organic layer was separated, passed through a hydrophobic frit, and concentrated under reduced pressure to give CB11.2 as an oil, which was used in the subsequent step without further purification. m / z=246.1 [M+H]+.

[0432] Step 3: 1-(2-(3-bromo-4-fluorophenyl)pyrrolidin-1-yl)ethan-1-one (CB11.3) To a solution of 2-(3-bromo-4-fluorophenyl)pyrrolidine (CB11.2) (510 mg, 2.0 mmol) in THF (20 mL) and triethylamine (350 mL, 2.5 mmol) was added acetyl chloride (220 mL, 3.1 mmol). After stirring at room temperature for 4 h, the reaction was quenched with saturated NaHCO solution and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using 0-60% ethyl acetate to afford CB11.3 (310 mg, 52%) as a colorless, clear oil. 1 H NMR(400MHz,CDCl3)7.38-7.28(1H,m),7.12-7.02(2H,m),5.14-4.86(1H, m),3.77-3.57(2H,m),2.46-2.21(1H,m),2.13(3H,s),2.01-1.85(3H,m).

[0433] Step 4: 1-(2-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)pyrrolidin-1-yl)ethan-1-one (CB11) The desired product was prepared using 1-(2-(3-bromo-4-fluorophenyl)pyrrolidin-1-yl)ethan-1-one (CB11.3) following the representative procedure outlined in Method CB3 to give the crude product (CB11) as a reddish-brown oil, which was used in the subsequent step without further purification.

[0434] Method CB12 - 6-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzyl)-2-oxa-6-azaspiro[3.3]heptane (CB12) [ka] Step 1: 6-(3-Bromo-4-fluorobenzyl)-2-oxa-6-azaspiro[3.3]heptane (CB12.1) To a solution of 3-bromo-4-fluorobenzaldehyde (CB12.0) (250 mg, 1.23 mmol) in 2-propanol (10 mL) was added 2-oxa-6-azaspiro[3.3]heptane (244 mg, 2.46 mmol) and titanium(IV) isopropoxide (0.53 mL, 1.79 mmol). After stirring at room temperature overnight, the reaction was then treated with sodium borohydride (47 mg, 1.23 mmol). After stirring at room temperature for 1 hour, the reaction was quenched with 6 M aqueous HCl, stirred at room temperature for 2 hours, and neutralized to a pH of approximately 10 with 4 M aqueous NaOH. The reaction mixture was extracted into diethyl ether, and the organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was loaded onto an SCX cartridge and eluted with 10% (7N NH in MeOH) in DCM to give CB12.1 (234 mg, 66%) as a colorless oil. m / z=288.0 [M+H], 1H NMR (400MHz, CDCl3): δ 7.48-7.43(m,1H),7.16-7.11(m,1H),7.05(dd,J=8.3,8.3Hz,1H),4.74(s,4H),3.47(s,2H),3.35(s,4H).

[0435] Step 2: 6-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzyl)-2-oxa-6-azaspiro[3.3]heptane (CB12) To a degassed solution of 6-(3-bromo-4-fluorobenzyl)-2-oxa-6-azaspiro[3.3]heptane (CB12.1) (234 mg, 0.82 mmol) in 1,4-dioxane (5 mL) in a large carousel tube, bis(pinacolato)diboron (311 mg, 1.23 mmol), potassium acetate (241 mg, 2.45 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.04 mmol) were added. The reaction mixture was degassed and purged with nitrogen. After stirring the sealed tube at 115 °C for 3 h, the reaction mixture was allowed to cool to room temperature, and compound (CB12) was carried on to the next step without further purification.

[0436] Method CB13 - 1,1,1-trifluoro-2-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)-N,N-dimethylpropan-2-amine (CB13) [ka] Step 1: N-(2-(3-bromo-4-fluorophenyl)-1,1,1-trifluoropropan-2-yl)acetamide (CB13.1) A solution of 1-(3-bromo-4-fluorophenyl)ethan-1-one (CB13.0) (1.00 g, 4.61 mmol) in THF (15 mL) was placed under a nitrogen atmosphere and then treated with trimethyl(trifluoromethyl)silane (0.82 mL, 5.53 mmol) and tetrabutylammonium fluoride (1 M in THF, 0.23 mL, 0.23 mmol). After stirring at room temperature for 24 h, the reaction mixture was then charged with additional trimethyl(trifluoromethyl)silane (0.82 mL, 5.53 mmol). After stirring at room temperature for 2 h, the solvent was evaporated under reduced pressure and the crude residue was taken up in acetonitrile (10 mL). The solution was treated with sulfuric acid (1.0 mL, 18.8 mmol) and heated to 80 °C for 24 h. The reaction mixture was cooled to room temperature, neutralized by the dropwise addition of saturated aqueous sodium bicarbonate, and extracted into DCM (3 x 20 mL). The combined organic layers were washed with brine (30 mL), passed through a hydrophobic frit, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0-60% EtOAc in cyclohexane to afford CB13.1 (275 mg, 18%) as a white solid. m / z = 329.9 [M+H]+, 1 H NMR (400MHz, CDCl3): δ 7.60(d,J=4.8Hz,1H),7.39-7.33(m,1H),7.11(dd,J=8.5,8.5Hz,1H),6.05(s,1H),2.05(d,J=19.7Hz,6H).

[0437] Step 2: N-(2-(3-bromo-4-fluorophenyl)-1,1,1-trifluoropropan-2-yl)-N-methylacetamide (CB13.2) To a suspension of sodium hydride (60 wt% dispersion in mineral oil, 34 mg, 0.84 mmol) in DMF (3 mL) was added N-(2-(3-bromo-4-fluorophenyl)-1,1,1-trifluoropropan-2-yl)acetamide (CB13.1) (250 mg, 0.76 mmol). After stirring at room temperature for 2 h, iodomethane (0.05 mL, 0.84 mmol) was added. After heating at 85 °C for 16 h, the reaction was cooled to room temperature and quenched with 4% aqueous lithium chloride solution (10 mL). The mixture was extracted into DCM (3 × 15 mL), and the combined organic layers were washed with brine (20 mL), passed through a hydrophobic frit, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0–60% EtOAc in cyclohexane to afford CB13.2 (120 mg, 46%) as a colorless oil. m / z=343.9[M+H]+, 1 H NMR (400MHz, CDCl3): δ 7.50(d,J=5.1Hz,1H),7.08(dd,J=8.3,8.3Hz,2H),3.16(s,3H),2.10(s,3H),1.54(s,3H).

[0438] Step 3: 2-(3-bromo-4-fluorophenyl)-1,1,1-trifluoro-N-methylpropan-2-amine (CB13.3) A solution of N-(2-(3-bromo-4-fluorophenyl)-1,1,1-trifluoropropan-2-yl)-N-methylacetamide (CB13.2) (115 mg, 0.34 mmol) in ethanol (2 mL) and water (0.2 mL) was treated with aqueous hydrochloric acid (11 M, 0.15 mL, 1.68 mmol). After stirring at 100 °C for 4 days, the reaction was cooled to room temperature and the solvent was removed under reduced pressure to give CB13.3 (89 mg, 88%) as a white solid, which was used in the subsequent step without further purification. m / z = 302.0 [M+H]+.

[0439] Step 4: 1,1,1-trifluoro-2-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)-N-methylpropan-2-amine (CB13) A mixture of 2-(3-bromo-4-fluorophenyl)-1,1,1-trifluoro-N-methylpropan-2-amine (CB13.3) (89 mg, 0.30 mmol), bis(pinacolato)diboron (90 mg, 0.36 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (12 mg, 0.01 mmol), and potassium acetate (87 mg, 0.89 mmol) in 1,4-dioxane (4 mL) was degassed and purged with nitrogen. After stirring at 100 °C for 2.5 h, the reaction was cooled to room temperature and filtered through a Celite® pad (2.5 g) eluting with DCM. The filtrate was concentrated under reduced pressure to give crude CB13, which was used in the subsequent step without further purification.

[0440] Method CB14 -(2-Cyclopropyl-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)(piperidin-1-yl)methanone (CB14) [ka] Step 1: 4-Bromo-5-fluoro-2-iodobenzoic acid (CB14.1) Potassium permanganate (5.02 g, 31.8 mmol) was added to a solution of 4-bromo-5-fluoro-2-iodotoluene (CB14.0) (1.00 g, 3.18 mmol) in water (12 mL) and pyridine (8 mL). After stirring at 100 °C overnight, the reaction was allowed to reach room temperature, filtered through a pad of Celite, and washed with water (20 mL). The aqueous layer was washed with EtOAc (2 × 15 mL) and then acidified with HCl 2N to pH ∼1. The cloudy suspension was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The desired product (CB14.1) was isolated as a white solid and used in the next step without further purification (520 mg, 47%). m / z = 344.9 [M+H]+, 1H NMR(400MHz,DMSO):δ 12.6(s,1H),8.37(d,J=6.8Hz,1H),7.76(d,J=9.3Hz,1H).

[0441] Step 2: Methyl 4-bromo-5-fluoro-2-iodobenzoate (CB14.2) Sulfuric acid (0.04 mL, 0.754 mmol) was added to a solution of (CB14.1) (0.52 g, 1.51 mmol) in MeOH (0.8 mL). After stirring overnight at 65 °C, the reaction was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 x 8 mL). The organic solvent was evaporated under reduced pressure to give the desired compound (CB14.2) as a crystalline solid (420 mg, 78%). m / z = 358.9 [M+H]+, 1 H NMR (400MHz, CDCl3): δ 8.20(d,J=6.6Hz,1H),7.62(d,J=8.8Hz,1H),3.90(s,3H).

[0442] Step 3: Methyl 4-bromo-5-fluoro-2-vinylbenzoate (CB14.3) A degassed solution of (CB14.2) (500 mg, 1.39 mmol), potassium vinyltrifluoroborate (220 mg, 1.16 mmol), cesium carbonate (910 mg, 2.79 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (100 mg, 0.14 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and the solvent was evaporated. The crude was purified by silica gel chromatography eluting with 0-60% EtOAc in cyclohexane to give the title compound (CB14.3) (200 mg, 56%) as a clear solid. m / z = 259.1 [M+H]+, 1 H NMR(400MHz,CDCl3):δ 7.76(d,J=6.6Hz,1H),7.65(d,J=9.1Hz,1H),7.39(d,J=6.6Hz,1H),5.60(d,J=17.4Hz,1H),5.38(d,J=11.1Hz,1H),3.90(s,3H).

[0443] Step 4: Methyl 4-bromo-2-cyclopropyl-5-fluorobenzoate (CB14.4) A degassed solution of diethylzinc (1.5 mL, 1.54 mmol) in dry DCM (2 mL) at 0 °C was treated with a degassed solution of TFA (0.12 mL, 1.54 mmol) in dry DCM (1 mL). After stirring for 20 min at 0 °C, diiodomethane (0.12 mL, 1.54 mmol) in dry DCM (2 mL) was added. After stirring for 20 min at 0 °C, a solution of (CB14.3) (200 mg, 0.777 mmol) in dry DCM (1 mL) was added. After stirring for 120 min at room temperature, the reaction was quenched with NH4Cl (5 mL). The organic phase was collected, concentrated, and purified on silica gel (eluting with 0-70% EtOAc in cyclohexane) to give the title compound (CB14.4) (200 mg, 95%) as a clear solid. m / z = 273.1 [M+H]+ 1 H NMR (400MHz, CDCl3): δ 7.56(d,J=8.8Hz,1H),7.20(d,J=6.6Hz,1H),3.91(s,3H),2.65-2.53(m,1H),1.04-0.95(m,2H),0.64(q,J=5.4Hz,2H).

[0444] Step 5: 4-Bromo-2-cyclopropyl-5-fluorobenzoic acid (CB14.5) To a solution of (CB14.4) (200 mg, 0.732 mmol) in dry THF (10 mL) was added LiOH (2 M in water, 0.81 mL, 1.61 mmol). After stirring at room temperature overnight, the resulting precipitate was collected and used in the next step without further purification. m / z = 259.1 [M+H]+.

[0445] Step 6: (4-Bromo-2-cyclopropyl-5-fluorophenyl)(piperidin-1-yl)methanone (CB14.6) To a stirred solution of (CB14.5) (120 mg, 0.463 mmol) in dry THF (5 mL) was added 1-hydroxybenzotriazole (81 mg, 0.60 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (115 mg, 0.60 mmol). After stirring at room temperature for 1 h, DIPEA (0.24 mL, 1.39 mmol) and piperidine (0.05 mL, 0.55 mmol) were added. After stirring at room temperature for 3 h, the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 0-60% EtOAc in cyclohexane to afford the title compound (CB14.6) (74 mg, 49%) as a clear oil. m / z = 326.2 [M+H]+, 1 H NMR(400MHz,CDCl3):δ 7.06(d,J=6.3Hz,1H),6.93(d,J=8.1Hz,1H),3.79-3.61(m,2H),3.20(dd,J=5.4,5.4Hz, 2H),1.92-1.79(m,1H),1.67(t,J=11.6Hz,4H),1.50(d,J=4.3Hz,4H),1.01-0.75(m,2H).

[0446] Step 7: (2-Cyclopropyl-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)(piperidin-1-yl)methanone (CB14) To a mixture of (CB14.6) (74 mg, 0.23 mmol), bis(pinacolato)diboron (69 mg, 0.27 mmol), and potassium acetate (67 mg, 0.68 mmol) in 1,4-dioxane (4 mL) under a N atmosphere was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (9.3 mg, 0.01 mmol). After stirring at 100 °C for 3.5 h, the reaction was cooled to room temperature, filtered through Celite, and extracted with DCM (2 × 10 mL). The combined organic layers were concentrated in vacuo to give the product (CB14), which was used in the next step without further purification (81 mg, 95%). m / z = 373.2 [M+H].

[0447] The following boronate intermediates were prepared according to any of the intermediate methods CB1-CB14 described above. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8]

[0448] Method PB1 - Preparation of N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)cyclohexanecarboxamide (PB1) [ka] Step 1 of N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)cyclohexanecarboxamide (PB1) To a solution of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)aniline (CB2.0) (10 g, 0.0421 mol, 1.0 equiv.) in DCM (60 mL) and diisopropylethylamine (15 mL) was added cyclohexanecarbonyl chloride (509 mL, 0.08435 mol, 2.0 equiv.). After stirring at room temperature for 16 hours, the reaction mixture was diluted with DCM (500 mL) and washed with saturated sodium bicarbonate (300 mL) followed by water (300 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by trituration with diethyl ether (2×30 mL) to give the title compound PB1 (12.5 g, 85.35%). MS (ES): m / z 348.2 [M+H] + .

[0449] Method PB2 - Preparation of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)morpholin-3-one (PB2) [ka] Step 1. 4-(3-Bromophenyl)morpholin-3-one (PB2.1) To a solution of morpholin-3-one (1 g, 9.90 mmol, 1.0 equiv.) in 1,4-dioxane (100 mL) was added 1,3-dibromobenzene PB2.0 (2.6 g, 11.4 mmol, 1.1 equiv.) at room temperature. The reaction mixture was degassed under an argon atmosphere for 10 minutes, followed by the addition of cesium carbonate (6.2 g, 19.8 mmol, 2.0 equiv.), (palladium acetate) Pd(OAc)2 (0.21 g, 0.99 mmol, 0.1 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.8 g, 7.5 mmol, 0.1 equiv.). The reaction mixture was heated in three parallel reactions at 100 °C for 16 h. After completion of the reactions, the reaction mixtures were cooled to room temperature, combined, filtered, and concentrated under reduced pressure. The crude product was subjected to flash chromatography eluting with 0-30% ethyl acetate in hexane. The solvent was evaporated under reduced pressure to give the desired product (PB2.1) (3.0 g, 39.48%). MS (ES): m / z 258.1 [M+2H] +

[0450] Step 2. 6-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)morpholin-3-one (PB2) To a solution of 4-(3-bromophenyl)morpholin-3-one (PB2.1) (3.0 g, 11.7 mmol, 1.0 equiv.) in 1,4-dioxane (30 mL) was added bis(pinacolato)diborane (3.5 g, 14.0 mmol, 1.2 equiv.). The reaction mixture was degassed under argon for 10 min, followed by the addition of potassium acetate (3.4 g, 35.1 mmol, 3.0 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2) (0.85 g, 1.17 mmol, 0.1 equiv.). After stirring at 100 °C for 4 h, the reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product was subjected to flash chromatography, eluting with 10–80% ethyl acetate in hexanes. The solvent was evaporated under reduced pressure to give the desired product PB2 (3.2 g, yield: 90.11%). MS (ES): m / z 304.1 [M+H] +

[0451] Method PB3 - Preparation of 6-amino-2-fluoro-N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzamide (PB3) [ka] Step 1. Methyl 2-amino-6-fluorobenzoate (PB3.1) To a solution of 2-amino-6-fluorobenzoic acid (2 g, 12.892 mmol, 1.0 equiv.) in DCM (20 mL) and methanol (5 mL) at 0 °C under a nitrogen atmosphere was added (trimethylsilyl)diazomethane (0.6 M) (22 mL, 12.9 mmol, 1.0 equiv.). After stirring at room temperature for 3 h, the reaction mixture was slowly quenched with acetic acid until bubbling ceased. The reaction mixture was diluted with DCM (50 mL) and washed with saturated sodium bicarbonate solution (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 2% ethyl acetate in hexane to give PB3.1 (2.1 g, 96.29%). MS (ES): m / z 170.1 [M+H] +

[0452] Step 2. Methyl 6-amino-2-fluoro-3-bromobenzoate (PB3.2) To a solution of methyl 2-amino-6-fluorobenzoate PB3.1 (2.1 g, 12.416 mmol, 1.0 equiv.) in ethanol (20 mL) was added dropwise silver sulfate (2.1 g, 14.899 mmol, 1.2 equiv.) and bromine (2.98 g, 18.62 mmol, 1.5 equiv.) in ethanol at 0 °C. After stirring at room temperature for 3 h, the reaction mixture was quenched with sodium thiosulfate and ethyl acetate (100 ml). The mixture was filtered through a Celite bed, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 4% ethyl acetate in hexane to give PB3.2 (1.5 g, 48.71%). MS (ES): m / z 249.1 [M+H] +

[0453] Step 3. 6-Amino-2-fluoro-3-bromo-N,N-dimethylbenzamide (PB3.3) To a solution of methyl 6-amino-3-bromo-2-fluorobenzoate PB3.2 (1.4 g, 5.645 mmol, 1.0 equiv.) in toluene (10 mL) was added dimethylamine (2.0 M in THF) (4.8 mL, 9.596 mmol, 1.7 equiv.) and trimethylaluminum (2.0 M in THF) (4.8 mL, 9.596 mmol, 1.7 equiv.). After stirring at room temperature for 16 hours, the reaction mixture was quenched with cold water (100 mL) and ethyl acetate (150 mL). The mixture was filtered through a Celite bed, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 75% ethyl acetate in hexane to give PB3.3 (0.45 g, 30.54%). MS (ES): m / z 262.1 [M+H] +

[0454] Step 4. 6-Amino-2-fluoro-N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzamide (PB3) To a solution of methyl 6-amino-3-bromo-2-fluoro-n,n-dimethylbenzamidofluorobenzoate PB3.3 (0.4 g, 1.532 mmol, 1.0 equiv.) in 1,4-dioxane (8 mL), bis-pinacolatodiboron (1.17 g, 4.597 mmol, 3.0 equiv.) and potassium acetate (0.45 g, 4.597 mmol, 3.0 equiv.) were added. After degassing with argon gas for 15 minutes and stirring, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (xphos PdG2) (0.12 g, 0.153 mmol, 0.1 equiv.) was added at room temperature. After stirring at 120°C for 2.5 hours, the reaction mixture was quenched with water (50 ml). The aqueous layer was washed with ethyl acetate (100 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 2% methanol in DCM to give PB3 (0.4 g, 84.73%). MS (ES): m / z 309.1 [M+H] +

[0455] Method PB4 - Preparation of 1-ethyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)cyclobutane-1-carboxamide (PB4) [ka] Step 1. 1-Ethylcyclobutane-1-carboxylic acid (PB4.1) To a stirred solution of cyclobutanecarboxylic acid (1 g, 5.0 mmol, 1 equiv.) in dry THF was added lithium diisopropylamide (2 M in THF) (10 mL, 20.00 mmol, 2.0 equiv.) at 0 °C under an argon atmosphere. After stirring at 0 °C for 2 h, ethyl iodide (1.7 g, 11 mmol, 1.1 equiv.) was added. After stirring at room temperature for 16 h, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml × 3). The combined organic layers were washed with brine solution (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give PB4.1, which was used as such in the next step without further purification (1.2 g, 100%). 1 H NMR(DMSO-d6,400MHZ):12.08(s,1H),1.82(m,4H),1.60(m,2H),1.48(q,2H),0.94(t,3H).

[0456] Step 2. 1-Ethyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)cyclobutane-1-carboxamide (PB4) To a stirred solution of PB4.1 (1.2 g, 9.375 mmol, 1.2 equiv) in THF was added phosphorus oxychloride and pyridine at 0 °C. After stirring at 0 °C for 20 min, a solution of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)aniline (CB2.0) (2.554 g, 7.812 mmol, 1.0 equiv) in THF was added dropwise. After stirring at room temperature for 1 h, the reaction mixture was poured into water (100 ml), neutralized with sodium bicarbonate, and extracted with ethyl acetate (100 ml × 3). The combined organic layers were washed with brine solution (50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Combiflash chromatography eluting with 9% ethyl acetate in hexane to give pure PB4 (0.350 g, 10.75%). MS(ES): m / z 348.24[M+H]+.

[0457] Preparation of Compounds of the Invention Example 1: Method A—Preparation of 2-(2-fluoro-5-methoxyphenyl)-4-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1,6-naphthyridin-5(6H)-one (I-42) [ka] Step 1: 2,4-Dichloro-1,6-naphthyridin-5(6H)-one (1.1) To a solution of ethyl 4,6-dichloro-2-methylnicotinate (1.0) (20 g, 85.4 mmol) in tert-butanol (200 mL) was added 1,3,5-triazine (13.8 g, 170.8 mmol) and potassium tert-butoxide (19.1 g, 170.8 mmol). After stirring at 90° C. for 1 hour, the mixture was cooled to room temperature and evaporated under reduced pressure. The resulting residue was diluted with water (300 mL) and then acidified to approximately pH 5 using 2 M aqueous HCl. The resulting suspension was stirred at room temperature for 1 hour, after which the solid was collected by filtration and washed with water. The crude solid was suspended in 4:1 DCM:acetonitrile (250 mL) and stirred for 20 minutes. The solid was collected by filtration and washed with 1:1 DCM:diethyl ether (100 mL). Residual water was removed from the solid via azeotropic distillation with toluene (200 mL). Compound (1.1) was obtained as a brown solid (9.43 g, 51%) and used without further purification. m / z=215.9 [M+H] + , 1 H NMR (400MHz, DMSO): δ 11.82(s,1H),7.75(s,1H),7.60(t,J=5.9Hz,1H),6.59(d,J=7.1Hz,1H).

[0458] Step 2. 2-Chloro-4-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1,6-naphthyridin-5(6H)-one (1.2) To a 10-20 mL microwave tube charged with 2,4-dichloro-1,6-naphthyridin-5(6H)-one (1.1) (1.61 g, 7.5 mmol) and N,N-diisopropylethylamine (2.6 mL, 15 mmol) in n-butanol (12.0 mL), 1-(6-aminopyridin-3-yl)piperidin-4-ol (preparation described in WO 2015 / 131080, 1.59 g, 8.25 mmol) was added. After heating at 160 °C for 6 h in a Biotage Initiator® microwave synthesizer, the precipitate was isolated by filtration and washed sequentially with ethyl acetate (15 mL) and diethyl ether (40 mL). The reaction was carried out three times in parallel at the same scale and combined to give the crude product (1.2) (5.02 g, 60%) as a brown solid, which was used without further purification. m / z=372.5[M+H] + , 1 H NMR(400MHz,DMSO):δ 12.57(s,1H),11.90(d,J=3.8Hz,1H),8.43(s,1H),8.20-8.15(m,1H),7.53(d,J=6.6Hz,2H),7.07-7.02(m,1H),6.53(d,J=7.1 Hz,1H),4.76-4.72(m,1H),3.70(dd,J=3.4,4.2Hz,1H),3.61(s,2H),2.98-2.88(m,2H),1.89-1.87(m,2H),1.57-1.50(m,2H).

[0459] Step 3 - 2-(2-Fluoro-5-methoxyphenyl)-4-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1,6-naphthyridin-5(6H)-one (I-42) To a 2-5 mL microwave vial charged with 2-chloro-4-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1,6-naphthyridin-5(6H)-one (1.2) (100 mg, 0.269 mmol), 2-fluoro-5-methoxyphenylboronic acid (69 mg, 0.403 mmol) in dioxane (4.0 mL), water (0.5 mL), and KPO (228 mg, 1.08 mmol) was added XPhos Pd G2 catalyst (21 mg, 0.027 mmol). The mixture was degassed, purged with N2, and heated to 150 °C for 45 min on a Biotage Initiator® synthesizer. The mixture was loaded onto a Biotage-ISOLUTE® HM-N cartridge and purified by silica gel chromatography (eluting with 0-20% MeOH in DCM). The isolated yellow residue was treated with EtO, collected by filtration, washed with EtO, and dried under vacuum at 40 °C to give the title compound (I-42) (81 mg, 65%) as a yellow solid. m / z = 462 [M+H] + , 1 H NMR(400MHz,DMSO):δ 12.42(s,1H),11.68-11.62(m,1H),8.72(d,J=1.4Hz,1H),8.07(d,J=3.0Hz,1H), 7.50-7.46(m,2H),7.42(d,J=7.3Hz,1H),7.29(dd,J=9.0,10.5Hz,1H),7.11-7.0 1(m,2H),6.60(d,J=7.3Hz,1H),4.70(d,J=4.3Hz,1H),3.83(s,3H),3.68-3.61(m ,1H),3.57-3.49(m,2H),2.92-2.83(m,2H),1.88-1.80(m,2H),1.56-1.45(m,2H).

[0460] Example 2: Method B—Preparation of 2-(2,6-difluoro-3-methoxyphenyl)-4-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1,6-naphthyridin-5(6H)-one (I-92) [ka] Step 1: Ethyl 4-chloro-6-(2,6-difluoro-3-methoxyphenyl)-2-methylnicotinate (2.1) A solution of 2,6-difluoro-3-methoxy-bromobenzene (838 mg, 3.76 mmol) in dry THF (5 mL) was treated dropwise with isopropylmagnesium chloride lithium chloride complex solution (1.3 M in THF, 4.2 mL, 5.40 mmol) at −78° C. under a nitrogen atmosphere. After stirring at −78° C. for 40 min, zinc chloride (2 M in THF, 5.6 mL, 11.28 mmol) was added dropwise. After warming to 0° C. for 20 min, the organo-zinc suspension was added to a mixture of ethyl 4,6-dichloro-2-methylnicotinate (1.0) (550 mg, 2.35 mmol) and Pd(PPh) (272 mg, 0.235 mmol) in degassed and nitrogen-purged THF (7 mL). After stirring overnight at room temperature, the reaction was quenched with saturated NH4Cl and extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-60% EtOAc in cyclohexane gradient elution) to afford the title compound (2.1) (745 mg, 93%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ 7.39(s,1H),7.02-6.90(m,2H),4.49(q,J=7.2Hz,2H),3.90(s,3H),2.63(s,3H),1.44(dd,J=7.2,7.2Hz,3H).

[0461] Step 2: 4-chloro-2-(2,6-difluoro-3-methoxyphenyl)-1,6-naphthyridin-5(6H)-one (2.2) The reaction was carried out following the representative procedure outlined in Example 1, Method A, Step 1 to give the product (2.2). 1 H NMR(400MHz,DMSO):δ 11.67-11.67(m,1H),7.76(s,1H),7.53(d,J=7.3Hz,1H),7.41-7.33(m,1H),7.27-7.19(m,1H),6.63(d,J=7.3Hz,1H),3.90(s,3H).

[0462] Step 3: 2-(2,6-Difluoro-3-methoxyphenyl)-4-((5-(4-hydroxypiperidin-1-yl)pyridin-2-yl)amino)-1,6-naphthyridin-5(6H)-one (I-92) The reaction was carried out following the representative procedure outlined in Example 1, Step 2 to afford the product (I-92). 1 H NMR (400 MHz, DMSO): δ 12.45(s,1H),11.64(s,1H),8.35(s,1H),7.97(d,J=2.8Hz,1H),7.41-7.33(m ,2H),7.27-7.18(m,1H),7.10(dd,J=9.0,9.0Hz,1H),6.92(d,J=9.1Hz,1H),6 .47(d,J=7.3Hz,1H),4.60(d,J=4.0Hz,1H),3.82(s,3H),3.60-3.50(m,2H),3 .15-3.08(m,1H),2.82-2.73(m,2H),1.72(d,J=9.6Hz,2H),1.46-1.34(m,2H).

[0463] Example 3: Method C - Preparation of 4-((1-ethyl-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-2-(2-fluoro-5-methoxy-4-(piperidine-1-carbonyl)phenyl)-1,6-naphthyridin-5(6H)-one (I-228) [ka] Step 1. 4-Chloro-2-(2-fluoro-5-methoxy-4-(piperidine-1-carbonyl)phenyl)-1,6-naphthyridin-5(6H)-one (3.1) To a mixture of 2,4-dichloro-1,6-naphthyridin-5(6H)-one (1.1) (250 mg, 1.16 mmol), (5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)(piperidin-1-yl)methanone (CB1) (422 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium (134 mg, 10 mol%) in DME (5.0 mL) under a nitrogen atmosphere was added a solution of potassium carbonate (2 M in HO, 1.3 mL, 2.56 mmol). The reaction mixture was purged with a stream of nitrogen for 5 minutes and then heated at 100 °C for 1 hour in a Biotage Initiator microwave synthesizer. The crude reaction mixture was cooled to room temperature, filtered through a Celite® pad (2.5 g), and flushed with DCM. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-15% MeOH / DCM gradient elution) to give 3.1 (381 mg, 63% yield, 80% purity), which was carried on to the next step without further purification. m / z=416.7 [M+H] + .

[0464] Step 2. 4-Chloro-2-(2-fluoro-5-methoxy-4-(piperidine-1-carbonyl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-5(6H)-one (3.2) To a mixture of 4-chloro-2-(2-fluoro-5-methoxy-4-(piperidine-1-carbonyl)phenyl)-1,6-naphthyridin-5(6H)-one (3.1) (200 mg, 0.48 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.34 mL, 1.92 mmol) in THF (5.0 mL) that had been degassed with a stream of nitrogen for 5 min, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL, 2.40 mmol) was added. After stirring at room temperature for 16 h, the solvent was removed under reduced pressure, diluted with water (15 mL), and extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (15 mL), passed through a hydrophobic frit, and concentrated under reduced pressure. The crude material was purified using silica gel chromatography with 0-20% MeOH / DCM to give (3.2) (234 mg, 89% yield, 84% purity) as a yellow oil, with 16% unreacted (3.1) co-eluting. The compound was carried on to the next step without further purification. m / z=546.9 [M+H] + .

[0465] Step 3. 4-((1-ethyl-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-2-(2-fluoro-5-methoxy-4-(piperidine-1-carbonyl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-5(6H)-one (3.3) To a mixture of 4-amino-1-ethylpyrimidin-2(1H)-one (42 mg, 0.30 mmol), Xantphos (23 mg, 0.04 mmol), and cesium carbonate (92 mg, 0.28 mmol) in 1,4-dioxane (2.5 mL) was added 4-chloro-2-(2-fluoro-5-methoxy-4-(piperidine-1-carbonyl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-5(6H)-one (3.2) (110 mg, 0.20 mmol). The reaction mixture was degassed with a stream of nitrogen for 10 minutes, stirred at room temperature, degassed for an additional 5 minutes, treated with palladium(II) acetate (4.5 mg, 0.02 mmol), and then heated at 100° C. for 16 hours. The crude material was filtered through a pad of Celite® (2.5 g frit) eluting with 5% MeOH / DCM and then passed through a silica gel column with 0-20% MeOH / DCM to give the title compound (3.3) (88 mg, 67% yield, 62% purity), which was used without further purification. m / z=649.2 [M+H] + .

[0466] Step 4. 4-((1-ethyl-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-2-(2-fluoro-5-methoxy-4-(piperidine-1-carbonyl)phenyl)-1,6-naphthyridin-5(6H)-one (I-228) A solution of crude 4-((1-ethyl-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-2-(2-fluoro-5-methoxy-4-(piperidine-1-carbonyl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-5(6H)-one (3.3) (88 mg, 0.14 mmol) in DCM (1.0 mL) was treated dropwise with trifluoroacetic acid (0.50 mL). After stirring at room temperature for 16 h, the solvent was removed under reduced pressure. The crude material was neutralized with saturated aqueous sodium bicarbonate (5 mL) and extracted into DCM (3 x 5 mL). The combined organic layers were washed with brine (10 mL), passed through a hydrophobic frit, and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 4-((1-ethyl-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-2-(2-fluoro-5-methoxy-4-(piperidine-1-carbonyl)phenyl)-1,6-naphthyridin-5(6H)-one (I-228) (23 mg, 33%) as a white solid. m / z=519.7 [M+H] + , 1 H NMR(400MHz,DMSO):δ 12.98(s,1H),11.94(s,1H),9.35(s,1H),8.01(d,J=7.1Hz,1H),7.58-7 .49(m,2H),7.27(d,J=10.1Hz,1H),6.73(d,J=7.3Hz,1H),6.13(d,J=7. 1Hz,1H),3.86(s,3H),3.81(q,J=7.0Hz,2H),3.66-3.54(m,2H),3.19-3 .13(m,2H),1.61-1.56(m,4H),1.48-1.44(m,2H),1.22(t,J=...

Claims

1. A compound of formula I, 【Chemistry 95】 or a pharma- ceutically acceptable salt thereof, wherein: X is N or CR ３ and Y is N or CR ２ and Z is N or CR ２ and A is N or CR ２ and L 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 L is C １－４ A divalent saturated or unsaturated, linear or branched hydrocarbon chain, 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 - has been replaced by R １ But H;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 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from q R Ｃ has been replaced by the example Each R ２ are independently H;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; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 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, each of which is selected from r R Ｄ or R ２ is halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O)(NR)R, -S(O) ２ N.R. 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)R, -N(R)C(O)OR, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)S(O) ２ N.R. ２ , -N(R)S(O) ２ R or -P(O)R ２ and Each R ３ are independently H;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 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from s R Ｅ or R ３ is halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O)(NR)R, -S(O) ２ N.R. 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)R, -N(R)C(O)OR, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)S(O) ２ N.R. ２ , -N(R)S(O) ２ R or -P(O)R ２ and R ４ is H or C １－６ aliphatic, which is represented by t R Ｆ has been replaced by the example R Ｃ , R Ｄ , R Ｅ , and R Ｆ Each instance is independently oxo, halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. 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 N.R. 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 , R Ｄ , R Ｅ , and R Ｆ 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; 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; 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, each of which is substituted with u instances of R; 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; an optionally substituted group selected from: a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; a 6-11 membered saturated or unsaturated bicyclic heterocyclic ring having 1-2 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; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 1, 2, or 3; n is 0, 1, or 2; each of q, r, s, and t is independently 0, 1, 2, 3, or 4; A compound, or a pharma- ceutically acceptable salt thereof, wherein u is 0, 1, 2, 3, or 4.

2. The compound is a compound of formula II 【Chemistry 96】 2. The compound of claim 1, wherein:

3. The compound is a compound of formula III 【Chemistry 97】 2. The compound of claim 1, wherein:

4. The compound is a compound of formula IV 【Chemistry 98】 4. The compound according to claim 1, wherein:

5. The compound is a compound of formula V 【Chemistry 99】 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

6. The compound is a compound of formula VI 【Chemistry 100】 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

7. The compound is a compound of formula VII 【Chemistry 101】 4. The compound according to claim 1, wherein:

8. The compound is a compound of formula VIII 【Chemistry 102】 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

9. The compound is a compound of formula IX 【Chemistry 103】 4. The compound according to claim 1, wherein:

10. The compound is a compound of formula X 【Chemistry 104】 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

11. The compound is a compound of formula XI 【Chemistry 105】 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

12. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein X is -NR-.

13. R １ Let q be R Ｃ In the example, C is replaced １－６ Aliphatic; q R Ｃ phenyl substituted with q instances of R Ｃ a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with, for example, q R Ｃ a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with, for example, q R Ｃ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 12, wherein the heterocyclic ring is 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 with, for example,

14. R １ cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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 nyl, pyranyl, pyrazinyl, pyrazolidinyl, 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 R Ｃ 13. The compound according to any one of claims 1 to 12, wherein the compound is substituted by, for example,

15. R １ is phenyl, 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 q R Ｃ 13. The compound according to any one of claims 1 to 12, wherein the compound is substituted by, for example,

16. R １ but, 【Chemistry 106】 and In the formula, R Ｃ Each instance is independently halogen, -CN, -OR, -S(O) ２ R, -S(O)NR ２ , -C(O)NR ２ , C １－６ aliphatic; 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 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, 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; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from r instances of R and s instances of R. Ｄ or a pharma- ceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 15, wherein

17. R １ but, 【Chemistry 107】 and In the formula, R Ｃ Each instance of is independently -Me, -Et, -CH ２ N (CH ３ ) ２ , -CN, -CH ２ CN, -F, -OMe, -S(O) ２ Me, -CH ２ S (O) ２ Me, 【Chemistry 108】 【Chemistry 109】 17. The compound according to any one of claims 1 to 16, wherein:

18. R １ but, 【Chemistry 110】 【Chemistry 111】 【Chemistry 112】 【Chemistry 113】 18. The compound according to any one of claims 1 to 17, wherein:

19. R ２ But, 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 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from r R Ｄ or a pharma- ceutically acceptable salt thereof.

19. The compound according to any one of claims 1 to 18, wherein

20. R ２ is -H, -Et, -i-Pr, s-Bu, straight chain or branched pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, azetidinyl; 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; a 7-10 membered fused bicyclic ring having 1-3 nitrogen atoms; a 9 membered fused bicyclic ring having 1-3 nitrogen atoms, each of which is represented by r R Ｄ 20. The compound according to any one of claims 1 to 19, wherein the compound is substituted with an example of:

21. R ２ but, 【Chemistry 114】 【Chemistry 115】 【Chemistry 116】 21. The compound according to any one of claims 1 to 20, wherein:

22. R ２ but, 【Chemistry 117】 21. The compound according to any one of claims 1 to 20, wherein:

23. R ２ but, 【Chemistry 118】 21. The compound according to any one of claims 1 to 20, wherein:

24. R Ｄ each instance independently represents oxo, halogen, —CN, —OR, —C(O)R, —C(O)OR, —C(O)NR ２ , -N(R)C(O)R or R Ｄ Each instance of １－６ an optionally substituted group selected from aliphatic; 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 a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R Ｄ groups, together with the atoms to which each is attached, form a bridged, fused, or spiro 5-6 membered aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ｄ 24. The compound of any one of claims 1 to 23, wherein each instance of is independently optionally substituted with u instances of R, or a pharma- ceutically acceptable salt thereof.

25. R Ｄ each instance independently represents halogen, -CN, -OR, -C(O)NR ２ , or -NR ２ or R Ｄ Each instance of 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; Ｄ 24. The compound of any one of claims 1 to 23, wherein each instance of is independently substituted by u instances of R, or a pharma- ceutically acceptable salt thereof.

26. R ２ But, H, 【Chemistry 119】 【Chemistry 120】 【Chemistry 121】 【Chemistry 122】 【Chemistry 123】 【Chemical 124】 【Chemistry 125】 26. The compound according to any one of claims 1 to 25, wherein:

27. R ３ But, H, C １－６ aliphatic, or phenyl, each of which is s R Ｅ or each R ３ are independently -CN, halogen, -C(O)R, -C(O)OR, -C(O)NR ２ or -C(O)N(R)OR, or a pharma- ceutically acceptable salt thereof.

28. R ３ is H, -Me, -Et, or phenyl, each of which is represented by s R Ｅ or each R ３ is independently -CN, halogen, or -C(O)OR, or a pharma- ceutically acceptable salt thereof.

29. R ４ is H; or a pharma- ceutically acceptable salt thereof.

30. 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from those shown in Table 1, or a pharma- ceutically acceptable salt thereof.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

32. A composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31, for use as a medicament.

33. 32. A method of inhibiting HPK1 in a biological sample, comprising contacting the sample with a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31.

34. A composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31, for treating a HPK1 mediated disorder, disease or condition in a patient.

35. 35. The composition of claim 34, wherein the disorder is a proliferative disorder.

36. 36. The composition of claim 35, wherein the proliferative disorder is cancer.

37. 35. The composition of claim 34, wherein the disorder is associated with one or more activating mutations in HPK1.

38. 32. Use of a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31, in the manufacture of a medicament for treating an HPK1 mediated disorder, disease or condition in a patient.

39. 39. The use according to claim 38, wherein the disorder is a proliferative disorder.

40. 40. The use of claim 39, wherein the proliferative disorder is cancer.

41. 39. The use of claim 38, wherein the disorder is associated with one or more activating mutations in HPK1.

Images