HPK1 antagonists and uses thereof

Abstract

The present invention provides compounds useful for inhibiting HPK1 and treating HPK1-mediated disorders, compositions thereof, and methods of using the same for inhibiting HPK1 and treating HPK1-mediated disorders.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 900,152, filed on September 13, 2019, and U.S. Provisional Application No. 63 / 032,070, filed on May 29, 2020, under 35 U.S.C. §119(e), the contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0003] 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 present invention and methods of using the compositions to treat various disorders. Background Art

[0004] 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.

[0005] HPK1 has attracted much attention because it is mainly expressed 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), the B cell receptor (BCR) (Liou, J. et al., Immunity, 2000. 12(4): pp. 399-408), the 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 the Gs-coupled PGE2 receptor (EP2 and EP4) (Ikegami, R. et al., J Immunology, 1998. 274(19): pp. 13133-8). Immunol, 2001. 166(7): p. 4689-96). Thus, HPK1 regulates a wide variety of 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 anti-tumor immunity. HPK1 is primarily expressed by hematopoietic cells, including early progenitor cells. In T cells, HPK1 is believed 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, thereby causing the recruitment of 14-3-3 proteins bound to phosphorylated SLP76 and Gads, resulting in the release of SLP76-Gads-14-3-3 complexes from microclusters containing LAT (Lasserre et al. (2011), J Cell Biol 195(5): 839-853). HPK1 can also become activated in response to prostaglandin E2 (usually secreted by tumors), promoting tumor cells to evade the immune system.

[0006] HPK1 plays an important role in regulating the functions of various immune cells, and has been implicated in autoimmune diseases and anti-tumor immunity (Shui, JW et al., Nat Immunol, 2007. 8(1): 84-91; Wang, X. et al., J Biol Chem, 2012. 287(14): 11037-48). Summary of the invention

[0007] It has now been discovered that compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as HPK1 antagonists. In certain embodiments, the present invention provides compounds of the formulae presented herein.

[0008] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders or conditions associated with the modulation of signal transduction pathways involving HPK1 kinase. The diseases, disorders or conditions include those described herein.

[0009] The compounds provided herein are also useful for studying the HPK1 enzyme in biological and pathological phenomena; studying intracellular signal transduction pathways occurring in body tissues; and comparatively evaluating novel HPK1 inhibitors or other kinase regulators, signal transduction pathways, and cytokine levels in vitro or in vivo. DETAILED DESCRIPTION

[0010] 1. General Description of Certain Embodiments of the Invention:

[0011] In certain aspects, the present invention provides compounds of formula I:

[0012]

[0013] or a pharmaceutically acceptable salt thereof, wherein X, Z, R 1 , R 2 , R 3 Each of m and m is as defined below and described in the Examples herein, both individually and in combination.

[0014] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or diluent.

[0015] In some embodiments, the present invention provides a method of treating a disease, disorder or condition mediated by HPK1, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0016] 2. Compounds and Definitions:

[0017] The compounds of the present invention include compounds generally described herein and further described according to the categories, subclasses and species disclosed herein. Unless otherwise indicated, as used herein, the following definitions shall apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, ed., Smith, MB, and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0018] As used herein, the term "aliphatic group" means a straight chain (i.e., unbranched) or branched chain, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon or bicyclic hydrocarbon (also referred to herein as "carbocycle", "cycloaliphatic group" or "cycloalkyl") that is completely saturated or contains one or more unsaturated units, but is not an aromatic group, which has a single point of connection to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, a "cycloaliphatic group" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C 2-1 ... 3 -C 6 Hydrocarbons having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0019] As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic system with at least one bridge, i.e., carbocyclic or heterocyclic. As defined by IUPAC, a "bridge" is a non-branched chain of multiple atoms or an atom or a valence bond connecting two bridgeheads, wherein a "bridgehead" is any backbone atom of a ring system bonded to three or more backbone atoms (except hydrogen). In some embodiments, the 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 those groups described below, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted by one or more substituents as described for an aliphatic group. Alternatively or in addition, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0020]

[0021] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0022] The term "lower haloalkyl" refers to a C 1-4 Straight chain or branched chain alkyl.

[0023] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; a quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).

[0024] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0025] As used herein, the term "divalent C 1-8 (or C 1-6 )"saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene and alkynylene chains as defined herein, which are straight or branched.

[0026] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH 2 ) n-, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. Substituted alkylene chains are polymethylenes in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0027] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0028] The term "halogen" means F, Cl, Br or I.

[0029] The term "aryl", used alone or as part of a larger moiety, such as in "aralkyl", "aralkyloxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aromatic ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may bear one or more substituents. As used herein, also included within the scope of the term "aryl" are groups in which aromatic rings are fused to one or more non-aromatic rings, such as indanyl, phthalimido, naphthylimino, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0030] The terms "heteroaryl" and "heteroar-", 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; having 6, 10 or 14 pi electrons shared in the ring 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 basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein, unless otherwise specified, the radical or point of attachment is on the heteroaryl ring or on one of the rings to which the heteroaryl ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, The term "heteroaryl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl group and the heteroaryl group are independently and optionally substituted.

[0031] 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 saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. When used with respect to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or + NR (as in N-substituted pyrrolidinyl).

[0032] The heterocycle may be attached to its side group at any heteroatom or carbon atom to produce a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazapine, thiazepine, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently and optionally substituted.

[0033] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0034] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when multiple positions in any given structure may be substituted by multiple substituents selected from a specified group, the substituents at each position may be the same or different. The combinations of substituents contemplated by the present invention preferably form those combinations of substituents that are stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow its production, detection, and (in certain embodiments) its recovery, purification, and use for one or more purposes disclosed herein.

[0035] Suitable monovalent substituents on substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH 2 ) 0-4 R o ;-(CH 2 ) 0-4 OR o ; -O(CH 2 ) 0-4 R o 、-O-(CH 2 ) 0-4 C(O)OR o ;-(CH 2 ) 0-4 CH(OR o ) 2 ;-(CH 2 ) 0- 4 SR o ;-(CH 2 ) 0-4 Ph, which can be o Substitution; -(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph, which can be o Substitution; -CH=CHPh, which can be R o Substitution; -(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl, which may beo Substituted; -NO 2 ; -CN; -N 3 ; -(CH 2 ) 0-4 N(R o ) 2 ; -(CH 2 ) 0-4 N(R o )C(O)R o ; -N(R o )C(S)R o ; -(CH 2 ) 0-4 N(R o )C(O)NR o 2 ; -N(R o )C(S)NR o 2 ; -(CH 2 ) 0-4 N(R o )C(O)OR o ; -N(R o )N(R o )C(O)Ro; -N(R o )N(Ro)C(O)NR o 2 ; -N(R o )N(R o )C(O)OR o ; -N(R o )C(NR o )N(R o ) 2 ; -(CH 2 ) 0-4 C(O)R o ; -C(S)R o ; -(CH 2 ) 0-4 C(O)OR o ; -(CH 2 ) 0-4 C(O)SR o ; -(CH 2 ) 0-4 C(O)OSiR o 3 ; -(CH 2 ) 0- 4 OC(O)R o ; -OC(O)(CH 2 ) 0-4 SR o ; -SC(S)SRo ;-(CH 2 ) 0-4 SC(O)R o ;-(CH 2 ) 0-4 C(O)NR o 2 ;-C(S)NR o 2 ;-C(S)SR o ;-SC(S)SR o 、-(CH 2 ) 0-4 OC(O)NR o 2 ;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH 2 C(O)R o ;-C(NOR o )R o ;-(CH 2 ) 0-4 SSR o ;-(CH 2 ) 0-4 S(O) 2 R o ;-(CH 2 ) 0-4 S(O) 2 OR o ;-(CH 2 ) 0-4 OS(O) 2 R o ;-S(O) 2 NR o 2 ;-(CH 2 ) 0-4 S(O)R o ;-N(R o )S(O) 2 NR o 2 ;-N(R o )S(O) 2 R o ;-N(OR o )R o ;-C(NH)NR o 2 ;-P(O) 2 R o ;-P(O)R o 2 ;-OP(O)Ro 2 ;-OP(O)(OR o ) 2 ;-SiR o 3 ;-(C 1-4 Straight chain or branched chain alkylene)ON(R o ) 2 ; or -(C 1-4 Straight or branched alkylene)C(O)ON(R o ) 2 , where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, -CH 2 -(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definitions, two independent occurrences of R o Together with its one or more intervening atoms it forms a 3-12 membered saturated, partially unsaturated or aromatic mono- or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0036] R o (or two independent occurrences of R o Suitable monovalent substituents on the ring formed by the atoms interposed therewith are independently halogen, -(CH 2 ) 0-2 R · 、-(halogen R · )、-(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR · 、-(CH 2 ) 0-2 CH(OR · ) 2 ; -O(halogen R · ), -CN, -N 3 、-(CH 2 ) 0-2 C(O)R · 、-(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR · 、-(CH 2 )0-2 SR · 、-(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 、-(CH 2 ) 0-2 NHR · 、-(CH 2 ) 0-2 NR · 2 、-NO 2 、-SiR · 3 、-OSiR · 3 、-C(O)SR · 、-(C 1-4 Straight or branched chain alkylene)C(O)OR · or -SSR · , where each R · unsubstituted or, when preceded by "halo", substituted only by one or more halogens, and independently selected from C 1-4 Aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0037] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2 、=NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O) 2 R * , =NR * , =NOR * 、-O(C(R * 2 )) 2-3 O-or-S(C(R * 2 )) 2-3 S-, where each single occurrence of R * is selected from hydrogen; C which may be substituted as defined below 1-6aliphatic groups; and unsubstituted 5-6 membered saturated, partially unsaturated or aromatic rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to the adjacent substitutable carbon of an "optionally substituted" group include: -O(CR * 2 ) 2-3 O-, where each R appears alone * is selected from hydrogen, C which may be substituted as defined below 1-6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0038] R * Suitable substituents on the aliphatic group include halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH 2 、-NHR · 、-NR · 2 or-NO 2 , where each R · unsubstituted or, when preceded by "halo", substituted only by one or more halogens, and independently C 1-4 Aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0039] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Among them are independently hydrogen; C which may be substituted as defined below 1-6 aliphatic; unsubstituted -OPh; or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definitions, two independent occurrences of Together with its one or more intervening atoms it forms an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0040] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogen R· ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH 2 、-NHR · 、-NR · 2 or-NO 2 , where each R · unsubstituted or, when preceded by "halo", substituted only by one or more halogens, and independently C 1-4 Aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0041] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. 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 formed of amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 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.

[0042] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 alkyl) 4 Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0043] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, 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. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures including replacement of hydrogen by deuterium or tritium or replacement of carbon by 13 C or 14 Compounds with carbon substitutions enriched in C and having the structures of the present invention are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological analysis, or therapeutic agents according to the present invention. In certain embodiments, the warhead portion R of the provided compounds is 1 Contains one or more deuterium atoms. In certain embodiments, Ring B of provided compounds may be substituted with one or more deuterium atoms.

[0044] The drawn structures represent relative configuration unless the absolute configuration is labeled. The present invention encompasses both individual enantiomers and racemic mixtures.

[0045] As used herein, an "HPK1 antagonist" or "HPK1 inhibitor" is a molecule that reduces, inhibits, or otherwise reduces one or more biological activities of HPK1, such as serine / threonine kinase activity, recruitment to the TCR complex upon TCR activation, interaction with a protein binding partner (e.g., SLP76). Antagonism using an HPK1 antagonist does not necessarily indicate complete elimination of HPK1 activity. Alternatively, the activity may be reduced by a statistically significant amount, including, for example, a reduction in HPK1 activity of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100%, compared to an appropriate control. In some embodiments, an HPK1 antagonist reduces, inhibits, or otherwise reduces 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.The compounds disclosed herein bind directly to HPK1 and inhibit its kinase activity.

[0046] A "specific antagonist" is intended to be an agent that reduces, inhibits, or otherwise decreases the activity of a given target to a greater extent than an unrelated target. For example, an HPK1-specific antagonist reduces at least one biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other serine / threonine kinases). In some embodiments, the antagonist has an IC of 1000 to 1000. 50 Antagonists are directed against non-target IC 50 The compounds disclosed herein 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 kinases). In certain embodiments, an HPK1 antagonist specifically inhibits the serine / threonine kinase activity of HPK1. In some of these embodiments, the HPK1 antagonist has an IC of 1000 for HPK1 and an IC of 1000 for HPK1. 50 is the IC of an HPK1 antagonist against another serine / threonine kinase or another type of kinase (e.g., tyrosine kinase) 50 About 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of.

[0047] The compounds of the present invention can be tethered to a detectable moiety. It should be understood that the compounds are suitable for use as developers. A person of ordinary skill in the art will recognize that the detectable moiety can be connected to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently attached to a detectable moiety. Such moieties are well known to those of ordinary skill in the art and include groups containing, for example, carboxylate moieties, amino moieties, thiol moieties, or hydroxyl moieties (to name a few). It should be understood that such moieties can be directly or via a tethered group (e.g., a divalent saturated or unsaturated hydrocarbon chain) attached to the provided compound. In some embodiments, such moieties can be connected via click chemistry. In some embodiments, the moiety can be connected via 1,3-cycloaddition of an azide compound and an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41 , 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17 , those methods described in 52-57.

[0048] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety (e.g., primary and secondary labels) that is capable of being detected. Primary labels, such as radioactive isotopes (e.g., tritium, 32 P. 33 P. 35 S or 14 C), mass tags and fluorescent labels are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0049] As used herein, the term "secondary label" refers to a moiety that requires the presence of a second intermediate to produce a detectable signal, such as biotin and various protein antigens. In the case of biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. In the case of antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups serve as secondary labels because they transfer energy to another group in a non-radiative fluorescence resonance energy transfer (FRET) method, and the second group produces a detection signal.

[0050] 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, dialkylaminocoumarins, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosin, fluorescein, FAM, hydroxycoumarins, IRDye (IRD40, IRD 700, IRD 800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthylfluorescein, Oregon Green 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.

[0051] As used herein, the term "mass tag" refers to any moiety that can be specifically detected by means of its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophoretically released tags, such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceryl]isopicolinic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone and derivatives thereof. The synthesis and utility of these mass tags are described in U.S. Patents 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 with varying lengths and base compositions, dideoxynucleotides, oligonucleotides, oligopeptides with varying lengths and monomer compositions, oligosaccharides and other synthetic polymers. A wide variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds), with an appropriate mass range (100 Daltons to 2000 Daltons) can also be used as mass tags.

[0052] As used herein, the terms "measurable affinity" and "measurably inhibit" mean that there is a measurable change in HPK1 protein kinase activity between a sample comprising a compound or composition thereof and HPK1 protein kinase and an equivalent sample comprising HPK1 protein kinase lacking the compound or composition thereof.

[0053] 3. Description of exemplary embodiments:

[0054] As described above, in certain embodiments, the present invention provides a compound of formula I:

[0055]

[0056] or a pharmaceutically acceptable salt thereof, wherein:

[0057] Z is CR or N;

[0058] X is a covalent bond, -O-, -S-, -NR-, -S(O) 2 -、-S(O) 2 NR-, -S(O)-, -S(O)NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(O)N(R)O-, -OC(O)-, -OC(O)NR-, -N(R)C(O)O-, -N(R)C(O)-, -N(R)S(O) 2 -; or X is C 1-4 A divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by: -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 -;

[0059] R 1 Selected from C 1-6 aliphatic group; phenyl; 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which undergoes q occurrences of R C replace;

[0060] R 2 is a 6-11 membered saturated, partially unsaturated or unsaturated fused, bridged or spiro bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is R C replace;

[0061] R 3 is independently hydrogen or optionally substituted C 1-6 Aliphatic groups;

[0062] R C is independently at each occurrence oxo, halogen, -CN, -NO 2 、-OR、-SR、-NR 2 、-S(O) 2 R, -S(O) 2 NR 2 、-S(O)R、-S(O)NR 2 、-C(O)R、-C(O)OR、-C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 、-N(R)C(NR)NR 2 、-N(R)NR 2 、-N(R)S(O) 2 NR 2 、-N(R)S(O) 2 R, -N=S(O)R 2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR or -P(O)R 2 ; or R C is independently at each occurrence an optionally substituted group selected from: C 1-6 aliphatic; phenyl; naphthyl; 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 a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 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 6-11 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 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by r occurrences of R and s occurrences of R D replace;

[0063] R D is independently at each occurrence oxo, halogen, -CN, -NO 2 、-OR、-SR、-NR 2 、-S(O) 2 R, -S(O) 2 NR 2 、-S(O)R、-S(O)NR 2 、-C(O)R、-C(O)OR、-C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 、-N(R)C(NR)NR 2 、-N(R)NR 2 、-N(R)S(O) 2 NR 2 、-N(R)S(O) 2 R, -N=S(O)R 2 , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR or -P(O)R 2 ;

[0064] Each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from: C 1-6 aliphatic group; phenyl; naphthyl; 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 and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 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; 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 partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or:

[0065] Two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen; 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;

[0066] m is 0, 1, or 2;

[0067] Each q is independently 0, 1, 2, 3 or 4;

[0068] each r is independently 0, 1, 2, 3 or 4; and

[0069] Each s is independently 0, 1, 2, 3 or 4.

[0070] Z is CR or N as generally defined above.

[0071] In some embodiments, Z is CR. In some embodiments, Z is N.

[0072] In some embodiments, Z is CH. In some embodiments, Z is CCl. In some embodiments, Z is CF. In some embodiments, Z is CCH 3 .

[0073] In some embodiments, Z is selected from those depicted in Table 1 below.

[0074] As generally defined above, X is a covalent bond, -O-, -S-, -NR-, -S(O) 2 -、-S(O) 2NR-, -S(O)-, -S(O)NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(O)N(R)O-, -OC(O)-, -OC(O)NR-, -N(R)C(O)O-, -N(R)C(O)-, -N(R)S(O) 2 -; or X is C 1-4 A divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by: -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 -.

[0075] In certain embodiments, X is -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)N R-, -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) 2 NR-or-N(R)S(O) 2 -.

[0076] In some embodiments, X is C 1-4 A divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by: -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 -.

[0077] In certain embodiments, X is -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(O)N(R)O-, -OC(O)-, -OC(O)NR-, -N(R)C(O)O-, -N(R)C(O)-, -N(R)C(O)NR-, -N(R)C(NR)NR-, or -N(R)NR-.

[0078] In certain embodiments, X is -NR-. In certain embodiments, X is -NH-.

[0079] In some embodiments, X is selected from those depicted in Table 1 below.

[0080] As generally defined above, R 1 Selected from C 1-6 aliphatic group; phenyl; 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which undergoes q occurrences of R C replace.

[0081] In some embodiments, R 1 is R that appears q times C Substituted C 1-6 Aliphatic group; q occurrences of R C Substituted phenyl; q occurrences of R C Substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; q occurrences of R C substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; q occurrences of R C substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or q occurrences of R C Substituted 8-10 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0082] 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 replaced by q occurrences of R C replace.

[0083] In certain embodiments, R 1is phenyl, indanyl, tetrahydronaphthyl, acridinyl, acininyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, quinolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofurano[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolene, indolyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoindolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolinyl, iso thiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxetanyl, pyrimidinyl, phenanthene, phenanthene, phenanthene, phenanthene, phenanthiazinyl, phenanthiazinyl, phenanthiazinyl, phenanthiazinyl, phenanthiazinyl, phenanthiazinyl, phenanthiazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyryl oxazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quindolizinyl, quinoxalinyl, quinuclidine, 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, thianthyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, azetidinyl or dibenzopyranyl; each of which is q occurrences of R C replace.

[0084] In certain embodiments, R 1is phenyl, furanyl, furazolyl, 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, oxetanyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolyl, pyrazolidinyl, pyrazolyl quinolinyl, 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, azetidinyl or dibenzopyranyl; each of which is q occurrences of R C replace.

[0085] In certain embodiments, R 1 is furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxetanyl, pyrimidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridinyl, 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 R C replace.

[0086] In certain embodiments, R 1 is phenyl, pyrazolyl, pyridinyl, pyrazinyl or pyrimidinyl; each of which has q occurrences of R C replace.

[0087] In certain embodiments, R 1 is pyrazolyl or pyridinyl; each of which has q occurrences of R C replace.

[0088] In certain embodiments, R 1 is pyrazolyl or pyridinyl; each of which has q occurrences of R C Substitute; wherein each R C are independently halogen, -CN, -OR, -S(O) 2 R, -C(O)NR 2 , or R C is independently at each occurrence an optionally substituted group selected from the following: 1-6aliphatic group; 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 The group, together with the atoms to which it is attached, forms a bridged, fused or spiro 5-6 membered aromatic ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon and sulfur; wherein R C In each occurrence, optionally independently of R and R D replace.

[0089] In certain embodiments, R 1 yes

[0090]

[0091]

[0092] In certain embodiments, R 1 yes

[0093] In certain embodiments, R 1 yes

[0094]

[0095] Where R C is independently at each occurrence 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 a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is repeated for r occurrences of R and s occurrences of R D replace.

[0096] In certain embodiments, R 1 for

[0097]

[0098] Where R C is independently at each occurrence -Me, -Et, -CN, -F, -OMe, -S(O) 2 Me,

[0099]

[0100] In certain embodiments, R1 With its R C The substituents together are

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108] In certain embodiments, R 1 With its R C The substituents together are

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123] In certain embodiments, R 1 With its R CThe substituents together are

[0124]

[0125]

[0126] In some embodiments, R 1 Select from those depicted in Table 1 below.

[0127] As generally defined above, R 2 is a 6-11 membered saturated, partially unsaturated or unsaturated fused, bridged or spiro bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is R C replace.

[0128] In some embodiments, R 2 is a 6-11 membered saturated, partially unsaturated or unsaturated fused, bridged or spiro bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C replace.

[0129] In certain embodiments, R 2 is a 7-10 membered fused bicyclic ring having 1-3 nitrogen atoms; each of which has q occurrences of R C replace.

[0130] In certain embodiments, R 2 is a 9-membered fused bicyclic ring having 1-3 nitrogen atoms; each of which has q occurrences of R C Substitute; wherein each R C are independently halogen, -CN, -OR, -C(O)NR 2 、-NR 2 ; or R C is independently at each occurrence an optionally substituted group selected from the following: 1-6 aliphatic group; 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; wherein R C At each occurrence, independently, optionally, by r occurrences of R and s occurrences of R D replace.

[0131] In certain embodiments, R 2 yes

[0132]

[0133]

[0134] In certain embodiments, R 2 yes or

[0135] In certain embodiments, R 2 yes or

[0136] In certain embodiments, R 2 With its R C The substituents together are

[0137]

[0138]

[0139]

[0140]

[0141] In certain embodiments, R 2 With its R C The substituents together are

[0142] In some embodiments, R 2 Select from those depicted in Table 1 below.

[0143] As generally defined above, R 3 is independently hydrogen or optionally substituted C 1-6 Aliphatic group.

[0144] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is optionally substituted C 1-6 Aliphatic group.

[0145] In some embodiments, R 3 In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0146] In some embodiments, R 3 Select from those depicted in Table 1 below.

[0147] As generally defined above, R Cis independently at each occurrence oxo, halogen, -CN, -NO 2 、-OR、-SR、-NR 2 、-S(O) 2 R, -S(O) 2 NR 2 、-S(O)R、-S(O)NR 2 、-C(O)R、-C(O)OR、-C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 、-N(R)C(NR)NR 2 、-N(R)NR 2 、-N(R)S(O) 2 NR 2 、-N(R)S(O) 2 R, -N=S(O)R 2 , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR or -P(O)R 2 ; or R C is independently at each occurrence an optionally substituted group selected from the following: 1-6 aliphatic; phenyl; naphthyl; 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 a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 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; 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 replaced by r occurrences of R and s occurrences of R D replace.

[0148] In some embodiments, R C is independently at each occurrence oxo, halogen, -CN, -NO 2 、-OR、-SR、-NR 2 、-S(O) 2 R, -S(O) 2 NR 2、-S(O)R、-S(O)NR 2 、-C(O)R、-C(O)OR、-C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 、-N(R)C(NR)NR 2 、-N(R)NR 2 、-N(R)S(O) 2 NR 2 、-N(R)S(O) 2 R, -N=S(O)R 2 , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR or -P(O)R 2 ; or R C is independently at each occurrence an optionally substituted group selected from the following: 1-6 aliphatic group; phenyl; naphthyl; 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 a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 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; or a 6-11 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0149] In some embodiments, R C Oxo, halogen, -CN, -NO at each occurrence 2 、-OR、-SR、-NR 2 、-S(O) 2 R, -S(O) 2 NR 2 、-S(O)R、-S(O)NR 2 、-C(O)R、-C(O)OR、-C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2、-N(R)C(NR)NR 2 、-N(R)NR 2 、-N(R)S(O) 2 NR 2 、-N(R)S(O) 2 R, -N=S(O)R 2 , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR or -P(O)R 2 .

[0150] In some embodiments, R C is, at each occurrence, an optionally substituted group selected from the group consisting of: C 1-6 aliphatic group; phenyl; naphthyl; 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 a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 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; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0151] In some embodiments, R C is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is replaced by r occurrences of R and s occurrences of R D replace.

[0152] In some embodiments, R C is a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is D replace.

[0153] In some embodiments, R C is methyl, oxo, fluoro or methoxy.

[0154] In some embodiments, R C yes

[0155]

[0156]

[0157]

[0158]

[0159] In some embodiments, R C Yes - CHF 2 or chlorine.

[0160] In some embodiments, R C yes

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] In some embodiments, R C yes

[0167] In some embodiments, R C At each occurrence, it is selected from those depicted in Table 1 below.

[0168] As generally defined above, R D is independently at each occurrence oxo, halogen, -CN, -NO 2 、-OR、-SR、-NR 2 、-S(O) 2 R, -S(O) 2 NR 2 、-S(O)R、-S(O)NR 2 、-C(O)R、-C(O)OR、-C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 、-N(R)C(NR)NR 2 、-N(R)NR 2 、-N(R)S(O) 2 NR 2 、-N(R)S(O)2 R, -N=S(O)R 2 , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR or -P(O)R 2 .

[0169] In some embodiments, R D Oxo, halogen, -CN, -NO 2 、-OR、-SR、-NR 2 、-S(O) 2 R, -S(O) 2 NR 2 、-S(O)R、-S(O)NR 2 、-C(O)R、-C(O)OR、-C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 、-N(R)C(NR)NR 2 、-N(R)NR 2 、-N(R)S(O) 2 NR 2 、-N(R)S(O) 2 R, -N=S(O)R 2 , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR or -P(O)R 2 .

[0170] In some embodiments, R D is hydroxy, fluoro or methoxy.

[0171] In some embodiments, R D yes or

[0172] In some embodiments, R D It's oxygen.

[0173] In some embodiments, R D yes

[0174] In some embodiments, R D Select from those depicted in Table 1 below.

[0175] As generally defined above, each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic group; phenyl; naphthyl; 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; a 5-6 membered monocyclic heteroaryl ring having 1-4 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; 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 partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or:

[0176] The two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen; 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.

[0177] In some embodiments, R is methyl. In some embodiments, R is

[0178] In some embodiments, R is ethyl.

[0179] In some embodiments, R is

[0180] In some embodiments, R is selected from those depicted in Table 1 below.

[0181] As generally defined above, each hydrogen bonded to a carbon may optionally and independently be replaced with deuterium.

[0182] In some embodiments, hydrogen bound to the carbon is replaced with deuterium.

[0183] As generally defined above, m is 0, 1 or 2.

[0184] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0185] In some embodiments, m is selected from those depicted in Table 1 below.

[0186] 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.

[0187] In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2.

[0188] In some embodiments, q is selected from those depicted in Table 1 below.

[0189] 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.

[0190] In some embodiments, r is 1 or 2. In some embodiments, r is 2 or 3. In some embodiments, r is 2, 3, or 4.

[0191] In some embodiments, R is selected from those depicted in Table 1 below.

[0192] 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.

[0193] In some embodiments, s is 1 or 2. In some embodiments, s is 2 or 3. In some embodiments, s is 2, 3, or 4.

[0194] In some embodiments, s is selected from those depicted in Table 1 below.

[0195] In some embodiments, the present invention provides a compound of formula II:

[0196]

[0197] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each of is as defined above and described in the embodiments herein, both individually and in combination.

[0198] In some embodiments, the present invention provides a compound of formula III:

[0199]

[0200] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each of is as defined above and described in the embodiments herein, both individually and in combination.

[0201] In some embodiments, the present invention provides a compound of formula IV:

[0202]

[0203] or a pharmaceutically acceptable salt thereof, wherein R 2 and R C Each of is as defined above and described in the embodiments herein, both individually and in combination.

[0204] In some embodiments, the present invention provides a compound of formula V:

[0205]

[0206] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 Each of A and X is as defined above and described in the Examples herein, both alone and in combination.

[0207] In some embodiments, the present invention provides a compound of formula VI:

[0208]

[0209] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each of is as defined above and described in the embodiments herein, both individually and in combination.

[0210] In some embodiments, the present invention provides a compound of formula VII:

[0211]

[0212] or a pharmaceutically acceptable salt thereof, wherein R 2 and R C Each of is as defined above and described in the embodiments herein, both individually and in combination.

[0213] In some embodiments, the present invention provides a compound of formula XI-a or XI-b:

[0214]

[0215] or a pharmaceutically acceptable salt thereof, wherein R1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0216] In some embodiments, the present invention provides a compound of Formula XII-a or XII-b:

[0217]

[0218] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of a and q is as defined above and described in the Examples herein, both individually and in combination.

[0219] In some embodiments, the present invention provides a compound of Formula XIII-a or XIII-b:

[0220]

[0221] or a pharmaceutically acceptable salt thereof, wherein R C Each of a and q is as defined above and described in the Examples herein, both individually and in combination.

[0222] In some embodiments, the present invention provides a compound of Formula XIV-a or XIV-b:

[0223]

[0224] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0225] In some embodiments, the present invention provides a compound of Formula XV-a or XV-b:

[0226]

[0227] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of a and q is as defined above and described in the Examples herein, both individually and in combination.

[0228] In some embodiments, the present invention provides a compound of Formula XVI-a or XVI-b:

[0229]

[0230] or a pharmaceutically acceptable salt thereof, wherein R CEach of a and q is as defined above and described in the Examples herein, both individually and in combination.

[0231] In some embodiments, the present invention provides a compound of Formula XVII-a or XVII-b:

[0232]

[0233] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0234] In some embodiments, the present invention provides a compound of Formula XVIII-a or XVIII-b:

[0235]

[0236] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of a and q is as defined above and described in the Examples herein, both individually and in combination.

[0237] In some embodiments, the present invention provides a compound of Formula XIX-a or XIX-b:

[0238]

[0239] or a pharmaceutically acceptable salt thereof, wherein R C Each of a and q is as defined above and described in the Examples herein, both individually and in combination.

[0240] In some embodiments, the present invention provides a compound of formula XX-a or XX-b:

[0241]

[0242] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0243] In some embodiments, the present invention provides a compound of formula XXI-a or XXI-b:

[0244]

[0245] or a pharmaceutically acceptable salt thereof, wherein R 1 , R CEach of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0246] In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b:

[0247]

[0248] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0249] In some embodiments, the present invention provides a compound of formula XXIII-a or XXIII-b:

[0250]

[0251] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0252] In some embodiments, the present invention provides a compound of formula XXIV-a or XXIV-b:

[0253]

[0254] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0255] In some embodiments, the present invention provides a compound of formula XXV-a or XXV-b:

[0256]

[0257] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0258] In some embodiments, the present invention provides a compound of formula XXVI-a or XXVI-b:

[0259]

[0260] or a pharmaceutically acceptable salt thereof, wherein R 1 , RC Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0261] In some embodiments, the present invention provides a compound of formula XXVII-a or XXVII-b:

[0262]

[0263] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0264] In some embodiments, the present invention provides a compound of Formula XXVIII-a or XXVIII-b:

[0265]

[0266] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0267] In some embodiments, the present invention provides a compound of formula XXIX-a or XXIX-b:

[0268]

[0269] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0270] In some embodiments, the present invention provides a compound of formula XXX-a or XXX-b:

[0271]

[0272] or a pharmaceutically acceptable salt thereof, wherein R 1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0273] In some embodiments, the present invention provides a compound of formula XXXI-a or XXXI-b:

[0274]

[0275] or a pharmaceutically acceptable salt thereof, wherein R1 , R C Each of , x and q is as defined above and described in the Examples herein, both individually and in combination.

[0276] Exemplary compounds of the invention are set forth in Table 1 below.

[0277] Table 1. Selected compounds

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392] In some embodiments, the present invention provides a compound described in Table 1 above or a pharmaceutically acceptable salt thereof. The present invention provides a compound described in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described in Table 1 above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0393] 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.

[0394] In some embodiments, the present invention also provides a compound of formula I described herein or a pharmaceutical composition described herein for use in a method of inhibiting HPK1 as described herein, a method of enhancing an immune response in a subject in need thereof as described herein, and / or a method of treating an HPK1-dependent disorder as described herein.

[0395] In some embodiments, the present invention also provides a compound of Formula I described herein or a pharmaceutical composition described herein for use in a method of inhibiting HPK1 as described herein.

[0396] In some embodiments, the present invention also provides a compound of Formula I described herein or a pharmaceutical composition described herein for use in a method of enhancing an immune response in a subject in need thereof as described herein.

[0397] In some embodiments, the present invention also provides a compound of Formula I described herein or a pharmaceutical composition described herein for use in a method of treating an HPK1-dependent disorder as described herein.

[0398] In some embodiments, the present invention also provides the use of the compound of formula I described herein or the pharmaceutical composition described herein for the manufacture of a medicament for inhibiting HPK1, a medicament for enhancing the immune response of a subject in need thereof, and / or a medicament for treating an HPK1-dependent disorder.

[0399] In some embodiments, the present invention also provides the use of the compound of Formula I described herein or the pharmaceutical composition described herein for the manufacture of a medicament for inhibiting HPK1.

[0400] 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 enhancing an immune response in a subject in need thereof.

[0401] 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.

[0402] 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 use in a method of inhibiting HPK1 as described herein, for use in a method of enhancing an immune response in a subject in need thereof as described herein, and / or for use in a method of treating an HPK1-dependent disorder as described herein.

[0403] 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 use in a method of inhibiting HPK1 as described herein.

[0404] 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 use in a method of enhancing an immune response in a subject in need thereof as described herein.

[0405] 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 use in a method of treating an HPK1-dependent disorder as described herein.

[0406] 4. General Methods for Providing Compounds of the Invention

[0407] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds and by the methods described in detail in the Examples herein.

[0408] 5. Use, formulation and administration

[0409] Pharmaceutically acceptable compositions

[0410] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition of the present invention is effective to inhibit HPK1 or a mutation thereof in a biological sample or patient in a measurable manner. In certain embodiments, the amount of the compound in the composition of the present invention is effective to inhibit HPK1 or a mutant thereof in a biological sample or patient in a measurable manner. 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.

[0411] As used herein, the term "patient" means an animal, preferably a mammal and most preferably a human.

[0412] 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 formulated with it. 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 (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0413] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof.

[0414] As used herein, the term "inhibitory active metabolites or residues thereof" means metabolites or residues thereof that are also inhibitors of HPK1 or a mutant thereof.

[0415] 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 method comprising: contacting the compounds of the present invention with a mammal for a period of time sufficient to produce its metabolites. If the compounds of the present invention are bases, pharmaceutically acceptable desired salts can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, 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, pyranosidic acid (e.g., glucuronic acid or galacturonic acid), alpha hydroxy acids (e.g., citric acid or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid or cinnamic acid), sulfonic acids (e.g., p-toluenesulfonic acid or ethanesulfonic acid), or similar acids thereof. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids (e.g., glycine and arginine), ammonia, primary, secondary and tertiary amines, and cyclic amines (e.g., piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0416] The compounds of the present invention may be in the form of "prodrugs", which include compounds with moieties that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo by esterases or by other mechanisms that can activate drugs. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts", Journal of Pharmaceutical Science (J. Pharm. Sci.) 66: 1-19). Prodrugs can be prepared on the spot during the final separation and purification of the compound, or by reacting the free acid form or hydroxyl of the purified compound with a suitable esterifying agent, respectively. Hydroxyl groups can be converted into esters via carboxylic acid treatment. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetoxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl esters), substituted (e.g., substituted with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Also included are prodrugs that are converted into active forms in vivo via other mechanisms. In various aspects, the compounds of the invention are prodrugs of any formula herein.

[0417] The composition of the present invention can be administered orally, parenterally, by inhalation spray, body surface, rectum, nose, buccal, vaginal or by means of an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The composition is preferably administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions present in parenterally acceptable non-toxic diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media.

[0418] For this purpose, any mild non-volatile oil can be used, including synthetic mono- or di-glycerides. Fatty acids (e.g., oleic acid and its glyceride derivatives) are suitable for preparing injectables, as are pharmaceutically acceptable natural oils (e.g., olive oil or castor oil, especially their polyoxyethylated forms). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants (e.g., Tween, Span and other emulsifiers) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids or other dosage forms may also be used for the purpose of formulation.

[0419] The pharmaceutically acceptable compositions 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. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, suitable diluents include lactose and dry corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavoring agents or coloring agents may also be added as needed.

[0420] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the medicament with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0421] The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eyes, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for use in each of these areas or organs.

[0422] Topical administration to the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0423] For topical administration, the pharmaceutically acceptable composition provided can be formulated as a suitable ointment containing an active component suspended or dissolved in one or more carriers. The carrier for topical administration of the compound of the present invention includes, but is not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable composition provided can be formulated in the form of a suitable lotion or cream containing an active component 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 ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0424] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in pH-adjusted sterile isotonic saline with or without preservatives (e.g., benzalkonium chloride), or preferably solutions in pH-adjusted sterile isotonic saline. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions can be formulated in the form of an ointment (e.g., paraffinum).

[0425] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters that enhance bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants.

[0426] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered in the presence or absence of food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0427] The amount of the compound of the invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0428] It is also 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 used, age, body weight, general health, sex, diet, administration time, excretion rate, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the invention in the composition also depends on the specific compound in the composition.

[0429] Uses of compounds and pharmaceutically acceptable compositions

[0430] 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.

[0431] The compounds disclosed in the present invention can be used to inhibit the activity of HPK1 enzyme. HPK1 is a member of the germinal center kinase subfamily of Ste20-related serine / threonine kinases. HPK1 phosphorylates and activates MAP3K proteins (including MEKK1, MLK3 and TAK1), causing the activation of MAPK Jnk to exert the function of MAP4K.

[0432] In one embodiment, the presently disclosed subject matter relates to a method of inhibiting HPK1, the method comprising contacting HPK1 with an effective amount of a compound of the present invention or a pharmaceutical composition described herein.

[0433] In certain embodiments, the subject matter disclosed herein relates to a method for enhancing an immune response in an individual in need thereof, wherein the method comprises administering to an individual an effective amount of a compound of the present invention or a pharmaceutical composition described herein. In certain aspects of this embodiment, compared to before the administration of the compound or pharmaceutical composition, the T cells of the individual have at least one of the following: enhanced activation, enhanced activation, enhanced migration, enhanced proliferation, increased survival rate, and enhanced cytolytic activity. In certain aspects of this embodiment, T cell activation is characterized by an increase in the occurrence rate of γ-IFN+CD8 T cells or an increase in the production of IL-2 or granzyme B of T cells relative to before the administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the number of T cells increases compared to before the 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, compared to before the administration of the compound or pharmaceutical composition, the maturation and activation of the antigen presenting cells of the individual are enhanced. In certain aspects of this embodiment, the antigen presenting cells are dendritic cells. In certain aspects of this embodiment, the maturation of antigen presenting cells is characterized by an increase in the occurrence rate of CD83+ dendritic cells. In certain aspects of this embodiment, antigen presenting cell activation is characterized by increased expression of CD80 and CD86 on dendritic cells.

[0434] The compounds disclosed herein directly bind to HPK1 and inhibit its kinase activity. In some embodiments, the compounds disclosed herein reduce, inhibit or otherwise decrease HPK1-mediated phosphorylation of SLP76 and / or Gads.

[0435] The compounds disclosed herein may or may not be specific HPK1 antagonists. A specific HPK1 antagonist reduces the biological activity of HPK1 by an amount statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other serine / threonine kinases). In certain embodiments, the compounds disclosed herein specifically inhibit the serine / threonine kinase activity of HPK1. In some of these embodiments, the HPK1 antagonist has an IC of 1000 Å against HPK1. 50 is the IC of an HPK1 antagonist against another serine / threonine kinase or another type of kinase (e.g., tyrosine kinase) 50 About 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of.

[0436] The compounds disclosed herein can be used in methods for inhibiting HPK1. Such methods comprise contacting HPK1 with an effective amount of a compound of the invention. "Contacting" means that the compound is sufficiently adjacent to the isolated HPK1 enzyme or cells expressing HPK1 (e.g., T cells, B cells, dendritic cells) to enable the compound to bind to HPK1 and inhibit its activity. The compound can be contacted with HPK1 in vitro or in vivo, and in vivo contact is achieved by administering the compound to an individual.

[0437] Any method known in the art for measuring HPK1 kinase activity can be used to determine whether HPK1 has been inhibited, including in vitro kinase assays, immunoblotting with antibodies specific for phosphorylation targets of HPK1 (e.g., 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 T or B cell activation.

[0438] The compounds disclosed herein 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 cause or maintenance of the pathological condition. In some embodiments, the HPK1-dependent disorder is cancer.

[0439] The compounds disclosed herein can also be used to enhance the immune response of an individual in need thereof. Such methods comprise administering an effective amount of a compound of the present invention.

[0440] As used herein, "enhancing immune response" refers to the improvement of any immunogenic response to an antigen. Non-limiting examples of improvements in immunogenic responses to antigens include enhanced dendritic cell maturation or migration, enhanced T cell (e.g., CD4 T cell, CD8 T cell) activation, enhanced T cell (e.g., CD4 T cell, CD8 T cell) proliferation, enhanced B cell proliferation, increased T cell and / or B cell survival rate, antigen presentation improvement of antigen presenting cells (e.g., dendritic cells), improved antigen clearance, increased cytokine (e.g., interleukin-2) produced by T cells, enhanced resistance to immunosuppression induced by prostaglandin E2, and enhanced activation and / or lytic activity of CD8 T cells.

[0441] In some embodiments, the individual's CD8 T cells have enhanced activation, proliferation and / or cytolytic activity relative to prior to administration of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof. In some embodiments, CD8 T cell activation is characterized by increased CD44 expression and / or enhanced cytolytic activity in CD8 T cells. In some embodiments, CD8 T cell activation is characterized by increased expression of γ-IFN + The occurrence of CD8 T cells is increased. In some embodiments, the CD8 T cells are antigen-specific T cells.

[0442] In some embodiments, the maturation and activation of antigen presenting cells in a subject is enhanced relative to prior to administration of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof. In some embodiments, the antigen presenting cells are dendritic cells. In some embodiments, the maturation of antigen presenting cells is characterized by CD83 + Increased appearance of dendritic cells. In some embodiments, antigen presenting cell activation is characterized by increased expression of CD80 and CD86 on dendritic cells.

[0443] In some embodiments, the subject has reduced serum levels of the cytokine IL-10 and / or the chemokine IL-8 (human homolog of murine KC) relative to prior to administration of a compound of Formula I or Ia, or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof.

[0444] Engagement of the TCR can cause activation of HPK1, which acts as a negative regulator of the TCR-induced AP-1 response pathway. HPK1 is believed to negatively regulate T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204: 681-691) and Gads at Thr254, which causes the recruitment of 14-3-3 proteins bound to phosphorylated SLP76 and Gads, causing the release of SLP76-Gads-14-3-3 complexes from LAT-containing microclusters, causing T cell dysfunction, including loss of capacity and exhaustion (Lasserre et al. (2011), J Cell Biol 195(5): 839-853).

[0445] In some embodiments, administration of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof, to a subject results in enhanced T cell function.

[0446] Therefore, the compounds of the present invention disclosed in the present invention or their pharmaceutically acceptable salts, prodrugs, metabolites or derivatives are suitable for treating T cell dysfunction disorders. "T cell dysfunction disorders" are T cell disorders or conditions characterized by a reduced response to antigenic stimulation. In a specific embodiment, 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 a disorder in which the T cell capacity is lost or the ability to secrete cytokines, proliferate or perform lytic activity is reduced. In a specific aspect, the reduced response can cause ineffective control of pathogens or tumors expressing immunogens. Examples of T cell dysfunction disorders characterized by T cell dysfunction include acute infections of unknown origin, chronic infections, and tumor immunity.

[0447] Thus, the compounds disclosed herein are useful for treating conditions where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for the treatment of cancer.

[0448] The term "dysfunction" in the context of immune dysfunction refers to a state of reduced immune response to antigenic stimulation. The term includes common elements in which exhaustion and / or loss of ability to recognize antigens can occur, but the subsequent immune response is ineffective in controlling infection or tumor growth.

[0449] As used herein, the term "dysfunctional" also includes being resistant or unresponsive to antigen recognition, specifically, having a reduced ability to translate antigen recognition into downstream T cell effector functions (e.g., proliferation, cytokine production (e.g., IL-2, γ-IFN), and / or target cell killing).

[0450] The term "competence" refers to a state of unresponsiveness to antigenic stimulation caused by incomplete or insufficient signaling delivered via the T cell receptor (e.g., in the absence of ras activation, intracellular Ca +2 In the absence of costimulation, T cell competence loss can also be caused by antigenic stimulation, causing the cells to become resistant to subsequent antigenic activation even in the presence of costimulation. The presence of interleukin-2 can usually resolve the anergy. Competence loss T cells do not undergo clonal expansion and / or acquire effector functions.

[0451] The term "exhaustion" refers to T cell exhaustion, a state of T cell dysfunction caused by continuous TCR signaling, such as that occurring during a variety of chronic infections and cancers. It differs from capacity loss in that it is not caused by incomplete or insufficient signaling, but by continuous signaling. It is defined by adverse effector functions, persistent expression of inhibitory receptors, and transcriptional states that are different from functional effectors or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can be caused by exogenous negative regulatory pathways (such as immunoregulatory cytokines) as well as cellular endogenous negative regulatory (co-stimulatory) pathways (PD-1, B7-H3, B7-H4, etc.).

[0452] "Immunogenicity" refers to the ability of a particular substance to elicit an immune response. Tumors are immunogenic and enhancing tumor immunogenicity helps the immune response eliminate tumor cells.

[0453] "Enhancing T cell function" means inducing, causing or stimulating T cells to have a sustained or amplified biological function, or renewing or reactivating exhausted or inactive T cells. Examples of enhancing T cell function include: increased secretion of cytokines (e.g., gamma-interferon, IL-2, IL-12, and TNFα), increased proliferation, antigen reactivity (e.g., virus, pathogen, or tumor clearance) relative to such levels before intervention, and increased production of effector particles of CD8 T cells, such as granzyme B. In one embodiment, the level is enhanced by at least 50%, or 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner of measuring this enhancement is known to those of ordinary skill in the art.

[0454] "Tumor immunity" refers to the process in which a tumor evades immune recognition and clearance. Therefore, as a therapeutic concept, tumor immunity is "cured" when such evasion is reduced and the tumor is recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.

[0455] The present invention provides methods of modulating (eg, inhibiting) HPK1 activity, comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0456] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof.

[0457] In the methods described herein, a compound of the invention or a pharmaceutical composition thereof is administered to a subject having cancer.

[0458] In certain embodiments, the subject matter disclosed herein relates to a method for treating an HPK1-dependent disorder, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutical composition described herein. In certain aspects of this embodiment, the HPK1-dependent disorder is cancer. In certain aspects of this embodiment, the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma. In certain aspects of this embodiment, the cancer has an increased amount of T cell infiltration. In certain aspects of this embodiment, the individual's cancer cells selectively have increased expression of class I MHC antigen expression compared to before administration of the compound or composition.

[0459] In some embodiments, the subject matter disclosed herein relates to a method for treating chronic viral infection. In some embodiments, the subject matter disclosed herein relates to using HPK1 inhibitors as adjunctive therapy to increase vaccination efficacy.

[0460] 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.

[0461] In certain aspects, the invention provides methods of treating cell proliferative disorders including cancer, benign papillomatosis, gestational trophoblastic disease, and benign neoplastic diseases, such as cutaneous papillomas (warts) and genital papillomas.

[0462] In one aspect, the present 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 present invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0463] In certain embodiments, the cell proliferative disorder is cancer.

[0464] Examples of cancers that may be treated using the compounds of the invention include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or within the eye, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, carcinoma of the endometrium / endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, Disease), non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), solid tumors in children, lymphocytic lymphoma, bladder cancer, kidney cancer or urethral cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal 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 said cancers.

[0465] In some embodiments, cancers that can be treated using the compounds of the present invention include, but are not limited to, solid tumors (e.g., prostate cancer, colorectal cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood cancers (e.g., lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid 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 said cancers.

[0466] In certain embodiments, the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colorectal cancer, lung cancer, or sarcoma. In another embodiment, 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 cancer, prostate cancer, thyroid cancer, colorectal cancer, lung cancer, central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, and cholangiocarcinoma.

[0467] In certain embodiments, the cancer is selected from the group consisting of brain and spinal cord cancer, head and neck cancer, leukemia and blood cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, liver cancer and bile duct cancer, kidney cancer and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancer, and cancer of unknown primary (a cancer in which metastases are found but the site of the original cancer is unknown). In specific embodiments, the cancer is present in an adult patient; in other embodiments, the cancer is present in a pediatric patient. In specific embodiments, the cancer is associated with AIDS.

[0468] In another embodiment, the cancer is selected from brain cancer and spinal cord cancer. In a specific embodiment, the cancer is selected from the group consisting of: multiform astrocytoma, glioblastoma, astrocytoma and sensitive neuroblastoma (olfactory blastoma). In a specific embodiment, the brain cancer is selected from the group consisting of: astroglial tumors (e.g., pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, multiform xanthoastrocytoma, degenerative astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma and primary pediatric glioblastoma), oligodendroglial tumors (e.g., oligodendroglioma and degenerative oligodendroglioma). In certain embodiments, the brain cancer is selected from the group consisting of: glioma, glioblastoma multiforme, paraganglioma, and suprantentorial primordial neuroectodermal tumor (sPNET).

[0469] In certain embodiments, the cancer is selected from the group consisting of head and neck cancer, including nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, hypopharyngeal cancer, oral cancer (e.g., squamous cell carcinoma, lymphoma and sarcoma), lip cancer, oropharyngeal cancer, salivary gland tumors, laryngeal cancer (e.g., laryngeal squamous cell carcinoma, rhabdomyosarcoma) and eye cancer or ocular cancer. In certain embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.

[0470] In a particular embodiment, the cancer is selected from leukemia and hematological cancer. In a particular embodiment, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndrome, myelodysplasia / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), AML after MPN, AML after MDS, high-risk MDS or AML associated with del (5q), blastocyst chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytoma and multiple myeloma. The leukemia mentioned herein can be acute or chronic.

[0471] In certain embodiments, the cancer is selected from skin cancer. In certain embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell carcinoma, and basal cell carcinoma.

[0472] In particular embodiments, the cancer is selected from cancers of the reproductive system. In particular 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 particular instances of these embodiments, the cancer is breast cancer selected from the group consisting of ductal carcinoma and phyllodes tumor. In particular instances of these embodiments, the breast cancer can be male breast cancer or female breast cancer. In particular instances of these embodiments, the cancer is cervical cancer selected from the group consisting of squamous cell carcinoma and adenocarcinoma. In particular instances of these embodiments, the cancer is ovarian cancer selected from the group consisting of epithelial cancers.

[0473] In a particular embodiment, the cancer is selected from a cancer of the gastrointestinal system. In a particular embodiment, the cancer is selected from the group consisting of esophageal cancer, gastric cancer (also known as stomach cancer), gastrointestinal carcinoid, pancreatic cancer, gallbladder cancer, colorectal cancer and anal cancer. In examples of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid, gastrointestinal stromal tumor, gastric lymphoma, gastrointestinal lymphoma, solid pseudopapillary pancreatic tumor, pancreatoblastoma, islet cell tumor, pancreatic cancer (including acinar cell carcinoma and ductal adenocarcinoma), gallbladder adenocarcinoma, colorectal adenocarcinoma and anal squamous cell carcinoma.

[0474] In certain embodiments, the cancer is selected from liver cancer and bile duct cancer. In certain embodiments, the cancer is liver cancer (hepatocellular carcinoma). In certain embodiments, the cancer is bile duct cancer (cholangiocarcinoma); in examples of these embodiments, bile duct cancer is selected from the group consisting of intrahepatic bile duct cancer and extrahepatic bile duct cancer.

[0475] In a specific embodiment, the cancer is selected from kidney cancer and bladder cancer. In a specific embodiment, the cancer is a kidney cancer selected from the group consisting of: renal cell carcinoma, Wilms tumor, and transitional cell carcinoma. In a specific embodiment, the cancer is a bladder cancer selected from the group consisting of: urothelial carcinoma (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

[0476] In specific embodiments, the cancer is selected from bone cancer. In specific embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, and chordoma.

[0477] In particular embodiments, the cancer is selected from lung cancer. In particular embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, bronchogenic tumors, and pleuropulmonary blastoma.

[0478] In certain embodiments, the cancer is selected from malignant mesothelioma. In certain embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoid carcinoma.

[0479] In specific embodiments, the cancer is selected from a sarcoma. In specific 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.

[0480] In a particular embodiment, the cancer is selected from lymphoma. In a particular embodiment, 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, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphoma, and primary central nervous system lymphoma.

[0481] In particular embodiments, the cancer is selected from adenocarcinoma. In particular embodiments, the cancer is selected from the group consisting of adrenocortical carcinoma, pheochromocytoma, paraganglioma, pituitary tumor, thymoma, and thymic carcinoma.

[0482] In particular embodiments, the cancer is selected from thyroid cancer.In particular embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid cancer, papillary thyroid cancer, and follicular thyroid cancer.

[0483] In certain embodiments, the cancer is selected from a germ cell tumor. In certain embodiments, the cancer is selected from the group consisting of: a malignant extracranial germ cell tumor and a malignant extragonadal germ cell tumor. In certain instances of these embodiments, the malignant extragonadal germ cell tumor is selected from the group consisting of a non-seminoma and a seminoma.

[0484] In a particular embodiment, the cancer is selected from a cardiac tumor. In a particular embodiment, the cardiac tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0485] 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 skin papilloma (warts) and genital papilloma. In certain embodiments, gestational trophoblastic disease is selected from the group consisting of: hygroma and gestational trophoblastic neoplasia (e.g., invasive hydatidiform mole, choriocarcinoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor).

[0486] In some embodiments, the individual has melanoma. The melanoma may be in the early or late stages. In some embodiments, the individual has colorectal cancer. Colorectal cancer may be in the early or late stages. In some embodiments, the individual has non-small cell lung cancer. Non-small cell lung cancer may be in the early or late stages. In some embodiments, the individual has pancreatic cancer. Pancreatic cancer may be in the early or late stages. In some embodiments, the individual has hematologic malignancies. Hematologic malignancies may be in the early or late stages. In some embodiments, the individual has ovarian cancer. Ovarian cancer may be in the early or late stages. In some embodiments, the individual has breast cancer. Breast cancer may be in the early or late stages. In some embodiments, the individual has renal cell carcinoma. Renal cell carcinoma may be in the early or late stages. In some embodiments, the cancer has an elevated amount of T cell infiltration.

[0487] In some embodiments, cancers that can be treated with the compounds of the invention include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate gland), breast cancer, triple-negative breast cancer, colorectal cancer, and lung cancer (e.g., non-small cell lung cancer and small cell lung cancer). In addition, the present invention includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the invention.

[0488] In some embodiments, diseases and indications that may be treated using the compounds of the present invention include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, cancers of the nervous system, gynecological cancers, and skin cancers.

[0489] 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 lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0490] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0491] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, enchondroma hamartoma, and mesothelioma.

[0492] Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0493] Exemplary genitourinary tract cancers include cancers 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, teratothelioma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma).

[0494] Exemplary liver cancers include hepatoma (eg, hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0495] Exemplary bone cancers include, e.g., osteogenic sarcomas (e.g., osteosarcomas), fibrosarcomas, malignant fibrous histiocytomas, chondrosarcomas, Ewing's sarcoma, malignant lymphomas (reticulum cell sarcomas), multiple myeloma, malignant giant cell tumors, chordomas, osteochondromas (osteocartilaginous exostoses), benign enchondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, and giant cell tumors.

[0496] Exemplary cancers of the nervous system include cancers of the skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastomas, glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), and spinal cord (neurofibromas, meningiomas, gliomas, sarcomas), as well as neuroblastoma and Lhermitte-Duclos disease.

[0497] Exemplary gynecological cancers include cancers of the uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma of unspecified type), theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tube (carcinoma).

[0498] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, dysplastic nevus, lipoma, hemangioma, dermatofibroma and keloid. In some embodiments, diseases and indications that can be treated using the compounds of the invention include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer and urothelial cancer.

[0499] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal cancer and paranasal sinus cancer, thyroid cancer and parathyroid cancer.

[0500] In some embodiments, HPK1 inhibitors can be used to treat tumors that produce PGE2 (e.g., tumors that overexpress Cox-2) and / or tumors that produce adenosine (tumors that overexpress CD73 and CD39). Overexpression of Cox-2 has been detected in a variety of tumors, such as colorectal cancer, breast cancer, pancreatic cancer, and lung cancer, where it is associated with poor prognosis. It has been reported that in blood cancer models, such as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia) and in the embryonic cells of patients, there is overexpression of COX-2. CD73 is upregulated in various human cancers (including colorectal cancer, lung cancer, pancreatic cancer, and ovarian cancer). Importantly, the higher expression of CD73 is associated with tumor angiogenesis, invasiveness, and metastasis, and is associated with a shorter survival time in breast cancer patients.

[0501] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of any of the diseases mentioned herein; for example, preventing or reducing the risk of a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but has not yet experienced or manifested the pathology or symptoms of the disease.

[0502] The compounds disclosed in the present invention can be administered in any suitable manner known in the art. In some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts, prodrugs, metabolites or derivatives are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intratumorally or intranasally.

[0503] In some embodiments, the HPK1 antagonist is administered continuously. In other embodiments, the HPK1 antagonist is administered intermittently. Furthermore, treating a subject with an effective amount of an HPK1 antagonist may include a single therapy or may include a series of therapies.

[0504] It should be understood that the appropriate dosage of the active compound depends on a variety of factors within the knowledge of the ordinary skilled physician or veterinarian. The dosage of the active compound will vary, for example, depending on the age, weight, general health, sex and diet of the individual, the time of administration, the route of administration, the excretion rate and any drug combination.

[0505] It is also understood that the effective dose of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof used for treatment may be increased or decreased over a specific treatment period. Dosage changes may be caused by and become apparent from diagnostic assay results.

[0506] 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.

[0507] In the methods described herein, the methods may further comprise administering a chemotherapeutic agent to the individual. In certain aspects of this embodiment, the chemotherapeutic agent and the compound or composition are administered to the individual simultaneously. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the individual prior to administering the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the individual after administering the compound or composition.

[0508] As used herein, the term "treatment / treat / treating" refers to reversing, alleviating, delaying the onset of, or inhibiting the worsening of a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, therapy may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[0509] The term "administration" includes a route of introducing a compound into a subject to exert 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.

[0510] The term "effective amount" includes an amount effective to achieve the desired result at the desired dosage and time period. The effective amount of a compound may vary according to factors such as the individual's disease condition, age, and weight, and the ability of the compound to elicit a desired response in the individual. The dosage regimen may be adjusted to provide the optimal therapeutic response.

[0511] As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" mean administration of a compound, drug, or other substance so that it enters the patient's system and thereby undergoes metabolism and other similar processes.

[0512] The phrase "therapeutically effective amount" or "effective amount" means an amount of a compound of the invention that achieves the following effects: (i) treating or preventing a specific disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a specific disease, condition or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, condition or disorder described herein. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down and preferably stop to some extent) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down and preferably stop to some extent) 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 a drug can prevent the growth of existing cancer cells and / or kill existing cancer cells, it can 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).

[0513] The term "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In certain embodiments, the subject is a human.

[0514] Combination therapy

[0515] Depending on the specific condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a specific disease or condition are referred to as "appropriate for the disease or condition being treated."

[0516] In certain embodiments, provided combinations or compositions thereof are administered in combination with another therapeutic agent.

[0517] Examples of agents that may also be combined with the combinations of the present invention include, but are not limited to: therapies for Alzheimer's disease, e.g. and Therapies for HIV, such as ritonavir; therapies for Parkinson's Disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents used to treat multiple sclerosis (MS), such as beta interferon (e.g. and ), and mitoxantrone; for asthma treatments such as albuterol and Agents used to treat schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ionophores, agents for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for the treatment of liver diseases, such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for the treatment of blood disorders, such as corticosteroids, anti-leukemia agents and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., metabolic breakdown inhibitors) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), agents for the treatment of immunodeficiency disorders, such as gamma globulin.

[0518] In certain embodiments, the combination therapies of the invention, or pharmaceutically acceptable compositions thereof, are administered in combination with a monoclonal antibody or siRNA therapeutic.

[0519] Those additional agents may be administered separately from the provided combination therapy as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the invention into a single composition. If administered as part of a multiple dosing regimen, the two active agents may be provided simultaneously, sequentially, or within a certain time period of each other (usually within 5 hours of each other).

[0520] As used herein, the term "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combination of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form.

[0521] The amount of the other 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. The amount of the additional therapeutic agent in the compositions disclosed herein preferably ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0522] In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent can be administered together with the compound of formula I, or can be administered before or after the administration of the compound of formula I. Suitable therapeutic agents are described in further detail below. In certain embodiments, the compound of formula I can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of formula I can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0523] 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 and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac, and celecoxib, colchicine Corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone and its analogs, probenecid, allopurinol, febuxostat Sulfasalazine Antimalarial drugs, such as hydroxychloroquine and chloroquine Methotrexate Gold salts, such as gold thioglucosinolate gold thiomalate Auranofin D-Penicillamine ( or ), Azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and "anti-TNF" agents, such as etanercept Infliximab Golimumab Certolizumab pegol and adalimumab "Anti-IL-1" agents, such as anakinra and rilonacept Canakinumab Anti-Jak inhibitors, such as tofacitinib; antibodies, such as rituximab "Anti-T cell" agents, such as abatacept “Anti-IL-6” agents, such as tocilizumab diclofenac, cortisone, hyaluronic acid or ); monoclonal antibodies, such as tanezumab; anticoagulants, such as heparin ( or ) and warfarin Antidiarrheal medicines, such as diphenoxylate and loperamide Bile acid binders, such as cholestyramine, alosetron Lubiprostone Laxatives, such as milk of magnesia, polyethylene glycol and Anticholinergics or antispasmodics, such as dicyclomine Beta-2 agonists, such as albuterol ( HFA, HFA), levalbuterol Metaproterenol Pirbuterol acetate Terbutaline sulfate Salmeterol xinafoate and formoterol Anticholinergic drugs, such as ipratropium bromide and tiotropium Inhaled corticosteroids, such as beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone Budesonide Flunisolide Sodium cromoglycate Methylxanthines, such as theophylline ( ) and theophylline; IgE antibodies, such as omalizumab Nucleoside reverse transcriptase inhibitors, such as zidovudine Abacavir Abacavir / lamivudine Abacavir / lamivudine / zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / zidovudine Stavudine and zalcitabine Non-nucleoside reverse transcriptase inhibitors, such as delavirdine Efavirenz Nevairapine and etravirine Nucleotide reverse transcriptase inhibitors, such as tenofovir Protease inhibitors, such as amprenavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir and ritonavir Nelfinavir Ritonavir Saquinavir ( or ) and tipranavir Entry inhibitors, such as enfuvirtide and maraviroc Integrase inhibitors, such as raltegravir Cranberries (doxorubicin) Vincristine Bortezomib and dexamethasone Lenalidomide or any combination thereof.

[0524] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac and celecoxib; corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and their analogs; sulfasalazine Antimalarial medicines, such as hydroxychloroquine and chloroquine Methotrexate Gold salts, such as gold thioglucose gold thiomalate Auranofin D-Penicillamine ( or ); Azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and "anti-TNF" agents; for example, etanercept Infliximab Golimumab Certolizumab PEGylated Adalimumab "Anti-IL-1" agents, such as anakinra and linacept Antibodies, such as rituximab "Anti-T cell" agents, such as abatacept and “anti-IL-6” agents, such as tocilizumab

[0525] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac and celecoxib; diclofenac; cortisone; hyaluronic acid ( or ) and monoclonal antibodies, such as tanezumab.

[0526] In some embodiments, the present invention provides a method for treating cutaneous lupus erythematosus or systemic lupus erythematosus, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac and celecoxib; corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and their analogs; antimalarials, such as hydroxychloroquine and chloroquine Cyclophosphamide Methotrexate Azathioprine and anticoagulants, such as heparin ( or ) and warfarin

[0527] In some embodiments, the present invention provides a method of treating Crohn's disease, ulcerative colitis or inflammatory bowel disease, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of mesalamine Sulfasalazine Antidiarrheal medicines, such as diphenoxylate and loperamide Bile acid binders, such as cholestyramine; alosetron Lubiprostone Laxatives, such as milk of magnesia, polyethylene glycol and and anticholinergics or antispasmodics, such as dicyclomine Anti-TNF therapeutics; steroids; and antibiotics, such as metronidazole (Flagyl) or ciprofloxacin (ciprofloxacin).

[0528] In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from: Beta-2 agonists, such as albuterol ( HFA, HFA), levosalbutamol Metaproterenol Pirbuterol acetate Terbutaline sulfate Salmeterol Hydroxynaphthoate and formoterol Anticholinergic drugs, such as ipratropium bromide and tiotropium Inhaled corticosteroids, such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone Budesonide Flunisolide and Sodium cromoglycate Methylxanthines, such as theophylline and theophylline; and IgE antibodies, such as omalizumab

[0529] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of: a beta-2 agonist, such as albuterol ( HFA, HFA), levosalbutamol Metaproterenol Pirbuterol acetate Terbutaline sulfate Salmeterol Hydroxynaphthoate and formoterol Anticholinergics, such as ipratropium and tiotropium Methylxanthines, such as theophylline and theophylline; inhaled corticosteroids, such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone Budesonide Flunisolide and

[0530] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of: rituximab Cyclophosphamide Cranberries Vincristine Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0531] In another embodiment, the present invention provides a method of treating solid tumors, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from: rituximab Cyclophosphamide Cranberries Vincristine Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0532] In another embodiment, the present invention provides a method of treating a hematologic malignancy comprising administering to a patient in need thereof a compound of Formula I and an inhibitor of a hedgehog (Hh) signaling pathway. In some embodiments, the hematologic 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).

[0533] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from: rituximab Cyclophosphamide Cranberries Vincristine Prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0534] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from: bortezomib and dexamethasone Hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and lenalidomide

[0535] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of formula I and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lymeneuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, disease), opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody 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'sarteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease disease), chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvar pain, hyperproliferative disorders, transplant organ or tissue rejection, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergies (e.g., to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mite or cockroach calyx allergy), type I allergy, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epicondylitis, epididymitis, fasciitis, fibrositis,Gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, local pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia , B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also called plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer, or mast cell cancer (e.g., leptomeningeal tumor, mast cell leukemia, mast cell sarcoma, systemic mastectomy cytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including but not limited to rheumatoid arthritis), seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases, thromboembolic disorders (e.g., myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn of the skin, sinusitis, localized pneumonia, encephalitis, meningitis, Myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel disease, ulcerative colitis, Sjögren's disease, tissue transplant rejection, hyperacute transplant organ rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic conditions, Gouper's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,Septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Grave's disease.

[0536] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from cancer, neurodegenerative disorders, angiogenic disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathological immune conditions involving T cell activation, cardiovascular disorders and CNS disorders.

[0537] In another embodiment, the present invention provides a method for treating a disease or lessening the severity of a disease, comprising administering a compound of formula I and a PI3K inhibitor to a patient in need thereof, wherein the disease is selected from a benign or malignant tumor, carcinoma or solid tumor, sarcoma, glioblastoma, neuroblastoma, sarcoma, glioma ... blastoma, multiple myeloma or gastrointestinal cancer, in particular colorectal cancer or colorectal adenoma or head and neck tumors, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, neoplasia of epithelial characteristics, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin's or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma or leukemia; including Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome (including Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome). syndrome); or diseases in which the PI3K / PKB pathway is abnormally activated; asthma of any type or cause, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, 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, airway or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated with it, emphysema, and asthma treated with other drugs; exacerbation of airway hyperresponsiveness caused by inhaled medication, especially other inhaled medication; bronchitis of any type or origin, including but not limited to acute, arachidonic, catarrhal, croupus, chronic or tuberculous bronchitis; pneumoconiosis of any type or origin (inflammatory, general occupational lung disease, usually with chronic or acute airway obstruction, and caused by repeated inhalation of dust), including, for example, aluminosis, anthracis, asbestosis, stone dust, ostrich pneumoconiosis, siderosis, silicosis, fumigation and byssinosis;Loffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquired, conjunctivitis, dry eye, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and involving or with autoimmune reactions Inflammatory diseases of a nonspecific component or etiology, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia); cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, syndrome), idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine eye diseases, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), dry eye and vernal keratoconjunctivitis, pulmonary fibrosis, psoriatic arthritis, and glomerulonephritis (with or without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiomegaly, 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.

[0538] In some embodiments, the present invention provides a method of treating a disease or reducing its severity, comprising administering a compound of formula I and a Bcl-2 inhibitor to a patient in need thereof, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological tumor, or solid tumor.

[0539] In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments, the JH2 binding compound is a compound of formula I. Other suitable JH2 domain binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain binding compounds include those described in WO2015131080A1, which are incorporated herein by reference in their entirety.

[0540] Any effective dosage and any effective administration route for treating autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or disorders associated with transplantation or reducing their severity can be used to administer the compounds and compositions according to the methods of the invention. The exact amount required will vary with each individual, depending on the species, age and general condition of the individual, the severity of the infection, the specific agent, its mode of administration, and similar factors. The compounds of the present invention are preferably formulated in unit dosage form to achieve administration convenience and dosage uniformity. As used herein, the expression "unit dosage form" refers to a physical discontinuous unit of a medicament suitable for a patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used; and factors as are well known in the medical art. As used herein, the term "patient" means an animal, preferably a mammal and most preferably a human.

[0541] Depending on the severity of the infection being treated, the pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powder, ointment or drops), buccally, as an oral or nasal spray or the like. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg and preferably about 1 mg / kg to about 25 mg / kg of individual body weight / day, administered one or more times a day, to obtain the desired therapeutic effect.

[0542] 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, the liquid dosage form may contain: inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan; and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics.

[0543] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions present in parenterally acceptable nontoxic diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, USP and isotonic sodium chloride solutions can be used. In addition, sterile fixed oils are routinely used as solvents or suspension media. For this purpose, any mild fixed oils including synthetic monoglycerides or diglycerides can be used. In addition, fatty acids, such as oleic acid, are used when preparing injectables.

[0544] The injectable formulations may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0545] To prolong the effect of the compounds of the present invention, it is usually necessary to slow down the absorption of the subcutaneous or intramuscularly injected compound. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable storage forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer (e.g., polylactic acid-polyglycolide). Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable storage formulations can also be prepared by coating the compound in a liposome or microemulsion compatible with body tissues.

[0546] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0547] 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 carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) disintegrating agents, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0548] Solid compositions of similar types can also be used as fillers in soft-filled and hard-filled gelatin capsules, and the capsules use excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Tablets, dragees, capsules, pills and granules solid dosage forms can be prepared with coatings and shells, such as other coatings known in enteric coatings and pharmaceutical formulation technology. It can optionally contain an emulsifier, and can also have a composition that releases active ingredients only in or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. The example of an embedding composition that can be used includes polymeric substances and wax. Solid compositions of similar types can also be used as fillers in soft-filled and hard-filled gelatin capsules, and the capsules use excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0549] The active compound may also be present in a microencapsulated form together with one or more excipients as indicated above. Tablets, dragees, capsules, pills and granules solid dosage forms may be prepared with coatings and shells, such as enteric coatings, controlled release coatings and other coatings known in pharmaceutical formulation technology. In the solid dosage form, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). As in normal practice, such dosage forms may also include other substances in addition to inert diluents, such as lubricants for making tablets and other adjuvants for making tablets, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include a buffer. It may optionally contain an emulsifier, and may also have 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 usable embedding compositions include polymeric substances and waxes.

[0550] The dosage form for the body surface or transdermal administration of the compounds of the present invention includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be needed under aseptic conditions. It is also considered that ophthalmic formulations, ear drops and eye drops are within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms are prepared by dissolving or distributing the compound in an appropriate medium. Absorption enhancers can also be used to enhance the flow 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.

[0551] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0552] According to another embodiment, the present invention relates to a method for inhibiting the activity of HPK1 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising said compound. In certain embodiments, the present invention relates to a method for irreversibly inhibiting the activity of HPK1 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising said compound.

[0553] The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0554] Inhibiting HPK1 (or its mutant) activity in a biological sample is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological analysis.

[0555] Another embodiment of the present invention is directed to a method of inhibiting protein kinase activity in a patient comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound.

[0556] According to another embodiment, the present invention relates to a method of inhibiting the activity of HPK1 or a mutant thereof in a patient, comprising the step of 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 of reversibly or irreversibly inhibiting the activity of HPK1 or a mutant thereof in a patient, comprising the step of 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 of treating a HPK1 or mutant thereof mediated disorder in a patient in need thereof, comprising the step of administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0557] Depending on the particular condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of the 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."

[0558] The compounds of the present invention may also be used in combination with other therapeutic compounds to advantage. In some embodiments, the other therapeutic compound is an anti-proliferative compound. The anti-proliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-neoplastic antimetabolites; platinum compounds; compounds that target / reduce the activity of protein or lipid kinases and other anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bispecific inhibitors; Phosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target, reduce or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide Spindle kinesin inhibitors, such as 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 a compound that inhibits the production of estrogens (e.g., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively). The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane; and especially nonsteroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin TM Formestane is sold under the brand name Lentaron TM Fadrozole is sold under the brand name Afema TM Anastrozole is sold under the brand name Arimidex TM Letrozole is sold under the brand name Femara TM or Femar TM Amineglutethimide is sold under the trade name Orimeten TM The combination of the invention comprising a chemotherapeutic agent and an aromatase inhibitor is particularly useful in the treatment of hormone receptor positive tumors, such as breast tumors.

[0559] As used herein, the term "anti-estrogen" refers to compounds that antagonize the effects of estrogens at the level of the estrogen receptors. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex TM Raloxifene hydrochloride is sold under the brand name Evista TM Fulvestrant is sold under the brand name Faslodex TMAdministration. Combinations of the invention comprising a chemotherapeutic agent that is an antiestrogen are particularly useful in the treatment of estrogen receptor positive tumors, such as breast tumors.

[0560] As used herein, the term "antiandrogen" refers to any substance that is capable of inhibiting the biological effects of androgens and includes, but is not limited to, bicalutamide (Casodex TM As used herein, the term "gonadotropin agonist" includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is available under the trade name Zoladex TM Invest.

[0561] As used herein, the term "topoisomerase I inhibitors" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan is available, for example, in its marketed form, for example under the trademark Camptosar TM Topotecan is sold under the brand name Hycamptin TM Sale.

[0562] As used herein, the term "topoisomerase II inhibitors" include, but are not limited to, anthracyclines such as rhubarb (including lipid formulations such as Caelyx TM ), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone and the podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trade name Etopophos TM Teniposide is sold under the brand name VM 26-Bristol. Cranberries are sold under the brand name Acriblastin TM or Adriamycin TM Epirubicin is sold under the brand name Farmorubicin TM Idamycin is sold under the brand name Zavedos TM Mitoxantrone is sold under the trade name Novantron.

[0563] 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; cochicine and epothilone and its derivatives. Pacific paclitaxel is sold under the trade name Taxol TM Docetaxel is sold under the brand name Taxotere TM Vinblastine sulfate is sold under the trade name Vinblastin RP TM Vincristine sulfate is sold under the trade name Farmistin TM Sale.

[0564] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin. TM Ifosfamide is sold under the brand name Holoxan TM Sale.

[0565] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to a compound that inhibits histone deacetylase and has antiproliferative activity. Such compounds include, but are not limited to, suberoylanilide hydroxamic acid (SAHA).

[0566] The term "anti-neoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folic acid antagonists (e.g., pemetrexed). Capecitabine is marketed under the trade name Xeloda TM Gemcitabine is sold under the brand name Gemzar TM Sale.

[0567] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cis-platin, cisplatinum, and oxaliplatin. Carboplatin can be administered, for example, in the form in which it is marketed, for example, under the trademark Carboplat TM Administration. Oxaliplatin can be administered, for example, in the form in which it is marketed, for example under the trademark Eloxatin TM Invest.

[0568] As used herein, the term "compounds that target / reduce the activity of a protein or lipid kinase or a protein or lipid phosphatase or other anti-angiogenic compounds" includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor-receptor (PDGFR), such as compounds that target, reduce or inhibit the activity of PDGFR, especially compounds that inhibit PDGF receptors, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor-receptor (FGFR); c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce or inhibit the activity of IGF-IR, especially compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds that target, reduce or inhibit Trk receptor tyrosine kinase inhibitors; e) compounds that target, decrease or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, decrease or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, decrease or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, decrease or inhibit the activity of the c-kit receptor tyrosine kinase (which is part of the PDGFR family), such as compounds that target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase. 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, such as N-phenyl-2-pyrimidine-amine derivatives, such as 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 protein kinase C (PKC) members and members of the 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 (CDK) family, including staurosporine derivatives, such as midostaurin;Examples of other compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; Isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, such as compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, including imatinib mesylate (Gleevec; TM ) or tyrphostin, such as tyrphostin A23 / RG-50810; AG99; tyrphostin AG 213; tyrphostin AG1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG 555; AG494; tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) targeting, decreasing or inhibiting receptor tyrosine kinases (EGFR in the form of homodimers or heterodimers) 1 Compounds that inhibit the activity of the epidermal growth factor family of ErbB2, ErbB3, ErbB4) and its mutants, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, especially compounds, proteins or antibodies that inhibit EGF receptor tyrosine kinase family members (such as EGF receptor, ErbB2, ErbB3 and ErbB4) or bind to EGF or EGF-related ligands; CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin TM ), cetuximab (Erbitux TM), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3; and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, decrease or inhibit the activity of c-Met receptors, such as compounds that target, decrease or inhibit the activity of c-Met, especially compounds that inhibit the kinase activity of c-Met receptors n) compounds that target, reduce or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG- o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dac tolisib), XL-147, XL-765 and idelalisib; and q) compounds that target, decrease or inhibit the signaling effects of the hedgehog (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0569] The term "PI3K inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against one or more enzymes in the phosphatidylcholine-3-kinase family, including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101 and p87. Examples of PI3K inhibitors suitable for use in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparcoxib, picoxib, PF-4691502, BYL-719, datoxib, XL-147, XL-765, and idecoxib.

[0570] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity against bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0571] The term "SYK inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity on spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0572] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds that have inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, pan-Bcl-2 inhibitors of Ascenta, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenyang Pharmaceutical University (Shenyang Pharmaceutical University (Shenyang Pharmaceutical University (Shenyang Pharmaceutical University (Shenyang Pharmaceutical University (Shenyang Pharmaceutical University ( In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptide mimetic.

[0573] Further examples of BTK inhibiting compounds and conditions that can be treated by combinations of such compounds with the compounds of the invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0574] Further examples of SYK inhibiting compounds and conditions treatable by combinations of such compounds with compounds of the invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

[0575] Other examples of PI3K inhibitory compounds and conditions treatable by combinations of such compounds with the compounds of the invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

[0576] Further examples of JAK inhibitory compounds and conditions treatable by combinations of such compounds with compounds of the invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[0577] Other antiangiogenic compounds include compounds with another mechanism of activity (e.g., unrelated to protein or lipid kinase inhibition), such as thalidomide. TM ) and TNP-470.

[0578] Examples of proteasome inhibitors suitable for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporin A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0579] Compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase are, for example, phosphatase 1 inhibitors, phosphatase 2A inhibitors or CDC25 inhibitors, such as okadaic acid or a derivative thereof.

[0580] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-γ-tocopherol or δ-tocopherol, or α-γ-tocotrienol or δ-tocotrienol.

[0581] As used herein, the term cyclooxygenase inhibitors includes, but is not limited to, Cox-2 inhibitors 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex TM ), rofecoxib (Vioxx TM ), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluorophenylamino)phenylacetic acid, lumiracoxib.

[0582] As used herein, the term "bisphosphonates" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. TM Clodronic acid is sold under the trade name Bonefos TM Sold under the brand name Skelid TM Pamidronate is sold under the brand name Aredia TM Alendronate is sold under the brand name Fosamax TM Ibandronic acid is sold under the brand name Bondranat TM Risedronate is sold under the brand name Actonel TM Zoledronic acid is sold under the brand name Zometa TM The term "mTOR inhibitor" relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus Everolimus (Certican TM ), CCI-779 and ABT578.

[0583] As used herein, the term "heparinase inhibitor" refers to a compound that targets heparin sulfate, reduces or inhibits its degradation. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to lymphotropin or interferon.

[0584] As used herein, the term "inhibitor of Ras oncogenic isoforms (e.g., H-Ras, K-Ras, or N-Ras)" refers to compounds that target, decrease, or inhibit the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors", such as L-744832, DK8G557, or R115777 (Zarnestra TM As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces or inhibits the activity of telomerase. Compounds that target telomerase, reduce or inhibit its activity are particularly compounds that inhibit telomerase receptors, such as telomestatin.

[0585] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets methionine aminopeptidase, reduces or inhibits its activity. Compounds that target methionine aminopeptidase, reduce or inhibit its activity include but are not limited to bengamide or its derivatives.

[0586] As used herein, the term "proteasome inhibitor" refers to a compound that targets, decreases or inhibits proteasome activity. Compounds that target, decrease or inhibit proteasome activity include, but are not limited to, bortezomib (Velcade TM ) and MLN341.

[0587] As used herein, the term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) includes, but is not limited to, collagen peptide mimetic and non-peptide mimetic inhibitors, tetracycline derivatives, such as the hydrooxalyl ester peptide mimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0588] As used herein, the term "compounds for treating hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferons, 1-β-D-arabinofuranosylcytosine (ara-c) and busulfan (bisulfan); and ALK inhibitors, which are compounds that target, decrease or inhibit polymorphic lymphoma kinase; and Bcl-2 inhibitors.

[0589] Compounds that target, reduce or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R) are particularly compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0590] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity; compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG) (a geldanamycin derivative); other geldanamycin-related compounds; radicicol; and HDAC inhibitors.

[0591] As used herein, the term "anti-proliferative antibodies" includes, but is not limited to, trastuzumab (Herceptin TM ), trastuzumab-DM1, erbitux, bevacizumab (Avastin TM ), rituximab PRO64553 (anti-CD40) and 2C4 antibodies. Antibodies refer to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments as long as they exhibit the desired biological activity.

[0592] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be combined with standard leukemia therapy, especially used in combination with the therapy for the treatment of AML. Specifically, the compounds of the present invention can be administered in combination with, for example, farnesyl transferase inhibitors and / or other drugs suitable for the treatment of AML, such as daunomycin, adriamycin (Adriamycin), Ara-C, VP-16, teniposide, mitoxantrone, idarubicin (Idarubicin), carboplatin (Carboplatinum) and PKC412. In certain embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutations, comprising administering the compounds 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, lestaurtinib, sorafenib, and sunitinib.

[0593] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analog, which is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Targeted histone deacetylase (HDAC) inhibitors, compounds that reduce or inhibit its activity, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of an enzyme called histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 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-acrylamide or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, especially lactate. As used herein, somatostatin receptor antagonists refer to compounds that target, treat or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell destruction methods refer to methods such as ionizing radiation. The term "ionizing radiation" referred to above and below means ionizing radiation that occurs in the form of electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha particles and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, in Cancer, Principles and Practice of Oncology, Devita et al., eds., 4th edition, Vol. 1, pp. 248-275 (1993).

[0594] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C to resist ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0595] Also included are compounds, proteins or monoclonal antibodies to VEGF, such as 1-(4-chlorophenylamino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chlorophenylamino)-4-(4-pyridylmethyl)phthalazine succinate, Angiostatin TM ;Endostatin TM ; anthranilamide; 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 TM ).

[0596] As used herein, photodynamic therapy refers to a therapy that uses certain chemicals called photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with, for example, Visudyne TM and porfimer sodium.

[0597] As used herein, angiostatic steroids refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0598] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0599] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone 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.

[0600] The compounds of the present invention are also suitable for use as adjunctive therapeutic compounds in combination with other drugs such as anti-inflammatory drugs, bronchodilators or antihistamines, particularly for the treatment of obstructive or inflammatory airway diseases such as those mentioned above, for example as a synergist of the therapeutic activity of the drug or as a method of reducing the required dose or potential side effects of the drug. The compounds of the present invention may be mixed with other bulk drugs in the form of a fixed pharmaceutical composition or they may be administered alone, before, at the same time or after other bulk drugs. Therefore, the present invention includes a combination of the compounds of the present invention as described above with anti-inflammatory drugs, bronchodilators, antihistamines or antitussive bulk drugs, the pharmaceutical composition of the compounds of the present invention and the bulk drugs being the same or different.

[0601] 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, BIIL284, ONO4057, SB 209247; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast ( GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenergic receptor agonists, such as salbutamol (hydroxyterbuterol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol and especially formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi) and glycopyrrolate.

[0602] Suitable antihistamine APIs include cetirizine hydrochloride, acetamide phenol, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0603] Other useful combinations of the compounds of the invention with anti-inflammatory drugs are combinations with antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, especially CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

[0604] The structures of active compounds identified by code numbers, generic or trade names are available from the official standard compendium "The Merck Index" or from databases, for example Patents International (eg IMS World Publications).

[0605] Exemplary Immuno-Oncology Agents

[0606] In some embodiments, one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to an agent that effectively enhances, stimulates and / or upregulates an immune response in a subject. In some embodiments, the administration of an immuno-oncology agent together with the compounds of the invention has a synergistic effect in treating cancer.

[0607] The immuno-oncology agent can be, for example, a small molecule drug, an antibody or a biological molecule or a small molecule. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized or human antibody.

[0608] In some embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in expansion of antigen-specific T cell responses.

[0609] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to homologous TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL , TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3 , EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0610] In some embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (eg, IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines), or a cytokine that stimulates T cell activation to stimulate an immune response.

[0611] In some embodiments, the combination of the compounds of the present invention and immuno-oncology agents can stimulate T cell responses. In some embodiments, immuno-oncology agents are: (i) antagonists (e.g., immune checkpoint inhibitors) of proteins that inhibit T cell activation, such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0612] In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells. In some embodiments, the immuno-oncology agent is an antagonist of KIR, such as lirilumab.

[0613] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to a CSF-1R antagonist, such as a CSF-1R antagonist antibody, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249, WO13169264, WO14 / 036357).

[0614] In some embodiments, the immuno-oncology agent is selected from agonists that bind positive co-stimulatory receptors; blockers, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells by inhibiting receptors to reduce signaling; agents that overcome unique immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell energy or exhaustion); and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0615] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonist CTLA-4 antibody. In some embodiments, the antagonist CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0616] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to the planned death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonist PD-1 antibody. In some embodiments, the antagonist PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab) or MEDI-0680 (AMP-514; WO2012 / 145493). In some embodiments, the immuno-oncology agent can be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, referred to as AMP-224.

[0617] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonist PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0618] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonist LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0619] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonist CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0620] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonist GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116), or MK-4166 (WO11 / 028683).

[0621] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that decomposes kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0622] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonist OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0623] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonist OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0624] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0625] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonist CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0626] In some embodiments, the immuno-oncology agent is MGA271 (directed against B7H3) (WO 11 / 109400).

[0627] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, inotuzumab, ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0628] In some embodiments, the immuno-oncology agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses, increase the number of tumor tissue structures, including some tumor types that have not been conventionally considered sensitive to immunotherapy. See, for example, Okazaki, T. et al., (2013), Nat. Immunol. 14, 1212-1218; Zou et al., (2016), Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab ( Bristol-Myers Squibb's (also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in RCC patients who experience disease progression during or after prior anti-angiogenic therapy.

[0629] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide ( Celgene); Lenalidomide ( ingenol mebutate ( LEO Pharmaceuticals).

[0630] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T ( Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec ( BioVex / Amgen (formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable skin, subcutaneous and nodular lesions in melanoma. In some embodiments, the additional therapeutic agent is selected from an oncolytic virus therapy, such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase-(TK-) deficient vaccinia virus engineered to express GM-CSF for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep ( Oncolytic Biotech, a biopharmaceutical company focused on colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic cancer (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT 00861627), a variant of a respiratory enteric orphan virus (reovirus) that does not replicate in cells without RAS activation in multiple cancers; enadenotucirev (NG-348, PsiOxus, formerly ColoAd1), an adenovirus engineered to express full-length CD80 and antibody fragments specific for the T-cell receptor CD3 protein in ovarian cancer (NCT02028117), metastatic or advanced epithelial tumors (e.g., colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer) (NCT02636036); ONCOS-102 (Targovax / formerly Anko) or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

[0631] In some embodiments, the immuno-oncology agent is selected from JX-929 (Sinagen / formerly Kinle Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Tagovail / formerly Anko), peptide-based immunotherapeutics targeting difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5 / 3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (Vira Therapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to generate antigen-specific CD8+ T cell responses.

[0632] In some embodiments, the immuno-oncology agent is a T cell engineered to express a chimeric antigen receptor or CAR. T cells engineered to express such a chimeric antigen receptor are called CAR-T cells.

[0633] The following CAR has been constructed, which consists of the following: a binding domain that can be derived from a natural ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, and an intracellular domain as the functional end of a T cell receptor (TCR), such as a fusion of a CD3-ζ signaling domain from a TCR that can generate an activation signal in a T lymphocyte. Upon antigen binding, such CARs are connected to endogenous signaling pathways in effector cells and generate activation signals similar to those triggered by the TCR complex.

[0634] For example, in some embodiments, the CAR-T cell is one of those described in U.S. Pat. No. 8,906,682 (June et al.; incorporated herein by reference in its entirety), which discloses a CAR-T cell that is engineered to include an extracellular domain having an antigen binding domain (e.g., a domain that binds to CD19), fused to an intracellular signaling domain of a T cell antigen receptor complex ζ chain (e.g., CD3ζ). When expressed in T cells, the CAR is able to redirect antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, more than 200 clinical trials using CAR-T in various indications are in progress. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0635] In some embodiments, the immunostimulant is an activator of retinoic acid receptor-related orphan receptor γ (RORγ). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells and the differentiation of innate immune cell subsets (e.g., NK cells) that express IL-17. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0636] In some embodiments, the immunostimulator is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is a kind of immunostimulatory CpG, which is being studied for use in B cell lymphoma, follicular lymphoma and other lymphomas (NCT02254772). The agonists or activators of TLR8 that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which are being studied for use in head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0637] Other immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex The following are some of the products: (i) anti-CD27 monoclonal antibody (BMS-986178, Innate Pharma, Bristol-Myers Squibb), an anti-OX40 monoclonal antibody (BMS-986178, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody (lirilumab, IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody (monalizumab, IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody (andecaliximab, GS-5745, Gilead Sciences), an anti-MMP9 antibody (MK-4166, Merck & Co.), an anti-GITR monoclonal antibody (Merck & Co.).

[0638] In some embodiments, the immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a Toll-like receptor, and an activator of RORγt.

[0639] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 and a soluble IL-15 binding protein IL-15 receptor α chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0640] In some embodiments, the immuno-oncology agent is selected from the tumor immunotherapy agents described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology", Cancer Therapy 2015, Vol. 14, pp. 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule targeting an immuno-oncology target selected from the small molecules targeting an immuno-oncology target listed in Table 2 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule targeting an immuno-oncology target selected from the small molecule agents listed in Table 2 of Jerry L. Adams et al.

[0641] In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents", Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pp. 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent targeting a pathway as described in Peter L. Toogood.

[0642] In some embodiments, the immuno-oncology agent is selected from Sandra L. Ross et al., "Bispecific T cell engagers Antibody constructs capable of mediating the killing of bystander tumor cells (Bispecific T cellengager Antibody constructs can mediate bystander tumor cell killing)”, PLoS ONE12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a bispecific T cell engager Antibody constructs. In some embodiments, bispecific T cell engagers The antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager The antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager Antibody constructs activate T cells. In some embodiments, bispecific T cell engagers The antibody construct activates T cells, releasing cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on neighboring cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, inducing bystander cell lysis. In some embodiments, the bystander cell is in a solid tumor. In some embodiments, the lysed bystander cell is near Activated T cells. In some embodiments, the adjacent cells comprise tumor-associated antigen (TAA) negative cancer cells. In some embodiments, the adjacent cells comprise EGFR negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the immuno-oncology agent is a tumor-infiltrating T cell that is amplified ex vivo. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly connects T cells to tumor-associated surface antigens (TAA).

[0643] Exemplary immune checkpoint inhibitors

[0644] In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0645] The term "checkpoint inhibitor" as used herein relates to an agent suitable for preventing cancer cells from evading the patient's immune system. One of the main mechanisms of anti-tumor immune destruction is called "T cell exhaustion", which is caused by long-term exposure to antigens that cause upregulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints to prevent uncontrolled immune responses.

[0646] PD-1 and co-inhibitory receptors such as cytotoxic T lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuator (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), lymphocyte activation gene-3 (Lag-3; CD223) and other receptors are often referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular information to indicate whether cell cycle progression and other intracellular signaling processes should proceed.

[0647] In some embodiments, the immune checkpoint inhibitor is an antibody against PD-1. PD-1 binds to the planned cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thereby suppressing the tumor's ability to suppress the host's anti-tumor immune response.

[0648] In some embodiments, the checkpoint inhibitor is a biological therapeutic agent or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from the following: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand selected from the following checkpoint proteins: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody vaccine, or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

[0649] Checkpoint inhibitors include any agent that blocks or inhibits the inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors may include small molecule inhibitors or may include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors or antibodies, which bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be used as blocking or inhibiting targets include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belonging to CD2 family molecules and in all NK, γδ and memory CD8 +(αβ) T cells), CD160 (also known as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biotherapeutics or small molecules that bind and block or inhibit the activity of one or more of the following: CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to, tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody) and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0650] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of: nivolumab Ipilimumab and pembrolizumab In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Bristol-Myers Squibb); Pedrizumab (anti-PD-1 antibody, Merck); Ipilimumab (anti-CTLA-4 antibody, Bristol-Myers Squibb); Durvalumab (anti-PD-L1 antibody, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Genentech).

[0651] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, levolumab, IPH2101, pembrolizumab and tremelimumab.

[0652] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody being tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), cutaneous squamous cell carcinoma (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); pilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1 in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab ( Pfizer / Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1 in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; AstraZeneca) is a fully human monoclonal antibody against CTLA-4 that has been studied in clinical trials for multiple indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung cancer, and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, hepatocellular carcinoma, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic pleomorphic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody being studied in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0653] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors available in the present invention include TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody studied in advanced malignancies (NCT02608268).

[0654] In some embodiments, the checkpoint inhibitor is an inhibitor of a T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immunoreceptor on certain T cells and NK cells. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and TIGIT monoclonal antibody (NCT03119428).

[0655] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is studied in malignancies (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein that is studied in melanoma (NCT02676869), adenocarcinoma (NCT02614833), and metastatic breast cancer (NCT00349934).

[0656] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists being studied in clinical trials include: PF-04518600 / PF-8600 (Pfizer), an agonist anti-OX40 antibody in metastatic renal cancer (NCT03092856) and advanced cancer and tumors (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonist anti-OX40 antibody in a Phase 1 cancer trial (NCT02528357); MEDI0562 (Medimmune / AstraZeneca), an agonist anti-OX40 antibody in advanced solid tumors (NCT023 18394 and NCT02705482); MEDI6469, an agonist anti-OX40 antibody in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705) (Medimmune / AstraZeneca); and BMS-986178 (Bristol-Myers Squibb), an agonist anti-OX40 antibody in advanced cancer (NCT02737475).

[0657] Check point inhibitors useful in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists being studied in clinical trials include utomilumab (PF-05082566, Pfizer), an agonist anti-CD137 antibody for diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and tumors (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonist anti-CD137 antibody for melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonist anti-CD137 antibody for metastatic or locally advanced malignancies (NCT03881488).

[0658] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists studied in clinical trials include: varlilumab (CDX-1127, Celldex Therapeutics), agonist anti-CD27 antibodies in head and neck squamous cell carcinoma, ovarian carcinoma, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918), lymphoma (NCT01460134) and glioma and astrocytoma (NCT02924038).

[0659] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being studied in clinical trials include: TRX518 (Leap Therapeutics), an agonist anti-GITR antibody in malignant melanoma and other solid malignancies (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonist in solid tumors and lymphomas (NCT 02740270), an agonist anti-GITR antibody in advanced cancer (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonist anti-GITR antibody in solid tumors (NCT02132754); and MEDI1873 (Medimmune / AstraZeneca), an agonist hexameric GITR-ligand molecule with a human IgG1 Fc domain in advanced solid tumors (NCT02583165).

[0660] Checkpoint inhibitors that can be used in the present invention include inducible T cell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists being studied in clinical trials include: MEDI-570 (Medimmune), an agonist anti-ICOS antibody in lymphoma (NCT02520791); GSK3359609 (Merck), an agonist anti-ICOS antibody in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonist anti-ICOS antibody in Phase 1 (NCT02904226).

[0661] Checkpoint inhibitors useful in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharmaceuticals / Bristol-Myers Squibb), an anti-KIR antibody in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharmaceuticals) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharmaceuticals), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2) in lymphoma (NCT02593045).

[0662] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors studied in clinical trials include: ALX-148 (Alexo Therapeutics), an antagonist variant of (SIRPa) that binds to CD47 and prevents CD47 / SIRPa-mediated signaling in Phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a Phase 1 clinical trial (NCT02890368 and NCT02663518) that is produced by connecting the N-terminus of the CD47 binding domain of SIRPa to the Fc domain of human IgG1, works by binding to human CD47 and preventing it from delivering its "do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis ( eat) signal to macrophages; CC-90002 (Celgene), an anti-CD47 antibody in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.) in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0663] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody in solid tumors (NCT02754141).

[0664] Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes (STING, also known as transmembrane protein 173 or TMEM173). Agonists of STING that are being studied in clinical trials include: MK-1454 (Merck), an agonist synthetic cyclic dinucleotide in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonist synthetic cyclic dinucleotide in Phase 1 (NCT02675439 and NCT03172936).

[0665] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors studied in clinical trials include: pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor in colorectal cancer, pancreatic cancer, metastatic and advanced cancer (NCT02777710), and melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022 855, Eli Lilly), an anti-CSF-1R antibody in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide, Novartis), an orally effective inhibitor of CSF1R in advanced solid tumors (NCT02829723).

[0666] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptors studied in clinical trials include monalizumab (IPH2201, Innate Pharmaceuticals), anti-NKG2A antibodies in head and neck tumors (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0667] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pirizumab.

[0668] The compounds of the invention may also be used in combination with known treatment methods, such as administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

[0669] The compounds of the present invention may be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapies may be administered in the form of a fixed combination of the compounds of the present invention and one or more other therapeutic compounds or staggered or independent of each other, or a fixed combination and a combination of one or more other therapeutic compounds. In addition or in addition, the compounds of the present invention may be combined with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention or a combination thereof, especially for tumor therapy. As described above, in the context of other treatment strategies, long-term therapy is also possible, and adjuvant therapy is also possible. Other possible therapies are therapies that maintain the patient's status after tumor regression, or even chemoprevention (e.g., for patients at risk).

[0670] Those other agents may be administered separately with the composition containing the compounds of the invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed with the compounds of the invention into a single composition. If administered as part of a multiple dosing regimen, the two active agents may be provided simultaneously, sequentially, or within a certain time period of each other (usually within 5 hours of each other).

[0671] As used herein, the term "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or administered together in a single unit dosage form. Therefore, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0672] The amount of the compound of the invention and the additional therapeutic agent (in those compositions comprising additional therapeutic agents as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dose of between 0.01-100 mg / kg body weight / day of the compound of the invention can be administered.

[0673] In those compositions that include another therapeutic agent, the other therapeutic agent and the compounds of the invention may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions, the other therapeutic agent may be administered at a dose of between 0.01-1,000 micrograms per kilogram of body weight per day.

[0674] The amount of the other therapeutic agent present in the compositions of the invention will not exceed the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of the additional therapeutic agent in the compositions disclosed herein is preferably in the range of about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0675] The compounds of the invention or their pharmaceutical compositions may also be incorporated into compositions for coating implantable medical devices (e.g., prostheses, artificial valves, vascular grafts, intravascular stents, and catheters). Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. An implantable device coated with a compound of the invention is another embodiment of the invention.

[0676] Examples

[0677] As depicted in the following examples, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods depict the synthesis of certain compounds of the present invention, the following general methods and other methods known to those of ordinary skill in the art can be applied to all compounds as described herein and subclasses and species of each of these compounds. Other compounds of the present invention are prepared by methods substantially similar to the methods described herein in the examples and methods known to those of ordinary skill in the art.

[0678] Synthetic intermediates

[0679] Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1).

[0680]

[0681] Step-1 Synthesis of tert-butyl 4-(6-nitropiperidin-3-yl)piperazine-1-carboxylate (Intermediate AA1-1)

[0682] To a solution of 5-bromo-2-nitropyridine (3.0 g, 14.76 mmol, 1.0 equiv) and tert-butyl piperazine-1-carboxylate (4.2 g, 22.58 mmol, 1.5 equiv) in anhydrous DMSO (10.0 mL) was added triethylamine (2.25 g, 22.27 mmol, 1.5 equiv) and lithium chloride (0.63 g, 14.76 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at 70 ° C for 20 hours. After the reaction was complete, the reaction mixture was poured into ice water and the solid product was collected by filtration. The solid was triturated with n-pentane to obtain intermediate AA1-1 (3.0 g, 65.84%) MS (ES) m / z 309.33 (M+H) + .

[0683] Step-2 Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Intermediate AA1).

[0684] To a suspension of 10% Pd / C (2.2 g) in methanol (50 mL) was added a solution of intermediate AA1-1 (4.0 g, 12.98 mmol) in methanol (10 mL) under nitrogen atmosphere. 2 (gas) was bubbled into the reaction mixture for 3 hours. After the reaction was completed, the reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure to give intermediate AA1 (2.4 g, 55.39%). MS (ES): m / z 279.24 [M+H] + .

[0685] Synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine (Intermediate AA2).

[0686]

[0687] Step-1 Synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine (Intermediate AA2).

[0688] 5-(4-Methylpiperazin-1-yl)pyridin-2-amine (Intermediate AA2) (1.0 g, 70.84%) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and 1-methylpiperazine in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (General Procedure Intermediate AA1) MS (ES) m / z 193.2 (M+H) + .

[0689] Synthesis of 5-(N-morpholinyl)pyridin-2-amine (Intermediate AA3).

[0690]

[0691] Step-1 Synthesis of 5-(N-morpholinyl)pyridin-2-amine (Intermediate AA3).

[0692] 5-(N-Morpholinyl)pyridin-2-amine (Intermediate AA3) (1.0 g, 64.84%) was prepared from 5-bromo-2-nitropyridine (Intermediate AA3-1) and morpholine in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (General Procedure Intermediate AA1) MS (ES) m / z 180.33 (M+H) + .

[0693] Synthesis of tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate AA6).

[0694]

[0695] Step-1: Synthesis of tert-butyl 3-(6-nitropiperidin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate AA6-1).

[0696] To a solution of 5-bromo-2-nitropyridine (Intermediate AA1-1) (1.0 g, 4.9 mmol, 1.0 equiv) in 1,4-dioxane (13.0 mL) at room temperature were added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.05 g, 4.9 mmol, 1.0 equiv) and tripotassium phosphate (2.03 g, 14.7 mmol, 3.0 equiv). After degassing with argon for 20 min, Pd 2 dba 3 (0.45 g, 0.49 mmol, 0.1 eq.) and xanthene phosphine (0.57 g, .98 mmol, 0.2 eq.) were added to the reaction mixture. After heating at 120 ° C for 3 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic layer was washed with brine (100 mL) solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography (0-40% gradient elution, EtOAc / hexane) to obtain the title compound (Intermediate AA6-1) (0.500 g, 30.35%). MS (ES): m / z 334.3 (M+H) + .

[0697] Step-2 Synthesis of tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate AA6).

[0698] tert-Butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate AA6) (0.430 g, 94.4%) was prepared in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (General Process Intermediate AA1). MS (ES): m / z 304 (M+H) + .

[0699] Synthesis of 1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol (Intermediate AA7).

[0700]

[0701] Step-1 Synthesis of 1-(5-methoxy-6-nitropiperidin-3-yl)piperidin-4-ol (Intermediate AA7-2)

[0702] To a solution of 5-bromo-3-methoxy-2-nitropyridine (Intermediate AA7-1) (0.5 g 2.1 mmol, 1.0 equiv) in anhydrous DMSO (6 mL) was added piperidin-4-ol (0.35 g, 2.6 mmol, 1.2 equiv), potassium carbonate (1.7 g, 12.0 mmol, 6.0 equiv) and tetrabutylammonium iodide (0.22 g, 0.6 mmol, 0.3 equiv) at room temperature. After heating at 90 °C for 2 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with brine (100 mL) solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography (0-40% gradient elution, EtOAc / hexane) to obtain the title compound (Intermediate AA7-1) (0.3 g, 56.24%). MS(ES):m / z 254.2(M+H) + .

[0703] Step-2 Synthesis of 1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol (Intermediate AA7)

[0704] 1-(6-Amino-5-methoxypyridin-3-yl)piperidin-4-ol (Intermediate AA7) (0.2 g, 74.73%) was prepared in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (General Process Intermediate AA1). MS (ES): m / z 224.2 (M+H) + .

[0705] Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)-4-methylpiperidine-1-carboxylate (Intermediate AA9)

[0706]

[0707] Step-1 Synthesis of (E)-ethyl 3-(6-chloropyridin-3-yl)-2-cyanobut-2-enoate (Intermediate AA9-2).

[0708] To a solution of 1-(6-chloropyridin-3-yl)ethan-1-one (10.0 g, 64.51 mmol, 1.0 equiv) and ethyl 2-cyanoacetate (7.2 g, 64.51 mmol, 1.0 equiv) in toluene (35 mL) was added ammonium acetate (1.0 g, 12.90 mmol, 0.2 equiv) and acetic acid (4 mL). After stirring at 140 °C in a dean stark assembly for 6 hours, the reaction mixture was diluted with sodium bicarbonate solution (150 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (200 mL), purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain the crude material. This material was used in the next step without purification. Intermediate AA9-2 (15.0 g, 96.09%) MS (ES) m / z 251.05 (M+H) +

[0709] Step-2: Synthesis of 4-(6-chloropyridin-3-yl)-4-methyl-2,6-dioxopiperidine-3,5-dicarbonitrile (Intermediate AA9-3).

[0710] To a solution of intermediate AA9-2 (14.9 g, 59.6 mmol) and 2-cyanoacetamide (6.0 g, 71.52 mmol, 1.2 equiv) in ethanol (130 mL) was added sodium hydroxide (2.86 g, 71.52 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, a 1M potassium hydrogen sulfate solution was added to the reaction mixture. After stirring at 10 ° C, a solid was precipitated from the solution. The solid was filtered and dried in a high vacuum to obtain intermediate AA9-3, which was used in the next step without purification. (20.0 g, 98.12%). MS (ES): m / z 289.04 [M+H] +

[0711] Step-3 Synthesis of 4-(6-chloropyridin-3-yl)-4-methylpiperidine-2,6-dione (Intermediate AA9-4).

[0712] To a solution of intermediate AA9-3 (20.0 g, 69.44 mmol) in water (12 mL) was added sulfuric acid (12 mL) dropwise at 10 ° C. After stirring at 110 ° C for 7 hours, solid sodium hydroxide was added at 0 ° C. The reaction mixture was filtered and washed with DCM containing 10% methanol. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a liquid substance. Urea (40 g) was added to this crude material and stirred at 140 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate (1 L) and saturated sodium bicarbonate solution (500 mL). The organic layer was collected, washed with brine solution (300 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain intermediate AA9-4, which was used in the next step without purification. (2.2 g, 13.31%). MS (ES): m / z 239.05 [M+H] +

[0713] Step-4: Synthesis of 1-benzyl-4-(6-chloropyridin-3-yl)-4-methylpiperidine-2,6-dione (Intermediate AA9-5).

[0714] To a solution of intermediate AA9-4 (1.2 g, 5.02 mmol) in acetone (50 mL) was added potassium carbonate (1.38 g, 10.04 mmol, 2.0 equiv) and stirred at 0 ° C. Benzyl bromide (0.94 g, 5.52 mmol, 1.1 equiv) was added to the reaction mixture and then stirred at 70 ° C for 2 hours. After the reaction was completed, the reaction mixture was distilled to remove acetone. The residue was diluted with water (150 mL) and extracted with ethyl acetate (70 mL × 3). The combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude material. The residue was purified by column chromatography, eluted with 25% ethyl acetate / hexane to obtain intermediate AA9-5 (1.5 g, 90.74%). MS (ES): m / z 329.10 [M + H] +

[0715] Step-5 Synthesis of 5-(1-benzyl-4-methylpiperidin-4-yl)-2-chloropyridine (Intermediate AA9-6).

[0716] To a solution of intermediate AA9-5 (1.2 g, 3.65 mmol) in anhydrous THF (20 mL) was added lithium aluminum hydride (1.0 M in THF) (14 mL, 14.06 mmol, 4.0 equiv) at -5 °C. After stirring at 70 °C for 1 hour, the reaction mixture was concentrated. The residue was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude material. This material was purified by column chromatography, eluting with 1.2% ethyl acetate / hexane to obtain intermediate AA9-6 (0.4 g, 36.43%). MS (ES): m / z 301.2 [M+H]+

[0717] Step-6: Synthesis of N-(5-(1-benzyl-4-methylpiperidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide (Intermediate AA9-7).

[0718] A solution of intermediate AA9-6 (1.6 g, 5.33 mmol), cyclopropanecarboxamide (0.679 g, 7.99 mmol, 1.5 eq.) and cesium carbonate (5.1 g, 15.99 mmol, 3.0 eq.) in 1,4-dioxane (20 mL) was stirred at N 2 After 15 minutes, Xantphos (0.308 g, 0.53 mmol, 0.1 eq.) and Pd 2 (dba) 3 (0.487 g, 0.53 mmol, 0.1 eq.). After stirring at 120 °C for 16 h, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography eluting with a 2.5% gradient of methanol / DCM to obtain intermediate AA9-7 (1.6 g, 69.94%) as a brown solid. MS (ES): m / z=350.2 [M+H] +

[0719] Step-7 Synthesis of N-(5-(4-methylpiperidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide (Intermediate AA9-8).

[0720] To a solution of intermediate AA9-7 (0.5 g, 1.43 mmol) in methanol (10 mL) was added 10% Pd / C (0.250 g, hydrogenated at atmospheric pressure for 6 hours at room temperature. After the reaction was completed, the reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to obtain a crude material, which was used in the next step without purification. Intermediate AA9-8 (0.450 g, 94.32%). MS (ES): m / z 260.1 [M+H] + ,

[0721] Step-8 Synthesis of tert-butyl 4-(6-(cyclopropanecarboxamido)pyridin-3-yl)-4-methylpiperidine-1-carboxylate (Intermediate AA9-9).

[0722] To a solution of intermediate AA9-8 (0.450 g, 1.73 mmol) in DCM (20 mL) was added trimethylamine (0.524, 5.19 mmol, 3.0 equiv) and DMAP (0.021 g, 0.173 mmol, 0.1 equiv). Di-tert-butyl dicarbonate (0.754, 3.46 mmol, 2.0 equiv) was then added dropwise to the reaction mixture. After stirring at room temperature for 2 hours, the reaction mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with a saline solution, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude material. The residue was purified by column chromatography, eluted with DCM containing 2.5% methanol to obtain intermediate AA9-9 (0.450 g, 72.15%). MS (ES): m / z 360.2 [M + H] +

[0723] Step-9: Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)-4-methylpiperidine-1-carboxylate (Intermediate-AA9).

[0724] To a solution of intermediate AA9-9 (0.450 g, 1.25 mmol) in methanol (10 mL) was added sodium hydroxide (0.5 g, 12.5 mmol, 10.0 equiv). After stirring at 50 ° C for 16 hours, the reaction mixture was poured into water (70 mL) and extracted with DCM (40 mL×3). The combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude material. The residue was purified by column chromatography, eluting with DCM containing 4.0% methanol to obtain intermediate-AA9 (0.210 g, 57.57%). MS (ES): m / z 292.2 [M+H] +

[0725] Synthesis of 2-(1-(6-aminopyridin-3-yl)piperidin-3-yl)propan-2-ol (Intermediate AA13).

[0726]

[0727] Step-1 Synthesis of 1-(6-nitropiperidin-3-yl)piperidine-3-carboxylic acid ethyl ester (Intermediate AA13-2)

[0728] 1-(6-Nitropiperidin-3-yl)piperidine-3-carboxylic acid ethyl ester (Intermediate AA13-2) (1.5 g, 36.34%) was prepared from 5-bromo-2-nitropyridine (Intermediate AA2-1) and 1-ethyl piperidine-3-carboxylate in a manner similar to that described for tert-butyl 4-(6-nitropiperidin-3-yl)piperazine-1-carboxylate (General Process Intermediate AA1). MS (ES): m / z 280.14 [M+H] +

[0729] Step-2 Synthesis of ethyl 1-(6-aminopyridin-3-yl)piperidine-3-carboxylate (Intermediate AA13-3).

[0730] 1-(6-Aminopyridin-3-yl)piperidine-3-carboxylic acid ethyl ester (Intermediate AA13-3) was prepared in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (General Process Intermediate AA1) from 1-(6-nitropiperidin-3-yl)piperidine-3-carboxylate ethyl ester (Intermediate AA13-2) (1.2 g, 89.62%). MS (ES): m / z 250.15 [M+H] +

[0731] Step-3 Synthesis of 2-(1-(6-aminopyridin-3-yl)piperidin-3-yl)propan-2-ol (Intermediate AA13).

[0732] To a solution of 1-(6-aminopyridin-3-yl)piperidine-3-carboxylic acid ethyl ester (intermediate AA13-3) (2.0 g, 8.03 mmol) in THF (15 mL) was added dropwise a 3N solution (20 mL) of methylmagnesium bromide (3N in THF). After stirring at room temperature for 1 hour, the reaction mixture was quenched with ice-cold water (100 mL) and filtered on a celite bed. The filtrate was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. The crude compound was purified by column chromatography (0-80% gradient elution, EtOAc / hexane) to obtain the title compound (intermediate AA13) (0.200 g, 10.60%). MS (ES): m / z 236.17 [M+H] +

[0733] Synthesis of 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyridin-2-amine (Intermediate AA14).

[0734]

[0735] Step-1 Synthesis of 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyridin-2-amine (Intermediate AA14).

[0736] 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyridin-2-amine (Intermediate AA14) (0.330 g, quantitative yield) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane in a manner similar to that described for tert-butyl 4-(6-nitropiperidin-3-yl)piperazine-1-carboxylate (General Procedure Intermediate AA1). MS (ES): m / z 192.5 [M+H] + .

[0737] Synthesis of 1-(6-bromopyridin-3-yl)-4-((N-morpholinyl)methyl)piperidin-4-ol (Intermediate AA15).

[0738]

[0739] Step-1 Synthesis of 1-(6-bromopyridin-3-yl)-4-((N-morpholinyl)methyl)piperidin-4-ol (Intermediate AA15).

[0740] 4-((N-morpholinyl)methyl)piperidin-4-ol (0.64 g, 3.0 mmol, 1.5 eq.) and cesium carbonate (2.1, 6.0 mmol, 3.0 eq.) were added to a solution of 2-bromo-5-iodopyridine (0.6 g, 2.0 mmol) in 1,4-dioxane (6 mL). After degassing with nitrogen for 10 minutes, 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (0.125 g, 0.02 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium (0.2 g, 0.2 mmol, 0.1 eq.) were added under a nitrogen atmosphere. The reaction mixture was heated to 120 ° C and maintained for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL) solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material, which was purified using combi-flash silica gel eluting with 4% methanol / DCM to obtain intermediate AA15 (0.2 g, 26.56%). MS (ES): m / z 357.26 [M+H] +

[0741] Synthesis of 1-(6-chloro-4-methoxypyridin-3-yl)piperidin-4-ol (Intermediate AA18).

[0742]

[0743] Step-1 Synthesis of 6-chloro-4-methoxypyridin-3-amine (Intermediate AA18-2).

[0744] To a solution of 2-chloro-4-methoxy-5-nitropyridine (Intermediate AA18-1) (2.0 g, 10.6 mmol) in ethanol (8 mL) was added SnCl 2 .2H 2 O (9.6 g, 63.8 mmol, 6.0 equiv). After stirring at 90 ° C for 30 minutes, the reaction mixture was quenched with 3M NaOH solution (100 mL) and extracted with DCM (100 mL). The combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. The residue was purified by column chromatography eluting with 15-20% ethyl acetate / hexane to obtain intermediate AA18-2. LCMS purity 100%, MS (ES): m / z 159.03 [M+H] +

[0745] Step-2 Synthesis of 1-(6-chloro-4-methoxypyridin-3-yl)piperidin-4-one (Intermediate AA18-3)

[0746] To a refluxing slurry of sodium carbonate (1.51 g, 14 mmol, 1.5 equiv) in MeOH (8 mL) was added a solution of intermediate AA18-2 (1.5 g, 9.5 mmol) in MeOH (2 mL) and 1,5-dichloropentan-3-one (1.6 g, 9.5 mmol, 1.0 equiv). After stirring at 50 ° C. for 16 hours, the reaction mixture was concentrated in vacuo to give the crude material, which was purified by column chromatography eluting with 20-25% ethyl acetate / hexanes to obtain intermediate AA18-3 (1.2 g, 80.01%) MS (ES): 241.07 m / z [M+H] + .

[0747] Step-3 Synthesis of 1-(6-chloro-4-methoxypyridin-3-yl)piperidin-4-ol (Intermediate AA18)

[0748] To a solution of intermediate AA18-3 (1.2 g, 5 mmol) in MeOH (12 mL) was added NaBH 4(0.228 g, 6 mmol, 1.2 eq.). After stirring for 30 minutes, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL) solution, dried over sodium sulfate, and concentrated under reduced pressure to give a crude material, which was purified using combi-flash silica gel eluting with 15-20% ethyl acetate / hexane to give intermediate AA18. MS (ES): 243 m / z [M+H]+.

[0749] Synthesis of 2-(6-aminopyridin-3-yl)-2-azaspiro[3.3]heptan-6-ol (Intermediate AA19).

[0750]

[0751] Step-1 Synthesis of 2-(6-aminopyridin-3-yl)-2-azaspiro[3.3]heptan-6-ol (Intermediate AA19)

[0752] 2-(6-Aminopyridin-3-yl)-2-azaspiro[3.3]heptan-6-ol (Intermediate AA19) (0.600 g, 98.23%) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and 2-azaspiro[3.3]heptan-6-ol in a manner similar to that described for tert-butyl 4-(6-nitropiperidin-3-yl)piperazine-1-carboxylate (General Procedure Intermediate AA1). MS (ES): m / z 206.12 [M+H] + .

[0753] Synthesis of 1-(6-aminopyridin-3-yl)-4-(methoxymethyl)piperidin-4-ol (Intermediate AA20).

[0754]

[0755] Step-1 Synthesis of 1-(6-aminopyridin-3-yl)-4-(methoxymethyl)piperidin-4-ol (Intermediate AA20).

[0756] 1-(6-Aminopyridin-3-yl)-4-(methoxymethyl)piperidin-4-ol (Intermediate AA20) (0.600 g, 96.54%) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and 4-(methoxymethyl)piperidin-4-ol in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (General Procedure Intermediate AA1). MS (ES): m / z 238.12 [M+H] +

[0757] Synthesis of 5-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-amine (Intermediate AA21).

[0758]

[0759] 5-(2-Oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-amine (Intermediate AA21) (0.3 g, 75.76%) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and 2-oxa-7-azaspiro[3.5]nonane in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (General Procedure Intermediate AA1). MS (ES): m / z 220.2 (M+H) + .

[0760] Synthesis of 5-(1,4-oxazepan-4-yl)pyridin-2-amine (Intermediate AA22).

[0761]

[0762] 5-(1,4-Oxazepan-4-yl)pyridin-2-amine (Intermediate AA22) (0.300 g, 57.76%) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and 1,4-oxazepane in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (General Procedure Intermediate AA1). MS (ES): m / z 194.15 [M+H] +

[0763] Synthesis of (1R,3r,5S)-8-(6-aminopyridin-3-yl)-8-azabicyclo[3.2.1]octan-3-ol (Intermediate AA23).

[0764]

[0765] (1R,3r,5S)-8-(6-aminopyridin-3-yl)-8-azabicyclo[3.2.1]octan-3-ol (Intermediate AA23) (1.8 g, 94.7%) was prepared from 5-bromo-2-nitropyridine (Intermediate AA1-1) and (1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-ol in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (General Process Intermediate AA1). MS (ES): m / z 219.2 (M+H) + .

[0766] Synthesis of 5-(azetidin-1-ylsulfonyl)-2-chloropyridine (Intermediate AA25).

[0767]

[0768] Step-1 Synthesis of intermediate AA25-2

[0769] Prepared as described in WO2020 / 89026.

[0770] Step-2 Synthesis of 5-(azetidin-1-ylsulfonyl)-2-chloropyridine (Intermediate AA25).

[0771] A solution of 5-(azetidin-1-ylsulfonyl)-2-chloropyridine (Intermediate AA25-2) (400 mg, 1.51 mol) in aqueous ammonia solution (3000 mL) was stirred at 80° C. for 16 hours. After the reaction was completed, the reaction was concentrated in vacuo to obtain the title compound (Intermediate AA25) (200 mg, 78.74%) as a white solid. MS (ES): m / z 214.59 [M+H] +

[0772] Synthesis of 5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine (Intermediate AA30).

[0773]

[0774] Step-1: Synthesis of (3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30-2).

[0775] To a solution of 5-fluoro-2-nitropyridine (1.0 g, 7.04 mmol, 1.0 equiv) in dimethyl sulfoxide (13.0 mL) was added (3aR, 6aS)-rel-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (1.05 g, 7.04 mmol, 1.0 equiv) and N,N-diisopropylethylamine (10 equiv, 70.4 mmol) at room temperature. After stirring at 120 °C for 1 hour, the reaction mixture was poured into water and extracted with ethyl acetate (100 mL×3). The organic layer was washed with brine (100 mL×3) solution. The combined organic layers were concentrated under reduced pressure at 45 °C to obtain intermediate AA30-2 (2 g, 172.5%). MS (ES): m / z 236.33 (M+H) + .

[0776] Step-2 Synthesis of 5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine (Intermediate AA30).

[0777] Synthesis of 5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine (Intermediate AA30) (0.600 g, 96.54%) was prepared from (3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30-2) in a manner similar to that described for tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (General Procedure Intermediate AA1). MS (ES): m / z 238.12 [M+H] +

[0778] Synthesis of 5-((cyclobutylmethyl)sulfonyl)pyridin-2-amine (Intermediate AA32).

[0779]

[0780] Step-1 Synthesis of 2-chloro-5-((cyclobutylmethyl)sulfonyl)pyridine (Intermediate AA32-2).

[0781] To a solution of 6-chloropyridine-3-sulfonyl chloride (2.0 g, 9.43 mmol) in water (40 mL) was added sodium bicarbonate (1.73 g, 9.43 mmol) and sodium sulfite (1.18 g, 9.43 mmol). After stirring at 40 ° C for 1 hour, the reaction mixture was concentrated by high vacuum to give a solid. To a solution of the solid in N'N-DMF (20 mL) was added (bromomethyl)cyclobutane (1.68 g, 11.3 mmol, 1.2 equiv) and pyridine (0.679 g, 11.3 mmol). After stirring at room temperature for 16 hours, the reactant was concentrated, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material, which was purified using column chromatography eluting with 15% ethyl acetate / hexanes to obtain intermediate AA32-2 (0.900 g, 27.29%). MS (ES): m / z 246.03 [M+H] +

[0782] Step-2 Synthesis of 5-((cyclobutylmethyl)sulfonyl)pyridin-2-amine (Intermediate AA32).

[0783] To a solution of methanolic ammonia (5 mL) was added 2-chloro-5-((cyclobutylmethyl)sulfonyl)pyridine (0.900 g, 3.65 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted in water and extracted with ethyl acetate. The combined organic solutions were concentrated under reduced pressure to give the crude material. The residue was purified by column chromatography eluting with 30% ethyl acetate / hexanes to give intermediate AA32 (0.100 g, 12.06%). MS (ES): m / z 227.12 [M+H] + .

[0784] Synthesis of 1-(2-aminopyridin-4-yl)piperidin-4-ol (Intermediate AA34).

[0785]

[0786] 1-(2-Aminopyridin-4-yl)piperidin-4-ol (Intermediate AA34) (1.37 g, 83.29%) was prepared from 4-chloro-2-nitropyridine (Intermediate AA34-1) and piperidin-4-ol in a manner similar to that described for 1-(6-amino-5-methoxypyridin-3-yl)piperidin-4-ol (General Procedure Intermediate AA7). MS (ES): m / z 194.12 [M+H] +

[0787] Synthesis of 1-(6-aminopyridin-3-yl)azepan-4-ol (Intermediate AA37).

[0788]

[0789] 1-(6-Aminopyridin-3-yl)azepan-4-ol (Intermediate AA37) (0.500 g, 81.76%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and azepan-4-ol in a manner similar to that described for 5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-amine (General Procedure Intermediate AA30). MS (ES): m / z 208.14 [M+H] +

[0790] Synthesis of 5-(2-(methoxymethyl)(N-morpholinyl))pyridin-2-amine (Intermediate AA39).

[0791]

[0792] 5-(2-(Methoxymethyl)(N-morpholinyl))pyridin-2-amine (Intermediate AA37) (0.700 g, 79.4%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 2-(methoxymethyl)morpholine in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 224.14 [M+H] +

[0793] Synthesis of 4-(6-aminopyridin-3-yl)-1,4-oxazepan-6-ol (Intermediate AA43).

[0794]

[0795] 4-(6-Aminopyridin-3-yl)-1,4-oxazepan-6-ol (Intermediate AA43) (0.7 g, 61.56%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 1,4-oxazepan-6-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Process Intermediate AA30). MS (ES): m / z 210.26 [M+H] +

[0796] Synthesis of (S)-2-(4-(6-aminopyridin-3-yl)morpholin-2-yl)propan-2-ol (Intermediate AA48)

[0797]

[0798] (S)-2-(4-(6-Aminopyridin-3-yl)morpholin-2-yl)propan-2-ol (Intermediate AA43) (0.7 g, 61.56%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and (S)-2-(morpholin-2-yl)propan-2-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). (4 g, 75%). MS (ES): m / z 237.15 [M+H] +

[0799] Synthesis of ((3R,4R)-1-(6-aminopyridin-3-yl)-4-fluoropiperidin-3-ol (Intermediate AA49)

[0800]

[0801] (3R,4R)-1-(6-Aminopyridin-3-yl)-4-fluoropiperidin-3-ol (Intermediate AA49) (0.500 g, 63.44%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and (3R,4R)-4-fluoropiperidin-3-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 212.11 [M+H] +

[0802] Synthesis of 1-(6-aminopyridin-3-yl)-2-methylpiperidin-4-ol (Intermediate AA50)

[0803]

[0804] 1-(6-Aminopyridin-3-yl)-2-methylpiperidin-4-ol (Intermediate AA50) (0.900 g, 93.75%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 2-methylpiperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Process Intermediate AA30) MS (ES): m / z 207 [M+H] +

[0805] Synthesis of (1R,2S)-2-((6-aminopyridin-2-yl)oxy)cyclopentan-1-ol (Intermediate AA51)

[0806]

[0807] Step-1 Synthesis of (1R,2S)-2-((6-nitropiperidin-2-yl)oxy)cyclopentan-1-ol (Intermediate AA51-2)

[0808] To a solution of 2-chloro-6-nitropyridine (3.0 g, 18.98 mmol, 1.0 equiv) and (1R,2S)-cyclopentane-1,2-diol (2.3 g, 22.77 mmol, 1.2 equiv) in anhydrous DMF (36 mL) was added potassium carbonate (7.8 g, 56.94 mmol, 3.0 equiv) at room temperature. After stirring at 120 °C for 16 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 120 mL). The combined organic extracts were washed with brine (100 mL), purified by Na 2 SO 4Dry, filter and concentrate under reduced pressure to obtain the crude material. The residue was purified by column chromatography using a gradient of 3.0% ethyl acetate / hexanes to obtain intermediate AA51-2 (0.330 g, 8.0%). MS (ES) m / z 225.08 (M+H) + .

[0809] Step-2 Synthesis of (1R,2S)-2-((6-aminopyridin-2-yl)oxy)cyclopentan-1-ol (Intermediate AA51)

[0810] To a suspension of intermediate AA51-2 (0.3 g, 1.33 mmol) in methanol (10 mL) was added 10% Pd / C (0.250 g) at room temperature and hydrogenated at atmospheric pressure for 6 hours. After the reaction was complete, the reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to obtain a crude material, which was used in the next step without purification. Intermediate AA51 (0.268 g, 98.12%). MS (ES): m / z 195.1 [M+H] + ,

[0811] Synthesis of 1-(1-(6-aminopyridin-3-yl)piperidin-3-yl)ethan-1-ol (Intermediate AA52)

[0812]

[0813] 1-(1-(6-Aminopyridin-3-yl)piperidin-3-yl)ethan-1-ol (Intermediate AA52) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 2-methylpiperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Process Intermediate AA30). (1.1 g, 78.6%) MS (ES): m / z 222.1 [M+H] +

[0814] Synthesis of (3R,4S)-1-(6-aminopyridin-3-yl)-4-fluoropiperidin-3-ol (Intermediate AA54)

[0815]

[0816] (3R,4S)-1-(6-Aminopyridin-3-yl)-4-fluoropiperidin-3-ol (Intermediate AA54) (1.0 g, 76.13%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and (3R,4S)-4-fluoropiperidin-3-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 212.11 [M+H] +

[0817] Synthesis of 1-(6-aminopyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)piperidin-4-ol (Intermediate AA55)

[0818]

[0819] 1-(6-Aminopyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)piperidin-4-ol (Intermediate AA55) (0.8 g, 87.75%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-((4-methylpiperazin-1-yl)methyl)piperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 306.2 [M+H] +

[0820] Synthesis of 1-(6-aminopyridin-3-yl)-4-((dimethylamino)methyl)piperidin-4-ol (Intermediate AA56)

[0821]

[0822] 1-(6-Aminopyridin-3-yl)-4-((dimethylamino)methyl)piperidin-4-ol (Intermediate AA56) (0.85 g, 86.53%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-((dimethylamino)methyl)piperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 251.4 [M+H] +

[0823] Synthesis of 1-(6-aminopyridin-3-yl)-4-(N-morpholinyl)piperidin-4-ol (Intermediate AA58)

[0824]

[0825] 1-(6-Aminopyridin-3-yl)-4-(N-morpholinyl)piperidin-4-ol (Intermediate AA58) (0.40 g, 44.34%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-(N-morpholinyl)piperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Process Intermediate AA30). MS (ES): m / z 277.4 [M+H] +

[0826] Synthesis of 5-((oxetane-3-ylmethyl)sulfonyl)pyridin-2-amine (Intermediate AA59)

[0827]

[0828] 5-((Oxetane-3-ylmethyl)sulfonyl)pyridin-2-amine (Intermediate AA59) (0.19 g, 89.94%) was prepared from 6-chloropyridine-3-sulfonyl chloride (Intermediate AA32-1) and 3-(bromomethyl)oxetane in a manner similar to that described for 5-((cyclobutylmethyl)sulfonyl)pyridin-2-amine (General Procedure Intermediate AA32). MS (ES): m / z 277.4 [M+H] +

[0829] Synthesis of 5-(2-((dimethylamino)methyl)(N-morpholinyl))pyridin-2-amine (Intermediate AA63)

[0830]

[0831] 5-(2-((Dimethylamino)methyl)(N-morpholinyl))pyridin-2-amine (Intermediate AA63) (0.60 g, 74.34%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and N,N-dimethyl-1-(morpholin-2-yl)methanamine in a manner similar to 5-(3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Process Intermediate AA30). MS (ES): m / z 237.4 [M+H] +

[0832] Synthesis of 1-(6-aminopyridin-3-yl)-3-((dimethylamino)methyl)piperidin-3-ol (Intermediate AA64)

[0833]

[0834] 1-(6-Aminopyridin-3-yl)-3-((dimethylamino)methyl)piperidin-3-ol (Intermediate AA64) (0.60 g, 78%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 3-((dimethylamino)methyl)piperidin-3-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 251.4 [M+H] +

[0835] Synthesis of 4-(6-aminopyridin-3-yl)-1-(2-(dimethylamino)ethyl)piperidin-2-one (Intermediate AA65)

[0836]

[0837] Step-1 Synthesis of 4-bromo-1-(2-(dimethylamino)ethyl)pyridin-2(1H)-one (Intermediate AA65-1)

[0838] Prepared as described in WO 2009 / 74812 A1.

[0839] Step-2, 3, 4 Synthesis of 4-(6-aminopyridin-3-yl)-1-(2-(dimethylamino)ethyl)piperidin-2-one (Intermediate AA65)

[0840] 4-(6-aminopyridin-3-yl)-1-(2-(dimethylamino)ethyl)piperidin-2-one (Intermediate AA65) (1 g, 65.65%) was prepared from 4-bromo-1-(2-(dimethylamino)ethyl)pyridin-2(1H)-one (Intermediate AA65-1) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in a manner similar to that described for 4-(6-aminopyridin-3-yl)-1-methylpiperidin-2-one (Intermediate AA8). MS (ES): m / z 266.4 [M+H] +

[0841] Synthesis of 1-(6-aminopyridin-3-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-ol (Intermediate AA66).

[0842]

[0843] 1-(6-Aminopyridin-3-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-ol (Intermediate AA66) (1.5 g, 90.90%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-(pyrrolidin-1-ylmethyl)piperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30) MS (ES): m / z 277.3 [M+H] +

[0844] Synthesis of 1-(6-aminopyridin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)piperidin-3-ol (Intermediate AA67).

[0845]

[0846] 1-(6-Aminopyridin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)piperidin-3-ol (Intermediate AA67) (0.80 g, 79%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 3-((4-methylpiperazin-1-yl)methyl)piperidin-3-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 306.4 [M+H] +

[0847] Synthesis of 1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperidin-3-ol (Intermediate AA69)

[0848]

[0849] 1-(6-Aminopyridin-3-yl)-3-(methoxymethyl)piperidin-3-ol (Intermediate AA69) (0.9 g, 84%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 3-(methoxymethyl)piperidin-3-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Process Intermediate AA30). MS (ES): m / z 238.4 [M+H] +

[0850] Synthesis of 4-(6-aminopyridin-3-yl)-4-azaspiro[2.5]octan-6-ol (Intermediate AA70)

[0851]

[0852] 4-(6-Aminopyridin-3-yl)-4-azaspiro[2.5]octan-6-ol (Intermediate AA70) (0.17 g, 94%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-azaspiro[2.5]octan-6-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 220.4 [M+H] +

[0853] Synthesis of (3S,4S)-1-(6-aminopyridin-3-yl)-3-fluoropiperidin-4-ol (Intermediate AA72)

[0854]

[0855] (3S,4S)-1-(6-Aminopyridin-3-yl)-3-fluoropiperidin-4-ol (Intermediate AA72) (2.5 g, 52%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and (3S,4S)-3-fluoropiperidin-4-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Process Intermediate AA30) MS (ES): m / z 212.2 [M+H] +

[0856] Synthesis of ((1R,5S)-3-(6-aminopyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-ol (Intermediate AA73)

[0857]

[0858] (1R,5S)-3-(6-aminopyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-ol (Intermediate AA73) (0.9 g, 93%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and (1R,5S)-3-azabicyclo[3.2.1]octan-8-ol in a manner similar to 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Process Intermediate AA30). MS (ES): m / z 220.2 [M+H] +

[0859] Synthesis of 4-(6-aminopyridin-2-yl)-1-methylpiperidin-4-ol (Intermediate AA74)

[0860]

[0861] Step-1 Synthesis of 4-(6-bromopyridin-2-yl)-1-methylpiperidin-4-ol (Intermediate AA74-2).

[0862] To intermediate AA74-1 (7.5 g, 31.77 mmol) dissolved in THF (25 mL) was added a solution of n-butyl lithium (19 mL, 1.59 mmol, 1.5 equiv) in diethyl ether (35 mL) at -78 °C. After stirring at -78 °C for 30 min, 1-methylpiperidin-4-one (3.6 g, 31.77 mmol) was added. After stirring at -78 °C for 45 min, the reaction mixture was diluted with sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were washed with brine (200 mL), purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by trituration with diethyl ether to obtain intermediate AA74-2 (3 g, 34.91%). MS (ES) m / z 272.2 (M+H) +

[0863] Step-2 Synthesis of N-(6-(4-hydroxy-1-methylpiperidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide (Intermediate AA74-3).

[0864] To a solution of intermediate AA74-2 (1.7 g, 6.29 mmol) in 1,4-dioxane (20 mL) were added cyclopropanecarboxamide (0.641 g, 7.54 mmol, 1.2 equiv) and CS 2 CO 3 (6.1 g, 18.87 mmol, 3.0 eq.) 2 After degassing for 15 minutes under a flow rate, Xantphos (0.363 g, 0.62 mmol, 0.1 eq.) and Pd 2 (dba) 3 (0.567 g, 0.62 mmol, 0.1 eq.). After stirring at 110 °C for 2 h, the reaction mixture was cooled to room temperature, diluted with water (90 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography, eluting with 2.0% methanol in DCM to obtain intermediate AA74-3 (1.7 g, 98.48%), MS (ES): m / z = 276.2 (M+H) +

[0865] Step-3 Synthesis of 4-(6-aminopyridin-2-yl)-1-methylpiperidin-4-ol (Intermediate AA74).

[0866] To a solution of intermediate AA74-3 (1.7 g, 6.18 mmol) in methanol: water (30 mL: 5 mL) was added sodium hydroxide (2.47 g, 61.8 mmol, 10 equiv). After stirring at 80 ° C for 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) at 10 ° C and acidified with 1N hydrochloric acid, and the pH was adjusted to about 6-6.5. The solution was extracted with DCM (3×30 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was used in the next step without purification. Intermediate AA74 (0.750 g, 58.61%) MS (ES): m / z=208.2 (M+H) +

[0867] Synthesis of 1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperidin-4-ol (Intermediate AA77)

[0868]

[0869] Step-1 Synthesis of 3-(hydroxymethyl)-1-(6-nitropiperidin-3-yl)piperidin-4-ol (Intermediate AA77-1)

[0870] 3-(Hydroxymethyl)-1-(6-nitropiperidin-3-yl)piperidin-4-ol (Intermediate AA77-1) (2.1 g, 59%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 3-(hydroxymethyl)piperidin-4-ol in a manner similar to that described for (3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30-2). MS (ES): m / z 254.2 [M+H] +

[0871] Step-2 Synthesis of 3-(methoxymethyl)-1-(6-nitropiperidin-3-yl)piperidin-4-ol (Intermediate AA77-2)

[0872] To a solution of 3-(hydroxymethyl)-1-(6-nitropiperidin-3-yl)piperidin-4-ol (intermediate AA77-1) (1.0 g, 3.9 mmol) in THF (25 mL) and sodium hydride (60%) (0.189 g, 7.9 mmol, 2 eq) was added MeI (0.2 mL, 4.6 mmol, 1.2 eq) at 0 °C. After stirring at room temperature for 10 minutes, the reaction mixture was diluted with ice-cold water (50 mL) and extracted into ethyl acetate (100 mL×3). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified using column chromatography eluting with 50% ethyl acetate / hexane to obtain intermediate AA77-2 (0.600 g, 55%) MS (ES): m / z 267.2 [M+H] +

[0873] Step-3 Synthesis of 1-(6-aminopyridin-3-yl)-3-(methoxymethyl)piperidin-4-ol (Intermediate AA77)

[0874] 1-(6-Aminopyridin-3-yl)-3-(methoxymethyl)piperidin-4-ol (Intermediate AA77) (0.9 g, 92%) was prepared from 3-(methoxymethyl)-1-(6-nitropiperidin-3-yl)piperidin-4-ol (Intermediate AA77-2) in a manner similar to that described for (3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate AA30-2). MS (ES): m / z 238.2 [M+H] +

[0875] Synthesis of tert-butyl 3-(6-chloropyridin-2-yl)azetidine-1-carboxylate (Intermediate AA78).

[0876]

[0877] Step-1 Synthesis of tert-butyl 3-(6-chloropyridin-2-yl)azetidine-1-carboxylate (Intermediate AA78)

[0878] At room temperature in N 2To a solution of Zn powder (0.830 g, 12.72 mmol, 1.2 eq) in anhydrous THF (25 mL) was added 1,2-dibromoethane (0.298 g, 1.59 mmol, 0.15 eq) under atmosphere. After stirring at 80 °C for 10 min, the reaction mixture was cooled and trimethylsilyl chloride (0.16 g, 1.48 mmol, 0.14 eq) dissolved in THF was added. After stirring at room temperature for 45 min, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (3.0 g, 10.60 mmol) in THF was added. After stirring at room temperature for 2 hours, a solution of tris(dibenzylideneacetone)dipalladium(0) (0.096 g, 0.106 mmol, 0.01 eq.), tri(2-furyl)phosphine (0.123 g, 0.53 mmol, 0.05 eq.) and intermediate AA78-1 (2.76 g, 11.55 mmol, 1.09 eq.) in THF was added. After stirring at 60 °C for 16 hours, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were washed with brine (300 mL) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography eluting with 20% ethyl acetate / hexane to afford Intermediate AA78 (1.2 g, 42.14%) MS (ES) m / z 269.2 (M+H) +

[0879] Synthesis of 6-(1-methylpiperidin-3-yl)pyridin-2-amine (Intermediate AA80)

[0880]

[0881] Step-1 Synthesis of tert-butyl 6-nitro-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate (Intermediate AA80-1)

[0882] A 100 mL sealed tube was charged with 2-chloro-6-nitropyridine (intermediate AA51-1) (2 g, 12.61 mmol, 1.0 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (4.67 g, 15.13 mmol, 1.2 equiv), K 2 CO 3(5.26g, 37.8mmol), 1,4-dioxane (32mL) and water (8mL). The mixture was degassed and purged with argon for 10 minutes. The reaction mixture was treated with Pdcl2(dppf)DCM (0.51g, 0.635mmol, 0.05 equivalent), purged with argon for 5 minutes, and heated at 100°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200mL) and water (200mL). The organic layer was collected and the aqueous phase was extracted with ethyl acetate (200mL×2), the combined organic extracts were washed with brine (100mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography, eluted with 50% ethyl acetate / hexane to obtain intermediate AA80-1) (2.4g, 62%) MS (ES): m / z306.2[M+H] +

[0883] Step-2 Synthesis of 6-nitro-1',2',5',6'-tetrahydro-2,3'-bipyridine (Intermediate AA80-2)

[0884] Trifluoroacetic acid (8 mL) was added dropwise to a solution of 6-nitro-5,6-dihydro-[2,3-bipyridine]-1'(2H)'-carboxylic acid tert-butyl ester (AA80-1) (2.4 g, 7.86 mmol) in DCM (40 mL) at 0 ° C at room temperature. After stirring for 1 hour, the reaction mixture was quenched with saturated sodium bicarbonate (200 mL) solution and extracted in DCM (100 mL×3). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography, eluted with 50% ethyl acetate / hexane to obtain intermediate AA80-2) (1.6 g, 99%). MS (ES): m / z 206.10 [M+H] +

[0885] Step-3 Synthesis of 1'-methyl-6-nitro-1',2',5',6'-tetrahydro-2,3'-bipyridine (Intermediate AA80-3)

[0886] To a solution of 6-nitro-1',2',5',6'-tetrahydro-2',3'-bipyridine (Intermediate AA80-2) (1.6 g, 7.84 mmol, 1.0 equiv) in DMF (20 mL) was added K 2 CO 3(3.24 g, 23.52 mmol, 3.0 equiv) and iodomethane (3.3 g, 23.52 mmol, 3.0 equiv). After stirring for 4 hours, the reaction mixture was diluted with ethyl acetate (200 mL) and water (200 mL). The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (200 mL×2). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography, eluted with 40% ethyl acetate / hexane to obtain the material (intermediate AA80-3) (1.4 g, 81%). MS (ES): m / z 220.19 [M+H] +

[0887] Step-4 Synthesis of 6-(1-methylpiperidin-3-yl)pyridin-2-amine (Intermediate AA80).

[0888] 6-(1-Methylpiperidin-3-yl)pyridin-2-amine (Intermediate AA80) (1 g, 90%) was prepared from 1'-methyl-6-nitro-1',2',5',6'-tetrahydro-2,3'-bipyridine (Intermediate AA80-3) in a manner similar to (3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Process Intermediate AA30-2). MS (ES): m / z 192.2 [M+H] +

[0889] Synthesis of 5-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyridin-2-amine (Intermediate AA81)

[0890]

[0891] Step-1 Synthesis of 5-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyridin-2-amine (Intermediate AA81)

[0892] 5-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-amine (Intermediate AA81) (0.9 g, 93%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 8-oxa-3-azabicyclo[3.2.1]octane in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 206.2 [M+H] +

[0893] Synthesis of 6-([1,3'-bipyrrolidine]-1'-yl)pyridin-2-amine (Intermediate AA83).

[0894]

[0895] 5-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-amine (Intermediate AA83) (0.6 g, 93%) was prepared from 2-chloro-6-nitropyridine (Intermediate AA51-1) and 1,3'-dipyrrolidine in a manner similar to that described for tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (General Process Intermediate AA6). MS (ES): m / z 233.2 [M+H] +

[0896] Synthesis of 5-(4-methyl-4-(N-morpholinyl)piperidin-1-yl)pyridin-2-amine (Intermediate AA84)

[0897]

[0898] 5-(4-Methyl-4-(N-morpholinyl)piperidin-1-yl)pyridin-2-amine (Intermediate AA84) (0.7 g, 91%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-(4-methylpiperidin-4-yl)morpholine in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 277.3 [M+H] +

[0899] Synthesis of (1-(6-aminopyridin-3-yl)-4-methylpiperidin-4-yl)methanol (Intermediate AA85).

[0900]

[0901] (1-(6-Aminopyridin-3-yl)-4-methylpiperidin-4-yl)methanol (Intermediate AA85) (0.5 g, 92%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-(4-methylpiperidin-4-yl)morpholine in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropyridin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 222.3 [M+H] +

[0902] Synthesis of tert-butyl 1-(6-aminopyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (Intermediate AA86).

[0903]

[0904] 1-(6-Aminopyridin-2-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (Intermediate AA86) (1.1 g, 89%) was prepared from 2-chloro-6-nitropyridine (Intermediate AA51-1) and hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester in a manner similar to that described for tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (General Process Intermediate AA6). MS (ES): m / z 305.2 [M+H] +

[0905] Synthesis of 7-(6-aminopyridin-3-yl)-2,7-diazaspiro[4.5]decan-1-one (Intermediate AA86)

[0906]

[0907] 7-(6-Nitropiperidin-3-yl)-2,7-diazaspiro[4.5]decan-1-one (Intermediate AA87-1) (1.0 g, 89%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 2,7-diazaspiro[4.5]decan-1-one in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrolepyrrole (General Procedure Intermediate AA30). MS (ES): m / z 347.3 [M+H] + .

[0908] Synthesis of 1-(6-chloro-5-fluoropyridin-3-yl)piperidin-4-ol (Intermediate AA88)

[0909]

[0910] Step-1 Synthesis of 8-(6-chloro-5-fluoropyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (Intermediate AA88-2).

[0911] In N 2 Intermediate AA88-1 (1.0 g, 4.80 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (0.755 g, 5.28 mmol, 1.1 equiv.) and K 2 CO 3 A solution of (2.0 g, 14.4 mmol, 3.0 eq) in toluene (10 mL) was degassed. After 15 min, Xantphos (0.552 g, 0.96 mmol, 0.2 eq) and Pd 2 (dba) 3(0.439 g, 0.48 mmol, 0.1 eq.). After stirring at 110 °C for 2 h, the reaction mixture was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (80 mL) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography using 15% ethyl acetate / hexane to obtain intermediate AA88-2 (0.7 g, 54.01%). MS (ES): m / z = 273.2 (M+H) +

[0912] Step-2 Synthesis of 1-(6-chloro-5-fluoropyridin-3-yl)piperidin-4-one (Intermediate AA88-3).

[0913] A solution of intermediate AA88-2 (0.7 g, 2.57 mmol) in 50% HCl (35 mL) was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was quenched with water (70 mL) and extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was used in the next step without purification. Intermediate AA88-3 (0.6 g, 95.41%). MS (ES): m / z = 229.05 (M+H) +

[0914] Step-3 Synthesis of 1-(6-chloro-5-fluoropyridin-3-yl)piperidin-4-ol (Intermediate AA88)

[0915] To a solution of intermediate AA88-3 (0.6 g, 2.63 mmol) in THF (15 mL) was added sodium borohydride (0.150 g, 3.94 mmol, 1.5 eq) portionwise at room temperature. After stirring at room temperature for 30 min, the reaction mixture was quenched into water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (50 mL), purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography using 40% ethyl acetate / hexane to obtain intermediate AA88 (0.5 g, 82.61%). MS (ES): m / z = 231.2 (M+H) +

[0916] Synthesis of 5-(4-((N-morpholinyl)methyl)piperidin-1-yl)pyridin-2-amine (Intermediate AA89)

[0917]

[0918] 5-(4-((N-morpholinyl)methyl)piperidin-1-yl)pyridin-2-amine (Intermediate AA89) (0.5 g, 92%) was prepared from 5-fluoro-2-nitropyridine (Intermediate AA30-1) and 4-(piperidin-4-ylmethyl)morpholine in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 277.3 [M+H] +

[0919] Synthesis of tert-butyl 4-(6-bromopyridin-2-yl)-4-methylpiperidine-1-carboxylate (Intermediate AA90)

[0920]

[0921] 4-(6-Bromopyridin-2-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-methyl ester (Intermediate AA90-1) was synthesized as described in CA2988721A1

[0922] Step-1 Synthesis of tert-butyl 4-(6-bromopyridin-2-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate AA90-2)

[0923] To a solution of intermediate AA90-1 (1.2 g, 3.00 mmol) in THF (15 mL) was added lithium aluminum hydride (2 M in THF) (4.5 mL, 9.0 mmol, 3.0 equiv) dropwise at 0 °C. After stirring at 70 °C for 1 hour, the reaction mixture was quenched into water (120 mL) and extracted with ethyl acetate (3 x 70 mL). The combined organic extracts were washed with brine (100 mL), purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography using 10% ethyl acetate / hexane to obtain intermediate AA90-2 (1.0 g, 89.62%). MS (ES): m / z = 371.2 (M+H) +

[0924] Step-2 Synthesis of tert-butyl 4-(6-bromopyridin-2-yl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (Intermediate AA90-3).

[0925] To a solution of intermediate AA90-2 (1.0 g, 2.70 mmol) in DCM (10 mL) was added trimethylamine (0.5 mL, 4.05 mmol, 1.5 eq) and DMAP (10 mg). Methanesulfonyl chloride (0.22 mL, 2.97 mmol, 1.1 eq) was added dropwise to the reaction mixture at 0 °C and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched in water (90 mL) and extracted with ethyl acetate (2 x 70 mL). The combined organic extracts were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was used in the next step without purification. Intermediate AA90-6 (1.0 g, 82.62%) MS (ES): m / z = 450.2 (M+H) +

[0926] Step-3 Synthesis of tert-butyl 4-(6-bromopyridin-2-yl)-4-methylpiperidine-1-carboxylate (Intermediate AA90).

[0927] To a solution of intermediate AA90-3 (1.0 g, 2.22 mmol) in DMF (30 mL) was added sodium iodide (0.661 g, 4.44 mmol, 2.0 equiv) and zinc powder (0.725 g, 11.1 mmol, 5.0 equiv). After stirring at 110 ° C. for 40 hours, the reaction mixture was filtered. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic solution was dried, filtered and concentrated. The residue was purified by silica gel chromatography using 10% ethyl acetate / DCM to obtain intermediate AA90 (0.2 g, 25.30%) MS (ES): m / z=355.2 (M+H) +

[0928] Synthesis of 2-(1-(4-aminophenyl)piperidin-3-yl)propan-2-ol (Intermediate AA91).

[0929]

[0930] 2-(1-(4-Aminophenyl)piperidin-3-yl)propan-2-ol (Intermediate AA91) (0.6 g, 92%) was prepared from 1-fluoro-4-nitrobenzene (Intermediate AA91-1) and 2-(piperidin-3-yl)propan-2-ol in a manner similar to that described for 5-(3aR,6aS)-5-(6-nitropiperidin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (General Procedure Intermediate AA30). MS (ES): m / z 2235.3 [M+H] +

[0931] Synthesis of 2-chloro-6-(1-methylazetidin-3-yl)pyridine (Intermediate AA92).

[0932]

[0933] Step-1 Synthesis of tert-butyl 3-(6-chloropyridin-2-yl)azetidine-1-carboxylate (Intermediate AA92-1)

[0934] In N 2 To a solution of Zn powder (407 mg, 6.2 mmol, 1.2 eq) in THF (10 mL) was added 1,2-dibromoethane (146 mg, 0.78 mmol, 0.15 eq) under atmosphere. After stirring at 80 °C for 10 min, the reaction was cooled at room temperature and TMS-Cl (79 mg, 0.72, 0.14 eq) and tert-butyl 3-iodoazetidine-1-carboxylate (1.38 g, 5.7 mmol, 1 eq) in THF (5 mL) were added. After stirring at room temperature for 2 h, Intermediate-AA78-1 (1.5 g, 5.2 mmol, 1 eq), Pd 2 (dba) 3 (47 mg, 0.052 mmol, 0.01 eq) and tri(2-furyl)phosphine (60 mg, 0.26 mmol, 0.05 eq). After stirring at 55 °C for 16 hours, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain the crude product, which was purified by silica gel chromatography eluting with 10% ethyl acetate / hexane to obtain intermediate AA92-1 (390 mg, 29.62%). MS (ES): m / z=269.26 (M+H) +

[0935] Step-2 Synthesis of 2-(azetidin-3-yl)-6-chloropyridine (Intermediate AA92-2)

[0936] 2-(Azetidin-3-yl)-6-chloropyridine (Intermediate AA92-2) (155 g, 88%) was prepared from tert-butyl 3-(6-chloropyridin-2-yl)azetidine-1-carboxylate (Intermediate AA92-1) in a manner similar to that described in Step-2 of Intermediate AA80-2. MS (ES): m / z 169.7 [M+H] +

[0937] Step-3 Synthesis of 2-chloro-6-(1-methylazetidin-3-yl)pyridine (Intermediate AA92)

[0938] 2-Chloro-6-(1-methylazetidin-3-yl)pyridine (Intermediate AA92) (120 mg, 78%) was prepared from 2-(azetidin-3-yl)-6-chloropyridine (Intermediate AA92-1) in a manner similar to that described in Step-3 of Intermediate AA80-3. MS (ES): m / z 184.5 [M+H] + .

[0939] Synthesis of 5-(2-(2-(dimethylamino)propan-2-yl)(N-morpholinyl))pyridin-2-amine (Intermediate-AA93)

[0940]

[0941] Step-1 Synthesis of 2-(4-phenylmethylmorpholin-2-yl)propan-2-amine (Intermediate-AA93-2)

[0942] A solution of Ce(VI)Cl (36.6 g, 148.51 mmol, 2.0 equiv) in anhydrous THF (150 mL) was stirred at 45 °C for 2 hours. The reaction mixture was cooled to room temperature and Intermediate-AA93-1 (15.0, 74.25 mmol) was added. The reaction mixture was then cooled to -10 °C and methyllithium (3M) (61.0 mL, 185.62 mmol, 2.5 equiv) was added. After stirring for 30 minutes, the reaction mixture was filtered through a celite bed, diluted with water (100 mL), and extracted with DCM (3 x 70 mL). The combined organic extracts were washed with brine (60 mL), purified by Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave the crude material, which was used in the next step without further purification. (Intermediate-AA93-2) (10.0 g, 57.54%) as a brown solid. MS (ES): m / z = 235.18 [M+H] +

[0943] Step-2 Synthesis of 2-(4-phenylmethylmorpholin-2-yl)-N,N-dimethylpropan-2-amine (Intermediate-AA93-3)

[0944] To a solution of Intermediate-AA93-2 (10.0 g, 42.73 mmol) and formaldehyde (2.56 g, 85.46 mmol, 2.0 equiv) in dichloroethane (100 mL) was added trimethylamine (12 mL, 85.46 mmol, 2.0 equiv). A...

Claims

1. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is:

3. A pharmaceutical composition comprising the compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. A compound according to claim 1 or claim 2, or a pharmaceutical composition according to claim 3, for use as a medicament.

5. Use of a compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, in the preparation of a medicament for treating cancer in a patient.

6. The use according to claim 5, wherein the cancer is associated with one or more activating mutations in HPK1.

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