Piperidinyl-methyl-purine amine d-tartrate salts, crystalline forms, and their use in treatment of medical diseases and conditions

Abstract

The present invention provides piperidinyl-methyl-purine amine D-tartrate salts, crystalline forms, pharmaceutical compositions, their use in inhibition of NSD2, and their use in the treatment of diseases or conditions, such as cancer.

Description

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 343,225, filed May 18, 2022, which is incorporated herein by reference in its entirety. Field of the Invention

[0003] The present invention provides piperidinyl-methyl-purineamine D-tartrate salts, crystalline forms, pharmaceutical compositions, uses thereof in inhibiting NSD2, and uses thereof in treating diseases or conditions such as cancer. Background Art

[0004] Cancer has always been a significant health problem, despite a large amount of research efforts and scientific progress reported in the literature for the treatment of the disease. Solid tumors (including prostate cancer, breast cancer and lung cancer) are still highly prevalent in the world population. The current treatment options for these cancers are not effective for all patients and / or can have substantial adverse side effects. New treatments are needed to address this unmet need in cancer treatment.

[0005] 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 regulator that plays a role in tumorigenesis. 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 tract, lung, liver, ovary, skin, uterus, breast, prostate, and glioblastoma. Additionally, pediatric cancer genomes appear particularly likely to contain NSD2 mutations. Ultimately, upregulation of NSD2 has been associated with aggressive tumor behavior and poor clinical outcomes. Certain compounds that inhibit NSD2 are described in International Patent Application Publication WO 2021 / 028854. Additional compounds that inhibit NSD2 would benefit patients suffering from NSD2-related diseases or conditions.

[0006] The present invention addresses the foregoing needs and provides other related advantages. SUMMARY OF THE INVENTION

[0007] The present invention provides piperidinyl-methyl-purine amine D-tartrate salts, crystalline forms, pharmaceutical compositions, uses thereof in inhibiting NSD2, and uses thereof in treating diseases or conditions such as cancer. In particular, one aspect of the present invention provides a compound which is a D-tartrate salt of the following compound:

[0008]

[0009] In certain embodiments, the compound is in crystalline form. One benefit 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 is available in an anhydrous form and has low hygroscopicity in long-term stability studies. For example, (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 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-difluoroethan-1-ol free base Another benefit 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 shows higher solubility in water compared to the fumarate 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. Yet another benefit 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 exhibits very good long-term storage stability, showing high purity and no detectable loss of crystallinity after storage in a one-year stability study as measured by XRPD analysis. Further description of additional features of the compound is described in the detailed description of the invention. The compound can be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0010] 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 comprises administering to a subject in need thereof 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-difluoroethane-1-ol, D-tartrate, to treat the disease or condition.

[0011] Another aspect of the present invention provides a method for inhibiting the activity of nuclear SET domain-containing protein 2 (NSD2). The method comprises 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, to inhibit the activity of the NSD2. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Depicting the X-ray powder diffraction pattern of a 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 salt, as further described in Example 4.

[0013] Figure 2 Describe the X-ray powder diffraction pattern of the 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 salt, as further described in Example 4.

[0014] Figure 3 Thermogravimetric analysis and differential scanning calorimetry curves describing 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 salt are further described in Example 4.

[0015] Figure 4Depicting 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 salt as further described in Example 4.

[0016] Figure 5 The results of dynamic vapor sorption experiments 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 are described as further described in Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention provides piperidinyl-methyl-purine amine D-tartrate salts, crystalline forms, pharmaceutical compositions, uses thereof in inhibiting NSD2, and uses thereof in treating diseases or conditions such as cancer. One of the piperidinyl-methyl-purine amine D-tartrate salts is the D-tartrate salt of (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purine-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethane-1-ol. One benefit 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 is available in an anhydrous form and has low hygroscopicity in long-term stability studies. For example, (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 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-difluoroethan-1-ol free base Another benefit 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 shows higher solubility in water compared to the fumarate 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. Yet another benefit 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 exhibits very good long term storage stability, showing a high degree of purity and no detectable loss of crystallinity after storage in a one year stability study as measured by XRPD analysis.Unless otherwise specified, the practice of the present invention uses conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry and immunology. The techniques are explained in, for example, the following documents: "Comprehensive Organic Synthesis" (BM Trost & I. Fleming, eds., 1991-1992); "Handbook of experimental immunology" (DM Weir & C.C. Blackwell, eds.); "Current protocols in molecular biology" (FM Ausubel et al., eds., 1987, and periodic updates); and "Current protocols in immunology" (JE Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety.

[0019] 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. In addition, where a variable is not defined, the previous definition of that variable applies.

[0020] definition

[0021] The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. These definitions apply regardless of whether a term is used alone or in combination with other terms, unless otherwise specified. Thus, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "-O-alkyl", etc. For the purposes of the present invention, the chemical elements are defined in accordance with the CAS version, Handbook of Chemistry and Physics, 75 th Additionally, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, which is incorporated herein by reference in its entirety.

[0022] The term "aliphatic" or "aliphatic group", as used herein, means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain, which is fully saturated or contains one or more unsaturated units; or a monocyclic hydrocarbon or a bicyclic hydrocarbon, which is fully saturated or contains one or more unsaturated units, but which is not aromatic (also referred to herein as "cycloaliphatic"), which has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In certain 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 certain embodiments, "cycloaliphatic" refers to a monocyclic C3-C6 hydrocarbon, which is fully saturated or contains one or more unsaturated units, but which is not aromatic, which has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0023] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic ring, which is saturated or has one or more unsaturated units, with one or more atoms shared between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as positive fusion or spirocyclic ring. As used herein, the term "heterobicyclic" is a subset of "bicyclic", which requires one or more heteroatoms to be present in one or both rings of the bicyclic ring. The heteroatom may be present at the ring junction and is optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfone and sulfonic acid moieties), phosphorus (including oxidized forms such as phosphoric acid moieties), boron, etc. In certain 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 ring, which is saturated or partially unsaturated, with at least one bridge. As defined by IUPAC, "bridge" is an unbranched atomic chain or atom or valence bond connecting two bridgeheads, wherein "bridgehead" is any backbone atom of a ring system, which is bonded to three or more backbone atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. The bridged bicyclic group is well known in the art and includes those groups described below, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents described for aliphatic groups. Additional or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted.

[0024] The term "lower alkyl" refers to a C 1-4 Straight chain or branched alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0025] The term "lower haloalkyl" refers to a C 1-4 A straight-chain or branched alkyl group which is substituted with one or more halogen atoms.

[0026] The term "heteroatom" means oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (such as N-substituted pyrrolidinyl))).

[0027] The term "unsaturated" as used herein means that a moiety has one or more units of unsaturation.

[0028] As used herein, the term "divalent C 1-8 (or C1-6 )"saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene and alkynylene chains, which are straight or branched, as defined herein.

[0029] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene chain in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0030] The term "-(C0 alkylene)-" refers to a bond. Accordingly, the term "-(C0 alkylene)-" refers to a bond. 0-3 "alkylene)-" encompasses a bond (i.e., C0) and -(C 1-3 alkylene)-group.

[0031] The term "halogen" means F, Cl, Br or I.

[0032] The term "aryl" used alone or as part of a larger group such as "aralkyl", "aralkyloxy" or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc., which may carry one or more substituents. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthalimidyl, phenanthridinyl or tetrahydronaphthyl, etc.

[0033] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy" refer to groups having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; having 6, 10 or 14 π electrons shared in a cyclic array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, quinolinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-" as used herein also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein, unless otherwise specified, the residue 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, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroaromatic," any of which terms include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0034] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic residue" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety which is saturated or partially unsaturated and has one or more, preferably one to four heteroatoms in addition to carbon atoms, as defined above. The term "nitrogen" when used to describe the ring atoms of the heterocycle includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).

[0035] The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic residues include, but are not limited to, tetrahydrofuranyl, tetrahydrothienylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine Base, oxazepine Base, thiazolin The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic residue" are used interchangeably herein and include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. The heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl moieties are independently optionally substituted.

[0036] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0037] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, whether preceded by the term "optionally" or not, the term "substituted" means that one or more hydrogens of the specified moiety are replaced with suitable substituents. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and in the case where more than one position of any given structure can be substituted with more than one substituent selected from a specified group, the substituent may be the same or different at each position. The substituent combinations 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 a compound that is substantially unchanged when subjected to the following conditions: the conditions allow its preparation, detection, and in certain embodiments its recovery, purification, and use for one or more of the intended uses disclosed herein.

[0038] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ; -O(CH2) 0-4 R o ,-O-(CH2) 0-4 C(O)ORo ; -(CH2) 0-4 CH(OR o )2; -(CH2) 0-4 SR o ; -(CH2) 0-4 Ph, which can be used with R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be used with R o Substitution; -CH=CHPh, which can be replaced by R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which can be used with R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2; -(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ; -(CH2) 0-4 C(O)R o ;-C(S)R o ; -(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 C(O)SR o ; -(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0- 4SR-, SC(S)SRo ; -(CH2) 0-4 SC(O)R o ; -(CH2) 0-4 C(O)NR o 2; -C(S)NR o 2; -C(S)SR o ;-SC(S)SR o , -(CH2) 0-4 OC(O)NR o 2; -C(O)N(OR o )R o ; -C(O)C(O)R o ; -C(O)CH2C(O)R o ;-C(NOR o )R o ; -(CH2) 0- 4SSR o ; -(CH2) 0-4 S(O)2R o ;

[0039] -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ; -S(O)2NR o 2; -S(O)(NR o )R o ; -S(O)2N=C(NR o 2)2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ; -C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 Straight chain or branched alkylene)ON(R o )2; or -(C 1-4 Straight chain or branched alkylene) C(O)ON(R o )2.

[0040] Each Ro are independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur), or, notwithstanding the above definitions, two independent occurrences of R o Together with one or more of its intervening atoms, it forms a 3-12-membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur), which may be in R o The saturated carbon atom of o Optionally substituted with monovalent substituents independently selected from: halogen, -(CH2) 0-2 R · ,-(halogenated R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · , -(CH2) 0-2 CH(OR · )2; -O(halogenated R · ), -CN, -N3, -(CH2) 0-2 C(O)R · , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · , -(CH2) 0-2 SR · , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · , -(CH2) 0-2 NR · 2, -NO2, -SiR · 3, -OSiR · 3, -C(O)SR · ， -(C 1-4 Straight chain or branched alkylene)C(O)OR · , or -SSR · .

[0041] Each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur), and wherein each R · is unsubstituted or, in the case of pre-halogenation, substituted only with one or more halogens; or wherein the optional substituents on the saturated carbon are independently selected from =O, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * , =NR * , =NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2-3 The divalent substituent of S-, or the divalent substituent attached to a vicinal substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, where R * Each independent occurrence of is selected from hydrogen, C 1-6 Aliphatic or unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur).

[0042] In R * It is C 1-6 In the case of aliphatic * Optionally use halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, wherein each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur), and wherein each R · is unsubstituted or, in the case of pre-halogenation, is substituted only with one or more halogens.

[0043] The optional substituents on the substitutable nitrogen are independently

[0044] or Among them are independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh, or unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur), or, two independent occurrences of Together with its one or more intervening atoms, it forms an unsubstituted 3-12-membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur); wherein It is C 1-6 In the case of aliphatic Optionally use halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, wherein each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur), and wherein each R · is unsubstituted or, in the case of pre-halogenation, is substituted only with one or more halogens.

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are described in the literature. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of compounds can include those derived from suitable inorganic and organic acids and bases.

[0046] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomeric) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) isomeric mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, including replacement of hydrogen by deuterium or tritium or enrichment of carbon by 13 C or 14 Compounds having the present structures with carbon substituted at C are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention.

[0047] A mixture of diastereomers can be separated into its individual diastereomers based on their physicochemical differences by methods known to those skilled in the art (such as, for example, chromatography and / or fractional crystallization). Enantiomers can be separated as follows: by reacting a mixture of enantiomers with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acyl chloride), the mixture is converted into a mixture of diastereomers, the diastereomers are separated and the individual diastereomers are converted (e.g., hydrolyzed) into the corresponding pure enantiomers. Alternatively, the particular enantiomer of the compounds of the invention can be prepared by asymmetric synthesis. Further still, in the case where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxylic acid), a diastereomer salt is formed with an appropriate optically active acid or base, the diastereomers thus formed are subsequently split by chromatographic means known in the art or fractional crystallization, and the pure enantiomers are subsequently recovered.

[0048] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other or other selected stereoisomers. The chiral centers in the compounds of the invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. In addition, where the compounds described herein can exist as atropisomers (e.g., substituted biaryl rings), all forms of such atropisomers are considered part of the present invention.

[0049] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a compound is referred to by both a chemical structure and a chemical name and there is an ambiguity between the structure and the name, the structure shall prevail. It should also be noted that any carbon and heteroatom with unsatisfied valences in the description, schemes, examples, and tables herein is assumed to have a sufficient number of hydrogen atoms to satisfy the valences.

[0050] The terms "a" and "an" as used herein mean "one or more" and include the plural unless the context does not permit.

[0051] Unless otherwise specified, the term "about" means within ±10% of the stated value. The invention encompasses embodiments wherein the values ​​are within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0052] The term "alkyl" refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10 or 1-6 carbon atoms, referred to herein as C1-C 12 Alkyl, C1-C 10 Alkyl and C1-C6 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, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0053] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons derived from a cycloalkane, referred to herein as a "C3-C6 cycloalkyl". Exemplary cycloalkyls include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl.

[0054] The term "haloalkyl" refers to an alkyl group which is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, etc. The term "haloalkylene" refers to a divalent haloalkyl group.

[0055] The term "hydroxyalkyl" refers to an alkyl group which is substituted with at least one hydroxyl group. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0056] The terms "alkenyl" and "alkynyl" are art-understood and refer to unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0057] The term "alkoxy" or "alkoxy" is understood in the art and refers to an alkyl group as defined above, with an oxygen residue attached thereto. Representative alkoxy groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. The term "haloalkoxy" refers to an alkoxy group that is substituted with at least one halogen. Exemplary haloalkoxy groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.

[0058] The term "oxo" is art-understood and refers to a "=0" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0059] symbol Indicate the attachment point.

[0060] When any substituent or variable occurs more than one time in any constituent or compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence unless otherwise indicated.

[0061] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, and it is contemplated that the invention encompasses both solvated and unsolvated forms. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. The physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, such as where one or more solvent molecules are incorporated into the crystalline solid lattice, the solvate can be isolated. "Solvate" encompasses both solution phase and separable solvates. "Hydrate" is a solvate in which the solvent molecule is H2O.

[0062] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism to be treated by the methods of the present invention. The organism preferably includes, but is not limited to, mammals (e.g., mice, monkeys, horses, cows, pigs, dogs, cats, etc.), and most preferably includes humans.

[0063] The term "IC 50 " is understood in the art and refers to the concentration of compound required to achieve 50% inhibition of the target.

[0064] As used herein, the term "effective amount" refers to an amount of a compound sufficient to cause a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory, or preventive result). An effective amount can be given in one or more administrations, applications, or metered dosing and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treatment" includes any effect, such as a reduction, decrease, regulation, improvement, or elimination effect, which causes improvement in a condition, disease, disorder, or the like, or improvement of its symptoms.

[0065] As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with an inert or active carrier, making the composition particularly suitable for diagnostic or therapeutic use, either in vivo or ex vivo.

[0066] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier, such as phosphate buffered saline solution, water, emulsions (such as, for example, oil / water or water / oil emulsions), and various types of wetting agents. The composition can also include stabilizers and preservatives. Examples of carriers, stabilizers, and adjuvants are described, for example, in Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0067] For therapeutic use, salts of the compounds of the invention are intended to be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0068] Throughout the specification, where compositions are described as having, including, or comprising particular components; or where processes and methods are described as having, including, or comprising particular steps, it is contemplated that there are additional compositions of the invention consisting essentially of, or consisting of, said components; and there are processes and methods according to the invention consisting essentially of, or consisting of, said processing steps.

[0069] In general, compositions specified in percentages are by weight unless otherwise specified.

[0070] I. D-tartrate 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

[0071] 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 benefit 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 is available in an anhydrous form and has low hygroscopicity in long-term stability studies. For example, (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 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-difluoroethan-1-ol free base Another benefit 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 shows higher solubility in water compared to the fumarate 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. Yet another benefit 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 exhibits very good long-term storage stability, showing high purity and no detectable loss of crystallinity after storage in a one-year stability study as measured by XRPD analysis. The compounds are described in more detail below. The compounds can be used in the methods of treatment and pharmaceutical compositions described herein. Exemplary compounds are described in the following sections. Exemplary procedures for preparing the compounds are described in the Examples.

[0072] One aspect of the present invention provides a compound which is a D-tartrate salt of:

[0073]

[0074] In certain embodiments, the molar ratio of D-tartaric acid to:

[0075]

[0076] In certain embodiments, the compound is in crystalline form.

[0077] 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 angle (2θ): 15.1 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 17.7 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 19.0 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 21.4 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 22.7±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 24.3±0.2.

[0078] 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%.

[0079] In certain embodiments, the crystalline form is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, interlayer spacing d, and relative intensity (expressed as a percentage relative to the most intense peak):

[0080]

[0081]

[0082] In certain embodiments, the crystalline form is characterized by having substantially Figure 1 The X-ray powder diffraction pattern is shown.

[0083] In certain embodiments, the crystalline form is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, interlayer spacing d, and relative intensity (expressed as a percentage relative to the most intense peak):

[0084]

[0085]

[0086] In certain embodiments, the crystalline form is characterized by having substantially Figure 2 The X-ray powder diffraction pattern is shown.

[0087] The X-ray powder diffraction pattern can be obtained using CuKα radiation. The temperature for obtaining the X-ray powder diffraction pattern can be, for example, 25±2 degrees Celsius.

[0088] In certain embodiments, the compound has an onset melting point determined by differential scanning calorimetry in the range of about 225 degrees Celsius to about 240 degrees Celsius. In certain embodiments, the compound has an onset melting point determined by differential scanning calorimetry at about 233 degrees Celsius. In certain embodiments, the compound has a peak melting point 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 peak melting point determined by differential scanning calorimetry at about 241 degrees Celsius. In certain embodiments, the compound has a peak melting point determined by differential scanning calorimetry at about 241 degrees Celsius. Figure 4 Substantially identical differential scanning calorimetry curves are shown.

[0089] In certain embodiments, the compound is further characterized in that the compound does not increase in weight by more than 10% when exposed to an atmosphere transitioning from 5% to 95% relative humidity during a dynamic vapor sorption procedure. In certain embodiments, the compound is further characterized in that the compound does not increase in weight by more than 5% when exposed to an atmosphere transitioning from 5% to 95% relative humidity during a dynamic vapor sorption procedure. In certain embodiments, the compound has Figure 5 Essentially the same adsorption isotherms are shown.

[0090] The above specification describes multiple embodiments involving 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. This patent application specifically contemplates all combinations of the embodiments.

[0091] II. Therapeutic Use of D-Tartrate 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

[0092] 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. Accordingly, one aspect of the invention provides methods for treating diseases or conditions mediated by nuclear SET domain-containing protein 2 (NSD2). The method comprises administering to a subject in need thereof 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 treat the disease or condition. In certain embodiments, the particular compound is a compound as defined in one of the embodiments above.

[0093] 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 tumors, osteosarcoma, multiple myeloma, neuroblastoma, leukemia (particularly acute lymphoblastic leukemia), non-Hodgkin lymphoma (particularly mantle cell lymphoma), and pulmonary hypertension.

[0094] In certain embodiments, the disease or condition mediated by NSD2 is cancer.

[0095] In certain embodiments, the disease or condition mediated by NSD2 is selected from solid tumors, leukemias, myelomas, lymphomas, and hypertension. In certain embodiments, the disease or condition mediated by NSD2 is a solid tumor. In certain embodiments, the disease or condition mediated by NSD2 is selected from leukemias, myelomas, and lymphomas. In certain embodiments, the disease or condition mediated by NSD2 is leukemia. In certain embodiments, the disease or condition mediated by NSD2 is myeloma. In certain embodiments, the disease or condition mediated by NSD2 is lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is hypertension.

[0096] 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 tumors, osteosarcoma, multiple myeloma, neuroblastoma, leukemia, non-Hodgkin lymphoma, or pulmonary 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 hypertension.

[0097] In certain embodiments, the disease or condition mediated by NSD2 is acute lymphoblastic leukemia, squamous cell carcinoma of the skin, 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 squamous cell carcinoma of the skin. In certain embodiments, the disease or condition mediated by NSD2 is mantle cell lymphoma.

[0098] 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.

[0099] 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 myeloid 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.

[0100] 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.

[0101] In certain embodiments, the disease or condition mediated by NSD2 is lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is Hodgkin lymphoma or non-Hodgkin lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is Hodgkin lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is non-Hodgkin 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.

[0102] In certain embodiments, the disease or condition mediated by NSD2 is myeloma.

[0103] In certain embodiments, the disease or condition mediated by NSD2 is thyroid cancer. In certain embodiments, the disease or condition mediated by NSD2 is colon cancer.

[0104] 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.

[0105] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is an elderly human.

[0106] Another aspect of the 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 preparation of a medicament. In certain embodiments, the medicament is used to treat a disease or condition described herein, such as cancer.

[0107] Yet another aspect of the 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).

[0108] In addition, 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) 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 comprises 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, to inhibit the activity of the NSD2. In certain embodiments, the specific compound is a compound defined in one of the above embodiments.

[0109] III. Combination Therapy

[0110] Another aspect of the present invention provides combination therapy. The compounds 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-difluoroethane-1-ol D-tartrate) can be used in combination with additional therapeutic agents to treat diseases or conditions such as cancer.

[0111] Accordingly, in certain embodiments, the present invention provides methods of treating the disclosed diseases or conditions, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In certain embodiments, the methods comprise co-administering one additional therapeutic agent. In certain embodiments, the methods comprise co-administering two additional therapeutic agents.

[0112] As part of a multiple dose regimen, one or more other therapeutic agents may be administered separately from the compounds of the invention or compositions. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition. If administered as a multiple dose regimen, one or more other therapeutic agents and the compounds of the invention or compositions may be administered simultaneously, sequentially, or one time period apart from each other.

[0113] In certain embodiments, the additional therapeutic agent is an anticancer agent, an antiallergic agent, an antinausea agent (or antiemetic agent), a pain reliever, a cytoprotective agent, or a combination thereof. In certain embodiments, the additional therapeutic agent is an anticancer agent, an analgesic agent, an anti-inflammatory agent, or a combination thereof.

[0114] In certain embodiments, the additional therapeutic agent is an anticancer agent or a chemotherapeutic agent. Examples of anticancer agents contemplated for use in the combination therapy of the present invention include, but are not limited to, erlotinib, bortezomib, fulvestrant, sunitinib, imatinib mesylate, letrozole, finasunate, platinum drugs such as oxaliplatin, carboplatin, and cisplatin, finasunate, fluorouracil, rapamycin, folinic acid, lapatinib, lonafarnib, sorafenib, gefitinib, camptothecin, topotecan, bryostatin, adolesin (ad ezelesin, anthracycline, carzeresin, biszeresin, dolastatin, auristatins, duocarmycin, eleutherobin, taxanes such as paclitaxel or docetaxel, cyclophosphamide, doxorubicin, vincristine, prednisone or prednisolone, other alkylating agents such as nitrogen mustard, chlorambucil, and ifosfamide, antimetabolites such as azathioprine or mercaptopurine, other microtubule inhibitors (vinca alkaloids such as vincristine, vinblastine, vinorelbine, and vindesine, and taxanes), podophyllotoxins (etoposide, teniposide, etoposide phosphate, and epipodophyllotoxin), topoisomerase inhibitors, other cytotoxins such as actinomycin, daunorubicin, valrubicin, idarubicin, edrecolomab, epirubicin, bleomycin, plicamycin, mitomycin, and other anticancer antibodies (cetuximab, bevacizumab, ibritumomab, abavolumab, adelimumab, afutuzumab, alacizumab, alemtuzumab, anatumomab, apolituzumab, baviximab, belimumab, bivacizumab maytansine, rantumomab, vebutuximab, mecanizumab, catumazomab, cetuximab, pocitalumab, citumumab, clivatuzumab tetraxetan, canagliflozin, daclizumab, daclizumab, detumumab, emeticholic acid, edrecolomab, etuzumab, epratuzumab, ertumaxomab, edarizumab, fatuzumab, fentolimumab, fesutuzumab, galiximab, vegbatuzumab, gemtuzumab, ibritumomab tiuxetan, inotuzumab ozogamicin, intolumab, ipilimumab, itumumab, labetuzumab, lexalimumab, lintuzumab, rucamumab, ruximab , mapatumumab, matuzumab, milatuzumab, mitumomab, tadalafil, tadalafil, netumumab, nimotuzumab, ofatumumab, oratumumab, motuzumab, orgovolumab, panitumumab, pemtumomab, pertuzumab, pintumumab, plinumumab, ramucirumab, rituximab, rotuximab, rituximab, sirolimus, tetravaltane, patamumomab, tetumomab, tesitumomab, tegasizumab, tositumomab, or 131I-tositumomab, trastuzumab, tumelimumab, tuocotuzumab, veltuzumab, vesiculotuzumab, volocixumab, votumomab, zalumab, zalumab, IGN-101, MDX-010, ABX-EGR, EMD72000, ior-t1, MDX-220, MRA, H-11scFv, 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 antibodies, SGN-30, TRAIL-RI MAb, prostate cancer antibodies, H22xKi-r, ABX-Mai, Imuteran, Monopharm-C), and antibody-drug conjugates (antibody-drug conjugates) comprising any of the above agents (particularly auristatins MMAE and MMAF, maytansines such as DM-1, calicheamycins, or various cytotoxins).

[0115] In certain embodiments, the additional therapeutic agent is selected from anaroazole Bicalutamide Bleomycin sulfate Busulfan Busulfan Injection Capecitabine N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin Carmustine Chlorambucil Cisplatin Claribine Cyclophosphamide ( or ), cytarabine, cytarabine Cytarabine liposome injection Dacarbazine Actinomycin D (Actinomycin D, ), daunorubicin hydrochloride Daunorubicin citrate liposome injection Dexamethasone, docetaxel Doxorubicin Hydrochloride Etoposide Fludarabine phosphate 5-Fluorouracil Flutamide Tezacitabine, gemcitabine (difluorodeoxycytidine), hydroxyurea Idabi Ifosfamide Irinotecan L-Asparaginase Calcium folinate, melphalan 6-Mercaptopurine Methotrexate Mitoxantrone Gemtuzumab ozogamicin (MYLOTARGTM), paclitaxel nab-paclitaxel Phoenix (Yttrium90 / MX-DTPA), pentostatin, polyphenylpropanone 20 and carmustine implants Tamoxifen citrate Teniposide 6-thioguanine, thiotepa, tirapazamine Topotecan hydrochloride for injection Vinblastine Vincristine Vinorelbine

[0116] 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 a particular embodiment, the compounds of the invention are combined with another therapeutic agent selected from the group consisting of vemurafenib, dabrafenib, LGX818, trametinib, MEK162, LEE011, PD-0332991, panobinostat, vorinstat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib, panitumumab, vandetanib, INC280, everolimus, sirolimus, BMK120, BYL719 or CLR457, or a combination thereof.

[0117] 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., ), dabrafenib (e.g., ), dacarbazine, recombinant interferon alfa-2b (e.g., A), ipilimumab, trametinib (e.g., ), pegylated interferon alfa-2b (e.g., SYLATRONTM), Vemurafenib (e.g., ), and ipilimumab (e.g., ).

[0118] For the treatment of ovarian cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride Carboplatin Cyclophosphamide Cisplatin Liposomal doxorubicin hydrochloride Gemcitabine Hydrochloride Topotecan Hydrochloride and paclitaxel

[0119] For the treatment of thyroid cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride Cabozantinib-S-malate Vandetanib

[0120]

[0121] For the treatment of colon cancer, the additional therapeutic agent is selected from fluorouracil (e.g., ), bevacizumab Irinotecan hydrochloride Capecitabine Cetuximab Oxaliplatin Calcium folinate Regorafenib Panitumumab and ziv-aflibercept

[0122] For the treatment of lung cancer, the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., FOLEX ), paclitaxel Paclitaxel albumin stabilized nanoparticle formulation Afatinib dimaleate Pemetrexed disodium Bevacizumab Carboplatin Cisplatin Crizotinib Erlotinib Hydrochloride Gefitinib and gemcitabine hydrochloride

[0123] For the treatment of pancreatic cancer, the other therapeutic agent may be selected from fluorouracil Erlotinib Hydrochloride Gemcitabine Hydrochloride and mitomycin or mitomycin C (MITOZYTREX™, ).

[0124] For the treatment of cervical cancer, the additional therapeutic agent is selected from bleomycin Cisplatin and topotecan hydrochloride

[0125] For the treatment of head and neck cancer, the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., FOLEX ), fluorouracil Bleomycin Cetuximab Cisplatin and docetaxel

[0126] For the treatment of leukemia, including chronic myelomonocytic leukemia (CMML), the additional therapeutic agent is selected from bosutinib Cyclophosphamide Cytarabine Dasatinib Imatinib mesylate Ponatinib Nilotinib Homitacin

[0127] In some cases, during or after administration, patients may experience allergic reactions to the compounds of the invention and / or other anticancer agents. Thus, antiallergic agents may be administered to minimize the risk of allergic reactions. Suitable antiallergic agents include corticosteroids, such as dexamethasone (e.g., ), beclomethasone (e.g. ), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate; e.g., Hydrocortisone phosphate, HYDROCORT and ), prednisolone (e.g. and ), prednisone (e.g., LIQUID and ), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate; e.g., and ); antihistamines, such as diphenhydramine (e.g. ), hydroxyzine, and cyproheptadine; and bronchodilators, such as beta-adrenergic receptor agonists, albuterol (e.g., ), and terbutaline

[0128] In other cases, patients may experience nausea during and after administration of the compounds of the invention and / or other anticancer agents. Thus, antiemetics may be administered to prevent nausea (epigastric) and vomiting. Suitable antiemetics include aprepitant Ondansetron Granisetron HCl Lorazepam ( Dexamethasone Prochlorperazine Cassopitant and ), and combinations thereof.

[0129] In still other cases, medications are prescribed to relieve pain experienced during the treatment period to make the patient more comfortable. Common over-the-counter analgesics such as Opioid analgesics such as hydrocodone / acetaminophen or hydrocodone / acetaminophen (e.g. ), morphine (e.g. or ), oxycodone (e.g. or ), oxymorphone hydrochloride and fentanyl (e.g., ) is also used for moderate or severe pain.

[0130] In addition, cytoprotectants (such as neuroprotectants, free radical scavengers, cardioprotectants, anthracycline antibiotic extravasation neutralizers, nutrients, etc.) can be used as adjunctive therapy to protect normal cells from treatment toxicity and limit organ toxicity. Suitable cytoprotectants include amifostine Glutamine, Dimethoate Mesna Right rezoxan or ), Zali Roden and folinic acid (also called calcium folinate, lecithin and folinic acid).

[0131] In yet another aspect, the compounds of the invention may be used in combination with known therapeutic procedures (eg, with hormone administration or in radiotherapy). In certain cases, the compounds of the invention may be used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiotherapy.

[0132] The dosage and dosing regimen of the active ingredients used in the combination therapy can be determined by the attending clinician. In certain embodiments, the compounds 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-difluoroethane-1-ol D-tartrate) and additional therapeutic agent(s) are administered at doses generally used when the agent is used as a monotherapy for the treatment of a disease or condition. In other embodiments, a 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 the additional therapeutic agent(s) are administered at doses that are lower than doses generally used when the agents are used as monotherapy to treat a disease or condition. In certain embodiments, a 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 the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.

[0133] In certain embodiments, the compounds 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) and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow for the use of lower doses of one or more agents and / or less frequent dosing of one or more agents of the combination therapy. Lower doses or less frequent dosing of one or more agents may reduce the toxicity of a treatment without reducing the efficacy of the treatment.

[0134] Yet another aspect of the invention is a kit comprising a therapeutically effective amount of a 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), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above. In certain embodiments, the kit further comprises instructions, such as instructions for treating a disease described herein.

[0135] IV. Pharmaceutical Composition and Dosing Considerations

[0136] As indicated above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds described above, and one or more pharmaceutically acceptable carriers (additives) and / or diluents formulated therewith. The pharmaceutical compositions can be specially formulated for administration in solid or liquid form, including those suitable for the following: (1) oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, such as those targeted for buccal, sublingual and systemic absorption, pills, powders, granules, pastes for application to the tongue; (2) parenteral administration, such as by subcutaneous, intramuscular, intravenous or epidural injection, as, for example, a sterile solution or suspension or a sustained release formulation; (3) topical administration, such as a cream, ointment or a controlled release patch or spray applied to the skin; (4) intravaginal or intrathecal administration, such as a pessary, cream or foam; (5) sublingual administration; (6) ocular administration; (7) transdermal administration; or (8) nasal administration. In certain embodiments, the present invention provides a pharmaceutical composition comprising a 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 a pharmaceutically acceptable carrier.

[0137] The phrase "therapeutically effective amount" as used herein means an amount of a compound, substance, or composition comprising a compound of the invention effective to produce some desired therapeutic effect in at least a subpopulation of cells in an animal, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0138] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0139] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0140] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0141] Preparaton of the present invention includes those suitable for oral, nasal, local (including buccal and sublingual), rectal, vaginal and / or parenteral administration. Preparaton can be conveniently in unit dosage form and can be prepared by any method known in the field of pharmaceutics. The amount of active ingredient that can be combined with carrier material to produce single dosage form will depend on the main body being treated, specific mode of administration changes. The amount of active ingredient that can be combined with carrier material to produce single dosage form will generally be the amount of the compound producing the therapeutic effect. In general, in 100 percent, the scope of this amount will be about 0.1 percent to about 99 percent, preferably about 5 percent to about 70 percent, most preferably about 10 percent to about 30 percent active ingredient.

[0142] In certain embodiments, the formulations of the present invention comprise excipients selected from cyclodextrins, cellulose, liposomes, micelle formers such as bile acids, and polymer carriers such as polyesters and polyanhydrides; and compounds of the present invention. In certain embodiments, the aforementioned formulations make the compounds of the present invention orally bioavailable.

[0143] Methods for preparing these formulations or compositions include the step of combining a compound of the present invention with a carrier and, optionally, one or more additional ingredients. The formulations are generally 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.

[0144] 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), powders, granules, 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 pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the present invention as the active ingredient. The compounds of the present invention may also be administered as a bolus, electuary or paste.

[0145] In a solid dosage form of the invention for oral administration (capsules, tablets, pills, lozenges, powders, granules, troches, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dibasic calcium phosphate and / or any of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids, or the like. Salt, and sodium carbonate; (5) dissolution retardants, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glyceryl monostearate, and nonionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 composition may also contain a buffer. Solid compositions of a similar type may also be used as fillers in soft and hard shell gelatin capsules, using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0146] Tablets can be prepared by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared with a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surface active or dispersing agent. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0147] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as lozenges, capsules, pills and granules, can optionally be obtained or prepared with coatings and shells such as enteric coatings and other coatings well known in the field of pharmaceutical preparations. They can also be formulated with, for example, hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres that provide a varying ratio of desired release characteristics to provide a slow or controlled release of the active ingredient therein. They can be formulated for rapid release, such as freeze-drying. They can be sterilized as follows: for example, by filtering through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium just before use. These compositions can also optionally contain an opacifier and can be a composition that releases one or more active ingredients only or preferentially in certain parts of the gastrointestinal 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 a microencapsulated form, if appropriate, with one or more of the excipients described above.

[0148] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may also contain an inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0149] 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.

[0150] Suspensions, in addition to the active compounds, may contain 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.

[0151] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be in the form of suppositories, which may be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers (including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates) and which are solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.

[0152] 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.

[0153] Dosage forms for topical or transdermal administration of the compounds of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

[0154] 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.

[0155] In addition to the compounds of this invention, powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0156] The additional advantage of transdermal patches is that they provide controlled delivery of the compounds of the invention to the body. The dosage form can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate of the flow can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0157] Ophthalmic formulations, eye ointments, powders, solutions, etc. are also contemplated as being within the scope of this invention.

[0158] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0159] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0160] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Preventing the effects of microorganisms on the subject compound can be ensured by including various antibacterial and antifungal agents such as hydroxyphenyl esters, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. in the composition. In addition, prolonged absorption of injectable drug forms may be caused by including agents that delay absorption such as aluminum monostearate and gelatin.

[0161] In some cases, it is desirable to slow down the absorption of drugs injected subcutaneously or intramuscularly in order to prolong the effect of the drug. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The drug absorption rate depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a drug form administered parenterally can be achieved by dissolving or suspending the drug in an oil vehicle.

[0162] Injectable depot dosage forms are prepared as follows: a microcapsule matrix of the subject compound is formed in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the properties of the specific polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by embedding the drug in liposomes or microemulsions compatible with body tissues.

[0163] In case the compounds of the present invention are administered to humans and animals as drugs, they can be administered as such or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably 10 to 30%) of an active ingredient in combination with a pharmaceutically acceptable carrier.

[0164] The preparations of the invention can be given orally, parenterally, topically or rectally. They are of course given in a form suitable for each route of administration. For example, they are given in tablet or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., by injection, infusion or inhalation; topically by lotion or ointment; and rectally by suppository. Oral administration is preferred.

[0165] The phrases "parenteral administration" and "administered parenterally" as used herein refer to 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, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0166] The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" as used herein refer to administration of a compound, drug, or other substance that does not enter the central nervous system directly but instead enters the patient's system and thereby undergoes metabolism and other similar processes, an example being subcutaneous administration.

[0167] These compounds can be administered to humans and other animals for therapeutic purposes by any suitable route of administration, including oral, nasal (by, for example, spray), rectal, vaginal, parenteral, intracisternal and topical (by powders, ointments or drops), including buccal and sublingual.

[0168] Independently of the selected administration route, the compound of the present invention and / or the pharmaceutical composition of the present invention, which can be used in a suitable hydrated form, is formulated into a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art.

[0169] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0170] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or its ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or substances used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0171] A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can begin dosing the compound of the invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0172] Typically, the appropriate daily dose of the compounds of the invention is the amount of the compound at the lowest dose that effectively produces a therapeutic effect. The 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. In the case where the compounds described herein are administered together with another agent (e.g., as a sensitizer), the effective amount may be less than the amount when the agent is used alone.

[0173] If desired, the effective daily dose 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 form. The preferred dosage administration is once a day.

[0174] The invention further provides unit dosage forms (such as tablets or capsules) comprising a therapeutically effective amount of a compound described herein for treating a disease or condition described herein. Example

[0175] The invention now generally described will be more readily understood by reference to the following examples, which are included for the sole purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention. The starting materials described herein can be obtained from commercial sources or can be readily prepared from commercially available materials using transformations known to those skilled in the art.

[0176] 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

[0177]

[0178] (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 the slurry was added D-tartaric acid (1.1 eq) dissolved in water (1.5 mL) over approximately one hour. The resulting mixture was warmed to 65° C. and maintained at that temperature for two days. The resulting slurry was then cooled to ambient temperature, filtered, and the collected solids were dried in a vacuum oven to provide the title compound in 77% yield as a crystalline solid.

[0179] 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

[0180]

[0181] (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 the slurry was added D-tartaric acid (1.1 eq) dissolved in water (0.75 mL) over approximately one hour. The resulting mixture was warmed to 50° C. and maintained at that temperature for two days. The resulting slurry was then cooled to ambient temperature, filtered, and the collected solids were dried in a vacuum oven to provide the title compound in 79% yield as a crystalline solid.

[0182] 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

[0183]

[0184] (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 isopropanol (15 mL) at ambient temperature. To the slurry was added D-tartaric acid (1.1 eq) dissolved in water (0.75 mL) over approximately one hour. The resulting mixture was warmed to 50° C. and maintained at that temperature for two days. The resulting slurry was then cooled to ambient temperature, filtered, and the collected solids were dried in a vacuum oven to provide the title compound in 74% yield as a crystalline solid.

[0185] 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

[0186]

[0187] The following analyses were 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 prepared according to the procedure of Example 1: X-ray powder diffraction, simultaneous thermogravimetric analysis and differential scanning calorimetry, differential scanning calorimetry, dynamic vapor sorption (analysis of hygroscopicity), Karl Fischer titration, and proton nuclear magnetic resonance spectroscopy.

[0188] X-ray powder diffraction was performed using 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 geometry). Samples were prepared on Si zero-return wafers. The XRPD parameters using the Rigaku MiniFlex 600 were:

[0189]

[0190] The XRPD parameters using the Bruker D8 Advance are:

[0191]

[0192] The X-ray powder diffraction pattern of one batch of the title compound is Figure 1 Provided in the table below. Figure 1 Tabulated characteristics of the X-ray powder diffraction pattern of , listing the diffraction angle 2θ, the interlayer spacing d and the relative intensity (expressed as a percentage relative to the most intense peak):

[0193] X-ray powder diffraction pattern data

[0194]

[0195]

[0196] The X-ray powder diffraction pattern of the second batch of the title compound is Figure 2 Provided in the table below. Figure 2 Tabulated characteristics of the X-ray powder diffraction pattern of , listing the diffraction angle 2θ, the interlayer spacing d and the relative intensity (expressed as a percentage relative to the most intense peak):

[0197] X-ray powder diffraction pattern data

[0198]

[0199] Simultaneous Thermogravimetric Analysis and Differential Scanning Calorimetry with Mettler Toledo TGA / DSC3+ The protective gas and flushing gas were nitrogen at flow rates of 20-30 mL / min and 50-100 mL / min, respectively. The sample (5-10 mg) was weighed directly into a sealed aluminum pan with a pinhole and analyzed according to the following parameters: ramp method, heating rate 10.0 °C / min, temperature range 30 to 300 °C. The differential scanning calorimetry curve and thermogravimetric analysis curve of the title compound are Figure 3 Available in.

[0200] Separate differential scanning calorimetry analysis using a Mettler Toledo DSC 3+ (method gas flow rate 60.00 mL / min) or TA Discovery DSC (method gas flow rate 50.00 mL / min). For either instrument, samples (1-5 mg) were weighed directly into a 40 μL sealed aluminum pan with a pinhole and analyzed according to the following parameters: isotropic method, heating rate 10.0°C / min, temperature range 30 to 300°C, and method gas N2. The differential scanning calorimetry curve of the title compound obtained according to this procedure is Figure 4 Available in.

[0201] The hygroscopicity of the title compound was analyzed by dynamic vapor sorption. Dynamic vapor sorption was performed with a Q5000SA. The sample (5-15 mg) was loaded into a metal quartz sample pan, suspended from a microbalance, and exposed to a humidified nitrogen stream. The weight change was an empty reference pan matched to the opposite side of the sample suspended from the microbalance. The sample was kept at each humidity level for a minimum of 10 minutes and was only advanced to the next humidity level when the weight change between measurements (interval: 5 s) was <0.002% or 60 minutes had passed. The following procedure was used:

[0202] 1. Balanced at 50% RH

[0203] 2.50% to 5% (50%, 35%, 20%, and 5%)

[0204] 3.5% to 95% (5%, 20%, 35%, 50%, 65%, 80%, and 95%)

[0205] 4.95% to 5% (95%, 80%, 65%, 50%, 35%, 20%, and 5%)

[0206] 5.5% to 50% (5%, 20%, 35%, and 50%).

[0207] The results of hygroscopicity analysis by dynamic vapor sorption are described in Figure 5 , where a weight increase of 4.858% was observed in the case of transition from 5% to 95% relative humidity.

[0208] The water content of the title compound was analyzed by Karl Fischer (KF) titration and determined to have a water content of 1.22 wt%. Karl Fischer (KF) titration to determine water was performed using a Mettler Toledo C20S coulometric KF titrator equipped with a current generator cell with diaphragm, and a double platinum needle electrode. The detection range of the instrument is 1 ppm to 5% water. Aquastar TM The CombiCoulomat diaphragmless reagent was used in both the anodic and cathodic compartments. Approximately 0.03-0.10 g of sample was dissolved in the anodic compartment and titrated until the solution potential dropped below 100 mV. A Hydranal 1 wt% water standard was used for verification prior to sample analysis.

[0209] By proton nuclear magnetic resonance spectroscopy ( 1 H NMR) analysis of the title compound confirmed the absence of residual solvent above the detection limit and 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. Proton NMR ( 1 H NMR) spectra were performed on a Bruker Avance 500MHz spectrometer. The solid was dissolved in 0.60-0.75mL of a deuterated solvent in a 4mL vial, transferred to an NMR tube (Wilmad 5mm thin wall 8" 200MHz, 506-PP-8) and analyzed according to the following parameters:

[0210] parameter value temperature 300K Probe 5mm PABBO BB-1H / D Z-GRD Z113652 / 0159 Scan number 32 Relaxation delay 30.000s Pulse Width 14.0000μs Collection time 3.2506s Spectrum analyzer frequency 500.13MHz

[0211] At pH 6.8 and 37°C, the crystalline form exhibited an aqueous solubility of >2.0 mg / mL after both 30 minutes and 24 hours. Additionally, as described in Example 5 below, the crystalline material showed good stability in accelerated stability studies.

[0212] Example 5 - Accelerated Stability Study

[0213] 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 prepared as described in Example 1 was studied for accelerated stability. Approximately 12 mg of the solid was placed in a 4-mL vial, which was then covered with absorbent paper (Kimwipe). The vial was stored in a stability room at 75% relative humidity generated at 40°C for 6 days. The recovered salt was analyzed by HPLC, showing good chemical stability: 99.53 area percent purity before the study and 99.45 area percent purity after the study. The recovered salt was analyzed by XRPD, showing no crystalline change.

[0214] Example 6 - One-year stability study

[0215] A one-year stability study was conducted on a 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 an XRDP pattern as described in Example 4. Specifically, 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 25°C ± 2°C and a relative humidity of 60% ± 5% for 1 year. 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 salt were analyzed in this experiment at the following time points: day 0 (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 determined by coulometry Karl Fischer (CKF) assay, purity determined by ultra performance liquid chromatography (UPLC), and total amount of related substances. XRPD analysis was performed on compound samples at day 0 and at the 12 month time point.

[0216] The results of the stability study are provided in the table below. The stability study results show that the tested 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 storage stability. For example, 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 very little change in water content during the 12-month stability study. Additionally, it was determined by UPLC analysis that 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 salt maintained a high level of purity and that the XRPD spectrum obtained for 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 salt stored for 12 months matched the XRPD spectrum obtained for the compound at the beginning of the stability study (i.e., day 0).

[0217] Results of stability study at 25°C ± 2°C and 60% ± 5% relative humidity

[0218]

[0219] Example 7 - Six Month Stability Study at Elevated Temperature & Relative Humidity

[0220] A six-month stability study was conducted on a 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 an XRDP pattern as described in Example 4. Specifically, 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 and a relative humidity of 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 salt were analyzed in this experiment at the following time points: day 0 (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 determined by coulometry Karl Fischer (CKF) assay, purity determined by ultra performance liquid chromatography (UPLC), and total amount of related substances. XRPD analysis was performed on compound samples at day 0 and at the 6 month time point.

[0221] The results of the stability study are provided in the table below. The stability study results show that 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 salt tested has good storage stability. 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 salt has low hygroscopicity, as evidenced by very little change in water content during the 6-month stability study. Additionally, it was determined by UPLC analysis that 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 salt maintained a high level of purity, and the XRPD spectrum obtained for 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 salt stored for 6 months matched the XRPD spectrum obtained for the compound at the beginning of the stability study (i.e., day 0).

[0222] Results of stability study at 40°C ± 2°C and 75% ± 5% relative humidity

[0223]

[0224] Example 8 - Analysis of Water Solubility

[0225] The solubility of the test compounds was evaluated in two different fluids: (a) water and (b) fasted state simulated intestinal fluid. The test compounds analyzed were:

[0226] ● 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 described in Example 4 (hereinafter "Compound A");

[0227] ●(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 fumarate (hereinafter "Compound B");

[0228] ●(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").

[0229] Aliquots of the test compound were placed in a liquid at a temperature of 37°C and the concentration of the dissolved test compound was determined after 24 hours. The pH of the solution at 24 hours was also measured. The results are provided in the table below.

[0230] Test compound solubility

[0231]

[0232] pH value of liquid medium

[0233]

[0234] 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

[0235]

[0236] In a reactor vessel, (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), and the temperature of the reactor vessel was adjusted to a range of 30°C to 40°C, and the reactor vessel was under nitrogen. The resulting mixture was filtered, ethanol (36.4 kg) was added and the mixture was concentrated under reduced pressure. Ethanol (18, 18, 19, 19 kg) was added several times 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 slowly added to the reactor vessel. The resulting mixture was seeded 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 (20 g). The resulting mixture was maintained at a temperature in the range of 45°C to 55°C and 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).

[0237] 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

[0238]

[0239] (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 (23 kg) was added. More ethanol (60 kg) was added to the resulting mixture and the reactor temperature was adjusted to 60-70°C before the reaction mixture was transferred to another reactor vessel at 60-70°C and clarified via filtration. The reactor was washed with ethanol (35 kg) and the resulting mixture was transferred to a receiving reactor via clarification. The reactor was maintained at a temperature ranging from 60°C to 70°C. D-Tartaric acid (4.7 kg) was mixed with ethanol (11.5 kg) and water (1.5 kg), and the resulting mixture was stirred at 20-30°C and then added to 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. Subsequently, the reactor was further cooled to a temperature in the range of 10° C. to 20° C., the mixture was then filtered, and the separated filter cake was washed twice with a 95% ethanol / water solution (20, 19 kg). The separated material was then dried to provide the title compound (16.8 kg). 1 H NMR (DMSO, 300MHz) 8.53 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.68 (dd, J=12.4, 7.4Hz, 1H), 7.33 (s, 2H), 7.13 (dd, J=12.9, 7.3Hz, 7.05 (s, 1H), 6.27 (td, J=54.4, 3.4Hz, 1H), 5.59 (br s, 2H), 4.01-3.88 (m, 2H), 3.85 (s, 3H), 3.19 (d, J=11.8Hz, 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 + ).

[0240] Join by reference

[0241] The entire disclosures of each patent document and scientific article mentioned herein are incorporated by reference for all intents.

[0242] Equivalent method

[0243] The present invention may be embodied in other specific forms without departing from its purport or essential features. Therefore, the aforementioned embodiments are considered to be exemplary in all aspects and do not limit the invention described herein. Thus, the scope of the present invention is indicated by the appended claims rather than the foregoing description, and it is expected to cover all changes within the equivalent meaning and scope of the claims.

Claims

1. A compound which is a D-tartrate salt of:

2. The compound of claim 1, wherein the molar ratio of D-tartaric acid to the following compound is about 1:1:

3. The compound of claim 1 or 2, wherein the compound is in crystalline form.

4. The compound of claim 3, wherein 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.

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

2.

6. The compound of claim 4 or 5, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 17.7±0.

2.

7. The compound of any one of claims 4 to 6, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 19.0±0.

2.

8. The compound of any one of claims 4 to 7, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 21.4±0.

2.

9. The compound of any one of claims 4 to 8, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 22.7±0.

2.

10. The compound of any one of claims 4 to 9, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 24.3±0.

2.

11. The compound of any one of claims 4 to 10, wherein the relative intensity of the peak at said diffraction angle (2θ) is at least 25%.

12. The compound of any one of claims 4 to 10, wherein the relative intensity of the peak at said diffraction angle (2θ) is at least 15%.

13. The compound according to claim 3, characterized in that The following X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, interlayer spacing d and relative intensity (expressed as a percentage relative to the most intense peak):

14. The compound of claim 3, wherein the X-ray powder diffraction pattern is substantially as shown in Figure 1.

15. The compound of claim 3, wherein the X-ray powder diffraction pattern is substantially as shown in Figure 2.

16. The compound of any one of claims 3-15, wherein the compound has an onset melting point in the range of about 225 degrees Celsius to about 240 degrees Celsius as determined by differential scanning calorimetry.

17. The compound of any one of claims 3-15, wherein the compound has an onset melting point of about 233 degrees Celsius as determined by differential scanning calorimetry.

18. The compound of any one of claims 3-15, wherein the compound has a differential scanning calorimetry curve substantially the same as that shown in Figure 4.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier.

20. A method for treating a disease or condition mediated by nuclear SET domain-containing protein 2 (NSD2), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-18 to treat the disease or condition.

21. The method of claim 20, wherein the disease or condition mediated by NSD2 is cancer.

22. The method of claim 20, wherein the disease or condition mediated by NSD2 is selected from the group consisting of solid tumors, leukemia, myeloma, lymphoma, and hypertension.

23. The method of claim 20, 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 tumors, osteosarcoma, multiple myeloma, neuroblastoma, leukemia, non-Hodgkin lymphoma, or pulmonary hypertension.

24. The method of claim 20, wherein the disease or condition mediated by NSD2 is acute lymphoblastic leukemia, squamous cell carcinoma of the skin, or mantle cell lymphoma.

25. The method of any one of claims 20-24, wherein the subject is a human.

26. A method for inhibiting the activity of nuclear SET domain-containing protein 2 (NSD2), comprising contacting NSD2 with an effective amount of a compound according to any one of claims 1 to 18 to inhibit the activity of said NSD2.

Images