Pharmaceutical compositions containing piperidinyl methylpurine amines and their use in the treatment

Abstract

The present invention provides pharmaceutical compositions comprising piperidylmethylpurine amines and their use for inhibiting NSD2 and treating diseases or disorders, such as cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 63 / 431,771, filed December 12, 2022, the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present invention provides pharmaceutical compositions comprising piperidinylmethylpurine amine and uses thereof for inhibiting NSD2 and treating diseases or conditions such as cancer. Background Art

[0004] Despite extensive research and scientific advances in cancer treatment, the disease remains a significant health problem. Solid tumors, including prostate, breast, and lung cancer, remain common in the global population. Current treatment options for these cancers are not effective for all patients and / or may result in severe adverse side effects. New therapies 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 modifier that plays a role in tumorigenesis. A variety of human cancers are associated with NSD2 overexpression and / or activating point mutations. (Coussens et al., J.Biol.Chem.293 (2018) 13750-13654.) For example, it is reported that NSD2 is highly expressed in human cancers (including bladder cancer, brain cancer, gastrointestinal cancer, lung cancer, liver cancer, ovarian cancer, skin cancer, uterine cancer, breast cancer, prostate cancer and glioblastoma). In addition, the pediatric cancer genome seems particularly likely to contain NSD2 mutations. Finally, upregulation of NSD2 is associated with aggressive tumor behavior and poor clinical outcomes. International patent application publication WO 2021 / 028854 describes certain compounds that inhibit NSD2. Pharmaceutical compositions of such compounds possess the properties desired for commercial production and would benefit patients suffering from NSD2-related diseases or disorders.

[0006] The present invention satisfies the above-identified needs and provides other related advantages. Summary of the Invention

[0007] The present invention provides a pharmaceutical composition comprising piperidinylmethylpurine amine and its use for inhibiting NSD2 and treating diseases or conditions such as cancer. Specifically, one aspect of the present invention provides a pharmaceutical composition comprising:

[0008] (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by:

[0009] or a pharmaceutically acceptable salt thereof;

[0010] (b) at least 40% weight / weight microcrystalline cellulose;

[0011] (c) at least 10% weight / weight pregelatinized starch;

[0012] (d) at least 2% weight / weight of cross-linked carboxymethyl cellulose or a pharmaceutically acceptable salt thereof; and

[0013] (e) at least 0.75% w / w of stearic acid or a pharmaceutically acceptable salt thereof.

[0014] Further descriptions of additional pharmaceutical compositions are described in the detailed description. For example, another aspect of the present invention provides a pharmaceutical composition comprising:

[0015] (a) 17% w / w to 25% w / w of a compound of formula I, wherein formula I is D-tartrate;

[0016] (b) 51% to 56% weight / weight microcrystalline cellulose;

[0017] (c) about 20% weight / weight pregelatinized starch;

[0018] (d) about 4% weight / weight croscarmellose sodium; and

[0019] (e) about 1.5% w / w magnesium stearate.

[0020] Yet another aspect of the present invention provides a pharmaceutical composition comprising:

[0021] (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by:

[0022] or a pharmaceutically acceptable salt thereof; and

[0023] (b) at least 60% weight / weight of a diluent selected from microcrystalline cellulose, pregelatinized starch, or a combination thereof.

[0024] Another aspect of the present invention provides a tablet for oral administration, wherein the tablet comprises the pharmaceutical composition described herein.

[0025] Another aspect of the present invention provides a method for preparing a pharmaceutical composition, comprising the steps of:

[0026] (i) providing a first mixture, the first mixture comprising:

[0027] (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by:

[0028] or a pharmaceutically acceptable salt thereof;

[0029] (b) at least 40% weight / weight microcrystalline cellulose;

[0030] (c) at least 10% weight / weight pregelatinized starch;

[0031] (d) at least 2% weight / weight of cross-linked carboxymethyl cellulose or a pharmaceutically acceptable salt thereof; and

[0032] (e) at least 0.75% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof;

[0033] (ii) subjecting the first mixture to roller compaction to produce a compacted mixture; and

[0034] (iii) subjecting the compacted mixture to a compression force to produce a compressed pharmaceutical composition.

[0035] Another aspect of the present invention provides a pharmaceutical composition prepared according to the aforementioned method.

[0036] Another aspect of the present invention provides a method for treating a disease or condition mediated by NSD2 in a subject. The method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein to treat the disease or condition, as further described in the detailed description.

[0037] Another aspect of the present invention provides a method for inhibiting the activity of nuclear SET domain-containing protein 2 (NSD2), comprising contacting NSD2 with an effective amount of a pharmaceutical composition described herein, as further described in the detailed description. DETAILED DESCRIPTION

[0038] The present invention provides pharmaceutical compositions comprising piperidinylmethylpurine amine and their use for inhibiting NSD2 and treating diseases or conditions such as cancer. Unless otherwise indicated, the practice of the present invention employs conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in "Comprehensive Organic Synthesis" (BM Trost & I. Fleming, ed., 1991-1992); "Handbook of experimental immunology" (DM Weir & C.C. Blackwell, ed.); "Current protocols in molecular biology" (FM Ausubel et al., ed., 1987, and periodic updates); and "Current protocols in immunology" (JE Coligan et al., ed., 1991), each of which is incorporated herein by reference in its entirety.

[0039] The following subsections set forth various aspects of the present invention; however, the aspects of the present invention described in a particular section are not limited to any particular section. In addition, when a variable is not accompanied by a definition, the previous definition of the variable shall prevail.

[0040] definition

[0041] The compounds of the present invention include those compounds generally described herein and further described by the classes, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. Unless otherwise indicated, these definitions apply regardless of whether the term is used alone or in combination with other terms. Thus, the definition of "alkyl" applies to the "alkyl" portion of "alkyl" as well as "-O-alkyl" and the like. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999; and "March's Advanced Organic Chemistry", 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0042] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "cycloaliphatic") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0043] As used herein, the term "bicyclic" or "bicyclic ring system" refers to any bicyclic ring system having one or more common atoms between the two rings of the ring system, saturated or having one or more unsaturated units, i.e., carbocyclic or heterocyclic. Therefore, the term includes any allowed ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a "bicyclic" subgroup that requires one or more heteroatoms to be present in one or both rings of the bicyclic ring. Such heteroatoms may be present in the ring junction and are optionally substituted and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, such as sulfones and sulfonates), phosphorus (including oxidized forms, such as phosphates), boron, etc. In some embodiments, 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 having at least one bridge bond, saturated or partially unsaturated, i.e., carbocyclic or heterocyclic. As defined by IUPAC, "bridge bond" is a non-branched atomic chain or atom or valence bond connecting two bridgeheads, wherein "bridgehead" is any backbone atom bonded to three or more backbone atoms (excluding hydrogen) of a ring system. In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridged bicyclic groups are well known in the art and are included in the groups described below, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as described for an aliphatic group. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic groups include:

[0044]

[0045] Exemplary bridged double rings include:

[0046]

[0047] 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.

[0048] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl.

[0049] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; a quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0050] The term "unsaturated" as used herein means that the moiety has one or more units of unsaturation.

[0051] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain” refers to divalent alkylene, alkenylene and alkynylene chains as defined herein that are straight or branched.

[0052] 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. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0053] The term "-(C0 alkylene)-" refers to a bond. Thus, the term "-(C0 alkylene)-" 0-3 Alkylene)-" encompasses bonds (i.e., C0) and -(C 1-3 alkylene)-group.

[0054] The term "alkenylene" refers to a divalent alkenyl group. Substituted alkenylene chains are polymethylene groups containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0055] The term "halogen" means F, Cl, Br or I.

[0056] The term "aryl" used alone or as part of a larger moiety as in "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 that may bear one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, and the like. Groups in which an aromatic ring is fused to one or more non-aromatic rings (such as dihydroindanyl, phthalimide, naphthimide, phenanthridinyl, or tetrahydronaphthyl, etc.) are also included within the scope of the term "aryl" as used herein. The term "phenylene" refers to a polyvalent phenyl group having an appropriate number of open valences to account for the group to which it is attached.

[0057] 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 pi electrons shared in the ring arrangement; 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 a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaromatic-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein, unless otherwise specified, an attachment group or point is located on the heteroaromatic ring or on one of the rings fused to the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl and tetrahydroisoquinolyl. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which includes rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0058] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen," when used with respect to a ring atom of a 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).

[0059] Heterocycle can be connected to its side group at any heteroatom or carbon atom that produces stable structure, and any one of ring atoms can be optionally substituted.The example of such saturated or partially unsaturated heterocyclic radical includes but is not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazepine, thiazepine, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic group" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinium, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl portion and the heterocyclyl portion are independently optionally substituted. The term "oxoheterocyclyl" refers to a heterocyclyl substituted with an oxo group. The term "heterocyclylene" refers to a polyvalent heterocyclyl group having an appropriate number of open valences to account for the groups attached thereto. For example, "heterocyclylene" is a divalent heterocyclyl group when two groups are attached thereto; "heterocyclylene" is a trivalent heterocyclyl group when three groups are attached thereto.

[0060] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. As defined herein, the term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0061] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. Typically, whether or not the term "optionally" is present, the term "substituted" means that one or more hydrogens of the designated moiety are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in a given structure can be substituted by more than one substituent selected from a specified group, the substituents may be the same or different at each position. The substituent combinations contemplated by the present invention are preferably those that form stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow compound preparation, detection, and in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0062] Each optional substituent on a substitutable carbon is independently selected from the following monovalent substituents: halogen; -(CH2); 0–4 R o; –(CH2) 0–4 OR o ;-O(CH2) 0-4 R o 、–O–(CH2) 0–4 C(O)OR o ; –(CH2) 0–4 CH(OR o )2;–(CH2) 0– 4SR o ; –(CH2) 0–4 Ph, which can be R o Substitution; –(CH2) 0–4 O(CH2) 0–1 Ph, which can be R o Substitution; –CH=CHPh, which can be replaced by R o Substitution; –(CH2) 0–4 O(CH2) 0–1 -pyridyl, which may be 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) 0–4C(O)OSiR o 3;–(CH2) 0–4 OC(O)R o ; –OC(O)(CH2) 0–4 SR–、SC(S)SR o ; –(CH2) 0–4 SC(O)R o ; –(CH2) 0–4 C(O)NR o 2;–C(S)NR o 2;–C(S)SR o ;–SC(S)SR o 、-(CH2) 0–4 OC(O)NR o 2;-C(O)N(OR o )R o ;–C(O)C(O)R o ;–C(O)CH2C(O)R o ;–C(NOR o )R o ; -(CH2) 0–4 SSR o ; -(CH2) 0–4 S(O)2R o ; –(CH2) 0–4 S(O)2OR o ; –(CH2) 0–4 OS(O)2R o ;–S(O)2NR 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 linear or branched alkylene)O–N(R o )2; or –(C1–4 linear or branched alkylene) C(O)O–N(R o )2.

[0063] Each R o are independently hydrogen, C 1–6 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, -CH2-(5-6 membered heteroaromatic ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or regardless of the above definitions, two independent occurrences of R o Together with their intervening atoms, they form 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 is substituted by a divalent substituent selected from =O and =S; or each R o Optionally substituted with monovalent substituents independently selected from halogen, -(CH2) 0–2 R · 、–(halogen R · ),–(CH2) 0–2 OH, –(CH2) 0–2 OR · 、–(CH2) 0–2 CH(OR · )2;-O(halogen R · ), –CN, –N3, –(CH2) 0–2 C(O)R · 、–(CH2) 0–2 C(O)OH, –(CH2) 0–2 C(O)OR · 、–(CH2) 0–2 SR · 、–(CH2) 0–2 SH, –(CH2) 0–2 NH2, –(CH2) 0–2 NHR · 、–(CH2) 0–2 NR · 2. –NO2, –SiR · 3. –OSiR · 3. -C(O)SR · 、–(C 1–4 linear or branched alkylene)C(O)OR · or –SSR · .

[0064] Each R · Independently selected from C 1–4Aliphatic, –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 · unsubstituted or, when preceded by a halo, substituted only with one or more halogens; or wherein the optional substituents on a saturated carbon are divalent substituents 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 S—, or a divalent substituent attached to an ortho-substitutable carbon of an “optionally substituted” group is —O(CR * 2) 2–3 O–, where each independent occurrence of R * Selected from hydrogen, C 1–6 An aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0065] When R * C 1–6 When aliphatic, R * Optionally halogen, –R · 、-(halogen R · ),-OH, –OR · 、–O(halogen R · ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · ,–NR · 2 or –NO2, where each R · Independently selected from C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · It is unsubstituted or, when preceded by a halo group, is substituted only by one or more halo groups.

[0066] The optional substituents on the substitutable nitrogen are independently or Each of these are independently hydrogen, C 1–6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independent occurrences of Together with their intervening atoms, they form 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 when C 1–6 When aliphatic, Optionally halogen, –R · 、-(halogen R · ),-OH, –OR · 、–O(halogen R · ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · ,–NR · 2 or –NO2, where each R · Independently selected from C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0– 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 · It is unsubstituted or, when preceded by a halo group, is substituted only by one or more halo groups.

[0067] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with human and lower animal tissues without producing excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment and with a commensurate and reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids and bases and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0068] In addition, acids generally considered suitable for forming pharmaceutically acceptable salts from basic pharmaceutical compounds have been discussed, for example, by P. Stahl et al., Camille G. (ed.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, DC Con their website). The disclosures of these are incorporated herein by reference.

[0069] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Further pharmaceutically acceptable salts include (when appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cation salts formed using counterions such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.

[0070] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers as well as mixtures of enantiomers, diastereoisomers, and geometric (or conformational) isomers of the present compounds are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the present compounds are within the scope of the present invention.

[0071] A mixture of diastereoisomers can be separated into their individual diastereomers by known methods (such as, for example, by chromatography and / or fractional crystallization) based on their physicochemical differences. Enantiomer mixtures can be converted into diastereoisomer mixtures by reacting with appropriate optically active compounds (e.g., chiral auxiliary agents, such as chiral alcohols or methoxy-trifluoromethylphenylacetyl chloride (Mosher'sacid chloride)), separating diastereomers and converting (e.g., hydrolyzing) individual diastereomers into corresponding pure enantiomers to separate enantiomers. Alternatively, specific enantiomers of the compounds of the present invention can be prepared by asymmetric synthesis. Furthermore, when a molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxylic acid), diastereomeric salts are formed with appropriate optically active acids or bases, and the formed diastereomers are then separated by fractional crystallization or chromatographic means known in the art, and the pure enantiomers are subsequently recovered.

[0072] 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 may have the S or R configuration as defined by the IUPAC 1974 recommendations. In addition, if the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered part of this invention.

[0073] Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. If both a chemical structure and a chemical name are used to refer to a compound, and there is an ambiguity between the structure and the name, the structure controls. It should also be noted that any carbon and heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein are assumed to have the sufficient number of hydrogen atoms to satisfy the valences.

[0074] Unless otherwise indicated, the term "about" refers to within ±10% of the stated value. The present invention encompasses embodiments where the value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0075] As used herein, the terms "a" and "an" mean "one or more" and include the plural unless the context is inappropriate.

[0076] The term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched chain 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, and the like.

[0077] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbon atoms derived from a cycloalkane, referred to herein as, for example, "C3-C6 cycloalkyl." Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl.

[0078] The term "haloalkyl" refers to an alkyl group 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.

[0079] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups of similar length that may replace the alkyl groups described above, but that contain at least one double or triple bond, respectively.

[0080] The term "alkoxy" or "alkoxy" is art-recognized and refers to an alkyl group as defined above having an oxygen group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. The term "haloalkoxy" refers to an alkoxy group substituted with at least one halogen. Exemplary haloalkoxy groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, etc. The term "hydroxyalkoxy" refers to an alkoxy group substituted with at least one hydroxyl group. Exemplary hydroxyalkoxy groups include -OCH2CH2OH, -OCH2C(H)(OH)CH2CH2OH, etc. The term "alkyleneoxy" refers to a divalent alkoxy group.

[0081] The term "oxo" is art-recognized and refers to a "=0" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0082] symbol Indicates an attachment point.

[0083] 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 stated.

[0084] 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. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, etc.), and most preferably include humans.

[0085] The term "compound" as used herein refers to a molecular weight sufficient to weigh, test for its structural characteristics, and have demonstrable utility (e.g., an amount that can be shown to be active in an assay, in vitro test, or in vivo test, or an amount that can be administered to a patient and provide a therapeutic benefit).

[0086] As used herein, the term "effective amount" refers to an amount of a compound sufficient to produce a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory or preventive result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or route of administration.

[0087] As used herein, the term "treat," ...

[0088] 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 in vivo or ex vivo diagnostic or therapeutic use.

[0089] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier such as phosphate buffered saline solution, water, emulsions (e.g., such as oil / water emulsions or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Edition, Mack Publ. Co., Easton, PA

[1975] .

[0090] Throughout this 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 additionally compositions of the invention consisting essentially of, or consisting of, those components, and that there are processes and methods of the invention consisting essentially of, or consisting of, those process steps.

[0091] Generally, percentages of compositions specified are by weight unless otherwise specified.

[0092] I. Pharmaceutical Compositions

[0093] The present invention provides pharmaceutical compositions comprising piperidinylmethylpurine amine. The pharmaceutical compositions can be used in the treatment methods described herein. The following sections describe exemplary pharmaceutical compositions and exemplary procedures for preparing the pharmaceutical compositions.

[0094] Part A - First Pharmaceutical Composition

[0095] One aspect of the present invention provides a pharmaceutical composition comprising:

[0096] (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by:

[0097] or a pharmaceutically acceptable salt thereof;

[0098] (b) at least 40% weight / weight microcrystalline cellulose;

[0099] (c) at least 10% weight / weight pregelatinized starch;

[0100] (d) at least 2% weight / weight of cross-linked carboxymethyl cellulose or a pharmaceutically acceptable salt thereof; and

[0101] (e) at least 0.75% w / w of stearic acid or a pharmaceutically acceptable salt thereof.

[0102] The first pharmaceutical composition can be further described according to additional features, such as the amounts and properties of the ingredients of the pharmaceutical composition. A more detailed description of these features is provided below. The present invention encompasses all permutations and combinations of these features.

[0103] For example, in certain embodiments, the pharmaceutical composition comprises at least 50% weight / weight of microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises 45% weight / weight to 65% weight / weight of microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises 50% weight / weight to 56% weight / weight of microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises 52% weight / weight to 54% weight / weight of microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises about 53% weight / weight of microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises 53% weight / weight of microcrystalline cellulose.

[0104] In certain embodiments, the pharmaceutical composition comprises at least 15% weight / weight pregelatinized starch. In certain embodiments, the pharmaceutical composition comprises at least 20% weight / weight pregelatinized starch. In certain embodiments, the pharmaceutical composition comprises 15% weight / weight to 25% weight / weight pregelatinized starch. In certain embodiments, the pharmaceutical composition comprises 18% weight / weight to 22% weight / weight pregelatinized starch. In certain embodiments, the pharmaceutical composition comprises about 20% weight / weight pregelatinized starch. In certain embodiments, the pharmaceutical composition comprises 20% weight / weight pregelatinized starch.

[0105] In certain embodiments, the pharmaceutical composition comprises at least 4% weight / weight croscarmellose, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 3% weight / weight to 5% weight / weight croscarmellose, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises about 4% weight / weight croscarmellose, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 4% weight / weight croscarmellose, or a pharmaceutically acceptable salt thereof.

[0106] In certain embodiments, the croscarmellose or pharmaceutically acceptable salt thereof is croscarmellose sodium.

[0107] In certain embodiments, the pharmaceutical composition comprises at least 1% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises at least 1.5% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 1% weight / weight to 2% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises about 1.5% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 1.5% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof.

[0108] In certain embodiments, stearic acid or a pharmaceutically acceptable salt thereof is an alkaline earth metal salt of stearic acid. In certain embodiments, stearic acid or a pharmaceutically acceptable salt thereof is magnesium stearate.

[0109] In certain embodiments, the pharmaceutical composition comprises at least 15% weight / weight of a compound of Formula I. In certain embodiments, the pharmaceutical composition comprises at least 20% weight / weight of a compound of Formula I. In certain embodiments, the pharmaceutical composition comprises 10% weight / weight to 30% weight / weight of a compound of Formula I. In certain embodiments, the pharmaceutical composition comprises 15% weight / weight to 25% weight / weight of a compound of Formula I. In certain embodiments, the pharmaceutical composition comprises 18% weight / weight to 24% weight / weight of a compound of Formula I. In certain embodiments, the pharmaceutical composition comprises 20% weight / weight to 22% weight / weight of a compound of Formula I. In certain embodiments, the pharmaceutical composition comprises about 21% weight / weight of a compound of Formula I. In certain embodiments, the pharmaceutical composition comprises 21% weight / weight of a compound of Formula I.

[0110] In certain embodiments, the compound of formula I is In certain embodiments, the compound of formula I is In certain embodiments, the compound of formula I is In certain embodiments, the compound of formula I is of the fumarate.

[0111] Part B - Second Pharmaceutical Composition

[0112] Another aspect of the present invention provides a pharmaceutical composition comprising:

[0113] (a) 17% w / w to 25% w / w of a compound of formula I, wherein formula I is D-tartrate;

[0114] (b) 51% to 56% weight / weight microcrystalline cellulose;

[0115] (c) about 20% weight / weight pregelatinized starch;

[0116] (d) about 4% weight / weight croscarmellose sodium; and

[0117] (e) about 1.5% w / w magnesium stearate.

[0118] The second pharmaceutical composition can be further described according to additional features, such as the amounts and properties of the ingredients of the pharmaceutical composition. A more detailed description of these features is provided below. The present invention encompasses all permutations and combinations of these features.

[0119] For example, in certain embodiments, the pharmaceutical composition comprises 19% w / w to 23% w / w of a compound of Formula I. In certain embodiments, the pharmaceutical composition comprises 20% w / w to 22% w / w of a compound of Formula I. In certain embodiments, the pharmaceutical composition comprises about 21% w / w of a compound of Formula I. In certain embodiments, the pharmaceutical composition comprises 21% w / w of a compound of Formula I.

[0120] In certain embodiments, the pharmaceutical composition comprises 52% w / w to 55% w / w microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises 53% w / w to 54% w / w microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises 53% w / w microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises 53% w / w microcrystalline cellulose.

[0121] Part C - Third Pharmaceutical Composition

[0122] Another aspect of the present invention provides a pharmaceutical composition comprising:

[0123] (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by:

[0124] or a pharmaceutically acceptable salt thereof; and

[0125] (b) at least 60% weight / weight of a diluent selected from microcrystalline cellulose, pregelatinized starch, or a combination thereof.

[0126] The third pharmaceutical composition can be further described according to additional features, such as the amounts and properties of the ingredients of the pharmaceutical composition. A more detailed description of these features is provided below. The present invention encompasses all permutations and combinations of these features.

[0127] For example, in certain embodiments, the pharmaceutical composition further comprises a lubricant. In certain embodiments, the lubricant is stearic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the lubricant is magnesium stearate.

[0128] In certain embodiments, the pharmaceutical composition further comprises a disintegrant. In certain embodiments, the disintegrant is an alkali metal starch glycolate, crospovidone, cross-linked carboxymethyl cellulose or a pharmaceutically acceptable salt thereof, or a combination thereof. In certain embodiments, the disintegrant is an alkali metal starch glycolate. In certain embodiments, the disintegrant is cross-linked carboxymethyl cellulose or a pharmaceutically acceptable salt thereof. In certain embodiments, the disintegrant is an alkali metal cross-linked carboxymethyl cellulose. In certain embodiments, the disintegrant is crospovidone.

[0129] In certain embodiments, the pharmaceutical composition further comprises a binding agent. In certain embodiments, the binding agent is polyvinyl pyrrolidone, hydroxypropyl cellulose or a combination thereof. In certain embodiments, the binding agent is polyvinyl pyrrolidone. In certain embodiments, the binding agent is hydroxypropyl cellulose. In certain embodiments, the binding agent is a combination of polyvinyl pyrrolidone and hydroxypropyl cellulose.

[0130] In certain embodiments, the pharmaceutical composition further comprises water.

[0131] Part D - Fourth Pharmaceutical Composition

[0132] Another aspect of the present invention provides a pharmaceutical composition comprising:

[0133] (a) a compound of formula I, wherein formula I is represented by:

[0134] or a pharmaceutically acceptable salt thereof; and

[0135] (b) Diluent.

[0136] Section E - Additional Characteristics of the First, Second, Third, and Fourth Pharmaceutical Compositions

[0137] The first, second, third and fourth pharmaceutical compositions can be further characterized according to additional features, such as the bulk density of the pharmaceutical composition, the tap density of the pharmaceutical composition and other features. A more detailed description of these features is provided below. All permutations and combinations of these features are encompassed by the present invention.

[0138] For example, in certain embodiments, the pharmaceutical composition has a viscosity of at least 0.2 g / cm 3 In certain embodiments, the pharmaceutical composition has a bulk density of at least 0.3 g / cm 3 In certain embodiments, the pharmaceutical composition has a bulk density of at least 0.4 g / cm 3 In certain embodiments, the pharmaceutical composition has a bulk density of at least 0.5 g / cm 3 In certain embodiments, the pharmaceutical composition has a bulk density of at least 0.6 g / cm 3 In certain embodiments, the pharmaceutical composition has a bulk density of 0.5 to 0.7 g / cm 3 In certain embodiments, the pharmaceutical composition has a bulk density of 0.55 to 0.6 g / cm 3 Bulk density within the range.

[0139] In certain embodiments, the pharmaceutical composition has a viscosity of at least 0.2 g / cm 3 In certain embodiments, the pharmaceutical composition has a tap density of at least 0.3 g / cm 3 In certain embodiments, the pharmaceutical composition has a tap density of at least 0.4 g / cm 3 In certain embodiments, the pharmaceutical composition has a tap density of at least 0.5 g / cm 3 In certain embodiments, the pharmaceutical composition has a tap density of at least 0.6 g / cm 3 In certain embodiments, the pharmaceutical composition has a tap density of at least 0.7 g / cm 3 In certain embodiments, the pharmaceutical composition has a tap density of at least 0.8 g / cm 3 In certain embodiments, the pharmaceutical composition has a tap density of 0.6 to 0.8 g / cm 3 In certain embodiments, the pharmaceutical composition has a tap density of 0.7 to 0.75 g / cm 3 The tap density is within the range.

[0140] In certain embodiments, the pharmaceutical composition does not contain phosphates. In certain embodiments, the pharmaceutical composition does not contain alkali metal or alkaline earth metal phosphates. In certain embodiments, the pharmaceutical composition does not contain alkaline earth metal phosphates. In certain embodiments, the pharmaceutical composition does not contain calcium phosphates. In certain embodiments, the pharmaceutical composition does not contain mannitol.

[0141] II. Tablets

[0142] Another aspect of the present invention provides tablets. Such tablets may contain the pharmaceutical composition described herein and are for oral administration.

[0143] Thus, one aspect of the present invention provides a tablet for oral administration, comprising the pharmaceutical composition described herein.

[0144] In certain embodiments, the tablet has a hardness of at least 6 kP. In certain embodiments, the tablet has a hardness of at least 7 kP. In certain embodiments, the tablet has a hardness of at least 8 kP. In certain embodiments, the tablet has a hardness in the range of about 6 kP to about 8 kP.

[0145] In certain embodiments, the tablet contains about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg 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. In certain embodiments, the tablet contains about 25 mg 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. In certain embodiments, the tablet contains about 50 mg 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. In certain embodiments, the tablet contains about 75 mg 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. In certain embodiments, the tablet contains about 150 mg 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.

[0146] In certain embodiments, the tablet contains about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg 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 or a pharmaceutically acceptable salt thereof. In certain embodiments, the tablet contains about 25 mg 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 or a pharmaceutically acceptable salt thereof. In certain embodiments, the tablet contains about 50 mg 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 or a pharmaceutically acceptable salt thereof. In certain embodiments, the tablet contains about 75 mg 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 or a pharmaceutically acceptable salt thereof. In certain embodiments, the tablet contains about 150 mg 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 or a pharmaceutically acceptable salt thereof.

[0147] III. Methods for preparing pharmaceutical compositions

[0148] Another aspect of the present invention provides a method for preparing a pharmaceutical composition. For example, one aspect of the present invention provides a method for preparing a pharmaceutical composition, the method comprising the following steps:

[0149] (i) providing a first mixture, the first mixture comprising:

[0150] (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by:

[0151] or a pharmaceutically acceptable salt thereof;

[0152] (b) at least 40% weight / weight microcrystalline cellulose;

[0153] (c) at least 10% weight / weight pregelatinized starch;

[0154] (d) at least 2% weight / weight of cross-linked carboxymethyl cellulose or a pharmaceutically acceptable salt thereof; and

[0155] (e) at least 0.75% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof;

[0156] (ii) subjecting the first mixture to roller compaction to produce a compacted mixture; and

[0157] (iii) subjecting the compacted mixture to a compression force to produce a compressed pharmaceutical composition.

[0158] In certain embodiments, the method further comprises the steps of:

[0159] (i) providing a starting mixture, the starting mixture comprising:

[0160] (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by:

[0161] or a pharmaceutically acceptable salt thereof;

[0162] (b) at least 40% weight / weight microcrystalline cellulose;

[0163] (c) at least 10% weight / weight pregelatinized starch;

[0164] (d) at least 2% weight / weight of cross-linked carboxymethyl cellulose or a pharmaceutically acceptable salt thereof; and

[0165] (e) at least 0.2% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof;

[0166] (ii) applying the starting mixture to a screen to remove particles having a diameter greater than about 991 microns, thereby producing a filtered mixture; and

[0167] (iii) blending the filtered mixture with magnesium stearate to form the first mixture.

[0168] Another aspect of the present invention provides a pharmaceutical composition prepared according to the method described herein.

[0169] IV. Therapeutic Applications

[0170] The pharmaceutical compositions described herein provide therapeutic benefits for subjects suffering from cancer and other diseases or conditions. Accordingly, one 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 pharmaceutical composition described herein to treat the disease or condition.

[0171] Examples of diseases or conditions mediated by NSD2 include, but are not limited to, breast cancer, cervical cancer, skin cancer (particularly squamous cell carcinoma of the skin), ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia (particularly acute lymphoblastic leukemia), non-Hodgkin's lymphoma (particularly mantle cell lymphoma), and pulmonary hypertension.

[0172] In certain embodiments, the disease or condition mediated by NSD2 is cancer.

[0173] In certain embodiments, the disease or condition mediated by NSD2 is selected from a solid tumor, a leukemia, a myeloma, a lymphoma, 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 a leukemia, a myeloma, and a lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is a leukemia. In certain embodiments, the disease or condition mediated by NSD2 is a myeloma. In certain embodiments, the disease or condition mediated by NSD2 is a lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is hypertension.

[0174] In certain embodiments, the disease or condition mediated by NSD2 is breast cancer, cervical cancer, skin cancer, ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia, non-Hodgkin's lymphoma, or pulmonary 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.

[0175] In certain embodiments, the disease or condition mediated by NSD2 is acute lymphoblastic leukemia, cutaneous squamous cell carcinoma, or mantle cell lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is acute lymphoblastic leukemia. In certain embodiments, the disease or condition mediated by NSD2 is cutaneous squamous cell carcinoma. In certain embodiments, the disease or condition mediated by NSD2 is mantle cell lymphoma.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] In certain embodiments, the disease or condition mediated by NSD2 is myeloma.

[0181] 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.

[0182] In certain embodiments, the cancer overexpresses NSD2. In certain embodiments, the cancer has an NSD2 mutation. 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.

[0183] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is an elderly human.

[0184] Another aspect of the present invention provides the use of a pharmaceutical composition described herein (such as the first, second, third, or fourth pharmaceutical composition, or other pharmaceutical compositions in Part I) in the manufacture of a medicament. In certain embodiments, the medicament is used to treat a disease or condition described herein, such as cancer.

[0185] Another aspect of the invention provides use of a pharmaceutical composition described herein (e.g., the first, second, third, or fourth pharmaceutical composition, or other pharmaceutical compositions in Part I) for treating a disease or condition such as a disease or condition described herein (e.g., cancer).

[0186] In addition, the pharmaceutical compositions described herein, such as the first, second, third, or fourth pharmaceutical compositions, or other pharmaceutical compositions in Part I, inhibit the activity of nuclear SET domain-containing protein 2 (NSD2). Therefore, 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 pharmaceutical composition described herein (such as the first, second, third, or fourth pharmaceutical composition, or other pharmaceutical compositions in Part I) to inhibit the activity of NSD2.

[0187] The ability of a pharmaceutical composition to bind to NSD2 and / or inhibit NSD2 activity can be tested according to any of a variety of assays known in the art, including, for example, LC-MS / MS enzymatic assays to monitor SAH production, cellular FRET assays, cellular ELISA assays, methyltransferase enzyme luminescent assays to monitor SAH production, and radioactive assays using tritium-labeled SAM. Such assays are described, for example, in WO 2021 / 028854 and Coussens, NP et al. J. Biol. Chem. (2018) Vol. 293, No. 35, pp. 13750-13755; the entire contents of each of which are hereby incorporated by reference.

[0188] VI. Combination Therapy

[0189] Another aspect of the present invention provides combination therapies.The pharmaceutical compositions described herein can be used in combination with additional therapeutic agents to treat a disease or condition, such as cancer.

[0190] Thus, in some embodiments, the present invention provides a method of treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition disclosed herein and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents.

[0191] One or more other therapeutic agents may be administered separately from the pharmaceutical compositions of the present invention as part of a multiple-dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form mixed with the pharmaceutical compositions of the present invention in a single composition. If administered as a multiple-dose regimen, the one or more other therapeutic agents and the compounds or compositions of the present invention may be administered simultaneously, sequentially, or at intervals of time.

[0192] In certain embodiments, the additional therapeutic agent is an anticancer agent, an antiallergic agent, an antiemetic (or antiemetic drug), an analgesic, a cytoprotective agent, or a combination thereof. In certain embodiments, the additional therapeutic agent is an anticancer agent, an analgesic, an anti-inflammatory agent, or a combination thereof.

[0193] 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, finasulate, platinums (such as oxaliplatin, carboplatin, and cisplatin), finasulate, fluorouracil, rapamycin, leucovorin, lapatinib, lonafamidis, sorafenib, gefitinib, camptothecin, topotecan, bryostatin, adezetaxine, anthracyclines, , kazelesin, bisargyl, dolastatin, auristatin, 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, as well as taxanes class), 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, abagovolumab, and selenomethoxazole). agovomab), adecatumumab, afutuzumab, alacizumab, alemtuzumab, anatumomab, apolizumab, bavituximab, belimumab, bivatuzumab mertansine, blinatumomab, brentuximab vedotin, cantuzumab mertansine, catumazomab, cetuximab, citatuzumab ogatox, cixutumumab, and clivatuzumab.tetraxetan), conatumumab, dacetuzumab, daclizumab, detumomab, ecoromeximab, edrecolomab, elotuzumab, epratuzumab, ertumaxomab, etaracizumab, farletuzumab, figitumumab, fresolimumab, galiximab, gembatumumab vedotin, gemtuzumab, ibritumomab tiuxetan, inotuzumab ozogamicin), intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lucatumumab, lumilisimab, mapatumumab, matuzumab, milatuzumab, mitumomab, nacolomab tafenatox, naptumomabestafenatox, necitumumab, nimotuzumab, ofatumumab, olaratumab, oportuzumab monatox), oregovomab, panitumumab, pemtumomab, pertuzumab, pintumomab, pritumumab, ramucirumab, rilotumumab, robatumumab, rituximab, sibrotuzumab, tacatuzumabtetraxetan), taplitumomab paptox, tenatumomab, ticilimumab, tigatuzumab, tositumomab, or 131 I-tositumomab, trastuzumab, tremelimumab, tuocotuzumab celmoleukin, veltuzumab, visilizumab, volocixumab, votumumab, zalutumumab, zanolimumab, 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 antibody, SGN-30, TRAIL-RI MAb, prostate cancer antibody, H22xKi-r, ABX-Mai, Imuteran, Monopharm-C), and antibody-drug conjugates comprising any of the above agents, particularly auristatins MMAE and MMAF, maytansinoids such as DM-1, calicheamicin, or various cytotoxins.

[0194] In certain embodiments, the additional therapeutic agent is selected from anastrozole Bicalutamide Bleomycin sulfate Busulfan Busulfan Injection Capecitabine

[0195] N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin Carmustine Chlorambucil Cisplatin Cladribine Cyclophosphamide ( or ), cytarabine, cytosine arabinoside Cytarabine liposome injection Dacarbazine Dactinomycin (actinomycin D, ), daunorubicin hydrochloride Daunorubicin citrate liposome injection Dexamethasone, docetaxel Doxorubicin hydrochloride Etoposide Fludarabine phosphate 5-Fluorouracil Flutamide Tizalcitabine, gemcitabine (difluorodeoxycytidine), hydroxyurea Idabit Ifosfamide Irinotecan L-asparaginase Calcium folinate, melphalan 6-Mercaptopurine Methotrexate Mitoxantrone Gemtuzumab ozogamicin (MYLOTARGTM), paclitaxel Albumin-bound paclitaxel Phoenix (yttrium-90 / MX-DTPA), pentostatin, polyphenylpropanone 20, and carmustine implants Tamoxifen citrate Teniposide 6-thioguanine, thiotepa, tirapazamine Topotecan Hydrochloride for Injection Vinblastine vincristine and vinorelbine

[0196] In certain embodiments, the additional therapeutic agent can inhibit BRAF, MEK, CDK4 / 6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or a combination thereof. In specific embodiments, the compounds of the present invention are combined with another therapeutic agent selected from vemurafenib, dabrafinib, LGX818, trametinib, MEK162, LEE011, PD-0332991, panobinostat, verinostat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib, panitumumab, vandetanib, INC280, everolimus, simolimus, BMK120, BYL719 or CLR457, or a combination thereof.

[0197] 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 α-2b (e.g., A), ipilimumab, trametinib (e.g., ), pegylated interferon α-2b (e.g., SYLATRON™), vemurafenib (e.g., )) and ipilimumab (e.g., ).

[0198] 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

[0199] For the treatment of thyroid cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride Cabozantinib-S-malate and vandetanib

[0200] 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

[0201] For the treatment of lung cancer, the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., ), paclitaxel Paclitaxel albumin-stabilized nanoparticle formulation Afatinib bismaleate Pemetrexed disodium Bevacizumab Carboplatin Cisplatin Crizotinib Erlotinib hydrochloride Gefitinib and gemcitabine hydrochloride

[0202] For the treatment of pancreatic cancer, other therapeutic agents may be selected from fluorouracil Erlotinib hydrochloride Gemcitabine hydrochloride and mitomycin or mitomycin C (MITOZYTREX™, ).

[0203] For the treatment of cervical cancer, the additional therapeutic agent is selected from bleomycin Cisplatin and topotecan hydrochloride

[0204] For the treatment of head and neck cancer, the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., ), fluorouracil Bleomycin Cetuximab Cisplatin and docetaxel

[0205] 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 and omacetamol methylsuccinate

[0206] In some cases, patients may develop an allergic reaction to the pharmaceutical compositions of the present invention and / or other anticancer agents during or after administration. Therefore, 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,

[0207] HYDROCORT and ), prednisolone (eg, DELTA- and ), prednisone (e.g., 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, salbutamol (e.g., ) and terbutaline

[0208] In other cases, patients may experience nausea during or after administration of the pharmaceutical compositions of the present invention and / or other anticancer agents. Therefore, antiemetics may be administered to prevent nausea (epigastric) and vomiting. Suitable antiemetics include aprepitant Ondansetron Granisetron hydrochloride Lorazepam Dexamethasone Prochlorperazine Caso Flat and ) and their combinations.

[0209] In other cases, medications are prescribed to relieve pain experienced during treatment sessions and make the patient feel more comfortable. Common over-the-counter analgesics are often used. Opioid analgesics, such as hydrocodone / paracetamol, hydrocodone / acetaminophen (e.g., ), morphine (e.g., or ), oxycodone (e.g., or ), oxymorphone hydrochloride and fentanyl (e.g., ), also for moderate or severe pain.

[0210] In addition, cytoprotectants (such as neuroprotectants, free radical scavengers, cardioprotectants, anthracycline 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 Youleizosan ( or ), Zali Roden and folinic acid (also known as folinate, lecithin, and folic acid).

[0211] In yet another aspect, the pharmaceutical compositions of the present invention can be used in combination with known treatments, such as hormone or radiation therapy. In some cases, the pharmaceutical compositions of the present invention can be used as radiosensitizers, particularly for treating tumors that are poorly sensitive to radiation therapy.

[0212] The dosage and administration regimen of the active ingredient used in the combination therapy can be determined by the attending clinician. In certain embodiments, pharmaceutical compositions as described herein (e.g., the first, second, third or fourth pharmaceutical compositions, or other pharmaceutical compositions in Part I) and one or more additional therapeutic agents are administered at a dosage lower than the dosage typically employed when these agents are used as monotherapy for treating a disease or illness. In other embodiments, pharmaceutical compositions as described herein (e.g., the first, second, third or fourth pharmaceutical compositions, or other pharmaceutical compositions in Part I) and one or more additional therapeutic agents are administered at a dosage lower than the dosage typically employed when these agents are used as monotherapy for treating a disease or illness. In certain embodiments, pharmaceutical compositions as described herein (e.g., the first, second, third or fourth pharmaceutical compositions, or other pharmaceutical compositions in Part I) and one or more additional therapeutic agents are present in the same composition, and the composition is suitable for oral administration.

[0213] In certain embodiments, the pharmaceutical compositions described herein (e.g., the first, second, third, or fourth pharmaceutical compositions, or other pharmaceutical compositions in Part I) and one or more additional therapeutic agents can act additively or synergistically. A synergistic combination can allow the use of lower doses of one or more agents and / or less frequent administration of one or more agents of the combination therapy. Lower doses or less frequent administration of one or more agents can reduce the toxicity of a therapy without reducing the efficacy of the therapy.

[0214] Another aspect of the invention is a kit comprising a therapeutically effective amount of a pharmaceutical composition described herein (e.g., the first, second, third, or fourth pharmaceutical composition, or other pharmaceutical compositions in Part I) 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.

[0215] VII. Application

[0216] The pharmaceutical compositions of the present invention can be administered orally, parenterally, topically or rectally, and are most preferably administered orally. The terms "parenteral administration" and "parenteral administration" as used herein refer to forms of administration other than enteral and topical administration, typically by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraocular, intracardial, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0217] As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" refer to administration of a compound, drug, or other substance other than directly to the central nervous system so that it enters the patient's entire body and thereby undergoes metabolism and other similar processes, such as subcutaneous administration.

[0218] Actual dosage amounts of the pharmaceutical compositions of the present invention may be varied to provide an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0219] The selected dosage level will depend upon a variety of factors, including the activity of the specific pharmaceutical composition of this invention employed, the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific pharmaceutical composition 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.

[0220] A doctor or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a doctor or veterinarian can start the dosage of the pharmaceutical composition of the present invention at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0221] In general, the suitable daily dose of the pharmaceutical composition of the present invention will be the amount of the pharmaceutical composition at the lowest dose that effectively produces a therapeutic effect. This effective dose will generally depend on the above factors. Preferably, the pharmaceutical composition 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, even more preferably about 0.5 mg / kg to about 50 mg / kg; wherein "mg" refers to the mass of the compound of Formula I, and "kg" refers to the mass of the patient. When the pharmaceutical composition described herein is co-administered with another agent (e.g., as a sensitizer), the effective amount may be lower than the effective amount when the agent is used alone.

[0222] If desired, the effective daily dose of the pharmaceutical composition may be administered as two, three, four, five, six or more sub-doses divided at appropriate intervals throughout the day, optionally in unit dosage form.Preferred administration is once a day.

[0223] The present invention further provides unit dosage forms (such as tablets or capsules) comprising a therapeutically effective amount of a pharmaceutical composition described herein for treating a disease or condition described herein.

[0224] Example

[0225] Now that the invention has been generally described, it will be more readily understood with reference to the following examples, which are included solely for the 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.

[0226] Example 1 - Preparation of a formulation 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 D-tartrate

[0227] Four different formulations containing Compound 1 were prepared and tested for storage stability. Compound 1 is the D-tartrate salt of:

[0228]

[0229] The experimental procedures and results are provided below.

[0230] Part I - Experimental Procedure

[0231] Formulations 1, 2, 3, and 4 described below were prepared according to the following general procedure: the required amount of each component was weighed, sieved, and mixed to produce a mixture, which was milled and then sieved through a 30-mesh screen to provide the final formulation.

[0232] Table 1. Formulations 1 to 4.

[0233]

[0234] Aliquots of each of Formulations 1, 2, 3, and 4 were subjected to stability testing. Specifically, an amount of each formulation sufficient to provide 11.4 mg of Compound 1 was transferred to a glass vial, which was then capped. The vials were stored at 40°C / 75% relative humidity for three to six weeks. The samples were analyzed by HPLC to determine the amount of related substances in the formulations.

[0235] Part II - Results

[0236] The results of the stability study are provided below in Table 2. The results show that at three weeks, the percentage of related substances increased in Formulations 1, 2, and 3. The results show that at six weeks, the percentage of related substances increased in Formulations 1, 2, 3, and 4.

[0237] Table 2.

[0238]

[0239] Example 2 - Preparation of additional formulations 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 D-tartrate

[0240] Three different formulations containing Compound 1 were prepared and tested for storage stability. Compound 1 is the D-tartrate salt of:

[0241]

[0242] The experimental procedures and results are provided below.

[0243] Part I - Experimental Procedure

[0244] The following Formulations 5, 6, and 7 were prepared according to the following general procedure: the required amount of each component was weighed, sieved, and mixed to produce a mixture (except water), the mixture was ground (in the presence of water for Formulation 6 containing water), and then sieved through a 30 mesh screen to provide the final formulation.

[0245] Table 1 - Formulation 5, Formulation 6, and Formulation 7.

[0246]

[0247] Aliquots of each of Formulations 5, 6, and 7 were subjected to stability testing. Specifically, an amount of each formulation sufficient to provide 11.4 mg of Compound 1 was transferred to a glass vial bottle, which was then capped. The glass vials were stored at (a) 40°C / NMT 25% relative humidity or (b) 40°C / 75% relative humidity. The samples were analyzed by HPLC to determine the amount of related substances in the formulations.

[0248] Part II - Results

[0249] The results of the stability studies are provided below in Tables 2 and 3. Table 2 shows the results for samples stored at 40°C / 25% relative humidity. Table 3 shows the results for samples stored at 40°C / 75% relative humidity.

[0250] Table 2.

[0251]

[0252] Table 3.

[0253]

[0254] Example 3 - Preparation of a formulation 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 D-fumarate

[0255] Three different formulations containing Compound 2 were prepared and tested for storage stability. Compound 2 is the fumarate salt of:

[0256]

[0257] The experimental procedures and results are provided below.

[0258] Part I - Experimental Procedure

[0259] The following Formulations 8, 9, and 10 were prepared according to the following general procedure: the required amount of each component was weighed, sieved, and mixed to produce a mixture (except water), the mixture was ground (in the presence of water for Formulation 9 containing water), and then sieved through a 30 mesh screen to provide the final formulation.

[0260] Table 1 - Formulation 8, Formulation 9, and Formulation 10.

[0261]

[0262] Aliquots of each of Formulations 8, 9, and 10 were subjected to stability testing. Specifically, an amount of each formulation sufficient to provide 14.3 mg of Compound 2 was transferred to a glass vial, which was then capped. The glass vials were stored at (a) 40°C / NMT 25% relative humidity or (b) 40°C / 75% relative humidity. The samples were analyzed to determine the amount of related substances in the formulations.

[0263] Part II - Results

[0264] The results of the stability studies are provided below in Tables 2 and 3. Table 2 shows the results for samples stored at 40°C / 25% relative humidity. Table 3 shows the results for samples stored at 40°C / 75% relative humidity.

[0265] Table 2.

[0266]

[0267] Table 3.

[0268]

[0269] Example 4 - Preparation of tablets containing a formulation 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

[0270] Two different formulations containing Compound 1 were prepared and compressed to form tablets. Compound 1 is the D-tartrate salt of:

[0271]

[0272] The experimental procedures and results are provided below.

[0273] Part I - Experimental Procedure

[0274] Formulations 11 and 12 described below were prepared according to the following general procedure: the required amount of each component was weighed, sieved and mixed to produce a mixture, the mixture was milled, and then sieved through a 30 mesh screen to provide the final formulation.

[0275] Table 1 - Formulation 11 and Formulation 12.

[0276]

[0277] Tablets were formed from Formulation 11. Additionally, tablets were formed from Formulation 12. Round, flat tablets were prepared by compressing the formulation using a single punch manual press.

[0278] Part II - Results

[0279] To produce tablets from Formulation 11, a pressure of at least 5,100 psi was required. Tablets formed from Formulation 11 using a pressure of 5,100 psi had the properties listed below in Table 2. Tablets formed from Formulation 11 using a pressure of 8,000 psi had the properties listed below in Table 2.

[0280] Table 2.

[0281]

[0282] To produce tablets from Formulation 12, a pressure of at least 5,300 psi was required. Tablets formed from Formulation 12 using a pressure of 5,300 psi had the properties listed below in Table 3. Tablets formed from Formulation 12 using a pressure of 8,000 psi had the properties listed below in Table 3.

[0283] Table 3.

[0284]

[0285] Example 5 Preparation of tablets containing different formulations 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

[0286] A formulation containing Compound 1 was prepared and compressed to form tablets. Compound 1 is the D-tartrate salt of:

[0287]

[0288] The experimental procedures and results are provided below.

[0289] Part I - Experimental Procedure

[0290] Formulation 13 described below was prepared according to the following general procedure: the required amount of each component was weighed, sieved and mixed to produce a mixture, the mixture was milled, and then sieved through a 30 mesh screen to provide the final formulation.

[0291] Table 1 - Formulation 13.

[0292] Components in the preparation Amount of component (% w / w) Compound 1 23.2 microcrystalline cellulose 51.8 Pregelatinized starch 20.0 Croscarmellose sodium 4.00 magnesium stearate 1.00 Total mass of preparation (mg) 500

[0293] Tablets were formed from Formulation 13. Tablets were prepared by compressing the formulation using a single punch manual press.

[0294] Part II - Results

[0295] Can be applied < Tablets of Formulation 13 were prepared using a pressure of 3,200 psi. Tablets formed from Formulation 13 using a pressure of 2,200 psi had the properties listed below in Table 3. Round, flat tablets formed from Formulation 13 using a pressure of 3,200 psi had the properties listed below in Table 3.

[0296] Table 3.

[0297]

[0298] Example 6 - Preparation of tablets containing a formulation 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-fumarate

[0299] Two different formulations containing Compound 2 were prepared and compressed to form tablets. Compound 2 is the fumarate salt of:

[0300]

[0301] The experimental procedures and results are provided below.

[0302] Part I - Experimental Procedure

[0303] Formulations 14 and 15 described below were prepared according to the following general procedure: the required amount of each component was weighed, sieved and mixed to produce a mixture, the mixture was milled, and then sieved through a 30 mesh screen to provide the final formulation.

[0304] Table 1 - Formulation 14.

[0305]

[0306]

[0307] Table 2 - Formulation 15.

[0308] Components in the preparation Amount of component (% w / w) Compound 2 26.6 microcrystalline cellulose 43.4 Pregelatinized starch 24.0 Croscarmellose sodium 5.0 magnesium stearate 1.0 Total mass of preparation (mg) 500

[0309] Tablets were formed from Formulation 14. Additionally, tablets were formed from Formulation 15. Round, flat tablets were prepared by compressing the formulation using a single punch manual press.

[0310] Part II - Results

[0311] Can be applied < Tablets of Formulations 14 and 15 were prepared using a pressure of 3,400 psi. Tablets formed from Formulation 14 had the properties listed below in Table 3. Tablets formed from Formulation 15 had the properties listed below in Table 4.

[0312] Table 3.

[0313]

[0314] Table 4.

[0315]

[0316] Example 7 - Tablet preparation of a formulation 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 D-tartrate using a rotary tablet press

[0317] A formulation containing Compound 1 was prepared and tablets were formed using a rotary tablet press. Compound 1 is the D-tartrate salt of:

[0318]

[0319] The experimental procedures and results are provided below.

[0320] The following Formulation 16 was prepared according to the following general procedure: Compound 1 and excipients were blended in a diffusion mixer (V-Blender) to produce a mixture, and the mixture was then screened using a co-mil equipped with a 991 micron screen at 1200 rpm to provide Formulation 16. The components of Formulation 16 are shown in Table 1 below.

[0321] Table 1 - Formulation 16.

[0322] Components in the preparation Percentage weight / weight (%) Compound 1 21.8 microcrystalline cellulose 53.2 Pregelatinized starch 20.0 Croscarmellose sodium 4.0 magnesium stearate 1.0

[0323] Formulation 16 was fed to a rotary tablet press to produce tablets. The target tablet weight was 150 mg, and the target tablet hardness was 8 kP. Visual observation revealed that Formulation 16 had poor flow properties, which adversely affected the ability to manufacture tablets on the rotary tablet press. The poor flow properties of Formulation 16 resulted in significant variability in the processing and specifications of the resulting tablets. For example, the tablet weights of the tablets produced ranged from 50 mg to 90 mg. Therefore, the target tablet weight could not be achieved.

[0324] Example 8 - Tablet preparation of a formulation 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 fumarate using a rotary tablet press

[0325] A formulation containing Compound 2 was prepared and tablets were formed using a rotary tablet press. Compound 2 is the fumarate salt of:

[0326]

[0327] The experimental procedures and results are provided below.

[0328] The following Formulation 17 was prepared according to the following general procedure: Compound 2 and excipients were blended in a diffusion mixer (V-Blender) to produce a mixture, and the mixture was then screened using a co-mil equipped with a 991 micron screen at 1200 rpm to provide Formulation 17. The components of Formulation 17 are shown in Table 1 below.

[0329] Table 1 - Formulation 17.

[0330] Components in the preparation Percentage weight / weight (%) Compound 2 23.2 microcrystalline cellulose 51.8 Pregelatinized starch 20.0 Croscarmellose sodium 4.0 magnesium stearate 1.0

[0331] Formulation 17 was fed to a rotary tablet press to prepare tablets. The target weight per tablet was 900 mg and the target hardness per tablet was 18 kP. Visual observation revealed that Formulation 17 had poor flow properties, which adversely affected the ability to prepare tablets using the rotary tablet press. The poor flow properties of Formulation 17 resulted in significant variability in the process and specifications of the resulting tablets. Weight variations outside the specified range (900 mg) were observed. + 45 mg), and the target hardness of the tablets was not achieved.

[0332] Example 9- Tablet preparation of a formulation 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 D-tartrate using a dry granulation procedure

[0333] Formulation 16 was subjected to a roller compactor (gap width: 2 mm; compaction force: 5 kN / cm; roller compactor speed: 1.5 rpm, screen size: 1.25 mm) to produce granules. The granules were mixed with magnesium stearate (weight ratio of granules to magnesium stearate: 99.5 to 0.5) to produce a final blend. Visual observation revealed that the final blend had satisfactory flow properties and could be easily formed into tablets using a rotary tablet press.

[0334] Table 1 below shows the particle size in the formulation before and after roller compaction. The data in Table 1 show that after roller compaction, the particle size in the formulation increased significantly. Specifically, the average particle size (d 50 is about 300 microns) than the average particle size in the preparation before rolling (d 50 An aliquot of Formulation 16 was compressed to a target weight of 150 mg to form tablets, and the properties of the tablets are shown in Table 2.

[0335] Table 1.

[0336] Preparation before rolling Preparation after rolling Mesh size Cumulative % of material retained Cumulative % of material retained 20 1.2 25.3 40 4.7 53.7 60 10.1 62.7 80 15.0 68.2 100 20.7 72.6 200 39.2 86.7 325 100 100.0

[0337]

[0338] feature data Average weight, mg (range, n=10) 151.0(147.6–153.6) Average hardness, kP (range, n=10) 8.7(7.6–9.7) Average thickness, mm (range, n=10) 3.54(3.49–3.60) Disintegration time h:min:sec (n=6, no disc) 0:02:11

[0339] Example 10 - Tablet preparation of a formulation 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 fumarate using a dry granulation procedure

[0340] Formulation 17 was subjected to a roller compactor (gap width: 2 mm; compaction force: 5 kN / cm; roller compactor speed: 1.5 rpm, screen size: 1.25 mm) to produce granules. The granules were mixed with magnesium stearate (the weight ratio of granules to magnesium stearate was 99.5 to 0.5) to produce a final mixture. Visual observation revealed that the final mixture had satisfactory flow properties and tablets could be easily prepared from the final mixture using a rotary tablet press. Aliquots of Formulation 17 were compressed into target weights of 150 mg and 900 mg to provide tablets. The properties of the tablets are shown in Table 1.

[0341] Table 1.

[0342]

[0343] Example 11 -Preparation of film-coated tablets

[0344] Tablets containing Compound 1 prepared according to the procedure of Example 9 above were film coated. The procedure and results are provided below. Compound 1 is the D-tartrate salt of:

[0345]

[0346] Tablets weighing 900 mg were spray-coated to provide an Opadry Pink film coating on the tablets. Procedurally, the tablets were heated and then sprayed with a spray mixture (wherein the mixture contained water, hypromellose, lactose monohydrate, titanium dioxide, polyethylene glycol, red iron oxide, triacetin, and a colorant) to achieve a weight gain of approximately 4% w / w due to spraying, and the resulting film-coated tablets were dried. The resulting film-coated tablets had a film coating of 4% w / w of the entire tablet.

[0347] Example 12 -Tablet stability study

[0348] Tablets containing Compound 1 prepared according to the procedures described in Examples 9 and 11 above were subjected to stability studies. The tablets were stored at 25°C and 60% relative humidity for up to 18 months. The tablets were analyzed for appearance, purity, and moisture content at the intervals listed in Table 1 below. The tablets used in the studies were (i) tablets containing 25 mg of Compound 1, (ii) tablets containing 150 mg of Compound 1, or (iii) tablets containing 150 mg of Compound 1, wherein the tablets had a film coating (corresponding to the film-coated tablets described in Example 11).

[0349] Compound 1 is the D-tartrate salt of:

[0350]

[0351] Table 1.

[0352]

[0353] Incorporated by Reference

[0354] The entire disclosure of each patent document and scientific article mentioned herein is incorporated by reference for all purposes.

[0355] Equivalent solutions

[0356] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The above embodiments are therefore to be considered in all respects as illustrative rather than restrictive of the invention described herein. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalence of the claims are intended to be encompassed therein.

Claims

1. A pharmaceutical composition comprising: (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by: or a pharmaceutically acceptable salt thereof; (b) at least 40% weight / weight microcrystalline cellulose; (c) at least 10% weight / weight pregelatinized starch; (d) at least 2% weight / weight of croscarmellose or a pharmaceutically acceptable salt thereof; and (e) at least 0.75% w / w of stearic acid or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises at least 50% weight / weight microcrystalline cellulose.

3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 45% to 65% weight / weight of microcrystalline cellulose.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 50% to 56% weight / weight of microcrystalline cellulose.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 52% to 54% weight / weight of microcrystalline cellulose.

6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises about 53% weight / weight microcrystalline cellulose.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the pharmaceutical composition comprises at least 15% weight / weight pregelatinized starch.

8. The pharmaceutical composition of any one of claims 1 to 6, wherein the pharmaceutical composition comprises at least 20% weight / weight pregelatinized starch.

9. The pharmaceutical composition of any one of claims 1 to 6, wherein the pharmaceutical composition comprises 15% to 25% weight / weight of pregelatinized starch.

10. The pharmaceutical composition of any one of claims 1 to 6, wherein the pharmaceutical composition comprises 18% to 22% weight / weight of pregelatinized starch.

11. The pharmaceutical composition of any one of claims 1 to 6, wherein the pharmaceutical composition comprises about 20% weight / weight pregelatinized starch.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the pharmaceutical composition comprises at least 4% weight / weight of croscarmellose or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition of any one of claims 1 to 11, wherein the pharmaceutical composition comprises 3% w / w to 5% w / w of cross-linked carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition of any one of claims 1 to 11, wherein the pharmaceutical composition comprises about 4% weight / weight of croscarmellose or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the cross-linked carboxymethylcellulose or a pharmaceutically acceptable salt thereof is cross-linked carboxymethylcellulose sodium.

16. The pharmaceutical composition of any one of claims 1 to 15, wherein the pharmaceutical composition comprises at least 1% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of any one of claims 1 to 15, wherein the pharmaceutical composition comprises at least 1.5% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of any one of claims 1 to 15, wherein the pharmaceutical composition comprises 1% w / w to 2% w / w of stearic acid or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition of any one of claims 1 to 15, wherein the pharmaceutical composition comprises about 1.5% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition of any one of claims 1 to 19, wherein the stearic acid or a pharmaceutically acceptable salt thereof is an alkaline earth metal salt of stearic acid.

21. The pharmaceutical composition of any one of claims 1 to 19, wherein the stearic acid or a pharmaceutically acceptable salt thereof is magnesium stearate.

22. The pharmaceutical composition of any one of claims 1 to 21, wherein the pharmaceutical composition comprises at least 15% weight / weight of the compound of formula I.

23. The pharmaceutical composition of any one of claims 1 to 21, wherein the pharmaceutical composition comprises at least 20% weight / weight of the compound of formula I.

24. The pharmaceutical composition of any one of claims 1 to 21, wherein the pharmaceutical composition comprises 15% to 25% weight / weight of the compound of formula I.

25. The pharmaceutical composition of any one of claims 1 to 21, wherein the pharmaceutical composition comprises 18% to 24% weight / weight of the compound of formula I.

26. The pharmaceutical composition of any one of claims 1 to 21, wherein the pharmaceutical composition comprises 20% to 22% weight / weight of the compound of formula I.

27. The pharmaceutical composition of any one of claims 1 to 21, wherein the pharmaceutical composition comprises about 21% weight / weight of the compound of formula I.

28. The pharmaceutical composition of any one of claims 1 to 27, wherein the compound of formula I is tartrate.

29. The pharmaceutical composition of any one of claims 1 to 27, wherein the compound of formula I is D-tartrate.

30. The pharmaceutical composition of any one of claims 1 to 27, wherein the compound of formula I is L-tartrate.

31. The pharmaceutical composition of any one of claims 1 to 27, wherein the compound of formula I is of the fumarate.

32. A pharmaceutical composition comprising: (a) 17% w / w to 25% w / w of a compound of formula I, wherein formula I is D-tartrate; (b) 51% to 56% weight / weight microcrystalline cellulose; (c) about 20% weight / weight pregelatinized starch; (d) about 4% weight / weight croscarmellose sodium; and (e) about 1.5% w / w magnesium stearate.

33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition comprises 19% to 23% weight / weight of the compound of formula I.

34. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition comprises 20% to 22% weight / weight of the compound of formula I.

35. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition comprises about 21% weight / weight of the compound of formula I.

36. The pharmaceutical composition of any one of claims 32 to 35, wherein the pharmaceutical composition comprises 52% to 55% weight / weight of microcrystalline cellulose.

37. The pharmaceutical composition of any one of claims 32 to 35, wherein the pharmaceutical composition comprises 53% to 54% weight / weight of microcrystalline cellulose.

38. The pharmaceutical composition of any one of claims 32 to 35, wherein the pharmaceutical composition comprises 53% weight / weight microcrystalline cellulose.

39. A pharmaceutical composition comprising: (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by: or a pharmaceutically acceptable salt thereof; and (b) at least 60% weight / weight of a diluent selected from microcrystalline cellulose, pregelatinized starch, or a combination thereof.

40. The pharmaceutical composition of claim 39, wherein the pharmaceutical composition further comprises a lubricant.

41. The pharmaceutical composition of claim 40, wherein the lubricant is stearic acid or a pharmaceutically acceptable salt thereof.

42. The pharmaceutical composition of claim 40, wherein the lubricant is magnesium stearate.

43. The pharmaceutical composition of any one of claims 39 to 42, wherein the pharmaceutical composition further comprises a disintegrant.

44. The pharmaceutical composition of claim 43, wherein the disintegrant is alkali metal starch glycolate, crospovidone, cross-linked carboxymethyl cellulose or a pharmaceutically acceptable salt thereof, or a combination thereof.

45. The pharmaceutical composition of claim 43, wherein the disintegrant is croscarmellose or a pharmaceutically acceptable salt thereof.

46. ​​The pharmaceutical composition of claim 43, wherein the disintegrant is alkali metal croscarmellose.

47. The pharmaceutical composition of any one of claims 39 to 46, wherein the pharmaceutical composition further comprises a binder.

48. The pharmaceutical composition of claim 47, wherein the binder is polyvinylpyrrolidone, hydroxypropylcellulose, or a combination thereof.

49. The pharmaceutical composition of claim 47, wherein the binder is polyvinylpyrrolidone.

50. The pharmaceutical composition of claim 47, wherein the binder is hydroxypropyl cellulose.

51. The pharmaceutical composition of any one of claims 39 to 50, wherein the pharmaceutical composition further comprises water.

52. A tablet for oral administration comprising the pharmaceutical composition of any one of claims 1 to 51.

53. The tablet of claim 52, wherein the tablet has a hardness of at least 7 kP.

54. A method for preparing a pharmaceutical composition, comprising the steps of: (i) providing a first mixture, the first mixture comprising: (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by: or a pharmaceutically acceptable salt thereof; (b) at least 40% weight / weight microcrystalline cellulose; (c) at least 10% weight / weight pregelatinized starch; (d) at least 2% weight / weight of croscarmellose or a pharmaceutically acceptable salt thereof; and (e) at least 0.75% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof; (ii) subjecting the first mixture to roller compaction to produce a compacted mixture; as well as (iii) subjecting the compacted mixture to a compression force to produce a compressed pharmaceutical composition.

55. The method of claim 54, further comprising the steps of: (i) providing a starting mixture, the starting mixture comprising: (a) at least 10% weight / weight of a compound of formula I, wherein formula I is represented by: or a pharmaceutically acceptable salt thereof; (b) at least 40% weight / weight microcrystalline cellulose; (c) at least 10% weight / weight pregelatinized starch; (d) at least 2% weight / weight of croscarmellose or a pharmaceutically acceptable salt thereof; and (e) at least 0.2% weight / weight of stearic acid or a pharmaceutically acceptable salt thereof; (ii) applying the starting mixture to a screen to remove particles having a diameter greater than about 991 microns, thereby producing a filtered mixture; as well as (iii) blending the filtered mixture with magnesium stearate to form the first mixture.

56. A pharmaceutical composition prepared according to the method of claim 54 or 55.

57. A method for treating a disease or condition mediated by nuclear SET domain-containing protein 2 (NSD2), the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 51 or 56 to treat the disease or condition.

58. The method of claim 57, wherein the disease or condition mediated by NSD2 is cancer.

59. The method of claim 57, wherein the disease or condition mediated by NSD2 is selected from the group consisting of solid tumors, leukemia, myeloma, lymphoma, and hypertension.

60. The method of claim 57, wherein the disease or condition mediated by NSD2 is myeloma.

61. The method of claim 57, wherein the disease or condition mediated by NSD2 is breast cancer, cervical cancer, skin cancer, ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia, non-Hodgkin's lymphoma, or pulmonary hypertension.

62. The method of claim 57, wherein the disease or condition mediated by NSD2 is acute lymphoblastic leukemia, cutaneous squamous cell carcinoma, or mantle cell lymphoma.

63. The method of any one of claims 57 to 62, wherein the subject is a human.

64. A method of inhibiting the activity of nuclear SET domain-containing protein 2 (NSD2), the method comprising contacting NSD2 with an effective amount of the pharmaceutical composition of any one of claims 1 to 51 or 56 to inhibit the activity of NSD2.

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