WO2021263203A1 - Cxcr4 inhibitors and uses thereof - Google Patents

Cxcr4 inhibitors and uses thereof Download PDF

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Publication number
WO2021263203A1
WO2021263203A1 PCT/US2021/039245 US2021039245W WO2021263203A1 WO 2021263203 A1 WO2021263203 A1 WO 2021263203A1 US 2021039245 W US2021039245 W US 2021039245W WO 2021263203 A1 WO2021263203 A1 WO 2021263203A1
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compound
cancer
ring
independently selected
carcinoma
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PCT/US2021/039245
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French (fr)
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Elyse Marie Josee Bourque
Renato Skerlj
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X4 Pharmaceuticals, Inc.
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Publication of WO2021263203A1 publication Critical patent/WO2021263203A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • CX-C chemokine receptor type 4 also known as fusin or cluster of differentiation 184 (CD184)
  • CD184 fusin or cluster of differentiation 184
  • GPCR G-protein coupled receptor
  • CXCR4 carries out multiple roles and is principally expressed in the hematopoietic and immune systems.
  • CXCR4 was initially discovered as one of the co-receptors involved in human immunodeficiency virus (HIV) cell entry.
  • CXCL12 previously designated SDF-1 ⁇ , is the only known ligand for CXCR4.
  • CXCR4 mediates migration of stem cells during embryonic development as well as in response to injury and inflammation.
  • Multiple roles have been demonstrated for CXCR4 in human diseases such as cellular proliferative disorders, Alzheimer’s disease, HIV, rheumatoid arthritis, pulmonary fibrosis, and others.
  • expression of CXCR4 and CXCL12 have been noted in several tumor types.
  • CXCL12 is expressed by cancer-associated fibroblast (CAFs) and is often present at high levels in the tumor microenvironment (TME).
  • CAFs cancer-associated fibroblast
  • TEE tumor microenvironment
  • CXCR4/CXCL12 has been associated with a poor prognosis and with an increased risk of metastasis to lymph nodes, lung, liver, and brain, which are sites of CXCL12 expression.
  • CXCR4 is frequently expressed on melanoma cells, particularly the CD133+ population that is considered to represent melanoma stem cells; in vitro experiments and murine models have demonstrated that CXCL12 is chemotactic for such cells.
  • the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.
  • CXC receptor type 4 CXC receptor type 4
  • diseases, disorders, and conditions include cellular proliferative disorders (e.g., cancer) such as those described herein.
  • DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention: [0008] Compounds of the present invention and pharmaceutically acceptable salts thereof are useful as inhibitors of CXCR4.
  • the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R 1 is independently R, halogen, -CN, -OR, -N(
  • 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.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • 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.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 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.
  • the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • 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).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. 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.
  • Exemplary bicyclic rings include: Exemplary bridged bicyclics include: [0013] The term “lower alkyl” refers to a C 1-4 straight or branched alkyl group.
  • lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • 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.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, e.g. 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.
  • 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.
  • halogen means F, Cl, Br, or I.
  • 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.
  • aryl may be used interchangeably with the term “aryl ring.”
  • 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.
  • aryl 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 the like.
  • heteroaryl and heteroheteroar- used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, e.g.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • 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 the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin– 3(4H)–one.
  • heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle 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, e.g. one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
  • 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.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • 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 every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable 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.
  • Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –
  • R is C1–6 aliphatic
  • R is optionally substituted with halogen
  • R , -(hal each R ⁇ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 hete toms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ⁇ is u stituted or where preceded by halo is substituted only with one or more halogens.
  • each R ⁇ is independently hydrogen, C 1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, 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; wherein when R ⁇ is C 1–6 aliphatic, R ⁇ is optionally substituted with halogen, –R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , – O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ ,
  • 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, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, 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, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • 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, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • 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, loweralkyl sulfonate and aryl sulfonate.
  • 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, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-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.
  • a warhead moiety, R 1 of a provided compound comprises one or more deuterium atoms.
  • an inhibitor is defined as a compound that binds to and /or inhibits CXCR4 with measurable affinity.
  • an inhibitor has an IC50 and/or binding constant of less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change in CXCR4 activity between a sample comprising a compound of the present invention, or composition thereof, and CXCR4, and an equivalent sample comprising CXCR4, in the absence of said compound, or composition thereof.
  • the present invention provides a compound of Formula I: I or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R 1 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L 1 -R 6 ; each -R is independently hydrogen or an optionally substituted group selected from
  • Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is an 8- 10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0040] In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0041] In some embodiments, Ring A is selected from:
  • Ring A is selected from those depicted in Table 1, below.
  • each R 1 is independently R, halogen, -CN, -OR, -N(R) 2 , - NO 2 , -N 3 , -SR, or -L 1 -R 6 .
  • R 1 is R.
  • R 1 is halogen.
  • R 1 is -CN.
  • R 1 is -OR.
  • R 1 is -N(R)2.
  • R 1 is -NO2.
  • R 1 is -N3.
  • R 1 is -SR.
  • R 1 is -L 1 -R 6 .
  • R 1 is hydrogen.
  • R 1 is an optionally substituted C1-6 aliphatic group.
  • R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R 1 is an optionally substituted phenyl.
  • R 1 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring.
  • R 1 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 1 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 1 is selected from hydrogen, halogen, C 1-6 alkyl (optionally substituted with 1, 2, or 3 halogens), -CN, -N(R)2, -OR, -SR, -S(O)R 6 , -SO2R 6 , -SO2NHR 6 ,
  • ch -R is independently hydrogen, - CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3; or each -R is independently hydrogen or methyl; or -R is hydrogen.
  • R 1 is selected from hydrogen, halogen, C 1-6 alkyl, -CN, -
  • each -R is independently hydrogen, -CH 2 -phenyl, phenyl, C 1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3; or each -R is independently hydrogen or methyl; or -R is hydrogen.
  • R 1 is hydrogen, halogen, C 1-6 alkyl, -CN, -OR, -SR, or -N(R) 2 .
  • R 1 is selected from those depicted in Table 1, below.
  • each L 1 is independently a covalent bond or a C1-6 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)- , -(R)NC(S)-, -(R)NC(S)
  • L 1 is a covalent bond. In some embodiments, L 1 is a C1-6, C2- 6, C 3-6 , C 4-6 , C 1-5 , C 2-5 , C 3-5 , C 1-4 , or C 2-4 bivalent straight or branched, optionally substituted hydrocarbon chain.
  • L 1 is a C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 1-5 , C 2-5 , C 3-5 , C 1-4 , or C2-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N
  • L 1 is a C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 1-5 , C 2-5 , C 3-5 , C 1-4 , or C 2-4 bivalent straight or branched, optionally substituted hydrocarbon chain.
  • L 1 is a C1-6, C2-6, C3-6, C4-6, C1-5, C2-5, C3-5, C1-4, or C2-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, - C(S)-, or -Cy-, and each -R is independently hydrogen, -CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CHF 2 , or -CH 2 CF 3 ; or each -R is independently hydrogen or methyl;
  • L 1 is selected from those depicted in Table 1, below.
  • each -Cy- is independently a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • -Cy- is a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • -Cy- is an optionally substituted phenylene.
  • -Cy- is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • - Cy- is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • - Cy- is an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • -Cy- is an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • -Cy- is selected from those depicted in Table 1, below.
  • R 2 is with one -CN, -N(R)2, or -C(O)N(R)2 group and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - S-, -SO-, or -SO 2 -.
  • R 2 is me embodiments, R 2 is C 1-6 aliphatic group substituted with one -CN, -N(R)2, or -C(O)N(R)2 group and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO 2 -.
  • R 2 is a C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 1-5 , C 2-5 , C 3-5 , C 1-4 , C 2-4 , or C 1-3 straight or branched aliphatic group substituted with one -CN, -N(R)2, or -C(O)N(R)2.
  • R 2 is a C1-6, C2-6, C3-6, C4-6, C1-5, C2-5, C3-5, C1-4, C2-4, or C1-3 straight or branched aliphatic group substituted with one -CN, -N(R) 2 , or -C(O)N(R) 2 and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO2-.
  • R 2 is a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 straight or branched aliphatic group substituted with one -CN, -N(R)2, or -C(O)N(R)2.
  • R 2 is a C1, C2, C3, C4, C5, C6, C7, or C8 straight or branched aliphatic group substituted with one -CN, - N(R) 2 , or -C(O)N(R) 2 and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO2-.
  • R 2 is -(CH2)1-6-CN, -(CH2)1-6-N(R)2, or -(CH2)1-6-C(O)N(R)2.
  • each -R is independently hydrogen, -CH 2 -phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, - CH2CHF2, or -CH2CF3; or each -R is independently hydrogen or methyl; or -R is hydrogen.
  • R 2 is selected from those depicted in Table 1, below.
  • L 2 is a covalent bond or a C1-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -or C(S)-.
  • L 2 is a a covalent bond.
  • L 2 is a C1-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -or C(S)-.
  • L 2 is a C1, C2, C3, or C4 bivalent, straight-chain, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, - SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -or C(S)-.
  • L 2 is a C 1 , C 2 , C 3 , or C 4 bivalent, straight-chain, hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, or -S-; and L 2 is optionally substituted with 1, 2, or 3 substituents independently selected from deuterium, halogen, -OR, -SR, -N(R)2, or -CN.
  • L 2 is -O-, -S-, -N(R)-, -CH2-, -CH2CH2-, -CH2CH2CH2-, CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(CH 3 )CH 2 -, or -C(CH 3 ) 2 CH 2 -, and L 2 is optionally substituted with 1, 2, or 3 substituents independently selected from deuterium or halogen.
  • L 2 is selected from one of those depicted in Table 1, below.
  • Ring B is phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, an 8-10 membered partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is phenyl.
  • Ring B is an 8-10 membered bicyclic aromatic carbocyclic ring.
  • Ring B is an 8-10 membered partially unsaturated carbocyclic ring. In some embodiments, Ring B is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is an 8-10 membered bicyclic partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is phenyl or a 5- or 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is a 5-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is a 5-membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen or oxygen.
  • Ring B is a 5- membered monocyclic heteroaromatic ring having 1-2 nitrogen heteroatoms.
  • Ring B is a 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is a 6-membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen or oxygen. In some embodiments, Ring B is a 6- membered monocyclic heteroaromatic ring having 1-3 nitrogen heteroatoms. [0079] In some embodiments, Ring B is pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl (e.g., 1,3,5-triazinyl).
  • Ring B is imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl. [0080] In some embodiments, Ring B is selected from one of those depicted in Table 1, below. [0081] As defined generally above, R 3 is hydrogen or C 1-3 aliphatic optionally substituted with 1, 2 or 3 substituents independently selected from deuterium or halogen. [0082] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C1-3 aliphatic optionally substituted with 1, 2 or 3 substituents independently selected from deuterium or halogen.
  • R 5 is -R.
  • R 5 is halogen.
  • R 5 is -CN.
  • R 5 is –OR.
  • R 5 is - N(R)2.
  • R 5 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 is an optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 5 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 5 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 5 is hydrogen, C 1-6 alkyl, halogen, -CN, -CF 3 , -CD 3 , cyclopropyl, ethynyl, -OCH 3 , -OC me embo 5 diments, R is methyl.
  • R 5 is selected from those depicted in Table 1, below.
  • each R 6 is independently hydrogen or C 1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
  • R 6 is hydrogen. In some embodiments, R 6 is C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. [0096] In some embodiments, R 6 is C 1-3 alkyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 6 is methyl, ethyl, or isopropyl. [0097] In some embodiments, R 6 is selected from those depicted in Table 1, below.
  • R 7 is R.
  • R 7 is halogen.
  • R 7 is -CN.
  • R 7 is -OR.
  • R 7 is -N(R)2.
  • R 7 is -NO2.
  • R 7 is -N3.
  • R 7 is -SR.
  • R 7 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • n is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3. [00103] As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3.
  • p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3. [00105] As defined generally above, q is 0, 1, 2, or 3. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2.
  • the compound of Formula I or pharmaceutically acceptable salt thereof is provided such that e same as By way of explanation and for purposes of clarity, it is understood that not define the identical chemical moiety as .
  • the compound of Formula I is not a symmetrical compound.
  • Ring A is 2-pyridyl and R 5 is not the same as R 2 .
  • Ring A is 2-pyridyl and R 5 is not attached at the 2- or 6-position (i.e., the same location on the pyridyl ring as as R 2 ).
  • Ring A is not a 2-pyridyl.
  • R 5 is methyl.
  • the present invention provides a compound of Formula II-a or II-b: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula III-a, III-b, III-c, III-d, or III-e: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , R 5 , R 7 , L 2 , n, and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula IV-a or IV-b:
  • the present invention provides a compound of Formula V-a, V-b, or V-c: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , m, n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula VI-a, VI-b, VI-c, or VI-d:
  • R 3 is hydrogen.
  • R 3 is methyl.
  • R 5 is methyl, isopropyl, halogen, -OMe, or -CF3.
  • the present invention provides a compound of Formula VII-a or VII-b: VII-a VII-b or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , m, and n is as defined above and described in embodiments herein, both singly and in combination.
  • R 5 is methyl, isopropyl, halogen, -OMe, or -CF 3 .
  • the present invention provides a compound of Formula VIII- a, VIII-b, VIII-c, VIII-d, VIII-e, or VIII-f: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 3 , R 5 , R 7 , L 2 , n, and q is as defined above and described in embodiments herein, both singly and in combination.
  • R 5 is methyl, isopropyl, halogen, -OMe, or -CF 3 .
  • the present invention provides a compound of Formula IX-a, IX-b, IX-c, IX-d, IX-e, or IX-f:
  • the present invention provides a compound of Formula X: or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or a 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R 1 is independently hydrogen, deuterium, C 1-4 alkyl, halogen, -CN, -OR, -N(R) 2 , -NO 2 , -N 3 , -SR, or -L 1 -R 6 ; each -R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic
  • the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. 4.
  • General Methods of Providing the Present Compounds [00119]
  • the compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.
  • PG protecting group
  • LG leaving group
  • transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated.
  • Such groups and transformations are described in detail in March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B.
  • LG includes, but is not limited to, halogens (e.g. fluoride, chloride, bromide, iodide), sulfonates (e.g.
  • oxygen protecting group includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5 th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference.
  • Suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4- (ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9- fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.
  • Amino protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5 th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which is incorporated herein by reference.
  • Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like.
  • Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
  • an aldehyde according to structure A may be condensed with a ketone such as acetone in the presence of a base to yield intermediate B, for example by following General Procedures E or F.
  • the General Procedures are described in more detail in the Exemplification, below.
  • Condensation with an amine such as NH 2 R 3 , e.g. methylamine, and an aldehyde of structure C provides compounds of structure D.
  • such compounds are CXCR4 inhibitors according to the present invention.
  • compounds of structure D are reduced according to General Procedure A to provide compounds of structure E.
  • cross-coupling (such as Pd-catalyzed coupling) may be performed to provide compounds of structure E.
  • Compounds of structure F may be prepared by halogenation or formation of another leaving group such as triflate.
  • Scheme 2 [00128] Alternatively, as shown in Scheme 2, piperidone compounds of structure G may be reduced according to General Procedure A to afford compounds of structure H and subsequently reacted with an appropriate electrophile of formula LG-R 3 , wherein LG refers to an appropriate leaving group such as halide or mesylate, affording compounds of structure I. 5.
  • compositions 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 CXCR4, or a mutant thereof, in a biological sample or in a patient.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit CXCR4, or a mutant thereof, in a biological sample or in a patient.
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for oral administration to a patient.
  • 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.
  • 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.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate,
  • 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.
  • the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of CXCR4, or a mutant thereof.
  • Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • 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.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful 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.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • 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.
  • pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration.
  • 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.
  • 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.
  • 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.
  • provided pharmaceutically 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.
  • provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00142] In some embodiments, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • compositions 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. In some embodiments, 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.
  • 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.
  • compositions described herein are generally useful for the inhibition of CXCR4 or a mutant thereof.
  • activity of a compound utilized in this invention as an inhibitor of CXCR4, or a mutant thereof may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of CXCR4, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to CXCR4.
  • treatment refers 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.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • 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).
  • CXCR4-mediated disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which CXCR4, or a mutant thereof, is known to play a role.
  • the present invention relates to treating or lessening the severity of one or more diseases in which CXCR4, or a mutant thereof, are known to play a role.
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder.
  • Cellular Proliferative Disorders [00151] The present invention features methods and compositions for the diagnosis and prognosis of cellular proliferative disorders (e.g., cancer) and the treatment of these disorders by targeting CXCR4.
  • Cellular proliferative disorders described herein include, e.g., cancer, obesity, and proliferation-dependent diseases.
  • Cancer includes, in one embodiment, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom’s macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcom
  • leukemias e.g., acute leukemia
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • the cancer is acoustic neuroma, astrocytoma (e.g.
  • GBM Glioblastoma
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
  • Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, 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, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymph
  • the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPN
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • the present invention provides a method for treating a cancer that presents as a solid tumor, such as a sarcoma, carcinoma, or lymphoma, comprising the step of administering a disclosed compound, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas.
  • the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pan
  • the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepato
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian cancer ova
  • the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma.
  • HCC hepatocellular carcinoma
  • the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments,
  • the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST.
  • MPNST peripheral nerve sheath tumors
  • the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma. [00163] In some embodiments, the present invention provides a method of treating a cancer selected from leukemias; Waldenstrom’s macroglobulinemia; multiple myeloma; heavy chain disease; and solid tumors, including sarcomas and carcinomas, including fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, renal cell carcinoma, colon carcinoma, colorectal carcinoma, pancreatic cancer, breast cancer, ova
  • the present invention further features methods and compositions for the diagnosis, prognosis and treatment of viral-associated cancers, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
  • HSV human immunodeficiency virus
  • HPV human papilloma virus
  • HTLV-I human T-cell leukemia virus type I
  • the present invention provides a method for treating a tumor in a patient in need thereof, comprising administering to the patient any of the compounds, salts or pharmaceutical compositions described herein.
  • the tumor comprises any of the cancers described herein.
  • the tumor comprises melanoma cancer.
  • the tumor comprises breast cancer.
  • the tumor comprises lung cancer.
  • the the tumor comprises small cell lung cancer (SCLC). In some embodiments, the the tumor comprises non-small cell lung cancer (NSCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
  • the tumor is treated by arresting further growth of the tumor. In some embodiments, the tumor is treated by reducing the size (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the size of the tumor prior to treatment.
  • tumors are treated by reducing the quantity of the tumors in the patient by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the quantity of tumors prior to treatment.
  • Primary Immune Deficiencies [00168]
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a primary immunodeficiency disease or disorder, comprising administering to a patient in need thereof an effective amount of a disclosed compound or pharmaceutically acceptable salt thereof.
  • the method treats, e.g. ameliorates, a symptom of a primary immunodeficiency, such as neutropenia.
  • Primary immune deficiencies treatable by the methods of the present invention may be present at birth (i.e., congenital), acquired after birth, idiotypic and/or cyclic, and include: warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome; severe congenital neutropenia (SCN), such as those arising from G6PC3 deficiency (McDermott et al. (2010) Blood 116:2793-2802); GATA2 deficiency (Mono MAC syndrome) (Maciejweski-Duval et al. (2015) J. Leukoc. Biol. 5MA0815-288R (Epub.
  • the present invention provides a method for treating a primary immune deficiency, such as neutropenia, chronic idiopathic neutropenia (CIN), severe CIN, cyclic neutropenia, G6PC3 Deficiency, or Glycogen Storage Disease Ib, comprising administering to a patient in need thereof an effective amount of a disclosed compound.
  • a disclosed compound or pharmaceutically acceptable salt thereof is co-administered with filgrastim (G-CSF) to treat the primary immunodeficiency.
  • a disclosed compound or pharmaceutically acceptable salt thereof is co- administered with G-CSF to treat CIN.
  • a disclosed compound or pharmaceutically acceptable salt thereof is administered to a patient who has previously been administered G-CSF to treat a primary immunodeficiency, such as CIN.
  • the disclosed compound replaces G-CSF therapy.
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer, an autoimmune disorder, a primary immune deficiency, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone-related disorder, liver disease, or a cardiac disorder.
  • unit dosage form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and for example from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the invention relates to a method of inhibiting CXCR4 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.
  • the invention relates to a method of inhibiting CXCR4, 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.
  • the invention relates to a method of irreversibly inhibiting CXCR4, 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.
  • biological sample 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.
  • Another embodiment of the present invention relates to a method of inhibiting CXCR4 in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of inhibiting CXCR4, 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.
  • the invention relates to a method of irreversibly inhibiting CXCR4, 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.
  • the present invention provides a method for treating a disorder mediated by CXCR4, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof.
  • additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as “appropriate for the disease, or condition, being treated.”
  • the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co- administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • the additional therapeutic agent is selected from an immunostimulatory therapeutic compound. In some embodiments, the immunostimulatory therapeutic compound is selected from elotuzumab, mifamurtide, an agonist or activator of a toll- like receptor, or an activator of ROR ⁇ t. [00189] In some embodiments, the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor.
  • the method comprises administering to the patient in need thereof three therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, an immunostimulatory therapeutic compound, and an immune checkpoint inhibitor.
  • therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, an immunostimulatory therapeutic compound, and an immune checkpoint inhibitor.
  • Other checkpoint inhibitors include OX40 agonists.
  • OX40 agonists that are being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer 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-My
  • CD137 also called 4-1BB
  • CD137 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).
  • 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).
  • Other checkpoint inhibitors that may be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.
  • GITR glucocorticoid-induced tumor necrosis factor receptor
  • 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 (NCT 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 IgG1 Fc domain, in advanced solid tumors (NCT02583165).
  • TRX518 Leap Therapeutics
  • checkpoint inhibitors that may be used in the present invention include inducible T-cell co-stimulator (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).
  • Other checkpoint inhibitors that may be used in the present invention include killer IgG-like receptor (KIR) inhibitors.
  • KIR killer IgG-like receptor
  • 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).
  • CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha 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 IgG1, 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);
  • 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).
  • Other checkpoint inhibitors that may 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).
  • MK-1454 Merck
  • ADU- S100 MIW815, Aduro Biotech/Novartis
  • an agonistic synthetic cyclic dinucleotide in Phase 1 (NCT02675439 and NCT03172936).
  • Other checkpoint inhibitors that may be used in the present invention include CSF1R inhibitors.
  • CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R 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-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6- yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid
  • NKG2A receptor inhibitors that may 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).
  • the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
  • the present invention provides a method of treating cancer in a patient in need thereof, wherein said method comprises administering to said patient a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents selected from an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6 inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor.
  • IDO indoleamine (2,3)-dioxygenase
  • PARP Poly ADP ribose polymerase
  • HDAC histone deacetylase
  • CDK4/CDK6 CDK4/CDK6 inhibitor
  • PI3K phosphatidylinositol 3 kinase
  • the IDO inhibitor is selected from epacadostat, indoximod, capmanitib, GDC-0919, PF-06840003, BMS:F001287, Phy906/KD108, or an enzyme that breaks down kynurenine.
  • the PARP inhibitor is selected from olaparib, rucaparib, or niraparib.
  • the HDAC inhibitor is selected from vorinostat, romidepsin, panobinostat, belinostat, entinostat, or chidamide.
  • the CDK 4/6 inhibitor is selected from palbociclib, ribociclib, abemaciclib or trilaciclib.
  • the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor.
  • the method comprises administering to the patient in need thereof three therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6 inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor, and a third therapeutic agent selected from an immune checkpoint inhibitor.
  • a second therapeutic agent selected from an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6 inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor
  • the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
  • Another immunostimulatory therapeutic that may be used in the present invention 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).
  • Another immunostimulatory therapeutic that may be used in the present invention is recombinant human interleukin 12 (rhIL-12).
  • 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).
  • heterodimeric IL-15 hetIL-15, Novartis/Admune
  • IL15:sIL-15RA soluble IL-15 binding protein IL-15 receptor alpha chain
  • the PI3K inhibitor is selected from idelalisib, alpelisib, taselisib, pictilisib, copanlisib, duvelisib, PQR309, or TGR1202.
  • the present invention provides a method of treating cancer in a patient in need thereof, wherein said method comprises administering to said patient a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents selected from a platinum-based therapeutic, a taxane, a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
  • the platinum-based therapeutic is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, or satraplatin.
  • the taxane is selected from paclitaxel, docetaxel, albumin- bound paclitaxel, cabazitaxel, or SID530.
  • the therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise interfere with the replication of rapidly proliferating cells is selected from trabectedin, mechlorethamine, vincristine, temozolomide, cytarabine, lomustine, azacitidine, omacetaxine mepesuccinate, asparaginase Erwinia chrysanthemi, eribulin mesylate, capacetrine, bendamustine, ixabepilone, nelarabine, clorafabine, trifluridine, or tipiracil.
  • the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor.
  • a third therapeutic agent such as an immune checkpoint inhibitor.
  • the method comprises administering to the patient in need thereof three therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from a platinum-based therapeutic, a taxane, a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells, and a third therapeutic agent selected from an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
  • any one of the foregoing methods further comprises the step of obtaining a biological sample from the patient and measuring the amount of a disease-related biomarker.
  • the biological sample is a blood sample.
  • the disease-related biomarker is selected from circulating CD8+ T cells or the ratio of CD8+ T cells:Treg cells.
  • the present invention provides a method of treating an advanced cancer, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof, either as a single agent (monotherapy), or in combination with a chemotherapeutic, a targeted therapeutic, such as a kinase inhibitor, and/or an immunomodulatory therapy, such as an immune checkpoint inhibitor.
  • the 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.
  • the additional therapeutic agent is a kinase inhibitor or VEGF- R antagonist.
  • Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi).
  • VEGFR inhibitors such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®, Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Nov
  • kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S.
  • the additional therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake.
  • Approved mTOR inhibitors useful in the present invention include everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).
  • the additional therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor.
  • PARP Poly ADP ribose polymerase
  • Approved PARP inhibitors useful in the present invention include olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); and niraparib (Zejula®, Tesaro).
  • Other PARP inhibitors being studied which may be used in the present invention include talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).
  • the additional therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor.
  • PI3K inhibitors useful in the present invention include idelalisib (Zydelig®, Gilead).
  • PI3K inhibitors being studied which may be used in the present invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).
  • the additional therapeutic agent is a proteasome inhibitor.
  • Approved proteasome inhibitors useful in the present invention include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda).
  • the additional therapeutic agent is a histone deacetylase (HDAC) inhibitor.
  • Approved HDAC inhibitors useful in the present invention include vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); and belinostat (Beleodaq®, Spectrum Pharmaceuticals).
  • HDAC inhibitors being studied which may be used in the present invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).
  • the additional therapeutic agent is a CDK inhibitor, such as a CDK 4/6 inhibitor.
  • Approved CDK 4/6 inhibitors useful in the present invention include palbociclib (Ibrance®, Pfizer); and ribociclib (Kisqali®, Novartis).
  • CDK 4/6 inhibitors being studied which may be used in the present invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).
  • the additional therapeutic agent is an indoleamine (2,3)- dioxygenase (IDO) inhibitor.
  • IDO inhibitors being studied which may be used in the present invention include 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); and an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics).
  • the additional therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).
  • PDGF platelet-derived growth factor
  • EGF epidermal growth factor
  • EGFR antagonists which may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly).
  • Approved EGFR antagonists which may be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca).
  • the additional therapeutic agent is an aromatase inhibitor.
  • Approved aromatase inhibitors which may be used in the present invention include exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).
  • the additional therapeutic agent is an antagonist of the hedgehog pathway.
  • Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for treatment of basal cell carcinoma.
  • the additional therapeutic agent is a folic acid inhibitor.
  • Approved folic acid inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).
  • the additional therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor.
  • CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).
  • the additional therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor.
  • IDH isocitrate dehydrogenase
  • IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).
  • the additional therapeutic agent is an arginase inhibitor.
  • Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).
  • the additional therapeutic agent is a glutaminase inhibitor.
  • Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).
  • the additional therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells.
  • Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (Rituxan®, Genentech/BiogenIdec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2,
  • the additional therapeutic agent is a topoisomerase inhibitor.
  • Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).
  • the additional therapeutic agent is a nucleoside inhibitor, or other therapeutic that interfere with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
  • nucleoside inhibitors or other therapeutics include trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotax
  • the additional therapeutic agent is a platinum-based therapeutic, also referred to as platins.
  • Platins cause cross-linking of DNA, such that they inhibit DNA repair and/or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells.
  • Approved platinum-based therapeutics which may be used in the present invention include cisplatin (Platinol®, Bristol-Myers Squibb); carboplatin (Paraplatin®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (Eloxitin® Sanofi-Aventis); and nedaplatin (Aqupla®, Shionogi).
  • platinum-based therapeutics which have undergone clinical testing and may be used in the present invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).
  • the additional therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division.
  • Approved taxane compounds which may be used in the present invention include paclitaxel (Taxol®, Bristol- Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis/Celgene), and cabazitaxel (Jevtana®, Sanofi- Aventis).
  • Other taxane compounds which have undergone clinical testing and may be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008).
  • the additional therapeutic agent is an inhibitor of anti- apoptotic proteins, such as BCL-2.
  • Approved anti-apoptotics which may be used in the present invention include venetoclax (Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen).
  • Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).
  • the present invention provides a method of treating prostate cancer comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in combination with an additional therapeutic agent that interferes with the synthesis or activity of androgens.
  • Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (Zytiga®, Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals).
  • the additional therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens.
  • Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).
  • the additional therapeutic agent is an inhibitor of bone resorption.
  • an approved therapeutic which inhibits bone resorption is Denosumab (Xgeva®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases.
  • Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).
  • the additional therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2.
  • Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53.
  • ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).
  • the additional therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFß).
  • Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165).
  • the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787).
  • the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978.
  • TGF-beta trap such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978.
  • M7824 Merck KgaA - formerly MSB0011459X
  • NCT02699515 a bispecific, anti-PD-L1/TGFß trap compound
  • NCT02517398 NCT02517398
  • M7824 is comprised of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFß “trap.” Additional Co-Administered Therapeutic Agents – Targeted Therapeutics and Immunomodulatory Drugs [00248] In some embodiments, the additional therapeutic agent is selected from a targeted therapeutic or immunomodulatory drug. Adjuvant therapies with targeted therapeutics or immunomodulatory drugs have shown promising effectiveness when administered alone but are limited by the development of tumor immunity over time or evasion of the immune response.
  • the present invention provides a method of treating cancer, such as a cancer described herein, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in combination with an additional therapeutic agent such as a targeted therapeutic or an immunomodulatory drug.
  • 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).
  • the immunomodulatory therapeutic is a cancer vaccine.
  • 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.
  • the additional therapeutic 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 virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCTTCT016225
  • the additional therapeutic agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus 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-hTNF ⁇ - IRES-hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engine
  • the present invention comprises administering to said patient a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with a T-cell engineered to express a chimeric antigen receptor, or CAR.
  • a T-cell engineered to express such chimeric antigen receptor are referred to as a CAR-T cells.
  • 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.
  • TCR T-cell receptor
  • the CAR-T cell is one of those described in U.S.
  • Patent 8,906,682 (June; hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta).
  • an antigen binding domain such as a domain that binds to CD19
  • CD3 zeta intracellular signaling domain of the T cell antigen receptor complex zeta chain
  • the CAR When expressed in the T cell, the CAR is able to redirect antigen recognition based on the antigen binding specificity.
  • CD19 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.
  • the additional therapeutic agent is an immunostimulatory drug.
  • 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.
  • the present invention provides a method of treating cancer, such as a cancer described herein, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in combination with an additional therapeutic agent such as a immunostimulatory drug, such as an immune checkpoint inhibitor.
  • an additional therapeutic agent such as a immunostimulatory drug, such as an immune checkpoint inhibitor.
  • the compound and the checkpoint inhibitor are administered simultaneously or sequentially.
  • a compound disclosed herein is administered prior to the initial dosing with the immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is administered prior to the initial dosing with the compound disclosed herein.
  • the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist.
  • a CXCR4 antagonist such as a compound disclosed herein or a pharmaceutically acceptable salt thereof is administered in combination with nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); or atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).
  • nivolumab anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb
  • pembrolizumab anti-PD-1 antibody, Keytruda®, Merck
  • ipilimumab anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb
  • durvalumab anti-PD
  • immune checkpoint inhibitors suitable for use in the present invention include 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-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric
  • 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).
  • Another paradigm for immune-stimulation is the use of oncolytic viruses.
  • the present invention provides a method for treating a patient by administering a CXCR4 antagonist such as a compound disclosed herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in combination with an immunostimulatory therapy such as oncolytic viruses.
  • Approved immunostimulatory oncolytic viruses which may be used in the present invention include talimogene laherparepvec (live, attenuated herpes simplex virus, Imlygic®, Amgen).
  • the additional therapeutic agent is an activator of retinoic acid receptor-related orphan receptor ⁇ (ROR ⁇ t).
  • ROR ⁇ t is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells.
  • An activator of ROR ⁇ t, that is being studied which may be used in the present invention is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).
  • the additional therapeutic agent is an agonist or activator of a toll-like receptor (TLR).
  • TLR toll-like receptor
  • 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).
  • 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
  • NCT02608268 is an anti-TIM-3 antibody which is being studied in advanced malignancies
  • checkpoint inhibitors that may be used in the present invention include inhibitors 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).
  • Checkpoint inhibitors that may be used in the present invention also include inhibitors 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).
  • immune-oncology agents that may be used in the present invention in combination with CXCR4 inhibitors such as a compound disclosed herein 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 Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GI
  • gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize.
  • a compound of the current invention may also be used to advantage in combination with other antiproliferative compounds.
  • antiproliferative compounds include, but are not limited to checkpoint inhibitors; 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 inhibitor
  • checkpoint inhibitor as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient.
  • T-cell exhaustion 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.
  • 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 signalling processes should proceed.
  • the checkpoint inhibitor is a biologic therapeutic or a small molecule.
  • the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof.
  • the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDLl, PDL2, PDl, 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.
  • the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDLl, PDL2, PDl, 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.
  • the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof.
  • the interleukin is IL-7 or IL-15.
  • the interleukin is glycosylated IL-7.
  • the vaccine is a dendritic cell (DC) vaccine.
  • Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors may include small molecule inhibitors or may include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands.
  • Illustrative checkpoint molecules that may 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, ⁇ , and memory CD8 + ( ⁇ ) T cells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands.
  • CTLA-4 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, ⁇ , and memory CD8 + ( ⁇ ) T cells
  • CD160 also referred to as BY55
  • 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 Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-Ll 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).
  • CTLA-4 blocking antibody PD-Ll 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
  • Checkpoint protein ligands include, but are not limited to PD-Ll, PD-L2, B7-H3, B7- H4, CD28, CD86 and TIM-3.
  • the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist.
  • the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®).
  • 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.
  • MK-3475 lambrolizumab
  • BMS-936558 nivolumab
  • CT-011 pidilizumab
  • AMP-224 pidilizumab
  • MDX-1105 MEDI4736
  • MPDL3280A MPDL3280A
  • BMS-936559 ipilimumab
  • lirlumab IPH2101, pembrolizumab (Keytruda®)
  • tremelimumab tremelimumab
  • 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 AromasinTM.
  • Formestane is marketed under the trade name LentaronTM. Fadrozole is marketed under the trade name AfemaTM. Anastrozole is marketed under the trade name ArimidexTM. Letrozole is marketed under the trade names FemaraTM or FemarTM. Aminoglutethimide is marketed under the trade name OrimetenTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
  • the term "antiestrogen” as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • Tamoxifen is marketed under the trade name NolvadexTM.
  • Raloxifene hydrochloride is marketed under the trade name EvistaTM.
  • Fulvestrant can be administered under the trade name FaslodexTM.
  • 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.
  • 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 (CasodexTM).
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name ZoladexTM.
  • topoisomerase I inhibitor 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 CamptosarTM.
  • Topotecan is marketed under the trade name HycamptinTM.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CaelyxTM), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide is marketed under the trade name EtopophosTM.
  • Teniposide is marketed under the trade name VM 26-Bristol
  • Doxorubicin is marketed under the trade name AcriblastinTM or AdriamycinTM.
  • 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; discodermolides; cochicine and epothilones and derivatives thereof.
  • Paclitaxel is marketed under the trade name TaxolTM.
  • Docetaxel is marketed under the trade name TaxotereTM.
  • Vinblastine sulfate is marketed under the trade name Vinblastin R.PTM.
  • Vincristine sulfate is marketed under the trade name FarmistinTM.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
  • Cyclophosphamide is marketed under the trade name CyclostinTM. Ifosfamide is marketed under the trade name HoloxanTM.
  • histone deacetylase inhibitors or "HDAC 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).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • Gemcitabine is marketed under the trade name GemzarTM.
  • 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 CarboplatTM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark EloxatinTM.
  • 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 (PDGFR),
  • 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-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting 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, TYK2, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin;
  • PI3K inhibitor 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 PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇ , PI3K- C2 ⁇ , Vps34, p110- ⁇ , p110- ⁇ , p110- ⁇ , p110- ⁇ , p85- ⁇ , p85- ⁇ , p55- ⁇ , p150, p101, and p87.
  • 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.
  • Bcl-2 inhibitor 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), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ.
  • Bcl-2 inhibitor includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.
  • SYK inhibitor 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.
  • SYK spleen tyrosine kinase
  • Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
  • SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference.
  • PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.
  • JAK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (ThalomidTM) and TNP-470.
  • 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.
  • 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.
  • Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, ⁇ - ⁇ - or ⁇ - tocopherol or ⁇ - ⁇ - or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, such as celecoxib (CelebrexTM), etoricoxib, valdecoxib, or lumiracoxib.
  • bisphosphonates includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid is marketed under the trade name DidronelTM.
  • Clodronic acid is marketed under the trade name BonefosTM.
  • Tiludronic acid is marketed under the trade name SkelidTM.
  • Pamidronic acid is marketed under the trade name ArediaTM.
  • Alendronic acid is marketed under the trade name FosamaxTM.
  • Ibandronic acid is marketed under the trade name BondranatTM.
  • Risedronic acid is marketed under the trade name ActonelTM.
  • Zoledronic acid is marketed under the trade name ZometaTM.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CerticanTM), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88.
  • biological response modifier as used herein refers to a lymphokine or interferons.
  • inhibitor of Ras oncogenic isoforms such as H-Ras, K-Ras, or N-Ras
  • inhibitor of Ras oncogenic isoforms refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a “farnesyl transferase inhibitor” such as L-744832, DK8G557 or R115777 (ZarnestraTM).
  • telomerase inhibitor 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 telomestatin.
  • methionine aminopeptidase inhibitor 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.
  • proteasome inhibitor 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 (VelcadeTM) and MLN 341.
  • 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.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1- ⁇ -D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors 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.
  • HSP90 inhibitors 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 of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HerceptinTM), Trastuzumab-DM1, erbitux, bevacizumab (AvastinTM), rituximab (Rituxan ® ), PRO64553 (anti-CD40) and 2C4 Antibody.
  • antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • 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.
  • compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • drugs useful for the treatment of AML such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 ' -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
  • HDAC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]- amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl) ⁇ 2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically 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.
  • ionizing radiation 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.
  • EDG binders and ribonucleotide reductase inhibitors.
  • EDG binders refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • 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-1H-isoindole-1 ,3-dione derivatives.
  • VEGF vascular endothelial growth factor
  • compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; AngiostatinTM; EndostatinTM; anthranilic acid amides; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor 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 (AvastinTM).
  • VEGF aptamer such as Macugon
  • Photodynamic therapy 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 VisudyneTM and porfimer sodium.
  • Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11- ⁇ -epihydrocotisol, cortexolone, 17 ⁇ -hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
  • 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.
  • 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).
  • a compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • 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.
  • 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.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound 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.
  • 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.
  • the 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 the particular mode of administration.
  • 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.
  • 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 that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 ⁇ g/kg body weight/day of the additional therapeutic agent can be administered.
  • 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.
  • the 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.
  • the 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).
  • patients using stents or other implantable devices risk clot formation or platelet activation.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • EXEMPLIFICATION General Synthetic Methods [00325] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereafter should be considered to be disclosed. Temperatures are given in degrees centigrade.
  • the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.
  • compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
  • LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization and except as otherwise indicated, the general LCMS conditions were as follows: Waters X Bridge C18 column (50 mm*4.6 mm*3.5 ⁇ m), Flow Rate: 2.0 mL/min, the column temperature: 40 °C.
  • Example 1 Synthesis of I-47 and I-48 Synthetic Scheme for I-47 and I-48 [00352] The synthesis of 1-1 Following general procedure K, to the solution of 1-0 (5.0 g, 21.7 mmol) and tert-butyl acetate (7.6 g, 65.2 mmol) in THF (30 mL) at -50 °C was added LiHMDS (65 mL, 1 M) in portions, then the mixture was allowed to stirred at room temperature overnight. After completion of the reaction as indicated by LCMS, the mixture was poured into water and concentrated to remove THF, then extracted with DCM.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X- Bridge C18 (50mm *4.6 mm*3.5 ⁇ m)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min. Purity: 94.3%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% CH 3 CN] in 0.1 min and under this condition for 0.7 min. Purity: 94.6%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 5% [water + 10 mM NH 4 HCO 3 ] and 95% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 94.5%.
  • LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: >99%.
  • Example 2 Synthesis of I-28 Synthetic Scheme for I-28 Following general procedure Q, 2-1 (350 mg, yield: 59.5%) was obtained as yellow oil.
  • LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 98.76%.
  • Example 3 Synthesis of I-65 and I-72 Synthetic Scheme for I-65 and I-72 [00368] The synthesis of 3-1 To a solution of 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (3-A, 100 mg crude, 0.26 mmol) in anhydrous THF (10 mL) was added LDA (2M in THF, 296 mg, 5.29 mmol) dropwise at -60 °C under N2 protection, the mixture was stirred at -60 °C for 1 hour, followed by adding a solution of 3-0 (800 mg, 1.80 mmol) in 5 mL THF, then the mixture was stirred at -60 °C for 2 hours.
  • LDA 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole
  • LCMS (Agilent LCMS 1200-6120, Column: Phenomenex Kinetex EVO (50mm *4.6 mm*2.6 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.75 min, then under this condition for 0.8 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.1 min.) Purity: 80.38 %.
  • LCMS (Agilent LCMS 1200-6120, Column: Phenomenex Kinetex EVO (50mm *4.6 mm*2.6 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.75 min, then under this condition for 0.8 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.1 min.) Purity: 87.22 %.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min.) Purity: 100.00 %.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min).
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X- Bridge C18 (50 mm*4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min).
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min) Purity: 99.54 %.
  • Example 5 Synthesis of I-21 and I-23 Synthetic Scheme for I-21 and I-23 Following general procedure Q, 5-1 (500 mg, yield: 63.5%) was obtained as yellow oil.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min. Purity: 100.00%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 100.00 %.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm*4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.5 min, then under this condition for 1.5 min, finally changed to 90% [water + 10 mM NH 4 HCO 3 ] and 10% [CH 3 CN] in 0.1 min and under this condition for 0.5 min.).
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min. Purity: 98. 88%.
  • Example 7 Synthesis of I-3 and I-3a Synthetic Scheme for I-3 and I-3a [00390] The synthesis of 7-1 Following general procedure K, crude 7-1 (12.0 g, 95.3% yield) was obtained as brown oil solid, which were used in the next step without further purification.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min). Purity: 97.82%.
  • Example 8 Synthesis of I-10 Synthetic Scheme for I-10 Following general procedure S, trimethylsilylacetylene (546 mg, 5.56 mmol, 3 eq) was added to the suspension of 8-0 (800 mg, 1.85 mmol), Pd(PPh 3 ) 2 Cl 2 (130 mg, 0.185 mmol, 0.1 eq), CuI (35 mg, 0.185 mmol, 0.1 eq) in dry THF (30 mL) and Et 3 N (10 mL) under N 2 atmosphere. Then the mixture was stirred at 60 o C overnight and cooled to room temperature, filtered and concentrated in vacuum. The residue was purified by column chromatography to give 8-1 (681 mg, yield: 82%) as an off-white solid.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 48.14%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 61.85%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 96.16 %.
  • LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 72.53%.
  • LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min.) Purity: 81.7 %.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.).
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.).
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min.) Purity: 81.27%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.).
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 98.86%.
  • Example 11 Synthesis of I-84 Synthetic Scheme for I-84 [00426] Synthesis of 11-1. [00427] Following General Procedure W, To a suspension of LAH (35.2 mg, 0.90 mmol) in THF (4 mL) was added a solution of ethyl 6-((2R, 6S)-1-(tert-butoxycarbonyl)-6-(3- chloropyridin-2-yl) piperidin-2-yl) picolinate (11-0200 mg, 0.45 mmol) in THF (2 mL) at 0 °C under N 2 . The mixture was stirred at 0 °C for 1 h, and then water (0.045 mL), NaOH aq.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min.) Purity: 88.70%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min.) Purity: 73.32%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Colum Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min.) Purity: 68.83%.
  • Example 12 Synthesis of I-36 Synthetic Scheme for I-36 [00433] Synthesis of 12-1. [00434] To a solution of ethyl 6-((2R,6S)-1-(tert-butoxycarbonyl)-6-(3-methylpyridin-2- yl)piperidin-2-yl)picolinate (12-0, 800 mg, 1.88 mmol) in MeOH (10 mL) was added 2 M LiOH solution (2.8 mL, 5.64 mmol) at room temperature, then the mixture was stirred at room temperature overnight.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 97.02%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X- Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 88.12%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min.) Purity: 94.86%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min.) Purity: 75.29%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min.) Purity: 96.54%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 80.58%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH 3 CN] in 0.1 min and under this condition for 0.7 min.) Purity: 98.08%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 94.65%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 91.97%.
  • LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 ⁇ m); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: 57.70%.
  • Example 16 REGA Screening Assay Intracellular CXCL-12-induced calcium mobilization assay
  • Intracellular calcium mobilization induced by chemokines or chemokine-derived peptides were evaluated using a calcium responsive fluorescent probe and a FLIPR system.
  • the CXCR-4 transfected U87 cell line (U87.CXCR4) cells were seeded in gelatine-coated black-wall 96-well plates at 20,000 cells per well and incubated for 12 hours. Cells were then loaded with the fluorescent calcium probe Fluo-2 acetoxymethyl at 4 ⁇ M final concentration in assay buffer (Hanks’ balanced salt solution with 20 mM HEPES buffer and 0.2% bovine serum albumin, pH 7.4) for 45 min at 37 °C.
  • the intracellular calcium mobilization induced by the CXCL-12 was then measured at 37 °C by monitoring the fluorescence as a function of time in all the wells simultaneously using a fluorometric imaging plate reader (FLIPR Tetra, Molecular Devices).
  • FLIPR Tetra fluorometric imaging plate reader
  • Chemokine (CXCL12-AF647) binding inhibition assay [00462] Jurkat cells expressing CXCR4 were washed once with assay buffer (Hanks’ balanced salt solution with 20 mM HEPES buffer and 0.2% bovine serum albumin, pH 7.4) and then incubated for 15 min at room temperature with the test compounds diluted in assay buffer at dose-dependent concentrations. Subsequently, CXCL12-AF647 (25 ng/mL) was added to the compound-incubated cells. The cells were incubated for 30 min at room temperature.
  • assay buffer Hors’ balanced salt solution with 20 mM HEPES buffer and 0.2% bovine serum albumin, pH 7.4
  • CXCL12-AF647 25 ng/mL
  • the cells were washed twice in assay buffer, fixed in 1% paraformaldehyde in PBS, and analyzed on the FL4 channel of a FACSCalibur flow cytometer equipped with a 635-nm red diode laser (Becton Dickinson, San Jose, CA, USA).
  • the compound numbers correspond to the compound numbers in Table 1.
  • Compounds having an activity designated as “A” provided an IC 50 of 1 to 100 nM; compounds having an activity designated as “B” provided an IC50 of >100 nm to ⁇ 1 ⁇ M; compounds having an activity designated as “C” provided an IC50 of 1 ⁇ M to ⁇ 2.5 ⁇ M; and compounds having an activity designated as “D” provided an IC 50 of 2.5 ⁇ M or greater.
  • Table 3 Inhibition of Ca 2+ Signalling and Inhibition of CXCL12 Binding C C C [00465] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

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Abstract

The present invention relates to compounds and methods of inhibiting C-X-C receptor type 4 (CXCR4). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various diseases.

Description

CXCR4 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Serial Nos. 63/044,632, filed June 26, 2020; and 63/132,308, filed December 30, 2020; the entire contents of which are incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION [0002] The present invention provides compounds useful as inhibitors of C-X-C receptor type 4 (CXCR4). The invention also provides pharmaceutical compositions comprising compounds of the present invention and methods of using such compounds in the treatment of various diseases. BACKGROUND OF THE INVENTION [0003] C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or cluster of differentiation 184 (CD184), is a seven transmembrane G-protein coupled receptor (GPCR) belonging to Class I GPCR or rhodopsin-like GPCR family. Under normal physiological conditions, CXCR4 carries out multiple roles and is principally expressed in the hematopoietic and immune systems. CXCR4 was initially discovered as one of the co-receptors involved in human immunodeficiency virus (HIV) cell entry. Subsequent studies showed that it is expressed in many tissues, including brain, thymus, lymphatic tissues, spleen, stomach, and small intestine, and also specific cell types such as hematopoietic stem cells (HSC), mature lymphocytes, and fibroblasts. CXCL12, previously designated SDF-1α, is the only known ligand for CXCR4. CXCR4 mediates migration of stem cells during embryonic development as well as in response to injury and inflammation. Multiple roles have been demonstrated for CXCR4 in human diseases such as cellular proliferative disorders, Alzheimer’s disease, HIV, rheumatoid arthritis, pulmonary fibrosis, and others. For example, expression of CXCR4 and CXCL12 have been noted in several tumor types. CXCL12 is expressed by cancer-associated fibroblast (CAFs) and is often present at high levels in the tumor microenvironment (TME). In clinical studies of a wide range of tumor types, including breast, ovarian, renal, lung, and melanoma, expression of CXCR4/CXCL12 has been associated with a poor prognosis and with an increased risk of metastasis to lymph nodes, lung, liver, and brain, which are sites of CXCL12 expression. CXCR4 is frequently expressed on melanoma cells, particularly the CD133+ population that is considered to represent melanoma stem cells; in vitro experiments and murine models have demonstrated that CXCL12 is chemotactic for such cells. [0004] Furthermore, there is now evidence implicating the CXCL12/CXCR4 axis in contributing to the loss or lack of tumor responsiveness to angiogenesis inhibitors (also referred to as “angiogenic escape”). In animal cancer models, interference with CXCR4 function has been demonstrated to alter the TME and sensitize the tumor to immune attack by multiple mechanisms such as elimination of tumor re-vascularization and increasing the ratio of CD8+ T cells to Treg cells. These effects result in significantly decreased tumor burden and increased overall survival in xenograft, syngeneic, and transgenic cancer models. See Vanharanta et al. (2013) Nat Med 19: 50-56; Gale and McColl (1999) BioEssays 21: 17-28; Highfill et al. (2014) Sci Transl Med 6: ra67; Facciabene et al. (2011) Nature 475: 226-230. [0005] These data underscore the significant, unmet need for CXCR4 inhibitors to treat the many diseases and conditions mediated by aberrant or undesired expression of the receptor, for example in cellular proliferative disorders. SUMMARY OF THE INVENTION [0006] It has now been found that compounds of the present invention, and pharmaceutically acceptable salts thereof, are effective as CXCR4 inhibitors. In one aspect, the present invention provides a compound of Formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. [0007] Compounds of the present invention, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are useful for treating a variety of diseases, disorders, and conditions associated with CXC receptor type 4 (CXCR4). Such diseases, disorders, and conditions include cellular proliferative disorders (e.g., cancer) such as those described herein. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention: [0008] Compounds of the present invention and pharmaceutically acceptable salts thereof are useful as inhibitors of CXCR4. Without wishing to be bound by any particular theory, it is believed that compounds of the present invention, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, inhibit the activity of CXCR4 and thus treat certain diseases, such as cancer. [0009] In one aspect, the present invention provides a compound of Formula I:
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R1 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6; each -R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each L1 is independently a covalent bond or a C1-6 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-; each -Cy- is independently a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R2 is a C1-6 aliphatic group substituted with one -CN, -N(R)2, or -C(O)N(R)2
Figure imgf000005_0001
group and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO2-; L2 is a covalent bond or a C1-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -or C(S)-; Ring B is phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, an 8-10 membered partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 is hydrogen or C1-3 aliphatic optionally substituted with 1, 2 or 3 substituents independently selected from deuterium or halogen; each R4 is independently hydrogen, deuterium, halogen, -CN, -OR6, or C1-4 alkyl, or two R4 groups on the same carbon are optionally taken together to form =NR6, =NOR6, =O, or =S; each R5 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6, or two R5 groups on the same carbon atom are optionally taken together to form =NR, =NOR, =O, =S, or a spirocyclic 3-6 membered carbocyclic ring; each R6 is independently hydrogen or C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each R7 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6; or two R7 groups on the same carbon atom are optionally taken together to form =O or =S; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, or 3;
Figure imgf000006_0001
provided that is not the same as . 2. Compounds and Definitions: [0010] 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, 75th Ed. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7th Edition, John Wiley & Sons, 2013, the entire contents of which are hereby incorporated by reference. [0011] 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 C3-C6 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. [0012] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 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. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. 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. Exemplary bicyclic rings include:
Figure imgf000008_0001
Exemplary bridged bicyclics include:
Figure imgf000008_0002
[0013] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0014] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0015] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)). [0016] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0017] 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. [0018] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, e.g. 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. [0019] The term “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. [0020] The term “halogen” means F, Cl, Br, or I. [0021] 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. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system 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 the like. [0022] 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, e.g. 5, 6, or 9 ring atoms; having 6, 10, or 14 ^ 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 quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin– 3(4H)–one. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [0023] 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, e.g. 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 N–substituted pyrrolidinyl). [0024] 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, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. [0025] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [0026] 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 every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are 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. [0027] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –
Figure imgf000011_0001
[0028] Each R ^ is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- 6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the 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 by a divalent substituent on a saturated carbon atom of R ^ selected from =O and =S; or each R ^ is optionally substituted with a monovalent substituent independently selected from halogen, – [0029] Each R ^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^ is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR* 2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R* 2))2–3O–, or – S(C(R*2))2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is –O(CR*2)2–3O–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0030] When R is C1–6 aliphatic, R is optionally substituted with halogen, R , -(hal
Figure imgf000013_0001
Figure imgf000013_0002
each R ^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 hete toms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^ is u stituted or where
Figure imgf000013_0003
preceded by halo is substituted only with one or more halogens. [ ] p g p y ,
Figure imgf000013_0004
Figure imgf000013_0005
rein each R† is independently hydrogen, C1–6 aliphatic,
Figure imgf000013_0006
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, 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; wherein when R† is C1–6 aliphatic, R† is optionally substituted with halogen, –R ^, -(haloR ^), -OH, –OR ^, – O(haloR ^), –CN, –C(O)OH, –C(O)OR ^, –NH2, –NHR ^, –NR ^ 2, or –NO2, wherein each R ^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^ is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0032] 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, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, 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, 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–toluenesulfonate, undecanoate, valerate salts, and the like. [0033] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. 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, loweralkyl sulfonate and aryl sulfonate. [0034] 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, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all 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 a 13C- or 14C-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. In certain embodiments, a warhead moiety, R1, of a provided compound comprises one or more deuterium atoms. [0035] As used herein, the term “inhibitor” is defined as a compound that binds to and /or inhibits CXCR4 with measurable affinity. In certain embodiments, an inhibitor has an IC50 and/or binding constant of less than about 100 µM, less than about 50 µM, less than about 1 µM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. [0036] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in CXCR4 activity between a sample comprising a compound of the present invention, or composition thereof, and CXCR4, and an equivalent sample comprising CXCR4, in the absence of said compound, or composition thereof. 3. Description of Exemplary Embodiments: [0037] In one aspect, the present invention provides a compound of Formula I:
Figure imgf000015_0001
I or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R1 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6; each -R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each L1 is independently a covalent bond or a C1-6 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-; each -Cy- is independently a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R2 is a C1-6 aliphatic group substituted with one -CN, -N(R)2, or -C(O)N(R)2
Figure imgf000016_0001
group and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO2-; L2 is a covalent bond or a C1-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -or C(S)-; Ring B is phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, an 8-10 membered partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 is hydrogen or C1-3 aliphatic optionally substituted with 1, 2 or 3 substituents independently selected from deuterium or halogen; each R4 is independently hydrogen, deuterium, halogen, -CN, -OR6, or C1-4 alkyl, or two R4 groups on the same carbon are optionally taken together to form =NR6, =NOR6, =O, or =S; each R5 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6, or two R5 groups on the same carbon atom are optionally taken together to form =NR, =NOR, =O, =S, or a spirocyclic 3-6 membered carbocyclic ring; each R6 is independently hydrogen or C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each R7 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6; or two R7 groups on the same carbon atom are optionally taken together to form =O or =S; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, or 3; provided that
Figure imgf000017_0002
he same as
Figure imgf000017_0001
[0038] As defined generally above, Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0039] In some embodiments, Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is an 8- 10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0040] In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0041] In some embodiments, Ring A is selected from:
Figure imgf000018_0001
Figure imgf000019_0001
[0044] In some embodiments, Ring A is selected from those depicted in Table 1, below. [0045] As defined generally above, each R1 is independently R, halogen, -CN, -OR, -N(R)2, - NO2, -N3, -SR, or -L1-R6. [0046] In some embodiments, R1 is R. In some embodiments, R1 is halogen. In some embodiments, R1 is -CN. In some embodiments, R1 is -OR. In some embodiments, R1 is -N(R)2. In some embodiments, R1 is -NO2. In some embodiments, R1 is -N3. In some embodiments, R1 is -SR. In some embodiments, R1 is -L1-R6. [0047] In some embodiments, R1 is hydrogen. In some embodiments, R1 is an optionally substituted C1-6 aliphatic group. In some embodiments, R1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R1 is an optionally substituted phenyl. In some embodiments, R1 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R1 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0048] In some embodiments, R1 is selected from R, halogen, -CN, -OR, -N(R)2, -SR, C1-6 aliphatic, or -L1-R6, wherein -L1- is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -C(S)-, or -Cy-; wherein the C1-6 hydrocarbon chain is optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -N(R)2, - NO2, -N3, =NR, =NOR, =O, =S, -OR, -SR, -SO2R, -S(O)R, -R, -Cy-R, -C(O)R, -C(O)OR, - OC(O)R, -C(O)N(R)2, -(R)NC(O)R, -OC(O)N(R)2, -(R)NC(O)OR, -N(R)C(O)N(R)2, - SO2N(R)2, -(R)NSO2R, -C(S)R, or -C(S)OR; and each -R is independently hydrogen, -CH2- phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, - CF3, -CH2CHF2, or -CH2CF3; or each -R is independently hydrogen or methyl; or -R is hydrogen. [0049] In some embodiments, R1 is selected from hydrogen, halogen, C1-6 alkyl (optionally substituted with 1, 2, or 3 halogens), -CN, -N(R)2, -OR, -SR, -S(O)R6, -SO2R6, -SO2NHR6,
Figure imgf000021_0001
ch -R is independently hydrogen, -
Figure imgf000021_0002
CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3; or each -R is independently hydrogen or methyl; or -R is hydrogen. [0050] In some embodiments, R1 is selected from hydrogen, halogen, C1-6 alkyl, -CN, -
Figure imgf000021_0003
Figure imgf000022_0001
Figure imgf000022_0002
and each -R is independently hydrogen, -CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3; or each -R is independently hydrogen or methyl; or -R is hydrogen. [0051] In some embodiments, R1 is hydrogen, halogen, C1-6 alkyl, -CN, -OR, -SR, or -N(R)2. [0052] In some embodiments, R1 is selected from those depicted in Table 1, below. [0053] As defined generally above, each L1 is independently a covalent bond or a C1-6 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)- , -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-. [0054] In some embodiments, L1 is a covalent bond. In some embodiments, L1 is a C1-6, C2- 6, C3-6, C4-6, C1-5, C2-5, C3-5, C1-4, or C2-4 bivalent straight or branched, optionally substituted hydrocarbon chain. In some embodiments, L1 is a C1-6, C2-6, C3-6, C4-6, C1-5, C2-5, C3-5, C1-4, or C2-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)- , -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-. [0055] In some embodiments, L1 is a C1-6, C2-6, C3-6, C4-6, C1-5, C2-5, C3-5, C1-4, or C2-4 bivalent straight or branched, optionally substituted hydrocarbon chain. In some embodiments, L1 is a C1-6, C2-6, C3-6, C4-6, C1-5, C2-5, C3-5, C1-4, or C2-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, - C(S)-, or -Cy-, and each -R is independently hydrogen, -CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3; or each -R is independently hydrogen or methyl; or -R is hydrogen. [0056] In some embodiments, L1 is selected from those depicted in Table 1, below. [0057] As defined generally above, each -Cy- is independently a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0058] In some embodiments, -Cy- is a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, -Cy- is an optionally substituted phenylene. In some embodiments, -Cy- is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, - Cy- is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, - Cy- is an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Figure imgf000024_0001
[0060] In some embodiments, -Cy- is selected from those depicted in Table 1, below. [0061] As defined generally above, R2 is
Figure imgf000024_0002
with one -CN, -N(R)2, or -C(O)N(R)2 group and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - S-, -SO-, or -SO2-. [0062] In some embodiments, R2 is me embodiments, R2 is C1-6
Figure imgf000024_0003
aliphatic group substituted with one -CN, -N(R)2, or -C(O)N(R)2 group and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO2-. [0063] In some embodiments, R2 is a C1-6, C2-6, C3-6, C4-6, C1-5, C2-5, C3-5, C1-4, C2-4, or C1-3 straight or branched aliphatic group substituted with one -CN, -N(R)2, or -C(O)N(R)2. In some embodiments, R2 is a C1-6, C2-6, C3-6, C4-6, C1-5, C2-5, C3-5, C1-4, C2-4, or C1-3 straight or branched aliphatic group substituted with one -CN, -N(R)2, or -C(O)N(R)2 and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO2-. [0064] In some embodiments, R2 is a C1, C2, C3, C4, C5, C6, C7, or C8 straight or branched aliphatic group substituted with one -CN, -N(R)2, or -C(O)N(R)2. In some embodiments, R2 is a C1, C2, C3, C4, C5, C6, C7, or C8 straight or branched aliphatic group substituted with one -CN, - N(R)2, or -C(O)N(R)2 and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO2-. [0065] In some embodiments, R2 is -(CH2)1-6-CN, -(CH2)1-6-N(R)2, or -(CH2)1-6-C(O)N(R)2. [0066] In some embodiments of R2, each -R is independently hydrogen, -CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, - CH2CHF2, or -CH2CF3; or each -R is independently hydrogen or methyl; or -R is hydrogen. [0067] In some embodiments, R2 is selected from those depicted in Table 1, below. [0068] As defined generally above, L2 is a covalent bond or a C1-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -or C(S)-. [0069] In some embodiments, L2 is a a covalent bond. In some embodiments, L2 is a C1-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -or C(S)-. [0070] In some embodiments, L2 is a C1, C2, C3, or C4 bivalent, straight-chain, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, - SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -or C(S)-. [0071] In some embodiments, L2 is a C1, C2, C3, or C4 bivalent, straight-chain, hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, or -S-; and L2 is optionally substituted with 1, 2, or 3 substituents independently selected from deuterium, halogen, -OR, -SR, -N(R)2, or -CN. [0072] In some embodiments, L2 is -O-, -S-, -N(R)-, -CH2-, -CH2CH2-, -CH2CH2CH2-, CH2CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)CH2-, or -C(CH3)2CH2-, and L2 is optionally substituted with 1, 2, or 3 substituents independently selected from deuterium or halogen. [0073] In some embodiments, L2 is selected from one of those depicted in Table 1, below. [0074] As defined generally above, Ring B is phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, an 8-10 membered partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0075] In some embodiments, Ring B is phenyl. In some embodiments, Ring B is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring B is an 8-10 membered partially unsaturated carbocyclic ring. In some embodiments, Ring B is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is an 8-10 membered bicyclic partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0076] In some embodiments, Ring B is phenyl or a 5- or 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0077] In some embodiments, Ring B is a 5-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is a 5-membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen or oxygen. In some embodiments, Ring B is a 5- membered monocyclic heteroaromatic ring having 1-2 nitrogen heteroatoms. [0078] In some embodiments, Ring B is a 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is a 6-membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen or oxygen. In some embodiments, Ring B is a 6- membered monocyclic heteroaromatic ring having 1-3 nitrogen heteroatoms. [0079] In some embodiments, Ring B is pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl (e.g., 1,3,5-triazinyl). In some embodiments, Ring B is imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl. [0080] In some embodiments, Ring B is selected from one of those depicted in Table 1, below. [0081] As defined generally above, R3 is hydrogen or C1-3 aliphatic optionally substituted with 1, 2 or 3 substituents independently selected from deuterium or halogen. [0082] In some embodiments, R3 is hydrogen. In some embodiments, R3 is C1-3 aliphatic optionally substituted with 1, 2 or 3 substituents independently selected from deuterium or halogen. [0083] In some embodiments, R3 is hydrogen, methyl, ethyl, -CD3, or -CH2CF3. In some embodiments, R3 is hydrogen. In some embodiments, R3 is methyl. [0084] In some embodiments, R3 is selected from those depicted in Table 1, below. [0085] As defined generally above, each R4 is independently hydrogen, deuterium, halogen, - CN, -OR6, or C1-4 alkyl, or two R4 groups on the same carbon are optionally taken together to form =NR6, =NOR6, =O, or =S. [0086] In some embodiments, R4 is hydrogen. In some embodiments, R4 is deuterium. In some embodiments, R4 is halogen. In some embodiments, R4 is –CN. In some embodiments, R4 is -OR6. In some embodiments, R4 is C1-4 alkyl. In some embodiments, two R4 groups on the same carbon are taken together to form =NR6, =NOR6, =O, or =S. [0087] In some embodiments, R4 is hydrogen, deuterium, halogen, -CN, C1-2 alkyl, or two R4 groups on the same carbon are taken together to form =O or =S. [0088] In some embodiments, R4 is selected from those depicted in Table 1, below. [0089] As defined generally above, each R5 is independently -R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6, or two R5 groups on the same carbon atom are optionally taken together to form =NR, =NOR, =O, =S, or a spirocyclic 3-6 membered carbocyclic ring. [0090] In some embodiments, R5 is -R. In some embodiments, R5 is halogen. In some embodiments, R5 is -CN. In some embodiments, R5 is –OR. In some embodiments, R5 is - N(R)2. In some embodiments, R5 is -NO2. In some embodiments, R5 is -N3. In some embodiments, R5 is -SR. In some embodiments, R5 is -L1-R6. In some embodiments, two R5 groups on the same carbon atom are taken together to form =NR, =NOR, =O, =S, or a spirocyclic 3-6 membered carbocyclic ring. [0091] In some embodiments, R5 is hydrogen. In some embodiments, R5 is an optionally substituted C1-6 aliphatic group. In some embodiments, R5 is a C1-6 alkyl group optionally substituted with 1, 2, 3, or 4 deuterium or halogen atoms. In some embodiments, R5 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R5 is an optionally substituted phenyl. In some embodiments, R5 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R5 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0092] In some embodiments, R5 is hydrogen, C1-6 alkyl, halogen, -CN, -CF3, -CD3, cyclopropyl, ethynyl, -OCH3, -OC me embo 5
Figure imgf000028_0001
diments, R is methyl. [0093] In some embodiments, R5 is selected from those depicted in Table 1, below. [0094] As defined generally above, each R6 is independently hydrogen or C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. [0095] In some embodiments, R6 is hydrogen. In some embodiments, R6 is C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. [0096] In some embodiments, R6 is C1-3 alkyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R6 is methyl, ethyl, or isopropyl. [0097] In some embodiments, R6 is selected from those depicted in Table 1, below. [0098] As defined generally above, each R7 is independently R, halogen, -CN, -OR, -N(R)2, - NO2, -N3, -SR, or -L1-R6; or two R7 groups on the same carbon atom are optionally taken together to form =O or =S. [0099] In some embodiments, R7 is R. In some embodiments, R7 is halogen. In some embodiments, R7 is -CN. In some embodiments, R7 is -OR. In some embodiments, R7 is -N(R)2. In some embodiments, R7 is -NO2. In some embodiments, R7 is -N3. In some embodiments, R7 is -SR. In some embodiments, R7 is -L1-R6. In some embodiments, two R7 groups on the same carbon atom are taken together to form =O or =S. [00100] In some embodiments, R7 is hydrogen. In some embodiments, R7 is an optionally substituted C1-6 aliphatic group. In some embodiments, R7 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R7 is an optionally substituted phenyl. In some embodiments, R7 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R7 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00101] In some embodiments, R7 is selected from R, halogen, -CN, -OR, -N(R)2, -SR, C1-6 aliphatic, or -L1-R6, wherein -L1- is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -C(S)-, or -Cy-; wherein the C1-6 hydrocarbon chain is optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -N(R)2, - NO2, -N3, =NR, =NOR, =O, =S, -OR, -SR, -SO2R, -S(O)R, -R, -Cy-R, -C(O)R, -C(O)OR, - OC(O)R, -C(O)N(R)2, -(R)NC(O)R, -OC(O)N(R)2, -(R)NC(O)OR, -N(R)C(O)N(R)2, - SO2N(R)2, -(R)NSO2R, -C(S)R, or -C(S)OR; and each -R is independently hydrogen, -CH2- phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, - CF3, -CH2CHF2, or -CH2CF3; or each -R is independently hydrogen or methyl; or -R is hydrogen. [00102] As defined generally above, m is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3. [00103] As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3. [00104] As defined generally above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3. [00105] As defined generally above, q is 0, 1, 2, or 3. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2. [00106] As defined generally above, the compound of Formula I or pharmaceutically acceptable salt thereof is provided such that e same as
Figure imgf000030_0002
Figure imgf000030_0001
By way of explanation and for purposes of clarity, it is understood that
Figure imgf000030_0003
not define the identical chemical moiety as . In some embodiments, the compound of Formula I is not a symmetrical compound. In some embodiments, Ring A is 2-pyridyl and R5 is not the same as R2. In some embodiments, Ring A is 2-pyridyl and R5 is not attached at the 2- or 6-position (i.e., the same location on the pyridyl ring as as R2). In some embodiments, Ring A is not a 2-pyridyl. In some embodiments, R5 is methyl. [00107] In some embodiments, the present invention provides a compound of Formula II-a or II-b:
Figure imgf000031_0001
or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R1, R2, R3, R4, R5, m, n, and p is as defined above and described in embodiments herein, both singly and in combination. [00108] In some embodiments, the present invention provides a compound of Formula III-a, III-b, III-c, III-d, or III-e:
Figure imgf000031_0002
or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R1, R2, R3, R5, R7, L2, n, and q is as defined above and described in embodiments herein, both singly and in combination. [00109] In some embodiments, the present invention provides a compound of Formula IV-a or IV-b:
Figure imgf000032_0001
or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R1, R2, R3, R4, R5, m, and p is as defined above and described in embodiments herein, both singly and in combination. [00110] In some embodiments, the present invention provides a compound of Formula V-a, V-b, or V-c:
Figure imgf000032_0002
or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, m, n, and p is as defined above and described in embodiments herein, both singly and in combination. [00111] In some embodiments, the present invention provides a compound of Formula VI-a, VI-b, VI-c, or VI-d:
Figure imgf000033_0001
VI-d or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R1, R2, R3, R4, R5, R7, L2, m, n, and q is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, R3 is hydrogen. In some embodiments, R3 is methyl. In some embodiments, R5 is methyl, isopropyl, halogen, -OMe, or -CF3. [00112] In some embodiments, the present invention provides a compound of Formula VII-a or VII-b:
Figure imgf000033_0002
VII-a VII-b or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, R5 is methyl, isopropyl, halogen, -OMe, or -CF3. [00113] In some embodiments, the present invention provides a compound of Formula VIII- a, VIII-b, VIII-c, VIII-d, VIII-e, or VIII-f:
Figure imgf000034_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, R7, L2, n, and q is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, R5 is methyl, isopropyl, halogen, -OMe, or -CF3. [00114] In some embodiments, the present invention provides a compound of Formula IX-a, IX-b, IX-c, IX-d, IX-e, or IX-f:
Figure imgf000035_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, R7, and q is as defined above and described in embodiments herein, both singly and in combination. [00115] In another aspect, the present invention provides a compound of Formula X:
Figure imgf000035_0002
or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or a 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R1 is independently hydrogen, deuterium, C1-4 alkyl, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6; each -R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each L1 is independently a covalent bond or a C1-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, - (R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, - (R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-; each -Cy- is independently a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R2 is p substituted with one -CN, -N(R)2, or -C(O)N(R)2
Figure imgf000036_0001
group and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO2-; L2 is a covalent bond or a C1-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -or C(S)-; Ring B is phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, an 8-10 membered partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 is hydrogen or C1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from deuterium or halogen; each R4 is independently hydrogen, deuterium, halogen, -CN, -OR6, or C1-4 alkyl, or two R4 groups on the same carbon are optionally taken together to form =NR6, =NOR6, =O, or =S; each R5 is independently hydrogen, C1-6 alkyl, halogen, -CN, -CF3, -CD3, cyclopropyl, ethynyl, -
Figure imgf000037_0001
each R6 is independently hydrogen or C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each R7 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6; or two R7 groups on the same carbon atom are optionally taken together to form =O or =S; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, or 2; and q is 0, 1, or 2; provided that
Figure imgf000037_0002
[00116] In some embodiments, Ring A is not
Figure imgf000038_0001
. e embodiments, Ring A is not
Figure imgf000038_0002
. [00117] Exemplary compounds of the invention are set forth in Table 1, below. Table 1: Exemplary Compounds
Figure imgf000038_0003
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
46 of 231
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
[00118] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. 4. General Methods of Providing the Present Compounds: [00119] The compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein. [00120] In the Schemes below, where a particular protecting group (“PG”), leaving group (“LG”), or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7th Edition, John Wiley & Sons, 2013, Comprehensive Organic Transformations, R. C. Larock, 3rd Edition, John Wiley & Sons, 2018, and Protective Groups in Organic Synthesis, P. G. M. Wuts, 5th edition, John Wiley & Sons, 2014, the entirety of each of which is hereby incorporated herein by reference. [00121] As used herein, the phrase “leaving group” (LG) includes, but is not limited to, halogens (e.g. fluoride, chloride, bromide, iodide), sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like. [00122] As used herein, the phrase “oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4- (ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9- fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl. [00123] Amino protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which is incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like. [00124] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See, for example, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7th Edition, John Wiley & Sons, 2013, the entirety of which is incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below. [00125] In one aspect, certain compounds of the present invention of Formula I, or subformulae thereof, are generally prepared according to Scheme 1 set forth below: Scheme 1
Figure imgf000066_0001
[00126] In Scheme 1 above, each of R1, R2, R3, R4, R5, Ring A, m, n, and p is as defined above and described in embodiments herein, both singly and in combination. [00127] As shown generally in Scheme 1, an aldehyde according to structure A may be condensed with a ketone such as acetone in the presence of a base to yield intermediate B, for example by following General Procedures E or F. The General Procedures are described in more detail in the Exemplification, below. Condensation with an amine such as NH2R3, e.g. methylamine, and an aldehyde of structure C, provides compounds of structure D. In some embodiments, such compounds are CXCR4 inhibitors according to the present invention. In other embodiments, compounds of structure D are reduced according to General Procedure A to provide compounds of structure E. In compounds of structure F where an appropriate leaving group (LG) is present, cross-coupling (such as Pd-catalyzed coupling) may be performed to provide compounds of structure E. Compounds of structure F may be prepared by halogenation or formation of another leaving group such as triflate. Scheme 2
Figure imgf000067_0001
[00128] Alternatively, as shown in Scheme 2, piperidone compounds of structure G may be reduced according to General Procedure A to afford compounds of structure H and subsequently reacted with an appropriate electrophile of formula LG-R3, wherein LG refers to an appropriate leaving group such as halide or mesylate, affording compounds of structure I. 5. Uses, Formulation and Administration, and Co-Administered Additional Therapeutic Agents Pharmaceutically acceptable compositions [00129] 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 CXCR4, 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 CXCR4, 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. [00130] 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. [00131] 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. [00132] As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of CXCR4, or a mutant thereof. [00133] 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, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, 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. [00134] 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 useful 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. [00135] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful 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. [00136] 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. [00137] 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. [00138] 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. [00139] 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 pharmaceutically 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. [00140] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or 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. [00141] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00142] In some embodiments, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food. [00143] 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. In some embodiments, 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. [00144] 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. The 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 [00145] Compounds and compositions described herein are generally useful for the inhibition of CXCR4 or a mutant thereof. [00146] The activity of a compound utilized in this invention as an inhibitor of CXCR4, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of CXCR4, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to CXCR4. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of CXCR4, or a mutant thereof, are set forth in the Examples below. [00147] 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. [00148] Provided compounds are inhibitors of CXCR4 and are therefore useful for treating one or more disorders associated with activity of CXCR4. Thus, in certain embodiments, the present invention provides a method for treating a CXCR4-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. [00149] As used herein, the terms “CXCR4-mediated” disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which CXCR4, or a mutant thereof, is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which CXCR4, or a mutant thereof, are known to play a role. [00150] In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder. Cellular Proliferative Disorders [00151] The present invention features methods and compositions for the diagnosis and prognosis of cellular proliferative disorders (e.g., cancer) and the treatment of these disorders by targeting CXCR4. Cellular proliferative disorders described herein include, e.g., cancer, obesity, and proliferation-dependent diseases. Such disorders may be diagnosed using methods known in the art. Cancer [00152] Cancer includes, in one embodiment, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom’s macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). [00153] In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma. [00154] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g. Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. [00155] In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient. [00156] Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, 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, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers. [00157] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma. [00158] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. [00159] In some embodiments, the present invention provides a method for treating a cancer that presents as a solid tumor, such as a sarcoma, carcinoma, or lymphoma, comprising the step of administering a disclosed compound, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas. In some embodiments, the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma. [00160] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. [00161] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. [00162] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma. [00163] In some embodiments, the present invention provides a method of treating a cancer selected from leukemias; Waldenstrom’s macroglobulinemia; multiple myeloma; heavy chain disease; and solid tumors, including sarcomas and carcinomas, including fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, renal cell carcinoma, colon carcinoma, colorectal carcinoma, pancreatic cancer, breast cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm’s tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, neuroblastoma, and retinoblastoma, comprising administering to a patient in need thereof an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof. [00164] The present invention further features methods and compositions for the diagnosis, prognosis and treatment of viral-associated cancers, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (See https://clinicaltrials.gov/ct2/show/ study/NCT02488759; see also https://clinicaltrials.gov/ct2/show/study/NCT0240886; https://clinicaltrials.gov/ct2/show/ NCT02426892). [00165] In some embodiments, the present invention provides a method for treating a tumor in a patient in need thereof, comprising administering to the patient any of the compounds, salts or pharmaceutical compositions described herein. In some embodiments, the tumor comprises any of the cancers described herein. In some embodiments, the tumor comprises melanoma cancer. In some embodiments, the tumor comprises breast cancer. In some embodiments, the tumor comprises lung cancer. In some embodiments, the the tumor comprises small cell lung cancer (SCLC). In some embodiments, the the tumor comprises non-small cell lung cancer (NSCLC). [00166] In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient. [00167] In some embodiments, the tumor is treated by arresting further growth of the tumor. In some embodiments, the tumor is treated by reducing the size (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the size of the tumor prior to treatment. In some embodiments, tumors are treated by reducing the quantity of the tumors in the patient by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the quantity of tumors prior to treatment. Primary Immune Deficiencies [00168] In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a primary immunodeficiency disease or disorder, comprising administering to a patient in need thereof an effective amount of a disclosed compound or pharmaceutically acceptable salt thereof. In some embodiments, the method treats, e.g. ameliorates, a symptom of a primary immunodeficiency, such as neutropenia. Primary immune deficiencies treatable by the methods of the present invention may be present at birth (i.e., congenital), acquired after birth, idiotypic and/or cyclic, and include: warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome; severe congenital neutropenia (SCN), such as those arising from G6PC3 deficiency (McDermott et al. (2010) Blood 116:2793-2802); GATA2 deficiency (Mono MAC syndrome) (Maciejweski-Duval et al. (2015) J. Leukoc. Biol. 5MA0815-288R (Epub. ahead of printing); idiopathic CD4+ T lymphocytopenia (ICL); and Wiskott-Aldrich Syndrome (WAS). In some embodiments, the present invention provides a method for treating a primary immune deficiency, such as neutropenia, chronic idiopathic neutropenia (CIN), severe CIN, cyclic neutropenia, G6PC3 Deficiency, or Glycogen Storage Disease Ib, comprising administering to a patient in need thereof an effective amount of a disclosed compound. [00169] In some embodiments, a disclosed compound or pharmaceutically acceptable salt thereof is co-administered with filgrastim (G-CSF) to treat the primary immunodeficiency. In some embodiments, a disclosed compound or pharmaceutically acceptable salt thereof is co- administered with G-CSF to treat CIN. In some embodiments, a disclosed compound or pharmaceutically acceptable salt thereof is administered to a patient who has previously been administered G-CSF to treat a primary immunodeficiency, such as CIN. In some embodiments, the disclosed compound replaces G-CSF therapy. [00170] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer, an autoimmune disorder, a primary immune deficiency, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone-related disorder, liver disease, or a cardiac disorder. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or disorder, the particular agent, its mode of administration, and the like. In some embodiments, compounds of the invention are formulated in unit dosage forms for ease of administration and uniformity of dosage. The expression “unit dosage form,” as used herein, refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “subject” or “patient,” as used herein, means an animal. In some embodiments, the subject or patient is a mammal, or, in some embodiments, a human. [00171] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and for example from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [00172] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00173] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic 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, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00174] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00175] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [00176] In some embodiments, compositions for rectal or vaginal administration are suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [00177] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00178] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00179] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00180] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. [00181] According to one embodiment, the invention relates to a method of inhibiting CXCR4 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. [00182] According to another embodiment, the invention relates to a method of inhibiting CXCR4, 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 CXCR4, 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. [00183] 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. [00184] Another embodiment of the present invention relates to a method of inhibiting CXCR4 in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. [00185] According to another embodiment, the invention relates to a method of inhibiting CXCR4, 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. According to certain embodiments, the invention relates to a method of irreversibly inhibiting CXCR4, 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 CXCR4, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein. Co-Administration of Additional Therapeutic Agents [00186] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” [00187] In some embodiments, the the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co- administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically. [00188] In some embodiments, the additional therapeutic agent is selected from an immunostimulatory therapeutic compound. In some embodiments, the immunostimulatory therapeutic compound is selected from elotuzumab, mifamurtide, an agonist or activator of a toll- like receptor, or an activator of ROR ^t. [00189] In some embodiments, the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor. In some embodiments, the method comprises administering to the patient in need thereof three therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, an immunostimulatory therapeutic compound, and an immune checkpoint inhibitor. [00190] Other checkpoint inhibitors that may be used in the present invention include OX40 agonists. OX40 agonists that are being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer 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). [00191] Other checkpoint inhibitors that may be used in the present invention include CD137 (also called 4-1BB) agonists. CD137 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). [00192] Other checkpoint inhibitors that may 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). [00193] Other checkpoint inhibitors that may 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 (NCT 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 IgG1 Fc domain, in advanced solid tumors (NCT02583165). [00194] Other checkpoint inhibitors that may be used in the present invention include inducible T-cell co-stimulator (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). [00195] Other checkpoint inhibitors that may be used in the present invention include killer IgG-like 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). [00196] Other checkpoint inhibitors that may 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 IgG1, 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). [00197] Other checkpoint inhibitors that may 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). [00198] Other checkpoint inhibitors that may 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). [00199] Other checkpoint inhibitors that may be used in the present invention include CSF1R inhibitors. CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R 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-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6- yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723). [00200] Other checkpoint inhibitors that may 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). [00201] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab. [00202] In another aspect, the present invention provides a method of treating cancer in a patient in need thereof, wherein said method comprises administering to said patient a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents selected from an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6 inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor. [00203] In some embodiments, the IDO inhibitor is selected from epacadostat, indoximod, capmanitib, GDC-0919, PF-06840003, BMS:F001287, Phy906/KD108, or an enzyme that breaks down kynurenine. [00204] In some embodiments, the PARP inhibitor is selected from olaparib, rucaparib, or niraparib. [00205] In some embodiments, the HDAC inhibitor is selected from vorinostat, romidepsin, panobinostat, belinostat, entinostat, or chidamide. [00206] In some embodiments, the CDK 4/6 inhibitor is selected from palbociclib, ribociclib, abemaciclib or trilaciclib. [00207] In some embodiments, the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor. In some embodiments, the method comprises administering to the patient in need thereof three therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6 inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor, and a third therapeutic agent selected from an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab. [00208] Another immunostimulatory therapeutic that may be used in the present invention 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). Another immunostimulatory therapeutic that may be used in the present invention is recombinant human interleukin 12 (rhIL-12). Another suitable 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). Recombinant human interleukin 12 (rhIL-12) has been tested in the clinic for many oncological indications, for example, as a therapy for lymphoma (NM-IL-12, Neumedicines, Inc.), (NCT02544724 and NCT02542124). [00209] In some embodiments, the PI3K inhibitor is selected from idelalisib, alpelisib, taselisib, pictilisib, copanlisib, duvelisib, PQR309, or TGR1202. [00210] In another aspect, the present invention provides a method of treating cancer in a patient in need thereof, wherein said method comprises administering to said patient a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents selected from a platinum-based therapeutic, a taxane, a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells. [00211] In some embodiments, the platinum-based therapeutic is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, or satraplatin. [00212] In some embodiments, the taxane is selected from paclitaxel, docetaxel, albumin- bound paclitaxel, cabazitaxel, or SID530. [00213] In some embodiments, the therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise interfere with the replication of rapidly proliferating cells is selected from trabectedin, mechlorethamine, vincristine, temozolomide, cytarabine, lomustine, azacitidine, omacetaxine mepesuccinate, asparaginase Erwinia chrysanthemi, eribulin mesylate, capacetrine, bendamustine, ixabepilone, nelarabine, clorafabine, trifluridine, or tipiracil. [00214] In some embodiments, the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor. In some embodiments, the method comprises administering to the patient in need thereof three therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from a platinum-based therapeutic, a taxane, a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells, and a third therapeutic agent selected from an immune checkpoint inhibitor. [00215] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab. [00216] In some embodiments, any one of the foregoing methods further comprises the step of obtaining a biological sample from the patient and measuring the amount of a disease-related biomarker. [00217] In some embodiments, the biological sample is a blood sample. [00218] In some embodiments, the disease-related biomarker is selected from circulating CD8+ T cells or the ratio of CD8+ T cells:Treg cells. [00219] In one aspect, the present invention provides a method of treating an advanced cancer, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof, either as a single agent (monotherapy), or in combination with a chemotherapeutic, a targeted therapeutic, such as a kinase inhibitor, and/or an immunomodulatory therapy, such as an immune checkpoint inhibitor. In some embodiments, the 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. [00220] In some embodiments, the additional therapeutic agent is a kinase inhibitor or VEGF- R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi). VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®, Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech/Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis). [00221] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen/Takeda). [00222] In some embodiments, the additional therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. Approved mTOR inhibitors useful in the present invention include everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer). [00223] In some embodiments, the additional therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. Approved PARP inhibitors useful in the present invention include olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); and niraparib (Zejula®, Tesaro). Other PARP inhibitors being studied which may be used in the present invention include talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.). [00224] In some embodiments, the additional therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. Approved PI3K inhibitors useful in the present invention include idelalisib (Zydelig®, Gilead). Other PI3K inhibitors being studied which may be used in the present invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics). [00225] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda). [00226] In some embodiments, the additional therapeutic agent is a histone deacetylase (HDAC) inhibitor. Approved HDAC inhibitors useful in the present invention include vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); and belinostat (Beleodaq®, Spectrum Pharmaceuticals). Other HDAC inhibitors being studied which may be used in the present invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China). [00227] In some embodiments, the additional therapeutic agent is a CDK inhibitor, such as a CDK 4/6 inhibitor. Approved CDK 4/6 inhibitors useful in the present invention include palbociclib (Ibrance®, Pfizer); and ribociclib (Kisqali®, Novartis). Other CDK 4/6 inhibitors being studied which may be used in the present invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics). [00228] In some embodiments, the additional therapeutic agent is an indoleamine (2,3)- dioxygenase (IDO) inhibitor. IDO inhibitors being studied which may be used in the present invention include 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); and an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics). [00229] In some embodiments, the additional therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca). [00230] In some embodiments, the additional therapeutic agent is an aromatase inhibitor. Approved aromatase inhibitors which may be used in the present invention include exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis). [00231] In some embodiments, the additional therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for treatment of basal cell carcinoma. [00232] In some embodiments, the additional therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly). [00233] In some embodiments, the additional therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan). [00234] In some embodiments, the additional therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010). [00235] In some embodiments, the additional therapeutic agent is an arginase inhibitor. Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences). [00236] In some embodiments, the additional therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences). [00237] In some embodiments, the additional therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (Rituxan®, Genentech/BiogenIdec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics). [00238] In some embodiments, the additional therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma). [00239] In some embodiments, the additional therapeutic agent is a nucleoside inhibitor, or other therapeutic that interfere with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells. Such nucleoside inhibitors or other therapeutics include trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine- based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology). [00240] In some embodiments, the additional therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and/or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells. Approved platinum-based therapeutics which may be used in the present invention include cisplatin (Platinol®, Bristol-Myers Squibb); carboplatin (Paraplatin®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (Eloxitin® Sanofi-Aventis); and nedaplatin (Aqupla®, Shionogi). Other platinum-based therapeutics which have undergone clinical testing and may be used in the present invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix). [00241] In some embodiments, the additional therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. Approved taxane compounds which may be used in the present invention include paclitaxel (Taxol®, Bristol- Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis/Celgene), and cabazitaxel (Jevtana®, Sanofi- Aventis). Other taxane compounds which have undergone clinical testing and may be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008). [00242] In some embodiments, the additional therapeutic agent is an inhibitor of anti- apoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740). [00243] In some embodiments, the present invention provides a method of treating prostate cancer comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in combination with an additional therapeutic agent that interferes with the synthesis or activity of androgens. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (Zytiga®, Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals). [00244] In some embodiments, the additional therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly). [00245] In some embodiments, the additional therapeutic agent is an inhibitor of bone resorption. An approved therapeutic which inhibits bone resorption is Denosumab (Xgeva®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases. Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis). [00246] In some embodiments, the additional therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613). [00247] In some embodiments, the additional therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFß). Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific, anti-PD-L1/TGFß trap compound (NCT02699515); and (NCT02517398). M7824 is comprised of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFß “trap.” Additional Co-Administered Therapeutic Agents – Targeted Therapeutics and Immunomodulatory Drugs [00248] In some embodiments, the additional therapeutic agent is selected from a targeted therapeutic or immunomodulatory drug. Adjuvant therapies with targeted therapeutics or immunomodulatory drugs have shown promising effectiveness when administered alone but are limited by the development of tumor immunity over time or evasion of the immune response. [00249] In some embodiments, the present invention provides a method of treating cancer, such as a cancer described herein, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in combination with an additional therapeutic agent such as a targeted therapeutic or an immunomodulatory drug. 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). [00250] In other embodiments, the immunomodulatory therapeutic 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, the additional therapeutic 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 virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, 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 ColoAd1), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the 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-1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered to express beta-galactosidase (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). [00251] In some embodiments, the additional therapeutic agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus 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-hTNFα- IRES-hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to raise an antigen-specific CD8+ T cell response. [00252] In some embodiments, the present invention comprises administering to said patient a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with 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. [00253] 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. [00254] For example, in some embodiments the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June; hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD19), fused to an intracellular signaling domain of 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 CD19, 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=1]. Additional Co-Administered Therapeutic Agents – Immunostimulatory Drugs [00255] In some embodiments, the additional therapeutic agent is an immunostimulatory drug. 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. The 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. [00256] In some embodiments, the present invention provides a method of treating cancer, such as a cancer described herein, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in combination with an additional therapeutic agent such as a immunostimulatory drug, such as an immune checkpoint inhibitor. In some embodiments, the compound and the checkpoint inhibitor are administered simultaneously or sequentially. In some embodiments, a compound disclosed herein is administered prior to the initial dosing with the immune checkpoint inhibitor. In certain embodiments, the immune checkpoint inhibitor is administered prior to the initial dosing with the compound disclosed herein. [00257] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some embodiments, a CXCR4 antagonist such as a compound disclosed herein or a pharmaceutically acceptable salt thereof is administered in combination with nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); or atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech). [00258] Other immune checkpoint inhibitors suitable for use in the present invention include 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-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; and 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). [00259] Another paradigm for immune-stimulation is the use of oncolytic viruses. In some embodiments, the present invention provides a method for treating a patient by administering a CXCR4 antagonist such as a compound disclosed herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in combination with an immunostimulatory therapy such as oncolytic viruses. Approved immunostimulatory oncolytic viruses which may be used in the present invention include talimogene laherparepvec (live, attenuated herpes simplex virus, Imlygic®, Amgen). [00260] In some embodiments, the additional therapeutic agent is an activator of retinoic acid receptor-related orphan receptor ^ (ROR ^t). ROR ^t is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells. An activator of ROR ^t, that is being studied which may be used in the present invention is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862). [00261] In some embodiments, the additional therapeutic 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). [00262] Other checkpoint inhibitors that may be used in the present invention include inhibitors 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). [00263] Other checkpoint inhibitors that may be used in the present invention include inhibitors 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). [00264] Checkpoint inhibitors that may be used in the present invention also include inhibitors 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). [00265] Other immune-oncology agents that may be used in the present invention in combination with CXCR4 inhibitors such as a compound disclosed herein 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 Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody. [00266] Other additional therapeutic agents that may be used in the present invention include glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE. gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize. [00267] A compound of the current invention may also be used to advantage in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to checkpoint inhibitors; 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 Conforma 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, PD181461 from Pfizer and leucovorin. [00268] 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. [00269] 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 signalling processes should proceed. [00270] In one aspect, the checkpoint inhibitor is a biologic therapeutic or a small molecule. In another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof. In a further aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDLl, PDL2, PDl, 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 an additional aspect, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDLl, PDL2, PDl, 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 an aspect, the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof. In a further aspect, the interleukin is IL-7 or IL-15. In a specific aspect, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine. [00271] Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors may include small molecule inhibitors or may include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that may 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, γδ, and memory CD8+ (αβ) 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 Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-Ll 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-Ll, PD-L2, B7-H3, B7- H4, CD28, CD86 and TIM-3. [00272] 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®). [00273] 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. [00274] 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 hormone receptor positive tumors, such as breast tumors. [00275] 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. [00276] 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™). The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™. [00277] 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™. [00278] The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, 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. [00279] 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; discodermolides; 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™. [00280] 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™. [00281] The term "histone deacetylase inhibitors" or "HDAC 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). [00282] The 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™. [00283] 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™. [00284] 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 AxI receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the 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-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting 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, TYK2, 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; lsis 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); l) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1 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, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the 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 (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib). [00285] 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 PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K- C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in 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. [00286] The 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), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), 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. [00287] The 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. [00288] 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. [00289] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference. [00290] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference. [00291] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference. [00292] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference. [00293] 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. [00294] 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. [00295] 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. [00296] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, α- γ- or δ- tocopherol or α- γ- or δ-tocotrienol. [00297] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, such as celecoxib (Celebrex™), etoricoxib, valdecoxib, or lumiracoxib. [00298] 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. [00299] The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons. [00300] The term "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 "farnesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (Zarnestra™). 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 telomestatin. [00301] 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. [00302] 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. [00303] The 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. [00304] The 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-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase. [00305] 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. [00306] 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 of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors. [00307] The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity. [00308] 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, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412. [00309] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2'-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. 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-1H-indol-3-yl)-ethyl]- amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically 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., 4th Edition, Vol.1 , pp.248-275 (1993). [00310] 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. The 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-1H-isoindole-1 ,3-dione derivatives. [00311] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor 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 (Avastin™). [00312] 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. [00313] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone. [00314] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone. [00315] 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. [00316] 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). [00317] 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. [00318] 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. [00319] 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. [00320] 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 compound 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. [00321] The 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 the particular mode of administration. In some embodiments, 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. [00322] 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 that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 ^g/kg body weight/day of the additional therapeutic agent can be administered. [00323] 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. In some embodiments, the 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. [00324] The 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 General Synthetic Methods [00325] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereafter should be considered to be disclosed. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. [00326] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. [00327] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Abbreviations equiv or eq: molar equivalents o/n: overnight rt: room temperature UV: ultra violet HPLC: high pressure liquid chromatography Rt: retention time LCMS or LC-MS: liquid chromatography-mass spectrometry NMR: nuclear magnetic resonance CC: column chromatography TLC: thin layer chromatography sat: saturated aq: aqueous Ac: acetyl DCM: dichloromethane DCE: dichloroethane DEA: diethylamine DMF: dimethylformamide DMSO: dimethylsulfoxide ACN or MeCN: acetonitrile DIPEA: diisopropylethylamine EA or EtOAc: ethyl acetate BINAP: (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene TEA: triethylamine THF: tetrahydrofuran TBS: tert-butyldimethylsilyl KHMDS: potassium hexamethyl disilylazide Tf: trifluoromethanesulfonate Ms: methanesulfonyl NBS: N-bromosuccinimide PE: petroleum ether TFA: trifluoroacetic acid MMPP: magnesium monoperoxyphthalate HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid Hexafluorophosphate NCS: N-chlorosuccinimide Cy: cyclohexyl Tol: toluene DMP: Dess-Martin periodinane IBX: 2-iodoxybenzoic acid PMB: p-methoxybenzyl SEM: [2-(Trimethylsilyl)ethoxy]methyl XPhos or X-Phos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [00328] General information: All evaporations were carried out in vacuo with a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC) was performed on silica gel plates, spots were visualized by UV light (214 and 254 nm). Purification by column and flash chromatography was carried out using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. All 1H NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts are reported in δ values in parts per million (ppm) with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), integration (i.e. number of protons). LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization and except as otherwise indicated, the general LCMS conditions were as follows: Waters X Bridge C18 column (50 mm*4.6 mm*3.5 µm), Flow Rate: 2.0 mL/min, the column temperature: 40 °C. [00329] General procedure A (Wolff-Kishner Reduction): A mixture of 2,6-diaryl piperidin-4-one (concentration 0.1-1 M), KOH (20 equiv.) and N2H4•H2O (40 equiv.) in diethylene glycol was stirred for about 2 hours at 80 °C and then at approx.150-200 °C until the reaction completed. After cooled down to room temperature, the reaction mixture was diluted with water and extracted with DCM or another appropriate solvent. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography to give the desired 2,6-diaryl piperidine. [00330] General procedure B (N-Alkylation of 2,6-diaryl piperidine): To a solution of 2,6- diaryl piperidine (concentration 0.1-1 M ) in DMF or MeCN was added corresponding halide or mesylate (2 equiv.) and K2CO3 (2 equiv.) under Ar atmosphere. The mixture was stirred at 80 °C overnight, then it was diluted with H2O and extracted with DCM. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give desired N-alkylated target. [00331] General procedure C (Reaction of alcohols with methanesulfonyl chloride): To a solution of alcohol (concentration 0.1-1 M) and Et3N (approx. 2.5 equiv.) in DCM was added MsCl (1.2-1.4 equiv.) dropwise at -70 °C, and the reaction mixture was stirred at room temperature for 30 mins, then the resulting mixture was quenched with NaHCO3 (aq.) and extracted with DCM. The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the corresponding mesylate. [00332] General procedure D (Reaction of mesylates or halides with 2,6-diaryl piperidine): A mixture of 2,6-diaryl piperidine (concentration 0.1-1 M), corresponding mesylate or halide (approx. 2-3 equiv.), KI (0.2-0.3 equiv.), DIPEA (2-3 equiv.) in DMF or MeCN was stirred overnight at 60-80 °C and filtered. The filtrate was purified by prep-HPLC to get the alkylated 2,6-diaryl piperidine. [00333] General procedure E (Reaction of aryl aldehyde with acetone to give 4-(heteroaryl or aryl)but-3-en-2-one: A mixture of corresponding aryl aldehyde (concentration 0.1-1 M), acetone (20 equiv.) and K2CO3 (1.5-2 equiv.) in toluene/EtOH/H2O (5:2:1) was stirred at 80 °C for approx.13 hours and cooled down to room temperature. After diluted with EA, The reaction mixture was filtered through basic silica gel column and washed with DCM/MeOH (100/1). The filtrate was concentrated in vacuum to give 4-(heteroaryl or aryl)but-3-en-2-one which was used in the next step without further purification. [00334] General procedure F (Reaction of aryl aldehyde with acetone to give 4-(heteroaryl or aryl)but-3-en-2-one): To a mixture of aryl aldehyde (concentration 0.1-1 M) in acetone were added a solution of NaOH (approx.8 M, 1.5 equiv.) in H2O at 0 °C. The mixture was stirred at 0 °C for 1 hour. Then it was warmed to room temperature and stirred another 2 hours. The solution was adjusted pH to 8 with 35% HCl aq., dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 4- (heteroaryl or aryl)but-3-en-2-one. [00335] General procedure G (Buchwald coupling of aryl bromide with alkyl amine): A mixture of aryl bromide (concentration 0.1-1 M), alkyl amine (2 equiv., 0.2-2 M), Pd(OAc)2 (0.1- 0.15 equiv.), BINAP (0.2-0.3 equiv.), and Cs2CO3 (2-4 equiv.) in toluene was stirred at 75-120 °C overnight. After completed, the reaction mixture was concentrated in vacuum and purified by column chromatography to afford the desired product. [00336] General procedure H (Suzuki coupling of aryl bromide with aryl boronic acid): aryl bromide (concentration 0.1-1 M), aryl boronic acid (1.1-1.5 equiv.), PdCl2(dppf) (0.05-0.08 equiv.), and Na2CO3 aq. (1 M, 2.5 equiv.) in 1,4-dioxane was stirred at 80-100 °C for 10 min. under microwave irradiation. After the reaction was completed, the mixture was diluted with water and the aqueous layer was extracted with DCM 3 times. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum and the residue was purified by silica gel column. [00337] General procedure I (reductive amination of secondary amine to tertiary amine): To a mixture of secondary amine (concentration 0.1-1 M), corresponding aldehyde or ketone (1- 2 equiv.) and NaBH(OAc)3 (3-6 equiv.) in DCM was added several drops of acetic acid, and then the mixture was stirred at room temperature for 2-18 h. The mixture was neutralized with saturated NaHCO3 aqueous solution to pH = 8-9 and extracted with DCM. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give the desired tertiary amine. [00338] General procedure J (Boc cleavage of N-Boc protected amines): To a solution of N-Boc protected amine (concentration 0.1-1 M) in DCM was added TFA (1/15 volume of DCM) at room temperature. The reaction mixture was stirred for 2 h, then concentrated and saturated NaHCO3 aqueous solution was added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the free amine as the desired product. [00339] General procedure K (Reaction of aryl ester with EA or tert-butyl acetate to give 3-oxopropanoate): To the solution of aryl ester (concentration 0.1-1 M) and EA or tert-butyl acetate (3-6 equiv.) in THF at -50 °C was added LiHMDS (3 equiv.) in portions, then the mixture was allowed to stirred at room temperature overnight. After completion of the reaction as indicated by LCMS, the mixture was poured into water and concentrated to remove THF, then extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to give desired product which was used in the next step without further purification. [00340] General procedure L (Michael addition reaction): A mixture of 3-oxopropanoate (concentration 0.1-1 M), 2-en-1-one (1.5 equiv.) and K2CO3 (2 equiv.) in CH3CN was stirred at room temperature overnight. After completion of the reaction was indicated by LCMS, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography to give desired product. [00341] General procedure M (Reaction of de-tert-butyl acetate to give 1,5-dione): A solution of 2-tert-butyl formate-1,5-dione (concentration 0.1-1 M) in DCM was added TFA (1/1 volume of DCM), and the solution was stirred at room temperature overnight. After completion of the reaction as indicated by LCMS, the solution was concentrated in vacuum, to the residue was added DCM, the pH adjusted to 9 with NaHCO3 aq., and then extracted with DCM. The combined organic layer was washed by brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum and the residue was purified by silica gel column to give desired product. [00342] General procedure N (Cyclization reaction of 1,5-dione): A solution of 1,5-dione (concentration 0.1-1 M), NH4OAc (10 equiv.), AcOH (1.1 equiv.), KOH (0.25 equiv.), and NaBH3CN(1.5 equiv.) in CH3OH was stirred at room temperature overnight and heated at reflux overnight again under N2 protection. After completion of the reaction as indicated by LCMS, the solution was concentrated in vacuum, the residue was extracted with DCM. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude, which was purified by silica gel column chromatograph to give desired product. [00343] General procedure P (Reaction of N-Boc protection): A solution of free amine (concentration 0.1-1 M), (Boc)2O (1.5-3 equiv.), and TEA (2-4 equiv.) in THF was heated at reflux overnight. After completion of the reaction as indicated by LCMS, the solution was concentrated in vacuum, the residue was extracted with DCM. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude, which was purified by silica gel column chromatograph to give N-Boc protected amines. [00344] General procedure Q (Insertion reaction of carbonyl with aryl bromide): A mixture of aryl bromide (concentration 0.1-1 M), Pd(dppf)Cl2 (0.1-0.3 equiv.) and TEA (2 equiv.) in DMF/EtOH (1/1) was stirred at 70 °C for 2 hours under CO protection. After completion of the reaction as indicated by LCMS, the solution was quenched by water, extracted with EA. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude, which was purified by silica gel column chromatograph to give desired product. [00345] General procedure R (Reaction of aryl bromide with ethyl arylate to diaryl ketone): A solution of aryl bromide (1.3-2.5 eq.) in THF was slowly added n-BuLi (1.3-2.5 eq.) at -70 °C, and the solution was stirred at -50 °C for 30 minutes, and then a solution of ethyl arylate (concentration 0.1-1 M) in THF was added at -70 °C, the solution was stirred at the same temperature for another 10 minutes. After completion of the reaction as indicated by LCMS, the solution was quenched by NH4Cl aq., extracted with DCM. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude, which was purified by silica gel column chromatograph to give desired product. [00346] General procedure S (Sonogashira cross-coupling): A mixture of aryl bromide (concentration 0.1-1 M), terminal alkynes (3 equiv.), CuI (0.1 equiv.), Pd(PPh3)2Cl2 (0.1 equiv.) and DIPEA (2 equiv.) in THF was stirred at 60 °C for 2 h under N2 atmosphere. After LCMS indicated the reaction was completed, the reaction mixture was cooled to room temperature and concentrated in vacuum and the residue was purified by column chromatography to give desired product. [00347] General procedure T (Reduction of olefins or alkynes): A mixture of olefins or alkynes (concentration 0.1-0.2 M) and Pd/C (10%) in MeOH was stirred at room temperature for 4 h under H2 atmosphere. After LCMS indicated the reaction was completed, the reaction mixture was filtered through Celite and concentrated to give desired product. [00348] General procedure U (Hydrogenation of diarylmethyl methanesulfonate (OMs) with Pd/C): A mixture of diarylmethyl methanesulfonate (concentration 0.1-0.2 M) and Pd/C (10-50%) in THF was stirred at room temperature for 1 to 2 days under H2 atmosphere. After completion of the reaction as indicated by LCMS, the reaction mixture was filtered through Celite and concentrated to give crude product, which was purified by column chromatography to give desired product. [00349] General procedure V (Tertiary alcoholization of arylmethyl with 2,4- dimethylpentan-3-one): To a solution of arylmethyl compound (concentration 0.1-0.2 M) and 2,4-dimethylpentan-3-one in THF was added LDA or LiHMDS at -30 °C, then the mixture was stirred at -30 °C for 4 h to overnight. After completion of the reaction as indicated by LCMS, the reaction mixture was quenched by aq. NH4Cl and extracted with DCM. The combined organic layer was washed by brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give crude product, which was purified by silica gel column chromatograph to give desired product. [00350] General procedure W (Reduction of ester to alcohol): To a suspension of lithium aluminum hydride (LAH) (2 equiv.) in THF was added a solution of ester (concentration 0.1-0.2 M) in THF at 0 °C under N2. The mixture was stirred at 0 °C for 1 h, and then water (6 equiv.), NaOH aq. (15%, 6 equiv.), and water (18 equiv.) were added to the mixture at 0 °C to quench the reaction. The mixture was returned to room temperature. Anhydrous Na2SO4 was added to the mixture, filtered and concentrated in vacuum to give desired product. [00351] General procedure X (Reduction of Weinreb amide to aldehyde): To a solution of Weinreb amide (concentration 0.1-0.2 M) in THF was added diisobutyl aluminum hydride (DIBAL-H) (1 M in toluene, 3 equiv.) dropwise at -60 °C, and then the reaction mixture was stirred at this temperature for 0.5 hour. H2O (6 equiv.) was added slowly, the reaction mixture was stirred at room temperature for 10 min. 15% NaOH aq. (6 equiv.) was added slowly, the reaction mixture was stirred at room temperature for 10 min. H2O (18 equiv.) was added slowly, the reaction mixture was stirred at room temperature for 10 min. MgSO4 was added and the mixture was filtered, the filtrate was concentrated under vacuum to give crude product, which was purified by silica gel column chromatography to give desired product.
Example 1: Synthesis of I-47 and I-48 Synthetic Scheme for I-47 and I-48
Figure imgf000122_0001
[00352] The synthesis of 1-1
Figure imgf000122_0002
Following general procedure K, to the solution of 1-0 (5.0 g, 21.7 mmol) and tert-butyl acetate (7.6 g, 65.2 mmol) in THF (30 mL) at -50 °C was added LiHMDS (65 mL, 1 M) in portions, then the mixture was allowed to stirred at room temperature overnight. After completion of the reaction as indicated by LCMS, the mixture was poured into water and concentrated to remove THF, then extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to give 1-1 (5.0 g, yield: 77%) as a pale yellow solid, which was used for next step straightly. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 88.4%. Rt = 2.247 min; MS Calcd.: 299.0; MS Found: 244.2 [M-56 + H]+. [00353] The synthesis of 1-2
Figure imgf000123_0001
Following general procedure L, a mixture of 1-1 (5.0 g, 16.66 mmol), 1-B (3.7 g, 24.99 mmol) and K2CO3 (4.6 g, 33.32 mmol) in CH3CN (100 mL) was stirred at room temperature overnight. After completion of the reaction as indicated by LCMS, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography to give 1-2 (5.0 g, yield: 67%) as yellow solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X- Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 94.3%. Rt = 2.472 min; MS Calcd.: 446.1; MS Found: 447.3 [M + H]+. [00354] The synthesis of 1-3
Figure imgf000123_0002
Following general procedure M, a solution of 1-2 (5.0 g, 11.18 mmol) in DCM (50 mL) was added TFA (50 mL), and the solution was stirred at room temperature overnight. After completion of the reaction as indicated by LCMS, the solution was concentrated in vacuum, the residue was added DCM, adjusted pH to 9 with NaHCO3 aq., extracted with DCM. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude, which was purified by silica gel column chromatograph to give 1-3 (3.0 g, yield: 77 %) as yellow solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 95.8%. Rt = 2.258 min; MS Calcd.: 346.0; MS Found: 347.2 [M + H]+. [00355] The synthesis of 1-4
Figure imgf000124_0001
Following general procedure N, a solution of 1-3 (3.0 g, 8.67 mmol), NH4OAc (6.7 g, 86.7 mmol), AcOH (572 mg, 9.54 mmol), KOH (121 mg, 2.17 mmol), and NaBH3CN (819 mg, 13.0 mmol) in CH3OH (100 mL) was stirred at room temperature overnight and heated at reflux overnight again under N2 protection. After completion of the reaction as indicated by LCMS, the solution was concentrated in vacuum, the residue was extracted with DCM. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude, which was purified by silica gel column chromatograph to give 1-4 (2.0 g, yield: 70%) as brown oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 91.2%. Rt = 2.064 min; MS Calcd.: 331.1; MS Found: 332.3 [M + H]+. [00356] The synthesis of 1-5
Figure imgf000125_0001
Following general procedure P, a solution of 1-4 (2.0 g, 6.04 mmol), (Boc)2O (2.0 g, 9.06 mmol), and TEA (1.2 g, 12.08 mmol) in THF (50 mL) was heated at reflux overnight. After completion of the reaction as indicated by LCMS, the solution was concentrated in vacuum, the residue was extracted with DCM. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude, which was purified by silica gel column chromatograph to give 1-5 (2.0 g, yield: 77%) as a yellow solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 92.9%; Rt = 2.673 min; MS Calcd.: 431.1; MS Found: 432.3 [M + H]+. [00357] The synthesis of 1-6
Figure imgf000125_0002
Following general procedure Q, a mixture of 1-5 (2.0 g, 4.64 mmol), Pd(dppf)Cl2 (679 mg, 0.93 mmol) and TEA (937 mg, 9.28 mmol) in DMF/EtOH (1/1, 30 mL) was stirred at 70 °C for 2 hours under CO protection. After completion of the reaction as indicated by LCMS, the solution was quenched by water, extracted with DCM. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude, which was purified by silica gel column chromatograph to give 1-6 (1.2 g, yield: 61 %) as yellow solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 89.7%. Rt = 1.963 min; MS Calcd.: 425.2; MS Found: 426.3 [M + H]+. [00358] The synthesis of 1-7
Figure imgf000126_0001
Following general procedure R, a solution of 2-bromo-3-methylpyridine (243 mg, 2.82 mmol) in THF (10 mL) was slowly added n-BuLi (2.5 M, 1.24 ml, 3.11 mmol) at -70 °C, and the solution was stirred at -50 °C for 30 minutes, and then a solution of 1-6 (600 mg, 1.41 mmol) in THF (5 ml) was added at -70 °C, the solution was stirred at the same temperature for another 10 minutes. After completion of the reaction as indicated by LCMS, the solution was quenched by NH4Cl aq., extracted with DCM. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude, which was purified by silica gel column chromatograph to give 1-7 (400 mg, yield: 60%) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 94.6%. Rt = 2.500 min; MS Calcd.: 472.3; MS Found: 473.2 [M + H]+. [00359] The synthesis of 1-8
Figure imgf000127_0001
Following general procedure J, a solution of 1-7 (400 mg, 0.85 mmol) and TFA (3 ml) in DCM (6 mL) was stirred at room temperature overnight. After completion of the reaction as indicated by LCMS, the solution was concentrated in vacuum, the residue was added DCM, adjusted pH to 9 with NaHCO3 aq., extracted with DCM. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude, which was purified by silica gel column chromatograph to give 1-8 (300 mg, yield: 95 %) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 94.5%. Rt = 1.589 min; MS Calcd.: 372.2; MS Found: 373.3 [M + H]+. [00360] The synthesis of I-48
Figure imgf000127_0002
Following general procedure A, a mixture of 1-8 (150 mg, 0.40 mmol), hydrazine hydrate (806 mg, 16.13 mmol) and potassium hydroxide (452 mg, 8.06 mmol) in diethylene glycol (10 mL) was stirred at 80 °C for 1 h under argon atmosphere, after then warmed to 130 °C and stirred for 4 hours. After completion of the reaction indicated by LCMS, the mixture was quenched with water, and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum and the residue was purified by prep-HPLC to give I-48 (63 mg, yield: 44%) as light-yellow oil. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: >99%. Rt = 1.876 min; MS Calcd.: 358.2; MS Found: 359.2 [M + H] +. HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min. Purity: >99%. Rt = 9.199 min. 1H NMR (400 MHz, CD3OD): δ 8.43 (d, J = 3.6 Hz, 1H), 8.29 (d, J = 3.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 2H), 7.57 (dd, J = 7.6, 0.8 Hz, 1H), 7.23-7.17 (m, 3H), 7.05 (d, J = 8.0 Hz, 1H), 4.39 (d, J = 4.4 Hz, 2H), 4.22 (dd, J = 11.6, 2.0 Hz, 1H), 3.99 (dd, J = 12.0, 2.0 Hz, 1H), 2.41 (s, 3H), 2.38 (s, 3H), 2.08-2.04 (m, 1H), 1.96-1.84 (m, 3H), 1.54-1.47 (m, 2H). [00361] The synthesis of I-47
Figure imgf000128_0001
Following general procedure I, to a solution of crude I-48 (150 mg, 0.42 mmol), formaldehyde (37%, 204 mg, 2.51 mmol) and NaBH3CN (53 mg, 0.84 mmol) in MeOH (5 mL) was added AcOH (1 drop), and the mixture was stirred at room temperature overnight. After completion of the reaction indicated by LCMS, the mixture was quenched by saturated NaHCO3 aqueous, and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the residue, which was purified by prep-HPLC to give I-47 (44 mg, yield: 28%) as light yellow oil. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 30 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: >99%. Rt = 2.054 min; MS Calcd.: 372.2; MS Found: 373.2 [M + H]+. HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min. Purity: >99%. Rt = 9.981 min. 1H NMR (400 MHz, CD3OD): δ 8.38 (br, 1H), 8.32 (d, J = 4.0 Hz, 1H), 7.70- 7.60 (m, 4H), 7.26-7.19 (m, 2H), 6.86 (d, J = 7.6 Hz, 1H), 4.36 (s, 2H), 3.61 (d, J = 8.0 Hz, 1H), 3.31 (br, 1H), 2.53 (s, 3H), 2.28 (s, 3H), 1.94-1.86 (m, 3H), 1.76 (s, 3H), 1.72-1.63 (m, 3H).
Example 2: Synthesis of I-28 Synthetic Scheme for I-28
Figure imgf000130_0001
Following general procedure Q, 2-1 (350 mg, yield: 59.5%) was obtained as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 94.95%, Rt = 1.87 min; MS Calcd.: 339.2; MS Found: 340.2 [M+H]+. [00363] The synthesis of 2-2
Figure imgf000131_0001
To a suspension of LAH (78 mg, 2.06 mmol) in THF (20 mL) was added a solution of 2-1 (350 mg, 1.03 mmol) in THF (10 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h, then water (0.08 mL), NaOH aq. (15%, 0.08 mL), and water (0.24 mL) were added to the mixture at 0 °C to quench the reaction. The mixture was returned to room temperature. Anhydrous Na2SO4 was added to the mixture, filtered and concentrated in vacuum to give the 2-2 (300 mg, yield: 97.8%) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 76.55%, Rt = 1.43 min; MS Calcd.:297.2; MS Found: 298.2 [M+H]+. [00364] The synthesis of 2-3
Figure imgf000131_0002
Following general procedure C, To a solution of 2-2 (130 mg, 0.44 mmol) and Et3N (133 mg, 1.32 mmol) in DCM (15 mL) was added MsCl (75 mg, 0.66 mmol) under Ar protection at 0 °C. Then the mixture was returned to room temperature and stirred for 2 h. NaHCO3 aq. (10 mL) was added to the mixture, extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give 2-3 (150 mg, yield: 91.4%) as yellow oil. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 82.12%, Rt = 1.92 min; MS Calcd.: 375.2; MS Found: 376.2 [M+H]+. [00365] The synthesis of 2-4
Figure imgf000132_0001
To a solution of 2-3 (150 mg, 0.4 mmol) in acetone (10 mL) was added LiBr (104 mg, 1.2 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. water (10 mL) was added to the mixture, extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give 2-4 (120 mg, yield: 83.4%) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 56.70%, Rt = 2.14 min; MS Calcd.: 359.2; MS Found: 360.2 [M+H]+. [00366] The synthesis of 2-5
Figure imgf000133_0001
To a solution of 2-4 (120 mg, 0.33 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl - 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (139 mg, 0.5 mmol), Cs2CO3 (215 mg, 0.66 mmol) in THF (20 mL) and water (5 mL) was added Pd(dppf)Cl2 (22 mg, 0.03 mmol) at room temperature under Ar protection. The mixture was stirred at 70 °C for 3 h. The mixture was filtered, the filtrate was concentrated in vacuum to give the residue, which was purified by prep-TLC to give the desired compound 2-5 (50 mg, yield: 34.8%) as yellow oil. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 74.06%, Rt = 1.85 min; MS Calcd.: 431.3; MS Found: 432.3 [M+H]+. [00367] The synthesis of I-28:
Figure imgf000134_0001
A solution of 2-5 (50 mg, 0.15 mmol) in HCl/MeOH (5 mL) was stirred at room temperature overnight. Then the reaction mixture was concentrated to give the residue, which was added NaHCO3 aq. to adjust the pH = 8. The mixture was extracted with DCM (20 mL), washed with water, dried over MgSO4, filtered, and evaporated to give crude, which was purified by prep- HPLC to provide I-28 (8.5 mg, 21.1% yield) as yellow oil. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 98.76%. Rt =1.84 min; MS Calcd.:347.3; MS Found: 347.3 [M + H]+. HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity: 100.00%. Rt = 8.44 min. 1H NMR (400 MHz, CDCl3) δ: 8.50 (s, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.45-7.43 (m, 2H), 7.27 (s, 1H), 7.10-7.07 (m, 2H), 6.14 (s, 1H), 4.23-4.14 (m, 2H), 3.60 (q, J = 11.2 Hz, 1H), 3.32-3.28 (m, 1H), 2.47 (brs, 3H), 2.01-1.74 (m, 4H), 1.62 (s, 4H), 1.61-1.58 (m, 1H). Example 3: Synthesis of I-65 and I-72 Synthetic Scheme for I-65 and I-72
Figure imgf000135_0001
[00368] The synthesis of 3-1
Figure imgf000135_0002
To a solution of 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (3-A, 100 mg crude, 0.26 mmol) in anhydrous THF (10 mL) was added LDA (2M in THF, 296 mg, 5.29 mmol) dropwise at -60 °C under N2 protection, the mixture was stirred at -60 °C for 1 hour, followed by adding a solution of 3-0 (800 mg, 1.80 mmol) in 5 mL THF, then the mixture was stirred at -60 °C for 2 hours. After completion of the reaction indicated by LCMS, the mixture was poured into sat. NH4Cl solution and extracted with DCM=30:1 (20 mL * 3). The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (PE:EA=20:1) to give 3-1 (750 mg, 62%) as light-yellow syrup. LCMS (Agilent LCMS 1200-6120, Column: Phenomenex Kinetex EVO (50mm *4.6 mm*2.6 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.75 min, then under this condition for 0.8 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.1 min.) Purity: 80.38 %. Rt = 2.324 min; MS Calcd.: 675.2; MS Found: 676.2 [M+H]+. [00369] The synthesis of 3-2
Figure imgf000136_0001
To a solution of 3-1 (750 mg, 1.11 mmol) in dry MeOH (10 mL) was added NaBH4 (85 mg, 2.22 mmol) dropwise at 0 °C under N2 protection, the mixture was stirred at 0 °C for 1 hour. After completion of the reaction indicated by LCMS, the mixture was poured into iced water and acidified by 1M HCl solution to pH=4, then basified by NaHCO3 solution to pH=8. The mixture was extracted with DCM and washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuum to give 3-2 (720 mg, 96%) as light-yellow syrup, which was used in the next step without purification . [00370] The synthesis of 3-3
Figure imgf000137_0001
Following general procedure C, 3-3 (650 mg crude) was obtained as brown oil, which was used in the next step without purification . [00371] The synthesis of 3-4
Figure imgf000137_0002
To a solution of 3-3 (650 mg, 0.86 mmol) in THF (50 mL) was added Pd/C (200 mg), the mixture was stirred at room temperature under H2 atmosphere for 36 hours. After completion of the reaction indicated by LCMS, the mixture was filtered by Celite and the filtrate was diluted with DCM (20 mL x 3) and washed with sat. NaHCO3 (20 mL x 2), the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (DCM:MeOH=70:1) to give 3-4 (200 mg, 20%) as light-yellow syrup. LCMS (Agilent LCMS 1200-6120, Column: Phenomenex Kinetex EVO (50mm *4.6 mm*2.6 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.75 min, then under this condition for 0.8 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.1 min.) Purity: 87.22 %. Rt = 2.194 min; MS Calcd.: 583.2; MS Found: 584.3 [M+H]+. [00372] The synthesis of I-72
Figure imgf000138_0001
To a solution of 3-4 (200 mg, 0.34 mmol) in DCM (5 mL) was added TFA (5 mL), the mixture was stirred at room temperature overnight. After completion of the reaction indicated by LCMS, the reaction mixture was concentrated in vacuum to give a residue, diluted with water and adjusted to pH = 9 by NaOH solution, then extracted with DCM (150 mL * 3).The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give the crude (180 mg), 80 mg of it was purified by prep-HPLC to give I-72 (12.8 mg, 11%) as brown oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 100.00 %. Rt = 1.808 min; MS Calcd.: 353.1; MS Found: 354.3 [M + H]+. HPLC (Agilent HPLC 1200, Column: L- column2 ODS (150mm *4.6 mm*5.0 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] to 15% [total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 85% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 5 min, then under this condition for 10 min, finally changed to 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 0.1 min and under this condition for 5 min. Purity: 100.00 %, Rt = 8.176 min; MS Calcd.: 353.1; MS Found: 354.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ: 8.55 (dd, J = 4.0, 1.2 Hz, 1H), 7.84 (dd, J = 8.0, 0.8 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.31 (dd, J = 8.4, 4.8 Hz, 1H), 7.22 (dd, J = 7.6, 4.8 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.94 (s, 2H), 4.50 (dd, J = 8.8, 2.8 Hz, 1H), 4.24 (s, 2H), 4.03 (dd, J = 11.2, 2.8 Hz, 1H), 2.11-1.85 (m, 4H), 1.62 -1.41 (m, 2H). [00373] The synthesis of I-65:
Figure imgf000139_0001
Following general procedure I, I-65 (22 mg, 23%) was obtained as light-brown syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 100.00 %. Rt = 1.986 min; MS Calcd.: 367.2; MS Found: 368.3 [M + H]+. HPLC (Agilent HPLC 1200, Column: L- column2 ODS (150mm *4.6 mm*5.0 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] to 15% [total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 85% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 5 min, then under this condition for 10 min, finally changed to 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 0.1 min and under this condition for 5 min. Purity: 100.00 %, Rt = 9.326 min; MS Calcd.: 367.2; MS Found: 368.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ: 8.57 (d, J = 4.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.75-7.70 (m, 2H), 7.32 (dd, J = 8.0, 4.4 Hz, 1H), 7.05 (dd, J = 6.0, 2.4 Hz, 1H), 6.96 (s, 2H), 4.21 (s, 2H), 3.98 (d, J = 10.0 Hz, 1H), 3.37 (dd, J = 10.8, 2.8 Hz, 1H), 1.96-1.78 (m, 4H), 1.77 (s, 3H), 1.73-1.64 (m, 2H). Example 4: Synthesis of I-24 and I-26 Synthetic Scheme for I-24 and I-26 [
Figure imgf000140_0001
Following general procedure H, 4-1 (766 mg, yield: 85.8%) was obtained as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 97.06%, Rt = 1.95 min; MS Calcd.: 365.2; MS Found: 366.2 [M+H]+. [00375] The synthesis of 4-2
Figure imgf000141_0001
Following general procedure T, to a solution of 4-1 (615 mg, 1.68 mmol) in MeOH (20 ml) was added Pd(OH)2 (150 mg), and the mixture was stirred at 60 °C over night under H2 atmosphere. Then the mixture was cooled down to room temperature, filtered and concentrated to give the crude, which was purified by CC to give 4-2 (419 mg, yield: 67.8 %) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 82.47%, Rt = 1.87 min; MS Calcd.: 367.2; MS Found: 368.2 [M+H]+. [00376] The synthesis of 4-3
Figure imgf000141_0002
To a solution of 4-2 (100 mg, 0.27 mmol) in MeOH/H2O (10 ml/10 ml) was added NaOH (25 mg, 0.63 mmol), and the mixture was stirred at room temperature overnight. Then the mixture was acidified with 6N HCl aq. to pH = 7 and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum to give 4-3 (78 mg, yield: 84.5%) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X- Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 79.03%, Rt = 1.35 min; MS Calcd.: 339.2; MS Found: 340.2 [M+H]+. [00377] The synthesis of I-24:
Figure imgf000142_0001
To a solution of 4-3 (257 mg, 0.76 mmol) in THF (5 mL) was added (Boc)2O ( 248 mg, 1.14 mmol) and pyridine (72 mg, 0.91 mmol), and the mixture was stirred at room temperature for 0.5 h, followed by adding NH4HCO3 (240 mg, 3.04 mmol); and the mixture was stirred at room temperature overnight under N2 atmosphere. Then the mixture was acidified with 6N HCl aq. to pH = 7, extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum to give the crude, which was purified by prep- HPLC to give I-24 (83 mg, yield: 32.4%) as colorless oil. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: > 99 %. Rt = 1.57 min; MS Calcd.: 338.2; MS Found: 339.3 [M + H]+. HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity: 99.81%. Rt = 7.80 min. 1H NMR (400 MHz, CDCl3) δ: 8.40 (d, J = 3.2Hz, 1H), 7.80-7.50 (m, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.03-6.98 (m, 2H), 5.37 (brs, 1H), 3.55-3.38 (m, 1H), 3.26-3.22 (t, J = 6.8 Hz, 1H), 3.15 (s, 3H), 3.08 (t, J = 11.6 Hz, 2H), 2.76-2.68 (m, 1H), 2.66-2.58 (m, 1H), 2,40 (s, 3H), 1.94-1.83 (m, 3H) 1.75-1.70 (m, 3H). [00378] The synthesis of I-26:
Figure imgf000143_0001
To a solution of I-24 (110 mg, 0.33 mmol) in pyridine (3 mL) was added POCl3 (200 mg, 1.30 mmol) at 0 °C, and the mixture was stirred for 2 h at 0 °C. Then the mixture was quenched with water, basified by NaOH aq. to pH = 8 and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum to give the crude, which was purified by prep-HPLC to give I-26 (15 mg, yield: 14.4%) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min) Purity: 99.54 %. Rt = 1.80 min; MS Calcd.: 320.2; MS Found: 321.3 [M + H]+. HPLC (Agilent HPLC 1200, Column: Waters X- Bridge C18 (150 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min.). Purity: >99%. Rt = 8.90 min. 1H NMR (400 MHz, CDCl3) δ: 8.40 (s, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.42(d, J = 6.8 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 5.6 Hz, 2H), 3.51 (d, J = 10.4 Hz, 1H), 3.22 (d, J = 8.8 Hz, 1H), 3.03 (d, J = 6.4 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H), 2.48 (s, 3H), 2.08 (s, 3H), 1.92-1.72 (m, 3H), 1.56 (s, 3H). Example 5: Synthesis of I-21 and I-23 Synthetic Scheme for I-21 and I-23
Figure imgf000144_0001
Following general procedure Q, 5-1 (500 mg, yield: 63.5%) was obtained as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 90.59%, Rt = 2.44 min; MS Calcd.: 425.2; MS Found: 426.2 [M+H]+. [00380] The synthesis of 5-2
Figure imgf000145_0001
To a suspension of LAH (89 mg, 2.35 mmol) in THF (20 mL) was added a solution of 5-1 (500 mg, 1.18 mmol) in THF (10 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h, then water (0.09 mL), NaOH aq. (15%, 0.09 mL), and water (0.27 mL) were added to the mixture at 0 °C to quench the reaction. The mixture was returned to room temperature. Anhydrous Na2SO4 was added to the mixture, filtered and concentrated in vacuum to give the 5-2 (400 mg, yield: 88.7%) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 96.74%, Rt = 1.92 min; MS Calcd.:383.2; MS Found: 384.2 [M+H]+. [00381] The synthesis of 5-3
Figure imgf000146_0001
Following general procedure C, 5-3 (480 mg, yield: 99.7%) was obtaind as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 82.79%, Rt = 2.35 min; MS Calcd.:461.2; MS Found: 462.2 [M+H]+. [00382] The synthesis of 5-1
Figure imgf000146_0002
To a solution of 5-3 (600 mg, 1.3 mmol) in CH3CN (50 mL) was added TMSCN (193 g, 1.95 mmol), TBAF (1.95 mL, 1 N in THF, 1.95 mmol) and K2CO3 (269 mg, 1.95 mmol) at room temperature. The mixture was stirred at room temperature overnight. Water (20 mL) was added to the mixture, extracted with DCM (20 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give 5-4 (400 mg, yield: 78.4%) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 78.42%, Rt = 2.46 min; MS Calcd.: 392.2; MS Found: 393.2 [M+H]+. [00383] The synthesis of I-21:
Figure imgf000147_0001
Following general procedure J, I-21 (10 mg, yield: 8.9%) was obtained as colorless oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 100.00%. Rt =1.71 min; MS Calcd.: 292.3; MS Found: 293.3 [M + H]+. HPLC (Agilent HPLC 1200, Column: Waters X- Bridge C18 (150 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity: 99.77%. Rt = 7.75 min. 1H NMR (400 MHz, CDCl3) δ: 8.44 (d, J = 4.0 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.07-7.04 (m, 1H), 4.18 (d, J = 10.4 Hz, 1H), 3.99 (d, J = 10.8 Hz, 1H), 2.38 (s, 3H), 2.14-2.11 (m, 1H), 2.02-1.77 (m, 4H), 1.64-1.50 (m, 2H). [00384] The synthesis of I-23
Figure imgf000148_0001
To a solution of I-21 (300 mg, 1.03 mmol) in DMSO/H2O (10 mL/5 mL) were added KOH (173 mg, 3.09 mmol) and H2O2 (30%, in aqueous solution, 195 mg, 3.09 mmol) and stirred at room temperature overnight. The mixture was quenched with Na2SO3 aqueous solution, extracted with DCM (10 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give the residue, which was purified by prep-HPLC to give I-23 (12 mg, yield: 3.8%) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 100.00 %. Rt =1.42 min; MS Calcd.: 310.3; MS Found: 311.3 [M + H]+. HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity: 98.78%. Rt = 6.14 min. 1H NMR (400 MHz, CDCl3) δ: 8.42 (d, J = 4.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.08-7.05 (m, 1H), 5.47 (s, 1H), 4.20 (dd, J = 11.4, 2.0 Hz, 1H), 4.02 (dd, J = 11.4, 2.4 Hz, 1H), 3.74 (s, 2H), 2.38 (s, 3H), 2.22-2.10 (m, 2H), 2.02-1.99 (m, 1H), 1.88-1.82 (m, 2H), 1.60-1.48 (m, 2H). Example 6: Synthesis of I-14 and I-15 Synthetic Scheme for I-14 and I-15
Figure imgf000149_0001
[00385] The synthesis of 6-A
Figure imgf000149_0002
Following general procedure H, 6-A (500 mg, yield: 43%) was obtained as colorless oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 61.46%. Rt = 1.56 min; MS Calcd.:119.3; MS Found: 120.3 [M + H]+. [00386] The synthesis of 6-1
Figure imgf000150_0001
To a solution of 6-0 (0.6 g, 1.4 mmol), 6-A (198.4 mg, 1.7 mmol), trio-tolylphosphine (84.5 mg, 0.3 mmol), Et3N (280.8 mg, 2.8 mmol) in DMF (20 mL), was added Pd(PPh3)4 (160.7 mg, 0.14 mmol) under Ar protection and stirred at 130 °C overnight. Then the mixture was returned to room temperature, filtered and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography to give 6-1 (350 mg, yield: 54%) as an off-white solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 52.63, 43.00%. Rt = 2.30, 2.34 min; MS Calcd.: 470.3; MS Found: 471.3 [M + H]+. [00387] The synthesis of 6-2
Figure imgf000150_0002
Following general procedure T, 6-2 (300 mg, yield: 85%) was obtained as an off-white solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.5 min, then under this condition for 1.5 min, finally changed to 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] in 0.1 min and under this condition for 0.5 min.). Purity: 89.56%, Rt = 2.38 min; MS Calcd.: 472.3; MS Found: 473.3 [M+H]+. [00388] The synthesis of I-14
Figure imgf000151_0001
Following general procedure J, I-14 (100 mg, yield: 63%) was obtained as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 98. 88%. Rt = 1.87 min; MS Calcd.:372.3; MS Found: 373.4 [M + H]+. HPLC (Agilent HPLC 1200, Column: Waters X- Bridge C18 (150 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity: 100.00%. Rt = 8.63 min. 1H NMR (400 MHz, CDCl3) δ: 8.46 (d, J = 2.0 Hz, 1H), 8.43 (dd, J = 4.8, 1.2 Hz, 2H), 7.55-7.52 (m, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.20-7.17 (m, 2H), 7.05 (dd, J = 7.6, 4.8 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 4.20 (d, J = 9.2Hz, 1H), 3.98 (dd, J = 11.2, 2.4 Hz, 1H), 2.83 (t, J = 7.2 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 2.39 (s, 3 H), 2.16-2.06 (m, 2H), 2.05-2.00 (m, 1H), 1.85-1.59 (m, 6H). [00389] The synthesis of I-15
Figure imgf000152_0001
Following general procedure I, I-15 (20 mg, yield: 48%) was obtained as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 94.87%. Rt = 2.02 min; MS Calcd.: 386.3; MS Found: 387.4 [M + H]+. HPLC (Agilent HPLC 1200, Column: Waters X- Bridge C18 (150 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity: 100.00%. Rt = 9.53 min. 1H NMR (400 MHz, CDCl3) δ: 8.47-8.42 (m, 3H), 7.57 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.41 (dd, J = 12.8, 7.6 Hz, 2H), 7.19 (dd, J = 7.6, 4.8 Hz, 1H), 7.06 (t, J = 7.6, 4.8 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 3.58 (d, J = 9.4 Hz, 1H), 3.30 (d, J = 12.8 Hz, 1H), 2.87 - 2.83 (m, 2H), 2.70-2.66 (m, 2H), 2.52 (s, 2H), 2.10 (s, 5H), 2.07-1.87 (m, 4H), 1.80 (s, 3H).
Example 7: Synthesis of I-3 and I-3a Synthetic Scheme for I-3 and I-3a
Figure imgf000153_0001
[00390] The synthesis of 7-1
Figure imgf000153_0002
Following general procedure K, crude 7-1 (12.0 g, 95.3% yield) was obtained as brown oil solid, which were used in the next step without further purification. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min) Purity: 59.11%. Rt = 1.87 min; MS Calcd.: 271.0; MS Found: 272.0 [M + H]+. [00391] The synthesis of 7-2
Figure imgf000154_0001
Following general procedure L, 7-2 (12.0 g, 64.9% yield) was obtained as brown oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min) Purity: 93.85%. Rt = 2.27 min; MS Calcd.: 418.0; MS Found: 419.0 [M + H]+. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 4.4 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26-7.23 (m, 1H), 4.60 (t, J = 7.0 Hz, 1H), 4.11-4.07 (m, 2H), 3.30 (t, J = 7.4 Hz, 2H), 2.51 (s, 3H), 2.37-2.30 (m, 2H), 1.10 (t, J = 6.0 Hz, 3H).
Figure imgf000155_0001
A solution of 7-2 (12.0 g, 19.5 mmol) in conc. HBr aq. (150 mL) was stirred at reflux for 2 h. Then it was concentrated in vacuo to get rid of HBr. The residue was dissolved in H2O (40 mL), adjusted pH to 9 with 20% NaOH aq., extracted with DCM (3 × 100 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated to give the crude, which was purified by column chromatography to provide 7-3 (7.0 g, 70.4% yield) as a brown solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 91.17 %. Rt = 2.18 min; MS Calcd.: 346.0; MS Found: 347.0 [M + H]+.1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 4.4 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.64-7.56 (m, 2H), 7.52- 7.50 (m, 1H), 7.26-7.23 (m, 1H), 3.26-3.22 (m, 4H), 2.51 (s, 3H), 2.10-2.03 (m, 2H). [00393] The synthesis of 7-4
Figure imgf000155_0002
Following general procedure N, 7-4 (2.5 g, 87.1% yield) was obtained as brown oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 72.50 %. Rt = 1.95 min; MS Calcd.: 331.0; MS Found: 332.0 [M + H]+. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 4.0 Hz, 1H), 7.46-7.26 (m, 4H), 7.01-6.98 (m, 1H), 4.14 (d,= 9.6 Hz, 1H), 3.95 (d, J =10.8 Hz, 1H), 2.49 (s, 3H), 2.06-1.99 (m, 2H), 1.79-1.69 (m, 2H), 1.59- 1.49 (m, 3H). [00394] The synthesis of 7-5
Figure imgf000156_0001
Following general procedure P, 7-5 (2.3 g, 70.7% yield) was obtained as a yellow solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10 mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10 mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10 mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10 mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10 mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10 mM AcONH4) water/CH3CN=100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 98.01%. Rt = 2.99 min; MS Calcd.: 431.2; MS Found: 432.2 [M + H]+. [00395] The synthesis of 7-6 and 7-7
Figure imgf000157_0001
A mixture of 7-5 (300 mg, 0.694 mmol), 7-B (132 mg, 1.39 mmol), CuBr (99 mg, 0.694 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (127 mg, 0.694 mmol), Cs2CO3 (564 mg, 1.73 mmol) in DMF (10 mL) was stirred at 135 °C overnight under Ar protection. Then the mixture was cooled to room temperature, filtered, the filtrate was poured into water, extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum and the residue was purified by column chromatography to give 7-6 (70 mg, 22.6% yield) as yellow oil and 7-7 (110 mg, 35.5% yield) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 71.41%. Rt = 2.58 min; MS Calcd.: 446.2; MS Found: 447.2 [M + H]+. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) water/CH3CN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) water/CH3CN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 84.78 %. Rt = 2.40 min; MS Calcd.: 446.2; MS Found: 447.2 [M + H]+. [00396] The synthesis of I-3
Figure imgf000158_0001
Following general procedure J, I-3 (10 mg, 18.4% yield) was obtained as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 97.82%. Rt = 1.78 min; MS Calcd.: 346.3; MS Found: 347.3 [M + H]+. HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity: 96.02%; Rt = 8.39 min. 1H NMR (400 MHz, CDCl3) δ: 8.42 (d, J=4.4 Hz, 1H), 8.29 (d, J=3.6 Hz, 1H), 7.76-7.70 (m, 2H), 7.42 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.11-6.93 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 4.17 (d, J=10.0 Hz, 1H), 3.96 (d, J=10.0 Hz, 1H), 2.37 (s, 3H), 2.10-2.02 (m, 3H), 1.83-1.76 (m, 2H), 1.59-1.55 (m, 2H). Example 8: Synthesis of I-10 Synthetic Scheme for I-10
Figure imgf000159_0001
Following general procedure S, trimethylsilylacetylene (546 mg, 5.56 mmol, 3 eq) was added to the suspension of 8-0 (800 mg, 1.85 mmol), Pd(PPh3)2Cl2 (130 mg, 0.185 mmol, 0.1 eq), CuI (35 mg, 0.185 mmol, 0.1 eq) in dry THF (30 mL) and Et3N (10 mL) under N2 atmosphere. Then the mixture was stirred at 60 oC overnight and cooled to room temperature, filtered and concentrated in vacuum. The residue was purified by column chromatography to give 8-1 (681 mg, yield: 82%) as an off-white solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 48.14%. Rt = 2.69 min; MS Calcd.: 449.7; MS Found: 450.7 [M+H]+. [00398] The synthesis of 8-2
Figure imgf000160_0001
KF (176 mg, 3.03 mmol) was added to the solution of 8-1 (681 mg, 1.51 mmol) in MeOH (30 mL) and DCM (30 mL). Then the mixture was stirred at room temperature for 2 h, then filtered and concentrated in vacuum. The residue was purified by column chromatography to give 8-2 (352 mg, yield: 62%) as an off-white solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min). Purity: 61.85%. Rt = 2.26 min; MS Calcd.: 377.7; MS Found: 378.7 [M+H]+. [00399] The synthesis of 8-3
Figure imgf000160_0002
Following general procedure S, 2-iodopyrimidine (212 mg, 1.03 mmol, 1.1 eq) was added to the solution of 8-2 (352 mg, 0.93 mmol), Pd(PPh3)2Cl2 (66 mg, 0.093 mmol), CuI (18 mg, 0.093 mmol) in dry THF (25 mL) and Et3N (10 mL) under N2 atmosphere. The mixture was stirred at 40 oC overnight, then cooled to room temperature, filtered and concentrated in vacuum. The residue was purified by column chromatography to give 8-3 (260 mg, yield: 61%) as a black solid.LCMS (Agilent 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 32%, Rt = 2.18 min; MS Calcd.: 455.7; MS Found: 456.7 [M+H]+. [00400] The synthesis of 8-4
Figure imgf000161_0001
Following general procedure T, A mixture of 8-3 (130 mg, 0.286 mmol) and Pd/C (13 mg) in MeOH (30 mL) was stirred at 40 oC under H2 atmosphere overnight. Then filtered and concentrated in vacuum. The residue was purified by column chromatography to give 8-4 (110 mg, yield: 84%) as black oil.LCMS (Agilent 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] to 10% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 90% [(total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 1.6 min, then under this condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [(total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 0.1 min and under this condition for 0.7 min). Purity: 37.71 %, Rt = 2.22 min; MS Calcd.: 459.7; MS Found: 460.7 [M+H]+. [00401] The synthesis of I-10
Figure imgf000162_0001
Following general procedure J, I-10 (4 mg, yield: 4.6%) was obtained as brown oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm)); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min. Purity: 96.16 %. Rt =1.60 min; MS Calcd.: 359.7; MS Found: 360.7 [M + H]+. HPLC (Agilent HPLC 1200, Column: Waters X- Bridge C18 (150 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity: 89.23%; Rt = 7.28 min. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 4.9 Hz, 2H), 8.45 (d, J = 4.2 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.09 (t, J = 4.9 Hz, 1H), 7.07-6.99 (m, 2H), 4.17 (d, J = 9.6 Hz, 1H), 3.94 (d, J = 10.2 Hz, 1H), 3.44 (dd, J = 8.7, 5.8 Hz, 2H), 3.39-3.29 (m, 2H), 2.39 (s, 3H), 2.10 (d, J = 12.6 Hz, 1H), 1.98 (d, J = 11.3 Hz, 2H), 1.86-1.77 (m, 2H), 1.59-1.57 (m, 2H). Example 9: Synthesis of I-34 Synthetic Scheme of I-34
Figure imgf000163_0001
[00402] The synthesis of 9-1
Figure imgf000163_0002
Following general procedure R, To a solution of 2, 6-dibromopyridine (3.52 g, 15 mmol) in dry THF (200 mL) was added slowly n-BuLi (5.2 mL, 13 mmol) at -78 °C, then the mixture was stirred at -78 °C for 30 min. After ethyl thiazole-4-carboxylate 9-0 (1.57 g, 10 mmol) was added to the mixture at -78 °C, the mixture was stirred at -78 °C for 1 hour. After completion of the reaction indicated by LCMS, the mixture was quenched by H2O (20 mL), and extracted with DCM (100 mL × 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (PE:EA=3:1) to give 9-1 (220 mg, 8.2%) as white solid. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 72.53%. Rt = 1.399 min; MS Calcd.: 267.9; MS Found: 269.1 [M + H]+. [00403] The synthesis of 9-2
Figure imgf000164_0001
Following general procedure T, 9-2 (2 g, 76.34%) was obtained as brown syrup.LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: 92.96%, t = 1.378 min; MS Calcd.: 262.04; MS Found: 263.2 [M + H]+. [00404] The synthesis of 9-3
Figure imgf000164_0002
To a solution of ethyl 6-(thiazole-4-carbonyl) picolinate (9-2, 1.1 g, 4.2 mmol) in dry MeOH (25 mL) was added NaBH4 (95.7 mg, 2.52 mmol) at 0 °C, the mixture was stirred at 0 °C for 30 min, After completion of the reaction indicated by LCMS, the mixture was quenched by H2O (20 mL), adjusted to pH = 3 by HCl solution, then adjusted to pH = 8 by NaHCO3 solution and extracted with DCM (20 mL × 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give 9-3 (1.0 g, 90.1%) as brown syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 90.45 %. Rt = 1.222 min; MS Calcd.: 264.06; MS Found: 265.2 [M +H]+. [00405] The synthesis of 9-4
Figure imgf000165_0001
Following general procedure C, 9-4 (54 mg, 43%) was obtained as brown syrup.LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 89.18%. Rt = 1.375 min; MS Calcd.: 342.03; MS Found: 279.2 [M -62+ H]+. [00406] The synthesis of 9-5
Figure imgf000165_0002
To a solution of ethyl 6-((methylsulfonyloxy) (thiazol-4-yl)methyl) picolinate (9-4, 1 g, 2.92 mmol) in EtOH (20 mL) was added Pd/C (50 mg) at room temperature, then the mixture was stirred at room temperature under H2 atmosphere overnight. After completion of the reaction indicated by LCMS, the mixture was filtered and the filtrate was concentrated in vacuum to give a residue, which was purified by column chromatography (PE: EA=3:1) to give ethyl 6-(thiazol- 4-ylmethyl)picolinate (9-5, 600 mg, 82.75%) brown syrup. LCMS (Agilent LCMS 1200- 6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 81.7 %. Rt = 1.352 min; MS Calcd.: 248.1; MS Found: 249.2 [M+H]+. [00407] The synthesis of 9-6
Figure imgf000166_0001
Following general procedure K, 9-6 (520 mg, 67.62%) was obtained as brown syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 82.17 %. Rt =1.682 min; MS Calcd.: 318.1; MS Found: 319.2 [M+H]+. [00408] The synthesis of 9-7
Figure imgf000167_0001
Following general procedure L, crude 9-7 (400 mg, 54.72%) was obtained was brown oil, used to the next step without purifity. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 64.88 %. Rt = 2.274 min; MS Calcd.: 465.2; MS Found: 466.1 [M + H]+. [00409] The synthesis of 9-8
Figure imgf000167_0002
Following general procedure M, 9-8 (280 mg, 89.45%) was obtained as brown syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 75.21%. Rt = 2.104 min; MS Calcd.: 365.1; MS Found: 366.1 [M + H]+. [00410] The synthesis of I-34
Figure imgf000168_0001
Following general procedure N, I-34 (45 mg, 24.9%) was obtained as brown syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 96.27%. Rt = 1.865 min; MS Calcd.: 350.2; MS Found: 351.3 [M + H]+. HPLC (Agilent HPLC 1200, Column: L- column2 ODS (150mm *4.6 mm*5.0 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] to 15% [total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 85% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 5 min, then under this condition for 10 min, finally changed to 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 0.1 min and under this condition for 5 min. Purity: 96.87%, Rt = 8.843 min; MS Calcd.: 350.2; MS Found: 351.2 [M+H]+.1H NMR (400 MHz, CD3OD) δ: 8.94 (d, J = 2 Hz, 1H), 8.41-8.40 (m, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.58 (dd, J = 7.6, 1.2 Hz, 1H), 7.34-7.33 (m, 1H), 7.27 (d, J = 7.6 Hz , 1H), 7.20-7.16 (m, 2H), 4.36 (m, 2H), 4.24 (dd, J = 7.6, 2.4 Hz, 1H), 4.06 (dd, J = 11.6, 2.4 Hz, 1H), 2.40 (s, 3 H), 2.11-2.08 (m, 1H), 1.99-1.85 (m, 3H), 1.64-1.51 (m, 2H).
Example 10: Synthesis of I-103 Synthetic Scheme for I-103
Figure imgf000169_0001
[00411] Synthesis of 10-B.
Figure imgf000169_0002
[00412] Following General Procedure V, 10-B (100 mg, 9%) was obtained as colorless oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 ℃; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: 80.95%, Rt = 1.582 min; MS Calcd.: 221.1; MS Found: 166.2 [M-56+H] +. [00413] Synthesis of 10-1.
Figure imgf000170_0001
[00414] Following General Procedure K, 10-1 (6.0 g, 75%) was obtained as yellow brown syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 ℃; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: 80.95%, Rt = 1.582 min; MS Calcd.: 221.1; MS Found: 166.2 [M-56+H]+. [00415] Synthesis of 10-2.
Figure imgf000170_0002
[00416] Following General Procedure L, 10-2 (700 mg, 55%) was obtained as yellow brown oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 ℃; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: 87.49%, Rt = 2.369 min; MS Calcd.: 466.0; MS Found: 467.0 [M+H] +. [00417] Synthesis of 10-3.
Figure imgf000171_0001
[00418] Following General Procedure M, 10-3 (460 mg, 86%) was obtained as yellow-brown oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 ℃; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 81.27%. Rt = 2.142 min; MS Calcd.: 366.0; MS Found: 367.1 [M+H]+. [00419] Synthesis of 10-4.
Figure imgf000171_0002
[00420] Following General Procedure N, 10-4 (440 mg, 99%) was obtained as light yellow syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 ℃; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: 69.37%, Rt = 1.954 min; MS Calcd.: 351.0; MS Found: 352.0 [M+H]+. [00421] Synthesis of 10-5.
Figure imgf000172_0001
[00422] Following General Procedure P, 10-5 (470 mg, 83%) was obtained as light yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 ℃; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: 96.18%, Rt = 1.799 min; MS Calcd.: 451.1; MS Found: 371.0 [M+H]+. [00423] Synthesis of 10-6.
Figure imgf000172_0002
[00424] To a solution of (2R,6S)-tert-butyl 2-(6-bromo-3-chloropyridin-2-yl)-6-(pyridin-2- yl)piperidine-1-carboxylate (10-5, 80 mg, 0.18 mmol), 2,4-dimethyl-3-(pyrimidin-2- ylmethyl)pentan-3-ol (10-B, 37 mg, 0.18 mmol), Pd(CF3COO)2 (3.0 mg, 0.009 mmol), Cy3P (5.0 mg, 0.018 mmol), Cs2CO3 (117 mg, 0.36 mmol) in xylene (10 mL) was stirred at 110 °C under N2 atmosphere for 4 h. After completion of the reaction indicated by LCMS, the mixture was filtered by Celite and concentrated in vacuum to give a residue, which was purified by column chromatography (DCM:MeOH=60:1) to give a residue, which was purified by column chromatography to give (2R,6S)-tert-butyl2-(3-chloro-6-(pyrimidin-2-ylmethyl)pyridin-2-yl)-6- (pyridin-2- yl)piperidine-1-carboxylate (10-6, 70 mg, 85%) as yellow syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 ℃; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: 78.35%, Rt = 2.018 min; MS Calcd.: 465.2; MS Found: 466.0 [M+H]+. [00425] Synthesis of I-103.
Figure imgf000173_0001
Following General Procedure J, I-103 (18.51 mg, 34%) was obtained as light brown oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 98.86%. Rt = 1.707 min; MS Calcd.: 365.14; MS Found: 366.0 [M + H]+. HPLC (Agilent HPLC 1200, Column: L- column2 ODS (150mm *4.6 mm*5.0 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] to 15% [total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 85% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 5 min, then under this condition for 10 min, finally changed to 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 0.1 min and under this condition for 5 min. Purity: 99.22%, Rt = 7.742 min; MS Calcd.: 365.14; MS Found: 366.0 [M+H]+.1H NMR (400 MHz, CD3OD) δ: 8.68 (d, J = 4.8 Hz, 2H), 8.58 (d, J = 4.4 Hz, 1H), 7.64 (td, J1 = 1.6 Hz, J2 = 7.6 Hz, J3 = 9.6 Hz 1H), 7.55(d, J = 8.4 Hz, 1H), 7.33(d, J = 8.0 Hz, 1H), 7.15(q, J = 4.4 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 4.51 (t, J = 15.2 Hz, 2H), 4.42 (d, J = 10.8 Hz, 1H), 4.00 (d, J = 10.8 Hz, 1H), 2.12-2.07 (m , 1H), 2.02-1.93 (m , 2H), 1.89-1.79 (m , 1H), 1.65-1.55 (m , 1H), 1.51-1.41 (m , 1H). Example 11: Synthesis of I-84 Synthetic Scheme for I-84
Figure imgf000174_0001
[00426] Synthesis of 11-1.
Figure imgf000174_0002
[00427] Following General Procedure W, To a suspension of LAH (35.2 mg, 0.90 mmol) in THF (4 mL) was added a solution of ethyl 6-((2R, 6S)-1-(tert-butoxycarbonyl)-6-(3- chloropyridin-2-yl) piperidin-2-yl) picolinate (11-0200 mg, 0.45 mmol) in THF (2 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h, and then water (0.045 mL), NaOH aq. (15%, 0.045 mL), and water (0.135 mL) were added to the mixture at 0 °C to quench the reaction. The mixture was returned to room temperature. Anhydrous Na2SO4 was added to the mixture, filtered and concentrated in vacuum to give the (2S, 6R)-tert-butyl 2-(3-chloropyridin-2-yl) -6-(6- (hydroxymethyl)pyridin-2-yl)piperidine-1-carboxylate (11-1, 190 mg, yield: 100.0%) as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 88.70%. Rt = 2.173 min; MS Calcd.:403.2; MS Found: 404.3 [M + H]+. [00428] Synthesis of 11-2.
Figure imgf000175_0001
[00429] Following General Procedure C, 11-2 (200 mg, 92.6%) was obtained as yellow oil. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 73.32%. Rt = 2.336 min; MS Calcd.: 481.1; MS Found:482.2 [M+H]+. [00430] Synthesis of 11-3.
Figure imgf000175_0002
[00431] To a suspension of NaH (60%) (8.1 mg, 0.21 mmol) in THF (3 mL) was added a solution of 1H-pyrazole (14.3 mg, 0.21 mmol) in THF (1 mL) at 0 °C for 30 min under N2, and then added a solution (2S,6R)-tert-butyl 2-(3-chloropyridin-2-yl)-6-(6-((methylsulfonyloxy)- methyl)pyridine-2-yl)piperidine-1-carboxylate (11-2, 100 mg, 0.21 mmol) in THF (1 mL), then the mixture was stirred at 70 °C overnight under N2 atmosphere. After completion of the reaction indicated by LCMS, the reaction mixture was poured into ice-water (5 mL), and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give (2R,6S)-tert-butyl 2-(6-((1H-pyrazol-1- yl)methyl)pyridin-2-yl)-6-(3-chloropyridin-2-yl)piperidine-1-carboxylate (11-3, 121 mg, crude) as yellow solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Colum Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 68.83%. Rt = 2.149 min; MS Calcd.:453.2; MS Found: 454.2 [M+H]+. [00432] Synthesis of I-84.
Figure imgf000176_0001
Following General Procedure J, I-84 (40.3 mg, 43%) was obtained as white solid. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 99.65%. Rt = 1.769 min; MS Calcd.: 353.1; MS Found: 354.2 [M + H]+. HPLC (Agilent HPLC 1200, Column: L-column2 ODS (150mm *4.6 mm*5.0 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] to 15% [total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 85% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 5 min, then under this condition for 10 min, finally changed to 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 0.1 min and under this condition for 5 min. Purity: 100%, Rt = 8.560 min; MS Calcd.: 353.1; MS Found: 354.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ: 8.55 (dd, J = 4.4, 1.2 Hz, 1H), 7.82 (dd, J = 6.0, 1.4 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.31-7.28 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.36 (d, J = 2.0 Hz, 1H), 5.50 (s, 2H), 4.47 (dd, J = 11.6, 2.8 Hz, 1H), 4.02 (dd, J = 11.6, 2.8 Hz, 1H), 2.16-1.87 (m, 4H), 1.55-1.38 (m, 2H).
Example 12: Synthesis of I-36 Synthetic Scheme for I-36
Figure imgf000178_0001
[00433] Synthesis of 12-1.
Figure imgf000178_0002
[00434] To a solution of ethyl 6-((2R,6S)-1-(tert-butoxycarbonyl)-6-(3-methylpyridin-2- yl)piperidin-2-yl)picolinate (12-0, 800 mg, 1.88 mmol) in MeOH (10 mL) was added 2 M LiOH solution (2.8 mL, 5.64 mmol) at room temperature, then the mixture was stirred at room temperature overnight. After completion of the reaction indicated by LCMS, the mixture was concentrated in vacuum, diluted with water and adjusted to pH = 6 by HCl solution, then extracted with DCM (20 mL x 3).The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give 6-((2R,6S)-1-(tert-butoxycarbonyl) -6-(3- methylpyridin-2-yl)piperidin-2-yl)picolinic acid (12-1, 650 g, crude) as brown solid, which was used directly in the next step without purification. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 97.02%. Rt = 1.444 min; MS Calcd.: 397.2; MS Found: 398.2 [M+H]+. [00435] Synthesis of 12-2.
Figure imgf000179_0001
[00436] Following General Procedure X, A mixture of 6-((2R,6S)-1-(tert-butoxycarbonyl) -6- (3-methylpyridin-2-yl)piperidin-2-yl)picolinic acid (12-1, 650 mg, 1.64 mmol), N,O- dimethylhydroxylamine hydrochloride (480 mg, 4.92 mmol), HATU (935 mg, 2.46 mmol) and TEA (994 mg, 9.84 mmol) in dry DMF (10 mL) was stirred at room temperature under N2 protection for 3 hours. After completion of the reaction indicated by LCMS, the mixture was poured into water (30 mL), extracted with EA (20 mL x 3). The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (PE:EA=10:1) to give (2R,6S)-tert-butyl 2-(6- (methoxy(methyl) carbamoyl) pyridin-2-yl)-6-(3-methylpyridin-2-yl)piperidine-1-carboxylate (12-2, 550 mg, 76%) as colorless syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X- Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 88.12%. Rt = 2.015 min; MS Calcd.: 440.2; MS Found: 441.2 [M+H]+. [00437] Synthesis of 12-3.
Figure imgf000180_0001
[00438] To a solution of (2R,6S)-tert-butyl 2-(6-(methoxy(methyl)carbamoyl)pyridin-2-yl)-6- (3-methylpyridin-2-yl) piperidine-1-carboxylate (12-2, 550 mg, 1.25 mmol) in anhydrous THF (10 mL) was added DIBAL-H (1 M in hexane, 2.5 mL, 2.50 mmol) slowly at -70 °C under N2 protection, the mixture was stirred at -70 °C for 1 hour. After completion of the reaction indicated by LCMS, the mixture was quenched by MeOH (5 mL) at -70 °C, then NaOH (15%, 20 ml) was added, the mixture was stirred at room temperature for 10 min, then extracted with DCM (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (PE:EA=20:1) to give (2R,6S)-tert-butyl 2-(6-formylpyridin-2-yl)-6-(3-methylpyridin-2- yl)piperidine-1- carboxylate (12-3, 400 mg, 84%) as colorless syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 94.86%. Rt = 2.183 min; MS Calcd.: 381.2; MS Found: 382.2 [M+H]+. [00439] Synthesis of 12-4.
Figure imgf000181_0001
[00440] To a solution of isothiazole (268 mg, 3.15 mmol) in anhydrous THF (7 mL) was added n-BuLi (2.5 M in hexane, 1.26 mL, 3.15 mmol) dropwise at -70 °C under N2 protection, the mixture was stirred at -70 °C for 40 min, followed by adding a solution of (2R,6S)-tert-butyl 2-(6-formylpyridin-2-yl)-6- (3-methylpyridin -2-yl)piperidine-1- carboxylate (12-3, 400 mg, 1.05 mmol) in anhydrous THF (1 mL), then the mixture was stirred at -70 °C for 1 hour. After completion of the reaction indicated by LCMS, the mixture was poured into sat. NH4Cl solution (20 mL), extracted with DCM (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (PE:EA=15:1) to give (2R,6S)-tert-butyl 2-(6-(hydroxyl (isothiazol-3-yl) methyl)pyridin-2-yl)-6-(3-methylpyridin-2-yl)piperidine-1-carboxylate (12-4, 200 mg, 41%) as light-yellow syrup. LCMS (Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 1.5 mL/min; Mobile Phase: from 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] in 0.8 min, then under this condition for 0.4 min, finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] and under this condition for 0.01 min). Purity: 92.13%. Rt = 0.561 min; MS Calcd.: 466.1; MS Found: 467.0 [M+H]+. [00441] Synthesis of 12-5.
Figure imgf000182_0001
[00442] Following General Procedure C, 12-5 (200 mg, crude) was obtained as brown syrup.which was used in the next step without purification. [00443] Synthesis of 12-6.
Figure imgf000182_0002
[00444] Following General Procedure U, 12-6 (100 mg, 60%) was obtained as light-brown syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 75.29%. Rt = 2.220 min; MS Calcd.: 450.1; MS Found: 451.0 [M+H]+. [00445] Synthesis I-36.
Figure imgf000183_0001
Following General Procedure J, I-36 (21 mg, 27%) was obtained as light-brown syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 96.54%. Rt = 1.884 min; MS Calcd.: 350.1; MS Found: 351.1 [M + H]+. HPLC (Agilent HPLC 1200, Column: L-column2 ODS (150mm *4.6 mm*5.0 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] to 15% [total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 85% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 5 min, then under this condition for 10 min, finally changed to 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 0.1 min and under this condition for 5 min. Purity: 99.70%, Rt = 8.994 min; MS Calcd.: 350.1; MS Found: 351.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ: 8.46 (d, J = 4.4, 1H), 8.36 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.10-7.05 (m, 3H), 4.46 (s, 2H), 4.21 (d, J = 8.0 Hz, 1H), 4.03 (d, J = 8.0 Hz, 1H), 2.39 (s, 3H), 2.16-2.14 (m, 2H), 1.87-1.80 (m, 2H), 1.72- 1.60 (m, 2H).
Example 13: Synthesis of I-88 Synthetic Scheme for I-88
Figure imgf000184_0001
[00446] Synthesis of 13-1.
Figure imgf000184_0002
[00447] A mixture of (2R,6S)-tert-butyl 2-(6-bromopyridin-2-yl)-6-(3-chloropyridin-2- yl)piperidine-1- carboxylate (13-0, 700 mg, 1.55 mmol), 4-methylpyrimidine (146 mg, 1.55 mmol), bis(3,5,3′,5′-dimethoxydibenzylideneacetone)palladium(0) (Pd(dmdba)2) (33 mg, 0.038 mmol), Xantphos (22 mg, 0.038 mmol), Cs2CO3 (1007 mg, 3.10 mmol) in 12 mL 1,4-dioxane was stirred at 100 °C under N2 atmosphere overnight. After completion of the reaction indicated by LCMS, the mixture was filtered by Celite and concentrated in vacuum to give a residue, which was purified by column chromatography (DCM:MeOH=70:1) to give a residue, which was purified by column chromatography to give (2S,6R)-tert-butyl 2-(3-chloropyridin-2-yl)-6- (6-(pyrimidin-4-ylmethyl)pyridin-2-yl)piperidine-1- carboxylate (13-1, 200 mg, 28%) as yellow syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 80.58%. Rt = 2.261 min; MS Calcd.: 465.1; MS Found: 466.0 [M+H]+. [00448] Synthesis of I-88.
Figure imgf000185_0001
Following General Procedure J, I-88 (35 mg, 22%) was obtained as light-brown syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 98.08%. Rt = 1.797 min; MS Calcd.: 365.1; MS Found: 366.0 [M + H]+. HPLC (Agilent HPLC 1200, Column: L-column2 ODS (150mm *4.6 mm*5.0 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] to 15% [total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 85% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 5 min, then under this condition for 10 min, finally changed to 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 0.1 min and under this condition for 5 min. Purity: 100.00%, Rt = 7.864 min; MS Calcd.: 365.1; MS Found: 366.0 [M+H]+.1H NMR (400 MHz, CD3OD) δ: 9.13 (d, J = 1.2 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 7.51 (dd, J = 4.4, 1.2 Hz, 1H), 7.66-7.57 (m, 2H), 7.36 (dd, J = 5.2, 1.6 Hz, 1H), 7.22 (d, J = 11.6 Hz, 1H), 7.15-7.12 (m, 2H), 4.48 (dd, J = 11.2, 2.4 Hz, 1H), 4.31 (s, 2H), 3.99 (dd, J = 11.2, 2.4 Hz, 1H), 2.13-1.80 (m, 4H), 1.63-1.43 (m, 2H). Example 14: Synthesis of I-93 Synthetic Scheme for I-93
Figure imgf000186_0001
[00449] Synthesis of 14-1.
Figure imgf000186_0002
[00450] To a solution of ethyl 6-((2R,6S)-1-(tert-butoxycarbonyl)-6-(3-chloropyridin-2- yl)piperidin-2-yl)picolinate (14-0, 8 g, 19.98 mmol) in MeOH (50 mL) was added 2M LiOH solution (27 mL, 53.93 mmol) at room temperature, then the mixture was stirred at room temperature overnight. After completion of the reaction was indicated by LCMS, the mixture was concentrated in vacuum, diluted with water and adjusted to pH = 6 by HCl solution, then extracted with DCM (150 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give 6-((2R,6S)-1- (tert-butoxycarbonyl) -6-(3- chloropyridin-2-yl)piperidin-2-yl)picolinic acid (14-1, 8 g, crude) as brown solid, which was used directly in the next step without purification. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 94.65%. Rt = 1.541 min; MS Calcd.: 417.2; MS Found: 418.2 [M+H]+. [00451] Synthesis of 14-2.
Figure imgf000187_0001
[00452] A mixture of 6-((2R,6S)-1- (tert-butoxycarbonyl) -6-(3-chloropyridin-2-yl)piperidin- 2-yl)picolinic acid (14-1, 8 g, 19.20 mmol), N,O-dimethylhydroxylamine hydrochloride (5.58 g, 57.6 mmol), HATU (10.9 g, 28.8 mmol) and TEA (11.6 g, 115.2 mmol) in dry DMF (150 mL) was stirred at room temperature under N2 protection for 3 hours. After completion of the reaction indicated by LCMS, the mixture was poured into water (200 mL), extracted with EA (150 mL x 3). The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (PE:EA=10:1) to give (2S,6R)-tert-butyl 2-(3-chloropyridin-2-yl)-6-(6-(methoxy(methyl) carbamoyl)pyridin-2-yl)piperidine-1-carboxylate (14-2, 7 g, 80%) as light-yellow syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 91.97%. Rt = 2.102 min; MS Calcd.: 460.2; MS Found: 461.3 [M+H]+. [00453] Synthesis of 14-3.
Figure imgf000188_0001
[00454] To a solution of oxazole (134 mg, 1.95 mmol) in anhydrous THF (5 mL) was added BH3•THF (1 M, 1.95 mL, 1.95 mmol) at room temperature, the mixture was stirred at room temperature under N2 protection for 1 hour, then the miture was cooled to -70 °C, and n-BuLi (2.5 M in hexane, 0.78 mL, 1.95 mmol) was added dropwise at -70 °C, then the mixture was stirred at -70 °C for 1 hour, followed by adding a solution of (2S,6R)-tert-butyl 2-(3- chloropyridin-2-yl)-6-(6-(methoxy(methyl)carbamoyl)pyridin-2-yl)piperidine-1- carboxylate (14-2, 300 mg, 0.65 mmol) in anhydrous THF (1.5 mL), then the mixture was stirred at -70 °C for 4 hours. After completion of the reaction indicated by LCMS, the mixture was poured into sat. NH4Cl solution (20 mL), extracted with DCM (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (PE:EA=30:1) to give (2S,6R)-tert-butyl 2-(3-chloropyridin- 2-yl)-6-(6-(hydroxy(oxazol-2-yl) methyl)pyridin-2-yl)piperidine-1-carboxylate (14-3, 150 mg, 49%) as yellow syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: 57.70%. Rt = 2.230 min; MS Calcd.: 470.2; MS Found: 471.0 [M+H]+. [00455] Synthesis of 14-4.
Figure imgf000189_0001
[00456] Following General Procedure C, 14-4 (180 mg, crude) was obtained as brown syrup, which was used in the next step without purification. [00457] Synthesis of 14-5.
Figure imgf000189_0002
[00458] Following General Procedure U, 14-5 (90 mg, 60%) was obtained as brown syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.). Purity: 81.44%. Rt = 2.367 min; MS Calcd.: 454.2; MS Found: 454.9 [M+H]+. [00459] Synthesis of I-93.
Figure imgf000190_0001
Following General Procedure J, I-93 (35 mg, 51%) was obtained as light-yellow syrup. LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm *4.6 mm*3.5 μm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.) Purity: 99.31%. Rt = 1.902 min; MS Calcd.: 354.1; MS Found: 355.0 [M + H]+. HPLC (Agilent HPLC 1200, Column: L-column2 ODS (150mm *4.6 mm*5.0 μm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] to 15% [total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 85% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 5 min, then under this condition for 10 min, finally changed to 90% [(total 10mM AcONH4) H2O/MeCN = 900/100 (v/v)] and 10% [total 10mM AcONH4) H2O/MeCN = 100/900 (v/v)] in 0.1 min and under this condition for 5 min. Purity: 99.02%, Rt = 8.819 min; MS Calcd.: 354.1; MS Found: 355.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ: 8.52-8.51 (m, 1H), 7.65-7.57 (m, 3H), 7.25 (d, J = 7.6 Hz, 1H), 7.14-7.06 (m, 3H), 4.51-4.45 (m, 1H), 4.35 (s, 2H), 4.03-3.97 (m, 1H), 2.71-2.61 (m, 1H), 2.13-2.08 (m, 1H), 2.07-1.96 (m, 3H), 1.86-1.79 (m, 1H), 1.62-1.44 (m, 2H). Example 15: Synthesis of Additional Compounds [00460] Additional exemplary compounds were prepared following methods substantially similar to those described above and herein. Data for these compounds are provided below.
Table 2: Characterization Data for Additional Exemplary Compounds
Figure imgf000191_0001
190 of 231
Figure imgf000192_0001
191 f 231
Figure imgf000193_0001
192 f 231
Figure imgf000194_0001
193 f 231
Figure imgf000195_0001
194 of 231
Figure imgf000196_0001
195 f 231
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
199 f 231
Figure imgf000201_0001
200 of 231
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
204 of 231
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
209 of 231
Figure imgf000211_0001
210 f 231
Figure imgf000212_0001
211 of 231
Figure imgf000213_0001
Figure imgf000214_0001
213 of 231
Figure imgf000215_0001
Figure imgf000216_0001
215 of 231
Figure imgf000217_0001
Example 16: REGA Screening Assay Intracellular CXCL-12-induced calcium mobilization assay [00461] Intracellular calcium mobilization induced by chemokines or chemokine-derived peptides were evaluated using a calcium responsive fluorescent probe and a FLIPR system. The CXCR-4 transfected U87 cell line (U87.CXCR4) cells were seeded in gelatine-coated black-wall 96-well plates at 20,000 cells per well and incubated for 12 hours. Cells were then loaded with the fluorescent calcium probe Fluo-2 acetoxymethyl at 4 µM final concentration in assay buffer (Hanks’ balanced salt solution with 20 mM HEPES buffer and 0.2% bovine serum albumin, pH 7.4) for 45 min at 37 °C. The intracellular calcium mobilization induced by the CXCL-12 (25-50 ng/mL) was then measured at 37 °C by monitoring the fluorescence as a function of time in all the wells simultaneously using a fluorometric imaging plate reader (FLIPR Tetra, Molecular Devices). The test compounds were added 15 minutes before the addition of CXCL-12 and monitored to see if compounds induced signals by themselves (agonistic properties). Chemokine (CXCL12-AF647) binding inhibition assay [00462] Jurkat cells expressing CXCR4 were washed once with assay buffer (Hanks’ balanced salt solution with 20 mM HEPES buffer and 0.2% bovine serum albumin, pH 7.4) and then incubated for 15 min at room temperature with the test compounds diluted in assay buffer at dose-dependent concentrations. Subsequently, CXCL12-AF647 (25 ng/mL) was added to the compound-incubated cells. The cells were incubated for 30 min at room temperature. Thereafter, the cells were washed twice in assay buffer, fixed in 1% paraformaldehyde in PBS, and analyzed on the FL4 channel of a FACSCalibur flow cytometer equipped with a 635-nm red diode laser (Becton Dickinson, San Jose, CA, USA). [00463] The percentages of inhibition of CXCL12-AF647 binding were calculated according to the formula: [1 – ((MFI – MFINC) / (MFIPC – MFINC))] x 100 where MFI is the mean fluorescence intensity of the cells incubated with CXCL12-AF647 in the presence of the inhibitor, MFINC is the mean fluorescence intensity measured in the negative control (i.e., autofluorescence of unlabeled cells), and MFIPC is the mean fluorescence intensity of the positive control (i.e., cells exposed to CXCL12-AF647 alone). Results of Assays [00464] Table 3 shows the activity of selected compounds of this invention in the assays described above. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as “A” provided an IC50 of 1 to 100 nM; compounds having an activity designated as “B” provided an IC50 of >100 nm to <1 μM; compounds having an activity designated as “C” provided an IC50 of 1 µM to <2.5 µM; and compounds having an activity designated as “D” provided an IC50 of 2.5 µM or greater. Table 3: Inhibition of Ca2+ Signalling and Inhibition of CXCL12 Binding C
Figure imgf000219_0001
C
Figure imgf000220_0001
C
Figure imgf000221_0001
[00465] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS We claim: 1. A compound of Formula I:
Figure imgf000222_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R1 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6; each -R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each L1 is independently a covalent bond or a C1-6 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-; each -Cy- is independently a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R2 is
Figure imgf000223_0001
group and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO2-; L2 is a covalent bond or a C1-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -or C(S)-; Ring B is phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, an 8-10 membered partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 is hydrogen or C1-3 aliphatic optionally substituted with 1, 2 or 3 substituents independently selected from deuterium or halogen; each R4 is independently hydrogen, deuterium, halogen, -CN, -OR6, or C1-4 alkyl, or two R4 groups on the same carbon are optionally taken together to form =NR6, =NOR6, =O, or =S; each R5 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6, or two R5 groups on the same carbon atom are optionally taken together to form =NR, =NOR, =O, =S, or a spirocyclic 3-6 membered carbocyclic ring; each R6 is independently hydrogen or C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; each R7 is independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, or -L1-R6; or two R7 groups on the same carbon atom are optionally taken together to form =O or =S; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, or 3; provided that
Figure imgf000224_0001
2. The compound of claim 1, wherein L2 is a covalent bond or a C1-4 bivalent, straight- chain, hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, or -S-; and L2 is optionally substituted with 1,
2, or 3 substituents independently selected from deuterium, halogen, -OR, -SR, -N(R)2, or -CN.
3. The compound of claim 1, wherein L2 is -O-, -S-, -N(R)-, -CH2-, -CH2CH2-, - CH2CH2CH2-, CH2CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)CH2-, or -C(CH3)2CH2-, and L2 is optionally substituted with 1, 2, or 3 substituents independently selected from deuterium or halogen.
4. The compound of any one of claims 1-3, wherein Ring B is phenyl or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
5. The compound of any one of claims 1-4, wherein R2 is is
Figure imgf000225_0001
a 5- or 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
6. The compound of any one of claims 1-5, wherein Ring B is pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl.
7. The compound of any one of claims 1-4, wherein R2 is a C1-5 straight or branched aliphatic group substituted with one -CN, -N(R)2, or -C(O)N(R)2 and wherein 1 or 2 methylene units of the aliphatic group are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -S-, -SO-, or -SO2-.
8. The compound of any one of claims 1-4, wherein R2 is -(CH2)1-6-CN, -(CH2)1-6-N(R)2, or -(CH2)1-6-C(O)N(R)2.
9. The compound of any one of claims 1-8, wherein Ring A is ,
Figure imgf000225_0002
Figure imgf000225_0003
10. The compound of any one of claims 1-8, wherein Ring A is
Figure imgf000225_0004
11. The compound of any one of claims 1-10, wherein R1 is selected from -R, halogen, -CN, -OR, -N(R)2, -SR, C1-6 aliphatic, or -L1-R6, wherein -L1- is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -C(S)-, or -Cy-; wherein the C1-6 hydrocarbon chain is optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -N(R)2, -NO2, -N3, =NR, =NOR, =O, =S, -OR, -SR, -SO2R, -S(O)R, -R, -Cy-R, - C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -(R)NC(O)R, -OC(O)N(R)2, -(R)NC(O)OR, - N(R)C(O)N(R)2, -SO2N(R)2, -(R)NSO2R, -C(S)R, or -C(S)OR; and each -R is independently hydrogen, -CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, - CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3.
12. The compound of any one of claims 1-11, wherein L1 is a C1-4 bivalent straight or branched, optionally substituted hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, or -Cy-.
13. The compound of any one of claims 1-12, wherein R3 is hydrogen.
14. The compound of any one of claims 1-12, wherein R3 is methyl.
15. The compound of any one of claims 1-14, wherein R4 is hydrogen, deuterium, halogen, - CN, C1-2 alkyl, or two R4 groups are present and taken together form =O or =S.
16. The compound of any one of claims 1-15, wherein R5 is hydrogen, C1-6 alkyl, halogen, - CN, -OCF3, cyclopropyl, ethynyl, -OCH
Figure imgf000226_0001
17. The compound of any one of claims 1-16, wherein the compound is of Formula II-a or II-b:
Figure imgf000226_0002
II-a II-b or a pharmaceutically acceptable salt thereof.
18. The compound of any one of claims 1-16, wherein the compound is of Formula III-a, III-b, III-c, III-d, or III-e:
Figure imgf000227_0001
or a pharmaceutically acceptable salt thereof.
19. The compound of any one of claims 1-16, wherein the compound is of Formula V-a, V-b, or V-c:
Figure imgf000227_0002
Figure imgf000228_0001
or a pharmaceutically acceptable salt thereof.
20. The compound of any one of claims 1-16, wherein the compound is of Formula VI-a, VI- b, VI-c, or VI-d: V
Figure imgf000228_0002
or a pharmaceutically acceptable salt thereof.
21. The compound of any one of claims 1-16, wherein the compound is of Formula VIII-a, VIII-b, VIII-c, VIII-d, VIII-e, or VIII-f:
Figure imgf000229_0001
or a pharmaceutically acceptable salt thereof.
22. The compound of any one of claims 1-16, wherein the compound is of Formula IX-a, IX- b, IX-c, IX-d, IX-e, or IX-f:
Figure imgf000229_0002
Figure imgf000230_0001
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1, wherein the compound is selected from those in Table 1, or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising a compound of any one of claims 1-23 and a pharmaceutically acceptable excipient.
25. A method of treating a cancer selected from the group consisting of leukemias; Waldenstrom’s macroglobulinemia; multiple myeloma; heavy chain disease; and solid tumors, wherein the solid tumor is selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, renal cell carcinoma, colon carcinoma, colorectal carcinoma, pancreatic cancer, breast cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, melanoma, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm’s tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, neuroblastoma, and retinoblastoma, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof.
26. A method of treating a primary immunodeficiency disease or disorder, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof.
27. The method of claim 26, wherein the primary immune deficiency disease or disorder is warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome; or a severe congenital neutropenia (SCN).
28. The method of claim 27, wherein the SCN arises from G6PC3 deficiency, GATA2 deficiency (Mono MAC syndrome), idiopathic CD4+ T lymphocytopenia (ICL); and Wiskott- Aldrich Syndrome (WAS).
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114921401A (en) * 2022-05-24 2022-08-19 灵知蓝诺(北京)生物技术有限公司 Method for extracting cells from mucus based on liquid-phase molecular sieve
CN115403510A (en) * 2022-08-11 2022-11-29 南方医科大学 PD-L1/CXCL12 double-target-point inhibitor, preparation method and application

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7501518B2 (en) * 2003-04-22 2009-03-10 Genzyme Corporation Methods of making 2,6-diaryl piperidine derivatives
US20170137401A1 (en) * 2014-05-16 2017-05-18 Emory University Chemokine CXCR4 and CCR5 Receptor Modulators and Uses Related Thereto
US20200123150A1 (en) * 2016-06-21 2020-04-23 X4 Pharmaceuticals, Inc. Cxcr4 inhibitors and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7501518B2 (en) * 2003-04-22 2009-03-10 Genzyme Corporation Methods of making 2,6-diaryl piperidine derivatives
US20170137401A1 (en) * 2014-05-16 2017-05-18 Emory University Chemokine CXCR4 and CCR5 Receptor Modulators and Uses Related Thereto
US20200123150A1 (en) * 2016-06-21 2020-04-23 X4 Pharmaceuticals, Inc. Cxcr4 inhibitors and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEMCOMPOUND 13 February 2015 (2015-02-13), ANONYMOUS : "4-[(2R,6S)-2-(3,5-dimethylpyridin-2-yl)-6-(3,6- dimethylpyridin-2-yl)piperidin-1-yl]butylurea", XP055896147, retrieved from PUBCHEM Database accession no. 89903872 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114921401A (en) * 2022-05-24 2022-08-19 灵知蓝诺(北京)生物技术有限公司 Method for extracting cells from mucus based on liquid-phase molecular sieve
CN115403510A (en) * 2022-08-11 2022-11-29 南方医科大学 PD-L1/CXCL12 double-target-point inhibitor, preparation method and application
CN115403510B (en) * 2022-08-11 2023-04-25 南方医科大学 PD-L1/CXCL12 double-target inhibitor, preparation method and application

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