HPK1 inhibitor synthesis and intermediates

Abstract

Described herein are processes for the preparation of substituted isoindolin-1-ones of formula (I) derivatives thereof, and intermediates thereto. Also provided are pharmaceutically acceptable compositions comprising the substituted isoindolin-1-ones prepared by described processes and methods of treating HPK1 disorders using the same.

Description

HPK1 INHIBITOR SYNTHESIS AND INTERMEDIATESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of priority to Indian Patent Provisional Application No.202411060324, filed August 9, 2024, the content of which is herein incorporated by reference.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to processes for the preparation of substituted isoindolin-l-ones that are userid as HPK1 inhibitors, derivatives thereof, and intermediates thereto.BACKGROUND OF THE INVENTION

[0003] Hematopoietic progenitor kinase 1 (HPK1, also known as MAP4K1) is a member of the MAP4K family of protein serine / threonine kinases, involved in negatively regulating signal transduction cascades in cells of hematopoietic lineage. Inhibition of HPK1 has the potential to enhance and prime a patient’s immune system to recognize and eliminate tumor cells and also to augment immune checkpoint blockade (ICB) therapies on T cell responses (Sawasdikosol and Burakoff. "A perspective on HPK1 as a novel immuno-oncology drug target." Elife 9 (2020): e55122).

[0004] Compound B:is a potent HPK1 inhibitor.

[0005] U.S. Patent No. 11,548,890 describes benchtop preparation of compound B. A need exists for alternative processes and intermediate compounds for the preparation of compound B and pharmaceutically acceptable salts thereof suitable for batch process scale-up. Such alternative processes and intermediate compounds are provided herein.SUMMARY OF THE INVENTION

[0006] Described herein is a process for preparing a compound of formula I:or solvate thereof, wherein:[Acid] is a suitable inorganic or organic acid.

[0007] In one aspect, compound A:prepared by a process disclosed herein, is described.

[0008] In one aspect, a process for preparing compound A:is described herein.

[0009] In one aspect, a process for preparing compound B:or solvate thereof, is described herein.

[0010] In one aspect, a process for preparing a compound of formula II:or solvate thereof is described herein, wherein: PG is a suitable nitrogen protecting group; and[Acid] is a suitable inorganic or organic acid.

[0011] In one aspect, a process for preparing a compound of formula III:or a salt or solvate thereof is described herein, wherein:PG is a suitable nitrogen protecting group; each R is independently selected from halogen, -OH, or an optionally substituted Ci-e aliphatic or -OCne aliphatic; or: two or three R groups are taken together with their intervening atoms to form an optionally substituted monocyclic, bicyclic, or bridged bicyclic ring; and x is 2 or 3.

[0012] In one aspect, a process for preparing a compound of formula IV :IV or a salt or solvate thereof is described herein, whereinPG is a suitable nitrogen protecting group; andLG2is a suitable leaving group.

[0013] In another aspect, a method of inhibiting HPK1, or a mutant thereof, in a patient is described, the method including administering to the patient a therapeutically effective amount of compound A:wherein compound A is prepared by tire process described herein.

[0014] These and other aspects of this disclosure will be apparent upon reference to the following detailed description. To this end. various references are set forth herein which describe in more detail certain background information and procedures and are each hereby incorporated by reference herein in their entirety.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 shows heat map results of Stage 1 catalyst screen #1. Number indicates ratio of Compound E to internal standard.

[0016] FIG. 2 shows bar chart results of Stage 1 catalyst screen #1.

[0017] FIG. 3 shows heat map results of Stage 1 catalyst screen #2. Number indicates ratio of CompoundE to internal standard.

[0018] FIG. 4 shows bar chart results of Stage 1 catalyst screen #2.

[0019] FIG. 5 shows bar chart results of Stage 1 catalyst screen #3.

[0020] FIG. 6 shows a plot of conversion vs time for Suzuki reaction (Stage 3) while varying base input

[0021] FIG. 7 shows a plot of conversion vs time for one-pot borylation Suzuki reactions with B2(OH)4and B2Pin2.

[0022] FIG. 8 shows a plot of solubility versus solvent composition for Compound C free base.

[0023] FIG. 9 shows solubility of Compound B in different alcohol / antisolvent mixtures.

[0024] FIG. 10 show s a LCAP of Compound B after an overnight age at 50 °C with 1.25 equiv. NaOMe.

[0025] FIG. 11 shows the ratio of Compound B to an internal standard over time at 40 °C with 0.1 equiv.NaOMe in EtOH (30 vol.).

[0026] FIG. 12 shows the stability of Compound B to deprotection conditions.

[0027] FIG. 13 shows solubility of L- and D-malic acid salts of Compound B in solvent / water mixtures.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS1. General Description of Certain Embodiments of the Invention:

[0028] Compounds of formula I are novel small molecule inhibitors of HPK1 identified through structure based drag design and Compound B was selected for clinical development based on potency against HPK1, its effects on T cell, B cell, and dendritic cell activation in vitro, and its ability to modulate immune responses and inhibit tumor growth in mouse tumor models. Compound B has high selectivity for HPK1 versus other kinases and has limited potential for other “off-target” effects at high multiples of the concentrations that inhibit HPK1 in vitro.

[0029] U.S. Patent No. 11,548,890 describes certain therapeutically beneficial compounds. Such compounds include ((S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4- (7-fluoroimidazo[l,2-a]pyridin-3-yl)isoindolin-l-one (“compound B”) having the structure:or a pharmaceutically acceptable salt thereof.

[0030] Compound B is designated 1-479 in US 11,548,890 and an alternate synthesis of compound B, which is different from that described in Exampe 21 of US 11,548,890, is described herein. It would be desirable to provide improved processes of preparing compound B, or pharmaceutically acceptable salts or solvates thereof. Accordingly, processes of preparing such compounds are described herein.

[0031] In the following disclosure, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is. as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0032] Reference throughout this specification to ‘'one embodiment’’ or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.2. Definitions:

[0033] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999. and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J.. John Wiley & Sons, New York: 2001.

[0034] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic Cs-Ce hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0035] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a ‘'bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. The term ‘'alkyl” refers to a CM 2 straight or branched saturated aliphatic group. In certain instances, alkyl refers to a Ci-s straight or branched saturated aliphatic group or a Ci .6 straight or branched saturated aliphatic group. The term “lower alkyl” refers to a C1-4 straight or branched alkyl group.

[0036] Exemplar}’ lower alkyl groups are methyl, ethyl, propyl, isopropyl (also referred to interchangeably herein as 2-propyl, iPr, ‘Pr and i-Pr), butyl, isobutyl (also referred to interchangeably herein as 2 -butyl, iBu, ‘Bu and i-Bu) and tert-butyl (also referred to interchangeably herein as 2-methyl-2 -propyl, tBu.lBu and t- Bu).

[0037] The term “alkenyl” refers to a C2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. In certain instances, alkenyl refers to a C2- or a C1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. Tire tenn “lower alkenyl” refers to a C2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. Alkenyl groups include both cis (Z) and trans (E) regioisomers. Exemplary lower alkenyl groups are vinyl, allyl, 2- propenyl,and butenyl isomers( )

[0038] Tire tenn “alkynyl” refers to a straight or branched partially unsaturated aliphatic groupcomprising at least one unsaturated carbon carbon triple bond. In certain instances, alkynyl refers to a C2-8or a C1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. The term “lower alkynyl” refers to a C2-4straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. Exemplary lower alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0039] Tire tenn “haloalkyl” refers to a straight or branched alkyl group that is substituted with one or more halogen atoms. The tenn “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0040] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphonis. or silicon (including, any oxidized form of nitrogen, sulfur, phosphonis, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2E7-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substitutcd pyrrolidinyl)).

[0041] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0042] As used herein, the term “bivalent C1-8(or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0043] Tire tenn “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0044] Tire tenn “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0045] The term “halogen” means F, Cl, Br, or I.

[0046] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen 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. Tire term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to. phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and tire like.

[0047] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5. 6, 9 or 10 ring atoms; having 6, 10, or 14 it electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, triazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2.3-triazolyl). 1,2,4-triazolyl, 1,2,5-triazolyl, 1.3,4-triazolyl, tetrazolyl. oxazolyl. isoxazolyl. oxadiazolyl, 1,2,3 -oxadiazolyl. 1,2,4-oxadiazolyl, 1.2.5— oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, indolizinyl, isoindolin-l-only, l,2-dihydro-3H-pyrrolo[3,4- c]pyridin-3-onyl, 2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-only, imidazo[l,2-a]pyridyl, imidazo[l,5- a]pyridyl, pyrazolo[l,5-a]pyridyl, pyrrolo[l,2-b]pyridazinyl, pyrrolo[l,2-a]pyrimidinyl, imidazo[l,2- b]pyridazinyl, imidazo[l,2-a]pyrimidinyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, ciimolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 47 / quinolizinyl. carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl. tetrahydroquinolinyl. and tetrahydroisoquinolinyl. A heteroaryl group may be mono- or bicyclic. The term “heteroary l” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a h ete roar yl wherein tire alkyl and heteroaryl portions independently are optionally substituted.

[0048] 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 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H- -pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in A' substituted pyrrolidinyl).

[0049] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl. oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl. 2-oxa-6-azaspiro[3.3]heptane. and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroary l, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Tire term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0050] 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 ary l or heteroaryl moictics, as herein defined.

[0051] As described herein, compounds of the invention may contain '‘optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at even' position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. Tire term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and. in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0052] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted”ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°. taken together with their intervening atom(s), form a 3- 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0053] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o-unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0054] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” groupC1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group includewherein each independent occurrence of R* is selected from hydrogen C,1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0055] Suitable substituents on the aliphatic group of R* include halogen,wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently h, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0056] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R:. -NRfr -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2R;. -S(O)2NRt2, -C(S)NRt2, - C(NH)NR'2. or -N(R')S(O)2R': wherein each R' is independently hydrogen C,1-6aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or. notwithstanding the definition above, two independent occurrences of R'. taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0057] Suitable substituents on the aliphatic group of R’f are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens,and is independently CM aliphatic, -CH2PI1, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0058] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example. S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmacally acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, 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-toluene sulfonate, undecanoate, valerate salts, and the like.

[0059] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium andsalts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0060] As used herein, the term “salt” refers to the pharmacally acceptable salts mentioned above and further salts that are commonly found in chemical synthesis but would not be suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like.

[0061] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers and Ra (or M) and Sa(or P) atropisomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0062] As used herein, the phrase “leaving group” (“LG”) refers to a functional group that is displaced from a molecule during a chemical reaction. Leaving groups include halogens, as well sulfonate groups, such as tosylate, triflate, and mesylate.

[0063] The term “protecting group” (“PG”) refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rdEd. , 1999, John Wiley & Sons, N.Y. and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971- 1996, John Wiley & Sons. N.Y. Representative nitrogen protecting groups include, but are not limited to, t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacctyl. trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl.3. Description of Exemplary Embodiments:

[0064] In one aspect, a process for preparing a compound of formula I:or solvate thereof is described herein, wherein: [Acid] is a suitable inorganic or organic acid.

[0065] In one aspect, compound A:prepared by a process disclosed herein, is described.

[0066] In one aspect, a process for preparing compound A:is described herein.

[0067] In one aspect, a process for preparing compound B:or solvate thereof, is described herein.

[0068] In one aspect, a process for preparing a compound of formula II:or solvate thereof is described herein, wherein:PG is a suitable nitrogen protecting group; and[Acid] is a suitable inorganic or organic acid.

[0069] In another aspect, a compound of formula II is compound C:or solvate thereof, as described herein.

[0070] In another aspect, a process for preparing a compound of formula III:or a salt or solvate thereof is described herein, wherein:PG is a suitable nitrogen protecting group;each R is independently selected from halogen, -OH, or an optionally substituted Cue aliphatic or -OCi e aliphatic; or: two or three R groups are taken together with their intervening atoms to form an optionally substituted monocyclic, bicyclic, or bridged bicyclic ring; and x is 2 or 3.

[0071] In another aspect, a compound of formula III is compound D:or solvate thereof, as described herein.

[0072] In one aspect, a process for preparing a compound of formula IV :or a salt or solvate thereof is described herein, whereinPG is a suitable nitrogen protecting group; andLG2is a suitable leaving group.

[0073] In one aspect, a compound of formula IV is compound E:or a salt or solvate thereof, as described herein.

[0074] In one aspect, compound F :or a salt or solvate thereof, for use in processes disclosed herein, is described.

[0075] In one aspect, compound F :or a salt or solvate thereof, is described herein.

[0076] As defined above and described herein, [Acid] is a suitable inorganic or organic acid. In some embodiments, a suitable inorganic acid is hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid. In some embodiments, a suitable organic acid is acetic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, fumaric acid, benzoic acid, methanesulfonic acid, or p-toluenesulfonic acid. In some embodiments, a suitable organic acid is L-malic acid.

[0077] As defined above and described herein, PG is a suitable nitrogen protecting group. In some embodiments, PG is t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxy carbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz). allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc). acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (Boc).

[0078] As defined above and described herein, each R is independently selected from halogen, -OH, or an optionally substituted Ci-6 aliphatic or -OCi e aliphatic, or two or three R groups are taken together with their intervening atoms to fonn an optionally substituted monocyclic, bicyclic, or bridged bicyclic ring.

[0079] In some embodiments, R is halogen. In some embodiments, R is -OH. In some embodiments. R is an optionally substituted Cue aliphatic. In other embodiments, two or three R groups are taken together with their intervening atoms to form an optionally substituted monocyclic or bicyclic ring.

[0080] As defined above and described herein, x is 2 or 3. In some embodiments, x is 2. In some embodiments, x is 3.some embodiments, -BRXis -B(OH)2.

[0082] As defined above and described herein, LG2is a suitable leaving group. In some embodiments, LG2is halogen or -SO2R1, wherein R1is an optionally substituted group selected from Cue aliphatic, - OCi-e aliphatic, and a monocyclic or bicyclic carbocyclic or heterocyclic ring. In some embodiments, LG2is halogen, mesylate, tosylate, or triflate. In some embodiments, LG2is halogen. In some embodiments. LG2is chloro.

[0083] In another aspect, a compound selected from one of those in Table 1, or a salt or solvate thereof, is described herein.Table 1: Intermediate and Target Compound(s)

[0084] In some embodiments, the present invention provides a compound as depicted in Table 1, above, or a salt or solvate thereof.4. Exemplary Methods of Synthesis:

[0085] As described above, methods of synthesizing compounds A, B, C, D, and compounds of formula I, II, III, or IV and salts or solvates thereof are provided herein. In some embodiments, the present compounds are generally prepared according to Scheme 1 set forth below:Scheme 1

[0086] In Scheme 1 above, LG1, LG2, LG3, PG, BRX. and [Add] are each as defined above and described m embodiments herein, both singly and in combination,

[0087] In one aspect, the present invention provides a process for preparing a compound of formula 1:or solvate thereof, wherein:[Acid] is a suitable inorganic or organic acid, comprising the step of: contacting compound B:or solvate thereof, with the suitable inorganic or organic acid under suitable conditions to form a compound of formula I, or solvate thereof.

[0088] As defined above and described herein, [Acid] is a suitable inorganic or organic acid. In some embodiments, a suitable inorganic acid is hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid. In some embodiments, a suitable organic acid is acetic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, fumaric acid, benzoic acid, methanesulfonic acid, or p-toluenesulfonic acid. In some embodiments, a suitable organic acid is L-malic acid.

[0089] In some embodiments, the suitable conditions to form a compound of formula I or solvate thereof comprises combining a mixture of compound B, or solvate thereof, and a suitable solvent with a suitableinorganic or organic acid or a mixture of a suitable inorganic or organic acid and a suitable solvent at a suitable temperature.

[0090] In some embodiments, a suitable inorganic acid is hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid. In some embodiments, a suitable organic acid is acetic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. In some embodiments, a suitable organic acid is L-malic acid.

[0091] A suitable solvent may be any solvent system (e.g., one solvent or a mixture of solvents) in which compound B and / or an acid are soluble, or are at least partially soluble. Examples of suitable solvents useful in the presently disclosed processes include, but are not limited to protic solvents, aprotic solvents, polar aprotic solvent, or mixtures thereof. In certain embodiments, suitable solvents include water, acetonitrile, ethers (e.g., diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran). esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate), alcohols (e.g., methanol, ethanol, isopropanol, or n-butanol), ketones (acetone, methyl ethyl ketone), or mixtures thereof. These and other such suitable solvents may be interchanged and are well known in the art, e.g., see, "Advanced Organic Chemistry". Jerry March, 5thedition, John Wiley and Sons, N.Y. In some embodiments, the solvent is one or more alcohols. In some embodiments, the solvent is aqueous alcohol (e.g., water and methanol, ethanol, isopropanol, or n-butanol). In some embodiments, the solvent is aqueous ethanol.

[0092] In some embodiments, the solvent is aqueous ethanol at a ratio of about 5: 1, 4: 1, 3: 1, or 2: 1 ethanol: water. In some embodiments, the solvent is aqueous ethanol at a ratio of about 3: 1 ethanol: water.

[0093] A suitable temperature can be any temperature which compound B and / or an acid are soluble, or are at least partially soluble. Examples of suitable temperatures include 0 ± 5 °C, 10 ± 5 °C, 20 ± 5 °C (e.g., room temperature), 30 ± 5 °C. 40 ± 5 °C, 50 ± 5 °C, 60 ± 5 °C. 70 ± 5 °C, 80 ± 5 °C, 90 ± 5 °C, or 100 ± 5 °C. In some embodiments, a suitable temperature is 50 ± 5 °C.

[0094] In some embodiments, the suitable conditions to form a compound of formula I or solvate thereof further comprise cooling a mixture of compound B, a suitable inorganic or organic acid, and a suitable solvent.

[0095] In some embodiments, the present invention provides a process for preparing a compound of formula I in greater than 4 kg. greater than 5 kg. greater than 10 kg, greater than 15 kg, greater than 20 kg, greater than 30 kg, greater than 40 kg, greater than 50 kg, greater than 60 kg, greater than 70 kg, greater than 80 kg, greater than 90 kg, or greater than 100 kg. In some embodiments, the amount of a compound of formula I prepared is greater than 5 kg. In some embodiments, tire amount of a compound of formula I prepared is greater than 15 kg.

[0096] In some embodiments, the present invention provides a process for preparing a compound of formula I without the use of column chromatography.

[0097] In some embodiments, the present invention provides a process for preparing a compound of formula I in greater than 90.0% ee, greater than 95.0% ee, greater than 96.0% ee, greater than 97.0% ee, greater than 98.0% ee, greater than 99.0% ee, greater than 99.1% ee, greater than 99.2% ee, greater than99.3% ee, greater than 99.4% ee, greater than 99.5% ee, greater than 99.6% ee. greater than 99.7% ee. or greater than 99.8% ee. In some embodiments, the ee of a compound of formula I prepared is greater than 99.0% ee. In some embodiments, the ee of a compound of formula I prepared is greater than 99.5% ee.

[0098] In some embodiments, the compound of formula I is compound A:A

[0099] In some embodiments, a process of preparing compound A is as described in Example 1 or 2, below.

[0100] In some embodiments, the present invention provides a process for preparing compound A in greater than 5 kg, greater than 10 kg, greater than 15 kg, greater than 20 kg, greater than 30 kg, greater than 40 kg, greater than 50 kg, greater than 60 kg, greater than 70 kg, greater than 80 kg. greater than 90 kg, or greater than 100 kg. In some embodiments, the amount of compound A prepared is greater than 5 kg. In some embodiments, the amount of compound A prepared is greater than 15 kg. In some embodiments, the amount of compound A prepared is as described in Examples 1 and 2, below.

[0101] In some embodiments, the present invention provides a process for preparing compound A without the use of column chromatography.

[0102] In some embodiments, the present invention provides a process for preparing compound A in greater than 90.0% ee, greater than 95.0% ee, greater than 96.0% ee. greater than 97.0% ee. greater than 98.0% ee, greater than 99.0% ee, greater than 99.1% ee, greater than 99.2% ee, greater than 99.3% ee, greater than 99.4% ee, greater than 99.5% ee, greater than 99.6% ee, greater than 99.7% ee, or greater than 99.8% ee. In some embodiments, the ee of compound A prepared is greater than 99.0% ee. In someembodiments, the ee of compound A prepared is greater than 99.5% ee. In some embodiments, the ee of compound A prepared is as described in Examples 1 and 2, below.

[0103] In one aspect, the present invention provides a process for preparing compound B:or solvate thereof, comprising the steps of: neutralizing and deprotecting a compound of formula II:or solvate thereof, wherein:PG is a suitable nitrogen protecting group; and[Acid] is a suitable inorganic or organic acid, under suitable neutralization and deprotection conditions to form a compound of formula H. or solvate thereof.

[0104] As defined above and described herein, PG is a suitable nitrogen protecting group. In some embodiments, PG is t-butyloxycarbonyl (Boc). ethyloxycarbonyl, methyloxy carbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (Boc).

[0105] As defined above and described herein, [Acid] is a suitable inorganic or organic acid. In some embodiments, a suitable inorganic acid is hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid. In some embodiments, a suitable organic acid is acetic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, fumaric acid, benzoic acid, methanesulfonic acid, or p-toluenesulfonic acid. In some embodiments, a suitable organic acid is L-malic acid.

[0106] In some embodiments, suitable neutralization conditions comprise combining a mixture of a compound of formula II, or solvate thereof, and a suitable solvent with a suitable neutralization reagent or a mixture of a suitable neutralization reagent and a suitable solvent at a suitable temperature.

[0107] In some embodiments, the suitable neutralization reagent may comprise any reagent that can neutralize a salt compound (e.g.. adjusting the pH so a salt compound converts to free base fonn). In some embodiments, the suitable neutralization reagent is a base (e.g., NaHCOs, Na2COs, or K3PO4). In some embodiments, the base is K3PO4.

[0108] The suitable neutralization conditions may comprise any solvent described infra. In some embodiments, the suitable neutralization conditions comprise aqueous ether (e.g., water and diisopropyl ether, methyl tert -butyl ether, tetrahydrofuran, or 2-methyltetrahydrofuran). In some embodiments, the suitable neutralization conditions comprise aqueous 2-methyltetrahydrofuran.

[0109] In some embodiments, the solvent is aqueous 2-methyltetrahydrofuran at a ratio of about 5: 1. 4: 1, 3: 1, or 2: 1 2-methyltetrahydrofuran:water. In some embodiments, the solvent is aqueous 2- methyltetrahydrofiiran at a ratio of about 3: 1 2-methyltetrahydrofuran: water.

[0110] A suitable temperature can be any temperature which a compound of formula II and / or a base are soluble, or are at least partially soluble. Examples of suitable temperatures include 0 ± 5 °C, 10 ± 5 °C, 20 ± 5 °C (e.g.. room temperature). 30 ± 5 °C, 40 ± 5 °C, 50 ± 5 °C, 60 ± 5 °C, 70 ± 5 °C. 80 ± 5 °C, 90 ± 5 °C, or 100 ± 5 °C. In some embodiments, a suitable temperature is room temperature.

[0111] In some embodiments, the suitable deprotection conditions comprise combining a mixture of a compound of formula II, or solvate thereof, and a suitable solvent with a suitable deprotection reagent or a mixture of a suitable deprotection reagent and a suitable solvent at a suitable temperature.

[0112] In some embodiments, the suitable deprotection reagent comprises palladium catalysts (e / g., Pd / C), acids (e.g., HC1 or trifluoroacetic acid), and / or bases (e.g., piperidine, ammonia, K2CO3, NaOMe, or methylamine). In some such embodiments, thesuitable deprotection conditions optionally comprise heating. According to embodiments described herein, the deprotection of a protecting group described above and herein includes those protecting groups and methods for their deprotection described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999. In some embodiments, PG is t-butyloxy carbonyl (Boc) and the suitable deprotection conditionscomprise contacting a compound of formula II with an acid or base. In some embodiments, the base is NaOMe. The step of deprotecting may comprises any solvent described infra. In some embodiments, the suitable deprotection conditions comprise an ether (e.g., diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or 2-methyltetrahydrofuran) and an alcohol (e.g., methanol, ethanol, isopropanol, or n- butanol). In some embodiments, the suitable deprotection conditions comprise aqueous 2- methyltetrahydrofuran and ethanol.

[0113] In some embodiments, the solvent is aqueous 2-methyltetrahydrofuran at a ratio of about 5: 1, 4: 1, 3: 1, or 2: 1 2-methyltetrahydrofuran:water. In some embodiments, the solvent is aqueous 2- methyltetrahydrofuran at a ratio of about 3: 1 2-methyltetrahydrofuran: water.

[0114] A suitable temperature can be any temperature which compound B and / or an acid are soluble, or are at least partially soluble. Examples of suitable temperatures include 0 ± 5 °C, 10 ± 5 °C, 20 ± 5 °C (e.g., room temperature), 30 ± 5 °C. 40 ± 5 °C, 50 ± 5 °C, 60 ± 5 °C. 70 ± 5 °C, 80 ± 5 °C, 90 ± 5 °C. or 100 ± 5 °C. In some embodiments, a suitable temperature is 50 ± 5 °C.

[0115] In some embodiments, the present invention provides a process for preparing compound B in greater than 5 kg, greater than 10 kg, greater than 15 kg, greater than 20 kg, greater than 30 kg, greaterthan 40 kg, greater than 50 kg, greater than 60 kg, greater than 70 kg, greater than 80 kg. greater than 90 kg, or greater than 100 kg. In some embodiments, the amount of compound B prepared is greater than 5 kg. In some embodiments, the amount of compound B prepared is greater than 15 kg. In some embodiments, the amount of compound B prepared is as described in Examples 1 and 2, below.

[0116] In some embodiments, the present invention provides a process for preparing compound B without the use of column chromatography.

[0117] In some embodiments, the present invention provides a process for preparing compound B in greater than 90.0% ee, greater than 95.0% ee, greater than 96.0% ee. greater than 97.0% ee, greater than 98.0% ee. greater than 99.0% ee. greater than 99.1% ee. greater than 99.2% ee, greater than 99.3% ee, greater than 99.4% ee, greater than 99.5% ee, greater than 99.6% ee, greater than 99.7% ee, or greater than 99.8% ee. In some embodiments, the ee of compound B prepared is greater than 99.0% ee. In some embodiments, the ee of compound B prepared is greater than 99.5% ee. In some embodiments, the ee of compound B prepared is as described in Examples 1 and 2, below.

[0118] In one aspect, the present invention provides a process for preparing a compound of formula II:or solvate thereof, wherein:PG is a suitable nitrogen protecting group; and [Acid] is a suitable inorganic or organic acid, comprising the steps of:(a) contacting a compound of formula III:or a salt or solvate thereof, wherein:PG is a suitable nitrogen protecting group; each R is independently selected from halogen, -OH, or an optionally substituted Ci-e aliphatic or -OCi-e aliphatic; or: two or three R groups are taken together with their intervening atoms to form an optionally substituted monocyclic, bicyclic, or bridged bicyclic ring; and x is 2 or 3. with a compound of formula V :or a salt or solvate thereof, wherein:LG3is a suitable leaving group, under suitable cross-coupling conditions to form a compound of formula Il-a:Il-a or solvate thereof, wherein:PG is a suitable nitrogen protecting group; and(b) contacting the compound of formula II-a with the suitable inorganic or organic acid under suitable conditions to form a compound of formula II, or solvate thereof.

[0119] As defined above and described herein, PG is a suitable nitrogen protecting group. In some embodiments. PG is t-butyloxycarbonyl (Boc). ethyloxycarbonyl, methyloxy carbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (Boc).

[0120] As defined above and described herein, [Acid] is a suitable inorganic or organic acid. In some embodiments, a suitable inorganic acid is hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid. In some embodiments, a suitable organic acid is acetic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, fumaric acid, benzoic acid, methanesulfonic acid, or p-toluenesulfonic acid. In some embodiments, a suitable organic acid is L-malic acid.

[0121] As defined above and described herein, each R is independently selected from halogen, -OH, or an optionally substituted Ci-6 aliphatic or -OCi e aliphatic, or two or three R groups are taken together with their intervening atoms to form an optionally substituted monocyclic, bicyclic, or bridged bicyclic ring.

[0122] In some embodiments, R is halogen. In some embodiments, R is -OH. In some embodiments, R is an optionally substituted Ci-e aliphatic. In other embodiments, two or three R groups are taken together with their intervening atoms to form an optionally substituted monocyclic or bicyclic ring.

[0123] As defined above and described herein, x is 2 or 3. In some embodiments, x is 2. In some embodiments, x is 3.

[0125] As defined above and described herein, LG3is a suitable leaving group. In some embodiments, LG3is halogen or -SO2R1, wherein R1is an optionally substituted group selected from C1-6 aliphatic, -OCi. e aliphatic, and a monocyclic or bicyclic carbocyclic or heterocyclic ring. In some embodiments, LG3is halogen, mesylate, tosylate, or triflate. In some embodiments, LG3is halogen. In some embodiments, LG3is iodine.

[0126] In some embodiments, the suitable cross-coupling conditions comprise a metal-catalyzed crosscoupling reaction. In certain embodiments, cross-coupling comprises palladium catalyzed cross-coupling (e.g., Suzuki cross-coupling). In some embodiments, the suitable cross-coupling conditions comprise contacting a palladium compound, an optional ligand, a base, a compound of formula III, a compound of formula V, and a suitable solvent at a suitable temperature. In some embodiments, the palladium compound comprises(tetrakis(triphenylphosphine) palladium), PdCl2[P(o- Tol)3]2(dichlorobis(tri-o- tolylphosphinc)palladium), Pd(dba)2(bis(dibcnzylidcncacctonc)palladium), Pd2(dbab (tris(dibenzylideneacetone) dipalladium), Pd(dppf)Cl2([1,1'- Bis(diphenylphosphino)ferrocene] dichloropalladium), Pd(dtbpf)Cl2([l,r-Bis(di-tert-butylphosphino)ferrocene]dichloro palladium), Pd- PEPPSI-IPentCl (dichlorofl, 3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium), palladacycle G2 ([2-(2'-amino-l,l'-biphenyl)]palladium chloride), and / or palladacycle G3 ([2-(2'-amino- I,I'-biphenyl)]palladium methanesulfonate). In some embodiments, the palladium compound comprises palladacycle G3.

[0127] In some embodiments, the ligand is XPhos (2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). RuPhos (2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl), diphenylphosphinobinapthyl (BINAP), diphenylphosphinoferrocene (DPPF), l,l’-bis(di-tert-butylphosphino)ferrocene (DTBPF), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos), 2-di(tcrt-butyl)phosphino-2'.4'.6'- triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos), 4,6-bis(diphenylphosphino)phenoxazine (N- XantPhos), (S)-l-[(RP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (Josiphose SL- J009-1), tri(o-tolyl)phosphine, cataCXium (di-adamantylalkylphosphine), Bretphos (2- (dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-l.l'-biphenyl), or any palladium crosscoupling ligand known to those of ordinary skill in the art, not limited to those described in Martin, R.. & Buchwald, S.L. (2008), ‘‘Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands”, Acc. Chem. Res. 41(11): 1461-1473; and Surry, D.S.; Buchwald, S.L. (2008), “Biaryl Phosphane Ligands in Palladium-Catalyzed Amination”, Angew. Chem. Int. Ed. 47(34):6338- 6361. In some embodiments, the ligand is Xantphos.

[0128] In some embodiments, the suitable cross-coupling conditions comprise a base. In some emebodiments, the base is or comprises NaOH, KOH, NaOt-Bu. LBUCO2K. K2CO3, CS2CO3, K3PO4, or any other bases described in the Hartwig and Surrey references above. In some embodiments, the base is K2CO3.

[0129] Tire suitable cross-coupling conditions may comprise any solvent described infra. In some embodiments, the suitable cross-coupling conditions comprise aqueous ether (e.g., water and diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or 2-methyltetrahydrofuran) and an alcohol (e.g.. methanol, ethanol, isopropanol, or n-butanol). In some embodiments, the suitable cross-coupling conditions comprise aqueous 2-methyltetrahydrofuran and methanol.

[0130] In some embodiments, the solvent is 2-methyltetrahydrofuran and methanol at a ratio of about 5: 1, 4: 1, 3: 1, or 2: 1 2-methyltetrahydrofuran:methanol. In some embodiments, the solvent is 2- methyltetrahydrofuran and methanol at a ratio of about 4: 1 2-methyltetrahydrofuran:methanol. In some embodiments, the solvent is aqueous 2-methyltetrahydrofuran and methanol.

[0131] A suitable temperature can be any temperature which a palladium compound, an optional ligand, a base, a compound of formula III, a compound of formula V are soluble, or are at least partially soluble. Examples of suitable temperatures include 0 ± 5 °C, 10 ± 5 °C, 20 ± 5 °C (e.g., room temperature), 30 ± 5 °C, 40 ± 5 °C, 50 ± 5 °C, 60 ± 5 °C, 70 ± 5 °C, 80 ± 5 °C, 90 ± 5 °C, or 100 ± 5 °C. In some embodiments, a suitable temperature is 60 ± 5 °C.

[0132] Cross-coupling techniques, palladium compounds, ligands, and salts, described supra, can be varied as known in the art, for example, by using techniques described in Palladium-Catalyzed Coupling Reactions, A. Molnar, 1stedition, Wiley-VCH, 2013.

[0133] In some embodiments, a compound of formula II~a prepared by the suitable cross-coupling conditions of part (a) above is contacted with the suitable inorganic or organic acid under suitable conditions to form a compound of formula 11, or solvate thereof in part (b).

[0134] In some embodiments, the suitable conditions to form a compound of formula II or solvate thereof comprise combining a mixture of a compound of formula II- a and a suitable solvent with a suitable inorganic or organic acid or a mixture of a suitable inorganic or organic acid and a suitable solvent at a suitable temperature.

[0135] In some embodiments, a suitable inorganic acid is hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid. In some embodiments, a suitable organic acid is acetic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. In some embodiments, a suitable organic acid is L-malic acid.

[0136] Tire suitable conditions to form a compound of formula II or solvate thereof may comprise any solvent described infra. In some embodiments, the suitable conditions to fonn a compound of fonnula II or solvate thereof comprises aqueous acetonitrile.

[0137] A suitable temperature can be any temperature which the free base fonn of a compound of formula H and / or an acid are soluble, or are at least partially soluble. Examples of suitable temperatures include 0 ± 5 °C, 10 ± 5 °C, 20 ± 5 °C (e.g., room temperature), 30 ± 5 °C, 40 ± 5 °C, 50 ± 5 °C, 60 ± 5 °C, 70 ± 5 °C, 80 ± 5 °C, 90 ± 5 °C, or 100 ± 5 °C. In some embodiments, a suitable temperature is 50 ± 5 °C.

[0138] In some embodiments, the suitable conditions to fonn a compound of formula II or solvate thereof further comprise cooling a mixture of a compound of formula ll~a, a suitable inorganic or organic acid, and a suitable solvent.

[0139] In some embodiments, the present invention provides a process for preparing a compound of formula II in greater than 4 kg, greater than 5 kg, greater than 10 kg, greater than 15 kg, greater than 20 kg, greater than 30 kg, greater than 40 kg, greater than 50 kg, greater than 60 kg, greater than 70 kg, greater than 80 kg, greater than 90 kg, or greater than 100 kg. In some embodiments, the amount of a compound of formula II prepared is greater than 5 kg. In some embodiments, the amount of a compound of formula II prepared is greater than 15 kg.

[0140] In some embodiments, the present invention provides a process for preparing a compound of formula II without the use of column chromatography.

[0141] In some embodiments, the present invention provides a process for preparing a compound of fonnula II in greater than 90.0% ee. greater than 95.0% ee, greater than 96.0% ee, greater than 97.0% ee, greater than 98.0% ee, greater than 99.0% ee, greater than 99. 1% ee. greater than 99.2% ee, greater than 99.3% ee. greater than 99.4% ee, greater than 99.5% ee, greater than 99.6% ee. greater than 99.7% ee. or greater than 99.8% ee. In some embodiments, the ee of a compound of formula II prepared is greater than 99.0% ee. In some embodiments, the ee of a compound of formula II prepared is greater than 99.5% ee.

[0142] In some embodiments, the compound of formula II is compound C:or solvate thereof.

[0143] In some embodiments, a process of preparing compound C or solvate thereof is as described in Example 1 or 2, below.

[0144] In some embodiments, the present invention provides a process for preparing compound C in greater than 5 kg, greater than 10 kg, greater than 15 kg, greater than 20 kg, greater than 30 kg, greaterthan 40 kg, greater than 50 kg, greater than 60 kg, greater than 70 kg, greater than 80 kg, greater than 90 kg, or greater than 100 kg. In some embodiments, the amount of compound C prepared is greater than 5 kg. In some embodiments, the amount of compound C prepared is greater than 15 kg. In some embodiments, the amount of compound C prepared is as described in Examples 1 and 2. below.

[0145] In some embodiments, the present invention provides a process for preparing compound C without the use of column chromatography.

[0146] In some embodiments, the present invention provides a process for preparing compound C in greater than 90.0% ee, greater than 95.0% ee. greater than 96.0% ee, greater than 97.0% ee, greater than 98.0% ee, greater than 99.0% ee, greater than 99.1% ee. greater than 99.2% ee, greater than 99.3% ee, greater than 99.4% ee. greater than 99.5% ee, greater than 99.6% ee, greater than 99.7% ee, or greater than 99.8% ee. In some embodiments, the ee of compound C prepared is greater than 99.0% ee. In some embodiments, the ee of compound C prepared is greater than 99.5% ee. In some embodiments, the ee of compound C prepared is as described in Examples 1 and 2, below.

[0147] In one aspect, the present invention provides a process for preparing a compound of formula formula III:or a salt or solvate thereof, wherein:PG is a suitable nitrogen protecting group; each R is independently selected from halogen, -OH, or an optionally substituted Ci-e aliphatic or -OC|.„ aliphatic; or: two or three R groups are taken together with their intervening atoms to form an optionally substituted monocyclic, bicyclic, or bridged bicyclic ring; and x is 2 or 3, comprising the step of: borylating a compound of formula IV:or a salt or solvate thereof, wherein:PG is a suitable nitrogen protecting group; andLG3is a suitable leaving group, under suitable borylation conditions to form a compound of formula III, or solvate thereof.

[0148] As defined above and described herein, PG is a suitable nitrogen protecting group. In some embodiments, PG is t-butyloxycarbonyl (Boc), ethyloxy carbonyl, methyloxy carbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (Boc).

[0149] As defined above and described herein, each R is independently selected from halogen, -OH, or an optionally substituted C1-6 aliphatic or -OC’i e aliphatic, or two or three R groups are taken together with their intervening atoms to form an optionally substituted monocyclic, bicyclic, or bridged bicyclic ring.

[0150] In some embodiments, R is halogen. In some embodiments, R is -OH. In some embodiments, R is an optionally substituted Ci-e aliphatic. In other embodiments, two or three R groups are taken together with their intervening atoms to form an optionally substituted monocyclic or bicyclic ring.

[0151] As defined above and described herein, x is 2 or 3. In some embodiments, x is 2. In some embodiments, x is 3.

[0153] As defined above and described herein, LG2is a suitable leaving group. In some embodiments, LG2is halogen or -SO2R1, wherein R1is an optionally substituted group selected from C1-6 aliphatic, -OCi. e aliphatic, and a monocyclic or bicyclic carbocyclic or heterocyclic ring. In some embodiments, LG2is halogen. In some embodiments, LG2is chloro.

[0154] In some embodiments, the suitable borylation conditions comprise cross-coupling conditions. In some embodiments, the suitable borylation conditions comprise a metal -catalyzed cross-coupling reaction. In certain embodiments, suitable borylation conditions comprise palladium catalyzed cross-coupling (e.g., Suzuki cross coupling). In some embodiments, suitable borylation conditions comprise contacting a palladium compound, an optional ligand, a borylation reagent, a base, a compound of formula IV, and a suitable solvent at a suitable temperature. In some embodiments, the palladium compound comprises Pd(OAc)2(palladium acetate), Pd(PPh3)4(tetrakis(triphenylphosphine) palladium), PdCl2[P(o- Tol)3]2(dichlorobis(tri-o- tolylphosphinc)palladium), Pd(dba)2(bis(dibcnzylidcncacctonc)palladium), Pd2(dba)3(tris(dibenzylideneacetone) dipalladium), Pd(dppf)Cl2([1,1 - Bis(diphenylphosphino)ferrocene] dichloropalladium), Pd(dtbpf)Cl2([l,r-Bis(di-tert-butylphosphino)ferrocene]dichloro palladium), Pd- PEPPSI-IPentCl (dichlorofl, 3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium), palladacycle G2 ([2-(2'-amino-I,r-biphenyl)]palladium chloride), and / or palladacycle G3 ([2-(2'-amino-Ll'-biphenyl)]palladium methanesulfonate). In some embodiments, the palladium compound comprises palladacycle G3.

[0155] In some embodiments, the ligand is XPhos (2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), RuPhos (2- Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl), diphenylphosphinobinapthyl (BINAP), diphenylphosphinoferrocene (DPPF), l,l’-bis(di-tert-butylphosphino)ferrocene (DTBPF), 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos), 2-di(tcrt-butyl)phosphino-2'.4'.6'- triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos), 4,6-bis(diphenylphosphino)phenoxazine (N- XantPhos), (S)-l-[(RP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (Josiphose SL- J009-1), tri(o-tolyl)phosphine, cataCXium (di-adamantylalkylphosphine), Brettphos (2- (dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-l.l'-biphenyl), or any palladium crosscoupling ligand known to those of ordinary skill in the art, not limited to those described in Martin, R._ & Buchwald, S.L. (2008), ‘‘Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands”, Acc. Chem. Res. 41(11): 1461-1473; and Surry, D.S.; Buchwald, S.L. (2008), “Biaryl Phosphane Ligands in Palladium-Catalyzed Amination”, Angew. Chem. Int. Ed. 47(34):6338- 6361. In some embodiments, the ligand is XPhos.

[0156] In some embodiments, suitable borylation conditions comprise a suitable borylation reagent. In some embodiments, the suitable borylation reagent is a source of boron that can be used to convert, for example, an aryl halide to an arylboronate compound (e g., breaking a carbon-halide bond and forming a carbon-boron bond). In some embodiments, the borylation reagent is tetrahydroxydiboron, trimethyl borate, triethyl borate, triisopropyl borate, 4,4,5,5-tetramethyl-l,3,2-dioxaborolane, 2-isopropoxy- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane, bis(pinacolato)diboron, bis(hexylene glycolato)diboron, bis(neopentyl glycolato)diboron. bis(2.4-dimethylpentane-2,4-glycolato)diboron. or bis(catecholato)diborane. In some embodiments, the borylation reagent is tetrahydroxy diboron.

[0157] In some embodiments, the suitable cross-coupling conditions comprise a base. In some embodiments, the base is or comprises NaOH, KOH, NaOt-Bu, t-BuCO2K, K2CO3, CS2CO3, K3PO4, or any other bases described in the Hartwig and Surrey references above. In some embodiments, the base is t- BUCO2K.

[0158] The suitable cross-coupling conditions may comprise any solvent described infra. In some embodiments, the suitable cross-coupling conditions comprise aqueous ether (e.g.. water and diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or 2-methyltetrahydrofiiran) and an alcohol (e g., methanol, ethanol, isopropanol, or n-butanol). In some embodiments, the suitable cross-coupling conditions comprise aqueous 2-mcthyltctrahydrofuran and methanol.

[0159] In some embodiments, the solvent is 2-methyltetrahydrofuran and methanol at a ratio of about 1:3, 1:2, 3:5, 4:5, or 1: 1 2-methyltetrahydrofuran:methanol. In some embodiments, the solvent is 2- methyltetrahydrofuran and methanol at a ratio of about 4:5 2-methyltetrahydrofuran:methanol. In some embodiments, the solvent is aqueous 2-mcthyltctrahydrofuran and methanol.

[0160] A suitable temperature can be any temperature which a palladium compound, an optional ligand, a borylation reagent, a base, and a compound of fonnula IV are soluble, or are at least partially soluble. Examples of suitable temperatures include 0 ± 5°C, 10 ± 5°C, 20 ± 5°C (e.g., room temperature), 30 ± 5°C, 40 ± 5°C, 50 ± 5°C, 60 ± 5°C, 70 ± 5°C, 80 ± 5°C, 90 ± 5°C, or 100 ± 5°C. In some embodiments, a suitable temperature is room temperature.

[0161] In some embodiments, the present invention provides a process for preparing a compound of formula III in greater than 4 kg, greater than 5 kg, greater than 10 kg, greater than 15 kg, greater than 20 kg, greater than 30 kg. greater than 40 kg, greater than 50 kg, greater than 60 kg. greater than 70 kg, greater than 80 kg, greater than 90 kg, or greater than 100 kg. In some embodiments, the amount of a compound of formula III prepared is greater than 5 kg. In some embodiments, the amount of a compound of fonnula III prepared is greater than 15 kg.

[0162] In some embodiments, the present invention provides a process for preparing a compound of formula III without the use of column chromatography.

[0163] In some embodiments, the present invention provides a process for preparing a compound of formula III in greater than 90.0% ee, greater than 95.0% ee, greater than 96.0% ee, greater than 97.0% ee, greater than 98.0% ee, greater than 99.0% ee, greater than 99. 1% ee, greater than 99.2% ee, greater than 99.3% ee, greater than 99.4% ee, greater than 99.5% ee, greater than 99.6% ee, greater than 99.7% ee, or greater than 99.8% ee. In some embodiments, the ee of a compound of fonnula III prepared is greater than 99.0% ee. In some embodiments, the ee of a compound of formula III prepared is greater than 99.5% ee.

[0164] In some embodiments, the compound of formula III is compound D:or a salt or solvate thereof.

[0165] In some embodiments, a process of preparing compound D or a salt or solvate thereof is as described in Example 1 or 2, below.

[0166] In some embodiments, the present invention provides a process for preparing compound D in greater than 5 kg, greater than 10 kg, greater than 15 kg, greater than 20 kg, greater than 30 kg, greater than 40 kg, greater than 50 kg, greater than 60 kg, greater than 70 kg, greater than 80 kg. greater than 90 kg, or greater than 100 kg. In some embodiments, the amount of compound D prepared is greater than 5 kg. In some embodiments, the amount of compound D prepared is greater than 15 kg. In some embodiments, the amount of compound D prepared is as described in Examples 1 and 2, below.

[0167] In some embodiments, the present invention provides a process for preparing compound D without the use of column chromatography.

[0168] In some embodiments, the present invention provides a process for preparing compound D in greater than 90.0% ee, greater than 95.0% ee, greater than 96.0% ee. greater than 97.0% ee. greater than 98.0% ee, greater than 99.0% ee, greater than 99.1% ee, greater than 99.2% ee, greater than 99.3% ee, greater than 99.4% ee, greater than 99.5% ee, greater than 99.6% ee, greater than 99.7% ee, or greater than 99.8% ee. In some embodiments, the ee of compound D prepared is greater than 99.0% ee. In some embodiments, the ee of compound D prepared is greater than 99.5% ee. In some embodiments, the ee of compound D prepared is as described in Examples 1 and 2, below.

[0169] In one aspect, the present invention provides a process for preparing a compound of formula IV:IV or a salt or solvate thereof, wherein:PG is a suitable nitrogen protecting group; andLG2is a suitable leaving group, comprising the step of: contacting a compound of formula VI :or a salt or solvate thereof, wherein:PG is a suitable nitrogen protecting group; andLG1and LG2are independently suitable leaving groups. with compound F :F or a salt or solvate thereof, under suitable cross-coupling conditions to form a compound of formula IV. or a salt or solvate thereof.

[0170] As defined above and described herein, PG is a suitable nitrogen protecting group. In some embodiments, PG is t-butyloxycarbonyl (Boc), ethyloxy carbonyl, methyloxy carbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc). acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (Boc).

[0171] As defined above and described herein, LG1is a suitable leaving group. In some embodiments, LG1is halogen or -SO2R1, wherein R1is an optionally substituted group selected from Ci-e aliphatic, -OCi. e aliphatic, and a monocyclic or bicyclic carbocyclic or heterocyclic ring. In some embodiments, LG1is halogen. In some embodiments. LG1is bromo.

[0172] As defined above and described herein, LG2is a suitable leaving group. In some embodiments, LG2is halogen or -SO2R1. wherein R1is an optionally substituted group selected from C1-6 aliphatic, -OCi. e aliphatic, and a monocyclic or bicyclic carbocyclic or heterocyclic ring. In some embodiments, LG2is halogen. In some embodiments, LG2is chloro.

[0173] In some embodiments, the suitable cross-coupling conditions include a metal-catalyzed crosscoupling reaction. In certain embodiments, cross-coupling comprises palladium catalyzed cross-coupling (e.g., Buchwald-Hartwig cross-coupling). In some embodiments, the suitable cross-coupling conditions comprise contacting a palladium compound, an optional ligand, a base, a compound of formula IV, compound F, and a suitable solvent at a suitable temperature. In some embodiments, the palladiumcompound comprises Pd(OAc)2 (palladium acetate), PdlPPIvL (tetrakis(triphenylphosphine) palladium), PdC12[P(o-Tol)3]2 (dichlorobis(tri-o- tolylphosphine palladium), Pd(dba)2(bis(dibenzylideneacetone)palladium), Pd2(dba)s (tris(dibenzylideneacetone) dipalladium), Pd(dppf)C12 ([1,1'- Bis(diphenylphosphino)ferrocene] dichloropalladium), Pd(dtbpf)C12 ([l,l’-Bis(di-tert- butylphosphino)ferrocene]dichloro palladium), Pd-PEPPSI-IPentCl (dichloro [1, 3 -bis(2,6-di-3- pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium), palladacycle G2 ([2-(2'-amino-l.l'- biphenyl)]palladium chloride), and / or palladacycle G3 ([2-(2'-amino-l,l'-biphenyl)]palladium methanesulfonate). In some embodiments, the palladium compound comprises palladacycle G3.

[0174] In some embodiments, the ligand is XPhos (2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), RuPhos (2- Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl), diphenylphosphinobinapthyl (BINAP), diphenylphosphinoferrocene (DPPF), l,r-bis(di-tert-butylphosphino)ferrocene (DTBPF), 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos), 2-di(tcrt-butyl)phosphino-2'.4'.6'- triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos), 4,6-bis(diphenylphosphino)phenoxazine (N- XantPhos), (S)-l-[(RP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (Josiphose SL- J009-1), tri(o-tolyl)phosphine, cataCXium (di-adamantylalkylphosphine), Brettphos (2- (dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-l.l'-biphenyl), or any palladium crosscoupling ligand known to those of ordinary skill in the art, not limited to those described in Martin, R._ & Buchwald, S.L. (2008), ‘‘Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands”, Acc. Chem. Res. 41(11): 1461-1473; and Surry, D.S.; Buchwald, S.L. (2008), “Biaryl Phosphane Ligands in Palladium-Catalyzed Amination”, Angew. Chem. Int. Ed. 47(34):6338- 6361. In some embodiments, the ligand is Xantphos.

[0175] In some embodiments, the suitable cross-coupling conditions comprise a base. In some embodiments, the base is or comprises NaOH. KOH, NaOt-Bu, t-BuCO2K, K2CO3, CS2CO3. K3PO4. or any other bases described in the Hartwig and Surrey references above. In some embodiments, the base is K3PO4.

[0176] The suitable cross-coupling conditions may comprise any solvent described infra. In some embodiments, the suitable cross-coupling conditions comprise aqueous ether (e.g., water and diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or 2-methyltetrahydrofuran). In some embodiments, the suitable cross-coupling conditions comprise 2-methyltetrahydrofuran. In some embodiments, tire suitable cross-coupling conditions comprise aqueous 2-methyltetrahydrofuran. In some embodiments, the aqueous 2-methyltetrahydrofuran is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5 v% water in 2-methyltetrahydrofuran. In certain embodiments, the aqueous 2-mcthyltctrahydrofuran is 0.9-1.2% v% water in 2-mcthyltctrahydrofuran. In certain embodiments, the aqueous 2-methyltetrahydrofuran is about 1.1 v% water in 2-methyltetrahydrofuran. Insome embodiments, the suitable cross-coupling conditions comprise 1.5 to 2.5 molar equivalents of water to a compound of formula IV. In some embodiments, the suitable cross-coupling conditions comprise about 2 molar equivalents of water to a compound of formula IV.

[0177] A suitable temperature can be any temperature which a palladium compound, an optional ligand, a base, a compound of fonnula VI, and a compound F are soluble, or are at least partially soluble. Examples of suitable temperatures include 0 ± 5 °C, 10 ± 5 °C, 20 ± 5 °C (e.g., room temperature), 30 ± 5 °C, 40 ± 5 °C, 50 ± 5 °C, 60 ± 5 °C, 70 ± 5 °C, 80 ± 5 °C, 90 ± 5 C, or 100 ± 5 °C. In some embodiments, a suitable temperature is 60 ± 5 °C.

[0178] Cross-coupling techniques, palladium compounds, ligands, and salts, described supra, can be varied as known in the art, for example, by using techniques described in Palladium-Catalyzed Coupling Reactions. A. Molnar, 1stedition, Wiley-VCH, 2013.

[0179] In some embodiments, the present invention provides a process for preparing a compound of formula IV in greater than 4 kg, greater than 5 kg, greater than 10 kg, greater than 15 kg, greater than 20 kg, greater than 30 kg, greater than 40 kg, greater than 50 kg, greater than 60 kg, greater than 70 kg, greater than 80 kg, greater than 90 kg, or greater than 100 kg. In some embodiments, the amount of a compound of formula IV prepared is greater than 5 kg. In some embodiments, the amount of a compound of formula IV prepared is greater than 15 kg.

[0180] In some embodiments, the present invention provides a process for preparing a compound of formula IV without the use of column chromatography.

[0181] In some embodiments, the present invention provides a process for preparing a compound of formula IV in greater than 90.0% ee, greater than 95.0% ee, greater than 96.0% ee, greater than 97.0% ee, greater than 98.0% ee, greater than 99.0% ee. greater than 99.1% ee, greater than 99.2% ee, greater than 99.3% ee, greater than 99.4% ee, greater than 99.5% ee, greater than 99.6% ee. greater than 99.7% ee, or greater than 99.8% ee. In some embodiments, the ee of a compound of formula IV prepared is greater than 99.0% ee. In some embodiments, the ee of a compound of formula IV prepared is greater than 99.5% ee.

[0182] In some embodiments, the compound of formula IV is compound E:or a salt or solvate thereof.

[0183] In some embodiments, a process of preparing compound E or a salt or solvate thereof is as described in Example 1 or 2. below.

[0184] In some embodiments, the present invention provides a process for preparing compound E in greater than 5 kg, greater than 10 kg. greater than 15 kg, greater than 20 kg, greater than 30 kg. greater than 40 kg, greater than 50 kg, greater than 60 kg, greater than 70 kg, greater than 80 kg, greater than 90 kg, or greater than 100 kg. In some embodiments, the amount of compound E prepared is greater than 5 kg. In some embodiments, the amount of compound E prepared is greater than 15 kg. In some embodiments, the amount of compound E prepared is as described in Examples 1 and 2, below.

[0185] In some embodiments, the present invention provides a process for preparing compound E without the use of column chromatography.

[0186] In some embodiments, the present invention provides a process for preparing compound E in greater than 90.0% ee, greater than 95.0% ee, greater than 96.0% ee, greater than 97.0% ee, greater than 98.0% ee, greater than 99.0% ee, greater than 99.1% ee, greater tiran 99.2% ee, greater than 99.3% ee, greater than 99.4% ee, greater than 99.5% ee, greater than 99.6% ee, greater than 99.7% ee, or greater than 99.8% ee. In some embodiments, the ee of compound E prepared is greater than 99.0% ee. In some embodiments, the ee of compound E prepared is greater than 99.5% ee. In some embodiments, the ee of compound E prepared is as described in Examples 1 and 2, below.

[0187] In some embodiments, the present invention provides compound F :or a salt or solvate thereof.

[0188] In one aspect, the present invention provides a process for preparing compound F:or a salt or solvate thereof, comprising the steps of:(i) mesylating compound 6:or a salt or solvate thereof under suitable conditions to form compound 7 :or a salt or solvate thereof,(ii) contacting compound 7 or a salt or solvate thereof with dimethylamine to form compound 8:or salt or solvate thereof, and(iii) deprotecting compound 8 or a salt or solvate thereof under suitable conditions to form compound F or a salt or solvate thereof.

[0189] In some embodiments, the suitable mcsylation conditions to form compound 7 or a salt or solvate thereof comprises methane sulfonic anhydride and an organic base, such as an amine base. In some embodiments, the suitable mesylation conditions to form compound 7 or a salt or solvate thereof is as described in Example 3, below.

[0190] In some embodiments, the suitable deprotection conditions to form compound F or a salt or solvate thereof comprises an acid. In some embodiments, the suitable deprotection conditions to form compound F or a salt or solvate thereof is as described in Example 3, below.

[0191] In some embodiments, the present invention provides any one of the following compounds:or a salt or solvate thereof.

[0192] In one aspect, the present invention provides a process for preparing compound 6:6 or a salt or solvate thereof, comprising the step of resolving compound 5:or a salt or solvate thereof under suitable conditions to form compound 6 or a salt or solvate thereof.

[0193] In some embodiments, the suitable conditions to resolve compound 5 comprises chiral chromatography, such as supercritical fluid chromatography (SFC). In some embodiments, the suitable conditions to resolve compound 5 is as described in Example 3, below.

[0194] In some embodiments, the present invention provides compound 5:or a salt or solvate thereof.

[0195] In one aspect, the present invention provides a process for preparing compound 5:or a salt or solvate thereof, comprising the steps of:(i) hydrogenating compound 3:or a salt or solvate thereof under suitable conditions to form compound 4:or a salt or solvate thereof, and(ii) reducing compound 4 or a salt of solvate thereof under suitable conditions to form compound 5 or a salt of solvate thereof.

[0196] In some embodiments, the suitable hydrogenation conditions to form compound 4 or a salt of solvate thereof comprises hydrogen and a palladium compound, such as palladium compound on carbon. In some embodiments, the suitable hydrogenation conditions to form compound 4 or salt of solvate thereof is as described in Example 3, below.

[0197] In some embodiments, the suitable reducing conditions to form compound 5 or a salt of solvate thereof comprises reducing agent, such as an aluminum hydride or borohydride compound. In some embodiments, the suitable reducing conditions to form compound 5 or salt of solvate thereof is as described in Example 3, below.

[0198] In some embodiments, the present invention provides any one of the following compounds:or a salt or solvate thereof.

[0199] In one aspect, the present invention provides a process for preparing compound 3:or a salt or solvate thereof, comprising the step of contacting compound 1 :or a salt or solvate thereof with furan-3-ylboronic acid under suitable cross-coupling conditions to form compound 3 or a salt of solvate thereof.

[0200] In some embodiments, the suitable cross-coupling conditions comprises palladium catalyzed crosscoupling, such as using a palladium compound and ligand. In some embodiments, the suitable crosscoupling conditions to form compound 3 or a salt of solvate thereof is as described in Example 3, below.

[0201] In some embodiments, the present invention provides compound 1:or a salt or solvate thereof.

[0202] In one aspect, the present invention provides a process for preparing compound 8:or a salt or solvate thereof, comprising the step of:(i) hydrogenating compound 9:or a salt or solvate thereof under suitable conditions to fonn compound 8 or a salt or solvate thereof.

[0203] In some embodiments, the suitable hydrogenation conditions to form compound 8 or a salt of solvate thereof comprises hydrogen, a rhodium compound, and chiral ligand. In some embodiments, the suitable hydrogenation conditions to fonn compound 4 or salt of solvate thereof is as described in Example 4, below.

[0204] In some embodiments, the present invention provides any one of the following compounds:or a salt or solvate thereof.5. Uses, Formulation and AdministrationPharmaceutically acceptable compositions

[0205] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit HPK1, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit HPK1, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[0206] The term ‘‘patient.” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0207] The term ‘'pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0208] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

[0209] As used herein, the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of HPK1, or a mutant thereof.

[0210] The subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of compounds of the invention. Metabolites include compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof. If the compound of the invention is a base, the desired pharmacally acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methane sulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or tire like. If the compound of the invention is an acid, the desired pharmacally acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0211] A compound of the invention can be in the form of a "prodrug," which includes compounds with moieties which can be metabolized in vivo. Generally, the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmacal Salts". J. Pharm. Sci. 66: 1-19). The prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g.. with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Prodrugs which are converted to active forms through other mechanisms in vivo are also included. In aspects, the compounds of the invention arc prodrugs of any of tire formulae herein.

[0212] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial. intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0213] For this purpose, any bland fixed oil may be employed including synthetic mono- or di -glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are usefill in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0214] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage fomr including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, usefill diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0215] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0216] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0217] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0218] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmacally acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0219] For ophthalmic use, provided pharmacally acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0220] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmacal formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0221] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such fonnulations may be administered with or without food. In some embodiments, pharmacally acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0222] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. 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.

[0223] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. Tire amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.Uses of Compounds and Pharmaceutically Acceptable Compositions

[0224] The compounds and compositions described herein are generally useful for the inhibition of kinase activity of one or more enzymes. In some embodiments the kinase inhibited by the compounds and methods of the invention is HPK1.

[0225] The presently disclosed compounds find use in inhibiting the activity of the enzyme HPK1. HPK1 is a member of the germinal center kinase subfamily of Ste20-related serine / threonine kinases. HPK1 functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKK1, MLK3 and TAK1, leading to the activation of the MAPK Jnk.

[0226] According to one embodiment, the invention relates to a method of inhibiting HPK1. or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. In certain embodiments, the invention relates to a method of irreversibly inhibiting HPK1, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[0227] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0228] Inhibition of HPK1 (or a mutant thereof) activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0229] According to another embodiment, the invention relates to a method of inhibiting activity of HPK 1 , or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. According to certain embodiments, the invention relates to a method of reversibly or irreversibly inhibiting one or more of HPK1, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by HPK1, or a mutant thereof, in a patient in needthereof, comprising the step of administering to said patient a Compound Iccording to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0230] In certain embodiments, the subject matter disclosed herein is directed to a method for enhancing an immune response in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of the invention or a pharmaceutical composition described herein. In certain aspects of this embodiment, the T cells in tire subject have at least one of enhanced priming, enhanced activation, enhanced migration, enhanced proliferation, enhanced survival, and enhanced cytolytic activity' relative to prior to the administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the T cell activation is characterized by an elevated frequency of y- IFN+ CD8 T cells or enhanced levels of IL-2 or granzyme B production by T cells relative to prior to administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the number of T cells is elevated relative to prior to administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the T cell is an antigen-specific CD8 T cell. In certain aspects of this embodiment, the antigen presenting cells in the subject have enhanced maturation and activation relative prior to tire administration of the compound or pharmacal composition. In certain aspects of this embodiment, the antigen presenting cells are dendritic cells. In certain aspects of this embodiment, the maturation of the antigen presenting cells is characterized by increased frequency of CD83+ dendritic cells. In certain aspects of this embodiment, the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells.

[0231] The presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity. In some embodiments, the presently disclosed compounds reduce, inhibit, or otherwise diminish the HPK1- mediated phosphorylation of SLP76 and / or Gads.

[0232] The presently disclosed compounds may or may not be a specific HPK1 antagonist. 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, the presently disclosed compounds specifically inhibit the serine / threonine kinase activity of HPK1. In some of these embodiments, the IC50 of the HPK1 antagonist for HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less of the IC5oof the HPK1 antagonist for another serine / threonine kinase or other type of kinase (e.g.. tyrosine kinase).

[0233] The presently disclosed compounds can be used in a method for inhibiting HPK1. Such methods comprise contacting HPK1 with an effective amount of a presently disclosed compound. By "contact" is intended bringing the compound within close enough proximity to an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., T cell, B cell, dendritic cell) such that the compound is able to bind to and inhibitthe activity of HPK1. The compound can be contacted with HPK1 in vitro or in vivo via administration of the compound to a subject.

[0234] Any method known in the art to measure the kinase activity of HPK1 may be used to determine if HPK1 has been inhibited, including in vitro kinase assays, immunoblots with antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads, or the measurement of a downstream biological effect of HPK1 kinase activity, such as the recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of the SLP76-Gads- 14-3-3 complex from LAT-containing microclusters, or T or B cell activation.

[0235] Tire presently disclosed compounds can be used to treat a HPK1 -dependent disorder. As used herein, a "HPK1 -dependent disorder" is a pathological condition in which HPK1 activity is necessary for the genesis or maintenance of the pathological condition. In some embodiments, tire HPK1 -dependent disorder is cancer.

[0236] The presently disclosed compounds also find use in enhancing an immune response in a subject in need thereof. Such methods comprise administering an effective amount of a compound of the invention.

[0237] As used herein, "enhancing an immune response" refers to an improvement in any immunogenic response to an antigen. Non-limiting examples of improvements in an immunogenic response to an antigen include enhanced maturation or migration of dendritic cells, enhanced activation of T cells (e.g., CD4 T cells, CD8 T cells), enhanced T cell (e.g., CD4 T cell, CD8 T cell) proliferation, enhanced B cell proliferation, increased survival of T cells and / or B cells, improved antigen presentation by antigen presenting cells (e.g., dendritic cells), improved antigen clearance, increase in production of cytokines by T cells (e.g., interleukin-2), increased resistance to prostaglandin E2-induced immune suppression, and enhanced priming and / or cytolytic activity of CD8 T cells.

[0238] In some embodiments, the CD8 T cells in the subject have enhanced priming, activation, proliferation and / or cytolytic activity relative to prior to the administration of the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the CD8 T cell priming is characterized by elevated CD44 expression and / or enhanced cytolytic activity in CD8 T cells. In some embodiments, the CD8 T cell activation is characterized by an elevated frequency of y-IFN+CD8 T cells. In some embodiments, the CD8 T cell is an antigen-specific T-cell.

[0239] In some embodiments, the antigen presenting cells in the subject have enhanced maturation and activation relative to prior to the administration of the 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 the antigen presenting cells is characterized by an increased frequency of CD83+dendritic cells. In some embodiments, the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells.

[0240] In some embodiments, the serum levels of cytokine IL- 10 and / or chemokine IL-8, a human homolog of murine KC, in the subject are reduced relative to prior to the administration of the compound of Formula I or la or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

[0241] Engagement of the TCR leads to HPK1 activation, which functions as a negative regulator of TCR- induced AP-1 response pathway. It is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, which leads to the recruitment of 14-3-3 proteins that bind to the phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, which leads to T cell dysfunction, including anergy and exhaustion (Lasserre et al. (2011) J Cell Biol 195(5):839-853).

[0242] In some embodiments, administration of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof to a subject results in an enhancement of T cell function.

[0243] Accordingly, the presently disclosed compounds of the invention or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof are useful in treating T cell dysfunctional disorders. A "T cell dysfunctional disorder" is a disorder or condition of T cells characterized by decreased responsiveness to antigenic stimulation. In a particular embodiment, a T cell dysfunctional disorder is a disorder that is specifically associated with increased kinase activity of HPK1. In another embodiment, a T cell dysfunctional disorder is one in which T cells are anergic or have decreased ability to secrete cytokines, proliferate, or execute cytolytic activity. In a specific aspect, the decreased responsiveness results in ineffective control of a pathogen or tumor expressing an immunogen. Examples of T cell dysfunctional disorders characterized by T-cell dysfunction include unresolved acute infection, chronic infection and tumor immunity.

[0244] Thus, the presently disclosed compounds can be used in treating conditions where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for the treatment of cancer.

[0245] The term "dysfunction" in tire context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation. The term includes the common elements of both exhaustion and / or anergy in which antigen recognition may occur, but the ensuing immune response is ineffective to control infection or tumor growth.

[0246] The term "dysfunctional", as used herein, also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., IL-2, y-IFN) and / or target cell killing.

[0247] The temi "anergy" refers to the state of unresponsiveness to antigen stimulation resulting from incomplete or insufficient signals delivered through the T-cell receptor (e.g. increase in intracellular Ca+2in the absence of ras-activation). T cell anergy can also result upon stimulation with antigen in the absence of co-stimulation, resulting in the cell becoming refractory to subsequent activation by the antigen even in the context of costimulation. The unresponsive state can often be overridden by the presence of Interleukin - 2. Anergic T-cells do not undergo clonal expansion and / or acquire effector functions.

[0248] The term "exhaustion" refers to T cell exhaustion as a state of T cell dysfunction that arises from sustained TCR signaling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it arises not through incomplete or deficient signaling, but from sustained signaling. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory’ T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) as well as cell intrinsic negative regulatory (costimulatory) pathways (PD-1, B7-H3, B7-H4, etc.).

[0249] "Immunogenecity" refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response.

[0250] “Enhancing T cell function" means to induce, cause or stimulate a T cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T cells. Examples of enhancing T cell function include: increased secretion of cytokines (e.g., y-interferon, IL-2, IL-12, and TNFa), increased proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance) relative to such levels before the intervention, and increased effector granule production by CD8 T cells, such as granzyme B. In one embodiment, the level of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%, 100%. 120%, 150%. 200%. The manner of measuring this enhancement is known to one of ordinary skill in tire art.

[0251] "Tumor immunity" refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance.

[0252] The present disclosure provides methods of modulating (e.g., inhibiting) HPK1 activity, said method comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments, a solid or salt form of this invention is for use in medicine.

[0254] In one aspect, provided herein is a method for treating of cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound of the invention or a pharmacally acceptable salt, prodrug, metabolite, or derivative thereof.

[0255] In the methods described herein, a compound of the invention or a pharmaceutical composition thereof is administered to a subject that has cancer. In some embodiments, a patient has a relapsed and / or refractory cancer. In some embodiments, a patient has a relapsed and / or refractory tumor. In some embodiments, a patient has a relapsed and / or refractory solid tumor. In some embodiments, a patient has a relapsed and / or refractory liquid tumor. In some embodiments, the patient has received at least one prior therapy. In some embodiments, the patient has received at least two prior therapies. In some embodiments, the patient has received at least three prior therapies. In some embodiments, the patient has received at least four prior therapies. In some embodiments, the patient has received at least five prior therapies. In some embodiments, the patient has received at least six prior therapies.

[0256] In certain embodiments, the subject matter disclosed herein is directed to a method for treating a HPK1 -dependent disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutical composition described herein. In certain aspects of this embodiment, the HPK1 -dependent disorder is a 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, a hematological malignancy , and a renal cell carcinoma. In certain aspects of this embodiment, the cancer has elevated levels of T-cell infiltration. In certain aspects of this embodiment, the cancer cells in the subject selectively have elevated expression of MHC class I antigen expression relative to prior to the administration of the compound or composition.

[0257] In some embodiments, the subject matter disclosed herein is directed to a method for treatment of chronic viral infections. In some embodiments, the subject matter disclosed herein is directed to tire use of an HPK1 inhibitor as an adjuvant treatment for increasing the efficacy of vaccination.

[0258] In some embodiments, the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0259] In certain aspects, the invention provides a method of treating cell proliferation disorders, including cancers, benign papillomatosis, gestational trophoblastic diseases, and benign neoplastic diseases, such as skin papilloma (warts) and genital papilloma.

[0260] In one aspect, the invention provides a method of treating a cell proliferation disorder in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, to the subject.

[0261] In certain embodiments, the cell proliferation disorder is cancer.

[0262] Examples of cancers that arc treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary' CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidennoid cancer, squamous cell cancer. T -cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.

[0263] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer, etc.), liquid tumors such as hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin ly mphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin ly mphoma or multiple myeloma) and combinations of said cancers.

[0264] In some embodiments, the present invention provides a method of treating a lymphoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the present invention provides a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0266] In some embodiments, the present invention provides a method of treating colon cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the present invention provides a method of treating esophageal cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the present invention provides a method of treating endometrial cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, the present invention provides a method of treating cervical cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, the present invention provides a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the present invention provides a method of treating uterine cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the present invention provides a method of treating urothelial cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the present invention provides a method of treating renal cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the present invention provides a method of treating kidney cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the present invention provides a method of treating liver cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the present invention provides a method of treating pancreatic cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the present invention provides a method of treating gastric cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the present invention provides a method of treating breast cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the present invention provides a method of treating lung cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the present invention provides a method of treating skin cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the present invention provides a method of treating cancers of the head and neck in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmacally acceptable salt thereof.

[0282] In some embodiments, tire present invention provides a method of treating thyroid cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, tire present invention provides a method of treating glioblastoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the present invention provides a method of treating sarcoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmacally acceptable salt thereof.

[0285] In some embodiments, the present invention provides a method of treating bladder cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0286] In certain embodiments, the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is selected from tire group consisting of glioma, glioblastoma multiforme, paraganglioma, supratentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, breast, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.

[0287] In certain embodiments, the cancer is selected from brain and spinal cancers, cancers of the head and neck, leukemia and cancers of the blood, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, liver and bile duct cancers, kidney and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, glandular cancers, thyroid cancers, heart tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancers, and cancers of unknown primary (cancers in which a metastasized cancer is found but the original cancer site is notknown). In particular embodiments, the cancer is present in an adult patient: in additional embodiments, the cancer is present in a pediatric patient. In particular embodiments, the cancer is AIDS-related.

[0288] In a further embodiment, the cancer is selected from brain and spinal cancers. In particular embodiments, the cancer is selected from the group consisting of anaplastic astrocytomas, glioblastomas, astrocytomas, and estheosioneuroblastomas (olfactory blastomas). In particular embodiments, the brain cancer is selected from the group consisting of astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary7adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma), oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma), ependymoma (e.g.. myxopapillary ependymoma, and anaplastic ependymoma); medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astorcytoma / malignant glioma, visual pathway7and hypothalamic glioma, and primary? central nervous system lymphoma. In specific instances of these embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and supratentorial primordial neuroectodermal tumors (sPNET).

[0289] In specific embodiments, the cancer is selected from cancers of the head and neck, including nasopharyngeal cancers, nasal cavity and paranasal sinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g., squamous cell carcinomas, lymphomas, and sarcomas), lip cancers, oropharyngeal cancers, salivary gland tumors, cancers of the larynx (e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas), and cancers of the eye or ocular cancers. In particular embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.

[0290] In specific embodiments, the cancer is selected from leukemia and cancers of the blood. In particular embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML. post-MDS AML, del(5q)-associated high risk MDS or AML. blastphase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytomas and multiple myelomas. Leukemias referenced herein may be acute or chronic.

[0291] In specific embodiments, the cancer is selected from skin cancers. In particular embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers.

[0292] In specific embodiments, the cancer is selected from cancers of the reproductive system. In particular embodiments, the cancer is selected from the group consisting of breast cancers, cervical cancers, vaginal cancers, ovarian cancers, prostate cancers, penile cancers, and testicular cancers. In specific instances of these embodiments, the cancer is a breast cancer selected from the group consisting of ductal carcinomas and phyllodes tumors, hr specific instances of these embodiments, the breast cancer may be male breast cancer or female breast cancer. In specific instances of these embodiments, the cancer is a cervical cancer selected from the group consisting of squamous cell carcinomas and adenocarcinomas. In specific instances of these embodiments, the cancer is an ovarian cancer selected from the group consisting of epithelial cancers.

[0293] In specific embodiments, the cancer is selected from cancers of the gastrointestinal system. In particular embodiments, tire cancer is selected from the group consisting of esophageal cancers, gastric cancers (also known as stomach cancers), gastrointestinal carcinoid tumors, pancreatic cancers, gallbladder cancers, colorectal cancers, and anal cancer. In instances of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas, gastrointestinal lymphomas, solid pseudopapillary tumors of the pancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomas including acinar cell carcinomas and ductal adenocarcinomas, gallbladder adenocarcinomas, colorectal adenocarcinomas, and anal squamous cell carcinomas.

[0294] In specific embodiments, the cancer is selected from liver and bile duct cancers. In particular embodiments, the cancer is liver cancer (hepatocellular carcinoma). In particular embodiments, the cancer is bile duct cancer (cholangiocarcinoma); in instances of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

[0295] In specific embodiments, the cancer is selected from kidney and bladder cancers. In particular embodiments, the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers. In particular embodiments, the cancer is a bladder cancer selected from the group consisting of urethelial carcinoma (a transitional cell carcinoma), squamous cell carcinomas, and adenocarcinomas.

[0296] In specific embodiments, the cancer is selected from bone cancers. In particular embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, and chordoma.

[0297] In specific embodiments, the cancer is selected from lung cancers. In particular embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancers, bronchial tumors, and plcuropulmonary blastomas.

[0298] In specific embodiments, the cancer is selected from malignant mesothelioma. In particular embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids.

[0299] In specific embodiments, tire cancer is selected from sarcomas. In particular embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma.

[0300] In specific embodiments, the cancer is selected from lymphomas. In particular embodiments, the cancer is selected from the group consisting of Hodgkin lymphoma (e.g., Reed-Stemberg cells), nonHodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoidcs. Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphomas, and primary central nervous system lymphomas.

[0301] In specific embodiments, the cancer is selected from glandular cancers. In particular embodiments, the cancer is selected from the group consisting of adrenocortical cancer, pheochromocytomas, paragangliomas, pituitary tumors, thymoma, and thymic carcinomas.

[0302] In specific embodiments, the cancer is selected from thyroid cancers. In particular embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas.

[0303] In specific embodiments, the cancer is selected from germ cell tumors. In particular embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors, hr specific instances of these embodiments, the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas.

[0304] In specific embodiments, the cancer is selected from heart tumors. In particular embodiments, the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0305] In specific embodiments, the cell-proliferation disorder is selected from benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases. In particular embodiments, the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma. In particular embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidifonn moles, and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental-site trophoblastic tumors, and epithelioid trophoblastic tumors).

[0306] In some embodiments, the subject has melanoma. The melanoma may be at early stage or at late stage. In some embodiments, the subject has colorectal cancer. The colorectal cancer may be at early stage or at late stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer may be at early stage or at late stage. In some embodiments, the subject has pancreatic cancer. Thepancreatic cancer may be at early stage or late state. In some embodiments, the subject has a hematological malignancy. The hematological malignancy may be at early stage or late stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer may be at early stage or at late stage. In some embodiments, the subj ect has breast cancer. The breast cancer may be at early stage or at late stage . In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma may be at early stage or at late stage. In some embodiments, the cancer has elevated levels of T-cell infiltration.

[0307] In some embodiments, cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, triple-negative breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer and small cell lung cancer). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.

[0308] In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0309] Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL). chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma. Waldenstrom's Macroglubulinemia. hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

[0310] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.

[0311] 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, chondromatous hamartoma, and mesothelioma.

[0312] Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), smallbowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0313] Exemplar}’ genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

[0314] Exemplar}' liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0315] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma. Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma ( osteocartilaginous exostoses ), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors

[0316] Exemplar}’ nervous system cancers include cancers of tire skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

[0317] Exemplar}' gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre -tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

[0318] Exemplar} skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple -negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[0319] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas, adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancers, thyroid and parathyroid cancers.

[0320] In some embodiments, HPK1 inhibitors may be used to treat tumors producing PGE2 (e.g. Cox-2 overexpressing tumors) and / or adenosine (CD73 and CD39 over-expressing tumors). Overexpression ofCox-2 has been detected in a number of tumors, such as colorectal, breast, pancreatic and lung cancers, where it correlates with a poor prognosis. Overexpression of COX-2 has been reported in hematological cancer models such as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia) as well as in patient's blast cells. CD73 is up-regulated in various human carcinomas including those of colon, lung, pancreas and ovary. Importantly, higher expression levels of CD73 are associated with tumor neovascularization, invasiveness, and metastasis and with shorter patient survival time in breast cancer.

[0321] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

[0322] The presently disclosed compounds may be administered in any suitable manner known in the art. In some embodiments, the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intratumorally, or intranasally.

[0323] In some embodiments, the HPK1 antagonist is administered continuously. In other embodiments, the HPK1 antagonist is administered intermittently. Moreover, treatment of a subject with an effective amount of a HPK1 antagonist can include a single treatment or can include a series of treatments.

[0324] It is understood that appropriate doses of the active compound depends upon a number of factors within the knowledge of the ordinarily skilled physician or veterinarian. The dose(s) of the active compound will vary, for example, depending upon the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination.

[0325] It will also be appreciated that the effective dosage of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays.

[0326] In some embodiments, the HPK1 antagonist is administered to the subject at a dose of between about 0.001 pg / kg and about 1000 mg / kg, including but not limited to about 0.001 pg / kg, 0.01 pg / kg, 0.05Mg / kg, 0.1 pg / kg, 0.5 ng / kg, 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 100 pg / kg, 250 pg / kg, 500 pg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 200 mg / kg.

[0327] In the methods described herein, tire method can further comprise administering a chemotherapeutic agent to the subject. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject simultaneously with the compound or the composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject prior to administration of the compound or the composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject after administration of the compound or the composition.

[0328] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0329] The term "administration" or "administering" includes routes of introducing tire compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal.

[0330] Tire term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.

[0331] The phrases "systemic administration," "administered systemically", "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.

[0332] The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with thecancer. To the extent the drug may prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0333] Tire term "subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.Combination Therapies

[0334] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as " §ppropriate for the disease, or condition, being treated.”

[0335] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

[0336] Examples of agents the combinations of this invention may also be combined with include, without limitation: treatments for Alzheimer’s Disease such as Aricept® and Excelon®; treatments for HIV such as ritonavir; treatments for Parkinson’s Disease such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif8), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine. cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil. interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and antiParkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immunodeficiency disorders such as gamma globulin.

[0337] In certain embodiments, combination therapies of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with a monoclonal antibody or an siRNA therapeutic.

[0338] Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage fomr, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0339] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0340] Tire amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably tire amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0341] In one embodiment, the present invention provides a composition comprising a solid or salt form described herein and one or more additional therapeutic agents. The therapeutic agent and solid or salt fonn may be administered together, or may be administered prior to or following administration of a solid or salt fomr. Suitable therapeutic agents are described in further detail below. In certain embodiments, a solid or salt form described herein may be administered up to 5 minutes, 10 minutes. 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a solid or salt fonn described herein may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours. 16 hours, 17 hours, or 18 hours following the therapeutic agent.

[0342] 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 solid or salt form described herein and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NS AIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and tire like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofm (Ridaura®). D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava K ) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti -IL- 1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Haris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®), “anti-IL-67’ agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®1), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA). levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Puhnocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®. cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®. Theolair®. Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), nonnucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nclfinavir (Viraccpt®), ritonavir (Norvir®), saquinavir (Fortovasc® or Invirasc®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress1®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron ®) in combination with lenalidomide (Revlimid ®), or any combination(s) thereof.

[0343] In another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofm (Ridaura®), D- penicillamine (Depen® or Cuprimine®). azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune1®), leflunomide (Arava1®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®) and “anti -IL-6” agents such as tocilizumab (Actemra®).

[0344] In some embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory dmgs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.

[0345] In some embodiments, the present invention provides a method of treating cutaneous lupus erythematosus or systemic lupus erythematosus comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0346] In some embodiments, the present invention provides a method of treating Crohn’s disesase, ulcerative colitis, or inflammatory bowel disease comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrhcals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone(Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0347] In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from Singulair®. beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HF A), levalbuterol (Xopenex®1), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®)) and fonnoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®). Afviar®. Symbicort®. and Dulera®, cromolyn sodium (Intal®). methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®>) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0348] In some embodiments, tire present invention provides a method of treating COPD comprising administering to a patient in need thereof a solid or salt fomi described herein and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®). metaproterenol (Alupent®). pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and fonnoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo- Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®). budesonide (Pulmocort®), flunisolide (Aerobid®). Afviar®. Symbicort®. and Dulera®.

[0349] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0350] In another embodiment, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0351] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a solid or salt form described herein and a Hedgehog (Hh) signaling pathway inhibitor. In some embodiments, tire hematological malignancy is DLBCL (Ramirez et al "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012), published online July 17).

[0352] 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 solid or salt form described herein and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0353] In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).

[0354] 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 solid or salt form described herein 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, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison’s disease, opsoclonusmyoclonus 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’s arteritis, temporal arteritis, warn autoimmune hemolytic anemia, Wegener’s granulomatosis, psoriasis, alopecia universalis, Behcet’s disease, chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferative disease, rejection of transplanted organs or tissues, Acquired Immunodeficiency Syndrome (AIDS, also known as HIV), type 1 diabetes, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plantpollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dennatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, 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, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorder, 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 known as plasma cell myeloma), non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of the bone and joints including, without limitation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter’s disease), Behcet’s disease, Sjogren’s syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, a thromboembolic disorder, (e.g., myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary by-pass, restenosis after aortocoronary7bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, deep venous thrombosis), inflammatory' pelvic disease, urethritis, skin sunbum, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dennatitis, gingivitis, appendicitis, pancreatitis, cholocy stitus, agammaglobulinemia, psoriasis, allergy, Crohn’s disease, irritable bowel syndrome, ulcerative colitis, Sjogren’s disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture’s syndrome, atherosclerosis. Addison’s disease, Parkinson’s disease, Alzheimer’sdisease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto’s thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome. Behcet’s disease, scleradenna, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves’ disease.

[0355] 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 solid or salt form described herein and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a honnone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin- induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.

[0356] In another embodiment, tire present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a solid or salt fonn described herein and a PI3K inhibitor, wherein tire disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidennal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, (including, for example, nonHodgkin’s Lymphoma (NHL) and Hodgkin’s lymphoma (also termed Hodgkin’s or Hodgkin’s disease)), a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary' carcinoma, seminoma, melanoma, or a leukemia, diseases include Cowden syndrome, Lhennitte-Dudos disease and Bannayan- Zonana syndrome, or diseases in which the PI3K / PKB pathway is aberrantly activated, asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection, acute lung injury' (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary , airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation ofairways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy, bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis, pneumoconiosis (an inflammatory , commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis. silicosis, tabacosis and byssinosis. Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidemrolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary^ cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal 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 disease caused by traumatic injury , glutamate neurotoxicity and hypoxia.

[0357] In some embodiments the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a solid or salt fomi described herein and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. 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-ccll lung cancer, non-small-ccll lung cancer, myelodysplastic syndrome, lymphoma, a hematological neoplasm, or solid tumor.

[0358] 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 solid or salt form described herein . Other suitable JH2 domain binding compounds include those described in W02014074660A1, WO2014074661A1. WO2015089143A1. Suitable JH1 domain binding compounds include those described in WO2015131080A 1.

[0359] A compound of the current invention may also be used to advantage in combination with other therapeutic compounds. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting / decreasing a protein or lipid kinase activity and further anti- angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies: compounds which target, decrease 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 Confonna Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD 181461 from Pfizer and leucovorin. The term "aromatase inhibitor" as used herein relates to a compound which inhibits estrogen production, for instance, 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, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™ Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of honnone receptor positive tumors, such as breast tumors.

[0360] The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

[0361] The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). Tire tenn "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0362] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0363] The tenn "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal fonnulation, such as Caelyx™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name Acriblastin ™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed, under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

[0364] The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin 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; discodennolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin R.P™. Vincristine sulfate is marketed under the trade name Farmistin™.

[0365] The term "alkylating agent" as used herein includes, but is not limited to. cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[0366] The term "histone deacetylase inhibitors" or "HD AC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0367] Tire term "antineoplastic antimetabolite" includes, but is not limited to, 5 -fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5 -azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[0368] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e g. under the trademark Eloxatin™.

[0369] The term "compounds targeting / decreasing a protein or lipid kinase activity: or a protein or lipid phosphatase activity: or further anti -angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which 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 targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors: e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family: f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting tire activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N- phcnyl-2-pyrimidinc-aminc derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing orinhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine / threonine kinases, members of the MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC family, and / or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1. Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isochinoline compounds: FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23 / RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl] amino (-benzoic acid adamantyl ester: NSC 680410, adaphostin): 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774. ZD 1839, ZM 105180: trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033. EKB- 569, GW-2016, El l, E2.4, E2.5, E6.2, E6.4, E2. l l, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit tire activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting 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-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting 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, dactolisib, XL-147, XL-765, and idelalisib; and: and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (14h) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib. itraconazole, erismodegib. and IPI-926 (saridegib).

[0370] The term “PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to PI3Ka, PI3Ky, PI3K5, PI3K0, PI3K-C2a, PI3K-C20, PI3K-C2y, Vps34, pl lO-a, pl 10-p,pl lO-y, pl 10-5, p85-a, p85-|3, p55-y, pl50, plOl, and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK- 474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0371] Tire term “BTK inhibitor” as used herein 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.

[0372] The term “SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0373] Tire term “Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT- 199. ABT- 731. ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl- 2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA 14-1 (and analogs thereof; see W02008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see W02004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ, of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.

[0374] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02008039218 and WO2011090760.

[0375] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02003063794, W02005007623, and W02006078846.

[0376] Further examples of P13K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02004019973, W02004089925, W02007016176, US8138347, W02002088112, W02007084786, W02007129161, W02006122806, W02005113554, and W02007044729.

[0377] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02009114512. W02008109943, W02007053452, W02000142246, and W02007070514.

[0378] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and TNP-470.

[0379] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3 -gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP- 18770, and MLN9708.

[0380] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25. such as okadaic acid or a derivative thereof.

[0381] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, a- y- or 8- tocopherol or a- y- or 8-tocotrienol.

[0382] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5 -methyl - 2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.

[0383] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0384] Tire term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. Tire term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons.

[0385] The temr "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a "famesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (Zamestra™). The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telome statin.

[0386] The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[0387] The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (Velcade™) and MLN 341.

[0388] Tire term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB- 2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0389] Tire term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-p-D- arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0390] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative. SU11248 and MLN518.

[0391] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity ofHSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.

[0392] The term "antiproliferative antibodies" as used herein includes, but is not limited to. trastuzumab (Herceptin™), Trastuzumab-DMl, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies fonned from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.

[0393] For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, famesyl transferase inhibitors and / or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Tcniposidc, Mitoxantronc, Idarubicin, Carboplatinum and PKC412. In some embodiments, the present invention provides a method of treatingAML associated with an ITD and / or D835Y mutation, comprising administering a compound of the present invention together with a one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitors are 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 inhibitors are selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0394] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 - alpha-hydroxy ribose (arabinoside) derivative of deoxy cytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. 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-lH-indol-3-yl)- ethyl]- amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl) {2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmacally acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha 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, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4thEdition, Vol. 1, pp. 248-275 (1993).

[0395] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. Tire term “ribonucleotide reductase inhibitors” 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 against ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.

[0396] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4- chloroanilino)-4-(4-pyridylmcthyl)phthalazinc succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (A vastin™).

[0397] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.

[0398] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11 -a-epihydrocotisol, cortexolone, 17a- hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

[0399] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.

[0400] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.

[0401] The compounds of the invention are also usefill as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. A compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance. Accordingly the invention includes a combination of a compound of the invention as hereinbefore described with an antiinflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of tire invention and said drug substance being in the same or different pharmaceutical composition.

[0402] 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 LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-l 1294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering- Plough), Arofylline (Almirall Prodesfarma), PD 189659 / PD168787 (Parke-Davis). AWD-12- 281 (Asta Medica), CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), VM554 / UM565 (Vemalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists: A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmctcrol fcnotcrol, procatcrol, and especially, fomrotcrol and pharmaceutically acceptable salts thereof. Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, inparticular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0403] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0404] Other useful combinations of compounds of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH- 55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]- methyl]tetrahydro-N,N-dimethyl-2H-pyran-4- aminium chloride (TAK-770).

[0405] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications).

[0406] Exemplary Immuno-Oncology agents

[0407] In some embodiments, one or more other therapeutic agent is an immuno-oncology agent. As used herein, the tenn “an immuno-oncology agent" refers to an agent which is effective to enhance, stimulate, and / or up-regulate immune responses in a subject. In some embodiments, the administration of an immuno- oncology agent with a compound of the invention has a synergic effect in treating a cancer.

[0408] An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, an antibody is a monoclonal antibody. In some embodiments, a monoclonal antibody is humanized or human.

[0409] In some embodiments, an immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses.

[0410] Certain of the stimulator}' and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory 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 co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes 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 / Fnl4, TWEAK, BAFFR, ED AR, XEDAR, TACI, APRIL,BCMA, LTpR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDAI, XEDAR, EDA2, TNFR1, Lymphotoxin a / TNF[3, TNFR2, TNFa, LT0R, Lymphotoxin al|32, FAS, FASL, RELT, DR6, TROY, NGFR.

[0411] In some embodiments, an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g. , IL-6, IL- 10, TGF-p, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.

[0412] In some embodiments, a combination of a compound of the invention and an immuno-oncology agent can stimulate T cell responses. In some embodiments, an immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g. , immune checkpoint inhibitors) such as CTLA-4, PD-1, PD- Ll, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or(ii) an agonist ofa protein that stimulates T cell activation such as B7-1, B7-2. CD28, 4-1BB (CD137), 4-1BBL, ICOS. ICOS-L. 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[0413] In some embodiments, an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonists of activating receptors on NK cells. In some embodiments, an immuno-oncology agent is an antagonist of KIR, such as lirilumab.

[0414] In some embodiments, an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0415] In some embodiments, an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically tire frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g.. block inhibitory receptor engagement (e.g , PD-L1 / PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti- CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse / prevent T cell energy or exhaustion) and agents that trigger innate immune activation and / or inflammation at tumor sites.

[0416] In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, an antagonistic CTLA- 4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0417] In some embodiments, an immuno-oncology agent is a PD-1 antagonist. In some embodiments, a PD-1 antagonist is administered by infusion. In some embodiments, an immuno-oncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death- 1 (PD-1)receptor and inhibits PD-1 activity. In some embodiments, a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), LIBTAYO (cemiplimab), TYVYT (sintilimab), TEVIMBRA (tislelizumab), or MEDI- 0680 (AMP -514; WO2012 / 145493). In some embodiments, an immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP-224.

[0418] In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. In some embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (W02007 / 005874), and MSB0010718C (WO2013 / 79174).

[0419] In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. In some embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, a LAG3 antibody is BMS- 986016 (W010 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (W008 / 132601, WO009 / 44273).

[0420] In some embodiments, an immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, a CD137 antibody is urelumab or PF-05082566 (WO 12 / 32433).

[0421] In some embodiments, an immuno-oncology agent is a GITR agonist. In some embodiments, a GITR agonist is an agonistic GITR antibody. In some embodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (W0006 / 105021, W0009 / 009116), or MK-4166 (WO 11 / 028683).

[0422] In some embodiments, an immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis): GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (W009 / 73620, WO009 / 1156652, WO1 1 / 56652, WO12 / 142237).

[0423] In some embodiments, an immuno-oncology agent is an 0X40 agonist. In some embodiments, an 0X40 agonist is an agonistic 0X40 antibody. In some embodiments, an 0X40 antibody is MEDI-6383 or MEDI-6469.

[0424] In some embodiments, an immuno-oncology agent is an OX40L antagonist. In some embodiments, an OX40L antagonist is an antagonistic 0X40 antibody. In some embodiments, an OX40L antagonist is RG-7888 (WO06 / 029879).

[0425] In some embodiments, an immuno-oncology agent is a CD40 agonist. In some embodiments, a CD40 agonist is an agonistic CD40 antibody. In some embodiments, an immuno-oncology agent is a CD40antagonist. In some embodiments, a CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, a CD40 antibody is lucatumumab or dacetuzumab.

[0426] In some embodiments, an immuno-oncology agent is a CD27 agonist. In some embodiments, a CD27 agonist is an agonistic CD27 antibody. In some embodiments, a CD27 antibody is varlilumab.

[0427] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO11 / 109400).

[0428] In some embodiments, an immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab. ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0429] In some embodiments, an immuno-oncology agent is an immunostimulatory agent. For example, antibodies blocking the PD-1 and PD-L1 inhibitory axis can unleash activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing numbers of tumor histologies, including some tumor types that conventionally have not been considered immunotherapy sensitive. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. Tire anti-PD-1 antibody nivolumab (OPDIVO®. Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has shown potential to improve the overall survival in patients with RCC who had experienced disease progression during or after prior anti-angiogenic therapy.

[0430] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics which may be used in the present invention include pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®. LEO Pharma).

[0431] In some embodiments, an immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (PROVENGE®, Dendreon / Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex / Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, an immuno- oncology agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia vims engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pclarcorcp (REOLYSIN®, Oncolytics Biotech), a variant of respiratory’ enteric orphan vims (reovims) which does not replicate in cells that are not RAS-activated, in numerouscancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for tire T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1 (GLV-lh68 / GLV-lhl53, Genelux GmbH), vaccinia viruses engineered to express betagalactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF. in bladder cancer (NCT02365818).

[0432] In some embodiments, an immuno-oncology agent is selected from JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia vims engineered to express cytosine deaminase, which is able to convert the prodrug 5-fluorocytosine to the cytotoxic drug 5- fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5 / 3-E2F-delta24-hTNFa-IRES-hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis vims (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis vims (LCMV), which can be further engineered to express antigens designed to raise an antigen-specific CD8 T cell response.

[0433] In some embodiments, an immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor, or CAR. The T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells.

[0434] CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3- zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes. Upon antigen binding, such CARs link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex.

[0435] For example, in some embodiments the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June et al.), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD 19), fused to an intracellular signaling domainof the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in the T cell, the CAR is able to redirect antigen recognition based on the antigen binding specificity. In the case of CD 19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently in progress employing CAR-T in a wide range of indications.[https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=l].

[0436] In some embodiments, an immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor y (RORyt). RORyt is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Th 17) and CD 8+ (Tcl7) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells. In some embodiments, an activator of RORyt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0437] In some embodiments, an immunostimulatory agent is an agonist or activator of a toll-like receptor (TLR). Suitable activators of TLRs include an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG which is being studied for B-cell, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 which may be used in the present invention include motolimod (VTX-2337. VentiRx Pharmaceuticals) which is being studied for squamous cell cancer of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).

[0438] 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 Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Phanna, 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.

[0439] In some embodiments, an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORyt.

[0440] In some embodiments, an immunostimulatory therapeutic 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 leukemias (NCT02689453). In some embodiments, an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, an IL- 15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL- 15 complexed to the soluble IL- 15 binding protein IL- 15 receptor alpha chain (IL15:sIL-15RA), which 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, a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0441] In some embodiments, an immuno-oncology agent is selected from those descripted in Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages 603-622, the content of which is incorporated herein by refenrece in its entirety. In some embodimetne. an immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, an immuno-oncology agent is a small molecule targeting an immuno- oncoloby target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, an immuno-oncology agent is a small molecule agent selectd from those listed in Table 2 of Jerry L. Adams et al.

[0442] In some embodiments, an immuno-oncology agent is selected from tire small molecule immuno- oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the content of which is incorporated herein by refenrece in its entirety. In some embodiments, an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood.

[0443] In some embodiments, an immune-oncology agent is a T Cell Engager (TCE). In some embodiments, the TCE is a bi-specific antibody, tri-specific antibody, or a BITE small molecule, such as teclistamab or talquetamab. In some embodiments, an immuno-oncology agent is selected from those described in Sandra L. Ross et al., “Bispecific T cell engager (BITE®) antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8): e0183390. In some embodiments, an immuno-oncology agent is a bispecific T cell engager (BITE®) antibody construct. In some embodimens, a bispecific T cell engager (BITE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodimens, a bispecific T cell engager (BITE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodimens, a bispecific T cell engager (BITE®) antibody construct activates T cells. In some embodimens, a bispecific T cell engager (BITE®) antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodimens, a bispecific T cell engager (BITE®) antibody construct activates T cells which result in induced bystander cell lysis. In some embodiments, tire bystander cells are in solid tumors. In some embodiments, the bystander cells being lysed are in proximity to the BITE®-acticvated T cells. In some embodiment, the bystander cells comprises tumor-associated antigen (TAA) negatgive cancer cells. In some embodiment, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, an immuno-oncology agent is an antibody which blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, an immuno-oncology agent is an ex vivo expanded tumor-infiltrating T cell. In someembodiments, an immuno -oncology agent is a bispecific antibody construct or chimeric antigen receptors (CARs) that directly connect T cells with tumor-associated surface antigens (TAAs).Exemplary Immune Checkpoint Inhibitors

[0444] In some embodiments, an immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0445] The term ‘'checkpoint inhibitor” as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient. One of the major mechanisms of anti-tumor immunity subversion is known as “T-cell exhaustion,” which results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.

[0446] 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 others are often referred to as a checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0447] In some embodiments, an immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL- 1, thus overriding the ability of tumors to suppress the host anti-tumor immune response.

[0448] In some embodiments, the checkpoint inhibitor is a biologic therapeutic 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, hi some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, T1M3. 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 interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

[0449] Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant maimer, the inhibitory’ pathways of the immune sy stem. Such inhibitors can include small molecule inhibitors or can include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immunecheckpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, y5, and memory CD8+(a|3) T cells), CD160 (also referred to 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, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, 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-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS- 936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl 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.

[0450] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD- L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti -PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PDLl antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-Ll antibody, TECENTRIQ®, Genentech).

[0451] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab.

[0452] In some embodiments, an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-ccll lymphoma and multiple myeloma; avclumab (BAVENCIO®, Pfizcr / Mcrck KGaA), also known as MSB0010718C), a fully human IgGl anti-PD-Ll antibody, in clinical trials for non-small celllung 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 in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).

[0453] In some embodiments, a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors that may be used in the present invention include TSR- 022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which is being studied in advanced malignancies (NCT02608268).

[0454] In some embodiments, a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells. TIGIT inhibitors that may be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0455] In some embodiments, a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0456] Checkpoint inhibitors that can be used in the present invention include 0X40 agonists. 0X40 agonists that are being studied in clinical trials include PF-04518600 / PF-8600 (Pfizer), an agonistic anti- 0X40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1cancer trials (NCT02528357); MEDI0562 (Medimmune / AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune / AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475).

[0457] Checkpoint inhibitors that can be used in the present invention include CD137 (also called 4-1BB) agonists. CD 137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981): and CTX-471 (Compass Therapeutics), an agonistic anti- CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).

[0458] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918): lymphomas (NCT01460134): and glioma and astrocytoma (NCT02924038).

[0459] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti -GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (N CT 02740270); INCAGN01876 (Incyte / Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune / AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgGl Fc domain, in advanced solid tumors (NCT02583165).

[0460] Checkpoint inhibitors that can be used in the present invention include inducible T-cell costimulator (ICOS, also known as CD278) agonists. ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune). an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).

[0461] Checkpoint inhibitors that can be used in the present invention include killer IgG-likc receptor (KIR) inhibitors. KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2). in lymphoma (NCT02593045).

[0462] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47 / SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgGl, acts by binding human CD47. and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338) and lymphoma (NCT02953509).

[0463] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors that are being 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).

[0464] Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173). Agonists of STING that are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

[0465] Checkpoint inhibitors that can be used in the present invention include CSF 1 R inhibitors. CSF 1 R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF 1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-lR antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254). and solid tumors (NCT02718911); and BLZ945 (4-[2((lR2R)-2-hydroxycyclohexylamino)-benzothiazol-6- yloxyl]-pyridine-2 -carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).

[0466] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0467] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab. ipilimumab, avelumab. durvalumab, atezolizumab, pidilizumab. cemiplimab, sintilimab, or tislelizumab.

[0468] A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[0469] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0470] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0471] Tire amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and tire particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of an inventive compound can be administered.

[0472] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only thattherapeutic agent. In such compositions a dosage of between 0.01-1,000 ug / kg body weight / day of the additional therapeutic agent can be administered.

[0473] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably tire amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0474] Tire compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, 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 risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.EXEMPLIFICATION

[0475] This section will describe the various different working examples that will be used to highlight the features of the invention(s).

[0476] The starting materials and reagents used in the preparation of the compounds in the present disclosure are either available from commercial suppliers such as Sigma-Aldrich (St. Louis, Mo.) or Fisher Scientific (Hampton, N.H.) or are prepared by methods known to those skilled in tire art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1- 17 (John Wiley and Sons, 1991). Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991). and March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition).

[0477] AbbreviationsSM Starting material Wrt With respect toVol. VolumeExample 1. 2 kg Synthesis of ((S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2- yl)amino)-4-(7-fluoroimidazo[l,2-a]pyridin-3-yl)isoindolin-l-one L-malic salt monohydrate(Compound A)Compound D SM2 77% Compound C 88%Compound B 91%

[0478] Stage 1: SMI (3.435 kg, 1.0 equiv.), Compound F (6.481 kg, 1.2 equiv), and potassium phosphate tribasic (4.969 kg, 1.5 equiv) were charged to a 160 L reactor and the system inert by vacuum / nitrogen purge. 2-Methyltetrahydrofuran (44.4 kg, 15 vol) and purified water (0.562 kg, 2 equiv) were added and the system inerted by two 1 bar nitrogen purges. Xantphos Pd G3 bis THF adduct (0.511 kg, 0.03 equiv) was added using a purovaso valve, the system inerted, and the batch wanned to 65 °C. The reaction was aged for 21 h. The reaction was cooled to 24 °C and quenched with 5 wt% NaCl solution (3.02 kg NaCl in 57.5 kg H2O, 17 vol). The aqueous layer was separated and then recharged into the vessel via a 1 microninline filter to remove rag. This operation was repeated one more time to remove additional rag. Using residual vacuum, a mixture of IM phosphoric acid solution (2.696 kg 85% H3PO4 and water 23.2 kg, 6.8 vol) and NaCl (0.345 kg) were charged to the organic layer. The layers were agitated and the layers separated. The acidic aqueous layer was charged back into the vessel followed by ethyl acetate (47.1 kg, 15 vol). A IM potassium carbonate solution (4.310 kg K2CO3 and 30.3 Kg H2O, 9.0 vol) was added over 8 min via dosing pump monitoring for gas evolution. The layers were agitated for 2 min and allowed to separate. The organic layer was washed with purified water (6.9 kg, 2 vol), agitated for 2 min, and the layers separated. The organic layer was dropped into a tared blue drum for assay. The organic layer was charged back into the vessel via a 1 micron inline filter. The contents of the vessel were concentrated from approx. 62 L to 21 L (6 vol) under reduced pressure maintaining internal temperature below 30 °C. Methanol (41 .4 kg, 15 vol) was charged and the contents of the vessel and concentrated from approx. 73 L to 21 L (6 vol) under reduced pressure maintaining internal temperature below 30 °C. Methanol (10.6 kg, 4 vol.) was charged to dilute to volume to 10 vols. The resulting slurry was aged at 20 °C for approx. 2 h. Purified water (13.9 kg, 4 vol) was charged over 34 mins and the slurry aged overnight at 20 °C. The product was filtered and the cake washed with a mixture of methanol (13.6 kg, 5 vol) and water (7.0 kg, 2 vol). The product was dried in a tray dryer at 40 °C under vacuum with a nitrogen purge for at least 23 h. Compound E was isolated as a yellow solid (6.412 kg, 85% yield, 99.8% ee).

[0479] Stage 2: Compound E (6.359 kg. 1.0 equiv) and potassium pivalate (2.939 kg, 1.6 equiv) were charged to a 400 L reactor and inerted by vacuum / nitrogen purge. 2 -Methyltetrahydrofuran (65.6 kg, 12 vol) and methanol (15.7 kg, 3 vol) were charged to the reactor and the system inerted by two 1 bar nitrogen purges. Tetrahydroxydiboron (1.876 kg, 1.6 equiv) and XPhos Pd G3 (0.112 kg, 0.01 equiv) were sequentially charged using an inerted charge cube apparatus and the system inerted with two 1 bar nitrogen purges. The reaction was stirred at 20 °C until borylation is complete (~1 h 40 min) and the resulting mixture was used directly in Stage 3.

[0480] Stage 3: SM2 (4.284 kg, 1 .25 equiv) was charged via the charge cube, followed by a IM solution of potassium carbonate (5.57 kg of K2CO3 in 38.2 kg of H2O, 3 equiv) via the solvent inlet. The system was then inerted. Xantphos Pd G3 bis THF adduct (0.621 kg, 0.043 equiv) was charged via the charge cube and the contents of the vessel heated to 58 °C and aged for ~17 h. Tire reaction was inerted and configured to vent via the process vent. The reaction was warmed to 66 °C internal temperature and aged until complete (~3.5 h) and inertion to remove any possible headspace H2generated from decomposition of B2(OH)4. The reaction was cooled to 25 °C and 2-methyltetrahydrofiiran (23.4 kg, 4 vol) charged. The biphasic system was agitated, left to settle, and the aqueous layer cut. The organic layer was washed with a 10 wt% NaCl solution (2.542 kg NaCl in 23.0 kg H2O, 4 vol) for 2 min and the aqueous layer cut. The organic layer was washed with purified water (27.4 kg, 4 vol) for 2 min and the aqueous layer cut. The organic layer wasdropped out of the vessel into a tared blue drum and recharge via a 1 micron inline filter. A line rinse with 2-methyltetrahydrofiiran (5.5 kg, 1 vol.) was performed. The contents of the vessel were concentrated from ~119 L to 45 L (5.9 vol) under reduced pressure maintaining internal temperature below 50 °C (max temp reached 37.9 °C). Acetonitrile (60.4 kg, 10 vol) was charged and the reaction held overnight at 20 °C. The contents of the vessel concentrated from -110 L to 45 L (5.9 vol) under reduced pressure maintaining internal temperature below 50 °C (max temperature reached 41.8 °C). Acetonitrile (61.0 kg. 10 vol) was charged and the contents of the vessel concentrated from -119 L to 45 L (5.9 vol) under reduced pressure maintaining internal temperature below 50 °C (max temperature reached 44.7 °C). Acetonitrile (12.6 kg, 2.1 vol) was charged to dilute the solution to 8 vol (-61 L). The reaction was warmed to 50 °C internal and a solution of a solution of L-malic acid (1.75 kg, 1 equiv) in purified water (1.22 kg, 0.16 vol) and acetonitrile (1.20 kg, 0.2 vol) was charged over 8 min using a dosing pump. A line rinse was performed with purified water (0.01 kg, 0.001 vol) and acetonitrile (0.39 kg, 0.07 vol). The reaction was cooled to 36 °C over 20 min and the reaction aged at 36 °C for -2 h until the confirmation of a seed bed. The reaction was cooled to 0 °C over 1 h and maintained at 0 °C overnight. The product was filtered and the cake washed with a 0 °C solution of acetonitrile (11.7 kg, 2 vol) mixed with purified water (0.31 kg, 0.04 vol) and then acetonitrile (18.0 kg, 2 vol). The product was dried in a tray dryer at 40 °C under vacuum with a nitrogen purge for -18 h. Compound C was isolated as a pale yellow solid (7.239 kg, 77% yield, 99.8% ee. 328 ppm Pd).

[0481] Stage 4: Compound C (7.13 kg, 1.0 equiv) was charged to a 160 L reactor followed by 2- methyltetrahydrofiiran (91.6 kg, 15 vol) and purified water (35.5 kg, 5 vol.) and the system inerted. A IM solution of potassium phosphate tribasic (5.25 kg K3PO4 in H2O 23.2 kg, 2.5 equiv) solution was added over 10 min and the contents aged at 20 °C for 30 min. The agitator was stopped and the lower aqueous layer cut. A 10 wt% NaCl solution (3.62 kg NaCl in 32.1 kg H2O, 5 vol) was charged, the layers agitated for 2 min and the aqueous layer cut. Water (35.7 kg, 5 vol) was charged, the layers agitated for 2 min and the aqueous layer cut. The organic layer was decanted into a tared blue drum and charged into the extraneous matter checked 400 L vessel via a 1 micron inline filter. The contents of the 400 L vessel were concentrated from -84 L to 30 L (5 vol) under reduced pressure maintaining internal temperature below 40 °C (max temp reached 32.9 °C). 2-Methyltetrahydrofuran (51.1 kg, 10 vol) was charged via the inline filter and the contents of the vessel concentrated from -100 L to 30 L (5 vol) under reduced pressure maintaining internal temperature below 40 °C (max temperature reached 34.0 °C). Ethanol (46.0 kg. 10 vol) was charged via the inline filter and the contents of the vessel concentrated from -84 L to 30 L (5 vol) under reduced pressure maintaining internal temperature below 40 °C (max temperature reached 36.5 °C). Ethanol was charged (160.1 kg, 35 vol) to the vessel via inline filter. The reaction was heated to 40 °C and sodium methoxide 25 wt% in methanol (0.320 kg, 0.15 equiv) was charged using residual vacuum. A line rinsewas performed with ethanol (0.4 kg). The reaction was aged for ~2 h, the jacket set to 20 °C, and the reaction quenched with acetic acid (0.084 kg, 0.14 equiv). A line rinse was performed with ethanol (0.4 kg). The reaction was cooled from 40 °C to 20 °C and aged overnight. The contents of the vessel were concentrated from ~232 L to 35 L (6 vol) under reduced pressure maintaining internal temperature below 35 °C (maximum temperature reached 29.8 °C). The crystallization was aged at 20-24 °C for at least 30 minutes. The product was filtered and the cake washed with twice with ethanol (7.4 kg, 2 vol). The product was dried in a tray dryer at 40 °C under vacuum with a nitrogen purge for at least 8 h. Compound B was isolated as a yellow solid (4.258 kg, 88% yield, 99.7% ee, 75 ppm Pd).

[0482] Stage 5: Compound B (4.19 kg, 1.0 equiv) was charged to the 160 L reactor via the manway followed by ethanol (50.7 kg, 13.5 vol) and purified water (18.9 kg, 4.5 vol) via a 1 micron inline filter. The reaction was warmed to 50-55 °C ±5 °C to fully dissolve the starting material. A solution of L-malic acid (1.22 kg, 1.05 equiv) in water (2.1 L, 0.5 vol) and ethanol (5.7 kg, 1.5 vol) was prepared giving a total weight of 9.02 kg. 50% by weight of the L-malic acid solution prepared above (4.54 kg) was added over 5 min and the solution seeded with Compound A (0.009 kg). After 10 min the seed had held and was allowed to age for a further 10 min. The remaining 50% of the L-malic acid solution was added over 60 min. A line rinse was performed with a mixture of water (0.25 kg) and ethanol (0.59 kg). The crystallization was held for 3 h at 50 °C, then cooled to 20 °C over 4 h and aged at 20 °C overnight. The product was filtered and the wet cake washed with a mixture of ethanol (6.6 kg. 2.0 vol) and water (2. 1 kg. 0.5 vol), followed by ethanol (6.6 kg, 2.0 vol). The product was dried in a tray dryer at 40 °C under vacuum with a nitrogen purge for 15 h. To rehydrate the bulk material, atray of water (0.715 kg) was placed in the sealed oven and the material aged for ~20 h at 20 °C without vacuum or nitrogen flow. Compound A was isolated as a light yellow solid (4.99 kg, 91% yield, 99.8% ee).Route Overview and Summary of 2 kg Synthesis

[0483] The route used for the 2 kg Compound A GMP campaign is shown in the scheme above. The synthesis consisted of five stages:• Stage 1: Buchwald amination coupling between two API SMs Compound F and SMI to afford Compound E.• Stage 2 / 3: A one-pot borylation / Suzuki coupling transforming Compound E into Compound C via Compound D. The Suzuki coupling partner SM2 is the 3rdAPI SM.• Stage 4: Salt break followed sodium methoxide mediated Boc group deprotection to afford API Compound B.• Stage 5: L-malic salt formation to afford the API final fonn Compound A.

[0484] In total, 4.99 kg of Compound A was prepared and after sampling 4.819 kg remained.

[0485] The synthetic route provided in U.S. Patent No. 11,548,890 was used to provide Compound B on multigram scale . For the stage 1 amination, Pd?dba3 and Xantphos were used, but the yield for the procedure was low (32%) and required column chromatography to isolate Compound E. Stage 2 involved the fomiation and isolation of boronic ester followed by Stage 3, a Pd / XPhos-catalysed Suzuki coupling to give free base Compound C. Stage 4 utilized TFA in DCM to remove the Boc group and provide Compound B. Each of stages 2-3 required column chromatography isolation not suitable for batch process scale-up.

[0486] After evaluating the existing chemistry, the following areas were identified for improvement: Stage 1 - Buchwald Amination• Lower catalyst loading and remove dioxane from procedure.• Improve yields and develop scalable process (not chromatographic isolation).• Screen reaction conditions using 24 well plates.Stage 2 / 3 - Borylation & Suzuki Coupling• Lower catalyst loading and remove dioxane from procedure.• Screen both reactions using 24 well plates.• Telescope Steps 2 and 3 into one scalable process.Step 4 - Deprotection / Final form• Remove TFA / DCM from process.• Develop alternative deprotection / isolation conditions based on desired final form.• Determine Pd level in final product and scavenge if necessary, as well as carryover of carbazole from preformed palladium catalysts.

[0487] On completion of the 2 Kg campaign, the following are considered highlights of the newly developed chemistry':• Optimization of palladium catalyzed cross coupling reactions. Removal of dioxane from the synthetic route entirely.• Development of an acid / base aqueous purification for Compound E and subsequent crystallization - avoiding chromatography and improving isolated yield.• Telescoping of Stages 2 / 3 into a one-pot borylation / Suzuki process which makes use of a mild room temperature boronic acid formation.• Development of an L-malic acid salt isolation of Compound C. overcoming the challenging isolation of the free base.• Complete redesign of Stage 4 to a sodium methoxide mediated deprotection which affords direct isolation of Compound B from the reaction medium by precipitation. Designing DCM out of the synthesis and replacement with the ethanol.• Design of an L-malic acid salt formation of Compound A using ethanol / water.• Controlling Pd levels as well as other impurity levels throughout the sequence by crystallization rather than scrubbing or re-working.• Delivering 4.99 kg of Compound A from 3.44 kg of Compound F in 52% yield over 5 steps.Stage 1 - Buchwald Amination

[0488] Stage 1 of the campaign was a Buchwald Hartwig coupling between Compound F and SMI to provide Compound E. The reaction was achieved using Xantphos Pd G3 and in MeTHF with solid K3PO4 as base. A carefully optimized charge of water was required ensure the solubility of enough base to turn over the reaction without causing system stall. An acid / base work up was implemented to purify Compound E away from the reaction stream impurities which allowed crystallization from a methanol / water solvent system.Reaction Development

[0489] Reaction development began with reactions using palladium (10 mol%) and Xantphos as shown in Table 2. To remove dioxane from the synthesis, THF was used at the onset. These reactions we performed using rac-Compound F. Using Xantphos ligand a source of palladium (Entry 1) full consumption of Compound F was observed while heating to 65 °C in a sealed reaction tube using CS2CO3 as base. Near identical results were observed when using the Buchwald generation 3 precatalyst (Entry 2) and an assay standard of rac-Compound E was obtained from these reactions using silica chromatography.

[0490] A brief look at copper coupling conditions using Cui (20 mol%) and DMEDA (40 mol%) with CS2CO3 in either toluene or DMAc were attempted, but full decomposition of SMI was observed and no product was observed. Efforts were focused on palladium from then on.Table 2 - Initial Reactions on Stage 1

[0491] Efforts then moved onto a brief Buchwald pre-catalyst screen using Xantphos, Brettphos, andXPhos Pd G3 at 5 mol% loading (Table 3). Xantphos was found to be a superior ligand vs Brettphos orXPhos at 65 °C (Entries 1-3) or at 40 °C (Entries 5-7). Using Xantphos Pd G3, the reaction conversion decreased overnight with decreasing temperature (Entries 1, 4, and 5).Table 3. Comparison of Xantphos, Brettphos, and XPhos Pd G3 catalysts in Stage 1

[0492] With Xantphos Pd G3 appearing superior to Brett and XPhos, a study of solvents was conducted under similar conditions (Table 4). MeTEIF and MeCN (Entries 2 and 3) had comparable results to THF (Entry 1) with near complete conversion achieved. Toluene and DMAc were inferior as solvent due to poor conversion (Entries 4 and 5). iPrOH and tBuOH also provided a high LCAP of Compound E but with increased consumption of SMI raising questions about background decomposition of SMI (Entries 6 and 7). THF, MeTHF, MeCN, iPrOH and tBuOH reactions were all repeated using biphenyl as an internal standard, which revealed the following rank oder,THF / MeTHF > MeCN, iPrOH, tBuOH in tenns of yield in relation to the IS.Table 4. Solvent Screen using Xantphos Pd G3

[0493] Building upon these results, a further pre-catalyst screen was conducted and the results compiled with those previously obtained (Table 5). From this study, Josiphos SL-J009-1 Pd G3 was found to be comparable to Xantphos Pd G3 in performance (Entries 1 and 2), but more expensive. The other ligands tried were inferior in terms of conversion (Entries 3-8).Table 5. Further Pre-Catalyst Screen for Stage 01

[0494] Taking most promising solvents from Table 4, the stability of SM 1 towards the reaction conditions was investigated (Table 6). A background decomposition reaction was revealed explaining why excess coupling agent could be folly consumed during the reaction screen with certain solvents. Both hydrolysis of the lactam, and homocoupling were observed by LCMS during these reactions. Tire stability of Compound F was also investigated and found to be stable to the reaction conditions.Table 6. Background Decomposition Study of SMI

[0495] To evaluate a large set of conditions, a 36-well plate screen comparing 6 catalysts, 3 solvents, and 2 bases was performed. These reactions were set up on 10 mg scale using biphenyl as an internal standard. The reactions were sealed in vials under nitrogen and heated to 65 °C overnight. The results were visualized in a heat map, with results in green representing the highest ratio of Compound E to biphenyl (FIG. 1).

[0496] The results in FIG. 2 show that NaOtBu is universally a poor base, due to the propensity to deprotect both SMI and Compound E during the reaction. Looking for both high conversion to Compound E and a high recover.’ of SM 1 (suppression of background reactions), both Xantphos and rac-BINAP in either MeCN or MeTHF were seen as the best conditions. While Xantphos in MeTHF boiled dry in this particular screen (possibly explaining the decomposition of SMI in this case), we had seen previously that this was a good system to future explore. iPrOH was not progressed further as a solvent due to the background instability of SMI towards the reaction conditions in this solvent.

[0497] A second screening plate was set up to study the lead hits (Xantphos, rac-BINAP, MeTHF, MeCN) with various bases (FIGs. 3-5). From the second screen, both LiHMDS and Na2COs were found to be universally poor bases, likely due to reagent degradation with the former and poor solubility with the latter. Xantphos Pd G3 in MeTHF with either CS2CO3, K3PO4, and DBU appeared to be the best conditions, while rac-BINAP Pd G3 in MeTHF with CS2CO3 was also promising.

[0498] At the end of the screening phase of the reaction development, the following conclusions were drawn:Catalyst (Xantphos Pd G3 vs rac-BINAP Pd G3)• Xantphos Pd G3 is cheaper to source than rac-BINAP Pd G3 on scale.• Xantphos Pd G3 is a more robust catalyst and works with a wider range of solvents and bases compared to rac-BINAP.Solvent (MeTHF vs MeCN)• MeTHF would provide a phase cut for aqueous work up.• Starting materials and product are more soluble in MeTHF than MeCN.• SMI is more stable in MeCN than MeTHF (under reaction conditions with Xantphos and CS2CO3). Base (CS2CO3 vs K3PO4 vs DBU)• CS2CO3 is an effective base - but has a high molecular weight and could produce off-gassing. As a heterogeneous base there are potential stirring issues to solve.• K3PO4 has a lower molecular weight than CS2CO3 and would not produce off-gassing. As a heterogeneous base there may be potential stirring issues to solve.• DBU is a homogeneous base. Would need to assess fate of DBU in work up stream.Reaction Optimisation

[0499] A sample of rac -Compound E obtained chromatographical ly was partitioned between 50 vol. of iPAc and 50 vol. of either IM HCL 3M AcOH, 1 M citric acid, or IM H3PO4 and the layers stirred overnight at room temperature. While AcOH was too weak to folly extract the product into the aqueous, IM HC1 was found to fully deprotect Compound E by removal of the Boc group. H3PO4 was found to provide a balance of extraction potential and stability of Compound E when compared with Citric acid. An acid extraction using IM H3PO4 and pH swing would be developed as a way of purifying Compound E moving forwards.

[0500] The rac-BINAP (5 mol%) conditions obtained from the catalyst screening using CS2CO3 ( 1.5 equiv.) and MeTHF (20 vol.) were scaled up to 500 mg in order to develop an aqueous work up that would remove the need for column chromatography. The equivalents of SMI were lowered from 1.5 to 1.3, and after 21 h at 65 °C the reaction was complete.

[0501] The following first pass work-up protocol was implemented:• At EOR, add 20 vol. iPAc and 20 vol H2O (wrt Compound F) - cut away aqueous to remove Cs salts.• Extract organic with IM H3PO4(20 vol.) and cut layers. Wash aqueous with iPAc (10 vol.) - Compound E partitions into aqueous leaving SMI, BINAP and carbazole related impurities in organic layer.• pH swing aqueous with IM NaHCOs (to pH 8) and extract resulting cloudy solid using iPAc (40 vol.).• Wash iPAc layer with water to remove trace inorganics.• Evaporate organics to dryness and dissolve oil in MTBE / n-heptane and concentrate to dryness until a solid fonns.

[0502] Using this procedure an 88% yield of Compound E was obtained (100 wt% by QNMR)

[0503] The stability of Compound E during the acid extraction was studied by partition into IM H3PO4 (1.5 equiv.) and monitoring the LCAP over time. Compound E was found to be stable over a period of 4 h at RT (100 to 99 LCAP at 210 nm), which decreased to 89 LCAP over 4 days due to acid-mediated deBoc occurring.

[0504] Several key hits uncovered from the catalysis screening were scaled up to 500 mg in order to better quantify the results (Table 7). During this scale up, the loading of SMI was reduced from 1.5 equiv. to 1.2 equiv. without impacting the reaction progress. The standard reaction set up involved weighing out all solids into a reaction vessel, inerting the headspace, and then charging N2-degassed solvents.Table 7. 0.5 g Scale Reactions to Quantify Catalysis Screening Hits

[0505] Using both CS2CO3 and K3PO4 the reaction proceeded to completion overnight and gave assay yields of -96% product, while DBU stalled out with 11% Compound F remaining (Entries 1-3). SMI was also -fully consumed using CS2CO3 and K3PO4 possibly due to the reduction in charge from 1.5 to 1.2 equiv. alongside the background decomposition reaction. Due to their near identical performance, K3PO4 was progressed as the lead base while CS2CO3 was put in reserve.

[0506] The impact of overhead stirring was next studied using a 50 mL Easy Max reactor. Enantiopure (ReCompound F was subjected to reaction conditions using K3PO4 as base, but conversion only reached 55 LCAP at 210 nm overnight at 65 °C (Table 8).Table 8. 750 mg Scale Amination using (R)-Compound F with Overhead Stirring

[0507] A KF analysis of the reaction slurry revealed the water content to be 0.05 wt%. Knowing that heterogeneous inorganic bases can be sensitive to overhead stirring, water (2 equiv.) was charged in order to facilitate the dissolution of K3PO4. After 4 h at 65 °C following the water charge, the reaction was judged to be complete by HPLC and given an aqueous work up. The following work up and rational was used:• At the EOR, quench with 5 wt% brine (10 vol.) and cut away the aqueous (pEI 11) to remove inorganics. Brine was found to provide a clear, quick settling phase cut and prevent the formation of rag precipitates.• Compound E was extracted into the aqueous layer using IM H3PO4 (1.5 equiv.) leaving <2 mg / mL in the organics. Compound E was found to have adequate stability in 1.5 equiv. H3PO4 at RT over 4 h.• The acidic aqueous layer was partitioned with EtOAc (20 vol.) and a pH swing to neutral (pH 7-8) performed using 0.7 M NaHCOs solution (3 equiv.). Having an organic layer present during the pH swing prevents the formation of an oily emulsion as Compound E is forced out of solution. <1 mg / mL Compound E in aqueous after pH swing.• (R)-Compound C free base was isolated as an orange solid after evaporation in 81% yield and 100 wt% by QNMR.

[0508] The water content tolerance of the amination was next studied using both K3PO4 and CS2CO3 on 100 mg scale with magnetic stirring using biphenyl as an internal standard (Table 9). With either base, the reaction conversion drops with increasing water content, with 2 equivalents of water appearing optimal. CS2CO3 appeared to have a greater tolerance for water content. K3PO4 was still deemed optimal on balance due to the lighter mass and ease of stirring.Table 9. Amination Water Spiking Experiments

[0509] After concluding water was crucial for reaction conversion, the amination was scaled up to 5 g with overhead stirring, while the volumes of MeTHF were decreased from 20 to 15 (Table 10).Table 10. 5 g Scale Amination using (R)-Compound F with Overhead Stirring

[0510] With the addition of water at the start of reaction (KF 0.37 wt% H2O) the reaction proceeded to 97% over 20 h at 65 °C as judged by LCAP. Following acid / base aqueous work up to purify the reactionstream, crude Compound E was solvent swapped into iPrOH (all volumes with respect to Compound F) and crystallized from iPrOH / H2O. (R)-Compound E was isolated in 87% yield (100 wt% by HPLC and QNMR) as a light yellow dense solid.

[0511] Having worked out a tentative isolation strategy using (R)-Compound E, attention was turned to the desired S-isomer Compound E (Table 11). The amination reaction proceeded typically, reaching full conversion after heating overnight at 65 °C. After quenching with brine and cutting the aqueous, an assay of the resulting organic showed a 100 % yield of Compound E and 0 % yield of Compound F. The reaction stream was purified using tire acid / base extraction protocol and then solvent swapped into iPrOH for an iPrOH / H2O crystallization.Table 11. 5 g Scale Amination using Compound F with Overhead Stirring

[0512] Unlike (R)-Compound E which fomred a dense solid from iPrOH / H2O (Compound E Form 1), the S-isomer of Compound E formed extremely fine hair-like needles which stuck fast the solution and prevented agitation (Compound E Form 2). Heat cycling and Ostwald ripening did not improve the crystal properties, which was likely to cause issues with when transferring to plant scale. XRD analysis of (R)- and (S)-Compound E solids isolated from iPrOH / H2O, showed that they were different forms, with the denser (R)-Compound E form 1 appearing “more cry stalline”. DSC analysis collaborated this, with the R isomer having a sharp melt at 142, while the S isomer had a lower melt at 125 °C.

[0513] Gratifyingly it was found that slurrying Compound E Form 2 in methanol ( 10 vol.) overnight transformed the crystals into Compound E Form 1, providing us with seed fortlie desired S-isomer. Seeding an iPrOH crystallization of Compound E with the newly acquired Form 1 did proliferate Fomi 1 but rather Form 2. However switching the crystallization solvent system to MeOH / H2O afforded the dense and crystalline Form 1 reliably onwards. Compound E had a slight instability in methanol whereby Boc deprotection could occur (1-3% decomposition overnight at 40 °C). Thus any solvent swap operations would be performed at low temperature <30 °C.

[0514] With the new crystallization in hand, the amination reaction was scaled up to 10 g with overhead stirring and the loading of Xantphos Pd G3 lowered to 3 mol% (Table 12). Following aqueous acid / base work up, Compound E was isolated in 88% yield from MeOH / H2O as a dense yellow solid.Table 12. 10 g Scale Amination using Compound F with Overhead Stirring

[0515] Since Compound F-2HC1 was another potential starting material, is was prudent to determine the feasibility of using the HC1 salt directly in Stage 1. After preliminary small scale experiments using magnetic stirring were successful, a 20 g scale reaction was conducted (Table 13). The reaction was perfonned in a 500 mL Radleys vessel with overhead stirring and since Compound F-2HC1 would be freebased in situ, the charge of K3PO4 was increased to 3 equiv.Table 13. 20 g Scale Amination using Compound F-2HC1 with Overhead Stirring

[0516] At first, 6 equiv. of water was required before Compound E-2HC1 would begin to dissolve. This charge of water caused significant gumming of K3PO4 on the walls of the vessel, and conversion reached only 24% after a 20 h stir at 65 °C. The water charge was increased sequentially until 21 equiv. was added, at which point the gummy residue became fully mobile in solution. The reaction progressed to 96% within 5 h of reaching 21 equiv. water. Due to the prolonged aging time of the reaction, the assay and isolated yield were justifiably lower. Nonetheless, the use of Compound F-2HC1 was validated by this experiment, and it could serve as reaction input with further optimization.

[0517] As the Stage 1 process started to take shape, stability experiments were conducted in order to determine hold points for the large scale production. An amination reaction was conducted using biphenyl as an internal standard and aliquots of reaction mixture subjected to stress tests in order to gage the stability of Compound E.• Reaction - A sample of end of reaction mixture was further aged at 65 °C - 94% assay remaining after 6 h, 85% after 24 h. While no new peaks were visible on HPLC, the assay suggested instability of Compound E towards prolonged reactions conditions. Extended aging would likely result in diminished yields.• Brine quench - Quench with 5 wt% brine to cut aqueous. Samples of organic phase stirred at RT and 40 °C - 100% assay remaining after 24 h in all cases. Organic after brine cut appears stable and is a hold point.• Acid extract - Extract Compound E from organic to aqueous using IM H3PO4. Samples of acidic aqueous phase aged at 2 °C. RT, and 40 °C - at RT 100% assay remaining after 6 h, 95% after 24 h with some deBoc product forming. At 40 °C, 81% assay after 6 h and 72% after 24 h, with deBoc product forming. Sample stable when kept at 2 °C for 24 h (100% assay remaining). The acid extract is not a hold point, but if phases do not cut within a working day the layers would be cooled for separation overnight.• pEI swing - Partition aqueous acid extract with EtOAc (10 vol.) and pH swing with IM K2CO3 (2 equiv). Aqueous pH 8. Samples of organic phase stirred at RT and 40 °C - 100% assay remaining after 24 h in all cases. Organic after pH swing appears stable and is a hold point.

[0518] A series of stress tests were conducted for Stage 1 as shown in Table 14. There was no evidence for product inhibition when spiking a reaction with 1.0 equiv of Compound E (Entry 1). The stirring rate was found to be critical, with a reaction taking 96 h to reach completion with 10% of the regular stirring speed (Entry 2). A 79% assay yield was obtained in this case, likely due to tire prolonged reaction time. Finally, inertion was found to be crucial for reaction performance, with an un-inerted reaction stalling out overnight and creating numerous impurities not observed under typical conditions (Entry 3). This un-inerted reaction could not be re-started after inerting by N2 sparge and addition of fresh catalyst.Table 14. Stage 1 Stress Tests

[0519] The effect of stirring rate was re-evaluated on 20 g scale using bulk K3PO4 whereby a reaction was intentionally set up with a rate slow enough to allow the base to pile up under the stirrer blades rather than distribute throughout the solution. The reaction took 44 h to reach 93% conversion, rather than the typical overnight time scale, but provided a respectable 84% isolated yield.

[0520] A reaction conducted using 0.75 equiv. K3PO4 reached 54% conversion (254 nm) after 23 h at 65 °C. After adding another 0.75 equiv. K3PO4, the reaction proceeded to >99.9% conversion (254 nm) after 36 h. This suggested a stalled, but inerted reaction could be restarted with additional base.

[0521] Modeling of K3PO4 in MeTHF suggested no issues with stirring power on scaling up to the plant.Stage 1 Conclusion

[0522] Stage 1 was successfully implanted using a palladium catalysed Buchwald Hartwig cross coupling which was optimized. An acid / base work up allowed for extensive purification of the reaction stream and removed the need for column chromatography. A robust McOH / FTO crystallization was developed which did not require seed.Stage 2 / 3: Borylation / Suzuki reaction

[0523] Stage 2 of the campaign was a mild room temperature borylation reaction of Compound E with 62(014)4 catalysed by XPhos Pd G3 to afford Compound D. The addition of methanol as cosolvent in MeTHF was found to be essential for this borylation to occur.

[0524] Stage 3 of the 2 Kg campaign was telescoped directly onto Stage 2, with the Suzuki coupling of Compound D and SM2 to afford Compound C free base catalyzed by Xantphos Pd G3. The isolation of Compound C free base in adequate yield and purity proved difficult, encouraging the development of a salt isolation which resulted in the isolation of Compound C in 77% yield across Stage 2 / 3.Reaction Screening with B2Pin2

[0525] The goal for Stage 2 / 3 was to develop a one-pot borylation-Suzuki procedure and the direct isolation of Compound C free base so telescoping Stages 2 and 3 together was attempted via rac-Compound D Bpin ester.

[0526] First we wished to remove dioxane from the reaction. Gratifyingly, the bory lation reaction was found to proceed faster in MeTHF and at a lower temperature (Table 15). The BPin ester could be isolated via precipitation from the crude mass via n-heptane. Partial hydrolysis of the BPin ester was found to occur, with Compound D being a major impurity in the resulting solid.Table 15. Removal of Dioxane from Borylation reaction with BiPini.

[0527] With dioxane removed from the procedure, we began to look at telescoping the BPin ester formation and Suzuki together. Following formation of BPin ester, degassed MeTHF and water were added to give 20 vol. of 4: 1 MeTHF / water and the remaining Suzuki reagents charged (catalyst, base, SM2). Using XPhos Pd G2, the Suzuki reaction was found to stall out at approx. 40-50% yield Compound C free base using various bases (Entries 1-4). The one-pot borylation Suzuki reaction could not be improved by using either CataXcium Pd G2 or Xantphos Pd G3 (Entries 5-7).Table 16. Attempted Telescoping of Stages 2 and 3 via BPin ester.

[0528] Tire use of B2Pin2in Stage 2 / 3 was superseded by B2(OH)4during the reaction development phase. Minor improvements were made to the B2Pin2borylation where the catalyst loading was lowered to 1 mol% XPhos Pd G3 and the KO Ac swapped for the KOPiv. The use of B2Pin2would briefly be returned to during the process optimisation phase of Stage 2 / 3.Reaction Screening via B2(OH)4

[0529] Inspired by recent catalytic borylations using B2(OH)4and KOPiv (Munteanu, C., J. Org. Chem., 2020, 85, 10334-10349), several screening reactions were conducted on 50 mg scale to implement this chemistry (Table 17). Reactions were set up under a nitrogen inerted atmosphere in sealed sample vials with magnetic stirring and degassed solvents. Without the addition of methanol the reaction was found to not proceed at room temperature over the course of an hour, likely due to the insoluble nature of B2(OH)4 in MeTHF. However after warming to 70 °C overnight, 38 LCAP of des-chloro rac-Compound E (IMP1)had formed (Entry 1). With methanol present (14 vol. MeTHF, 6 vol. MeOH), the reaction was found to fully convert to rac-Compound D overnight at room temperature (Entry 2). If warmed to 70 °C overnight, rac-Compound D was found to undergo dcborylation completely to IMP1 (Entry 3). As a test, SM2 (2 equiv.) and IM K2CO3 (3 equiv.) were added to Entry 2 at EOR and the mixture heated to reflux overnight. Gratifyingly, rac-Compound C free base was detected by HPLC and LCMS as the major reaction product, giving confidence that we could telescope Stages 2 and 3 into one process.

[0530] The catalyst loading was lowered from 10 to 5 mol% and the borylation reaction was scaled up to 200 mg (Table 17, Entry 4) in order to isolate rac-Compound D for use as an assay standard. An attempt to isolate rac-Compound D using the acid / base extraction method developed for Stage 1 was unsuccessful. rac-Compound D extracted poorly into the aqueous layer and provided a 36% isolated yield of rac- Compound D in low chemical purity due to the generation of multiple impurities during work up. The reaction was then repeated on 200 mg scale using 2.5 mol% catalyst (Entry 5). The reaction was quenched with 5 wt% brine (20 vol.), the organic layer passed through an inline filter, and rac-Compound D isolated via precipitation from iPrOH / n -heptane in 8% yield, allowing a working assay standard for the boronic acid intermediate. Using this assay standard, the yield of the borylation reaction was quantified as -100%.Table 17. Test Borylations using B2(OH)4.

[0531] Using an internal standard, the equivalents of B2(OH)4and KOPiv were varied (Table 18). All reactions were found to proceed to >99 LCAP with 4 h, though the conversion was slightly higher when using 2 equivalents of both reagents. Thus 2 equivalents of base and borylating agent were taken forwards. Of note, the reactions were essentially stable overnight at RT, albeit with a marginal increase in IMP 1. The use of lower equivalents of B2(OH)4(1.2 equiv.) was less effective.Table 18. B2(OH)4and KOPiv Equivalent Screen.

[0532] The results from Table 16 were telescoped into Stage 3 by the addition of 5 mol% XPhos Pd G3,IM K2CO3 (3 equiv.) and varying levels of SM2 (Table 16). Based on LCAP data, between 1.2 and 1.3 equiv of SM2 was deemed optimal for conversion vs 1. 1 and 1.4 equiv. A sample of rac-Compound C free base was isolated via silica chromatography to act as a working assay standard.Table 19. SM2 Equivalent Screen in One-pot Borylation Suzuki Reaction

[0533] The solvent composition and volumes for the borylation reaction was further studied (Table 20).The catalyst loading was lowered to 1 mol% and the volume of the reaction reduced from 20 to 15 (4: 1 MeTHF:MeOH) (Entry 1). Enantiopure Compound D was isolated via aqueous work up with 10 wt% brine (5 vol ), washing the organic layer with water (5 vol.), concentrating the organic layer, and slurrying the resulting gum in n-heptane until solid. The reaction was scaled up to 2 g, whereby the reaction was found to reach completion within 1 h, and Compound D isolated in 98 % yield using this method (Entry 2). The reaction did not proceed at all in either pure methanol or pure ethanol (Entries 3 and 4). showing the need for a MeTHF / MeOH solvent system.Table 20. Lowering Catalyst Loading and Varying Solvent Composition in Borylation Reaction.

[0534] A series of further optimization reactions were performed for the synthesis of Compound D. Performing the borylation reaction using Xantphos Pd G3 rather than XPhos Pd G3 was entirely unsuccessful. Other catalysts were not considered during this campaign. Other solvent mixtures were considered, but found to be less successful than MeTHF (12 vol.) with MeOH (3 vol.); the borylation does not proceed in pure MeTHF, or with McTHF / HjO (4: 1) (protodeborylation takes place). MeTHF / EtOH, or MeTHF / iPrOH do not convert. Lower quantities of MeOH (up to 7: 1 ratio) were tolerated with magnetic stirring, but result in the formation precipitates likely due to the decreased solubilizing power of MeOH.

[0535] The Compound D isolated in Table 18 Entry 2 was used to study the Suzuki reaction on approx. 10 mg scale using a 24 well plate (FIG. 5). With the aim of telescoping the Suzuki reaction onto the back of the borylation, the solvent system was maintained as MeTHF / MeOH. 6-8 pre-catalysts were screened against 3 aqueous inorganic bases using biphenyl as internal standard to assess the yield.

[0536] In all cases. Compound D was completely consumed overnight likely due to the 10 mol% catalyst loading implemented in the screen. An immediate trend observed from the collected data is that Compound C free base has a propensity to undergo deprotection to the Compound B over the course of the reaction. This appeared to correlate with the strength of the base used, with KOH in some cases providing complete deprotection to Compound B, while K2CO3 provided the greatest retention of Compound C free base. From the data collected. Xantphos Pd G3 using K2CO3 appeared to provide the greatest yield of Compound C free base and the cleanest reaction profile.

[0537] The reaction of Xantphos Pd G3 using 2M K2CO3 (highest yield of Compound C free base) and KOH (highest conversion to Compound B) were scaled up to 150 mg and the conversion vs time plotted using an internal standard (FIG. 6). The K2CO3 reaction was found to reach completion after approx. 9 h while the level of Compound B steadily builds during the overnight age. The reaction using KOH was noticeably slower, and did not fully deprotect to Compound B like had been seen in the catalysis screening. K2CO3 was seen as the superior base and progressed forwards.

[0538] Having demonstrated the borylation and Suzuki reactions separately, we began to focus on combining them into a one-pot procedure. At the same time we investigated the effect of methanol on the one-pot borylation Suzuki side by side (Table 21). The borylation reactions were conducted at room temperature, whereby solids were weighed out and inerted into a reaction vessel, and the reaction initiated by the addition of degassed solvents.

[0539] For Entry 1, on complete borylation by HPLC, Xantphos (5 mol%), SM2 (1.25 equiv). and 2M K2CO3 were charged to the vessel and the reaction re-inerted. The Suzuki reaction reached 98% completion overnight at 70 °C and provided a 76% internal standard yield of Compound C free base. By HPLC, the remaining mass balanced appeared to be predominantly Compound B via Boc deprotection. By comparison, Entry 2 was solvent swapped into MeTHF post-borylation prior to the Suzuki reaction. In the absence of methanol, the Suzuki reaction is slower, but cleaner, taking over a weekend to reach 88% conversion. Of note, there were only trace formation of Compound B by HPLC. Methanol appears to serve a dual purpose in the Suzuki reaction, both aiding in the miscibility of the organic and aqueous layers and increasing the rate of reaction, but also promoting deprotection of the labile Boc group.Table 21. Comparison of One-pot Borylation Suzuki Reaction with and without Methanol.

[0540] Scaling up tire one-pot borylation Suzuki reaction 10 mg to -150 mg using 2M K2CO3 it was observed that inorganics (K2CO3) would precipitate out of solution on addition to the MeTHF / MeOH reaction solution, likely due to partition of water into the organic layer. Replacing 2M and IM K2CO3 prevented this precipitation and provided an 88% assay yield of the Compound C free base (Table 22). The conditions shown in Table 22 were used as the foundations for the process development of Stage 2 / 3.Table 22. Using IM in the One-pot Borylation Suzuki Reaction.Reaction Optimisation

[0541] With a working set of conditions for a one-pot borylation Suzuki reaction, we began to optimize the process and attempt to design an isolation for Compound C free base. The reaction was scaled up to 2 g with overhead stirring and performed in parallel with both racemic and enantiopure Compound E in order to collect solubility data on each isomer (Table 23). On larger scale it was noticed the maximum temperature the Suzuki reaction could reach was 66 °C internal temperature.Table 23. 2 g Scale Stage 2 / 3 Reaction and Isolation from iPrOH / n-heptane

[0542] Both reactions proceeded to > 97% completion overnight at 66 °C and contained approx. 90% yield Compound C free base with 5% deprotection to Compound B (Table 24, Entry 1 and 2). The reactions were quenched with 10 wt% brine (5 vol. with respect to Compound E), washed with water (5 vol.) and solvent swapped into iPrOH (4 vol.) by concentration. Tire resulting solid was dissolved at 60 °C and n- heptane (4 vol.) added. On slow cool down to 20 °C overnight, a solid precipitate had fonned (24 mg / mL racemic. 34 mg / mL S-isomer). Further n-heptane (8 vol.) was added to decrease tire liquor loss, and the solids isolated. Even at a 3: 1 ratio of n-heptane to iPrOH, the liquor losses were still high (8.6 mg / mL racemic, 11.6 mg / mL S-isomer), and the phenomenon that the racemate was less soluble than the enantiopure compound became apparent.

[0543] During the optimization of the one-pot reaction, it was discovered that the B2Pin2 variant which had previously struggled with conversion could become viable if the methanol was charged for the Suzuki reaction. This provided two potential routes to access Compound C free base. The B2(OH)4and B2Pin2 variants were directly compared side by side (Table 24).Table 24. One-pot Borylation Suzuki Reactions Comparing B2(OH)4and B2Pin2.

[0544] Both borylation reactions were found to proceed in 1 h, however B2P1112 required refluxing conditions while B2(OH)4proceeded in 1 h (Entry 1 vs Entry 2). At ambient temperatures B2Pin2 had trace conversion. For the Suzuki phase of the reaction, the solvent composition of the B2Pin2 reaction was adjusted to 15 vol. 4: 1 MeTHF / MeOH (Entry 2). Following this, both reactions produced near identical reaction rates, assay yields, and impurity profiles. As shown in FIG. 7, Compound D BPin ester is hydrolyzed to Compound D in situ and there is typically 2% remaining at the end of reaction.

[0545] Based on their near-identical outcomes, B2(OH)4was taken forward as a result of its operational simplicity, milder reaction conditions, and simpler reaction profile.

[0546] As shown in FIG. 7, the level of Compound B appears to grow as a consequence of exposure to the reaction conditions over a prolonged period. A series of experiments were conducted where the equivalents of K2CO3 were lowered in an effort to decrease the deprotection of Compound C free base (Table 25). Decreasing the equivalents of base from 3 to 2 equiv. did not have an impact on the reaction, nor decrease the level of Compound B present (Entries 1-2). The reaction could not tolerate 1 equivalent of K2CO3 however, with the reaction stalling out at 45 LCAP conversion.Table 25. Varying Base Equivalents in Suzuki Reaction.

[0547] A series of further stress tests were conducted for Stages 2 and 3. In the borylation reaction (Table 26, Entry 1), inertion was found to be critical for successful conversion from Compound E to Compound D. The Suzuki reaction was found to be less sensitive to inertion. A borylation reaction conducted under typical conditions was charged with the appropriate reagents for Stage 3 and then uninerted by exposure to air. The reaction reached full completion overnight with a typical reaction profile. The water sensitivity of the borylation reaction was probed by spiking with either 1 or 2 equivalents of water (Table 26, Entry 2- 3). Water was found to slow down the borylation reaction but would still reach 94-95% conversion overnight.Table 26. Stress Tests Performed on Stage 2

[0548] A Suzuki reaction spiked with 30 mol% Compound B suggested there was no significant reaction inhibition from the Compound B generated.

[0549] Next, telescoping Stages 2 / 3 into Stage 4 was considered. If Compound B could be isolated in sufficiently purity, the campaign would benefit from reduced processing time by avoiding the isolation ofCompound C free base. A borylation Suzuki reaction was conducted on 4 g scale under the usual conditions(Table 27)Table 27. Telescope Process for Stages 2 / 3 and 4 and Direct Isolation of Compound B

[0550] At the end of work up, the crude reaction stream was solvent swapped into methanol (5 vol.) and then subjected to the deprotection conditions that were developed in parallel. Tire addition of NaOMc (0.9 equiv.) over 2 h at 45 °C caused Compound C free base to deBoc to Compound B and precipitate out of solution. The reaction was cooled to RT over 1 h and aged overnight. Compound B was isolated by fdtration at 10 mg / mL (~5 % losses) and although the yield was high (80% over 3 stages) the purity was low (95 wt% by QNMR and 94 LCAP at 254 nm). The impurities carried through were both the deBoc-des compound of Compound E (from carried through IMP1 generated in Stage 2 / 3), entrenched Compound C free base (caused by rapid precipitation) as well as other minor impurities. These impurities did not reject sufficiently in Stage 5, nor could Compound B isolated from the telescoped procedure be sufficiently purified by hot slurrying (EtOH or MeOH) to remove all problematic impurities prior Stage 5. As such this material would not achieve the desired target specifications for purity for delivery of Compound A.

[0551] Stage 2 / 3 was further scaled up to 10 g with overhead stirring Table 28. In a 100 mL EasyMax vessel at reflux, the reaction was found to reduce in volume by half overnight, during which the ratio of solvent changed from 4: 1 MeTHF / MeOH to 9: 1. After aqueous work up, the level of deprotection to Compound B was found to be higher than had been observed previously at 9.5% assay yield. Compound C free base was again isolated via aqueous work up and crystallization from iPrOH / n-heptane with high liquor losses and volumes. Compound C free base was isolated in a 70% corrected yield (92 LCAP at 254 nm) and 92% wt% by QNMR due to the entrenchment of process impurities along side Compound B (1.7 LCAP).Table 28. 10 g Scale Stage 2 / 3 Reaction and Isolation from iPrOH / n-heptane

[0552] With high liquor losses and low purity, the isolation of Compound C free base required improvement. The solubility of isolated Compound C free base in various solvent compositions was determined by HPLC assay (FIG. 8). From the data presented in FIG. 8, it was clear that water had a solubilizing effect on Compound C free base (up to 25% water) before a sharp drop off in solubility, while n-heptane and a more linear gradient but with poorer anti-solvent ability.

[0553] Attempted crystallizations of isolated Compound C free base were unsuccessful in solvent / water mixtures (iPrOH, EtOH, MeCN) due to their sharp solubility curves and propensity to form gums on addition of water, while solvent combinations with n-heptane (iPrOH, EtOH) suffered from high volumes and liquor losses.

[0554] This was further demonstrated on crude Compound C free base which had been obtained from aqueous work up at the end of Stage 3 and evaporation. Crude Compound C free base was slurried in 5 volumes of solvent overnight and the liquor loss and relevant impurities tracked, the results of which are shown in Table 29. A desired crystallization system would provide a low liquor loss of Compound C free base, while retaining as much Compound B as possible and rejecting undesired impurities. In all cases, the liquor loss was too high in the neat solvent, and anti-solvent addition (water or n-heptane) either diluted liquors or crystallized impurities.Table 29. Crystallisation Study of Crude Compound C Free Base using Water or n-Heptane as Antisolvent

[0555] The reaction was scaled up to 15 g in order to prepare more material to study the crystallization (Table 30). The reaction was performed in a 500 mL Radleys vessel with overhead stirring and set up underthe usual protocol (charge all Stage 2 solids to vessel, then charge Na-sparged solvents). In this particular experiment the level of IMP1 obtained in the borylation was unusually high (4 LCAP as opposed to <1 LCAP). This translated into an 8% assay yield after the Suzuki and work up. Tire crude reaction stream after work up was concentrated and used to study various crystallization systems.Table 30. 15 g scale Stage 2 / 3 reaction

[0556] Using the material produced in Table 30, a series of crystallization reactions were conducted on approx. 1-2 g scale (Table 31). Both iPAc / n-heptane and toluene / n-heptane solvent systems allowed for a high recovery of Compound C free base, albeit in low purity and with poor rejection of impurities (Entries 1-4). Specifically crystallization from such non-polar medium entrenched homocoupled SM2, a minor impurity in the Suzuki reaction, which did not reject sufficiently when progressed forward to Compound A. Slower anti-solvent addition crystallizations were attempted with iPrOH and EtOH using water, but the propensity for gumming could not be overcome in these cases (Entries 5-6).Table 31. Further Crystallization Study on Crude Compound C Free Base

[0557] It was hoped that improving the purity of the reaction stream would aid in the isolation of Compound C free base, and that meant decreasing the level of Compound B and IMP1 generated in the reaction. Lowering the temperature of the borylation reaction did not appreciably reduce the level of IMP1 formed (<1 LCAP), but did increase the reaction time to > 4 h.

[0558] It was shown in FIG. 7 that Compound C free base is decomposed to Compound B during the overnight age due to contact with aqueous base under the reaction conditions. Increasing the catalyst loading from 5 to 10 mol% Xantphos did not increase the rate of reaction and thus did not allow the reaction to reach completion within a working day, necessitating the need for the overnight age.

[0559] Tire assay yields of several >1 g scale reactions arc collated into Table 32 and were set up under otherw ise identical conditions. The variables include scale, vessel size, method of inertion, and reaction time. The level of Compound B appeared to be variable, being as low as 3.8% (Entry 1) and as high as 11.6% (Entry 7). This was not unique to the boronic acid route, and was similar when using the boronic ester 10 (Entry 8). Running the Suzuki reaction with a more dilute organic layer did not decrease the level of deprotection, nor did lowering the base equivalents (Entries 6 and 11). Entries 1-11 were all conducted at re...

Claims

CLAIMS1. A process lor preparing a compound of formula I:or solvate thereof, wherein:[Acid] is a suitable inorganic or organic acid, comprising the step of: contacting compound B:or solvate thereof, with the suitable inorganic or organic acid under suitable conditions to form a compound of formula I. or solvate thereof.

2. A process for preparing compound B as defined in claim 1, the process comprising the steps of: neutralizing and deprotecting a compound of formula II:or solvate thereof, wherein:PG is a suitable nitrogen protecting group; and [Acid] is a suitable inorganic or organic acid, under suitable neutralization and deprotection conditions to form a compound of formula B, or solvate thereof.

3. A process for preparing compound II as defined in claim 2, the process comprising the steps of:(a) contacting a compound of formula III:or a salt or solvate thereof, wherein:PG is a suitable nitrogen protecting group; each R is independently selected from halogen, -OH, or an optionally substituted Ci-e aliphatic or -OCi e aliphatic; or: two or three R groups are taken together with their intervening atoms to fonn an optionally substituted monocyclic, bicyclic, or bridged bicyclic ring; and x is 2 or 3, with compound of formula V :V or a salt or solvate thereof, wherein:LG3is a suitable leaving group, under suitable cross-coupling conditions to form a compound of formula II- a:or solvate thereof, wherein:PG is a suitable nitrogen protecting group; and(b) contacting the compound of formula II-a with the suitable inorganic or organic acid under suitable conditions to form a compound of formula II . or solvate thereof.

4. A process for preparing compound III as defined in claim 3, the process comprising the step of: borylating a compound of formula IV :IV or a salt or solvate thereof, wherein:PG is a suitable nitrogen protecting group;LG2is a suitable leaving group,under suitable borylation conditions to form a compound of formula III. or solvate thereof.

5. A process for preparing compound IV as defined in claim 4, the process comprising the step of: contacting a compound of formula VI:or a salt or solvate thereof, wherein:PG is a suitable nitrogen protecting group;LG1and LG2are independently suitable leaving groups, with compound F :or a salt or solvate thereof, under suitable cross-coupling conditions to form a compound of foimula IV, or a salt or solvate thereof.

6. The process of any one of claims 1-5, wherein [Acid] is hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, acetic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, fumaric acid, benzoic acid, methane sulfonic acid, or p- toluenesulfonic acid.

7. The process of any one of claims 1-6, wherein [Acid] is L-malic acid.

8. Tire process of any one of claims 2-7, wherein PG is t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl.

9. The process of any one of claims 2-8, wherein PG is t-butyloxycarbonyl (Boc).

10. The process of any one of claims 3-9, wherein LG3is halogen, mesylate, tosylate, or triflate.

11. Tire process of any one of claims 3-10, wherein LG3is iodine.

13. The process of any one of claims 3-12, wherein -BRXis -B(OH)3.

14. The process of any one of claims 4-13, wherein LG1is halogen, mesylate, tosylate, or triflate.

15. The process of any one of claims 4-14, wherein LG1is bromo.

16. Tire process of any one of claims 4-15, wherein LG2is halogen, mesylate, tosylate, or triflate.

17. The process of any one of claims 4-16, wherein LG2is chloro.

18. A process for preparing compound F as defined in claim 5, the process comprising the steps of:(i) mesylating compound 6:or a salt or solvate thereof under suitable conditions to fonn compound 7 :or a salt or solvate thereof,(ii) contacting compound 7 or a salt or solvate thereof with dimethylamine to form compound 8:or salt or solvate thereof, and(iii) deprotecting compound 8 or a salt or solvate thereof under suitable conditions to form compound F or a salt or solvate thereof.

19. A process for preparing compound 6 as defined in claim 18, the process comprising the step of resolving compound 5:5 or a salt or solvate thereof under suitable conditions to fonn compound 6 or a salt or solvate thereof.

20. A process for preparing compound 5 as defined in claim 19, the process comprising the steps of: (i) hydrogenating compound 3:or a salt or solvate thereof under suitable conditions to form compound 4:4 or a salt or solvate thereof, and(ii) reducing compound 4 or a salt of solvate thereof under suitable conditions to form compound 5 or a salt of solvate thereof.

21. A process for preparing compound 3 as defined in claim 20, the process comprising the step of contacting compound 1 :1 or a salt or solvate thereof with furan-3-ylboronic acid under suitable cross-coupling conditions to form compound 3 or a salt of solvate thereof.

22. The process of any one of claims 1-21, wherein the compound of formula I is compound A:

23. Tire process of any one of claims 2-22, wherein the compound of formula II is compound C:or solvate thereof.

24. The process of any one of claims 3-23, wherein the compound of formula III is compound D:or a salt or solvate thereof.

25. The process of any one of claims 4-24, wherein the compound of formula IV is compound E:or a salt or solvate thereof.

26. A method of inhibiting HPK1, or a mutant thereof, in a patient comprising administering to the patient a therapeutically effective amount of compound A:wherein compound A is prepared by the process of any one of claims 1-25.

27. A compound of any one of the following:(a) Formula II:or solvate thereof, wherein:PG is a suitable nitrogen protecting group; and [Acid] is a suitable inorganic or organic acid, (b) Formula III:or a salt or solvate thereof, wherein:PG is a suitable nitrogen protecting group; each R is independently selected from halogen, -OH, or an optionally substituted Ci-e aliphatic or -OCi e aliphatic; or: two or three R groups are taken together with their intervening atoms to form an optionally substituted monocyclic, bicyclic, or bridged bicyclic ring; and x is 2 or 3,(c) Formula IV:or a salt or solvate thereof, wherein:PG is a suitable nitrogen protecting group;LG3is a suitable leaving group, or(d)or a salt or solvate thereof.

28. Tire compound of claim 27, wherein the compound of formula II is compound C:or solvate thereof.

29. The compound of claim 27, wherein the compound of formula III is compound D:or a salt or solvate thereof.

30. Tire compound of claim 27, wherein the compound of formula IV is compound E:or a salt or solvate thereof.

31. The compound of claim 27 , wherein the compound is any one of the following:or a salt or solvate thereof.

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