CXCR4 inhibitors and uses thereof

Abstract

The present invention relates to CXCR4 inhibitors and their uses. The present invention provides compounds, compositions thereof, and methods of using the compounds and compositions.

Description

[0001] This application is a divisional application of the invention patent application with application date of June 21, 2017, application number 201780048803.6, and invention name “CXCR4 inhibitors and their uses”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 352,820, filed on June 21, 2016, and U.S. Provisional Application No. 62 / 456,526, filed on February 8, 2017, the contents of all of which are incorporated herein by reference in their entirety. Technical Field

[0004] The present invention relates to compounds and methods for inhibiting CXC receptor type 4 (CXCR4). The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using the compositions to treat various conditions. Background Art

[0005] CXC 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 the class I GPCR or rhodopsin-like GPCR family. Under normal physiological conditions, CXCR4 plays a variety of roles and is mainly expressed in the hematopoietic and immune systems. CXCR4 was originally discovered as one of the co-receptors involved in human immunodeficiency virus (HIV) cell invasion. Subsequent studies have shown that it is expressed in many tissues, including the brain, thymus, lymphoid tissue, spleen, stomach and small intestine, as well as specific cell types such as hematopoietic stem cells (HSC), mature lymphocytes and fibroblasts. CXCL12, formerly known as SDF-1α, is the only known ligand for CXCR4. CXCR4 mediates the migration of stem cells during embryonic development and in response to injury and inflammation. CXCR4 has been shown to play a variety of roles in human diseases such as cell proliferative conditions, Alzheimer's disease, HIV, rheumatoid arthritis, pulmonary fibrosis, etc. For example, the expression of CXCR4 and CXCL12 has been noted in several tumor types. CXCL12 is expressed by cancer-associated fibroblasts (CAFs) and is generally present at high levels in the tumor microenvironment (TME). In clinical studies of various tumor types including breast cancer, ovarian cancer, kidney cancer, lung cancer and melanoma, the expression of CXCR4 / CXCL12 has been associated with poor prognosis and an increased risk of metastasis to the lymph nodes, lungs, liver and brain as sites of CXCL12 expression. CXCR4 is often expressed on melanoma cells, particularly on CD133+ colonies that are considered to represent melanoma stem cells; in vitro experiments and mouse models have shown that CXCL12 is chemotactic for these cells.

[0006] In addition, there is now evidence that the CXCL12 / CXCR4 axis contributes to the loss or lack of tumor responsiveness to angiogenesis inhibitors (also known as "angiogenic escape"). In animal cancer models, it has been shown that interfering with CXCR4 function changes the TME and sensitizes tumors to immune attack through various mechanisms such as eliminating tumor angiogenesis and increasing the ratio of CD8+ T cells to Treg cells. These effects significantly reduce tumor burden and increase 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.

[0007] These data highlight the significant unmet need for CXCR4 inhibitors for the treatment of many diseases and disorders mediated by aberrant or undesirable expression of the receptor, such as in cell proliferative conditions. Summary of the Invention

[0008] It has been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as CXCR4 inhibitors. In one aspect, the present invention provides a compound of formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0011] The compounds of the present invention and pharmaceutically acceptable compositions thereof can be used to treat various diseases, conditions or disorders associated with CXC receptor type 4 (CXCR4). Such diseases, conditions or disorders include cell proliferative conditions (e.g., cancer), such as those described herein. DETAILED DESCRIPTION

[0012] 1. General Description of Certain Embodiments of the Invention:

[0013] The compounds of the present invention and their pharmaceutical compositions can be used as inhibitors of CXCR4. Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention and their pharmaceutical compositions can inhibit the activity of CXCR4, thereby treating certain diseases such as cancer.

[0014] It has been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as CXCR4 inhibitors. In one aspect, the present invention provides a compound of formula I:

[0015]

[0016] or a pharmaceutically acceptable salt thereof, wherein:

[0017] Ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; a phenyl group; an 8- to 10-membered bicyclic aromatic carbocycle; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0018] Each R 1 is independently -R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR or -L 1 -R 6 ;

[0019] Each R is independently hydrogen or selected from C 1-6 an aliphatic optionally substituted group; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; a phenyl group; an 8- to 10-membered bicyclic aromatic carbocycle; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0020] Each L 1 and L 2 are independently covalently bonded or C 1-8 a divalent linear or branched hydrocarbon chain in which one, two or three methylene units of the chain are independently and optionally substituted 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-, -SON(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-;

[0021] each -Cy- is independently a divalent optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; an optionally substituted phenylene ring; an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0022] R 2 is hydrogen, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, -L 2 -R 6 or optionally substituted C 1-8 aliphatic;

[0023] R 3 is hydrogen, optionally substituted C 1-6 Aliphatic or -L 3 -R 6 ;

[0024] L 3 It is C 1-6 a divalent linear or branched hydrocarbon chain in which one, two or three methylene units of the chain are independently and optionally substituted by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -C(S)- or -Cy-;

[0025] Each R 4 are independently hydrogen, deuterium, halogen, -CN, -OR 6 or C 1-4 Alkyl, or two R on the same carbon 4 The groups are optionally taken together to form =NR 6 、=NOR 6 , =O or =S;

[0026] Each R 5 are independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR or -L 1 -R 6 , or two R on the same saturated carbon atom 5 The groups are optionally taken together to form =NR, =NOR, =O, =S or a spirocyclic 3- to 6-membered carbocyclic ring;

[0027] Each R 6is independently hydrogen or C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1-6 alkyl;

[0028] m is 0, 1, 2, 3, or 4;

[0029] n is 0, 1, 2, 3, or 4; and

[0030] p is 0, 1, 2, 3, or 4.

[0031] 2. Compounds and definitions:

[0032] The compounds of the present invention include compounds generally described herein and further described by the classes, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition, ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0033] As used herein, the term "aliphatic" or "aliphatic group" means a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), with a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, with 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, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0034] As used herein, the term "bicycle" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic ring, saturated or with one or more unsaturated units, with one or more common atoms between the two rings of the ring system. Therefore, the term includes any allowed ring fusions, such as ortho-fusions or spirocycles. As used herein, the term "heterobicycle" is a subset of "bicyclic ring" that requires one or more heteroatoms to be present in one or both rings of the bicyclic ring. These heteroatoms can be present in the ring knot and are optionally substituted, and can 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, the bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. As used herein, the term "bridged bicyclic ring" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic ring, saturated or partially unsaturated, with at least one bridge. As defined by IUPAC, "bridge" is an unbranched chain or atom or valence bond consisting of atoms connecting two bridgeheads, wherein "bridgehead" is any backbone atom of a ring system, which is bound to three or more backbone atoms (excluding hydrogen). In certain embodiments, the bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. These bridged bicyclic groups are well known in the art, and include those groups described below, wherein each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted by one or more substituents described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bicyclic groups include:

[0035]

[0036] An exemplary bridged double ring includes:

[0037]

[0038]

[0039] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0040] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl.

[0041] The term "heteroatom" refers to 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, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0042] As used herein, the term "unsaturated" refers to a moiety having one or more units of unsaturation.

[0043] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain” refers to straight or branched divalent alkylene, alkenylene and alkynylene chains as defined herein.

[0044] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. Substituted alkylene chains are polymethylene groups in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include the substituents described below for substituted aliphatic groups.

[0045] The term "alkenylene" refers to a divalent alkenyl group. Substituted alkenylene chains are polymethylene groups containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0046] As used herein, the term "cyclopropenyl" refers to a divalent cyclopropyl radical of the structure:

[0047] The term "halogen" refers to F, Cl, Br or I.

[0048] The term "aryl" used alone or as part of a larger moiety, such as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system 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, including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may carry one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimido, naphthylimino, phenanthridinyl, or tetrahydronaphthyl.

[0049] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having from 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; sharing 6, 10, or 14 pi electrons in a cyclic array; and having from one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaryl ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaryl ring. Non-limiting examples include: indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, 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 groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which encompasses rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0050] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms in addition to carbon atoms, as defined above. The term "nitrogen" when used with respect to a ring atom of a heterocycle includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 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).

[0051] The heterocycle can be connected to its side group at any heteroatom or carbon atom that produces a stable structure, and any of the ring atoms can be optionally substituted. Examples of these saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazaheterocyclyl, oxazaheterocyclyl, sulphazaheterocyclyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclyl", "heterocyclic moiety", and "heterocyclic group" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings such as dihydroindole, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolyl. The heterocyclic group can be monocyclic or bicyclic. The term "heterocycloalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0052] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0053] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituents may be the same or different at each position. The substituent combinations contemplated by the present invention are preferably substituent combinations that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow it to be produced, detected, and in certain embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0054] Each optional substituent on a substitutable carbon is independently a monovalent substituent selected from the group consisting of: halogen; -(CH2); 0- 4R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o 、-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0-4 SR o ; -(CH2) 0-4 Ph, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substituted; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be replaced by R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0- 4N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o)C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR-、SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o 、-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o2;-S(O)(NR o )R o ;-S(O)2N=C(NR o 2)2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2.

[0055] Each R o are independently hydrogen; C 1-6 Aliphatic; -CH2Ph; -O(CH2) 0-1 Ph; -CH2-(5- to 6-membered heteroaryl ring); or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independently occurring R o Combined with one or more intervening atoms thereof to form a 3 to 12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, said heteroatoms being replaced by R o substituted with a divalent substituent selected from =O and =S on a saturated carbon atom of o Optionally substituted with monovalent substituents independently selected from halogen, -(CH2) 0-2 R · 、-(halogenated R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2;-O(halogenated R · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2)0-2 C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2) 0-2 SR · 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · .

[0056] Each R · Independently selected from C 1-4 Aliphatic; -CH2Ph; -O(CH2) 0-1 Ph; or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R · is unsubstituted or, if preceded by halo, substituted only with one or more halogens; or wherein the optional substituents on the saturated carbon are divalent substituents independently selected from the group consisting of: =O, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2-3 S-, or a divalent substituent attached to an ortho-substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, where each independent occurrence of R * Selected from hydrogen, C 1-6 Aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0057] When R * It is C 1-6 When aliphatic, R * Optionally halogen, -R ·、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R · is unsubstituted or, where preceded by halo, substituted only by one or more halogens.

[0058] The optional substituents on the substitutable nitrogen are independently or Each of these are independently hydrogen, C 1-6 an aliphatic, unsubstituted -OPh or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independent occurrences of joins one or more of its intervening atoms to form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when It is C 1-6 When aliphatic, Optionally halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R · is unsubstituted or, where preceded by halo, substituted only by one or more halogens.

[0059] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts with amino groups formed with the following acids: 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 salts with amino groups formed 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, camphor, sulfonate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoic acid, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, sodium p-toluenesulfonate, undecanoate, valerate, and the like.

[0060] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0061] Unless otherwise stated, structures depicted herein are also meant to encompass all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, structures depicted herein are also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures having a moiety that includes replacement of hydrogen by deuterium or tritium, or by 13 C- or 14 Compounds of the present invention having structures wherein C-enriched carbons are substituted carbons are within the scope of the present invention. According to the present invention, such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents. In certain embodiments, the warhead portion R of the provided compounds is 1 Includes one or more deuterium atoms.

[0062] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits CXCR4 with measurable affinity. In certain embodiments, the IC 50 and / or a 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.

[0063] As used herein, the terms "measurable affinity" and "measurable inhibition" refer to a measurable change in CXCR4 activity between a sample comprising a compound of the invention or composition thereof and CXCR4 and an equivalent sample comprising CXCR4 without the compound or composition thereof.

[0064] 3. Description of exemplary embodiments:

[0065] In one aspect, the present invention provides a compound of formula I:

[0066]

[0067] or a pharmaceutically acceptable salt thereof, wherein:

[0068] Ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; a phenyl group; an 8- to 10-membered bicyclic aromatic carbocycle; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0069] Each R 1 is independently -R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR or -L 1 -R 6 ;

[0070] Each R is independently hydrogen or selected from C 1-6 an aliphatic optionally substituted group; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; a phenyl group; an 8- to 10-membered bicyclic aromatic carbocycle; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0071] Each L 1 and L 2 are independently covalently bonded or C 1-8 a divalent linear or branched hydrocarbon chain in which one, two or three methylene units of the chain are independently and optionally substituted 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-, -SON(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-;

[0072] each -Cy- is independently a divalent optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; an optionally substituted phenylene ring; an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0073] R 2 is hydrogen, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, -L 2 -R 6 or optionally substituted C 1-8 aliphatic;

[0074] R3 is hydrogen, optionally substituted C 1-6 Aliphatic or -L 3 -R 6 ;

[0075] L 3 It is C 1-6 a divalent linear or branched hydrocarbon chain in which one, two or three methylene units of the chain are independently and optionally substituted by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -C(S)- or -Cy-;

[0076] Each R 4 are independently hydrogen, deuterium, halogen, -CN, -OR 6 or C 1-4 Alkyl, or two R on the same carbon 4 The groups are optionally taken together to form =NR 6 、=NOR 6 , =O or =S;

[0077] Each R 5 are independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR or -L 1 -R 6 , or two R on the same saturated carbon atom 5 The groups are optionally taken together to form =NR, =NOR, =O, =S or a spirocyclic 3- to 6-membered carbocyclic ring;

[0078] Each R 6 is independently hydrogen or C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1-6 alkyl;

[0079] m is 0, 1, 2, 3, or 4;

[0080] n is 0, 1, 2, 3, or 4; and

[0081] p is 0, 1, 2, 3, or 4.

[0082] As generally defined above, Ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; a phenyl group; an 8- to 10-membered bicyclic aromatic carbocycle; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0083] In some embodiments, Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is a phenyl group. 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 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0084] In some embodiments, Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0085] In some embodiments, Ring A is selected from:

[0086]

[0087] In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is

[0088] In some embodiments, Ring A is not

[0089] In some embodiments, Ring A is not imidazo[1,2-a]pyridine.

[0090] In some embodiments, Ring A is selected from those shown in Table 1 below.

[0091] As generally defined above, each R 1 are independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR or -L 1 -R 6 .

[0092] In some embodiments, R 1 is R. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is -N(R)2. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R1 Yes-L 1 -R 6 .

[0093] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is an optionally substituted C 1-6 In some embodiments, R 1 is an optionally substituted 3 to 8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 1 is an optionally substituted phenyl group. In some embodiments, R 1 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic ring. 1 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1 is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 1 is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0094] In some embodiments, R 1 Selected from R, halogen, -CN, -OR, -N(R)2, -SR, C 1-6 Aliphatic or -L 1 -R 6 , where L 1 It is C 1-6 A divalent straight or branched hydrocarbon chain wherein 1, 2 or 3 methylene units of the chain are independently and optionally substituted by -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -C(S)- or -Cy-; wherein said C 1-6 The aliphatic group is optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, -CN, -N(R)2, -NO2, -N3, =NR, =NOR, =O, =S, -OR, -SR, -S02R, -S02R, -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, -SON(R)2, -(R)NS02R, -C(S)R or -C(S)OR; and each R is independently hydrogen, -CH2-phenyl, phenyl, C 1-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2 or -CH2CF3; or each R is independently hydrogen or methyl; or R is hydrogen.

[0095] In some embodiments, R 1 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 、 and each R is independently hydrogen, -CH2-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.

[0096] In some embodiments, R 1 Selected from hydrogen, halogen, C 1-6 Alkyl, -CN, -N(R)2, -OR, -SR, and each R is independently hydrogen, -CH2-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.

[0097] In some embodiments, R 1 Select from those shown in Table 1 below.

[0098] As generally defined above, each L 1 and L 2 are independently covalently bonded or C 1-8 A divalent linear or branched hydrocarbon chain in which one, two or three methylene units of the chain are independently and optionally substituted 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-, -SON(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0099] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 It is C 1-8 In some embodiments, L 1 It is C 1-8 A divalent linear or branched hydrocarbon chain in which one, two or three methylene units of the chain are independently and optionally substituted 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-, -SON(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0100] In some embodiments, L 1 It is C 1-6 A divalent straight or branched hydrocarbon chain wherein 1, 2 or 3 methylene units of the chain are independently and optionally substituted by -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NSO2-, -C(S)- or -Cy-, and each R is independently hydrogen, -CH2-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.

[0101] In some embodiments, L 1 Select from those shown in Table 1 below.

[0102] In some embodiments, L 2 is a covalent bond. In some embodiments, L 2 It is C 1-8 In some embodiments, L 2 It is C 1-8A divalent linear or branched hydrocarbon chain in which one, two or three methylene units of the chain are independently and optionally substituted 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-, -SON(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0103] In some embodiments, L 2 It is C 1-6 A divalent straight or branched hydrocarbon chain wherein 1, 2 or 3 methylene units of the chain are independently and optionally substituted by -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NSO2-, -C(S)- or -Cy-, and each R is independently hydrogen, -CH2-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.

[0104] In some embodiments, L 2 Select from those shown in Table 1 below.

[0105] As generally defined above, each -Cy- is independently a divalent optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; an optionally substituted phenylene ring; an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0106] In some embodiments, -Cy- is a divalent optionally substituted 3 to 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 4 to 8 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, -Cy- is an optionally substituted 5 to 6 membered monocyclic heteroaromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, -Cy- is an optionally substituted 8 to 10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring with 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, -Cy- is an optionally substituted 8 to 10 membered bicyclic or bridged bicyclic heteroaromatic ring with 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0107] In some embodiments, -Cy- is

[0108] In some embodiments, -Cy- is selected from those shown in Table 1 below.

[0109] As generally defined above, R 2 is hydrogen, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR, -L 2 -R 6 or optionally substituted C 1-8 aliphatic.

[0110] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is -N(R)2. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 Yes-L 2 -R 6 In some embodiments, R 2 is an optionally substituted C 1-8 aliphatic.

[0111] In some embodiments, R 2 is hydrogen, halogen, -CN, -OR, -N(R)2, -SR, optionally substituted C 1-6 Aliphatic or -L 2 -R 6, where L 2 It is C 1-6 A divalent straight or branched hydrocarbon chain wherein 1, 2 or 3 methylene units of the chain are independently and optionally substituted by -O-, -C(O)-, -N(R)-, -S-, -SO-, -SO2-, -C(S)- or -Cy-; wherein said C 1-6 The aliphatic group is optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, -CN, -N(R)2, -NO2, -N3, =NR, =NOR, =O, =S, -OR, -SR, -S02R, -S02R, -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; wherein each R is independently hydrogen, -CH2-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.

[0112] In some embodiments, R 2 Selected from hydrogen, halogen, -CN, -OR, -N(R)2, C 1-6 Alkyl (optionally substituted by 1, 2 or 3 deuterium or halogen atoms), C 2-6 Alkynyl, -S(O)R 6 、-SO2R 6 、-SO2NHR 6 、-(CH2) 1-6 -N(R)R 6 、-(CH2) 1-6 -OR 6 or -(CH2) 0-6 -Cy-R 6 In some embodiments, R 2 Selected from hydrogen, halogen, -OR, -N(R)2, -S(O)R 6 、-SO2R 6 、-SO2NHR 6 、-(CH2) 1-6 -N(R)R 6 、-(CH2) 1-6 -OR 6 、 and each R is independently hydrogen, -CH2-phenyl, phenyl, C 1-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2 or -CH2CF3; or each R is independently hydrogen or methyl; or R is hydrogen.

[0113] In some embodiments, R 2 It is C 2-4 Alkynyl, -NH2, F, Cl, Br or I. In some embodiments, R 2 is hydrogen, Cl, -NH2 or ethynyl. In some embodiments, R 2 It's Cl.

[0114] In some embodiments, R 2 Select from those shown in Table 1 below.

[0115] As generally defined above, R 3 is hydrogen, optionally substituted C 1-6 Aliphatic or -L 3 -R 6 .

[0116] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an optionally substituted C 1-6 In some embodiments, R 3 Yes-L 3 -R 6 .

[0117] In some embodiments, R 3 is selected from hydrogen or C optionally substituted by 1, 2 or 3 groups independently selected from 1-6 Alkyl: deuterium, halogen, -CN, -N(R)2, -NO2, -N3, =NR, =NOR, =O, =S, -OR, -SR, -S02R, -S02R, -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. In some embodiments, R 3 Selected from hydrogen or C 1-6 alkyl (optionally substituted by 1, 2 or 3 deuterium or halogen atoms), -(CH2) 1-6 -CN, -(CH2) 1-6 -N(R)(R 6 ), -(CH2) 1-6 -OR 6 or -(CH2) 0-6 -Cy-R6 In some embodiments, R 3 Selected from hydrogen or C 1-6 alkyl (optionally substituted by 1, 2 or 3 deuterium or halogen atoms), -(CH2) 1-6 -CN, -(CH2) 1-6 -N(R)(R 6 ), -(CH2) 1-6 -OR 6 、 and each R is independently hydrogen, -CH2-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.

[0118] In some embodiments, R 3 is hydrogen or C optionally substituted by 1, 2 or 3 deuterium or halogen atoms, phenyl, pyridyl, -CN, -N(R)2 or -OR 1-6 Alkyl, wherein each R is independently hydrogen, -CH2-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. In some embodiments, R 3 To be optionally Pyridyl, -N(R)2, -CN or C substituted by 1, 2 or 3 deuterium or halogen atoms 1-4 Alkyl, where R is hydrogen or C 1-3 In some embodiments, R 3 is methyl, ethyl, -CD3 or -CH2CF3. In some embodiments, R 3 It's methyl.

[0119] In some embodiments, R 3 Select from those shown in Table 1 below.

[0120] As generally defined above, L 3 It is C 1-6 A divalent linear or branched hydrocarbon chain wherein one, two or three methylene units of the chain are independently and optionally substituted by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -C(S)- or -Cy-.

[0121] In some embodiments, L3 It is C 1-6 In some embodiments, L 3 It is C 1-6 A divalent linear or branched hydrocarbon chain wherein one, two or three methylene units of the chain are independently and optionally substituted by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -S-, -SO-, -SO2-, -C(S)- or -Cy-.

[0122] In some embodiments, L 3 Select from those shown in Table 1 below.

[0123] As generally defined above, each R 4 are independently hydrogen, deuterium, halogen, -CN, -OR 6 or C 1-4 Alkyl, or two R on the same carbon 4 The groups are optionally taken together to form =NR 6 、=NOR 6 , =O or =S.

[0124] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 Yes-OR 6 In some embodiments, R 4 It is C 1-4 In some embodiments, two R 4 The groups are optionally taken together to form =NR 6 、=NOR 6 , =O or =S.

[0125] In some embodiments, R 4 It is hydrogen, deuterium, halogen, -CN, C 1-2 Alkyl, or two R on the same carbon 4 The groups together form =O or =S.

[0126] In some embodiments, R 4 Select from those shown in Table 1 below.

[0127] As generally defined above, each R 5 are independently R, halogen, -CN, -OR, -N(R)2, -NO2, -N3, -SR or -L 1 -R6 or two R on the same saturated carbon atom 5 The groups are optionally taken together to form =NR, =NOR, =O, =S or a spirocyclic 3- to 6-membered carbocyclic ring.

[0128] In some embodiments, R 5 is R. In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 is -N(R)2. In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 Yes-L 1 -R 6 In some embodiments, two R 5 The groups taken together form =NR, =NOR, =O, =S or a spirocyclic 3- to 6-membered carbocyclic ring.

[0129] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is an optionally substituted C 1-6 In some embodiments, R 5 is C optionally substituted by 1, 2, 3 or 4 deuterium or halogen atoms 1-6 In some embodiments, R 5 is an optionally substituted 3 to 8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 5 is an optionally substituted phenyl group. In some embodiments, R 5 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic ring. 5 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 5 is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0130] In some embodiments, R 5 It is hydrogen, C 1-6 Alkyl, halogen, -CN, -CF3, -CD3, cyclopropyl, ethynyl, -OCH3, -OCF3 or In some embodiments, R 5 It's methyl.

[0131] In some embodiments, R 5 Select from those shown in Table 1 below.

[0132] As generally defined above, each R 6 is independently hydrogen or C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1-6 alkyl.

[0133] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1-6 alkyl.

[0134] In some embodiments, R 6 is C optionally substituted by 1, 2 or 3 deuterium or halogen atoms 1-3 alkyl.

[0135] In some embodiments, R 6 Select from those shown in Table 1 below.

[0136] As generally defined above, m is 0, 1, 2, 3, or 4. 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 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3.

[0137] As generally defined 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.

[0138] As generally defined 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.

[0139] In some embodiments, the present invention provides a compound of formula II-a or II-b:

[0140]

[0141] or a pharmaceutically acceptable salt thereof, wherein ring A, R, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、L 1 、L 2 、L 3 Each of -Cy-, m, n, and p is as defined above and described in the Examples herein, alone or in combination.

[0142] In some embodiments, the present invention provides a compound of formula III:

[0143]

[0144] or a pharmaceutically acceptable salt thereof, wherein ring A, R, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、L 1 、L 2 、L 3 Each of -Cy-, n, and p is as defined above and described in the Examples herein, alone or in combination.

[0145] In some embodiments, the present invention provides a compound of formula IV:

[0146]

[0147] or a pharmaceutically acceptable salt thereof, wherein ring A, R, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、L 1 、L 2 、L 3 Each of -Cy-, m, and p is as defined above and described in the Examples herein, alone or in combination.

[0148] In some embodiments, the present invention provides a compound of Formula V:

[0149]

[0150] or a pharmaceutically acceptable salt thereof, wherein ring A, R, R1 、R 2 、R 3 、R 4 、R 5 、R 6 , L 1 , L 2 , L 3 Each of -Cy-, m, and p is as defined above and described in the Examples herein, alone or in combination.

[0151] In some embodiments, the present invention provides a compound of formula VI:

[0152]

[0153] or a pharmaceutically acceptable salt thereof, wherein R, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , L 1 , L 2 , L 3 Each of -Cy-, m, n, and p is as defined above and described in the Examples herein, alone or in combination.

[0154] In some embodiments, the present invention provides a compound of formula VII:

[0155]

[0156] or a pharmaceutically acceptable salt thereof, wherein R, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , L 1 , L 2 , L 3 Each of -Cy-, m, n, and p is as defined above and described in the Examples herein, alone or in combination.

[0157] In some embodiments, the present invention provides a compound of Formula VIII-a or VIII-b:

[0158]

[0159] or a pharmaceutically acceptable salt thereof, wherein R, R 1 、R 2 、R 3 、R 4 、R 5 、R6 , L 1 , L 2 , L 3 Each of -Cy-, m, n, and p is as defined above and described in the Examples herein, alone or in combination.

[0160] In some embodiments, the present invention provides a compound of Formula IX:

[0161]

[0162] or a pharmaceutically acceptable salt thereof, wherein R, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , L 1 , L 2 , L 3 Each of -Cy-, -Cy-, and n is as defined above and described in the Examples herein, alone or in combination.

[0163] In some embodiments, the present invention provides a compound of Formula Xa, Xb, Xc, Xd or Xe:

[0164]

[0165] or a pharmaceutically acceptable salt thereof, wherein R, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , L 1 , L 2 , L 3 Each of -Cy-, -Cy-, and n is as defined above and described in the Examples herein, alone or in combination.

[0166] In some embodiments, the present invention provides a compound of formula XI:

[0167]

[0168] or a pharmaceutically acceptable salt thereof, wherein R, R 1 、R 2 、R 3 、R 5 、R 6 , L 1 , L 2 , L 3Each of -Cy-, -Cy-, and p is as defined above and described in the Examples herein, alone or in combination.

[0169] In some embodiments, the present invention provides a compound of Formula XII-a or XII-b:

[0170]

[0171] or a pharmaceutically acceptable salt thereof, wherein R, R 1 、R 2 、R 3 、R 5 、R 6 、L 1 、L 2 、L 3 Each of -Cy-, -Cy-, and p is as defined above and described in the Examples herein, alone or in combination.

[0172] In some embodiments, the present invention provides a compound of Formula XIII-a or XIII-b:

[0173]

[0174] or a pharmaceutically acceptable salt thereof, wherein R, R 2 、R 3 、R 6 、L 2 、L 3 Each of -Cy-, -Cy- and -Cy- is as defined above and described individually or in combination in the Examples herein. In some embodiments of Formula XIII-a or XIII-b, -Cy- is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is a 5- or 6-membered saturated or partially unsaturated monocyclic heterocycle having 2 nitrogen atoms.

[0175] In some embodiments, the present invention provides a compound of Formula XIV-a, XIV-b or XIV-c:

[0176]

[0177] or a pharmaceutically acceptable salt thereof, wherein R, R 2 、R 3 、R 5 、R 6 、L 2 、L 3 Each of -Cy-, -Cy-, and -Cy- is as defined above and described in the Examples herein, alone or in combination. In some embodiments of Formulas XIV-a, XIV-b, and XIV-c, R2 In some embodiments, R 2 In some embodiments, R 2 is Cl or Br. In some embodiments, R 2 In some embodiments, R 2 It is C 2-4 Alkynyl, -NH2, F, Cl, Br or I. In some embodiments, R 2 It is hydrogen, Cl, -NH2 or ethynyl.

[0178] Exemplary compounds of the present invention are listed in Table 1.

[0179] Table 1. Exemplary compounds

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] Note: Stereochemistry was arbitrarily assigned to 1-188 and 1-189; each compound was isolated in stereochemically enriched form; compound 1-149 corresponds to its racemate.

[0196]

[0197]

[0198]

[0199] In some embodiments, the present invention provides compounds set forth in Table 1 above, or pharmaceutically acceptable salts thereof.

[0200] 4. General methods for providing compounds of the present invention:

[0201] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semisynthetic methods known to those skilled in the art for similar compounds and by the methods described in detail in the Examples herein.

[0202] In the following schemes, where specific protecting groups ("PG"), leaving groups ("LG"), or transformation conditions are depicted, one of ordinary skill in the art will recognize that other protecting groups, leaving groups, and transformation conditions are also suitable and contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, MB Smith and J. March, 5th ed., John Wiley & Sons, 2001; Comprehensive Organic Transformations, RC Larock, 2nd ed., John Wiley & Sons, 1999; and Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, each of which is incorporated herein by reference in its entirety.

[0203] As used herein, the phrase "leaving group" (LG) includes, but is not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., methanesulfonate, toluenesulfonate, benzenesulfonate, bromobenzenesulfonate, nitrobenzenesulfonate, triflate), diazonium salts, and the like.

[0204] As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxy protecting groups, and the like. Hydroxyl protecting groups are well known in the art and include those described in detail in: Protecting Groups in Organic Synthesis, TW Green and PGM Woods, 3rd Edition, John Wiley & Sons, 1999; and Philip Kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994, the entire contents of which are incorporated herein by reference. Examples of suitable hydroxy protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, aryl alkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formates, benzoylformates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, sodium p-chlorophenoxyacetate, ethyl 3-phenylpropionate, methyl 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonates, 4-methoxy-crotonates, benzoates, benzyl p-terephthalate, ethyl 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 groups. Examples of such silyl ethers include trimethylsilyl, triethylsilane, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylchlorosilane, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, tert-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl ether, methylthiomethyl ether, (2-methoxyethoxy)methyl ether, benzyloxymethyl ether, β-(trimethylsilyl)ethoxymethyl ether, and tetrahydropyranyl ether. Examples of aryl alkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2-picolyl and 4-picolyl groups.

[0205] Amino protecting groups are well known in the art and include those described in detail in: Protecting Groups in Organic Synthesis, TW Green and PGM Woods, 3rd ed., John Wiley & Sons, 1999; and Philip Kosinski, "Protecting Groups", Stuttgart-Georg Thamey Publishers, New York, 1994, the entire contents of which are incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, and the like. Examples of such groups include: tert-butyloxycarbonyl (BOC), ethoxycarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethyloxycarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0206] Those skilled in the art will recognize that various functional groups such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitrile present in the compounds of the present invention can be converted into each other 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, and "March's Advanced Organic Chemistry", 5th edition, ed.: Smith MB and March J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference. Such interconversions may require one or more of the above-mentioned techniques, and certain methods for synthesizing the compounds of the present invention are described below.

[0207] 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:

[0208] Solution 1

[0209]

[0210] In Scheme 1 above, PG is a nitrogen protecting group, and R 1 、R 2 、R 3 、R 4 、R 5 Each of R, Ring A, m, n, and p is as defined above and described in the Examples herein, alone or in combination.

[0211] As generally shown in Scheme 1, aldehydes according to structure A can be condensed with ketones such as acetone in the presence of a base, for example, by following General Procedures E or F to produce intermediates B. The general procedures are described in more detail in the examples below. 3, such as methylamine and an aldehyde methylamine of structure C provide a compound of structure D. In some embodiments, these compounds are CXCR4 inhibitors according to the present invention. In other embodiments, a compound of structure D is reduced according to General Procedure A to provide a compound of structure E. In a compound of structure F, wherein R 2 is a suitable leaving group (LG) that can undergo cross-coupling (e.g., Pd-catalyzed coupling) to provide compounds of structure G. 2 is a hydrogen of structure F, then halogenation or formation of a leaving group such as triflate is performed prior to the coupling reaction. Alternatively, if R 2 If the hydrogen of structure F is employed, then alkylation, such as formylation with paraformaldehyde or DMF, can be used to provide certain compounds of structure G.

[0212] Option 2

[0213]

[0214] Alternatively, as shown in Scheme 2, piperidinone compounds of structure H can be reduced according to General Procedure A to provide compounds of structure I and subsequently reacted with compounds of formula LG-R 3 wherein LG is a suitable leaving group such as a halide or mesylate, thereby providing compounds of structure J.

[0215] 5. Use, Formulation and Administration and Co-administered Additional Therapeutic Agents

[0216] Pharmaceutically acceptable compositions

[0217] According to another embodiment of the present invention, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition of the present invention is such that CXCR4 or its mutant is effectively measurably suppressed in a biological sample or patient. In certain embodiments, the amount of the compound in the composition of the present invention is such that CXCR4 or its mutant is effectively measurably suppressed in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated to be administered to a patient in need of such compositions. In certain embodiments, the composition of the present invention is formulated to be administered orally to a patient.

[0218] As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0219] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partially saturated glyceride mixtures of combined fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0220] "Pharmaceutically acceptable derivative" refers to any non-toxic salt, ester, ester salt or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof.

[0221] As used herein, the term "inhibitory active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of CXCR4 or a mutant thereof.

[0222] The compositions of the present invention can be administered orally, parenterally, by inhalation spray application, topical application, rectally, nasally, buccally, vaginally or via an implantable drug reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable form of the compositions of the present invention can be aqueous or oily suspensions. These suspensions can be prepared according to technology known in the art, using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspension media.

[0223] For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and their glyceride derivatives can be used to prepare injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans and other emulsifiers or bioavailability enhancers (commonly used to make pharmaceutically acceptable solids, liquids or other dosage forms) can also be used for formulation purposes.

[0224] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, conventional carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When aqueous suspensions for oral use are required, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings or coloring agents may also be added.

[0225] Alternatively, for rectal administration, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories. The compositions can be prepared by mixing the medicament with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0226] The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the target of treatment comprises areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0227] Topical application to the lower intestinal tract may be accomplished in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0228] For topical application, the pharmaceutically acceptable compositions provided can be formulated in a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated in a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0229] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic pH-adjusted sterile saline, or preferably, solutions in isotonic pH-adjusted sterile saline, with or without preservatives such as benzyl ammonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0230] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. These compounds are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, halothane, and / or other conventional solubilizing or dispersing agents.

[0231] Most preferably, pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such preparations can be administered with or without food. In certain embodiments, pharmaceutically acceptable compositions of the present invention are formulated not to be administered with food. In other embodiments, pharmaceutically acceptable compositions of the present invention are formulated to be administered with food.

[0232] The amount of the compound of the invention that can be combined with the carrier materials to produce a single dosage form of the composition will vary depending on the subject being treated, the particular mode of administration, and preferably, provided compositions should be formulated so that a dosage of between 0.01 and 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0233] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

[0234] Uses of compounds and pharmaceutically acceptable compositions

[0235] The compounds and compositions described herein are generally useful for inhibiting CXCR4 or mutants thereof.

[0236] The activity of compounds used as inhibitors of CXCR4 or its mutants in the present invention can be determined in vitro, in vivo, or in cell lines. In vitro assays include assays for inhibition of CXCR4 or its mutants. Alternative in vitro assays quantify the ability of inhibitors to bind to CXCR4. Detailed conditions for determining the activity of compounds used as inhibitors of CXCR4 in the present invention are described in the Examples below.

[0237] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of a disease or condition as described herein, or one or more symptoms thereof, or inhibiting its progression. 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 before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other predisposing factors). Treatment may also be continued after symptoms subside, for example, to prevent or delay their recurrence.

[0238] The provided compounds are inhibitors of CXCR4 and are therefore useful in treating one or more conditions associated with CXCR4 activity. Accordingly, in certain embodiments, the present invention provides a method for treating a CXCR4-mediated condition comprising the steps of administering a compound of the present invention or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0239] As used herein, the term "CXCR4-mediated" condition, disease, and / or disorder refers to 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 is known to play a role.

[0240] In some embodiments, the present invention provides a method for treating one or more conditions, diseases, and / or disorders, wherein the conditions, diseases, or disorders include, but are not limited to, cell proliferative conditions.

[0241] Cell proliferative disorders

[0242] The present invention features methods and compositions for diagnosing and prognosing cell proliferative conditions (e.g., cancer) and treating these conditions by targeting CXCR4. Cell proliferative conditions described herein include, for example, cancer, obesity, and proliferation-dependent diseases. These conditions can be diagnosed using methods known in the art.

[0243] cancer

[0244] In one embodiment, cancer includes, but is not limited to, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute granulocytic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid 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, 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 cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0245] In some embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0246] In some embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I-pilocytic astrocytoma, grade II-low-grade astrocytoma, grade III-anaplastic astrocytoma, or grade IV-glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a subependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primitive neuroectodermal (PNET) tumor, or a schwannoma. In some embodiments, the cancer is a type that is more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic nerve glioma, a pineal tumor, a primitive neuroectodermal tumor (PNET), or a rhabdoid tumor. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or a pediatric patient.

[0247] In another embodiment, cancer includes but is not limited to mesothelioma, hepatocellular (liver and bile duct) cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, gastrointestinal cancer (gastric cancer, colorectal cancer and duodenal cancer), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, Adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0248] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, epithelial ovarian cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiocarcinoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid carcinoma; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis type 1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0249] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis type 1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0250] 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 steps of administering a disclosed compound or a pharmaceutically acceptable salt thereof to a patient in need thereof. Solid tumors typically include abnormal tissue masses that typically do not contain cysts or fluid areas. In some embodiments, the cancer is selected from the group consisting of: 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, epithelial ovarian cancer, ovarian cancer, carcinoma or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiocarcinoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid carcinoma; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; malignant peripheral nerve sheath tumor (MPNST) associated with neurofibromatosis type 1; Waldenstrom's macroglobulinemia; or medulloblastoma.

[0251] In some embodiments, the cancer is selected from the group consisting of renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis type 1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0252] In some embodiments, the cancer is selected from the group consisting of hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis type 1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0253] 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 (ovarian cancer or ovarian carcinoma). In some embodiments, the cancer is epithelial ovarian 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 cholangiocarcinoma. In some embodiments, the cancer is synovial sarcoma of soft tissue and bone. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid carcinoma. 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 tumor (MPNST). In some embodiments, the cancer is MPNST associated with neurofibromatosis type 1. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0254] The invention further features methods and compositions for the diagnosis, prognosis, and treatment of virus-associated cancers, including human immunodeficiency virus (HIV)-associated solid tumors, human papillomavirus (HPV)-16-positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type 1 (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 cancer, cervical cancer, vaginal cancer, vulvar cancer, head and neck squamous cell carcinoma, and Merkel cell carcinoma. (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; also see https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886 and https: / / clinicaltrials.gov / ct2 / show / NCT02426892)

[0255] 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 compound, salt, or pharmaceutical composition described herein. In some embodiments, the tumor comprises any cancer described herein. In some embodiments, the tumor comprises a melanoma. In some embodiments, the tumor comprises a breast cancer. In some embodiments, the tumor comprises a lung cancer. In some embodiments, the tumor comprises a small cell lung cancer (SCLC). In some embodiments, the tumor comprises a non-small cell lung cancer (NSCLC).

[0256] In some embodiments, a tumor is treated by preventing further growth of the tumor. In some embodiments, a 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 before treatment. In some embodiments, a tumor is treated by reducing the amount of the patient's tumor by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99% relative to the amount of the tumor before treatment.

[0257] Primary immunodeficiency

[0258] In some embodiments, the present invention provides a method for treating one or more conditions, diseases, and / or disorders, including but not limited to primary immunodeficiency diseases or conditions, comprising administering to a patient in need thereof an effective amount of a disclosed compound. Primary immunodeficiencies treatable by the methods of the invention include warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome; severe congenital neutropenia (SCN), particularly those caused by 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 print); idiopathic CD4+ T lymphocytopenia (ICL); and Wiskott-Aldrich Syndrome.

[0259] According to the method of the present invention, the compounds and compositions can be administered using any amount and any route of administration that is effective in treating or alleviating the severity of cancer, autoimmune disease, primary immunodeficiency, proliferative condition, inflammatory condition, neurodegeneration or neurological condition, schizophrenia, bone-related condition, liver disease or cardiac condition. The exact amount required will vary from subject to subject, according to the type, age and overall condition of the subject; the severity of the disease or condition; the specific agent; its mode of administration, etc. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and dosage uniformity. As used herein, the expression "dosage unit form" refers to a physically discrete dosage unit suitable for the patient to be treated. However, it should be understood that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound being employed; the specific composition being employed; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and rate of excretion of the specific compound being employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound being employed, and similar factors well known in the medical arts. As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0260] The pharmaceutically acceptable compositions of the present invention can be administered orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, as an oral spray or nasal spray, etc. to humans and other animals, depending on the severity of the disease or condition being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally daily, one or more times daily, at a dosage level of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg, of the subject's body weight, to obtain the desired therapeutic effect.

[0261] Liquid dosage forms for oral administration include but are not limited to pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (particularly, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral composition can also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and aromatics.

[0262] Injectable preparations such as sterile injectable aqueous or oily suspensions can be prepared according to known techniques, using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Adoptable acceptable vehicles and solvents include water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injections.

[0263] The injectable formulations can be sterilized, for example, by filtration through a bacteria-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.

[0264] In order to prolong the effect of the compounds of the present invention, it is generally desired to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oily vehicle. Injectable long-acting (depot) forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Long-acting injectable formulations are also prepared by trapping the compound in a liposome or microemulsion compatible with human tissue.

[0265] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0266] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these 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, polyvinyl pyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0267] Solid compositions of similar types can also be used as fillers in soft-filled gelatin capsules and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as other coatings known in the field of enteric coatings and pharmaceutical formulations. The dosage form can optionally contain an emulsifier and can belong to such a composition, which is such that the dosage form only releases one or more active ingredients, or preferably, optionally releases in a delayed manner in a specific part of the intestinal tract. The example of operable embedded composition comprises polymeric substances and wax. Solid compositions of similar types can also be used as fillers in soft-filled gelatin capsules and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycols.

[0268] The active compound can also be in microencapsulated form together with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release-controlled coatings and other coatings well known in the field of pharmaceutical formulations. In these solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. Under normal circumstances, in addition to inert diluents, these dosage forms can also include other substances, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer. The dosage form can optionally contain an emulsifier and can belong to a composition that is such that the dosage form only releases one or more active ingredients, or preferably, optionally releases in a delayed manner in a specific part of the intestinal tract. Examples of usable embedding compositions include polymeric substances and waxes.

[0269] The dosage form for topical or transdermal administration of the compound of the present invention comprises an ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active ingredient is mixed with a pharmaceutically acceptable carrier and any required preservative or buffer solution that may be required under aseptic conditions. Ophthalmic preparations, ear drops and eye drops are also contemplated to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of allowing the compound to be delivered to the body in a controlled manner. These dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. Rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or a gel.

[0270] According to one embodiment, the present invention relates to a method for inhibiting CXCR4 activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0271] According to another embodiment, the present invention relates to a method for inhibiting the activity of CXCR4 or a mutant thereof in a biological sample, comprising the steps of: contacting the biological sample with a compound of the present invention or a composition comprising the compound. In certain embodiments, the present invention relates to a method for irreversibly inhibiting the activity of CXCR4 or a mutant thereof in a biological sample, comprising the steps of: contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0272] As used herein, the term "biological sample" includes but is not limited to: cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0273] Another embodiment of the present invention is directed to a method of inhibiting CXCR4 in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound.

[0274] According to another embodiment, the present invention relates to a method of inhibiting the activity of CXCR4 or a mutant thereof in a patient, comprising the steps of administering to the patient a compound of the present invention or a composition comprising the compound. According to certain embodiments, the present invention relates to a method of irreversibly inhibiting the activity of CXCR4 or a mutant thereof in a patient, comprising the steps of administering to the patient a compound of the present invention or a composition comprising the compound. In other embodiments, the present invention provides a method for treating a condition mediated by CXCR4 or a mutant thereof in a patient in need thereof, comprising the steps of administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof. These conditions are described in detail herein.

[0275] Co-administration of additional therapeutic agents

[0276] Depending on the specific condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0277] In some embodiments, 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 simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of a disclosed compound and one or more additional therapeutic agents acts synergistically.

[0278] 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 RORγt.

[0279] In some embodiments, the method further comprises administering to the 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 the group consisting of a compound disclosed herein or a pharmaceutically acceptable salt thereof, an immunostimulatory therapeutic compound, and an immune checkpoint inhibitor.

[0280] Other checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists being studied in clinical trials include: PF-04518600 / PF-8600 (Pfizer), an agonist anti-OX40 antibody for metastatic renal cancer (NCT03092856) and advanced cancers and tumors (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonist anti-OX40 antibody in a Phase 1 cancer trial (NCT02528357); MEDI0562 (Medimmune / AstraZeneca) The companies are evaluating dapoxetine (AstraZeneca), an agonist anti-OX40 antibody for advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469 (Medical Immunology / AstraZeneca), an agonist anti-OX40 antibody for colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an agonist anti-OX40 antibody for advanced cancers (NCT02737475).

[0281] Other checkpoint inhibitors that can be used in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists being studied in clinical trials include: utomilumab (PF-05082566, Pfizer), which is an agonistic anti-CD137 antibody for diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and tumors (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), which is an agonistic anti-CD137 antibody for melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[0282] Other checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists currently under investigation in clinical trials include: varlilumab (CDX-1127, Celldex Therapeutics), an agonist anti-CD27 antibody, for use in squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma, and glioblastoma (NCT02335918); lymphoma (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0283] Other checkpoint inhibitors that may be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being studied in clinical trials include: TRX518 (Leap Therapeutics), an agonist anti-GITR antibody for malignant melanoma and other solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonist anti-GITR antibody for solid tumors and lymphomas (NCT02740270); INCAGN01876 (Incyte / Agenus), an agonist anti-GITR antibody for advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonist GITR antibody for solid tumors (NCT02132754); and MEDI1873 (Medical Immunology / AstraZeneca), a human IgG1 An agonistic hexameric GITR ligand with an Fc domain for advanced solid tumors (NCT02583165).

[0284] Other checkpoint inhibitors that can be used in the present invention include inducible T cell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists currently under investigation in clinical trials include: MEDI-570 (Medical Immunology), an agonist anti-ICOS antibody for lymphoma (NCT02520791); GSK3359609 (Merck), an agonist anti-ICOS antibody in Phase 1 (NCT02723955); and JTX-2011 (Jounce Therapeutics), an agonist anti-ICOS antibody in Phase 1 (NCT02904226).

[0285] Other checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors currently under investigation in clinical trials include: lirilumab (IPH2102 / BMS-986015, Innate Pharmaceuticals Pharma / Bristol-Myers Squibb), an anti-KIR antibody for leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma), for myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), for lymphoma (NCT02593045).

[0286] Other checkpoint inhibitors that can be used in the present invention include CD47 inhibitors that target the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors currently under investigation in clinical trials include: ALX-148 (Alexo Pharmaceuticals) =Therapeutics), which is an antagonist variant of (SIRPa), binds to CD47 and blocks CD47 / SIRPa-mediated signaling, in Phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), which is a soluble recombinant fusion protein generated by linking the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1, which works by binding to human CD47 and blocking it from transmitting a "don't eat" signal to macrophages, in Phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), which is an anti-CD47 antibody for leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven Pharmaceuticals). Seven, Inc.), for colorectal and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0287] Other checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors being studied in clinical trials include: MEDI9447 (Medical Immunology), which is an anti-CD73 antibody for solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), which is an anti-CD73 antibody for solid tumors (NCT02754141).

[0288] Other checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes protein (STING, also known as transmembrane protein 173 or TMEM173). STING agonists being studied in clinical trials include MK-1454 (Merck), an agonist synthetic cyclic dinucleotide for lymphoma (NCT03010176), and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonist synthetic cyclic dinucleotide in Phase 1 (NCT02675439 and NCT03172936).

[0289] Other checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors being studied in clinical trials include: pexidartinib (PLX3397, Plexxikon), which is a small molecule inhibitor of CSF1R for colorectal cancer, pancreatic cancer, metastatic and advanced cancer (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 (LY30 22855 (Lilly), an anti-CSF-1R antibody being tested in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid carboxamide, Novartis), an orally available CSF1R inhibitor being tested in advanced solid tumors (NCT02829723).

[0290] Other checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors currently being studied in clinical trials include monalizumab (IPH2201, Innate Pharmaceuticals), an anti-NKG2A antibody, for head and neck cancer (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0291] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0292] In another aspect, the present invention provides a method of treating cancer in a patient in need thereof, wherein the method comprises administering to the 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.

[0293] In some embodiments, the IDO inhibitor is selected from epacadostat, indoximod, capmanitib, GDC-0919, PF-06840003, BMS:F001287, Phy906 / KD108, or an enzyme that degrades kynurenine.

[0294] In some embodiments, the PARP inhibitor is selected from olaparib, rucaparib, or niraparib.

[0295] In some embodiments, the HDAC inhibitor is selected from vorinostat, romidepsin, panobinostat, belinostat, entinostat, or chidamide.

[0296] In some embodiments, the CDK 4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, or trilaciclib.

[0297] In some embodiments, the method further comprises administering a third therapeutic agent to the patient, such as an immune checkpoint inhibitor. In some embodiments, the method comprises administering to a patient in need three therapeutic agents selected from the following: 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.

[0298] Another immunostimulatory therapeutic that can 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 leukemia (NCT02689453). Another immunostimulatory therapeutic that can 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), which is a fusion complex consisting of a synthetic form of endogenous IL-15 complexed to a soluble IL-15 binding protein IL-15 receptor α chain (IL15:sIL-15RA), which has been tested in a Phase 1 clinical trial 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 a number of oncology indications, for example as a therapy for lymphoma (NM-IL-12, Neumedicines, Inc.) (NCT02544724 and NCT02542124).

[0299] In some embodiments, the PI3K inhibitor is selected from idelalisib, alpelisib, taselisib, pictilisib, copanlisib, duvelisib, PQR309, or TGR1202.

[0300] In another aspect, the present invention provides a method of treating cancer in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents selected from platinum-based therapeutics, taxanes, nucleoside inhibitors, or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

[0301] In some embodiments, the platinum-based therapeutic is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, or satraplatin.

[0302] In some embodiments, the taxane is selected from paclitaxel, docetaxel, nab-paclitaxel, cabazitaxel, SID530.

[0303] In some embodiments, the therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or would otherwise interfere with the replication of rapidly proliferating cells is selected from trabectedin, dichloromethane, vincristine, temozolomide, cytarabine, lomustine, azacitidine, homoharringtonine, asparaginase Erwinia chrysanthemi, eribulin mesylate, capacetrine, betamustine, ixabepilone, nelarabine, clorafabine, trifluridine, or tipiracil.

[0304] In some embodiments, the method further comprises administering to the patient a third therapeutic agent, such as an immune checkpoint inhibitor. In some embodiments, the method comprises administering to a patient in need thereof three therapeutic agents selected from the compounds disclosed herein or pharmaceutically acceptable salts 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 otherwise inhibits rapidly proliferating cells; and a third therapeutic agent selected from an immune checkpoint inhibitor.

[0305] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0306] In some embodiments, any of the above methods further comprises the steps of obtaining a biological sample from the patient and measuring the amount of a disease-associated biomarker.

[0307] In some embodiments, the biological sample is a blood sample.

[0308] In some embodiments, the disease-associated biomarker is selected from circulating CD8+ T cells or the ratio of CD8+ T cells to Treg cells.

[0309] In one aspect, the present invention provides a method for treating advanced cancer, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a single agent (monotherapy) or in combination with a chemotherapeutic agent, a targeted therapeutic agent 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, thereby hindering the tumor's ability to suppress the host's anti-tumor immune response.

[0310] In some embodiments, the additional therapeutic agent is a kinase inhibitor or a VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors that can be used in the present invention include: bevacizumab ( Genentech / Roche), which is an anti-VEGF monoclonal antibody; ramucirumab ( Eli Lilly), which is an anti-VEGFR-2 antibody, and ziv-aflibercept, also known as aflibercept (VEGF Trap) ( Regeneron / Sanofi); VEGFR inhibitors, such as regorafenib ( Bayer); vandetanib ( AstraZeneca); axitinib ( Pfizer); and lenvatinib ( Eisai); Raf inhibitors, such as sorafenib ( Bayer AG and Onyx); dabrafenib ( Novartis); and vemurafenib ( Genentech / Roche); MEK inhibitors, such as cobimetanib ( Exelexis / Genentech / Roche); trametinib ( Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib ( Novartis); nilotinib ( Novartis); dasatinib ( Bristol-Myers Squibb); bosutinib ( Pfizer); and ponatinib ( Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib ( AstraZeneca); erlotinib ( Genentech / Roche / Astellas); Lapatinib ( Novartis); afatinib ( Boehringer Ingelheim); osimertinib (targets activated EGFR, AstraZeneca); and brigatinib ( Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozantinib ( Ixelex); and multikinase inhibitors, such as sunitinib ( Pfizer); pazopanib ( Novartis); ALK inhibitors, such as crizotinib ( Pfizer); ceritinib ( Novartis); and alectinib ( Genentech / Roche); Bruton tyrosine kinase inhibitors, such as ibrutinib ( Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin ( Novartis).

[0311] 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 ( IY5511, Il-Yang Pharmaceuticals (South Korea); ruxolitinib ( Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Ixelex, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0312] In some embodiments, the additional therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis, and glucose uptake. Approved mTOR inhibitors that can be used in the present invention include: everolimus ( Novartis); temsirolimus ( Pfizer); and sirolimus ( Pfizer).

[0313] In some embodiments, the additional therapeutic agent is a poly ADP ribose polymerase (PARP) inhibitor. Approved PARP inhibitors that can be used in the present invention include: olaparib ( AstraZeneca); rucaparib ( Clovis tumors); and niraparib ( Other PARP inhibitors that can be used in the present invention include: talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0314] In some embodiments, the additional therapeutic agent is a phosphatidylinositol 3-kinase (PI3K) inhibitor. Approved PI3K inhibitors that can be used in the present invention include: idelalisib ( Other investigational PI3K inhibitors that may be used in the present invention include: apellisib (BYL719, Novartis); taselisib (GDC-0032, Genentech / Roche); pikrisib (GDC-0941, Genentech / Roche); kupanisib (BAY806946, Bayer); davilisib (formerly known as IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly known as RP5230, TG Therapeutics).

[0315] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors that can be used in the present invention include: bortezomib ( Takeda); carfilzomib( Amgen); and ixazomib ( Takeda).

[0316] In some embodiments, the additional therapeutic agent is a histone deacetylase (HDAC) inhibitor. Approved HDAC inhibitors that can be used in the present invention include: vorinostat ( Merck); romidepsin ( Celgene); panobinostat ( Novartis); and belinostat ( Spectrum Pharmaceuticals). Other HDAC inhibitors under investigation that may be used in the present invention include: entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide ( HBI-8000, Chipscreen Biosciences, China).

[0317] In some embodiments, the additional therapeutic agent is a CDK inhibitor, such as a CDK 4 / 6 inhibitor. Approved CDK 4 / 6 inhibitors that can be used in the present invention include: Palbociclib ( Pfizer); and Ribociclib ( Novartis). Other investigational CDK 4 / 6 inhibitors that may be used in the present invention include: bomazenil (Ly2835219, Eli Lilly); and birocinid (G1T28, G1 Therapeutics).

[0318] In some embodiments, the additional therapeutic agent is an indoleamine (2,3)-dioxygenase (IDO) inhibitor. Other IDO inhibitors under investigation that can be used in the present invention include: icandrostat (INCB024360, Incyte); dosimod (NLG-8189, NewLink Genetics Corporation); capacitinib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); and enzymes that break down kynurenine (kinases, Kyn Therapeutics).

[0319] 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 that can be used in the present invention include olaratumab ( Eli Lilly). Approved EGFR antagonists that can be used in the present invention include: cetuximab ( Eli Lilly); necitumumab ( Eli Lilly), panitumumab ( Amgen); and osimertinib (targeting activated EGFR, AstraZeneca).

[0320] In some embodiments, the additional therapeutic agent is an aromatase inhibitor. Approved aromatase inhibitors that can be used in the present invention include: exemestane ( Pfizer); anastazole ( AstraZeneca) and letrozole ( Novartis).

[0321] In some embodiments, the additional therapeutic agent is a hedgehog pathway antagonist. Approved hedgehog pathway inhibitors that can be used in the present invention include sonidegib ( Sun Pharmaceuticals); and vismodegib ( Genentech), both used to treat basal cell carcinoma.

[0322] In some embodiments, the additional therapeutic agent is a folate inhibitor. Approved folate inhibitors that can be used in the present invention include pemetrexed ( Eli Lilly).

[0323] In some embodiments, the additional therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. Investigational CCR4 inhibitors that may be used in the present invention include mogamulizumab ( Kyowa Hakko Kirin (Kyowa Hakko Kirin, Japan).

[0324] In some embodiments, the additional therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. Investigational IDH inhibitors that can be used in the present invention include: AG120 (Celestium; NCT02677922); AG221 (Celestium, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0325] In some embodiments, the additional therapeutic agent is an arginase inhibitor. Investigational arginase inhibitors that can be used in the present invention include: AEB1102 (PEGylated recombinant arginase, Aeglea Biotherapeutics), which is in Phase 1 clinical trial studies for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0326] In some embodiments, the additional therapeutic agent is a glutaminase inhibitor. Investigational glutaminase inhibitors that may be used in the present invention include CB-839 (Caritella Biosciences).

[0327] In some embodiments, the additional therapeutic agent is an antibody that binds to a tumor antigen, i.e., a protein expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include: rituximab ( Genentech / Biogen Idec); ofatumumab (anti-CD20, GlaxoSmithKline); obinutuzumab (anti-CD20, Genentech); ibritumomab (anti-CD20 and yttrium-90, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Janssen Biotech); dinutuximab (anti-glycolipid GD2, United Therapeutics); trastuzumab (anti-HER2, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Genentech); and pertuzumab (anti-HER2, Genentech); and brentuximab vedotin (anti-CD30 drug conjugate, Seattle Genetics).

[0328] In some embodiments, the additional therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors that can be used in the present invention include: irinotecan ( Merrimack Pharmaceuticals); topotecan ( GlaxoSmithKline). Topoisomerase inhibitors under investigation that may be used in the present invention include pixantrone ( CTI Biopharma.

[0329] In some embodiments, the additional therapeutic agent is a nucleoside inhibitor or other therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells. Such nucleoside inhibitors or other therapeutic agents include: trabectedin (a guanylating agent, Janssen Oncology); dichloromethyldiethylamine (alkylating agent, Actelion Pharmaceuticals); vincristine ( Eli Lilly; Teva Pharmaceuticals; Talon Therapeutics); temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazene-1-yl)-imidazole-4-carboxamide (MTIC), Merck); cytarabine injection (cytarabine, an antimetabolite cytidine analog, Pfizer); lomustine (alkylating agent, Bristol-Myers Squibb; NextSource Biotechnology); azacitidine (a pyrimidine nucleoside analog of cytosine, Neogene); Homoharringtonine (Cephalotaxine alkaloid) (protein synthesis inhibitor, Teva Pharmaceuticals); asparaginase from Erwinia chrysanthemi (an enzyme used to deplete asparagine, Lundbeck; EUSA Pharma); Eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic agent, Eisai); Cabazitaxel (microtubule inhibitor, tubulin-based antimitotic agent, Sanofi-Aventis); Capecitabine (thymidylate synthase inhibitor, Genentech); bendamustine (a bifunctional dichloromethyldiethylamine derivative believed to form interstrand DNA crosslinks, Cephalon / Teva); Ixabepilone (a semisynthetic analog of epothilone B, a microtubule inhibitor, and a tubulin-based antimitotic agent, Bristol-Myers Squibb); Nelarabine (a prodrug of a deoxyguanosine analog, a nucleoside metabolic inhibitor, Novartis); Clofarabine (a prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Sanofi-Aventis); and trifluridine and dipivefrin (thymidine nucleoside analogs and thymidine phosphorylase inhibitors, Taiho Oncology).

[0330] In some embodiments, the additional therapeutic agent is a platinum-based therapeutic agent, also known as platins. Platinums cause cross-linking of DNA, which inhibits DNA repair and / or DNA synthesis, primarily in rapidly reproducing cells, such as cancer cells. Approved platinum-based therapeutic agents that can be used in the present invention include: cisplatin ( Bristol-Myers Squibb); Carboplatin ( Bristol-Myers Squibb; and Teva; Pfizer); oxaliplatin ( Sanofi-Aventis); and nedaplatin ( Other platinum-based therapeutics that have undergone clinical trials and may be used in the present invention include: picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[0331] In some embodiments, the additional therapeutic agent is a taxane compound that causes the disruption of microtubules necessary for cell division. Approved taxane compounds that can be used in the present invention include: Paclitaxel ( Bristol-Myers Squibb), docetaxel ( Sanofi-Aventis; Sun Pharmaceuticals), albumin-bound paclitaxel (albumin-bound Abraxis / Celgene), and cabazitaxel ( Sanofi-Aventis.) Other taxane compounds that have undergone clinical trials and can be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008).

[0332] In some embodiments, the additional therapeutic agent is an inhibitor of an anti-apoptotic protein, such as BCL-2. Approved anti-apoptotic agents that can be used in the present invention include: venetoclax ( AbbVie / Genentech); and blinatumomab ( Other therapeutic agents targeting apoptotic proteins that have undergone clinical trials and can be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0333] In some embodiments, the present invention provides a method for 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 a pharmaceutical composition thereof, in combination with an additional therapeutic agent that interferes with androgen synthesis or activity. Approved androgen receptor inhibitors that can be used in the present invention include: enzalutamide ( Astellas / Medvesun Medical); approved androgen synthesis inhibitors include abiraterone ( Centocor / Ortho); approved gonadotropin-releasing hormone (GnRH) receptor antagonists (degaralix, Ferring Pharmaceuticals).

[0334] In some embodiments, the additional therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogen. Approved SERMs that can be used in the present invention include raloxifene ( Eli Lilly).

[0335] In some embodiments, the additional therapeutic agent is a bone resorption inhibitor. An approved therapeutic agent that inhibits bone resorption is Denosumab ( Amgen), an antibody that binds to RANKL and blocks its binding to its receptor RANK, which is found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells and mediates bone pathology in solid tumors with bone metastasis. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid ( Novartis).

[0336] In some embodiments, the additional therapeutic agent is an inhibitor of the interaction between two primary p53 inhibitory proteins: MDMX and MDM2. The inhibitors of the p53 inhibitory proteins under investigation that can be used in the present invention include ALRN-6924 (Aileron), which is a stapled peptide that 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).

[0337] In some embodiments, the additional therapeutic agent is an inhibitor of transforming growth factor beta (TGF-β or TGFβ). Investigational TGFβ protein inhibitors that can be used in the present invention include NIS793 (Novartis), an anti-TGFβ antibody that is undergoing clinical testing for the treatment of cancers including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and kidney cancer (NCT 02947165). In some embodiments, the inhibitor of TGFβ protein is fresolimumab (GC1008, Sanofi-Genzyme), which is undergoing research for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). In addition, in some embodiments, the additional therapeutic agent is a TGFβ trap, as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for the treatment of solid tumors is M7824 (Merck—formerly known as MSB0011459X), a bispecific anti-PD-L1 / TGFβ trap compound (NCT02699515); and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGFβ receptor II, acting as a TGFβ "trap."

[0338] Additional co-administered therapeutic agents—targeted therapeutics and immunomodulatory drugs

[0339] In some embodiments, the additional therapeutic agent is selected from a targeted therapeutic or an immunomodulatory drug. Adjuvant therapy with targeted therapeutics or immunomodulatory drugs has shown promising efficacy when administered alone, but is limited by the development of tumor immunity or evasion of the immune response over time.

[0340] In some embodiments, the present invention provides a method for treating cancer, such as the 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 a pharmaceutical composition thereof in combination with an additional therapeutic agent, such as a targeted therapeutic agent or an immunomodulatory drug. In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis in tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include: pomalidomide ( Celgene); Lenalidomide ( Ingenol methyl butyl ester ( LEO Pharmaceuticals (LEOPharma).

[0341] In other embodiments, the immunomodulatory therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T ( Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec ( BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable skin, subcutaneous, and lymph node lesions in melanoma. In some embodiments, the additional therapeutic agent is selected from an oncolytic virus therapy such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly known as Jennerex Biotherapeutics), a thymidine kinase-(TK-) deficient vaccinia virus engineered to express GM-CSF for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep ( Oncolytics Biotech, a variant of respiratory enteric orphan virus (reovirus) that does not replicate in non-RAS-activated cells, is being investigated for a number of cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic cancer (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly ColoAd1), an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, for ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (N CT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF, for melanoma (NCT03003676); and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux Pharmaceuticals, Inc. GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium iodide symporter (hNIS), respectively, which are being studied in peritoneal carcinoma (NCT01443260); fallopian tube cancer, ovarian cancer (NCT02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, for bladder cancer (NCT02365818).

[0342] In some embodiments, the additional therapeutic agent is selected from JX-929 (Sirajan / formerly known as Janelux Biopharmaceuticals), which is a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Talworks / formerly known as Onx), which are peptide immunotherapeutics targeting refractory RAS mutations; and TILT-123 (TILT Biotherapeutics), which is an engineered adenovirus designated: Ad5 / 3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (Vira Therapeutics), which is a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express a protein designed to increase antigen-specific CD8 + Antigens to which T cells respond.

[0343] In some embodiments, the present invention comprises administering to the 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. T cells engineered to express this chimeric antigen receptor are called CAR-T cells.

[0344] A CAR consisting of a binding domain has been constructed that can be derived from a natural ligand, a single-chain variable fragment (scFv) of a monoclonal antibody specific for a cell surface antigen, fused to an internal domain as the functional end of a T cell receptor (TCR), such as the CD3-ζ signaling domain from TCR, which is capable of generating activation signals in T lymphocytes. After antigen binding, these CARs connect to the endogenous signaling pathway in effector cells and generate activation signals similar to those initiated by the TCR complex.

[0345] For example, in some embodiments, the CAR-T cell is one of the cells described in U.S. Patent 8,906,682 (June; the entire contents of which are incorporated herein by reference), which discloses CAR-T cells that are engineered to include an extracellular domain having an antigen-binding domain (such as a domain that binds to CD19) fused to an intracellular signaling domain that complexes with the ζ chain of the T-cell antigen receptor (such as CD3ζ). When expressed in T cells, the CAR is able to redirect antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. More than 200 clinical trials are currently underway using CAR-T for various indications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0346] Additional co-administered therapeutic agents—immunostimulatory drugs

[0347] In some embodiments, the additional therapeutic agent is an immunostimulatory drug. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in a growing number of tumor histologies, including some tumor types that have not traditionally been considered sensitive to immunotherapy. See Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab ( Bristol-Myers Squibb's (also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in patients with RCC who have experienced disease progression during or after prior anti-angiogenic therapy.

[0348] In some embodiments, the present invention provides a method for treating cancer, such as a method for treating cancer as described herein, comprising administering an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in combination with an additional therapeutic agent such as an immunostimulatory drug (such as an immune checkpoint inhibitor) to a patient in need. In some embodiments, the compound and the checkpoint inhibitor are administered simultaneously or sequentially. In some embodiments, the compound disclosed herein is administered together with the immune checkpoint inhibitor prior to initial administration. In certain embodiments, the immune checkpoint inhibitor is administered together with the compound disclosed herein prior to initial administration.

[0349] 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 with nivolumab (an anti-PD-1 antibody, Bristol-Myers Squibb); Pembrolizumab (anti-PD-1 antibody, Merck); Ipilimumab (anti-CTLA-4 antibody, Bristol-Myers Squibb); Durvalumab (anti-PD-L1 antibody, AstraZeneca); or atezolizumab (anti-PD-L1 antibody, Genentech).

[0350] Other immune checkpoint inhibitors suitable for use with the present invention include: REGN2810 (Regeneron), an anti-PD-1 antibody being tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1 and is in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab ( Pfizer / Merck), 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 studied in clinical trials for multiple indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung cancer, non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, liver metastases, hepatocellular carcinoma, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Antijunx) is an anti-CTLA4 antibody that is being studied in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0351] Another example of immunostimulation 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 a pharmaceutical composition thereof, in combination with an immunostimulatory therapy, such as an oncolytic virus. Approved immunostimulatory oncolytic viruses that can be used in the present invention include telimozillahepatovirus (active attenuated herpes simplex virus, Amgen).

[0352] In some embodiments, the additional therapeutic agent is an activator of the retinoic acid receptor-related orphan receptor γt (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells and the differentiation of IL-17 expressing innate immune cell subsets such as NK cells. The RORγt activator under investigation that can be used in the present invention is LYC-55716 (Lycera), which is currently being evaluated in a clinical trial for the treatment of solid tumors (NCT02929862).

[0353] In some embodiments, the additional therapeutic agent is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is being studied for B cells, follicular and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being studied for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0354] Other checkpoint inhibitors that can be used in the present invention include inhibitors of T cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tessarro) is an anti-TIM-3 antibody that is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody that is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody that is being studied in advanced malignancies (NCT02608268).

[0355] Other checkpoint inhibitors that can be used in the present invention include inhibitors of T cell immunoreceptors or TIGIT, an immunoreceptor on certain T cells and NK cells, with Ig and ITIM domains. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0356] Checkpoint inhibitors that can be used in the present invention also include inhibitors of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), which is an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), which is also an anti-LAG-3 antibody, is being studied in malignancies (NCT03005782). IMP321 (Immutep SA), which is a LAG-3-Ig fusion protein, is being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0357] Other immuno-oncology agents that can be used in combination with CXCR4 inhibitors such as the compounds disclosed herein include: Urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; Vanlilumab (CDX-1127, Ceders Pharmaceuticals), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; Rilumab (IPH2102 / BMS-98601 5, Innate Pharmaceuticals, Bristol-Myers Squibb), which is an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharmaceuticals, AstraZeneca), which is an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), which is an anti-MMP9 antibody; MK-4166 (Merck & Co.), which is an anti-GITR monoclonal antibody.

[0358] Other additional therapeutic agents that can be used in the present invention include glembatumumab vedotin-monomethyl auristatin E (MMAE) (Cedex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE. gpNMB is a protein overexpressed by various tumor types that is associated with the metastatic ability of cancer cells.

[0359] The compounds of the present invention may also be used in combination with other antiproliferative compounds to produce advantages. 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 that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and additional antiangiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatase activity; gonadotropin-releasing hormone agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target, reduce or inhibit Flt-3 activity; Hsp90 inhibitors, such as those from Conforma Pharmaceuticals. 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 of the Therapeutics; temozolomide 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.

[0360] As used herein, the term "checkpoint inhibitor" refers to agents that can be used to prevent cancer cells from evading the patient's immune system. One of the main mechanisms of anti-tumor immune subversion is called "T cell exhaustion", which is caused by persistent antigen exposure that has led to the upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

[0361] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuator (BTLA; CD272), T-cell immunoglobulin and mucin domain-3 (Tim-3), and lymphocyte activation gene-3 (Lag-3; CD223) are commonly referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0362] In one aspect, the checkpoint inhibitor is a biotherapeutic agent 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 another aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In additional aspects, check point inhibitors inhibit the check point proteins selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG-3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or a combination thereof. On the one hand, check point inhibitors are immunostimulants, T cell growth factors, interleukins, antibodies, vaccines, or a combination thereof. In other aspects, interleukins are IL-7 or IL-15. In specific aspects, interleukins are glycosylated IL-7. In additional aspects, vaccines are dendritic cell (DC) vaccines.

[0363] Checkpoint inhibitors include any agent that blocks or inhibits the inhibitory pathway of the immune system in a statistically significant manner. These inhibitors may include small molecule inhibitors or may include antibodies that bind to and block or inhibit immune checkpoint receptors or their antigen binding fragments 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 (belonging to the CD2 family of molecules and in all NK, γδ and memory CD8 + (αβ) T cells), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies, antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of the following: CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Illustrative immune checkpoint inhibitors include tesilimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0364] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of: nivolumab ( ), Ipilimumab ( ) and pembrolizumab ( ).

[0365] 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 ( ) and tesililimumab.

[0366] As used herein, the term "aromatase inhibitor" relates to compounds that inhibit estrogen production, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, in particular atamestane, exemestane and formestane, and in particular non-steroidal, in particular aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is sold under the trade name Aromasin. TM (Aromasin TM Formestane is sold under the brand name Lantalong. TM (Lentaron TM ) is sold under the trade name Aferma TM (Afema TM ). Anastrozole is sold under the brand name Arimidex TM (Arimidex TM ). Letrozole is sold under the brand name Fulon TM (Femara TM ) or Fermat TM (Femar TM ). Aminoglutethimide is sold under the trade name Orimi TM (Orimeten TM The combination of the invention comprising a chemotherapeutic agent that is an aromatase inhibitor is particularly useful in the treatment of hormone receptor positive tumors, such as breast tumors.

[0367] As used herein, the term "antiestrogen" refers to compounds that antagonize the effects of estrogens at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is available under the trade name Nolvadex. TM (Nolvadex TM ) is sold under the trade name Evita. TM (Evista TM Fulvestrant is sold under the trade name Fulvestrant. TM (Faslodex TM The combination of the invention comprising a chemotherapeutic agent that is an antiestrogen is particularly useful in the treatment of estrogen receptor positive tumors, such as breast tumors.

[0368] As used herein, the term "antiandrogen" refers to any substance that is capable of inhibiting the biological effects of androgens and includes, but is not limited to, bicalutamide (Casodex). TM (Casodex TM )). As used herein, the term "gonadotropin-releasing hormone agonist" includes but is not limited to abarelix, goserelin and goserelin acetate. Goserelin is marketed under the trade name Zoladex. TM (Zoladex TM )Sale.

[0369] As used herein, the term "topoisomerase I inhibitors" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be marketed, for example, under the trademark irinotecan. TM (Camptosar TM Topotecan is marketed under the trade name Topotecan TM (Hycamptin TM )Sale.

[0370] As used herein, the term "topoisomerase II inhibitors" include but are not limited to anthracyclines such as doxorubicin (including liposomal formulations such as cyclin A and cyclin B). TM (Caelyx TM)), daunomycin, epirubicin, idarubicin and nemorubicin, anthraquinones - mitoxantrone and losoxantrone, and podophillotoxine - etoposide and teniposide. Etoposide is sold under the brand name etoposide TM (Etopophos TM Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name Adriamycin. TM (Acriblastin TM ) or adriamycin TM (Adriamycin TM ). Epirubicin is sold under the trade name Epirubicin TM (Farmorubicin TM ) is sold under the trade name Idarubicin. TM (Zavedos TM Mitoxantrone is sold under the trade name Novantron.

[0371] The term "microtubule active agent" refers to microtubule stabilizing compounds, microtubule destabilizing compounds and microtubule polymerization inhibitors, including but not limited to: taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; dermatolide; colchicine and epothilones and their derivatives. Paclitaxel is sold under the trade name Taxol TM (Taxol TM ) is sold under the trade name Taxotere. T M(Taxotere T Vinblastine sulfate is sold under the trade name Vinblastine RP TM (Vinblastin RP TM ) is sold under the trade name famustine. TM (Farmistin TM )Sale.

[0372] As used herein, the term "alkylating agent" includes but is not limited to cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name cyclophosphamide. TM (Cyclostin TM Ifosfamide is sold under the trade name and Lexan. TM (Holoxan TM )Sale.

[0373] The term "histone deacetylase inhibitor" or "HDAC inhibitor" relates to compounds that inhibit histone deacetylase and have antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0374] The term "antineoplastic antimetabolites" 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 sold under the brand name Xeloda. TM (Xeloda TM Gemcitabine is sold under the brand name Gemcitabine TM (Gemzar TM )Sale.

[0375] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cis-platin, cisplatinum, and oxaliplatin. Carboplatin can be obtained, for example, under the trademark Carboplatin. TM (Carboplat TM ). Oxaliplatin can be administered in the form marketed, for example, under the trademark Eleplatin. TM (Eloxatin TM ) is applied in the form of sales.

[0376] As used herein, the term "compounds that target / decrease the activity of a protein or lipid kinase; or a protein or lipid phosphatase; or another anti-angiogenic compound" includes but is not limited to: protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, decrease or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as compounds that target, decrease or inhibit the activity of PDGFR, in particular compounds that inhibit PDGF receptor, such as N-phenyl-2-pyrimidinyl-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, decrease or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, decrease or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, decrease or inhibit the activity of IGF-IR, in particular compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds that target, decrease or inhibit the activity of compounds that target, decrease or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds that target, decrease or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, decrease or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, decrease or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, decrease or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, decrease or inhibit the activity of the c-kit receptor tyrosine kinase. -Kit receptor tyrosine kinase family activity, in particular compounds that inhibit c-Kit receptor, such as imatinib; i) compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidinyl-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from Parke Davis; or dasatinib (BMS-354825); j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases; members of the MEK, SRC, JAK / pan-JAK (pan-JAK), FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC families; and / or members of the cyclin-dependent kinase family (CDK) comprising staurosporine derivatives, such as midostaurin;Examples of additional compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Imofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; Isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (Gleevec; TM ) or tyrosine phosphorylation inhibitors, such as tyrosine phosphorylation inhibitor A23 / RG-50810; AG 99; tyrosine phosphorylation inhibitor AG 213; tyrosine phosphorylation inhibitor AG 1748; tyrosine phosphorylation inhibitor AG 490; tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44 (+) enantiomer; tyrosine phosphorylation inhibitor AG 555; AG 494; tyrosine phosphorylation inhibitor AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adalfustine); l) compounds that target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, especially compounds, proteins or antibodies that inhibit EGF receptor tyrosine kinase family members, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin TM (Herceptin TM )), Cetuximab (Erbitux TM (Erbitux TM)), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, decrease or inhibit the activity of c-Met receptors, such as compounds that target, decrease or inhibit the activity of c-Met, especially compounds that inhibit c-M compounds that target, decrease or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, and tyrosine kinase. ), VX-509, AZD-1480, TG-101348, tofacitinib and ruxolitinib; o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib ), PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelanisib; and p) compounds that target, decrease or inhibit signaling of the hedgehog (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0377] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to, 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 that can be used in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupanib, picotensib, PF-4691502, BYL-719, daltonisib, XL-147, XL-765, and idelanisib.

[0378] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds that have inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitor, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitors (Infinite Pharmaceuticals / Novartis), Genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenyang Pharmaceutical University), obatoclax (and its analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (University of Michigan), 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.

[0379] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0380] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0381] Further examples of BTK inhibiting compounds and conditions that can be treated by such compounds in combination with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0382] Further examples of SYK inhibiting compounds and conditions that can be treated by such compounds in combination with the compounds of the present invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entire contents of which are incorporated herein by reference.

[0383] Additional examples of PI3K inhibitory compounds and conditions that can be treated by these compounds in combination with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, the entire contents of which are incorporated herein by reference.

[0384] Additional examples of JAK inhibitory compounds and conditions that can be treated by such compounds in combination with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entire contents of which are incorporated herein by reference.

[0385] Additional anti-angiogenic compounds include compounds with another mechanism for their activity, for example, unrelated to protein or lipid kinase inhibition, such as thalidomide (thalidomide TM (Thalomid TM )) and TNP-470.

[0386] Examples of proteasome inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0387] Compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[0388] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0389] As used herein, the term cyclooxygenase inhibitors includes but is not limited to Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives such as celecoxib (Celebrex TM (Celebrex TM )), rofecoxib (Violux TM (Vioxx TM )), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluorophenylamino)phenylacetic acid, lumiracoxib.

[0390] As used herein, the term "bisphosphonates" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. TM (Didronel TM Clodronic acid is sold under the trade name Gufushu TM (Bonefos TM ). Tiludronic acid is sold under the trade name Skelly TM (Skelid TM ). Pamidronate is sold under the trade name Acorda TM (Aredia TM ). Alendronate is sold under the trade name Fosamax TM(Fosamax TM ). Ibandronic acid is sold under the trade name Bondronate TM (Bondranat TM ) is sold under the trade name Antolan. TM (Actonel TM ). Zoledronic acid is sold under the brand name Zeta TM (Zometa TM The term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus ( ), Everolimus (Zhuodingkang TM (Certican TM )), CCI-779 and ABT578.

[0391] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparan sulfate. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or interferon.

[0392] As used herein, the term "inhibitor of an oncogenic isoform of Ras," such as H-Ras, K-Ras, or N-Ras, refers to a compound that targets, decreases, or inhibits the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor," such as L-744832, DK8G557, or R115777 (Zanestrazol). TM (Zarnestra TM As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of telomerase. Compounds that target, reduce, or inhibit telomerase activity are particularly compounds that inhibit the telomerase receptor, such as telomerase inhibitors.

[0393] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce or inhibit the activity of methionine aminopeptidase include but are not limited to bengamide or its derivatives.

[0394] As used herein, the term "proteasome inhibitor" refers to a compound that targets, reduces or inhibits the activity of the proteasome. Compounds that target, reduce or inhibit the activity of the proteasome include but are not limited to bortezomib (Velcade TM (Velcade TM )) and MLN 341.

[0395] As used herein, the term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamic acid peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0396] As used herein, the term "compounds for treating hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds that target, reduce or inhibit anaplastic lymphoma kinase.

[0397] Compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0398] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 client proteins through the ubiquitin proteasome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are particularly compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0399] As used herein, the term "anti-proliferative antibodies" includes but is not limited to: trastuzumab (Herceptin TM ), trastuzumab DM1, erbitux, bevacizumab (Avastin TM ), rituximab PRO64553 (anti-CD40) and 2C4 antibodies. Antibodies refer to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity.

[0400] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly in combination with the therapy for the treatment of AML. In particular, the compounds of the present invention can be used in combination with, for example, farnesyl transferase inhibitors and / or other drugs that can be used to treat AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC412.

[0401] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analog that is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogs of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes called histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly known as FR901228), trichostatin A, and compounds disclosed in US Pat. No. 6,552,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, especially lactate. As used herein, somatostatin receptor antagonists refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell damage methods refer to methods such as ionizing radiation. As used herein and hereinbelow, the term "ionizing radiation" refers to ionizing radiation produced as 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, in Cancer, in Principles and Practice of Oncology, Devita et al., eds., 4th ed., Vol. 1, pp. 248-275 (1993).

[0402] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including but not limited to: fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially for ALL in combination with ara-C) and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0403] Also specifically encompassed are those compounds, proteins or monoclonal antibodies to 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 TM (Angiostatin TM ); endostatin TM (Endostatin TM ); anthranilamide; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibodies, angiozyme (Angiozyme) (RPI 4610) and bevacizumab (Avastin TM ).

[0404] As used herein, photodynamic therapy refers to a therapy that uses certain chemicals called photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include the use of drugs such as Visudyne TM (Visudyne TM ) and porfimer sodium.

[0405] As used herein, angiogenesis-inhibiting steroids refers to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[0406] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0407] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or other compounds or compounds with other or unknown mechanisms of action.

[0408] The structures of active compounds identified by code names, generic names or trade names can be taken from actual editions of the standard compendium "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0409] The compounds of the present invention may also be used in combination with known treatments, such as administration of hormones or radiation. In certain embodiments, provided compounds are useful as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

[0410] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of fixed combinations or staggered administration of the compounds of the present invention with one or more other therapeutic compounds or administered independently of one another or in combination with one or more other therapeutic compounds. In addition or in addition, the compounds of the present invention may be administered in conjunction with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these for particular use in tumor treatment. Long-term therapy is also possible, as is adjuvant therapy in the context of other treatment strategies as described above. Other possible treatments are therapies that maintain the patient's status after tumor regression, or even chemopreventive therapy, for example, in patients at risk.

[0411] These additional agents can be administered separately from the composition containing the compounds of the invention as part of a multiple-dose regimen. Alternatively, those agents can be part of a single dosage form mixed with the compounds of the invention in a single composition. If administered as part of a multiple-dose regimen, the two active agents can be delivered simultaneously, sequentially, or within a period of time, typically within five hours of each other.

[0412] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered with another therapeutic agent simultaneously, sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0413] The amount of the compound of the invention and the additional therapeutic agent (in those compositions including additional therapeutic agents as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dose of 0.01 to 100 mg / kg body weight / day of the compound of the invention can be administered.

[0414] In those compositions that include an additional therapeutic agent, the additional therapeutic agent and the compounds of the invention may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dose of 0.01 to 1,000 μg / kg body weight / day.

[0415] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount normally administered in a composition comprising the therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein ranges from about 50% to 100% of the amount normally present in a composition comprising the agent as the only therapeutically active agent.

[0416] The compound of the present invention or its pharmaceutical composition can also be incorporated into the composition for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. For example, vascular stents have been used to overcome restenosis (restenosis of the vascular wall after injury). However, patients using stents or other implantable devices may have the risk of forming clots or platelet activation. These undesirable clots can be prevented or alleviated by pre-coating devices with pharmaceutically acceptable compositions comprising kinase inhibitors. An implantable device coated with the compounds of this invention is another embodiment of the present invention.

[0417] Example

[0418] General synthetic method

[0419] The following examples are intended to illustrate the present invention and should not be construed as limiting it. Unless otherwise stated, one or more tautomeric forms of the compounds of the examples described hereafter can be prepared in situ and / or in isolation. All tautomeric forms of the compounds of the examples described hereafter should be considered to have been disclosed. Temperature is given in degrees Celsius. If not otherwise mentioned, all evaporations are performed under reduced pressure, preferably between 15mm Hg and 100mm Hg (=20 to 133mbar). The structures of the final products, intermediates and starting materials are confirmed by standard analytical methods, such as microanalysis and spectroscopy characteristics such as MS, IR, NMR. The abbreviations used are conventional abbreviations in this area.

[0420] All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents and catalysts for synthesizing the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those of ordinary skill in the art (Houben-Weyl, 4th edition, 1952, Methods of Organic Synthesis, Thieme, Vol. 21). In addition, the compounds of the present invention can be produced by organic synthesis methods known to those of ordinary skill in the art as shown in the following examples.

[0421] As depicted in the examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be understood that although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, as well as other methods known to those of ordinary skill in the art, can be applied to all compounds as described herein and subclasses and categories of each of these compounds.

[0422] abbreviation

[0423] equiv or eq: molar equivalent

[0424] o / n: Overnight

[0425] rt: room temperature

[0426] UV: Ultraviolet

[0427] HPLC: High-pressure liquid chromatography

[0428] Rt: retention time

[0429] LCMS or LC-MS: Liquid Chromatography-Mass Spectrometry

[0430] NMR: Nuclear Magnetic Resonance

[0431] CC: Column chromatography

[0432] TLC: Thin layer chromatography

[0433] sat: saturated

[0434] aq: water

[0435] Ac:Acetyl

[0436] DCM: dichloromethane

[0437] DCE: dichloroethane

[0438] DEA: Diethylamine

[0439] DMF: dimethylformamide

[0440] DMSO: dimethyl sulfoxide

[0441] ACN or MeCN: acetonitrile

[0442] DIPEA: diisopropylethylamine

[0443] EA or EtOAc: ethyl acetate

[0444] BINAP: (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene

[0445] TEA: triethylamine

[0446] THF: Tetrahydrofuran

[0447] TBS: tert-butyldimethylsilyl

[0448] KHMDS: Potassium hexamethyldisilazide

[0449] Tf: trifluoromethanesulfonate

[0450] Ms:Methylsulfonyl

[0451] NBS: N-bromosuccinimide

[0452] PE: Petroleum ether

[0453] TFA: trifluoroacetic acid

[0454] MMPP: magnesium monoperoxyphthalate

[0455] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate

[0456] NCS: N-chlorosuccinimide

[0457] Cy:cyclohexyl

[0458] Tol: Toluene

[0459] DMP: Dess-Martin periodinane

[0460] IBX: 2-iodoacylbenzoic acid

[0461] PMB: paramethoxybenzyl

[0462] SEM: [2-(trimethylsilyl)ethoxy]methyl

[0463] X-phosphorus or X-phosphorus (XPhos or X-Phos): 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0464] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1 to 5 mmHg) at room temperature. Thin layer chromatography (TLC) was performed on silica gel plates and spots were visualized by UV light (214 nm and 254 nm). Purification by column chromatography and flash chromatography was performed using silica gel (200 to 300 mesh). Solvent systems are reported as mixtures by volume. All results were recorded on a Bruker 400 (400 MHz) spectrometer. 1 H NMR spectra. Deuterated solvent was used as internal standard and δ values ​​were reported in parts per million (ppm). 1 H chemical shift. 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 using electrospray ionization, and unless otherwise stated, 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, column temperature: 40°C.

[0465] General Procedure A (Wolff-Kishner Reduction): A mixture of 2,6-diarylpiperidin-4-one (concentration 0.1 to 1 M), KOH (20 equiv.), and N2H4·H2O (40 equiv.) in diethylene glycol was stirred at 80°C and then at about 150°C to 200°C for about 2 hours until the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give the 2,6-diarylpiperidine.

[0466] General Procedure B (N-alkylation of 2,6-diarylpiperidines): To a solution of 2,6-diarylpiperidine (concentration 0.1 to 1 M) in DMF or ACN under Ar atmosphere was added the corresponding halide or mesylate (2 equivalents) and KCO (2 equivalents). The mixture was stirred at 80°C overnight, then diluted with H0 and extracted with DCM. The combined organic layers were washed with water, dried over NaSO, filtered, and concentrated in vacuo to afford the desired N-alkylated target.

[0467] General Procedure C (Reaction of alcohol with methanesulfonyl chloride): To a solution of alcohol (concentration 0.1 to 1 M) and Et3N (about 2.5 eq) in DCM was added MsCl (1.2 to 1.4 eq) dropwise at -70°C and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was then quenched with aqueous NaHCO3 and extracted with DCM. The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the corresponding mesylate.

[0468] General Procedure D (Reaction of methanesulfonate or halide with 2,6-diarylpiperidine): A mixture of 2,6-diarylpiperidine (concentration 0.1 to 1 M), the corresponding methanesulfonate or halide (about 2 to 3 equiv), KI (0.2 to 0.3 equiv), DIPEA (2 to 3 equiv) in DMF or ACN was stirred at 60° C. to 80° C. overnight and filtered. The filtrate was purified by preparative HPLC to afford the alkylated 2,6-diarylpiperidine.

[0469] General Procedure E (Reaction of aromatic aldehydes with acetone to give 4-(heteroaryl or aryl)but-3-en-2-one): A mixture of the corresponding aromatic aldehyde (concentration 0.1 to 1 M), acetone (20 eq.) and KCO (1.5 to 2 eq.) in toluene / EtOH / H0 (5:2:1) was stirred at 80°C for about 13 hours and cooled to room temperature. After dilution with EA, the reaction mixture was filtered through a basic silica gel column and washed with DCM / MeOH (100 / 1). The filtrate was concentrated in vacuo to give 4-(heteroaryl or aryl)but-3-en-2-one, which was used in the next step without further purification.

[0470] General Procedure F (Reaction of aromatic aldehydes with acetone to give 4-(heteroaryl or aryl)but-3-en-2-one): To a mixture of aromatic aldehydes (concentration 0.1 to 1 M) in acetone was added a solution of NaOH (approximately 8 M, 1.5 equivalents) in H2O at 0°C. The mixture was stirred at 0°C for 1 hour. It was then warmed to room temperature and stirred for an additional 2 hours. The pH of the solution was adjusted to 8 with 35% aqueous HCl, 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.

[0471] General Procedure G (Buchwald coupling of aryl bromides with alkylamines): A mixture of aryl bromide (concentration 0.1 to 1 M), alkylamine (2 eq., 0.2 to 2 M), Pd(OAc)2 (0.1 to 0.15 eq.), BINAP (0.2 to 0.3 eq.) or Cs2CO3 (2 to 4 eq.) in toluene was stirred overnight at 75° C. to 120° C. Upon completion, the reaction mixture was concentrated under vacuum and purified by column chromatography to give the desired product.

[0472] General Procedure H (Suzuki coupling of aryl bromide and aryl boronic acid): Aryl bromide (concentration 0.1 to 1 M), aryl boronic acid (1.1 to 1.5 eq), PdCl2(dppf) (0.05 to 0.08 eq) and aqueous Na2CO3 (1 M, 2.5 eq) in 1,4-dioxane were stirred at 80°C to 100°C under microwave irradiation for 10 minutes. After completion of the reaction, the mixture was diluted with water and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column.

[0473] General Procedure I (Reductive Amination of Secondary to Tertiary Amines): To a mixture of a secondary amine (concentration 0.1 to 1 M), the corresponding aldehyde or ketone (1 to 2 equivalents) and NaBH(OAc) (3 to 6 equivalents) in DCM were added a few drops of acetic acid, and the mixture was then stirred at room temperature for 2 to 18 hours. The mixture was neutralized with saturated aqueous NaHCO to pH 8 to 9 and extracted with DCM. The organic layer was washed with brine, dried over NaSO, filtered and concentrated in vacuo to give the desired tertiary amine.

[0474] General Procedure J (Boc cleavage of N-Boc protected amines): To a solution of N-Boc protected amines (concentration 0.1 to 1 M) in DCM was added TFA (1 / 15 of the volume of DCM) at room temperature. The reaction mixture was stirred for 2 hours, then concentrated and saturated aqueous NaHCO3 was added, and the mixture was extracted with DCM. The organic extract was dried over Na2SO4, filtered and concentrated to give the free amine as the desired product.

[0475] General Procedure K (Halogenation of imidazo[1,2-a]pyridine to give 3-halogenated imidazo[1,2-a]pyridine): A mixture of an imidazo[1,2-a]pyridine derivative (concentration 0.1 to 1 M) and NBS or NCS (0.8 to 0.9 equiv) in DCM (10 mL) was stirred at room temperature for 1 hour. After completion of the reaction, the suspension was diluted with water and DCM, the separated organic layer was concentrated under vacuum, and the residue was purified by preparative HPLC to give the desired product.

[0476] Example 1: Synthesis of I-1 and I-3

[0477] Synthesis scheme of I-1 and I-3

[0478]

[0479] Synthesis of X4-014-H: Following general procedure E, X4-014-H was obtained as a yellow foam (1.9 g, 41%), which was 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 69.13%; retention time = 1.38 minutes; MS calculated value: 284.4; MS found value: 285.4 [M+H] + .

[0480] Synthesis of I-3: To a solution of X4-014-H (1.4 g, 4.9 mmol) in MeOH (20 mL) were added L-proline (227 mg, 1.97 mmol), 3-methylpicolinaldehyde (656 mg, 5.4 mmol) and aqueous MeNH2 (1.5 g, 40% wt, 19.72 mmol) sequentially. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by column chromatography to give a cis / trans mixture of I-3 (mg, 50%) as a yellow foam, which was used in the next step without further purification. The cis / trans mixture of I-3 (270 mg, 0.65 mmol) was purified by preparative TLC to give I-3 (30 mg, 11%) as a white 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes). I-3: purity: 92.86%. Retention time = 1.49 minutes (trans), 1.52 minutes (cis); MS calculated value: 418.3; MS found value: 419.4 [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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 5 minutes); purity: 97.88%. Retention time = 4.90 minutes. 1H NMR (400MHz, CDCl3) δ: 8.58-8.56 (m, 1H), 7.62 (s, 1H), 7.48 (dd, J = 1.2Hz, J = 7.6Hz, 1H), 7.36 (d, J = 8.8Hz 1H),7.19(dd,J=7.2Hz,J=8.8Hz,1H),7.13(dd,J=4.8Hz,J=7.6Hz,1H),6.34(d,J=6.4Hz,1H),4.03(dd,J=3.2Hz,J=12.0Hz,1H ), 3.93 (dd, J = 7.2Hz, J = 8.8Hz, 1H), 3.49 (s, 1H), 3.33-3.18 (m, 6H), 2.78-2.68 (m, 5H), 2.50 (s, 3H), 2.42 (s, 3H), 1.94 (s, 3H).

[0481] Synthesis of I-1: Following General Procedure A, a mixture of the cis / trans mixture of I-3 (770 mg, 1.84 mmol), KOH (2.1 g, 36.8 mmol) and N2H4·H2O (4.6 g, 80% wt, 73.6 mmol) in diethylene glycol was stirred at 80°C for 2 hours and then at 150°C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 276 mg of crude I-1, which was purified by preparative HPLC to give 80 mg of I-1 as a white 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes); purity: 96.44%. Retention time = 1.66 minutes; MS calculated value: 404.3; MS found value: 405.4 [M+H] +HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (over 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] over 0.1 minutes and continued under these conditions for 5 minutes); purity: 94.20%. Retention time = 4.44 minutes. 1 H NMR (400MHz, CD3OD) δ: 8.46 (s, 1H), 7.96 (s, 1H), 7.62 (d, J = 8.0Hz, 1H), 7.34-7.25 (m, 2H), 7.22-7.19 (m, 1H), 6.51 (d, J = 6.8Hz, 1H), 3.65 (d, J=10.0Hz,1H),3.46(d,J=8.4Hz,1H),3.17(s,4H),2.81(s,4H),2.51( s,3H),2.47(s,3H),2.05-1.94(m,4H),1.89(s,3H),1.79-1.68(m,2H).

[0482] Example 2: Synthesis of I-2

[0483] Synthesis scheme of I-2

[0484]

[0485] Synthesis of X4-027-A-1: To a solution of X4-027-A (731 mg, 5.0 mmol) and X4-E (806 mg, 5.0 mmol) in toluene (25 mL), EtOH (10 mL) and H o (5 mL) was added K cO (1.037 g, 7.5 mmol). The mixture was stirred overnight at 70 ° C under an Ar atmosphere. The mixture was then diluted with H o and extracted three times with DCM. The combined organic layer was dried over Na sO , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with DCM / MeOH / NH -H o (40 / 1 / 0.68) as eluent to obtain the product X4-027A-1 (952 mg, 66% yield) 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 68.23%; retention time = 1.55 minutes; MS calculated value: 298.1; MS found value: 290.1 ​​[M+H] + .

[0486] Synthesis of X4-027-4: To a solution of X4-027-A-1 (676 mg, 2.34 mmol) in MeOH (20 mL) was added NH / H O (5 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue was purified by preparative TLC to obtain X4-027-4 (170 mg, 23% yield) as a brownish-red 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes); purity: 96.20%. Retention time = 1.41 minutes; MS calculated value: 306.1; MS found value: 307.4 [M+H] + .

[0487] Synthesis of X4-027-5: Following General Procedure A, X4-027-5 (77 mg, 47% yield) was obtained as a brownish-red 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: 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 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 88.42%. Retention time = 1.47 minutes; MS calculated value: 292.2; MS found value: 293.1 [M+H] + .

[0488] Synthesis of X4-027-6: Following General Procedure B, X4-027-6 (180 mg, >100% yield) was obtained as a white solid, which was 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: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 48.71%. Retention time = 1.79 minutes; MS calculated value: 493.6; MS found value: 494.4 [M+H] + .

[0489] Synthesis of I-2: To a solution of crude X4-027-5 (170 mg, 0.25 mmol) in EtOH (3 mL) was added N 2 H 4 ·H 2 O (0.6 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue was purified by preparative HPLC to obtain I-2 (12 mg, 13% yield) as a white 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: 90% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] to 10% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] in 0.1 minute. AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] and continued under this condition for 0.7 min); purity: 98.47%; retention time = 1.26 min; MS calculated value: 363.5; MS found value: 364.3 [M+H] + . HPLC (Agilent HPLC 1200, column: L-column 2ODS (150mm*4.6mm*5.0μm); column temperature: 40°C; flow rate: 1.5mL / min; mobile phase: 90% [(10mM AcONH4 in total)H2O / ACN=9 / 1 (v / v)] and 10% [10mM AcONH4 in total)H2O / ACN=1 / 9 (v / v)] to 15% [10mM AcONH4 in total)H2O / ACN=9 / 1 (v / v)] and 85% [10mM AcONH4 in total)H2O / ACN=1 / 9 (v / v)] (within 5 minutes), then continued under these conditions for 10 minutes, and finally changed to 90% [(10mM AcONH4 in total)H2O / ACN=9 / 1 (v / v)] and 10% [10mM AcONH4 in total)H2O / ACN=1 / 9 (v / v)] in 0.1 minute. AcONH4)H2O / ACN=1 / 9 (v / v)] and continued under this condition for 5 minutes; purity: 98.11%. Retention time = 4.22 minutes. 1H NMR(CDCl3,400MHz)δ8.47(d,J=4.4Hz,1H),8.08(d,J=6.8Hz,1H),7.64(s,1H),7.56 (d,J=8.8Hz,1H),7.42(d,J=7.2Hz,1H),7.14-7.10(m,1H),7.06(dd,J=4.8Hz,7.6Hz, 1H),6.77-6.73(m,1H),4.02-3.99(m,1H),3.90-3.87(m,1H),2.52(s,3H),2.38-2.2 0(m,4H),2.02-1.86(m,4H),1.37-1.29(m,2H),1.13-1.01(m,1H),0.87-0.79(m,3H).

[0490] Example 3: Synthesis of I-4

[0491] Synthesis scheme of I-4

[0492]

[0493] Synthesis of X4-116-A: Following general procedure G, X4-116-A was obtained as a yellow solid (0.92 g, 24% yield). 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 92.35%; retention time = 1.81 minutes; MS calculated value: 504.7, MS measured value: 505.7 [M+1] + .

[0494] Synthesis of X4-116-B: Following general procedure A, X4-116-B was obtained as a light yellow solid (140 mg, 16% yield). 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 93.71%; retention time = 1.99 minutes; MS calculated value: 490.7, MS measured value: 491.7 [M+1] + .

[0495] Synthesis of 1-4: Following general procedure J, 1-4 was obtained as a light yellow solid (110 mg, 99% yield). 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] within 0.1 minutes and continued under this condition for 0.7 minutes); purity: 99.8%; retention time = 1.48 minutes; MS calculated value: 390.7; MS found value: 391.7 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 98.8%; retention time = 4.362 minutes; MS calculated value: 390.7; MS found value: 391.7 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.51(d,J=3.6Hz,1H),7.63(s,1H),7.43(d,J=7.2Hz,1H) ,7.33(d,J=8.8Hz,1H),7.12-7.16(m,1H),7.04-7.07(m,1H),6.27(d,J=7.2Hz ,1H),3.57(dd,J=11.2Hz,J=2.4Hz,1H),3.47(dd,J=10.0Hz,J=3.6Hz,1H),3.1 1-3.15(m,8H),2.47(s,3H),2.22(s,3H),1.97-2.06(m,4H),1.61-1.75(m,2H).

[0496] Example 4: Synthesis of I-5, I-6 and I-7

[0497] Synthesis schemes of I-5, I-6 and I-7

[0498]

[0499] Synthesis of X4-117-1

[0500] Following general procedure H, X4-117-1 was obtained as a yellow oil (63 mg, 32% yield). LCMS (Agilent LCMS1200-6120, 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: 90% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] to 10% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] in 0.1 minute. AcONH4)H2O / ACN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] and under this condition for 0.7 min); purity: 54.67%; retention time = 1.49 min (trans) and 1.53 min (cis); MS calculated value: 397.2; MS found value: 398.7 [M+H] + .

[0501] Preparation of I-5

[0502] Following general procedure A, 1-5 was obtained as an off-white solid (13 mg, 21% yield). LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 100.00%; retention time = 1.62 minutes; MS calculated value: 383.2; MS found value: 384.7 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 100.00%; retention time = 4.70 minutes; MS calculated value: 383.2; MS found value: 384.7 [M+H] + . 1 H NMR (400MHz, CDCl3) δ1.53-1.65(m,2H),1.81(s,3H),1.83-1.95(m,4H),2.37 (s,3H),3.37-3.40(m,1H),3.45-3.48(m,1H),6.72(d,J=6.8Hz,1H),6.96-6. 99(m,1H),7.15-7.18(m,1H),7.34(d,J=7.6Hz,1H),7.52(d,J=6.0Hz,2H),7. 56(d,J=9.2Hz,1H),7.71(s,1H),8.42(d,J=2.4Hz,1H),8.77(d,J=6.0Hz,2H).

[0503] Preparation X4-118-1

[0504] Following general procedure H, X4-118-1 (116 mg, 80% yield) was obtained from X4-101-1 (150 mg, 0.38 mmol) 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: 90% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] to 10% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] in 0.1 minute. AcONH4)H2O / ACN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] and under this condition for 0.7 min); purity: 82.37%; retention time = 1.63 min (trans) and 1.67 min (cis); MS calculated value: 397.7; MS found value: 398.7 [M+H] + .

[0505] Synthesis of I-6

[0506] Following general procedure A, 1-6 was obtained as a white solid (50 mg, 52% yield). LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 95.04%; retention time = 1.64 minutes; MS calculated value: 383.7; MS found value: 384.7 [M+H] +HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 100%; retention time = 4.79 minutes; MS calculated value: 383.7; MS found value: 384.7 [M+H] + . 1 H NMR (400MHz, CDCl3) δ1.53-1.81(m,2H),1.86(s,3H),1.89-2.01(m,4H),2.43(s,3H),3.41-3.45(m ,1H),3.51-3.55(m,1H),6.76(d,J=6.8Hz,1H),7.04(dd,J1=4.4Hz,J2=7.2Hz,1H),7.22-7.25(m,1 H),7.40(d,J=7.6Hz,1H),7.53(dd,J1=4.8Hz,J2=7.6Hz,1H),7.62(d,J=9.2Hz,1H),7.68(s,1H),8 .01-8.03(m,1H),8.48(d,J=3.2Hz,1H),8.79(dd,J1=1.2Hz,J2=5.2Hz,1H),8.86(d,J=1.6Hz,1H).

[0507] Synthetic X4-119-1

[0508] To a solution of X4-101-1 (500 mg, 1.3 mmol) in TEA and THF (20 mL, 1: 1) was added CuI (12 mg, 0.07 mmol) and PdCl(PPh) (92 mg, 0.13 mmol). The resulting mixture was heated to 60 ° C and stirred for 2 hours. After cooling to room temperature, the solid suspension was filtered through celite; The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography to obtain X4-119-1 (350 mg, 66% yield) 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: 90% [water+10 mM NH4HCO3] and 10% [CH3CN] to 5% [water+10 mM NH4HCO3] and 95% [CH3CN] (in 0.5 min), then continued under this condition for 1.5 min, and finally changed to 90% [water+10 mM NH4HCO3] and 10% [CH3CN] in 0.1 min and continued under this condition for 0.7 min); purity: 90.26%; retention time = 0.98 min; MS calculated value: 421.2; MS found value: 422.2 [M+H] + .

[0509] Synthetic X4-119-2

[0510] To a solution of X4-119-1 (350 mg, 0.83 mmol) in EtOH (20 mL) was added Pd (OH) (20% on carbon) (84 mg, 0.12 mmol), and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo, which was purified by column chromatography to obtain X4-119-2 (130 mg, 37% yield) as an off-white syrup. 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 96.78%; retention time = 1.60 minutes; MS calculated value: 425.2; MS found value: 426.2 [M+H] + .

[0511] Synthesis of I-7

[0512] Following general procedure A, 1-7 was obtained as an off-white solid (20 mg, 16% yield). LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 100.00%; retention time = 1.73 minutes; MS calculated value: 411.2; MS found value: 412.4 [M+H] + HPLC (Agilent LCMS 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: 95% [water+5% TFA] and 5% [CH3CN] to 0% [water+5% TFA] and 100% [CH3CN+5% TFA] (over 10 minutes), then continued under these conditions for 5 minutes, finally changing to 95% [water+5% TFA] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 5 minutes); purity: 90.39%. Retention time = 4.54 minutes. 1 HNMR (400MHz, CDCl3) δ: 8.60 (1H, dd, J1=4.8Hz, J2=0.8Hz), 8.50 (1H, br s),7.74(1H,s),7.61(1H,tt,J1=7.6Hz,J2=1.6Hz),7.47(1H,d,J=8.8Hz),7.42(1H,d,J=7.2Hz),7.19-7.04(4H,m),6.58(1H,d,J=6.8Hz), 3.57(1H,dd,J1=11.2Hz,J2=2.4Hz),3.50-3.45(1H,m),3.38-3.27(4H,m),2.48(3H,s),2.07-1.94(4H,m),1.90(3H,s),1.74-1.61(2H,m).

[0513] Example 5: Synthesis of I-8

[0514] Synthesis scheme of I-8

[0515]

[0516] Synthetic X4-120-1

[0517] Following General Procedure C, X4-120-1 (351 mg, 43% yield) was obtained as a brown solid, which was 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes). Purity: 88.46%; Retention time = 1.30 min; MS calculated value: 201.0; MS found value: 202.7 [M+H] + .

[0518] Synthesis of I-8

[0519] Following general procedure D, I-8 was obtained as a white solid (18 mg, 22% yield). LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 99.17%; retention time = 1.65 minutes; MS calculated value: 397.2; MS found value: 398.7 [M+H] +HPLC (Agilent HPLC 1200; column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under these conditions for 5 minutes); purity: 93.21%; retention time = 4.19 minutes. 1 H NMR (400MHz, CDCl3) δ1.60-1.71(m,2H),1.90-2.02(m,4H),2.56(s,3H),2.68-2.81(m,4H) ,3.99(t,J=6.8Hz,1H),4.10-4.13(m,1H),6.56(d,J=8.0Hz,1H),6.73(t,J=6.8Hz,1H),6. 84-6.87(m,1H),7.05-7.12(m,2H),7.28-7.29(m,1H),7.43(d,J=8.0Hz,1H),7.56(d,J=9. 2Hz, 1H), 7.61 (s, 1H), 8.04 (d, J = 6.8Hz, 1H), 8.19 (d, J = 4.0Hz, 1H), 8.48 (d, J = 4.0Hz, 1H).

[0520] Example 6: Synthesis of I-9

[0521] Synthesis scheme of I-9

[0522]

[0523] Synthetic X4-121-1

[0524] Following general procedure C, X4-121-1 (115 mg, 71% yield) was obtained as a brown oil, which was 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 44.91%; retention time = 1.11 minutes; MS calculated value: 202.0; MS found value: 203.7 [M+H] + .

[0525] Synthesis of I-9

[0526] Following general procedure B, 1-9 was obtained as an off-white solid (12 mg, 15% yield). LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under these conditions for 0.7 minutes); purity: 98.46%; retention time = 1.57 minutes; MS calculated value: 398.2; MS found value: 399.7 [M+H] + HPLC (Agilent HPLC 1200; column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 96.51%; retention time = 4.50 minutes. 1H NMR (400MHz, CDCl3) δ1.61-1.70(m,2H),1.94-2.06(m,4H),2.51(br,1H),2.56(s,3H),2.7 0-2.75(m,2H),2.79-2.83(m,1H),3.97-4.01(m,1H),4.12(dd,J1=2.8Hz,J2=11.2Hz,1H),6 .73-6.77(m,1H),7.07-7.15(m,2H),7.44(d,J=7.6Hz,1H),7.58(d,J=8.8Hz,1H),7.62(s, 1H), 7.92 (d, J = 1.2Hz, 1H), 8.06 (d, J = 6.4Hz, 1H), 8.12-8.14 (m, 2H), 8.49 (d, J = 4.0Hz, 1H).

[0527] Example 7: Synthesis of I-10

[0528] Synthesis scheme of I-10

[0529]

[0530] Synthetic I-10

[0531] Following general procedure B, 1-10 was obtained as a white solid (18 mg, 23% yield). LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 93.04%; retention time = 1.63 minutes; MS calculated value: 386.2; MS found value: 387.7 [M+H] +HPLC (Agilent HPLC 1200; column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minute and continued under this condition for 5 minutes); purity: 95.05%; retention time = 4.95 minutes. 1 H NMR (400MHz, CDCl3) δ1.59-1.66(m,2H),1.93-2.08(m,4H),2.51(s,3H),2.63-2.69(m,1H) ,2.87-2.94(m,1H),3.40(br,1H),3.71-3.75(m,1H),3.88(dd,J1=2.8Hz,J2=11.2Hz,1H),4 .04(dd,J1=2.4Hz,J2=11.2Hz,1H),5.96(t,J=2.0Hz,1H),6.73-6.78(m,2H),7.09-7.16(m, 3H), 7.45-7.46 (m, 2H), 7.56 (d, J = 8.8Hz, 1H), 8.03 (d, J = 6.8Hz, 1H), 8.52 (d, J = 3.6Hz, 1H).

[0532] Example 8: Synthesis of I-11

[0533] Synthesis scheme of I-11

[0534]

[0535] Synthesis of I-11

[0536] A mixture of I-1 (120 mg, 0.3 mmol) and acetic acid (0.5 mL) in 37% formaldehyde solution (10 mL) was stirred at 50 ° C for 24 hours, then 37% formaldehyde solution (5 mL) was added, and the mixture was stirred for another 48 hours at 50 ° C. After the reaction was completed, the suspension was adjusted to pH 8 with saturated sodium carbonate solution and extracted with DCM (20 mL). The organic layer was concentrated under vacuum, and the residue was purified by preparative HPLC to obtain I-11 (90 mg, 70% yield) as a white 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 99.25%; retention time = 1.54 minutes; MS calculated value: 434.3; MS found value: 435.3 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under these conditions for 5 minutes); purity: 95.82%; retention time = 4.28 minutes. 1H NMR (400MHz, CD3OD)1.81-1.60(m,2H),1.85(s,3H),1.97-2.01(m,2H),2.10-2.22( m,2H),2.45(s,6H),2.48-2.62(m,4H),2.95-3.11(m,4H),3.45-3.50(m,1H),3.62- 3.70(m,2H),5.32(d,J=13.6Hz,1H),5.71(br,1H),6.70-6.72(m,1H),7.19(dd,J1= 4.4Hz, J2=4.8Hz, 1H), 7.28-7.35 (m, 1H), 7.60 (d, J=7.6Hz, 1H), 8.39-8.46 (m, 1H).

[0537] Example 9: Synthesis of I-12

[0538] Synthesis scheme of I-12

[0539]

[0540] Synthetic I-12

[0541] To a solution of I-11 (50 mg, 0.11 mmol) in DCM (5 mL) was added thionyl chloride (20 mg, 0.17 mmol) at 0 ° C under an argon atmosphere, and the mixture was stirred at 0 ° C for 4 hours. After I-11 was completely converted, excess thionyl chloride was removed in vacuo; the residue was dissolved in MeOH (2 mL) and stirred at 0 ° C for another 2 hours. The mixture was neutralized with NH / MeOH and concentrated in vacuo. The residue was purified by column chromatography to obtain I-12 (10 mg, 20% yield) as a white 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: 90% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] to 10% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] in 0.1 minute. AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] and continued under this condition for 0.7 min); purity: 96.30%; retention time = 2.00 min; MS calculated value: 448.3; MS found value: 449.3 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under these conditions for 5 minutes); purity: 89.34%; retention time = 4.56 minutes. 1H NMR(400MHz,CD3OD)1.20(s,3H),1.55-1.65(m,2H),1.70(s,3H),1.84-1.92(m,2H) ,1.93-2.05(m,2H),2.32(s,3H),2.38-2.57(m,4H),2.83-2.94(m,4H),3.11-3.16( m,2H),3.41(s,3H),5.13(dd,J1=9.2Hz,J2=61.2Hz,1H),6.68(d,J=6.8Hz,1H),7.1 2(d,J=5.6Hz,1H),7.21-7.25(m,2H),7.52(d,J=7.2Hz,1H),8.23(d,J=2.0Hz,1H).

[0542] Example 10: Synthesis of I-13, I-14 and I-15

[0543] Synthesis schemes of I-13, I-14 and I-15

[0544]

[0545] Synthesis of I-13

[0546] Following General Procedure I, 1-13 (9 mg, 26% yield) was obtained as an off-white solid. LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 98.70%; retention time = 1.77 minutes; MS calculated value: 418.3; MS found value: 419.4 [M+H] +HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 90.08%; retention time = 4.50 minutes; MS calculated value: 418.3; MS found value: 419.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.51(d,J=3.6Hz,1H),7.62(s,1H),7.42(d,J=6.8Hz,1H),7.32( d,J=10.0Hz,1H),7.11-7.15(m,1H),7.05(dd,J=7.6Hz,J=4.8Hz,1H),6.28(d,J=7.2H z,1H),3.57(d,J=9.2Hz,1H),3.45-3.49(m,1H),3.18(s,4H),2.73(s,4H),2.55-2.61 (m,2H),2.48(s,3H),1.92-2.05(m,4H),1.90(s,3H),1.62-1.68(m,2H),1.78(t,3H).

[0547] Synthesis of I-14

[0548] A mixture of I-4 (33.0 mg, 0.085 mmol), X4-189-R (21.7 mg, 0.093 mmol) and DIPEA (12.1 mg, 0.094 mmol) in THF (4 mL) was stirred at 70 ° C for 4 hours. The mixture was cooled to room temperature, concentrated and diluted with saturated NaHCO aqueous solution (4 mL). The aqueous layer was extracted three times with DCM. The combined organic layer was washed with brine, dried over Na SO and filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC to obtain I-14 (8 mg, 20% yield) as an off-white 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 91.57%; retention time = 1.96 minutes; MS calculated value: 472.3; MS found value: 473.4 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 89.82%; retention time = 6.11 minutes; MS calculated value: 472.7; MS found value: 473.4 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.50-8.52(m,1H),7.61(s,1H),7.43(d,J=6.8Hz,1H),7. 33(d,J=8.8Hz,1H),7.14(dd,J=8.4Hz,J=7.2Hz,1H),7.04-7.07(m,1H),6.27( d,J=6.4Hz,1H),3.55-3.58(m,1H),3.45-3.49(m,1H),3.09-3.17(m,6H),2.96 -2.98(m,4H),2.47(s,3H),1.92-2.05(m,4H),1.90(s,3H),1.69-1.75(m,2H).

[0549] Synthetic I-15

[0550] Following general procedure I, 1-15 was obtained as an off-white solid (9 mg, 25% yield). LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 100.00%; retention time = 1.88 minutes; MS calculated value: 432.3; MS found value: 433.3 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 90.73%; retention time = 4.52 minutes; MS calculated value: 432.7; MS found value: 433.3 [M+H] + . 1H NMR(400MHz, CDCl3) δ8.51(d,J=4.0Hz,1H),7.63(s,1H),7.42(d,J=6.8Hz,1H),7.31 (d,J=8.8Hz,1H),7.11-7.15(m,1H),7.05(dd,J=7.6Hz,J=4.8Hz,1H),6.27(d,J=6.8 Hz,1H),3.57(d,J=10.0Hz,1H),3.45-3.50(m,1H),3.16(m,4H),2.80-2.84(s,5H),2 .48(s,3H),1.92-2.09(m,4H),1.91(s,3H),1.59-1.67(m,2H),1.15(d,J=6.4Hz,6H).

[0551] Example 11: Synthesis of I-16

[0552] Synthesis scheme of I-16

[0553]

[0554] Synthesis of I-16

[0555] Following general procedure D, 1-16 (23 mg, 17% yield) was obtained as a white solid. LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 98.43%; retention time = 1.77 minutes; MS calculated value: 448.2; MS found value: 449.2 [M+H] +HPLC (Agilent HPLC 1200; column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 94.25%; retention time = 5.10 minutes. 1 H NMR (400MHz, CDCl3) δ1.57-1.68(m,2H),1.92-1.96(m,2H),2.12-2.19(m,2H),2.26(s,3H),3 .40-3.44(m,1H),3.58-3.62(m,1H),3.74-3.77(m,1H),3.85-3.89(m,1H),6.33-6.34(m,1H) ,6.63-6.69(m,2H),6.79-6.87(m,2H),7.03-7.09(m,2H),7.17-7.18(m,1H),7.24(d,J=7.6H z,1H),7.36(m,1H),7.43(d,J=8.8Hz,1H),7.60(m,1H),7.88-7.92(m,2H),8.25-8.26(m,1H).

[0556] Example 12: Synthesis of I-17

[0557] Synthesis scheme of I-17

[0558]

[0559] Synthesis of I-17

[0560] Following general procedure K, 1-17 (180 mg, 84% yield) was obtained as a white solid. LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 96.10%; retention time = 1.89 minutes; MS calculated value: 482.2; MS found value: 483.3 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 95.40%; retention time = 5.00 minutes. 1 H NMR(400MHz,MeOD)1.19-1.52(m,2H),1.54-1.66(m,3H),1.70(s,3H),1.85-2 .01(m,2H),2.03-2.18(m,2H),2.31(s,3H),2.55-2.63(m,4H),2.77-2.86(m, 4H),3.50(br,2H),6.55(dd,J1=1.6Hz,J2=1.6Hz,1H),7.10(dd,J1=4.8Hz,J2 =5.2Hz,1H),7.18-7.25(m,2H),7.49(d,J=8.0Hz,1H),8.18(d,J=4.8Hz,1H).

[0561] Example 13: Synthesis of I-18

[0562] Synthesis scheme of I-18

[0563]

[0564] Synthetic I-18

[0565] Following general procedure K, 1-18 was obtained as a white solid (15 mg, 23% yield). LCMS (Agilent LCMS1200-6120, 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: 90% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] to 10% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] in 0.1 minute. AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] and continued under this condition for 0.7 min); purity: 94.68%; retention time = 2.02 min; MS calculated value: 438.2; MS found value: 439.2 [M+H] + . HPLC (Agilent HPLC 1200, column: L-column 2ODS (150mm*4.6mm*5.0μm); column temperature: 40°C; flow rate: 1.0ml / min; mobile phase: 90% [(total 10mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [total 10mM AcONH4)H2O / ACN=1 / 9 (v / v)] to 15% [total 10mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 85% [total 10mM AcONH4)H2O / ACN=1 / 9 (v / v)] (within 5 minutes), then continued under these conditions for 10 minutes, and finally changed to 90% [(total 10mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [total 10mM AcONH4)H2O / ACN=1 / 9 (v / v)] in 0.1 minute. AcONH4)H2O / ACN=1 / 9 (v / v)] and continued under this condition for 5 minutes); purity: 100%; retention time=6.60 minutes. 1HNMR(400MHz,CD3OD)1.18-1.55(m,2H),1.58-1.66(m,3H),1.70(s,3H),1.83-2 .01(m,2H),2.05-2.18(m,2H),2.30(s,3H),2.44-2.65(m,4H),2.79-2.87(m,4H ),3.37-3.58(m,2H),6.50(dd,J1=2.8Hz,J2=5.6Hz,1H),7.10(dd,J1=4.8Hz,J2 =7.6Hz,1H),7.16-7.22(m,2H),7.49(d,J1=7.2Hz,1H),8.18(d,J1=4.0Hz,1H).

[0566] Example 14: Synthesis of I-19

[0567] Synthesis scheme of I-19

[0568]

[0569] Synthetic I-19

[0570] Following general procedure K, 1-19 (11 mg, 31% yield) was obtained as an off-white solid. LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes); purity: 96.94%; retention time = 2.025 minutes; MS calculated value: 496.7; MS found value: 497.7 [M+H] +HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 ml / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 93.41%; retention time = 5.15 minutes; MS calculated value: 496.7; MS found value: 497.7 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.48(s,1H),7.42-7.37(m,2H),7.12(dd,J=8.8Hz,7.2Hz,1H),7.05(dd,J=7.6Hz,4.8Hz,1H),6.41(dd,J=7.2Hz,0.8Hz,1H),3.61(dd, J=11.2Hz,2.4Hz,2H),3.33-3.27(m,2H),2.97-2.85(m,4H),2.60-2.51(m,4H) ,2.46(s,3H),2.19-1.92(m,4H),1.78(s,3H),1.74-1.54(m,2H),1.15(t,3H).

[0571] Example 15: Synthesis of I-20

[0572] Synthesis scheme of I-20

[0573]

[0574] Preparation of I-20

[0575] Following general procedure K, 1-20 (12 mg, 29% yield) was obtained as an off-white solid. LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under these conditions for 0.7 minutes); purity: 96.27%; retention time = 2.140 minutes; MS calculated value: 510.7; MS found value: 511.7 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 ml / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under this condition for 5 minutes); purity: 96.35%; retention time = 5.268 minutes; MS calculated value: 510.7; MS found value: 511.7 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.47(s,1H),7.42-7.37(m,2H),7.14-7.10(m,1H),7.05(dd,J=7.6Hz,4.8Hz,1H),6.40(dd,J=7.2Hz,0.8Hz,1H),3.61(d,J=9.6H z,2H),3.34-3.28(m,2H),2.93-2.83(m,4H),2.79-2.69(m,3H),2.47(s,3H) ), 2.23-1.92 (m, 4H), 1.79 (s, 3H), 1.74-1.55 (m, 2H), 1.13 (d, J = 6.4Hz, 6H).

[0576] Example 16: Synthesis of I-21

[0577] Synthesis scheme of I-21

[0578]

[0579] Synthesis of 1-21: To a solution of 1-11 (50 mg, 0.12 mmol) in DCM (5 ml) was added thionyl chloride (20 mg, 0.17 mmol) at 0° C. under argon atmosphere, and the mixture was stirred at 0° C. for 4 hours. After 1-11 was completely consumed, the excess thionyl chloride was concentrated under vacuum, and the residue was dissolved in ethanol (2 mL) and stirred at 0° C. for another 2 hours. The suspension was diluted with DCM (20 ml) and saturated sodium bicarbonate (6 ml), and the separated organics were concentrated under vacuum and purified by preparative HPLC to obtain 1-21 (15 mg, 28% yield) as a white 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)H2O / ACN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=100 / 900 (v / v)] to 10% [(total 10 mM AcONH4)H2O / ACN=9 / 1 (v / v)] and 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] in 1.6 minutes, then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] in 0.1 minute. AcONH4)H2O / ACN=9 / 1 (v / v)] and 10% [(total 10 mM AcONH4)H2O / ACN=1 / 9 (v / v)] and continued under this condition for 0.7 min); purity: 95.10%; retention time = 2.08 min; MS calculated value: 462.3; MS found value: 463.3 [M+H] +. HPLC (Agilent HPLC 1200, column: L-column 2ODS (150mm*4.6mm*5.0μm); column temperature: 40℃; flow rate: 1.0mL / min; mobile phase: from 90% [(total 10mM AcONH4)H2O / ACN=9 / 1(v / v)] and 10% [total 10mM AcONH4)H2O / ACN=1 / 9(v / v)] to 15% [total 10mM AcONH4)H2O / ACN=9 / 1(v / v)] and 85% [total 10mM AcONH4)H2O / ACN=1 / 9(v / v)] in 5 minutes, then continued under this condition for 10 minutes, and finally changed to 90% [(total 10mM AcONH4)H2O / ACN=9 / 1(v / v)] and 10% [total 10mM AcONH4)H2O / ACN=1 / 9(v / v)] in 0.1 minute. AcONH4)H2O / ACN=1 / 9 (v / v)] and continued under this condition for 5 minutes); purity: 100%; retention time=6.50 minutes. 1 HNMR(400MHz,MeOD)1.21-1.24(m,3H),1.63-1.90(m,6H),1.98-2.19(m,4H),2.43(s,3H),2.4 6-2.56(m,2H),2.60-2.74(m,2H),2.94-3.05(m,4H),3.21-3.28(m,2H),3.50-3.64(m,2H),3. 73-3.79(m,2H),5.16-5.27(m,1H),5.37-5.42(m,1H),5.37-5.42(m,1H),6.79(d,J=7.6Hz,1H ), 7.23 (dd, J1 = 4.8Hz, J2 = 7.6Hz, 1H), 7.31-7.38 (m, 2H), 7.62 (d, J1 = 7.6Hz, 1H), 8.34 (s, 1H).

[0580] Example 17: Synthesis of I-34

[0581] Synthesis scheme of I-34

[0582]

[0583] Synthetic rac-X4-216-2

[0584]

[0585] A mixture of X4-216-1 (10.0 g, 58.0 mmol) and ethyl bromopyruvate (63.9 g, 12.9 mmol) in EtOH (60 mL) was stirred under reflux overnight. The mixture was then returned to room temperature, and the solid was collected by filtration to obtain X4-216-2 (10.0 g, yield: 64%) as a yellow 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: 90% [water+10 mM NH4HCO3] and 10% [CH3CN] to 5% [water+10 mM NH4HCO3] and 95% [CH3CN] (over 0.5 min), then continued under these conditions for 1.5 min, and finally changed to 90% [water+10 mM NH4HCO3] and 10% [CH3CN] over 0.1 min and continued under these conditions for 0.5 min). Purity: 89%, retention time = 0.97 min; MS calculated value: 267.9; MS found value: 268.9 [M+H] + .

[0586] Synthetic X4-216-3

[0587]

[0588] A mixture of X4-216-2 (10.0 g, 37.3 mmol), a fluorine reagent (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate)) (26.4 g, 74.6 mmol) and DMAP (4.55 g, 37.3 mmol) in CH2Cl2 / H2O (3 / 1, 40 mL) was stirred at 60 ° C overnight. The mixture was concentrated in vacuo. Water was added to the residue and extracted with DCM (150 mL×3). The combined organic layer was washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography to obtain X4-216-3 (3.00 g, yield: 28%) as a white solid. LCMS (Agilent LCMS 1200-6110, 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: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] over 0.05 minutes and continued under these conditions for 0.7 minutes). Purity: 99%, retention time = 1.64 minutes; MS calculated value: 286.0; MS found value: 287.1 [M+H] + .

[0589] Synthetic X4-216-4

[0590]

[0591] According to General Procedure G, X4-216-4 (1.00 g, yield: 62%) was obtained as a white solid. LCMS (Agilent LCMS 1200-6110, 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: 95% [water+0.05% TFA] and 5% [CH 3 CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH 3 CN+0.05% TFA] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH 3 CN+0.05% TFA] in 0.05 minutes and continued under this condition for 0.7 minutes). Purity: 96%, retention time = 0.58 min; MS calculated value: 306.1; MS found value: 307.2 [M+H] +.

[0592] Synthetic X4-216-5

[0593]

[0594] To a solution of X4-216-4 (1.00 g, 3.27 mmol) in DCM (20 mL) was added DIBAL-H (6.54 mL, 6.54 mmol) dropwise at -78 ° C, and the mixture was slowly returned to room temperature and stirred for another 2 hours. Water was added to the residue and the mixture was extracted with DCM (150 mL × 3). The combined organic layer was washed with salt water (50 mL × 2), over anhydrous Na2SO4, dried, filtered and concentrated in a vacuum. The residue was dissolved again in DCM (20 mL) and MnO2 (2.84 g, 32.7 mmol) was added. The mixture was stirred at room temperature overnight and filtered through diatomaceous earth. The filtrate was concentrated in a vacuum to obtain X4-013-5 (700 mg, yield: 82%) as a yellow 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: 90% [water+10 mM NH4HCO3] and 10% [CH3CN] to 5% [water+10 mM NH4HCO3] and 95% [CH3CN] (over 0.5 min), then continued under these conditions for 1.5 min, and finally changed to 90% [water+10 mM NH4HCO3] and 10% [CH3CN] over 0.1 min and continued under these conditions for 0.5 min). Purity: 77%, retention time = 0.99 min; MS calculated value: 262.1; MS found value: 263.0 [M+H] + .

[0595] Synthetic X4-216-6

[0596]

[0597] Following General Procedure E, X4-216-6 (500 mg, crude, 72%) was obtained as a yellow foam and used in the next step without further purification. 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: 90% [water+10 mM NH 4 HCO 3 ] and 10% [CH 3 CN] to 5% [water+10 mM NH 4 HCO 3 ] and 95% [CH 3 CN] (in 0.5 min), then continued 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 continued under this condition for 0.5 min). Purity: 71.5%; Retention time = 1.07 min; MS calculated value: 302.1; MS found value: 303.1 [M+H] + .

[0598] Synthetic X4-216-7

[0599]

[0600] To a solution of X4-216-6 (500 mg, 1.66 mmol) in MeOH (20 ml) was added L-proline (76.4 mg, 0.664 mmol), 3-methylpicolinaldehyde (223 mg, 1.83 mmol) and aqueous MeNH2 (206 mg, 40% w / w, 6.64 mmol). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 20: 1) to afford X4-216-7 (200 mg, 28%) as a yellow solid. LCMS (Agilent LCMS1200-6120, 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: 90% [water+10 mM NH4HCO3] and 10% [CH3CN] to 5% [water+10 mM NH4HCO3] and 95% [CH3CN] (over 0.5 min), then continued under these conditions for 1.5 min, and finally changed to 90% [water+10 mM NH4HCO3] and 10% [CH3CN] over 0.1 min and continued under these conditions for 0.5 min). Purity: 59.4%. Retention time = 1.13 min; MS calculated value: 436.2; MS found value: 437.0 [M+H] + .

[0601] Synthetic I-34

[0602]

[0603] Following general procedure A, 1-34 was obtained as a brown solid (7.70 mg, 7%). 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: 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 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4) water / CH3CN=100 / 900 (v / v)] in 0.1 minute. AcONH4) water / CH3CN = 900 / 100 (v / v)] and 10% [(total 10 mM AcONH4) water / CH3CN = 100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 91.15%. Retention time = 1.96 minutes; MS calculated value: 422.3; MS found value: 423.2 [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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 5 minutes). Purity: 92.8%. Retention time = 8.85 minutes. 1 H NMR (400MHz, CDCl3) δ8.47-8.49(m,1H),7.42-7.40(m,1H),7.19-7.16(m,1H) ,7.07-6.99(m,2H),6.18(d,J=7.2Hz,1H),3.58-3.54(m,1H),3.49-3.44(m,1H ),3.29-3.24(m,2H),2.98-2.79(m,4H),2.47(s,3H),2.39(s,3H),2.25-2.17 (m,2H),2.03-1.90(m,2H),1.85(s,3H),1.66-1.53(m,2H),1.42-1.22(m,2H).

[0604] Example 18: Synthesis of I-66

[0605] Synthesis scheme of I-66

[0606]

[0607] Synthetic X4-019-5

[0608]

[0609] To a solution of X4-019-4 (3.0 g, 1.73 mmol) and DME (120 ml) was added X4-019-4a (5.6 g, 3.03 mol) at room temperature, and the reaction mixture was stirred at 65 ° C for 4 hours. After being cooled to 10 ° C, the mixture was stirred for 1 hour and filtered. After washing with DME, the filtered solid was suspended in DME (120 ml) and 2MHCl aqueous solution (120 ml), and stirred at 75 ° C overnight. After being cooled to 10 ° C, the mixture was neutralized to pH=8 and filtered with 3M NaOH aqueous solution. The filter cake was washed with water and dried in a vacuum at 50 ° C to obtain X4-019-5 (2.81 g, 72% yield) as an off-white solid. LC-MS (Agilent LCMS 1200-6110, mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 0.05 minutes and continued under these conditions for 0.7 minutes). Purity: 94.5%, retention time = 1.26 minutes; MS calculated value: 223.96; MS found value: 225.1 [M+H] + .

[0610] X4-101-1 was prepared from intermediate X4-101-0 according to General Procedures E and F and methods described elsewhere herein using X4-019-5 and X4-117-B.

[0611] Synthetic X4-116-A

[0612]

[0613] According to General Procedure G, X4-116-A (0.92 g, 24%) was obtained as a yellow solid. LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes). Purity: 92.35%, retention time = 1.81 minutes; MS calculated value: 504.7, MS measured value: 505.7 [M+1] + .

[0614] Synthetic X4-116-B

[0615]

[0616] According to the general procedure A, X4-116-B (140 mg, 16%) was obtained as a light yellow solid. LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes). Purity: 93.71%, retention time = 1.99 minutes; MS calculated value: 490.7, MS measured value: 491.7 [M+1] + .

[0617] Synthesis of I-4

[0618]

[0619] Following General Procedure J, I-4 (110 mg, 99%) was obtained as a light 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: 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 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] in 0.1 minutes and continued under this condition for 0.7 minutes). Purity: 99.80%, retention time = 1.48 minutes; MS calculated value: 390.7; MS found value: 391.7 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 ml / min; mobile phase: 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] (within 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] within 0.1 minutes and continued under these conditions for 5 minutes). Purity: 98.78%, retention time = 4.362 minutes; MS calculated value: 390.7; MS found value: 391.7 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.51(d,J=3.6Hz,1H),7.63(s,1H),7.43(d,J=7.2Hz,1 H),7.33(d,J=8.8Hz,1H),7.16-7.12(m,1H),7.07-7.04(m,1H),6.27(d,J=7 .2Hz,1H),3.57(dd,J=11.2,2.4Hz,1H),3.47(dd,J=10.0,3.6Hz,1H),3.15- 3.11(m,8H),2.47(s,3H),2.22(s,3H),1.97-2.06(m,4H),1.75-1.61(m,2H).

[0620] Synthetic I-66

[0621]

[0622] To a solution of I-4 (350.0 mg, 0.90 mmol), X4-276-1 (626.4 mg, 3.6 mmol) in THF (5 mL) and MeOH (5 mL) was added NaBHCN (223.2 mg, 3.6 mmol) and AcOH (0.05 mL). The solution was then stirred at 60 ° C for 7 hours. After TLC showed that the reaction was complete, the mixture was concentrated, quenched with saturated NaCOaqueous solution (20 mL) and extracted with DCM (30 mL × 3). The combined organic layer was washed with brine (10 mL), dried over NaSO and filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC to obtain I-66 (170 mg, 44%) as an off-white 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes). Purity: 96.39%. Retention time = 1.94 minutes; MS calculated value: 430.3; MS found value: 431.4 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150mm*4.6mm*5.0μm); column temperature: 40℃; flow rate: 1.0mL / min; mobile phase: 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)] (over 5 minutes), then continued under these conditions for 10 minutes, and finally became 90% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] in 0.1 minutes and continued under these conditions for 5 minutes). Purity: 99.9%, retention time = 9.61 minutes. 1H NMR (400MHz, CDCl3) δ8.51 (d, J=3.6Hz, 1H), 7.63 (s, 1H), 7.43 (dd, J=7.6, 1.2Hz, 1H), 7.31 (d, J= 8.8Hz,1H),7.14-7.10(m,1H),7.05(dd,J=7.6,4.8Hz,1H),6.25(dd,J=7.2,0.8Hz,1H),3.59-3.5 6(m,1H),3.50-3.45(m,1H),3.11(s,4H),2.90(s,4H),2.48(s,3H),2.09-2.05(m,2H),1.97-1.93 (m,2H),1.91(s,3H),1.83-1.78(m,1H),1.74-1.61(m,2H),0.57-0.52(m,2H),0.51-0.46(m,2H).

[0623] Example 19: Synthesis of I-76

[0624] Synthesis scheme of I-76

[0625]

[0626] Synthetic X4-295-1

[0627]

[0628] To I-1 (150mg, 3.7mmol) in concentrated HSO4 (2ml) solution was slowly added concentrated nitric acid (1.6mL, 38mmol) by syringe at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into cold NaHCO3 aqueous solution and extracted with DCM. The organic layer was concentrated in vacuo, and the residue was purified by preparative TLC (DCM / CH3OH=8:1) to provide product X4-295-1 (40mg, 26% yield) as a yellow solid. LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] within 0.1 minutes and continued under this condition for 0.7 minutes. Purity: 50.59%. Retention time = 1.64 minutes; MS calculated value: 449.2; MS found value: 450.4 [M+H]+ .

[0629] Synthetic I-76

[0630]

[0631] To a solution of X4-295-1 (100 mg, 0.22 mmol) in ethyl acetate (10 ml) was added Pd (OH) / C (50 mg), and the mixture was stirred at 25 ° C for 36 hours under an H atmosphere. The mixture was then filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to obtain I-76 (80 mg, 87% yield) as an off-white 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] within 0.1 minutes and continued under these conditions for 0.7 minutes. Purity: 91.83%. Retention time = 1.66 minutes; MS calculated value: 419.6; MS found value: 420.4 [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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] within 0.1 minutes and continued under this condition for 5 minutes. Purity: 97.02%. Retention time = 8.05 minutes. 1HNMR (400MHz, CDCl3) δ8.50(d,J=3.6Hz,1H),7.55(1H,s),7.62(dd,J=7.6,1.2Hz,1H),7.32(dd,J=7.6,1.2Hz,1H),6.31(d,J=7.6Hz,1 H),6.15(d,J=7.6Hz,1H),4.30(brs,2H),3.57(dd,J=10.8,1.6Hz,1H,),3.42(dd,J=10.8,1.6Hz,1H,),3.05(s,4H),2.66(s,4H),2.44 -2.41(m,6H),2.03-1.87(m,4H),1.73 -1.59(m,5H).

[0632] Example 20: Synthesis of I-79

[0633] Synthesis scheme of I-79

[0634]

[0635] Synthetic X4-308-A-2

[0636]

[0637] To a solution of X4-308-A-3 (4.00 g, 18.52 mmol) and S1 (4.10 g, 27.71 mmol) in a solvent of toluene (36 mL) and water (4 ml) were added K3PO4 (11.80 g, 55.59 mmol), Pd(dppf)Cl2·DCM (1.51 g, 1.85 mmol) and PCy 3( 0.52 g, 1.85 mmol). The mixture was stirred at rt for 28 h and filtered; the filtrate was diluted with water, extracted with EA and concentrated to give the crude product, which was purified by CC to afford X4-308-A-2 (703 mg, 21.43%) as a 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes). Purity: 82.76%. Retention time = 1.51 minutes; MS calculated value: 177.1; MS found value: 178.3 [M+H]+ .

[0638] Synthetic X4-308-A-1

[0639]

[0640] To a solution of X4-308-A-2 (175 mg, 0.99 mmol) in THF (3.5 mL) was added NaBH 4 (150 mg, 3.96 mmol). The mixture was stirred at 70° C. overnight, cooled to room temperature, quenched with cold water, extracted with EA and concentrated to give X4-308-A-1 (120 mg, 81.45%) as a 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes). Purity: 89.49%. Retention time = 1.38 minutes; MS calculated value: 149.1; MS found value: 150.3 [M+H] + .

[0641] Synthetic X4-308-A

[0642]

[0643] To a solution of X4-308-A-1 (550 mg, 3.69 mmol) in DCM (3 ml) was added DMP (1.73 g, 4.08 mmol). The reaction mixture was then stirred at room temperature for 4 hours. After TLC showed that the reaction was complete, the reaction mixture was quenched with NaHCO3 aqueous solution and extracted with DCM. The organic layer was washed with salt water, dried over Na2SO4 and concentrated to give a crude product, which was purified with CC to give X4-308-A (210 mg, 38.70% yield) as a 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes). Purity: 98.67%. Retention time = 1.51 minutes; MS calculated value: 147.1; MS found value: 148.3 [M+H] + .

[0644] Synthesis X4-019-6

[0645]

[0646] To a solution of X4-019-5a (1.7 g, 16.7 mmol) and THF (10 ml) was added n-BuLi (5.6 ml, 14.1 mmol, 2.5 M in hexane) dropwise at -20 ° C. After stirring for 20 minutes at -20 ° C, a slurry of X4-019-5 (1.5 g, 6.7 mmol) in THF (30 ml) was added dropwise at -20 ° C. The mixture was stirred for 7 hours at -10 ° C. After quenching with saturated NH4Cl aqueous solution (pH = 8), the mixture was extracted with DCM / i-PrOH (10 / 1). The organic layer was washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain the product X4-019-6 (785 mg, 48%) as a yellow oil. LC-MS (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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes). Purity: 94.5%, retention time = 1.31 minutes; MS calculated value: 224.13; MS observed value: 245.1 [M+H] + .

[0647] Synthetic X4-014-H

[0648]

[0649] According to General Procedure E, X4-014-H (1.9 g, 41%) was obtained as a yellow foam. LCMS (Agilent LCMS1200-6120, 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes). Purity: 69.13%; Retention time = 1.38 minutes; MS calculated value: 284.4; MS found value: 285.4 [M+H] + .

[0650] Synthetic X4-308-1

[0651]

[0652] X4-308-1 (93 mg, 25.86%) was synthesized by reacting X4-308-A with X4-014-H in the presence of L-proline and methylamine as described above to obtain the desired product 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: 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 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4) water / CH3CN=100 / 900 (v / v)] in 0.1 minute. AcONH4) water / CH3CN = 900 / 100 (v / v)] and 10% [(total 10 mM AcONH4) water / CH3CN = 100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 38.95%. Retention time = 1.66 minutes; MS calculated value: 444.3; MS found value: 445.3 [M+H] + .

[0653] Synthetic I-79

[0654]

[0655] Following General Procedure A, I-79 (12 mg, 13.32%) was obtained as a light 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: 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] (over 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] over 0.1 minutes and continued under this condition for 0.7 minutes). Purity: 100.00%. Retention time = 1.756 min; MS calculated value: 430.3; MS found value: 431.4 [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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 5 minutes). Purity: 98.73%. Retention time = 8.82 minutes. 1 H NMR (400MHz, CDCl3) δ8.49 (s, 1H), 7.51 (s, 1H), 7.33-7.27 (m, 2H), 7.14 (dd, J = 9.0, 7.0Hz, 1H), 7.06 (dd,J=8.0,4.8Hz,1H),6.27(dd,J=7.2,0.8,1H),3.97(d,J=8.4Hz,1H),3.48(dd,J=11.6,2.4Hz,1H) ,3.18-3.14(m,4H),2.77-2.70(m,4H),2.43(s,3H),2.13-2.05(m,3H),1.99-1.94(2H,m),1.89(s,3H ),1.77(d,J=9.2Hz,1H),1.67-1.62(m,2H),1.07-1.00(m,2H),0.72-0.69(m,1H),0.68-0.51(m,1H).

[0656] Example 21: Synthesis of I-146

[0657] Synthesis scheme of I-146

[0658]

[0659] Synthetic X4-438-1

[0660]

[0661] A mixture of X4-014-H (2.5 g, 8.8 mmol), 3-methylpicolinaldehyde (1.1 g, 8.8 mmol), K2CO3 (1.8 g, 13.2 mmol) in toluene (100 ml) / EtOH (40 ml) / H2O (20 ml) was stirred at 80 ° C overnight. After the reaction was complete, the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash silica gel pad (3 cm) using EtOAc: petroleum ether = 1: 1 to DCM / MeOH = 100 / 1 to obtain 2.3 g of X4-438-1 as a yellow foam (yield: 68%), which was used directly in the next step. 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes). Purity: 77.36%; retention time = 1.59 minutes; MS calculated value: 387.2; MS found value: 388.3 [M+H] + .

[0662] Synthetic I-204

[0663]

[0664] To a solution of X4-438-1 (2.3 g, 5.9 mmol) in MeOH (120 ml) was added concentrated NH3 aqueous solution (5 ml, 20%, 59 mmol) at room temperature, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated in vacuo and the residue was purified by flash silica gel pad (3 cm) using DCM / MeOH=60 / 1 to 30 / 1 elution to obtain 1 g of I-204 (yield: 42%) as a yellow foam, which was used directly in the next step. 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes). Purity: 78.15%; retention time = 1.41 minutes; MS calculated value: 404.2; MS found value: 405.4 [M+H] + .

[0665] Synthetic I-187

[0666]

[0667] A mixture of I-204 (1 g, 2.5 mmol), KOH (2.8 g, 50 mmol) and N2H4·H2O (5 g, 100 mmol) in diethylene glycol (30 ml) was stirred at 80°C for 2 hours; then the N2H4·H2O was removed in vacuo while heating to 160°C and stirred at 160°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and quenched with H2O (90 ml) / DCM (120 ml). The resulting mixture was extracted with DCM (120 ml x 3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by CC (eluting with DCM / MeOH) to afford 220 mg (racemic) cis-I-187 (220 mg), 400 mg (racemic) mixture of cis / trans-I-187 (400 mg, trans:cis=4:5), and 270 mg (racemic) trans-I-187 (270 mg). Yield = 91%. 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: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] (within 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] within 0.1 minute and continued under this condition for 0.7 minutes). Cis: purity: 71.18%; retention time = 1.51 minutes; trans: purity: 64.10%; retention time = 1.48 minutes; mixed: purity: 84.07%; MS calculated value: 390.3; MS found value: 391.4 [M+H] + .

[0668] Synthetic X4-440-1

[0669]

[0670] To cis / trans-I-187 (300mg, 0.77mmol) solution in dichloromethane (10mL) add triethylamine (233mg, 2.30mmol) and di-tert-butyl dicarbonate (252mg, 1.15mmol), and mixture is stirred 4 hours at 40 DEG C.After the completion of the reaction, suspension is diluted with water (10mL) and dichloromethane (20mL).The organic layer separated is concentrated under vacuum, and residue is passed through preparation TLC purifying (being eluted with ethyl acetate) to obtain the X4-440-1 (100mg, 27%) that is white 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: 90% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] to 10% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] in 0.1 minute. AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 80.70%, retention time = 2.10 minutes; MS calculated value: 490.3; MS found value: 491.3 [M+H] + .

[0671] Synthetic X4-440-2

[0672]

[0673] Following General Procedure K, X4-440-2 was obtained as a white solid (80 mg, 100%). LCMS (Agilent LCMS1200-6120, 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: 90% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] to 10% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] in 0.1 minute. AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 96.33%, retention time = 2.14 minutes; MS calculated value: 524.3; MS found value: 525.2 [M+H] + .

[0674] Synthetic I-146

[0675]

[0676] Following General Procedure J, I-146 (11 mg, 17%) was obtained as a white 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes). Purity: 97.67%; Retention time = 1.70 min; MS calculated value: 424.2; MS found value: 425.4 [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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 10 minutes), then continued under this condition for 5 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] within 0.1 minutes and continued under this condition for 5 minutes). Purity: 97.60%, retention time = 8.21 minutes; MS calculated value: 424.2; MS found value: 425.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.40 (dd, J=4.8, 1.2Hz, 1H), 7.38 (dd, J=7.2, 1.6Hz, 1H), 7.32 ( dd,J=9.2,1.2Hz,1H),7.08(dd,J=8.8,7.2Hz,1H),7.02(dd,J=8.0,4.8Hz,1H),6.34 (dd,J=7.2,0.8Hz,1H),4.25-4.18(m,2H),3.29-3.25(m,2H),2.96-2.78(m,4H),2.5 3-2.46(m,2H),2.38(s,6H),2.16-2.11(m,1H),1.88-1.80(m,4H),1.72-1.65(m,2H).

[0677] Example 22: Synthesis of I-149, I-188, I-189 and I-205

[0678] Synthetic schemes of I-149, I-188, I-189, and I-205

[0679]

[0680] Synthetic X4-443-1

[0681]

[0682] To a solution of X4-014-H (2.0 g, 7.03 mmol) and X4-014-B (992.6 mg, 7.01 mmol) in toluene / EtOH / H o (5:2:1, 50 mL) was added KCO (1.46 g, 10.56 mmol). The mixture was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the residue was purified by column chromatography to obtain X4-443-1 (2.0 g, 70%) 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes). Purity: 79.84%. Retention time = 1.65 minutes; MS calculated value: 407.2; MS found value: 408.2 [M+H] + .

[0683] Synthetic I-205

[0684]

[0685] To a solution of X4-443-1 (2.0 g, 4.9 mmol) in MeOH (120 mL) is added NH The aqueous solution (20%, 4.2 mL, 49 mmol), and the mixture is stirred at room temperature overnight. The mixture is then concentrated in a vacuum, and the residue is purified by column chromatography to obtain I-205 (600 mg, 29% yield, 65% trans; 25% cis) 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under these conditions for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under these conditions for 0.7 minutes). Purity: 71.43%. Retention time = 1.44 minutes, 1.47 minutes; MS calculated value: 424.2; MS found value: 425.2 [M+H] + .

[0686] Synthesis of I-149, I-188 and I-189

[0687]

[0688] Following general procedure A, 1-149 (30 mg, 22% yield) was obtained as a light yellow solid. The solid was separated by SFC to obtain 1-188 (10 mg) and 1-189 (11 mg). 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: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] (1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes). Purity: 97.24%, retention time = 1.60 min; MS calculated value: 410.2; MS found value: 411.2 [M+H] + HPLC (Agilent HPLC 1200, column: L-column 2ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 90% [(10 mM AcONH4 in total)H2O / MeCN=900 / 100 (v / v)] and 10% [10 mM AcONH4 in total)H2O / MeCN=100 / 900 (v / v)] to 15% [10 mM AcONH4 in total)H2O / MeCN=900 / 100 (v / v)] and 85% [10 mM AcONH4 in total)H2O / MeCN=100 / 900 (v / v)] (within 5 minutes), then continued under this condition for 10 minutes, and finally changed to 90% [(10 mM AcONH4 in total)H2O / MeCN=100 / 900 (v / v)] in 0.1 minute. AcONH4) H2O / MeCN=900 / 100 (v / v)] and 10% [10 mM AcONH4) H2O / MeCN=100 / 900 (v / v) in total] and continued under this condition for 5 minutes). Purity: >99.00%, retention time = 5.63 minutes. 1H NMR (400MHz, CDCl3) δ8.59-8.50 (dd, J=4.8, 1.6Hz, 1H), 7.65-7.63 (m, 1H), 7.51 (s, 1 H),7.32(d,J=8.8Hz,1H),7.17-7.10(m,2H),6.27(dd,J=7.2,0.8Hz,1H),4.52(dd,J =11.2,2.4,1H),4.20-4.17(m,1H),3.14(s,4H),2.66(m,4H),2.40(s,3H),2.23-2.1 9(m,1H),2.15-2.11(m,1H),2.02-1.98(m,1H),1.89-1.77(m,2H),1.61-1.54(m,1H).

[0689] Example 23: Synthesis of I-154 and I-206

[0690] Synthesis scheme of I-154 and I-206

[0691]

[0692] Synthetic X4-449-1

[0693]

[0694] At 0 DEG C, to the solution of X4-027-A (10.0g, 68.42mmol) in dichloromethane (60mL) / water (20mL), fluorine reagent (10.0g, 68.42mmol) and 4-dimethylaminopyridine (10.0g, 68.42mmol) were added in parts, and the mixture was stirred at room temperature overnight. After the completion of the reaction, the suspension was separated and organic matter was concentrated under vacuum. The residue was passed through silica gel purification, eluted with petroleum ether / ethyl acetate 5: 1 to obtain X4-449-1 (6.0g, 54%) as a white 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: 90% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] to 10% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] in 0.1 minute. AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 63.38%, retention time = 0.94 minutes; MS calculated value: 164.0; MS found value: 165.2 [M+H] + .

[0695] Synthetic X4-451-1

[0696]

[0697] A mixture of X4-449-1 (1.3 g, 7.92 mmol) and 1-methylpiperazine (1.6 g, 15.84 mmol) in acetonitrile (10 mL) was stirred at 80 ° C for 1 hour, then diluted with dichloromethane (60 mL) and water (20 mL). The separated organic layer was concentrated under vacuum and then purified on silica gel, eluting with petroleum ether / ethyl acetate 3: 1 to obtain X4-449-1 (1.5 g, 78%) as a light white 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: 90% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] to 10% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] in 0.1 minute. AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 71.35%, retention time = 1.02 minutes; MS calculated value: 244.1; MS found value: 245.3 [M+H] + .

[0698] Synthetic X4-451-2

[0699]

[0700] Following General Procedure E, X4-451-2 was obtained as a yellow solid (580 mg, 33%). LCMS (Agilent LCMS1200-6120, 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: 90% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] to 10% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] in 0.1 minute. AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 93.40%, retention time = 1.27 minutes; MS calculated value: 284.2; MS found value: 285.2 [M+H] + .

[0701] Synthetic X4-451-3

[0702]

[0703] A mixture of X4-451-2 (400 mg, 1.41 mmol), potassium carbonate (293 mg, 2.12 mmol) and 3-methylpicolinaldehyde (188 mg, 1.55 mmol) in toluene (5 mL) / ethanol (2 mL) / water (1 mL) was stirred at 80 ° C. overnight. The mixture was diluted with dichloromethane (30 mL) and water (10 mL), and the separated organics were concentrated under vacuum and purified by flash silica gel column eluting with dichloromethane / methanol 100: 1 to obtain X4-451-3 (500 mg, 92%) 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: 90% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] to 10% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] in 0.1 minute. AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 75.42%, retention time = 1.65 minutes; MS calculated value: 387.2; MS found value: 388.2 [M+H] + .

[0704] Synthetic I-206

[0705]

[0706] A mixture of X4-451-3 (500 mg, 1.29 mmol) and ammonium hydroxide (878 mg, 12.90 mmol, 25% wt) in menthol (25 mL) was stirred at room temperature overnight. After completion of the reaction, the solvent was removed under vacuum, and the residue was purified by silica gel column eluting with dichloromethane / methanol 80:1 to afford I-206 (100 mg, 19%) as a light 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: 90% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] to 10% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] in 0.1 minute. AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 75.12%, retention time = 1.37 minutes; MS calculated value: 404.2; MS found value: 405.2 [M+H] + .

[0707] Synthetic I-154

[0708]

[0709] Following General Procedure A, I-154 (18 mg, 23%) was obtained as a pale white 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (over 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes and continued under this condition for 0.7 minutes). Purity: 99.55%; Retention time = 1.53 minutes; MS calculated value: 390.3; MS found value: 391.3 [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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (within 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] within 0.1 minutes and continued under these conditions for 5 minutes). Purity: 97.86%, retention time = 7.07 minutes. 1 H NMR (400MHz, CDCl3) δ8.40 (dd, J=4.4, 0.8Hz, 1H), 8.04 (d, J=6.8Hz, 1H), 7.49 (d, J=9.2 Hz,1H),7.37(dd,J=7.6,0.8Hz,1H),7.09-7.05(m,1H),7.00(dd,J=8.0,4.8Hz,1H),6.7 3-6.69(m,1H),4.29-4.23(m,1H),4.16-4.11(m,1H),3.43-3.11(m,4H),3.10-2.72(m, 4H),2.41(s,3H),2.36(s,3H),2.14-2.10(m,1H),1.90-1.76(m,4H),1.67-1.59(m,2H).

[0710] Example 24: Synthesis of I-187

[0711] Synthesis scheme of I-187

[0712]

[0713] According to the general procedure A, 30 mg of I-187 was obtained from I-204 (1 g, 2.5 mmol) as a white 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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 1.6 minutes), then continued under this condition for 1.4 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes and continued under this condition for 0.7 minutes). Cis: Purity: 97.37%; Retention time = 1.51 min; MS calculated value: 390.3; MS found value: 391.4 [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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (in 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] within 0.1 minutes and continued under these conditions for 5 minutes). Purity: 90.65%, retention time = 6.95 minutes. 1 H NMR (400MHz, CDCl3) δ8.43 (dd, J=4.8, 1.2Hz, 1H), 7.42 (dd, J=7.2, 1.6Hz, 1H), 7.31 ( d,J=9.2Hz,1H),7.13(dd,J=9.2,7.2Hz,1H),7.05(dd,J=7.6,4.8Hz,1H),6.27(dd,J= 7.2,1.2Hz,1H),4.24-4.21(m,1H),4.18-4.15(m,1H),3.14(s,4H),2.65(s,4H),2.4 0(s,6H),2.25-2.22(m,1H),2.15-2.12(m,1H),1.85-1.76(m,3H),1.72-1.65(m,2H).

[0714] Example 25: Synthesis of I-191

[0715] Synthesis scheme of I-191

[0716]

[0717] Synthetic X4-485-1

[0718]

[0719] A mixture of X4-014-H (1.0 g, 3.52 mmol), potassium carbonate (730 mg, 5.28 mmol) and 3-methylpicolinaldehyde (482 mg, 3.52 mmol) in toluene (25 mL) / ethanol (10 mL) / water (5 mL) was stirred overnight at 80° C. After completion of the reaction, the mixture was diluted with dichloromethane (50 mL) and water (10 mL), and the separated organics were concentrated under vacuum and purified by flash silica gel pad (3 cm) eluting with dichloromethane / methanol 80: 1 to afford X4-485-1 (1.0 g, 70%) 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: 90% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] to 10% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] in 0.1 minute. AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 82.63%, retention time = 1.67 minutes; MS calculated value: 403.2; MS found value: 404.2 [M+H] + .

[0720] Synthetic X4-485-2

[0721]

[0722] A mixture of X4-485-1 (1.0 g, 2.48 mmol) and ammonium hydroxide (1.7 g, 24.78 mmol, 25% wt) in methanol (50 mL) was stirred at room temperature overnight. After completion of the reaction, the organic layer was concentrated and purified by silica gel column chromatography using dichloromethane / methanol 50:1 elution to obtain X4-485-2 (600 mg, 58%) as a light yellow oil. LCMS (Agilent LCMS1200-6120, 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: 90% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] to 10% [(total 10 mM AcONH4)H2O / MeCN=900 / 100 (v / v)] and 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] (in 1.6 minutes), then continued under this condition for 2.4 minutes, and finally changed to 90% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] in 0.1 minute. AcONH4)H2O / MeCN=900 / 100 (v / v)] and 10% [(total 10 mM AcONH4)H2O / MeCN=100 / 900 (v / v)] and continued under this condition for 0.7 minutes. Purity: 82.42%, retention time = 1.35 minutes; MS calculated value: 420.2; MS found value: 421.3 [M+H] + .

[0723] Synthetic I-191

[0724]

[0725] Following general procedure A, 1-191 was obtained as a yellow solid (impure, 280 mg, 48%), and 140 mg was purified by preparative HPLC to obtain pure 1-191 (80 mg). 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: 90% [water+10 mM NH4HCO3] and 10% [CH3CN] to 5% [water+10 mM NH4HCO3] and 95% [CH3CN] (in 0.5 min), then continued under this condition for 1.5 min, and finally changed to 90% [water+10 mM NH4HCO3] and 10% [CH3CN] within 0.1 min and continued under this condition for 0.7 min. Purity: 100.00%; retention time = 1.08 min; MS calculated value: 406.2; MS found value: 407.1 [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: 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] (within 10 minutes), then continued under these conditions for 5 minutes, and finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] within 0.1 minutes and continued under these conditions for 5 minutes). Purity: 92.84%, retention time = 6.85 minutes; MS calculated value: 406.2; MS found value: 407.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.18 (t, J=6.0Hz, 1H). 7.53(s,1H),7.31(d,J=9.2Hz,1H),7.15-7.11(m,3H),6.26(dd,J=7.2,0.8Hz,1H),4.46(dd,J=1.6,1.2Hz,1H),4.19(d,J=10.0Hz,1H),3.85( s,3H),3.13(s,4H),2.65(s,4H),2.39(s,3H),2.24-2.20(m,1H),2.11 -2.07(m,1H),1.95-1.92(m,1H),1.86-1.76(m,3H),1.70-1.63(m,1H).

[0726] Example 26: Synthesis of Additional Exemplary Compounds

[0727] Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided below.

[0728] Table 2: Characterization Data of Additional Exemplary Compounds

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773] Example 27: Synthesis of I-207

[0774] Synthesis scheme of I-207

[0775]

[0776] Synthetic X4-618-9

[0777]

[0778] To a solution of X4-618-7 (2.0 g, 7.4 mmol), X4-618-8 (1.4 g, 11.3 mmol), CsCO (4.8 g, 14.7 mmol) in 1,2-dimethoxyethane / HO (40 mL / 8 mL) was added (Cy)P (416.1 mg, 1.5 mmol) and Pd(dppf)Cl CHCl (606.2 mg, 0.7 mmol) under a N atmosphere. The solution was then stirred at 95 ° C overnight and the mixture was cooled to room temperature, filtered and extracted with DCM (40 mL × 3). The combined organic layer was washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain X4-618-9 (1.0 g, yield: 50%) 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: 90% [water+10 mM NH4HCO3] and 10% [CH3CN] to 5% [water+10 mM NH4HCO3] and 95% [CH3CN] (over 0.5 min), then continued under these conditions for 1.5 min, and finally changed to 90% [water+10 mM NH4HCO3] and 10% [CH3CN] over 0.1 min and continued under these conditions for 0.5 min). Purity: 88.73%, retention time = 0.78 min; MS calculated value: 267.3; MS found value: 268.2 [M+H] + .

[0779] Synthetic X4-618-10

[0780]

[0781] To a solution of X4-618-9 (300 mg, 1.1 mmol), ethyl acetate (593.3 mg, 6.7 mmol) in THF (5 mL) was added LiHMDS (1 M in THF, 3.4 mL, 3.4 mmol) and stirred at room temperature overnight. The reactant was quenched with 2M HCl (50 mL) solution and washed with MTBE (3 × 10 mL). The pH was then adjusted to 9 with 40% NaOH (aqueous solution) and extracted with DCM (3 × 10 mL). The combined organic layer was washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain X4-619-10 (300 mg, yield: 86%) as a brown oil, which was used in the next step without further purification. 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: 90% [water+10 mM NH4HCO3] and 10% [CH3CN] to 5% [water+10 mM NH4HCO3] and 95% [CH3CN] (over 0.5 min), then continued under these conditions for 1.5 min, and finally changed to 90% [water+10 mM NH4HCO3] and 10% [CH3CN] over 0.1 min and continued under these conditions for 0.5 min). Purity: 90.84%, retention time = 0.87 min; MS calculated value: 309.3; MS found value: 310.2 [M+H] + .

[0782] Synthetic X4-618-11

[0783]

[0784] To a solution of X4-618-10 (200 mg, 0.6 mmol) and KCO (82.8 mg, 0.6 mmol) in CHCN (10 ml) was added X4-618-3 (147 mg, 1.0 mmol) under Ar protection. The mixture was stirred at room temperature overnight. The mixture was then poured into water (30 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous NaSO, filtered and concentrated in vacuo to obtain X4-619-11 (90 mg, yield: 30%) as a brown oil, which was used in the next step without further purification. 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: 90% [water+10 mM NH4HCO3] and 10% [CH3CN] to 5% [water+10 mM NH4HCO3] and 95% [CH3CN] (over 0.5 min), then continued under these conditions for 1.5 min, and finally changed to 90% [water+10 mM NH4HCO3] and 10% [CH3CN] over 0.1 min and continued under these conditions for 0.5 min). Purity: 75.81%, retention time = 1.04 min; MS calculated value: 456.3; MS found value: 457.2 [M+H] + .

[0785] Synthetic X4-618-12

[0786]

[0787] At 100 ° C, a solution of X4-618-11 (90 mg, 0.2 mmol) in concentrated HCl solution (2 mL) was stirred for 2 hours. It was then concentrated in vacuo. The residue was dissolved in H2O (10 mL), neutralized with 20% NaOH aqueous solution to adjust to pH>9, and extracted with DCM (3 × 10 mL). The combined organic layer was washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain the crude X4-619-12 (70 mg, yield: 92%) in a brown semi-solid, which was used in the next s...

Claims

1. A compound comprising formula I: or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer or primary immunodeficiency disease or condition, characterized in that The composition is administered to a patient in need thereof, wherein: Ring A is pyridyl; Each R 1 are independently hydrogen, C 1-6 aliphatic, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 2 nitrogen atoms, halogen, -CN, -OR, -N(R)2, -SR or -L 1 -R 6 ; Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; a phenyl group; an 8- to 10-membered bicyclic aromatic carbocycle; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L 1 Is a covalent bond or C 1-6 a divalent linear or branched hydrocarbon chain wherein one, two or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -N(R)-, -S-, S(O), -S(O)2-, -SON(R)-, -(R)NSO2- or -Cy-; L 2 Is a covalent bond or C 1-6 a divalent linear or branched hydrocarbon chain wherein 1, 2 or 3 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -S-, S(O), -S(O)2-, -SO2N(R)-, -(R)NSO2- or -Cy-; each -Cy- is independently a divalent optionally substituted phenylene; an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 2 is hydrogen, halogen, -CN, -OR, -N(R)2, -L 2 -R 6 or C optionally substituted with 1, 2 or 3 halogen, -CN, -N(R)2 or -OR groups 1-6 aliphatic; R 3 is hydrogen or C 1-6 straight or branched aliphatic chain; Each R 4 are independently hydrogen, deuterium, halogen, -CN, -OR 6 or C 1-4 Alkyl, or two R on the same carbon 4 The groups are optionally taken together to form =O or =S; Each R 5 are independently hydrogen, C 1-6 Alkyl, halogen, -CN, -OCF3, cyclopropyl, ethynyl, -OCH3, -CF3, -CD3 or Each R 6 is independently hydrogen or C optionally substituted by 1, 2, 3, 4, 5 or 6 deuterium or halogen atoms 1-6 alkyl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; and p is 0, 1, 2, 3, or 4.

2. The use according to claim 1, wherein ring A is 3. The method according to claim 2, wherein R 1 is selected from hydrogen, halogen, C optionally substituted by 1, 2 or 3 halogens 1-6 Alkyl, -CN, -N(R)2, -OR, -SR, -S(O)R 6 、-SO2R 6 、-SO2NHR 6 、 and each R is independently hydrogen, -CH2-phenyl, phenyl, C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2 or -CH2CF3.

4. The use according to claim 3, wherein R 1 yes 5. The method according to claim 1, wherein -Cy- is 6. The use according to claim 2, wherein R 2 is selected from hydrogen, halogen, -CN, -OR, -N(R)2, C optionally substituted by 1, 2 or 3 halogens 1-6 Alkyl, C 2-6 Alkynyl, -S(O)R 6 、-SO2R 6 、-SO2NHR 6 、-(CH2) 1-6 -N(R)R 6 、-(CH2) 1-6 -OR 6 or -(CH2) 0-6 -Cy-R 6 ; and each R is independently hydrogen, -CH2-phenyl, phenyl, C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2 or -CH2CF3.

7. The use according to claim 2, wherein R 2 Selected from hydrogen, halogen, -OR, -N(R)2, -S(O)R 6 、-SO2R 6 、-SO2NHR 6 、-(CH2) 1-6 -N(R)R 6 、-(CH2) 1-6 -OR 6 、 and each R is independently hydrogen, -CH2-phenyl, phenyl, C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2 or -CH2CF3.

8. The use according to claim 3, wherein R 2 It is hydrogen, -NH2, C 2-4 Alkynyl, F, Cl, Br, -CH2OH or I.

9. The use according to claim 3, wherein R 2 It is hydrogen or -CH2OH.

10. The use according to claim 3, wherein R 3 Is H or C 1-4 alkyl.

11. The use according to claim 3, wherein R 3 It's methyl.

12. The use according to claim 3, wherein R 4 is hydrogen, deuterium, halogen, -CN or C 1-2 alkyl.

13. The use according to claim 3, wherein R 4 It's hydrogen.

14. The use according to claim 3, wherein R 5 It is hydrogen, C 1-6 Alkyl, halogen, -OCF3, cyclopropyl, ethynyl, -OCH3, -CF3 or -CD3.

15. The use according to claim 3, wherein R 5 It's methyl.

16. The use according to claim 1, wherein the compound has formula VI:

17. The use according to claim 1, wherein the compound has the formula VII:

18. The use according to claim 1, wherein the compound has the formula VIII-a or VIII-b:

19. The use according to claim 1, wherein the compound has the formula IX:

20. The use according to claim 1, wherein the compound has the formula Xa, Xb, Xc, Xd or Xe:

21. The use according to claim 1, wherein the compound has the formula XI:

22. The use according to claim 1, wherein the compound has the formula VIII-a or VIII-b:

23. The use according to claim 1, wherein the compound has the formula XIV-a, XIV-b or XIV-c:

24. The use according to claim 1, wherein the compound is selected from one of the following: or a pharmaceutically acceptable salt thereof.

25. The method of claim 1 , wherein the cancer is selected from the group consisting of glioma, glioblastoma multiforme, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma, characterized in that the composition is administered to a patient in need thereof.

26. The use according to any one of claims 1-24, wherein the cancer is selected from the group consisting of: astrocytoma, chordoma, CNS lymphoma, brain stem glioma, mixed glioma, optic nerve glioma, subependymoma, metastatic brain tumor, pituitary tumor, and primitive neuroectodermal tumor, characterized in that the composition is administered to a patient in need thereof.

27. The use according to claim 26, wherein the astrocytoma is grade I - pilocytic astrocytoma, grade II - low-grade astrocytoma, grade III - anaplastic astrocytoma or grade IV - glioblastoma.

28. The use according to any one of claims 1-24, wherein the cancer is selected from the group consisting of juvenile pilocytic astrocytoma, pineal tumor, and rhabdoid tumor, characterized in that the composition is administered to a patient in need thereof.

29. The method of any one of claims 1-24, wherein the cancer is selected from the group consisting of leukemia, polycythemia vera, Hodgkin's disease, non-Hodgkin's disease, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and large B-cell lymphoma, characterized in that the composition is administered to a patient in need thereof.

30. The use according to claim 29, wherein the leukemia is selected from the group consisting of acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute granulocytic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, acute myeloid leukemia, adult T-cell leukemia, and chronic lymphocytic leukemia.

31. The use according to claim 1, wherein the primary immunodeficiency disease or condition is selected from the group consisting of: warts, hypogammaglobulinemia, infection, congenital myelocytic syndrome; severe congenital neutropenia and Wiskott-Aldrich syndrome, characterized in that the composition is administered to a patient in need thereof.

32. The use according to claim 1, wherein the primary immunodeficiency disease or condition is selected from those symptoms caused by the group consisting of: G6PC3 deficiency, GATA2 deficiency, idiopathic CD4+ T lymphocytopenia.

33. Use according to claim 32, wherein the primary immunodeficiency disease or condition is warts, hypogammaglobulinemia, infection, congenital myelopathy syndrome.

34. The use according to any one of claims 1-24 and 31-33, wherein the patient is an adult.

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