Piperidinyl-methyl-purinamine D-tartrate, crystalline forms, and their uses in treating medical diseases and conditions

Abstract

The present invention provides piperidinyl-methyl-purinamine D-tartrate salts, crystalline forms, pharmaceutical compositions, their use in inhibiting NSD2, and their use in treating diseases or conditions such as cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 343,225, filed May 18, 2022, which is incorporated by reference herein in its entirety.

[0002] FIELD OF THEINVENTION The present invention provides piperidinyl-methyl-purinamine D-tartrate salts, crystalline forms, pharmaceutical compositions, their use in inhibiting NSD2, and their use in treating diseases or conditions such as cancer. [Background technology]

[0003] Cancer remains a major health problem, despite the extensive research efforts and scientific advances reported in the literature to treat this disease. Solid tumors, including prostate, breast, and lung cancer, remain widespread among the world's population. Current treatment options for these cancers may not be effective for all patients and / or may have significant adverse side effects. New therapies are needed to address this unmet need in cancer therapy.

[0004] Nuclear receptor-binding SET domain protein 2 (NSD2), also known as multiple myeloma SET domain (MMSET) or Wolf-Hirschhorn syndrome candidate 1 (WHSC1), is an epigenetic modifier with a role in cancer development. Several human cancers are associated with NSD2 overexpression and / or activating point mutations. (Coussens et al., J. Biol. Chem. 293 (2018) 13750-13654.) For example, high expression of NSD2 has been reported in human cancers, including bladder, brain, gastrointestinal, lung, liver, ovary, skin, uterus, breast, prostate, and glioblastoma. Additionally, pediatric cancer genomes appear to be particularly likely to contain NSD2 mutations. Finally, upregulation of NSD2 is associated with aggressive tumor behavior and poor clinical outcomes. Certain compounds that inhibit NSD2 are described in International Patent Application Publication No. WO2021 / 028854. Additional compounds that inhibit NSD2 would be beneficial to patients suffering from an NSD2-related disease or condition.

[0005] The present invention addresses the above-mentioned needs and provides other related advantages. Summary of the Invention

[0006] The present invention provides piperidinyl-methyl-purinamine D-tartrate salts, crystalline forms, pharmaceutical compositions, their use in inhibiting NSD2, and their use in treating diseases or conditions, such as cancer. In particular, one aspect of the invention provides compounds that are D-tartrate salts of the following compounds: [ka] In certain embodiments, the compound is in crystalline form.One advantage of the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol is that it has low hygroscopicity. In contrast to the fumarate, sulfate, hydrochloride, and various other salts of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol, which were observed to form hydrates, the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol can be obtained in anhydrous form and had low hygroscopicity in long-term stability studies. Another advantage of the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol is that it is, for example, The main feature of the present invention is that it exhibits a higher solubility in water than either (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethane-1-fumarate salt or (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethane-1-fumarate salt.Yet another advantage of the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol is that it exhibited very good stability to long-term storage, exhibiting high purity after storage in a one-year stability study and no detectable loss of crystallinity as measured by XRPD analysis. Further description of additional characteristics of the compound are described in the detailed description. The compound can be part of a pharmaceutical composition that includes a pharma- ceutical acceptable carrier.

[0007] Another aspect of the present invention provides a method for treating a disease or condition mediated by nuclear SET domain-containing protein 2 (NSD2). The method includes administering a therapeutically effective amount of a compound described herein, such as the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol, to a subject in need thereof to treat the disease or condition.

[0008] Another aspect of the present invention provides a method for inhibiting the activity of nuclear SET domain-containing protein 2 (NSD2), comprising contacting NSD2 with an effective amount of a compound described herein, such as the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol, to inhibit the activity of the NSD2. [Brief description of the drawings]

[0009] [Figure 1]FIG. 1 depicts the X-ray powder diffraction diagram of one batch of crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate, as further described in Example 4.

[0010] [Diagram 2] FIG. 1 depicts the X-ray powder diffraction diagram of a second batch of crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate, as further described in Example 4.

[0011] [Diagram 3] As further described in Example 4, the thermogravimetric and differential scanning calorimetry curves of crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate are depicted.

[0012] [Figure 4] As further described in Example 4, the differential scanning calorimetry curve of crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate is depicted.

[0013] [Diagram 5]FIG. 1 depicts the results of a dynamic vapor sorption experiment performed on crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate, as further described in Example 4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present invention provides piperidinyl-methyl-purinamine D-tartrate salts, crystalline forms, pharmaceutical compositions, their use in inhibiting NSD2, and their use in treating diseases or conditions such as cancer. One such piperidinyl-methyl-purinamine D-tartrate salt is the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol. One advantage of the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol is that it has low hygroscopicity. In contrast to the fumarate, sulfate, hydrochloride, and various other salts of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol, which were observed to form hydrates, the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol can be obtained in anhydrous form and had low hygroscopicity in long-term stability studies.Another advantage of the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol is that it is, for example, The main feature of the present invention is that it exhibits a higher solubility in water than either (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethane-1-fumarate salt or (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethane-1-fumarate salt. Yet another advantage of the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol is that it has demonstrated very good stability to long term storage, exhibiting high purity after storage in a one year stability study and no detectable loss of crystallinity as measured by XRPD analysis. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in references such as "Comprehensive Organic Synthesis" (BM Trost & I. Fleming, eds., 1991-1992), "Handbook of experimental immunology" (DM Weir & CC Blackwell, eds.), "Current protocols in molecular biology" (FM Ausubel et al., eds., 1987, and periodically updated), and "Current protocols in immunology" (JE Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety.

[0015] Various aspects of the invention are described in the following sections, however, an aspect of the invention described in a particular section is not limited to any particular section. Further, if a variable is not accompanied by a definition, the previous definition of the variable takes precedence.

[0016] definition The compounds of the present invention include those generally described herein and are further illustrated into the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply whether a term is used alone or in combination with other terms, unless otherwise indicated. Thus, the definition of "alkyl" applies to the "alkyl" portion of "alkyl" and "-O-alkyl". For purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., both of which are incorporated herein by reference in their entireties. th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0017] The term "aliphatic" or "aliphatic group," as used herein, refers to a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "alicyclic"), and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" refers to a monocyclic C group that is fully saturated or contains one or more unsaturated units, but is not aromatic, and has a single point of attachment to the remainder of the molecule. 3 ~C 6 Refers to a hydrocarbon. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0018] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated, or having one or more unsaturated units, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho- or spiro-fused. As used herein, the term "heterobicyclic" is a subset of "bicyclic", requiring that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at the junctions of the rings, may be optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and the like. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain or valence bond of atom(s) connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, where each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more of the substituents described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.

[0019] The term "lower alkyl" means C 1~4It refers to a straight or branched chain alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0020] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1~4 It refers to a straight or branched chain alkyl group.

[0021] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including as in N-substituted pyrrolidinyl) is meant one or more of the following:

[0022] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0023] As used herein, "divalent C 1~8 (or C 1~6 The term "saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, which are straight or branched, as defined herein.

[0024] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH 2 ) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0025] "-(C 0The term "-(C alkylene)-" refers to a bond. 0~3 The term "alkylene)-" refers to a bond (i.e., C 0 ) and -(C 1~3 alkylene)-groups.

[0026] The term "halogen" means F, Cl, Br, or I.

[0027] The term "aryl," used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic and 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 invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0028] The terms "heteroaryl" and "heteroar-", e.g., "heteroaralkyl" or "heteroaralkoxy", used alone or as part of a larger moiety, refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, with 6, 10, or 14 pi-electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, quinolinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. 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 terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions are independently optionally substituted.

[0029] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocycle" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or . + It may be NR (as in N-substituted pyrrolidinyl).

[0030] A heterocycle may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions are independently optionally substituted.

[0031] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0032] As described herein, the compounds of the invention may include "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. The combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0033] Each optional substituent on a substitutable carbon is independently selected from halogen, -(CH 2 ) 0~4 R°, -(CH 2 ) 0~4 OR°, -O(CH 2 ) 0~4 R o , -O-(CH 2 ) 0~4 C(O)OR°, -(CH 2 ) 0~4 CH(OR°) 2 , -(CH 2 ) 0~4 SR°, R° may be substituted -(CH2 ) 0~4 Ph, R° may be substituted with -(CH 2 ) 0~4 O(CH 2 ) 0~1 Ph, R° may be substituted with -CH=CHPh, R° may be substituted with -(CH 2 ) 0~4 O(CH 2 ) 0~1 -Pyridyl, -NO 2 , -CN, -N 3 , -(CH 2 ) 0~4 N(R°) 2 , -(CH 2 ) 0~4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH 2 ) 0~4 N(R°)C(O)NR° 2 , -N(R°)C(S)NR° 2 , -(CH 2 ) 0~4 N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR° 2 , -N(R°)N(R°)C(O)OR°, -(CH 2 ) 0~4 C(O)R°, -C(S)R°, -(CH 2 ) 0~4 C(O)OR°, -(CH 2 ) 0~4 C(O)SR°, -(CH 2 ) 0~4 C(O)OSiR° 3 , -(CH 2 ) 0~4 OC(O)R°, -OC(O)(CH 2 ) 0~4 SR-, SC(S)SR°, -(CH 2 ) 0~4 SC(O)R°, -(CH 2 ) 0~4 C(O)NR° 2 , -C(S)NR° 2 , -C(S)SR°, -(CH 2 ) 0~4 OC(O)NR° 2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH 2 C(O)R°, -C(NOR°)R°, -(CH 2 ) 0~4 SSR°, -(CH 2 ) 0~4 S(O) 2 R°, -(CH 2 ) 0~4 S(O) 2 OR°, -(CH 2 ) 0~4 OS(O) 2 R°, -S(O) 2 NR° 2 , -S(O)(NR°)R°, -S(O) 2 N = C(NR° 2 ) 2 , -(CH 2 ) 0~4 S(O)R°, -N(R°)S(O) 2 NR° 2 , -N(R°)S(O) 2 R°, -N(OR°)R°, -C(NH)NR° 2 , -P(O) 2 R°, -P(O)R° 2 , -OP(O)R° 2 , -OP(O)(OR°) 2 , SiR° 3 , -(C 1~4 Linear or branched alkylene)ON(R°) 2 , or -(C 1~4 Linear or branched alkylene)C(O)ON(R°) 2 is selected from.

[0034] Each R° is independently hydrogen, C 1~6 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, -CH 2-(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or notwithstanding the above definition, two independent occurrences of R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which heteroatoms may be substituted by divalent substituents on a saturated carbon atom of R° selected from =O and =S; or each R° is independently selected from halogen, -(CH 2 ) 0~2 R ●λ , -(Halo R ● ), -(CH 2 ) 0~2 OH, -(CH 2 ) 0~2 OR ● , -(CH 2 ) 0~2 CH(OR ● ) 2 , -O(HaloR ● ), -CN, -N 3 , -(CH 2 ) 0~2 C(O)R ● , -(CH 2 ) 0~2 C(O)OH, -(CH 2 ) 0~2 C(O)OR ● , -(CH 2 ) 0~2 S.R. ● , -(CH 2 ) 0~2 SH, -(CH 2 ) 0~2 NH 2 , -(CH 2 ) 0~2 NHR ● , -(CH 2 ) 0~2 NR ● 2 , -NO 2 , -SiR ● 3 , -OSiR ● 3 , -C(O)SR● , -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● is optionally substituted with a monovalent substituent selected from

[0035] Each R ● is independently 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by halo, is substituted only with one or more halogens, or the optional substituents on the saturated carbons are independently: =O, =S, =NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R * , =NR * , =NOR * , -O(C(R * 2 )) 2~3 O- or -S(C(R * 2 )) 2~3 S- or a divalent substituent attached to a vicinal substitutable carbon of an "optionally substituted" group is selected from -O(CR * 2 ) 2~3 O- and R * Each independent occurrence of is hydrogen, C 1~6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] R * C 1~6 If aliphatic, R * is halogen, -R ●, -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 wherein each R ● is independently 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by halo, is substituted only with one or more halogens.

[0037] The optional substituents on a substitutable nitrogen are independently -R † , -NR † 2 , -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH 2 C(O)R † , -S(O) 2 R † , -S(O) 2 NR † 2 , -C(S)NR † 2 , -C(NH)NR † 2 , or -N(R † )S(O) 2 R † where each R † are independently hydrogen, C 1~6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R †two independent occurrences of together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; † C 1~6 If aliphatic, R † is halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 wherein each R ● is independently 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by halo, is substituted only with one or more halogens.

[0038] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are described in the literature. For example, S. M. Berge et al. describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of compounds can include those derived from suitable inorganic and organic acids and bases.

[0039] Unless otherwise specified, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, 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 specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the structures of the invention that include the replacement of a carbon with a C-enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention.

[0040] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods known to those skilled in the art, such as, for example, chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., hydrolysis). Alternatively, a specific enantiomer of a compound of the present invention can be prepared by asymmetric synthesis. Still further, if the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid), a diastereomeric salt can be formed with a suitable optically active acid or base, followed by separation of the diastereoisomers thus formed by fractional recrystallization or chromatographic means known in the art, and then the pure enantiomers are recovered.

[0041] The individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may be, for example, as racemates or mixed with all other stereoisomers or other selected stereoisomers.The chiral center(s) in the compounds of the present invention may have the S or R configuration as defined by IUPAC 1974 Recommendations.Furthermore, to the extent that the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered as part of the present invention.

[0042] Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure.When a chemical compound is referred to using both a chemical structure and a chemical name, and there is ambiguity between the structure and the name, the structure takes precedence.It should also be noted that any carbon and heteroatom with unsatisfied valences in the text, schemes, examples, and tables of this specification is assumed to have a sufficient number of hydrogen atoms (multiple) to satisfy the valences.

[0043] As used herein, the terms "a" and "an" mean "one or more" and include plurals unless the context is inappropriate.

[0044] Unless otherwise specified, the term "about" refers to within ±10% of the stated value. The invention includes embodiments where a value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0045] The term "alkyl" as used herein means any of the following: 1~ C 12 Alkyl, C 1~ C 10 Alkyl, and C 1~ C 6It refers to saturated straight or branched chain hydrocarbons, such as straight or branched groups of 1 to 12, 1 to 10, or 1 to 6 carbon atoms, referred to as alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0046] The term "cycloalkyl" is used herein to refer to, for example, "C" derived from cycloalkane. 3~ C 6 The term "cycloalkylene" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon radical of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, commonly referred to as "cycloalkyl." Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0047] The term "haloalkyl" refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 The term "haloalkylene" refers to a divalent haloalkyl group.

[0048] The term "hydroxyalkyl" refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2 CH 2 OH, -C(H)(OH)CH 3 , -CH 2 C(H)(OH)CH 2 CH 2 OH, etc.

[0049] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0050] The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. The term "haloalkoxyl" refers to an alkoxyl group substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -OCF 2 CF 3 etc.

[0051] The term "oxo" is art-recognized to refer to a "=O" substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0052] symbol [ka] indicates the point of attachment.

[0053] When any substituent or variable occurs more than one time in any constituent or compound of the present invention, unless otherwise stated, its definition on each occurrence is independent of its definition at every other occurrence.

[0054] One or more compounds of the present invention may exist in unsolvated and solvated forms with pharma- ceutically acceptable solvents such as water, and the present invention is intended to include both solvated and unsolvated forms. "Solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolatable solvates. "Hydrate" refers to a solvate in which the solvent molecules are H 2 O, a solvate.

[0055] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably, humans.

[0056] "I C 50 The term "concentration of a compound required to achieve 50% inhibition of a target" is art-recognized and refers to the concentration of a compound required to achieve 50% inhibition of a target.

[0057] As used herein, the term "effective amount" refers to an amount of a compound sufficient to achieve a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., such as alleviating, reducing, modulating, ameliorating, or eliminating, or relieving the symptoms thereof.

[0058] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0059] As used herein, the term "pharmaceutical acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions, etc.), and various types of wetting agents. The composition may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0060] For therapeutic use, the salts of the compounds of the invention are contemplated as pharma- ceutically acceptable. However, salts of acids and bases that are non-pharma-ceutically acceptable may also find use, for example, in the preparation or purification of a pharma-ceutically acceptable compound.

[0061] Throughout this specification, when compositions are described as having, including, or comprising specific components, or processes and methods are described as having, including, or comprising specific steps, it is additionally contemplated that there are compositions of the invention that consist essentially of or consist of the recited components, and that there are processes and methods of the invention that consist essentially of or consist of the recited processing steps.

[0062] Generally, compositions that specify percentages are by weight unless otherwise specified.

[0063] I. D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol The present invention provides a D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol. One advantage of the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol is that it has low hygroscopicity. In contrast to the fumarate, sulfate, hydrochloride, and various other salts of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol, which were observed to form hydrates, the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol can be obtained in anhydrous form and had low hygroscopicity in long-term stability studies. Another advantage of the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol is that it is, for example, The main feature of the present invention is that it exhibits a higher solubility in water than either (S)-1-(((R)-3-amino-1-(4-(6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethane-1-fumarate salt or (S)-1-(((R)-3-amino-1-(4-(6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethane-1-fumarate salt.Yet another advantage of the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol is that it exhibited very good stability to long-term storage, exhibited high purity after storage in a one-year stability study, and showed no detectable loss of crystallinity as measured by XRPD analysis. The compounds are described in more detail below. The compounds can be used in the pharmaceutical compositions and methods of treatment described herein. Exemplary compounds are described in the following sections. Exemplary procedures for making the compounds are described in the Examples.

[0064] One aspect of the present invention provides a compound which is the D-tartrate salt of the following compound: [ka]

[0065] In certain embodiments, the molar ratio of D-tartaric acid to the following compound is about 1:1: [ka]

[0066] In certain embodiments, the compound is in a crystalline form.

[0067] In certain embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 6.0±0.2, 8.8±0.2, 10.6±0.2, 10.9±0.2, 15.9±0.2, 20.9±0.2, and 23.9±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angles (2θ): 15.1±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angles (2θ): 17.7±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angles (2θ): 19.0±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angles (2θ): 21.4±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angles (2θ): 22.7±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at the following diffraction angles (2θ): 24.3±0.2.

[0068] In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 30%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 20%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 15%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 10%.

[0069] In certain embodiments, the crystalline form is characterized by the following X-ray powder diffraction pattern, expressed in terms of diffraction angles 2θ, interplanar distance d, and relative intensities (expressed as a percentage relative to the most intense peak): [Table 1-1] [Table 1-2]

[0070] In certain embodiments, the crystalline form is characterized as having an X-ray powder diffraction pattern substantially as shown in FIG.

[0071] In certain embodiments, the crystalline form is characterized by the following X-ray powder diffraction pattern, expressed in terms of diffraction angles 2θ, interplanar distance d, and relative intensities (expressed as a percentage relative to the most intense peak): [Table 2-1] [Table 2-2]

[0072] In certain embodiments, the crystalline form is characterized as having an X-ray powder diffraction pattern substantially as shown in FIG.

[0073] The X-ray powder diffraction pattern may be obtained using CuKα radiation. The temperature at which the X-ray powder diffraction pattern is obtained may be, for example, 25±2 degrees Celsius.

[0074] In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry in the range of about 225 degrees Celsius to about 240 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 233 degrees Celsius. In certain embodiments, the compound has a melting point peak as determined by differential scanning calorimetry in the range of about 235 degrees Celsius to about 250 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 241 degrees Celsius. In certain embodiments, the compound has a differential scanning calorimetry curve substantially the same as that shown in FIG. 4.

[0075] In certain embodiments, the compound is further characterized by an increase in weight of the compound of 10% or less when placed in an atmosphere that transitions from 5% to 95% relative humidity in a dynamic vapor sorption procedure. In certain embodiments, the compound is further characterized by an increase in weight of the compound of 5% or less when placed in an atmosphere that transitions from 5% to 95% relative humidity in a dynamic vapor sorption procedure. In certain embodiments, the compound has a sorption isotherm substantially the same as that shown in FIG. 5.

[0076] The above description describes several embodiments of the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol. The present patent application specifically contemplates all combinations of embodiments.

[0077] II. Therapeutic Uses of the D-Tartrate Salt of (S)-1-((R)-3-Amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol The compounds described herein, such as (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate described in Section I, provide therapeutic benefit to subjects suffering from cancer and other diseases or conditions. Thus, one aspect of the invention provides a method for treating a disease or condition mediated by nuclear SET domain containing protein 2 (NSD2). The method includes administering a therapeutically effective amount of a compound described herein, such as (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate, to a subject in need thereof to treat the disease or condition. In certain embodiments, the specific compound is a compound defined by one of the embodiments described above.

[0078] Examples of diseases or conditions mediated by NSD2 include, but are not limited to, breast cancer, cervical cancer, skin cancer (particularly cutaneous squamous cell carcinoma), ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia (particularly acute lymphoblastic leukemia), non-Hodgkin's lymphoma (particularly mantle cell lymphoma), and pulmonary arterial hypertension.

[0079] In certain embodiments, the NSD2-mediated disease or condition is cancer.

[0080] In certain embodiments, the NSD2-mediated disease or condition is selected from solid tumors, leukemia, myeloma, lymphoma, and hypertension. In certain embodiments, the NSD2-mediated disease or condition is a solid tumor. In certain embodiments, the NSD2-mediated disease or condition is selected from leukemia, myeloma, and lymphoma. In certain embodiments, the NSD2-mediated disease or condition is leukemia. In certain embodiments, the NSD2-mediated disease or condition is myeloma. In certain embodiments, the NSD2-mediated disease or condition is lymphoma. In certain embodiments, the NSD2-mediated disease or condition is hypertension.

[0081] In certain embodiments, the disease or condition mediated by NSD2 is breast cancer, cervical cancer, skin cancer, ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia, non-Hodgkin's lymphoma, or pulmonary arterial hypertension. In certain embodiments, the disease or condition mediated by NSD2 is breast cancer. In certain embodiments, the disease or condition mediated by NSD2 is cervical cancer. In certain embodiments, the disease or condition mediated by NSD2 is ovarian cancer. In certain embodiments, the disease or condition mediated by NSD2 is gastric cancer. In certain embodiments, the disease or condition mediated by NSD2 is prostate cancer. In certain embodiments, the disease or condition mediated by NSD2 is pancreatic cancer. In certain embodiments, the disease or condition mediated by NSD2 is hepatocellular carcinoma. In certain embodiments, the disease or condition mediated by NSD2 is head and neck cancer. In certain embodiments, the disease or condition mediated by NSD2 is peripheral nerve sheath tumor. In certain embodiments, the disease or condition mediated by NSD2 is osteosarcoma. In certain embodiments, the disease or condition mediated by NSD2 is multiple myeloma. In certain embodiments, the disease or condition mediated by NSD2 is neuroblastoma. In certain embodiments, the disease or condition mediated by NSD2 is pulmonary arterial hypertension.

[0082] In certain embodiments, the disease or condition mediated by NSD2 is acute lymphoblastic leukemia, cutaneous squamous cell carcinoma, or mantle cell lymphoma.In certain embodiments, the disease or condition mediated by NSD2 is acute lymphoblastic leukemia.In certain embodiments, the disease or condition mediated by NSD2 is cutaneous squamous cell carcinoma.In certain embodiments, the disease or condition mediated by NSD2 is mantle cell lymphoma.

[0083] In certain embodiments, the disease or condition mediated by NSD2 is lung cancer.In certain embodiments, the disease or condition mediated by NSD2 is small cell or non-small cell lung cancer.In certain embodiments, the disease or condition mediated by NSD2 is small cell lung cancer.In certain embodiments, the disease or condition mediated by NSD2 is non-small cell lung cancer.

[0084] In certain embodiments, the disease or condition mediated by NSD2 is leukemia.In certain embodiments, the disease or condition mediated by NSD2 is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or chronic myelomonocytic leukemia (CMML).In certain embodiments, the disease or condition mediated by NSD2 is AML.In certain embodiments, the disease or condition mediated by NSD2 is CML.In certain embodiments, the disease or condition mediated by NSD2 is CMML.

[0085] In certain embodiments, the disease or condition mediated by NSD2 is skin cancer.In certain embodiments, the disease or condition mediated by NSD2 is melanoma, basal cell carcinoma, or squamous cell carcinoma.In certain embodiments, the disease or condition mediated by NSD2 is melanoma.In certain embodiments, the disease or condition mediated by NSD2 is basal cell carcinoma.

[0086] In certain embodiments, the disease or condition mediated by NSD2 is lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is Hodgkin's lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is non-Hodgkin's lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is mantle cell lymphoma or diffuse large B-cell lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is diffuse large B-cell lymphoma.

[0087] In certain embodiments, the NSD2-mediated disease or condition is myeloma.

[0088] In certain embodiments, the NSD2-mediated disease or condition is thyroid cancer. In certain embodiments, the NSD2-mediated disease or condition is colon cancer.

[0089] In certain embodiments, the cancer overexpresses NSD2. In certain embodiments, the cancer has a mutation in NSD2. In certain embodiments, the cancer has an activating mutation in NSD2. In certain embodiments, the cancer has a t(4;14)(p16.3;q32.3) translocation in NSD2. In certain embodiments, the cancer has an E1099K mutation in NSD2. In certain embodiments, the cancer has a T1150A mutation in NSD2.

[0090] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a child. In certain embodiments, the subject is an elderly person.

[0091] Another aspect of the present invention provides the use of a compound described herein (such as the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease or condition described herein, such as cancer.

[0092] Another aspect of the present invention provides the use of a compound described herein (such as the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol) for treating a disease or condition, such as a disease or condition described herein (e.g., cancer).

[0093] Additionally, compounds described herein such as the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol inhibit the activity of nuclear SET domain containing protein 2 (NSD2). Accordingly, another aspect of the present invention provides a method of inhibiting the activity of nuclear SET domain containing protein 2 (NSD2). The method includes contacting NSD2 with an effective amount of a compound described herein, such as (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate salt to inhibit the activity of the NSD2. In certain embodiments, the specific compound is a compound defined by one of the embodiments described above.

[0094] III. Combination Therapy Another aspect of the present invention provides combination therapy.The compound described herein (e.g., (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate salt) can be used in combination with additional therapeutic agents to treat disease or condition such as cancer.

[0095] Thus, in some embodiments, the present invention provides a method of treating a disclosed disease or condition, comprising administering to a patient in need of treatment an effective amount of a compound disclosed herein 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.

[0096] One or more other therapeutic agents may be administered separately from the compound or composition of the present invention as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compound of the present invention in a single composition. When administered as a multiple dose regimen, one or more other therapeutic agents and the compound or composition of the present invention may be administered simultaneously, sequentially, or within a period of each other.

[0097] In certain embodiments, the additional therapeutic agent is an anti-cancer agent, an anti-allergy agent, an anti-emetic agent (or anti-emetic agent), an analgesic agent, a cytoprotective agent, or a combination thereof. In certain embodiments, the additional therapeutic agent is an anti-cancer agent, an analgesic agent, an anti-inflammatory agent, or a combination thereof.

[0098] In certain embodiments, the additional therapeutic agent is an anti-cancer or chemotherapeutic agent. Examples of anti-cancer agents contemplated for use in the combination therapy of the present invention include erlotinib, bortezomib, fulvestrant, sunitib, imatinib mesylate, letrozole, finasunate, platins such as oxaliplatin, carboplatin, and cisplatin, finasunate, fluorouracil, rapamycin, leucovorin, lapatinib, lonafamib, sorafenib, gefitinib, camptothecin, topotecan, bryostatin, adezelin, anthracyclines, and the like. Other agents include, but are not limited to, cyclophosphamide, doxorubicin, vincristine, prednisone or prednisolone, other alkylating agents such as mechlorethamine, chlorambucil, and ifosfamide, antimetabolites such as azathioprine or mercaptopurine, other microtubule inhibitors (vinca alkaloids such as vincristine, vinblastine, vinorelbine, and vindesine, as well as taxol ... Sun), podophyllotoxins (etoposide, teniposide, etoposide phosphate, and epipodophyllotoxin), topoisomerase inhibitors, other cytotoxins such as actinomycin, daunorubicin, valrubicin, idarubicin, edrecolomab, epirubicin, bleomycin, plicamycin, and mitomycin, as well as other anti-cancer antibodies (cetuximab, bevacizumab, ibritumomab, abagovomab, adecatumumab, afutuzumab, alacizumab, alemtuzumab, anatumomab, apolizumab, bavituximab, belim Mab, bivatuzumab mertansine, blinatumomab, brentuximab vedotin, cantuzumab mertansine, catemashomab, cetuximab, sitatuzumab bogatox, cixutumumab, clivatuzumab tetraxetan, conatumumab, dacetuzumab, daclizumab, detumomab, ecromeximab, edrecolomab, elotuzumab, epratuzumab, ertumaxomab, etaracizumab, faretuzumab, figitumumab, frezolimumab, galiximab, gembatumumab vedotin, gemtuzumab, ibritumomab tiuxetan,Inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lucatumumab, rumilicimab, mapatumumab, matuzumab, milatuzumab, mitumomab, nacolomab butafenatox, naptumomab estafenatox, necitumumab, nimotuzumab, ofatumumab, olarab tuzumab, oportuzumab monatox, oregovomab, panitumumab, pemtumomab, pertuzumab, pintumomab, pritumumab, ramucirumab, rilotumumab, lobatumumab, rituximab, sibrotuzumab, tacatuzumab tetraxetan, taplitumomab paptox, tenatumomab, ticilimumab, tigatuzumab, tositumomab, or 131 I-tositumomab, trastuzumab, tremelimumab, tuocuzumab celmoleukin, veltuzumab, visilizumab, volociximab, votumumab, zalutumumab, zanolimumab, IGN-101, MDX-010, ABX-EGR, EMD72000, ior-t1, MDX-220, MRA, H-11 scFv, huJ591, TriGem, TriAb, R3, MT-201, G-250, ACA-125, Onyvax-105, CD:-960, Cea-Vac, BrevaRex AR54, IMC-1C11, GlioMab-H, ING-1, anti-LCG MAbs, MT-103, KSB-303, Therex, KW2871, anti-HMI.24, anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-RI MAb, prostate cancer antibody, H22xKi-r, ABX-Mai, Imuteran, Monopharm-C), and antibody drug conjugates comprising any of the above agents (particularly the auristatins MMAE and MMAF, maytansinoids such as DM-1, calicheamicin, or various cytotoxins).

[0099] In certain embodiments, the additional therapeutic agent is anastrozole (ARIMIDEX®), bicalutamide (CASODEX®), bleomycin sulfate (BLENOXANE®), busulfan (MYLERAN®), busulfan injection (BUSULFEX®), capecitabine (XELODA®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (PARAPLATIN®), carmustine (BiCNU®), chlorambucil ( LEUKERAN®), cisplatin (PLATINOL®), cladribine (LEUSTATIN®), cyclophosphamide (CYTOXAN® or NEOSAR®), cytarabine, cytosine arabinoside (CYTOSAR-U®), cytarabine liposome injection (DEPOCYT®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, COSMEGAN®), daunorubicin hydrochloride (CERUBIDINE®), )), Daunorubicin Citrate Liposomal Injection (DAUNOXOME®), Dexamethasone, Docetaxel (TAXOTERE®), Doxorubicin Hydrochloride (ADRIAMYCIN®, RUBEX®), Etoposide (VEPESID®), Fludarabine Phosphate (FLUDARA®), 5-Fluorouracil (ADRUCIL®, EFUDEX®), Flutamide (EULEXIN®), Tezacitibine, Gemcitabine (Difluorodeoxycytidine), Hydroxypropyl 1,2-Difluorouracil (Hydroxypropyl 1,2-Difluorouracil ... roxiurea (HYDREA®), idarubicin (IDAMYCIN®), ifosfamide (IFEX®), irinotecan (CAMPTOSAR®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (ALKERAN®), 6-mercaptopurine (PURINETHOL®), methotrexate (FOLEX®), mitoxantrone (NOVANTRONE®), gemtuzumab ozogamicin (MYLOTARG™),Selected from paclitaxel (TAXOL®), nab-paclitaxel (ABRAXANE®), Phoenix (Yttrium 90 / MX-DTPA), pentostatin, polipheprosan 20 with carmustine implant (GLIADEL®), tamoxifen citrate (NOLVADEX®), teniposide (VUMON®), 6-thioguanine, thiotepa, tirapazamine (TIRAZONE®), topotecan hydrochloride for injection (HYCAMPTIN®), vinblastine (VELBAN®), vincristine (ONCOVIN®), and vinorelbine (NAVELBINE®).

[0100] In certain embodiments, the additional therapeutic agent is capable of inhibiting BRAF, MEK, CDK4 / 6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or a combination thereof. In certain embodiments, the compound of the present invention is combined with another therapeutic agent selected from vemurafinib, debrafinib, LGX818, trametinib, MEK162, LEE011, PD-0332991, panobinostat, belinostat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib, panitumumab, vandetanib, INC280, everolimus, simolimus, BMK120, BYL719 or CLR457, or a combination thereof.

[0101] In certain embodiments, the additional therapeutic agent is selected based on the disease or condition being treated. For example, in the treatment of melanoma, the additional therapeutic agent is selected from aldesleukin (e.g., PROLEUKIN®), dabrafenib (e.g., TAFINLAR®), dacarbazine, recombinant interferon alpha-2b (e.g., INTRON® A), ipilimumab, trametinib (e.g., MEKINIST®), pegylated interferon alpha-2b (e.g., PEGINTRON®, SYLATRON™), vemurafenib (e.g., ZELBORAF®), and ipilimumab (e.g., YERVOY®).

[0102] For the treatment of ovarian cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), carboplatin (PARAPLATIN®), cyclophosphamide (CYTOXAN®, NEOSAR®), cisplatin (PLATINOL®, PLATINOL-AQ®), doxorubicin hydrochloride liposomal (DOXIL®, DOX-SL®, EVACET®, LIPODOX®), gemcitabine hydrochloride (GEMZAR®), topotecan hydrochloride (HYCAMTIN®), and paclitaxel (TAXOL®).

[0103] For the treatment of thyroid cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), cabozantinib-S-malate (COMETRIQ®), and vandetanib (CAPRELSA®).

[0104] For the treatment of colon cancer, the additional therapeutic agent is selected from fluorouracil (e.g., ADRUCIL®, EFUDEX®, FLUOROPLEX®), bevacizumab (AVASTIN®), irinotecan hydrochloride (CAMPTOSTAR®), capecitabine (XELODA®), cetuximab (ERBITUX®), oxaliplatin (ELOXATIN®), leucovorin calcium (WELLCOVORIN®), regorafenib (STIVARGA®), panitumumab (VECTIBIX®), and ziv-aflibercept (ZALTRAP®).

[0105] For the treatment of lung cancer, the additional therapeutic agent may be methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX and selected from PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), paclitaxel (TAXOL®), paclitaxel albumin-stabilized nanoparticle formulation (ABRAXANE®), afatinib maleate (GILOTRIF®), pemetrexed disodium (ALIMTA®), bevacizumab (AVASTIN®), carboplatin (PARAPLATIN®), cisplatin (PLATINOL®, PLATINOL-AQ®), crizotinib (XALKORI®), erlotinib hydrochloride (TARCEVA®), gefitinib (IRESSA®), and gemcitabine hydrochloride (GEMZAR®).

[0106] For the treatment of pancreatic cancer, the other therapeutic agent may be selected from fluorouracil (ADRUCIL®, EFUDEX®, FLUOROPLEX®), erlotinib hydrochloride (TARCEVA®), gemcitabine hydrochloride (GEMZAR®), and mitomycin or mitomycin C (MITOZYTREXTM, MUTAMYCIN®).

[0107] For the treatment of cervical cancer, the additional therapeutic agent is selected from bleomycin (BLENOXANE®), cisplatin (PLATINOL®, PLATINOL-AQ®), and topotecan hydrochloride (HYCAMTIN®).

[0108] For the treatment of head and neck cancer, the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), fluorouracil (ADRUCIL®, EFUDEX®, FLUOROPLEX®), bleomycin (BLENOXANE®), cetuximab (ERBITUX®), cisplatin (PLATINOL®, PLATINOL-AQ®), and docetaxel (TAXOTERE®).

[0109] For the treatment of leukemia, including chronic myelomonocytic leukemia (CMML), the additional therapeutic agent is selected from bosutinib (BOSULIF®), cyclophosphamide (CYTOXAN®, NEOSAR®), cytarabine (CYTOSAR-U®, TARABINE PFS®), dasatinib (SPRYCEL®), imatinib mesylate (GLEEVEC®), ponatinib (ICLUSIG®), nilotinib (TASIGNA®), and omacetaxine mepesuxinate (SYNRIBO®).

[0110] In some cases, patients may experience allergic reactions to the compounds of the present invention and / or other anti-cancer drug(s) during or after administration. Therefore, anti-allergic agents may be administered to minimize the risk of allergic reactions. Suitable anti-allergic agents include corticosteroids such as dexamethasone (e.g., DECADRON®), beclomethasone (e.g., BECLOVENT®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, e.g., ALA-CORT®, hydrocortisone phosphate, Solu-CORTEF®, HYDROCORT Acetate®, and LANACORT®), prednisolone (e.g., DELTA-Cortel®, ORAPRED®, PEDIAPRED®, and PRELONE®), prednisone (e.g., DELTASONE®, LIQUID RED ... antihistamines such as RED®, METICORTEN®, and ORASONE®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, e.g., DURALONE®, MEDRALONE®, MEDROL®, M-PREDNISOL®, and SOLU-MEDROL®), diphenhydramine (e.g., BENADRYL®), hydroxyzone, and cyproheptadine, and bronchodilators such as beta-adrenergic receptor antagonists, albuterol (e.g., PROVENTIL®), and terbutaline (e.g., BRETHINE®).

[0111] In other cases, patients may experience nausea during and after administration of the compounds of the present invention and / or other anticancer drug(s). Therefore, antiemetics may be administered to prevent nausea (upper stomach) and vomiting. Suitable antiemetics include aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HCl (KYTRIL®), lorazepam (ATIVAN®), dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and Zunrisa®), and combinations thereof.

[0112] In still other cases, medications to reduce the pain experienced during treatment are prescribed to make the patient more comfortable. Common over-the-counter painkillers such as TYLENOL® are often used. Opioid painkillers such as hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphone hydrochloride (OPANA®), and fentanyl (e.g., DURAGESIC®) are also useful for moderate or severe pain.

[0113] In addition, cytoprotectants (e.g., neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, etc.) may be used as adjunctive therapy to protect normal cells from treatment toxicity and limit organ toxicity. Suitable cytoprotectants include amifostine (ETHYOL®), glutamine, dimesna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor, and folinic acid).

[0114] In yet another aspect, the compounds of the present invention can be used in combination with known therapeutic processes, for example with the administration of hormones or with radiation therapy. In certain cases, the compounds of the present invention can be used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0115] The dosage and dosing schedule of the active ingredients used in the combination therapy can be determined by the attending clinician.In certain embodiments, the compound described herein (e.g., (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate salt) and additional therapeutic agent(s) are administered in the dosage that is generally adopted when such agent is used as a monotherapy for treating a disease or condition. In other embodiments, a compound described herein (e.g., the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol) and the additional therapeutic agent(s) are administered at doses lower than those typically employed when such agents are used as monotherapy to treat a disease or condition. In certain embodiments, a compound described herein (e.g., the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol) and the additional therapeutic agent(s) are present in the same composition that is suitable for oral administration.

[0116] In certain embodiments, the compounds described herein (e.g., D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol) and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow for lower dosages of one or more agents of the combination therapy and / or less frequent administration of one or more agents. Lower dosages or less frequent administration of one or more agents may reduce the toxicity of the treatment without reducing the efficacy of the treatment.

[0117] Another aspect of the present invention is a kit comprising a therapeutically effective amount of a compound described herein (e.g., the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol), a pharma- ceutically acceptable carrier, vehicle or diluent, and, optionally, at least one additional therapeutic agent as listed above. In certain embodiments, the kit further comprises instructions, such as instructions for treating a disease described herein.

[0118] IV. Pharmaceutical Compositions and Dosage Considerations As indicated above, the present invention provides pharmaceutical compositions comprising one or more of the compounds described above in a therapeutically effective amount, formulated with one or more pharma- ceutical acceptable carriers (additives) and / or diluents.The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue, (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or as a sustained release formulation, (3) topical application, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin, (4) vaginal or rectal administration, e.g., as a vaginal suppository, cream, or foam, (5) sublingual, (6) ocular, (7) transdermal, or (8) nasal administration. In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein (e.g., the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol) and a pharma- ceutically acceptable carrier.

[0119] The phrase "therapeutically effective amount" as used herein means an amount of a compound, material, or composition, including a compound of the invention, that is effective to produce a desired therapeutic effect in at least a subpopulation of cells in an animal, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0120] The phrase "pharmacologically acceptable" is employed herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0121] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0122] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0123] The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may be conveniently presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0124] In certain embodiments, the formulations of the invention comprise an additive selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides, and a compound of the invention. In certain embodiments, the above formulations render the compounds of the invention orally bioavailable.

[0125] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0126] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powder, granules, each containing a predetermined amount of a compound of the present invention as the active ingredient, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0127] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) excipients or fillers, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) disintegrating agents such as paraffin, (6) absorption enhancers such as quaternary ammonium compounds, and surfactants such as poloxamers and sodium lauryl sulfate, (7) wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof, (10) coloring agents, and (11) controlled release agents such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be employed as excipients in soft and hard shell gelatin capsules using additives such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0128] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0129] Tablets and other solid dosage forms of the pharmaceutical composition of the present invention, such as dragees, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose in various proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They can be formulated for rapid release, for example, lyophilized. They can also be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be compositions that release the active ingredient(s) only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0130] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form can contain inert diluent commonly used in the art, such as water or other solvent, solubilizer, emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0131] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0132] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0133] Formulations of pharmaceutical compositions of the invention for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which are solid at room temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active compound.

[0134] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

[0135] Dosage forms for topical or transdermal administration of a compound of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0136] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0137] Powders and sprays can contain, in addition to the compounds of the invention, additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0138] Transdermal patch has the added advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be made by dissolving or dispersing the compound in suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0139] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0140] Pharmaceutical compositions of the invention suitable for parenteral administration contain one or more compounds of the invention in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0141] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0142] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action on the subject compounds may be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0143] In some cases, it is desirable to slow down the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of drugs.This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility.The absorption rate of drugs then depends on their dissolution rate, which in turn depends on crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0144] Injectable depot forms are prepared by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0145] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be administered by themselves or, for example, in combination with a pharma- ceutical acceptable carrier, as a pharmaceutical composition containing 0.1 to 99% (more preferably, 10 to 30%) of the active ingredient.

[0146] The preparations of the present invention can be administered orally, parenterally, topically or rectally.They are naturally administered in a form suitable for each administration route.For example, they are administered in tablet or capsule form, by injection, inhalation, eye drops, ointments, suppositories, etc., by administration by injection, infusion or inhalation, topically by lotion or ointment, rectally by suppositories.Oral administration is preferred.

[0147] The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0148] The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally," as used herein, refer to administration of a compound, drug, or other material other than directly into the central nervous system, e.g., subcutaneous administration, so that it enters the patient's system and thus is subject to metabolic and other similar processes.

[0149] These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally, e.g., by spray, rectally, intravaginally, parenterally, intracisternally, and topically, including buccal and sublingually, such as by powders, ointments, or drops.

[0150] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention are formulated into pharma- ceutical acceptable dosage forms by conventional methods known to those skilled in the art.

[0151] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0152] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention, or esters, salts, or amides thereof, employed, the route of administration, the timing of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical arts.

[0153] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0154] In general, a suitable daily dose of the compound of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Preferably, the compound is administered at about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compound described herein is co-administered with another agent (e.g., as a sensitizer), the effective amount may be less than when the agent is used alone.

[0155] If desired, the effective daily amount of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. Preferred administration is a single daily administration.

[0156] The present invention further provides unit dosage forms (such as tablets or capsules) containing a therapeutically effective amount of a compound described herein for the treatment of a disease or condition described herein. EXAMPLES

[0157] The invention generally described herein will be more readily understood by reference to the following examples, which are included merely for purposes of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention. Starting materials described herein can be obtained from commercial sources or can be readily prepared from commercially available materials using transformations known to those of ordinary skill in the art.

[0158] Example 1 - Preparation of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate [ka] (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol (1 g) was slurried in acetonitrile (13.5 mL) at ambient temperature. To this slurry was added D-tartrate salt (1.1 eq.) dissolved in water (1.5 mL) over a period of about 1 hour. The resulting mixture was warmed to 65° C. and held at this temperature for 2 days. The resulting slurry was then cooled to ambient temperature, filtered, and the collected solid was dried in a vacuum oven to provide the title compound in 77% yield as a crystalline solid.

[0159] Example 2—Preparation of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate [ka] (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol (1 g) was slurried in ethanol (15 mL) at ambient temperature. To this slurry was added D-tartrate salt (1.1 eq.) dissolved in water (0.75 mL) over a period of about 1 hour. The resulting mixture was warmed to 50° C. and held at this temperature for 2 days. The resulting slurry was then cooled to ambient temperature, filtered, and the collected solid was dried in a vacuum oven to provide the title compound in 79% yield as a crystalline solid.

[0160] Example 3—Preparation of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate [ka] (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol (1 g) was slurried in isopropyl alcohol (15 mL) at ambient temperature. To this slurry was added D-tartrate salt (1.1 eq.) dissolved in water (0.75 mL) over a period of about 1 hour. The resulting mixture was warmed to 50° C. and held at this temperature for 2 days. The resulting slurry was then cooled to ambient temperature, filtered, and the collected solid was dried in a vacuum oven to provide the title compound in 74% yield as a crystalline solid.

[0161] Example 4 - Characterization of crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate [ka] Crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate, prepared according to the procedure of Example 1, was analyzed by X-ray powder diffraction, simultaneous thermogravimetry and differential scanning calorimetry, differential scanning calorimetry, dynamic vapor sorption (to analyze hygroscopicity), Karl Fischer titration, and proton nuclear magnetic resonance spectroscopy.

[0162] X-ray powder diffraction was performed using either a Rigaku MiniFlex 600 or a Bruker D8 Advance equipped with a LYNXEYE detector. Both instruments were operated in reflection mode (i.e., Bragg-Brentano configuration). Samples were prepared on Si zero-return wafers. Parameters for XRPD using the Rigaku MiniFlex 600 were: [Table 3]

[0163] XRPD parameters using a Bruker D8 Advance were: [Table 4]

[0164] The X-ray powder diffractogram of one batch of the title compound is provided in Figure 1. Tabulated characteristics of the X-ray powder diffractogram of Figure 1 are provided in the table below, which lists the diffraction angles 2θ, interplanar distances d, and relative intensities (expressed as a percentage relative to the most intense peak). [Table 5-1] [Table 5-2]

[0165] The X-ray powder diffractogram of the second batch of the title compound is provided in Figure 2. Tabulated characteristics of the X-ray powder diffractogram of Figure 2 are provided in the following table, which lists the diffraction angles 2θ, interplanar distances d, and relative intensities (expressed as a percentage relative to the most intense peak). [Table 6-1] [Table 6-2]

[0166] Mettler Toledo TGA / DSC 3+ Simultaneous thermogravimetric analysis and differential scanning calorimetry were carried out using a 3000 psi 1 ...

[0167] Mettler Toledo DSC 3+Separate differential scanning calorimetry analyses were performed using a TA Discovery DSC (with a method gas flow of 60.00 mL / min) or a TA Discovery DSC (with a method gas flow of 50.00 mL / min). With either instrument, samples (1-5 mg) were weighed directly into 40 mL sealed aluminum pans with a pinhole and run using the following parameters: ramp method, heating rate of 10.0 °C / min, temperature range 30-300 °C, and method gas N 2 The differential scanning calorimetry curve for the title compound obtained according to this procedure is provided in FIG.

[0168] The title compound was analyzed for hygroscopicity by dynamic vapor sorption. Dynamic vapor sorption was performed using a Q5000SA. Samples (5-15 mg) were loaded into metal quartz sample pans, suspended from a microbalance, and exposed to a humidified nitrogen gas stream. Weight changes were relative to a matching empty reference pan opposite the sample suspended from the microbalance. Samples were held at each humidity level for a minimum of 10 minutes and progressed to the next humidity level only if there was a <0.002% change in weight between measurements (5 second interval) or 60 minutes had elapsed. The following program was used: Equilibration at 1.50% RH 2.50% to 5% (50%, 35%, 20%, and 5%) 3.5%~95% (5%, 20%, 35%, 50%, 65%, 80%, and 95%) 4.95% to 5% (95%, 80%, 65%, 50%, 35%, 20%, and 5%) 5.5% to 50% (5%, 20%, 35%, and 50%).

[0169] The results of the hygroscopicity analysis by dynamic vapor sorption are depicted in FIG. 5, where a 4.858% increase in weight was observed upon transition from 5% to 95% relative humidity.

[0170] The title compound was analyzed for water content by Karl Fischer (KF) titration and determined to have a water content of 1.22 wt%. Karl Fischer (KF) titration for the determination of water was performed using a Mettler Toledo C20S Coulometric KF Titrator equipped with a current generator cell with a diaphragm, and dual platinum pin electrodes. The detection range of the instrument is 1 ppm to 5% water. Aquastar™ CombiCoulomat fritless reagent was used in both the anodic and cathodic compartments. Approximately 0.03 to 0.10 g of sample was dissolved in the anodic compartment and titrated until the solution potential was below 100 mV. Hydranal 1 wt% water standard was used for validation prior to sample analysis.

[0171] The title compound was determined by proton nuclear magnetic resonance spectroscopy ( 1 The product was analyzed by H NMR) and determined to have no residual solvent above the detection limit and to have a 1.02:1.00 molar ratio of D-tartaric acid:(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol. 1 H NMR spectroscopy was performed on a Bruker Avance 500 MHz spectrometer. Solids were dissolved in 0.60-0.75 mL of deuterated solvent in 4 mL vials, transferred to NMR tubes (Wilmad 5 mm thin-walled 8" 200 MHz, 506-PP-8) and analyzed according to the following parameters: [Table 7]

[0172] This crystalline form exhibited an aqueous solubility of >2.0 mg / mL after both 30 minutes and 24 hours at pH 6.8 and 37° C. Additionally, this crystalline material demonstrated good stability in accelerated stability studies, as described in Example 5 below.

[0173] Example 5 - Accelerated Stability Study An accelerated stability study was performed on the crystalline form of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate salt prepared as described in Example 1. Approximately 12 mg of the solid was placed in a 4 mL vial, which was then covered with a Kimwipe. The vial was stored inside a stability chamber generating 75% relative humidity at 40° C. for 6 days. Analysis of the recovered salt by HPLC showed good chemical stability, i.e., 99.53 area percent purity before the study and 99.45 area percent purity after the study. Analysis of the recovered salt by XRPD showed no change in crystalline form.

[0174] Example 6 – 1-Year Stability Study A one-year stability study was performed on the crystalline form of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate having the XRDP pattern described in Example 4. In particular, aliquots of crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate were stored for one year at a temperature of 25° C.±2° C., where the relative humidity was 60%±5%. Samples of crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate were analyzed at the following time points in the experiment: 0 days (i.e., at the beginning of the experiment), 1 month, 3 months, 6 months, 9 months, and 12 months. The following parameters were evaluated at each time point: physical appearance, water content by coulometric Karl Fischer (CKF), purity by ultra-performance liquid chromatography (UPLC), and total amount of related substances. XRPD analysis was performed on compound samples at 0 days and 12 months.

[0175] The results of the stability study are provided in the following table. The stability study results show that the subject crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate has good stability to storage. For example, the crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate has low hygroscopicity as evidenced by little change in water content during the 12-month stability study. Additionally, crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate maintained a high level of purity by UPLC analysis, and the XRPD spectrum obtained on a sample of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate stored for 12 months matched the XRPD spectrum obtained on the compound at the start of the stability study (i.e., day 0). [Table 8]

[0176] Example 7 - 6-Month Stability Study at High Temperature and Relative Humidity A six-month stability study was performed on the crystalline form of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate having the XRDP pattern described in Example 4. In particular, aliquots of crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate were stored at a temperature of 40° C.±2° C., where the relative humidity was 75%±5%, for six months. Samples of crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate were analyzed at the following time points in the experiment: 0 days (i.e., at the beginning of the experiment), 1 month, 3 months, and 6 months. The following parameters were evaluated at each time point: physical appearance, water content by coulometric Karl Fischer (CKF), purity by ultra-performance liquid chromatography (UPLC), and total amount of related substances. XRPD analysis was performed on compound samples at 0 days and 6 months.

[0177] The results of the stability study are provided in the following table. The stability study results show that the subject crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate has good stability to storage. For example, the crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate has low hygroscopicity as evidenced by little change in water content during the 6-month stability study. Additionally, crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate maintained a high level of purity by UPLC analysis, and the XRPD spectrum obtained on a sample of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate stored for 6 months matched the XRPD spectrum obtained on the compound at the start of the stability study (i.e., day 0). [Table 9]

[0178] Example 8 - Water solubility analysis The solubility of test compounds was evaluated in two different fluids: (a) water and (b) simulated intestinal fluid under fasted conditions. The test compounds analyzed were: Crystalline (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate (hereinafter referred to as "Compound A") described in Example 4, (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethane-1-ol fumarate (hereinafter referred to as "Compound B"); (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol free base (hereinafter, "Compound C").

[0179] An aliquot of the test compound was placed in the liquid at a temperature of 37° C., and the concentration of dissolved test compound was then determined after 24 hours. The pH of the solution at 24 hours was also measured. The results are provided in the table below. [Table 10] [Table 11]

[0180] Example 9 - Preparation of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate [ka] (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol (2.28 kg) was dissolved in THF (20.7 kg) in a reactor vessel and the temperature of the reactor vessel was adjusted to a range of 30° C. to 40° C. while the reactor was under nitrogen. The resulting mixture was filtered, ethanol (36.4 kg) was added, and the mixture was concentrated under reduced pressure. Several times, ethanol (18, 18, 19, 19 kg) was added, and the mixture was concentrated under reduced pressure. The reactor vessel was warmed to a range of 45° C. to 55° C. D-tartaric acid (0.67 kg) was dissolved in water (2.3 kg) and added slowly to the reactor. The resulting mixture was seeded (20 g) with the desired polymorph (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate. The resulting mixture was held at a temperature in the range of 45° C. to 55° C., then cooled to a temperature in the range of 10° C. to 20° C., and then filtered. The resulting solid cake was washed with ethanol / water and dried to provide the title compound (2.77 kg).

[0181] Example 10 - Preparation of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate [ka] (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol (15.7 kg) was suspended in ethanol (110 kg) and water was added (23 kg). The resulting mixture was charged with more ethanol (60 kg), the temperature of the reactor was adjusted to 60-70 °C, and the reaction mixture was then transferred to another reactor vessel with clarification via filtration at 60-70 °C. The reactor was washed with ethanol (35 kg) and the resulting mixture was transferred to a receiving reactor via clarification. The reactor was kept at a temperature in the range of 60 °C to 70 °C. D-Tartaric acid (4.7 kg) was mixed with ethanol (11.5 kg), water (1.5 kg) and the resulting mixture was stirred at 20-30° C. and then dosed into a reactor containing (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol. The resulting mixture was seeded with the desired polymorph of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D-tartrate (0.17 kg), dosing of the D-tartaric acid / ethanol mixture was completed, and the reactor was cooled to a temperature in the range of 50° C. to 60° C. The reactor was then further cooled to a temperature in the range of 10° C. to 20° C., and the mixture was then filtered and the isolated filter cake was washed twice with 95% ethanol / water solution (20, 19 kg). The isolated material was then dried to provide the title compound (16.8 kg). 1H NMR (DMSO, 300 MHz) 8.53 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.68 (dd, J = 12.4, 7.4 Hz, 1H), 7.33 (s, 2H), 7.13 (dd, J = 12.9, 7.3 Hz, 7.05 (s, 1H), 6.27 (td, J = 54.4, 3.4 Hz, 1H), 5.59 (br s, 2H), 4.01-3.88 (m, 2H), 3.85 (s, 3H), 3.19 (d, J = 11.8 Hz, 1H), 3.06-2.88 (m, 3H), 1.92-1.74 (m, 3H).LRMS (ESI+) 547.2 (M+H + .HRMS (ESI+) 547.2190 (M+H + ).

[0182] Incorporation by Reference The entire disclosure of each of the patent documents and scientific articles referenced herein is incorporated by reference for all purposes.

[0183] Equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. The scope of the invention is therefore indicated by the appended claims rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. The following compounds are D-tartrate salts: 【Chemistry 1】

2. The compound according to claim 1, wherein the molar ratio of D-tartaric acid to the following compound is approximately 1:1: 【Chemistry 2】

3. The compound according to claim 1, wherein the compound is in a crystalline form.

4. The compound according to claim 3, wherein the crystalline form exhibits an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 6.0±0.2, 8.8±0.2, 10.6±0.2, 10.9±0.2, 15.9±0.2, 20.9±0.2, and 23.9±0.

2.

5. The compound according to claim 4, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 15.1 ± 0.

2.

6. The compound according to claim 5, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 17.7 ± 0.

2.

7. The compound according to claim 6, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 19.0 ± 0.

2.

8. The compound according to claim 7, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 21.4 ± 0.

2.

9. The compound according to claim 8, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 22.7 ± 0.

2.

10. The compound according to claim 9, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 24.3 ± 0.

2.

11. The compound according to claim 4, wherein the relative intensity of the peak at the diffraction angle (2θ) is at least 25%.

12. The compound according to claim 3, characterized by the following X-ray powder diffraction pattern expressed with respect to diffraction angle 2θ, interplane distance d, and relative intensity (expressed as a percentage of the strongest peak): Table 1-1 Table 1-2

13. The compound according to claim 3, wherein the X-ray powder diffraction pattern is substantially as shown in Figure 1 or 2.

14. The compound according to claim 4, wherein the compound has a melting point onset determined by differential scanning calorimetry in the range of approximately 225 degrees Celsius to approximately 240 degrees Celsius.

15. The compound according to claim 4, wherein the compound has substantially the same differential scanning calorimetry curve as that shown in Figure 4.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to claim 16 for treating a disease or condition mediated by nuclear SET domain-containing protein 2 (NSD2).

18. The pharmaceutical composition according to claim 17, wherein the disease or condition mediated by the NSD2 is cancer.

19. The pharmaceutical composition according to claim 17, wherein the disease or condition mediated by NSD2 is breast cancer, cervical cancer, skin cancer, ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia, non-Hodgkin lymphoma, or pulmonary hypertension.

20. The pharmaceutical composition according to claim 17, wherein the disease or condition mediated by NSD2 is multiple myeloma.

21. The pharmaceutical composition according to claim 17, wherein the disease or condition mediated by NSD2 is prostate cancer.

22. The pharmaceutical composition according to claim 17, wherein the disease or condition mediated by NSD2 is lung cancer.

23. The pharmaceutical composition according to claim 17, wherein the disease or condition mediated by NSD2 is non-small cell lung cancer.

24. The pharmaceutical composition according to claim 16 for inhibiting the activity of nuclear SET domain-containing protein 2 (NSD2).

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