Deuterium-enriched piperidinyl-methyl-purinamine and related compounds and their use in treating diseases and conditions - Patents.com

Abstract

The present invention provides deuterium-enriched piperidinyl-methyl-purinamine and related compounds, pharmaceutical compositions, their use for inhibiting NSD2, and their use in the treatment of diseases or conditions such as cancer.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 296,676, filed January 5, 2022, which is incorporated by reference herein in its entirety.

[0002] FIELD OF THEINVENTION The present invention provides deuterium-enriched piperidinyl-methyl-purinamine and related compounds, pharmaceutical compositions, their use for inhibiting NSD2, and their use in the treatment of diseases or conditions such as cancer. [Background technology]

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

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

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

[0006] The present invention provides deuterium-enriched piperidinyl-methyl-purinamines and related compounds, pharmaceutical compositions, their use for inhibiting NSD2, and their use in treating diseases or conditions, such as cancer. In particular, one aspect of the present invention provides a collection of deuterium-enriched piperidinyl-methyl-purinamines and related compounds, such as compounds represented by formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of additional collections of deuterium-enriched piperidinyl-methyl-purinamine and related compounds is provided in the detailed description. The compound may be part of a pharmaceutical composition that includes a pharma- ceutical acceptable carrier.

[0007] Another aspect of the present invention is a collection of difluoromethyl ketone substituted piperidinyl-methyl-purine amines and related compounds, including deuterium-enriched compounds such as those represented by formula II: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of additional collections of difluoromethylketone-substituted piperidinyl-methyl-purine amines and related compounds is provided in the detailed description. The compound may be part of a pharmaceutical composition that includes a pharma- ceutical acceptable carrier.

[0008] Another aspect of the present invention provides a method for treating disease or condition mediated by NSD2 in a subject.The method comprises administering a therapeutically effective amount of the compound described herein, such as the compound of formula I or II, to a subject in need thereof to treat disease or condition, as further described in the detailed description of the present invention.

[0009] Another aspect of the invention provides a method of inhibiting the activity of nuclear SET domain-containing protein 2 (NSD2), comprising contacting NSD2 with an effective amount of a compound described herein, such as a compound of Formula I or II, to inhibit the activity of the NSD2, as further described in the detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present invention provides deuterium-enriched piperidinyl-methyl-purinamine and related compounds, pharmaceutical compositions, their use for inhibiting NSD2, and their use in treating diseases or conditions such as cancer. The practice of the present invention employs conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology, unless otherwise indicated. Such techniques are described in such publications as "Comprehensive Organic Synthesis" (BM Trost & I. Fleming, eds., 1991-1992), "Handbook of experimental immunology" (DM Weir & CC Blackwell, eds.), "Current protocols in molecular biology" (FM Ausubel et al., eds., 1987, and periodically updated), and "Current protocols in immunology" (JE Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety.

[0011] Deuterium enrichment refers to the characteristic that a compound has an amount of deuterium that exceeds that of naturally occurring compounds or synthetic compounds prepared from substrates having a naturally occurring distribution of isotopes. Threshold amounts of deuterium enrichment are specified in certain instances in this disclosure, and all percentages given for the amount of deuterium present are molar percentages.

[0012] deuterium( 2 H) is 1 H is a stable, non-radioactive isotope of hydrogen and has an atomic mass of 2.014. Hydrogen is an isotope 1 H Hydrogen (i.e., protium), deuterium ( 2 H), and tritium ( 3 H). The natural abundance of deuterium is 0.015%. Those skilled in the art will recognize that in all chemical compounds that contain H atoms, the H atoms are actually 1 H Hydrogen, Deuterium ( 2 H), and tritium (3 H), recognizing that approximately 0.015% is deuterium. Thus, compounds having levels of deuterium that are enriched above their natural abundance of 0.015% are considered unnatural and, as a result, novel compared to their unenriched counterparts.

[0013] Various aspects of the invention are described in the following sections, however, an aspect of the invention described in a particular section is not limited to any particular section. Further, if a variable is not accompanied by a definition, the previous definition of the variable takes precedence.

[0014] definition The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply whether a term is used alone or in combination with other terms, unless otherwise indicated. Thus, the definition of "alkyl" applies to the "alkyl" portion of "alkyl" and "-O-alkyl". For purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., both of which are incorporated herein by reference in their entireties. th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0015] The term "aliphatic" or "aliphatic group," as used herein, refers to a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "alicyclic"), and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0016] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated, or having one or more unsaturated units, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho- or spiro-fused. As used herein, the term "heterobicyclic" is a subset of "bicyclic", requiring that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at the ring junction, may be optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and the like. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain or valence bond of atom(s) connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, where each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more of the substituents described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [ka]

[0017] Exemplary bridged bicyclic compounds include: [ka]

[0018] The term "lower alkyl" means C 1~4 It refers to a straight or branched chain alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0019] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1~4 It refers to a straight or branched chain alkyl group.

[0020] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including as in N-substituted pyrrolidinyl) is meant one or more of the following:

[0021] The term "unsaturated" as used herein means that a moiety has one or more units of unsaturation.

[0022] As used herein, "divalent C 1~8 (or C 1~6 The term "saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, which are straight or branched, as defined herein.

[0023] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0024] The term "-(C alkylene)-" refers to a bond. 0~3 The term "alkylene)-" refers to a bond (i.e., C) and -(C 1~3 alkylene)-groups.

[0025] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

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

[0027] The term "aryl," used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups such as indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl, in which an aromatic ring is fused to one or more non-aromatic rings. The term "phenylene" refers to a multivalent phenyl group having an appropriate number of open valencies to account for the groups attached to it. For example, "phenylene" is a phenylene when it has two groups attached to it (e.g., [ka] ), a divalent phenyl group, and "phenylene" is a divalent phenyl group when it has three groups attached to it (e.g., [ka] ), a trivalent phenyl group. The term "arylene" refers to a divalent aryl group.

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

[0029] The term "heteroarylene" refers to a polyvalent heteroaryl group having an appropriate number of open valences to describe the groups attached to it. For example, a "heteroarylene" is a divalent heteroaryl group when it has two groups attached to it, and a "heteroarylene" is a trivalent heteroaryl group when it has three groups attached to it. The term "pyridinylene" refers to a polyvalent pyridine radical having an appropriate number of open valences to describe the groups attached to it. For example, a "pyridinylene" is a polyvalent pyridine radical having an appropriate number of open valences to describe the groups attached to it (e.g., [ka] ), a divalent pyridine radical, and "pyridinylene" is a divalent pyridine radical when it has three groups attached to it (e.g., [ka] ), a trivalent pyridine radical.

[0030] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocycle" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or . + It may be NR (as in N-substituted pyrrolidinyl).

[0031] A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions are independently and optionally substituted. The term "oxoheterocyclyl" refers to a heterocyclyl substituted by an oxo group. The term "heterocyclylene" refers to a polyvalent heterocyclyl group having an appropriate number of open valencies to describe the groups attached to it. For example, a "heterocyclylene" is a divalent heterocyclyl group when it has two groups attached to it, and a "heterocyclylene" is a trivalent heterocyclyl group when it has three groups attached to it.

[0032] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0033] As described herein, the compounds of the invention may include "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. The combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0034] Each optional substitution on a substitutable carbon is independently selected from halogen, -(CH), 0~4 R ○ , -(CH2) 0~4 OR ○ , -O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ , -(CH2) 0~4 CH(OR ○ )2, -(CH2) 0~4 S.R. ○ , R ○ may be substituted with -(CH2) 0~4 Ph, R ○ may be substituted with -(CH2) 0~4 O(CH2) 0~1 Ph, R ○ -CH=CHPh, R ○ may be substituted with -(CH2) 0~4 O(CH2) 0~1 -Pyridyl, -NO2, -CN, -N3, -(CH2) 0~4 N(R○ )2、-(CH2) 0~4 N(R ○ )C(O)R ○ 、-N(R ○ )C(S)R ○ 、-(CH2) 0~4 N(R ○ )C(O)NR ○ 2、-N(R ○ )C(S)NR ○ 2、-(CH2) 0~4 N(R ○ )C(O)OR ○ 、-N(R ○ )N(R ○ )C(O)R ○ 、-N(R ○ )N(R ○ )C(O)NR ○ 2、-N(R ○ )N(R ○ )C(O)OR ○ 、-(CH2) 0~4 C(O)R ○ 、-C(S)R ○ 、-(CH2) 0~4 C(O)OR ○ 、-(CH2) 0~4 C(O)SR ○ 、-(CH2) 0~4 C(O)OSiR ○ 3、-(CH2) 0~4 OC(O)R ○ 、-OC(O)(CH2) 0~4 SR-、SC(S)SR ○ 、-(CH2) 0~4 SC(O)R ○ 、-(CH2) 0~4 C(O)NR ○ 2、-C(S)NR ○ 2、-C(S)SR ○ 、-SC(S)SR ○ 、-(CH2) 0~4 OC(O)NR ○ 2、-C(O)N(OR ○ )R ○ 、-C(O)C(O)R ○ 、-C(O)CH2C(O)R ○ 、-C(NOR ○ )R ○, -(CH2) 0~4 SSR ○ , -(CH2) 0~4 S(O)2R ○ , -(CH2) 0~4 S(O)2OR ○ , -(CH2) 0~4 OS(O)2R ○ , -S(O)NR ○ 2. -S(O)(NR ○ )R ○ , -S(O)2N=C(NR ○ 2) 2, -(CH2) 0~4 S(O)R ○ , -N(R ○ )S(O)NR ○ 2, -N(R ○ )S(O)2R ○ , -N(OR ○ )R ○ , -C(NH)NR ○ 2. -P(O)2R ○ , -P(O)R ○ 2. -OP(O)R ○ 2. -OP(O)(OR ○ )2, SiR ○ 3. -(C 1~4 Linear or branched alkylene)ON(R ○ )2, or -(C 1~4 Linear or branched alkylene)C(O)ON(R ○ ) 2 is a monovalent substituent selected from

[0035] Each R ○ are independently hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, R ○two independent occurrences of R taken together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, the heteroatoms being selected from =O and =S. ○ or each R ○ are independently hydrogen, -(CH2) 0~2 R ● , -(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 S.R. ● , -(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 ● is optionally substituted with a monovalent substituent selected from

[0036] Each R ● is independently 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ●is unsubstituted or, when preceded by halo, is substituted only with one or more halogens, or the optional substituents on the saturated carbons are independently: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O- or -S(C(R * 2)) 2~3 S- or the divalent substituents attached to adjacent substitutable carbons of the "optionally substituted" group are -O(CR * 2) 2~3 O- and R * Each independent occurrence of is hydrogen, C 1~6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] R * C 1~6 If aliphatic, R * is hydrogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is independently 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by halo, is substituted only with one or more halogens.

[0038] The optional substituents on a substitutable nitrogen are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † And each R † are independently hydrogen, C 1~6 an aliphatic, unsaturated -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R † two independent occurrences of together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; † C 1~6 If aliphatic, R † is hydrogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is independently 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by halo, is substituted only with one or more halogens.

[0039] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutical acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, and the like. These include salts such as lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0040] Additionally, acids generally considered suitable for the formation of pharma- ceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) 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) 33 201-217, Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York, and The Orange Book (Food & Drug Administration, Washington, DC, on its website), the disclosures of which are incorporated herein by reference.

[0041] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0042] 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, e.g., the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0043] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods known to those skilled in the art, such as, for example, chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) each individual diastereomer into its corresponding pure enantiomer. Alternatively, a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis. Still further, if the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid), diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and then recovering the pure enantiomers.

[0044] The individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may be, for example, racemic or mixed with all other stereoisomers or other selected stereoisomers. The chiral center(s) in the compounds of the present invention may have the S or R configuration as defined by IUPAC 1974 Recommendations. Furthermore, to the extent that the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered as part of the present invention.

[0045] Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure.When a chemical compound is referred to using both a chemical structure and a chemical name, and there is ambiguity between the structure and the name, the structure takes precedence.It should also be noted that any carbon and heteroatom with unsatisfied valences in the text, schemes, examples, and tables of this specification is assumed to have a sufficient number of hydrogen atoms (multiple) to satisfy the valences.

[0046] Unless otherwise specified, the term "about" refers to within ±10% of the stated value. The invention includes embodiments where a value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0047] As used herein, the terms "a" and "an" mean "one or more" and include the plural unless the context is inappropriate.

[0048] The term "alkyl" as used herein means any of C1 to C6 12 Alkyl, C1-C 10Alkyl refers to saturated straight or branched hydrocarbons, such as straight or branched groups of 1 to 12, 1 to 10, or 1 to 6 carbon atoms, referred to as 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, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0049] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, e.g., derived from cycloalkane, referred to herein as "C3-C6 cycloalkyl." Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0050] The term "haloalkyl" refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term "haloalkylene" refers to a divalent haloalkyl group.

[0051] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0052] The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. The term "haloalkoxyl" refers to an alkoxyl group substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like. The term "hydroxyalkoxyl" refers to an alkoxyl group substituted with at least one hydroxyl. Exemplary hydroxyalkoxyl groups include -OCH2CH2OH, -OCH2C(H)(OH)CH2CH2OH, and the like. The term "alkoxylene" refers to a divalent alkoxyl group.

[0053] The term "oxo" is art-recognized to refer to a "=O" substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0054] symbol" [ka] " indicates the point of attachment.

[0055] When any substituent or variable occurs more than one time in any constituent or compound of the present invention, unless otherwise stated, its definition on each occurrence is independent of its definition at every other occurrence.

[0056] One or more compounds of the present invention may exist in unsolvated and solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to include both solvated and unsolvated forms. "Solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, a solvate may be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolable solvates. Non-limiting examples of suitable solvates include ethanolate, methanolate, and the like. "Hydrate" is a solvate in which the solvent molecule is H2O.

[0057] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism that is treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably, humans.

[0058] As used herein, the term "compound" refers to a quantity of a molecule that has been weighed, tested for its structural identity, and sufficient to have a demonstrable use (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 to provide a therapeutic benefit).

[0059] Unless otherwise indicated, when D is specifically recited at a position or shown in a formula, the D represents a mixture of hydrogen and deuterium where the amount of deuterium is about 100% (i.e., the abundance of deuterium ranges from at least 90% up to 100%). In certain embodiments, the abundance of deuterium in D is 95%-100%, or 97%-100%. In certain embodiments, the abundance of deuterium in D is at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0060] "I C 50 The term "concentration of a compound required to achieve 50% inhibition of a target" is art-recognized and refers to the concentration of a compound required to achieve 50% inhibition of a target.

[0061] As used herein, the term "effective amount" refers to an amount of a compound sufficient to effect a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0062] As used herein, the term "treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., such as, for example, amelioration, alleviation, modulation, amelioration, or elimination, or the amelioration of a symptom thereof.

[0063] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic uses.

[0064] As used herein, the term "pharmaceutical acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions, etc.), and various types of wetting agents. The composition may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0065] Throughout this specification, when compositions are described as having, including, or comprising specific components, or processes and methods are described as having, including, or comprising specific steps, it is additionally contemplated that there are compositions of the invention that consist essentially of or consist of the recited components, and that there are processes and methods of the invention that consist essentially of or consist of the recited processing steps.

[0066] Generally, compositions that specify percentages are by weight unless otherwise specified.

[0067] I. Deuterium-enriched piperidinyl-methyl-purinamines and related compounds The present invention provides deuterium-enriched piperidinyl-methyl-purine amine and related compounds. The compounds can be used in the pharmaceutical compositions and methods of treatment described herein. Exemplary compounds are described in the following section, along with exemplary procedures for making the compounds.

[0068] One aspect of the present invention is a compound represented by formula I: [ka] or a pharma- ceutical acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R21 are independently H or Z; Z is H or D, provided that the abundance of deuterium in Z is at least 75%; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 is provided that at least one of

[0069] The definitions of the variables in formula I above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more of the chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0070] In certain embodiments, the compound is a compound of formula I.

[0071] As generally defined above, R 1 is H or Z. In certain embodiments, R 1 is H. In certain embodiments, R 1 is Z. In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 1 below.

[0072] As generally defined above, R 2is H or Z. In certain embodiments, R 2 is H. In certain embodiments, R 2 is Z. In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 1 below.

[0073] As generally defined above, R 3 is H or Z. In certain embodiments, R 3 is H. In certain embodiments, R 3 is Z. In certain embodiments, R 3 is selected from the groups depicted in the compounds of Table 1 below.

[0074] In certain embodiments, R 1 , R 2 , and R 3 is H. In certain embodiments, R 1 , R 2 , and R 3 is Z.

[0075] As generally defined above, R 4 is H or Z. In certain embodiments, R 4 is H. In certain embodiments, R 4 is Z. In certain embodiments, R 4 is selected from the groups depicted in the compounds of Table 1 below.

[0076] As generally defined above, R 5 is H or Z. In certain embodiments, R 5 is H. In certain embodiments, R 5 is Z. In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0077] As generally defined above, R 6 is H or Z. In certain embodiments, R 6is H. In certain embodiments, R 6 is Z. In certain embodiments, R 6 is selected from the groups depicted in the compounds of Table 1 below.

[0078] As generally defined above, R 7 is H or Z. In certain embodiments, R 7 is H. In certain embodiments, R 7 is Z. In certain embodiments, R 7 is selected from the groups depicted in the compounds of Table 1 below.

[0079] In certain embodiments, R 4 , R 5 , R 6 , and R 7 is H. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H.

[0080] As generally defined above, R 8 is H or Z. In certain embodiments, R 8 is H. In certain embodiments, R 8 is Z. In certain embodiments, R 8 is selected from the groups depicted in the compounds of Table 1 below.

[0081] As generally defined above, R 9 is H or Z. In certain embodiments, R 9 is H. In certain embodiments, R 9 is Z. In certain embodiments, R 9 is selected from the groups depicted in the compounds of Table 1 below.

[0082] In certain embodiments, R 8 and R9 is H. In certain embodiments, R 8 and R 9 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is H. In certain embodiments, R 1 , R 2 , R 3 , R 8 , and R 9 is Z.

[0083] As generally defined above, R 10 is H or Z. In certain embodiments, R 10 is H. In certain embodiments, R 10 is Z. In certain embodiments, R 10 is selected from the groups depicted in the compounds of Table 1 below.

[0084] As generally defined above, R 11 is H or Z. In certain embodiments, R 11 is H. In certain embodiments, R 11 is Z. In certain embodiments, R 11 is selected from the groups depicted in the compounds of Table 1 below.

[0085] In certain embodiments, R 10 and R 11 is H. In certain embodiments, R 10 and R 11 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , and R 11 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 8, R 9 , R 10 , and R 11 is H.

[0086] As generally defined above, R 12 is H or Z. In certain embodiments, R 12 is H. In certain embodiments, R 12 is Z. In certain embodiments, R 12 is selected from the groups depicted in the compounds of Table 1 below.

[0087] As generally defined above, R 13 is H or Z. In certain embodiments, R 13 is H. In certain embodiments, R 13 is Z. In certain embodiments, R 13 is selected from the groups depicted in the compounds of Table 1 below.

[0088] In certain embodiments, R 12 and R 13 is H. In certain embodiments, R 12 and R 13 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , and R 13 is H. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , and R 13 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , and R 13 is Z. In certain embodiments, R 8 , R 9 , R 12, and R 13 is Z.

[0089] As generally defined above, R 14 is H or Z. In certain embodiments, R 14 is H. In certain embodiments, R 14 is Z. In certain embodiments, R 14 is selected from the groups depicted in the compounds of Table 1 below.

[0090] As generally defined above, R 15 is H or Z. In certain embodiments, R 15 is H. In certain embodiments, R 15 is Z. In certain embodiments, R 15 is selected from the groups depicted in the compounds of Table 1 below.

[0091] As generally defined above, R 16 is H or Z. In certain embodiments, R 16 is H. In certain embodiments, R 16 is Z. In certain embodiments, R 16 is selected from the groups depicted in the compounds of Table 1 below.

[0092] As generally defined above, R 17 is H or Z. In certain embodiments, R 17 is H. In certain embodiments, R 17 is Z. In certain embodiments, R 17 is selected from the groups depicted in the compounds of Table 1 below.

[0093] In certain embodiments, R 14 , R 15 , R 16 , and R 17 is H. In certain embodiments, R 4 , R 5 , R 6 , R7 , R 10 , R 11 , R 14 , R 15 , R 16 , and R 17 is H.

[0094] As generally defined above, R 18 is H or Z. In certain embodiments, R 18 is H. In certain embodiments, R 18 is Z. In certain embodiments, R 18 is selected from the groups depicted in the compounds of Table 1 below.

[0095] As generally defined above, R 19 is H or Z. In certain embodiments, R 19 is H. In certain embodiments, R 19 is Z. In certain embodiments, R 19 is selected from the groups depicted in the compounds of Table 1 below.

[0096] In certain embodiments, R 18 and R 19 is H. In certain embodiments, R 12 , R 13 , R 18 , and R 19 is H. In certain embodiments, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R17 , R 18 , and R 19 is H.

[0097] In certain embodiments, R 18 and R 19 is Z. In certain embodiments, R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 8 , R 9 , R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , R 13 , R 18 , and R 19 is Z.

[0098] As generally defined above, R 20 is H or Z. In certain embodiments, R 20 is H. In certain embodiments, R 20 is Z. In certain embodiments, R 20 is selected from the groups depicted in the compounds of Table 1 below.

[0099] In certain embodiments, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , and R 20 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is H.

[0100] In certain embodiments, R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , and R 20 is Z. In certain embodiments, R 8 , R 9 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R1 , R 2 , R 3 , R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z.

[0101] As generally defined above, R 21 is H or Z. In certain embodiments, R 21 is H. In certain embodiments, R 21 is Z. In certain embodiments, R 21 is selected from the groups depicted in the compounds of Table 1 below.

[0102] In certain embodiments, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , and R 21 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21is H.

[0103] In certain embodiments, R 20 and R 21 is Z. In certain embodiments, R 12 , R 13 , R 18 , R 19 , and R 21 is Z. In certain embodiments, R 1 , R 2 , R 3 , and R 21 is Z. In certain embodiments, R 8 , R 9 , and R 21 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , R 13 , R 18 , R 19 , and R 21 is Z. In certain embodiments, R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 21 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 21 is Z.

[0104] As generally defined above, Z is hydrogen or deuterium, provided that the abundance of deuterium in Z is at least 75%. In certain embodiments, the abundance of deuterium in Z is at least 80%. In certain embodiments, the abundance of deuterium in Z is at least 85%. In certain embodiments, the abundance of deuterium in Z is at least 90%. In certain embodiments, the abundance of deuterium in Z is at least 95%. In certain embodiments, the abundance of deuterium in Z is at least 97%. In certain embodiments, the abundance of deuterium in Z is at least 99%. In certain embodiments, the abundance of deuterium in Z is about 100%.

[0105] As generally defined above, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 At least one of R is Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R20 , and R 21 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 At least two of R are Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 Two of are Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R18 , R 19 , R 20 , and R 21 At least three of R are Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 Three of R are Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 In certain embodiments, four or five of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R16 , R 17 , R 18 , R 19 , R 20 , and R 21 More than five of them are Z.

[0106] In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 One or more of is Z in the position where D is depicted in the compounds of Table 1 below.

[0107] In certain embodiments, the compound has an enantiomeric excess of at least 85%. In certain embodiments, the compound has an enantiomeric excess of at least 90%. In certain embodiments, the compound has an enantiomeric excess of at least 95%. In certain embodiments, the compound has an enantiomeric excess of at least 98%.

[0108] In certain embodiments, the compound has a diastereomeric ratio of at least 10:1. In certain embodiments, the compound has a diastereomeric ratio of at least 15:1. In certain embodiments, the compound has a diastereomeric ratio of at least 20:1. In certain embodiments, the compound has a diastereomeric ratio of at least 50:1. In certain embodiments, the compound has a diastereomeric ratio of at least 100:1.

[0109] The above description describes multiple embodiments for compounds of formula I. This patent application specifically contemplates all combinations of embodiments.

[0110] Another aspect of the present invention is a compound represented by formula IA: [ka] or a pharma- ceutical acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 are independently H or Z; Z is H or D, provided that the abundance of deuterium in Z is at least 75%; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 is provided that at least one of

[0111] The definition of the variables in formula IA above encompasses multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more of the chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0112] In certain embodiments, the compound is of formula IA.

[0113] As generally defined above, R 1 is H or Z. In certain embodiments, R 1 is H. In certain embodiments, R 1 is Z.

[0114] As generally defined above, R 2 is H or Z. In certain embodiments, R 2 is H. In certain embodiments, R 2 is Z.

[0115] As generally defined above, R 3 is H or Z. In certain embodiments, R 3 is H. In certain embodiments, R 3 is Z.

[0116] In certain embodiments, R 1 , R 2 , and R 3 is H. In certain embodiments, R 1 , R 2 , and R 3 is Z.

[0117] As generally defined above, R 4 is H or Z. In certain embodiments, R 4 is H. In certain embodiments, R 4is Z.

[0118] As generally defined above, R 5 is H or Z. In certain embodiments, R 5 is H. In certain embodiments, R 5 is Z.

[0119] As generally defined above, R 6 is H or Z. In certain embodiments, R 6 is H. In certain embodiments, R 6 is Z.

[0120] As generally defined above, R 7 is H or Z. In certain embodiments, R 7 is H. In certain embodiments, R 7 is Z.

[0121] In certain embodiments, R 4 , R 5 , R 6 , and R 7 is H. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H.

[0122] As generally defined above, R 8 is H or Z. In certain embodiments, R 8 is H. In certain embodiments, R 8 is Z.

[0123] As generally defined above, R 9 is H or Z. In certain embodiments, R 9 is H. In certain embodiments, R 9 is Z.

[0124] In certain embodiments, R 8 and R 9 is H. In certain embodiments, R 8 and R 9 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is H. In certain embodiments, R 1 , R 2 , R 3 , R 8 , and R 9 is Z.

[0125] As generally defined above, R 10 is H or Z. In certain embodiments, R 10 is H. In certain embodiments, R 10 is Z.

[0126] As generally defined above, R 11 is H or Z. In certain embodiments, R 11 is H. In certain embodiments, R 11 is Z.

[0127] In certain embodiments, R 10 and R 11 is H. In certain embodiments, R 10 and R 11 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , and R 11 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11is H.

[0128] As generally defined above, R 12 is H or Z. In certain embodiments, R 12 is H. In certain embodiments, R 12 is Z.

[0129] As generally defined above, R 13 is H or Z. In certain embodiments, R 13 is H. In certain embodiments, R 13 is Z.

[0130] In certain embodiments, R 12 and R 13 is H. In certain embodiments, R 12 and R 13 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , and R 13 is H. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , and R 13 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , and R 13 is Z. In certain embodiments, R 8 , R 9 , R 12 , and R 13 is Z.

[0131] As generally defined above, R 14 is H or Z. In certain embodiments, R 14is H. In certain embodiments, R 14 is Z.

[0132] As generally defined above, R 15 is H or Z. In certain embodiments, R 15 is H. In certain embodiments, R 15 is Z.

[0133] As generally defined above, R 16 is H or Z. In certain embodiments, R 16 is H. In certain embodiments, R 16 is Z.

[0134] As generally defined above, R 17 is H or Z. In certain embodiments, R 17 is H. In certain embodiments, R 17 is Z.

[0135] In certain embodiments, R 14 , R 15 , R 16 , and R 17 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 14 , R 15 , R 16 , and R 17 is H.

[0136] As generally defined above, R 18 is H or Z. In certain embodiments, R 18 is H. In certain embodiments, R 18 is Z. In certain embodiments, R 18 is selected from the groups depicted in the compounds of Table 1 below.

[0137] As generally defined above, R 19 is H or Z. In certain embodiments, R 19 is H. In certain embodiments, R 19 is Z.

[0138] In certain embodiments, R 18 and R 19 is H. In certain embodiments, R 12 , R 13 , R 18 , and R 19 is H. In certain embodiments, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 is H.

[0139] In certain embodiments, R 18 and R 19 is Z. In certain embodiments, R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 8 , R 9 , R12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , R 13 , R 18 , and R 19 is Z.

[0140] As generally defined above, R 20 is H or Z. In certain embodiments, R 20 is H. In certain embodiments, R 20 is Z.

[0141] In certain embodiments, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , and R 20 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is H.

[0142] In certain embodiments, R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , and R 20 is Z. In certain embodiments, R 8 , R 9 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z.

[0143] As generally defined above, R 21 is H or Z. In certain embodiments, R 21 is H. In certain embodiments, R 21 is Z.

[0144] In certain embodiments, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18, R 19 , R 20 , and R 21 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , and R 21 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 is H.

[0145] In certain embodiments, R 20 and R 21 is Z. In certain embodiments, R 12 , R 13 , R 18 , R 19 , and R 21 is Z. In certain embodiments, R 1 , R 2 , R 3 , and R 21 is Z. In certain embodiments, R 8 , R 9 , and R 21 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , R 13 , R 18 , R 19 , and R 21 is Z. In certain embodiments, R 8 , R9 , R 12 , R 13 , R 18 , R 19 , and R 21 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 21 is Z.

[0146] As generally defined above, Z is hydrogen or deuterium, provided that the abundance of deuterium in Z is at least 75%. In certain embodiments, the abundance of deuterium in Z is at least 80%. In certain embodiments, the abundance of deuterium in Z is at least 85%. In certain embodiments, the abundance of deuterium in Z is at least 90%. In certain embodiments, the abundance of deuterium in Z is at least 95%. In certain embodiments, the abundance of deuterium in Z is at least 97%. In certain embodiments, the abundance of deuterium in Z is at least 99%. In certain embodiments, the abundance of deuterium in Z is about 100%.

[0147] As generally defined above, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21At least one of R is Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 At least two of R are Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19, R 20 , and R 21 Two of are Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 At least three of R are Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 Three of R are Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R18 , R 19 , R 20 , and R 21 In certain embodiments, four or five of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 More than five of them are Z.

[0148] In certain embodiments, the compound has an enantiomeric excess of at least 85%. In certain embodiments, the compound has an enantiomeric excess of at least 90%. In certain embodiments, the compound has an enantiomeric excess of at least 95%. In certain embodiments, the compound has an enantiomeric excess of at least 98%.

[0149] In certain embodiments, the compound has a diastereomeric ratio of at least 10:1. In certain embodiments, the compound has a diastereomeric ratio of at least 15:1. In certain embodiments, the compound has a diastereomeric ratio of at least 20:1. In certain embodiments, the compound has a diastereomeric ratio of at least 50:1. In certain embodiments, the compound has a diastereomeric ratio of at least 100:1.

[0150] The above description describes multiple embodiments for compounds of formula IA. This patent application specifically contemplates all combinations of embodiments.

[0151] Another aspect of the present invention is a compound represented by formula IB: [ka] or a pharma- ceutical acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 are independently H or Z; Z is H or D, provided that the abundance of deuterium in Z is at least 75%; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 is provided that at least one of

[0152] The definition of the variables in formula IB above encompasses multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more of the chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0153] In certain embodiments, the compound is of formula IB.

[0154] In certain embodiments, the present invention provides a compound of formula IB, wherein each of the variables is defined above in the description of formula IA and is described herein both alone and in combination in the embodiments. For example, in certain embodiments, R 21 is Z. As another example, in certain embodiments, R 1 , R 2 , and R 3 is Z. As yet another example, in certain embodiments, R 1 , R 2 , and R 3 is Z and R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 is H.

[0155] The above description describes multiple embodiments for compounds of formula IB. This patent application specifically contemplates all combinations of embodiments.

[0156] Another aspect of the present invention is a compound represented by formula II: [ka] or a pharma- ceutical acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is independently H or Z; Z is H or D, provided that the abundance of deuterium in Z is at least 75%.

[0157] The definition of the variables in formula II above encompasses multiple chemical groups. The present application contemplates embodiments, for example, where i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more of the chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0158] In certain embodiments, the compound is of formula II.

[0159] As generally defined above, R 1 is H or Z. In certain embodiments, R 1 is H. In certain embodiments, R 1 is Z. In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 2 below.

[0160] As generally defined above, R 2is H or Z. In certain embodiments, R 2 is H. In certain embodiments, R 2 is Z. In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 2 below.

[0161] As generally defined above, R 3 is H or Z. In certain embodiments, R 3 is H. In certain embodiments, R 3 is Z. In certain embodiments, R 3 is selected from the groups depicted in the compounds of Table 2 below.

[0162] In certain embodiments, R 1 , R 2 , and R 3 is H. In certain embodiments, R 1 , R 2 , and R 3 is Z.

[0163] As generally defined above, R 4 is H or Z. In certain embodiments, R 4 is H. In certain embodiments, R 4 is Z. In certain embodiments, R 4 is selected from the groups depicted in the compounds of Table 2 below.

[0164] As generally defined above, R 5 is H or Z. In certain embodiments, R 5 is H. In certain embodiments, R 5 is Z. In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 2 below.

[0165] As generally defined above, R 6 is H or Z. In certain embodiments, R 6is H. In certain embodiments, R 6 is Z. In certain embodiments, R 6 is selected from the groups depicted in the compounds of Table 2 below.

[0166] As generally defined above, R 7 is H or Z. In certain embodiments, R 7 is H. In certain embodiments, R 7 is Z. In certain embodiments, R 7 is selected from the groups depicted in the compounds of Table 2 below.

[0167] In certain embodiments, R 4 , R 5 , R 6 , and R 7 is H. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H.

[0168] As generally defined above, R 8 is H or Z. In certain embodiments, R 8 is H. In certain embodiments, R 8 is Z. In certain embodiments, R 8 is selected from the groups depicted in the compounds of Table 2 below.

[0169] As generally defined above, R 9 is H or Z. In certain embodiments, R 9 is H. In certain embodiments, R 9 is Z. In certain embodiments, R 9 is selected from the groups depicted in the compounds of Table 2 below.

[0170] In certain embodiments, R 8 and R9 is H. In certain embodiments, R 8 and R 9 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is H. In certain embodiments, R 1 , R 2 , R 3 , R 8 , and R 9 is Z.

[0171] As generally defined above, R 10 is H or Z. In certain embodiments, R 10 is H. In certain embodiments, R 10 is Z. In certain embodiments, R 10 is selected from the groups depicted in the compounds of Table 2 below.

[0172] As generally defined above, R 11 is H or Z. In certain embodiments, R 11 is H. In certain embodiments, R 11 is Z. In certain embodiments, R 11 is selected from the groups depicted in the compounds of Table 2 below.

[0173] In certain embodiments, R 10 and R 11 is H. In certain embodiments, R 10 and R 11 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , and R 11 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 8, R 9 , R 10 , and R 11 is H.

[0174] As generally defined above, R 12 is H or Z. In certain embodiments, R 12 is H. In certain embodiments, R 12 is Z. In certain embodiments, R 12 is selected from the groups depicted in the compounds of Table 2 below.

[0175] As generally defined above, R 13 is H or Z. In certain embodiments, R 13 is H. In certain embodiments, R 13 is Z. In certain embodiments, R 13 is selected from the groups depicted in the compounds of Table 2 below.

[0176] In certain embodiments, R 12 and R 13 is H. In certain embodiments, R 12 and R 13 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , and R 13 is H. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , and R 13 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , and R 13 is Z. In certain embodiments, R 8 , R 9 , R 12, and R 13 is Z.

[0177] As generally defined above, R 14 is H or Z. In certain embodiments, R 14 is H. In certain embodiments, R 14 is Z. In certain embodiments, R 14 is selected from the groups depicted in the compounds of Table 2 below.

[0178] As generally defined above, R 15 is H or Z. In certain embodiments, R 15 is H. In certain embodiments, R 15 is Z. In certain embodiments, R 15 is selected from the groups depicted in the compounds of Table 2 below.

[0179] As generally defined above, R 16 is H or Z. In certain embodiments, R 16 is H. In certain embodiments, R 16 is Z. In certain embodiments, R 16 is selected from the groups depicted in the compounds of Table 2 below.

[0180] As generally defined above, R 17 is H or Z. In certain embodiments, R 17 is H. In certain embodiments, R 17 is Z. In certain embodiments, R 17 is selected from the groups depicted in the compounds of Table 2 below.

[0181] In certain embodiments, R 14 , R 15 , R 16 , and R 17 is H. In certain embodiments, R 4 , R 5 , R 6 , R7 , R 10 , R 11 , R 14 , R 15 , R 16 , and R 17 is H.

[0182] As generally defined above, R 18 is H or Z. In certain embodiments, R 18 is H. In certain embodiments, R 18 is Z. In certain embodiments, R 18 is selected from the groups depicted in the compounds of Table 2 below.

[0183] As generally defined above, R 19 is H or Z. In certain embodiments, R 19 is H. In certain embodiments, R 19 is Z. In certain embodiments, R 19 is selected from the groups depicted in the compounds of Table 2 below.

[0184] In certain embodiments, R 18 and R 19 is H. In certain embodiments, R 12 , R 13 , R 18 , and R 19 is H. In certain embodiments, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R17 , R 18 , and R 19 is H.

[0185] In certain embodiments, R 18 and R 19 is Z. In certain embodiments, R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 8 , R 9 , R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , R 13 , R 18 , and R 19 is Z.

[0186] As generally defined above, R 20 is H or Z. In certain embodiments, R 20 is H. In certain embodiments, R 20 is Z. In certain embodiments, R 20 is selected from the groups depicted in the compounds of Table 2 below.

[0187] In certain embodiments, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , and R 20 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is H.

[0188] In certain embodiments, R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , and R 20 is Z. In certain embodiments, R 8 , R 9 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R1 , R 2 , R 3 , R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z.

[0189] As generally defined above, Z is hydrogen or deuterium, provided that the abundance of deuterium in Z is at least 75%. In certain embodiments, the abundance of deuterium in Z is at least 80%. In certain embodiments, the abundance of deuterium in Z is at least 85%. In certain embodiments, the abundance of deuterium in Z is at least 90%. In certain embodiments, the abundance of deuterium in Z is at least 95%. In certain embodiments, the abundance of deuterium in Z is at least 97%. In certain embodiments, the abundance of deuterium in Z is at least 99%. In certain embodiments, the abundance of deuterium in Z is about 100%.

[0190] In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 At least one of R is Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 At least two of R are Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 Two of are Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 At least three of R are Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 Three of R are Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 In certain embodiments, four or five of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 More than five of them are Z.

[0191] In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 One or more of is Z in the position where D is depicted in the compounds of Table 2 below.

[0192] In certain embodiments, the compound has an enantiomeric excess of at least 85%. In certain embodiments, the compound has an enantiomeric excess of at least 90%. In certain embodiments, the compound has an enantiomeric excess of at least 95%. In certain embodiments, the compound has an enantiomeric excess of at least 98%.

[0193] The above description describes multiple embodiments for compounds of formula II. The present patent application specifically contemplates all combinations of embodiments.

[0194] Another aspect of the present invention is a compound represented by formula II-A: [ka] or a pharma- ceutical acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is independently H or Z; Z is H or D, provided that the abundance of deuterium in Z is at least 75%.

[0195] The definitions of the variables in formula II-A above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more of the chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0196] In certain embodiments, the compound is of formula II-A.

[0197] As generally defined above, R 1 is H or Z. In certain embodiments, R 1 is H. In certain embodiments, R 1 is Z.

[0198] As generally defined above, R 2 is H or Z. In certain embodiments, R 2 is H. In certain embodiments, R 2 is Z.

[0199] As generally defined above, R 3 is H or Z. In certain embodiments, R 3 is H. In certain embodiments, R 3 is Z.

[0200] In certain embodiments, R 1 , R 2 , and R 3 is H. In certain embodiments, R 1 , R 2 , and R 3 is Z.

[0201] As generally defined above, R 4 is H or Z. In certain embodiments, R 4 is H. In certain embodiments, R 4 is Z.

[0202] As generally defined above, R 5 is H or Z. In certain embodiments, R 5 is H. In certain embodiments, R 5 is Z.

[0203] As generally defined above, R 6 is H or Z. In certain embodiments, R 6 is H. In certain embodiments, R 6 is Z.

[0204] As generally defined above, R 7 is H or Z. In certain embodiments, R 7 is H. In certain embodiments, R 7 is Z.

[0205] In certain embodiments, R 4 , R 5 , R 6 , and R 7is H. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H.

[0206] As generally defined above, R 8 is H or Z. In certain embodiments, R 8 is H. In certain embodiments, R 8 is Z.

[0207] As generally defined above, R 9 is H or Z. In certain embodiments, R 9 is H. In certain embodiments, R 9 is Z.

[0208] In certain embodiments, R 8 and R 9 is H. In certain embodiments, R 8 and R 9 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is H. In certain embodiments, R 1 , R 2 , R 3 , R 8 , and R 9 is Z.

[0209] As generally defined above, R 10 is H or Z. In certain embodiments, R 10 is H. In certain embodiments, R 10 is Z.

[0210] As generally defined above, R 11is H or Z. In certain embodiments, R 11 is H. In certain embodiments, R 11 is Z.

[0211] In certain embodiments, R 10 and R 11 is H. In certain embodiments, R 10 and R 11 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , and R 11 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is H.

[0212] As generally defined above, R 12 is H or Z. In certain embodiments, R 12 is H. In certain embodiments, R 12 is Z.

[0213] As generally defined above, R 13 is H or Z. In certain embodiments, R 13 is H. In certain embodiments, R 13 is Z.

[0214] In certain embodiments, R 12 and R 13 is H. In certain embodiments, R 12 and R 13 is Z. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R12 , and R 13 is H. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , and R 13 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , and R 13 is Z. In certain embodiments, R 8 , R 9 , R 12 , and R 13 is Z.

[0215] As generally defined above, R 14 is H or Z. In certain embodiments, R 14 is H. In certain embodiments, R 14 is Z.

[0216] As generally defined above, R 15 is H or Z. In certain embodiments, R 15 is H. In certain embodiments, R 15 is Z.

[0217] As generally defined above, R 16 is H or Z. In certain embodiments, R 16 is H. In certain embodiments, R 16 is Z.

[0218] As generally defined above, R 17 is H or Z. In certain embodiments, R 17 is H. In certain embodiments, R 17 is Z.

[0219] In certain embodiments, R 14 , R 15 , R16 , and R 17 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 14 , R 15 , R 16 , and R 17 is H.

[0220] As generally defined above, R 18 is H or Z. In certain embodiments, R 18 is H. In certain embodiments, R 18 is Z. In certain embodiments, R 18 is selected from the groups depicted in the compounds of Table 1 below.

[0221] As generally defined above, R 19 is H or Z. In certain embodiments, R 19 is H. In certain embodiments, R 19 is Z.

[0222] In certain embodiments, R 18 and R 19 is H. In certain embodiments, R 12 , R 13 , R 18 , and R 19 is H. In certain embodiments, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14, R 15 , R 16 , R 17 , R 18 , and R 19 is H.

[0223] In certain embodiments, R 18 and R 19 is Z. In certain embodiments, R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 8 , R 9 , R 12 , R 13 , R 18 , and R 19 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 8 , R 9 , R 12 , R 13 , R 18 , and R 19 is Z.

[0224] As generally defined above, R 20 is H or Z. In certain embodiments, R 20 is H. In certain embodiments, R 20 is Z.

[0225] In certain embodiments, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is H. In certain embodiments, R4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , and R 20 is H. In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is H.

[0226] In certain embodiments, R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , and R 20 is Z. In certain embodiments, R 8 , R 9 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 1 , R 2, R 3 , R 8 , R 9 , R 12 , R 13 , R 18 , R 19 , and R 20 is Z.

[0227] As generally defined above, Z is hydrogen or deuterium, provided that the abundance of deuterium in Z is at least 75%. In certain embodiments, the abundance of deuterium in Z is at least 80%. In certain embodiments, the abundance of deuterium in Z is at least 85%. In certain embodiments, the abundance of deuterium in Z is at least 90%. In certain embodiments, the abundance of deuterium in Z is at least 95%. In certain embodiments, the abundance of deuterium in Z is at least 97%. In certain embodiments, the abundance of deuterium in Z is at least 99%. In certain embodiments, the abundance of deuterium in Z is about 100%.

[0228] In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 At least one of R is Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 At least two of R are Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 Two of are Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 At least three of R are Z. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 Three of R are Z. In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 In certain embodiments, four or five of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 More than five of them are Z.

[0229] In certain embodiments, the compound has an enantiomeric excess of at least 85%. In certain embodiments, the compound has an enantiomeric excess of at least 90%. In certain embodiments, the compound has an enantiomeric excess of at least 95%. In certain embodiments, the compound has an enantiomeric excess of at least 98%.

[0230] The above description describes multiple embodiments for compounds of formula II-A. This patent application specifically contemplates all combinations of embodiments.

[0231] Another aspect of the invention provides a compound of Table 1 or 2, below, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1 or 2, below. In certain embodiments, the compound is a compound of Table 1, below, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, below. In certain embodiments, the compound is a compound of Table 2, below, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 2, below, [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0232] The method for preparing the compounds described herein is illustrated in the following synthetic scheme. The scheme is provided for the purpose of illustrating the present invention, and is not intended to limit the scope or spirit of the present invention. The starting materials shown in the scheme can be obtained from commercial sources or can be prepared based on procedures described in the literature. Additional strategies for preparing starting materials and non-deuterium-enriched piperidinyl-methyl-purine amines and related compounds are described, for example, in WO2021 / 028854, the entirety of which is incorporated herein by reference.

[0233] In the schemes, it is understood by one skilled in the art of organic synthesis that the functionality present on the various portions of the molecules should be compatible with the reagents and reactions proposed. Substituents that are incompatible with the reaction conditions will be apparent to one skilled in the art and therefore alternative methods (e.g., use of protecting groups or alternative reactions) are suggested. Protecting group chemistry and strategies are described, for example, in “Protecting Groups in Organic Synthesis”, TW Greene and PG M Huts, 30 US 6,311,421, incorporated herein by reference in its entirety.rd These methods are well known in the art, as described in detail in the New York Times, John Wiley & Sons, 1999.

[0234] The synthetic route illustrated in Scheme 1 is a general method for preparing deuterium-enriched piperidinyl-methyl-purine amines and related compounds H. A halophenol A (X is a halogen such as Br or I) is reacted with methylation conditions (e.g., a base such as K2CO3 or DIPEA) and a methylating agent B [commercially available iodomethane or perdeuterated iodomethane, LG]. 1 is a leaving group such as iodide]), followed by metallation of the halide X (e.g., using lithium / halogen exchange, optionally followed by conversion to, for example, an organozinc, boronic ester, or boronic acid [e.g., using a trialkyl boronate and hydrolysis of the resulting boronic ester]), followed by transition metal mediated coupling with pyridine C (LG 2 is a leaving group such as bromide, iodide, or sulfonate, and LG 3 is a leaving group such as fluoride, chloride, or sulfonate, and R is an appropriate group such as methyl, ethyl, ethyl, or benzyl) to give the arylated pyridine ester D. A is -C(OH)(R 21 )-C(R 20 )F2 or -C(O)-C(R 20 )F2 and PG 1Condensation of pyridine D (e.g., using nucleophilic aromatic substitution conditions with a base such as K2CO3 or DIPEA in a polar aprotic solvent such as DMSO) followed by reduction of the ester group (e.g., using a metal hydride such as LiAlH4, or a metal deuteride such as the commercially available LiAlD4) gives the hydroxymethylpyridine F. Activation of the hydroxyl group of pyridine F, either in a separate step (e.g., using a base such as tosyl chloride and DIPEA, e.g., to a sulfonate salt) or in situ (e.g., under Mitsunobu conditions), and substitution with a protected adenine G (PG 2 is a protecting group such as Boc), followed by global deprotection (e.g., PG 1 and / or PG 2 and / or reduction, such as hydrogenolysis, where at least one of 1 and / or PG 2 Using acidic conditions such as TFA or HCl where at least one of is Boc) provides deuterium-enriched piperidinyl-methyl-purine amines and related compounds H. Scheme 1. [ka]

[0235] Deuterium enrichment can also be included in piperidine intermediate E of Scheme 1, for example, as illustrated in Scheme 2. Piperidine-2,6-dione A (PG is a protecting group such as benzyl) is subjected to hydrolysis conditions (e.g., using LiOH and H2O2 in an alcoholic solvent such as EtOH) followed by Lossen / Hofman / Curtius / Schmidt rearrangement to provide aminopiperidine B. Reduction of the 2,6-dione (e.g., using a metal hydride such as LiAlH4 or NaBH4, a metal deuteride such as commercially available LiAlD4 or NaBD4, a borane such as BH3 or BD3, or a combination thereof) followed by deprotection (e.g., using reduction such as hydrogenolysis when PG is benzyl) provides piperidine C, which can be deuterium enriched. Some examples of deuterium incorporation in piperidine-2,6-diones are provided, for example, in US 2007 / 0276001, and in Perrin, CL, et al., J. Am. Chem. Soc. (2005) vol. 127, no. 26, pp. 9641-9647. Scheme 2. [ka]

[0236] The synthetic route illustrated in Scheme 3 is ASpecific methods for preparing piperidine-2,6-dione A of Scheme 2, including those in which groups can be deuterium enriched. Aldol addition of piperidine-2,6-dione A to aldehyde B (or its equivalent such as acetal or hemiacetal) gives alcohol C. Resolution of alcohol C (e.g., using chiral chromatography) gives single stereoisomer D. Alternatively, oxidation of alcohol C gives ketone E. Reduction of ketone E (e.g., using a deuterium enriched reducing agent such as commercially available LiAlD4), followed by resolution (e.g., using chiral chromatography) gives single stereoisomer F. Alternatively, use of a deuterium enriched stoichiometric reducing agent (e.g., BD3 or D2) and a chiral catalyst (e.g., oxazaboridine or ruthenium / 1,2-diphenylethane-1,2-diamine catalyst) gives single stereoisomer F without chiral chromatography. Enantiomers and diastereomers of alcohols D and F are prepared as single stereoisomers using similar procedures. Finally, ketone E can alternatively be deuterated via its enol or enolate (e.g., using DO and acid or base catalysis) to give α-deutero ketone G. Scheme 3. [ka]

[0237] The modular synthetic routes illustrated in Schemes 1, 2, and 3 can also be easily modified by one skilled in the art to provide additional deuterium-enriched piperidinyl-methyl-purine amines and related compounds by performing functional group transformations, such as oxidation and reduction with deuterium-enriched reagents, on the intermediate and final compounds. Such functional group transformations are well known in the art, for example, as described in "Comprehensive Organic Synthesis" (BM Trost & I. Fleming, eds., 1991-1992).

[0238] The compounds described herein can be provided in isolated or purified form.An isolated or purified compound is a group of compounds that is separated from its environment, such as from a crude reaction mixture when made in a laboratory setting, or removed from its natural environment when naturally occurring.Examples of the purity of isolated compounds include, for example, at least 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, 95% by weight, up to 100% by weight.

[0239] Another aspect of the present invention provides a unit quantum of the deuterium-enriched compound described herein, such as an amount of at least (a) 1 μg of the disclosed deuterium-enriched compound, (b) 1 mg, or (c) 1 gram. In further embodiments, the quantum is, for example, at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, or 1 mole of the compound. The amount also encompasses laboratory scale (e.g., gram scale, including 1, 2, 3, 4, 5 g, etc.), kilo laboratory scale (e.g., kilogram scale, including 1, 2, 3, 4, 5 kg, etc.), and industrial or commercial scale (e.g., multiple kilograms or more, including 100, 200, 300, 400, 500 kg, etc.) amounts, as these are more useful in the actual manufacture of pharmaceutical products. Industrial / commercial scale refers to the amount of product produced in a batch designed for clinical trials, formulation, sale / distribution to the general public, etc.

[0240] II. Therapeutic Uses of Deuterium-Enriched Piperidinyl-Methyl-Purinamine and Related Compounds Deuterium-enriched piperidinyl-methyl-purinamine and related compounds described herein, such as compounds of formula I or II, or other compounds of section I, provide therapeutic benefits to 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 includes administering a therapeutically effective amount of a compound described herein, such as a compound of formula I or II, to a subject in need thereof to treat the disease or condition. In certain embodiments, the compound is a compound of formula I or II as defined by one of the embodiments described above.

[0241] Examples of diseases or conditions mediated by NSD2 include, but are not limited to, breast cancer, cervical cancer, skin cancer (particularly cutaneous squamous cell carcinoma), ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia (particularly acute lymphoblastic leukemia), non-Hodgkin's lymphoma (particularly mantle cell lymphoma), and pulmonary arterial hypertension.

[0242] In certain embodiments, the NSD2-mediated disease or condition is cancer.

[0243] In certain embodiments, the NSD2-mediated disease or condition is selected from solid tumors, leukemia, myeloma, lymphoma, and hypertension. In certain embodiments, the NSD2-mediated disease or condition is a solid tumor. In certain embodiments, the NSD2-mediated disease or condition is selected from leukemia, myeloma, and lymphoma. In certain embodiments, the NSD2-mediated disease or condition is leukemia. In certain embodiments, the NSD2-mediated disease or condition is myeloma. In certain embodiments, the NSD2-mediated disease or condition is lymphoma. In certain embodiments, the NSD2-mediated disease or condition is hypertension.

[0244] In certain embodiments, the disease or condition mediated by NSD2 is breast cancer, cervical cancer, skin cancer, ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia, non-Hodgkin's lymphoma, or pulmonary arterial hypertension. In certain embodiments, the disease or condition mediated by NSD2 is breast cancer. In certain embodiments, the disease or condition mediated by NSD2 is cervical cancer. In certain embodiments, the disease or condition mediated by NSD2 is ovarian cancer. In certain embodiments, the disease or condition mediated by NSD2 is gastric cancer. In certain embodiments, the disease or condition mediated by NSD2 is prostate cancer. In certain embodiments, the disease or condition mediated by NSD2 is pancreatic cancer. In certain embodiments, the disease or condition mediated by NSD2 is hepatocellular carcinoma. In certain embodiments, the disease or condition mediated by NSD2 is head and neck cancer. In certain embodiments, the disease or condition mediated by NSD2 is peripheral nerve sheath tumor. In certain embodiments, the disease or condition mediated by NSD2 is osteosarcoma. In certain embodiments, the disease or condition mediated by NSD2 is multiple myeloma. In certain embodiments, the disease or condition mediated by NSD2 is neuroblastoma. In certain embodiments, the disease or condition mediated by NSD2 is pulmonary arterial hypertension.

[0245] 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.

[0246] 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.

[0247] In certain embodiments, the disease or condition mediated by NSD2 is leukemia.In certain embodiments, the disease or condition mediated by NSD2 is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or chronic myelomonocytic leukemia (CMML).In certain embodiments, the disease or condition mediated by NSD2 is AML.In certain embodiments, the disease or condition mediated by NSD2 is CML.In certain embodiments, the disease or condition mediated by NSD2 is CMML.

[0248] 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.

[0249] In certain embodiments, the disease or condition mediated by NSD2 is lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is Hodgkin's lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is non-Hodgkin's lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is mantle cell lymphoma or diffuse large B-cell lymphoma. In certain embodiments, the disease or condition mediated by NSD2 is diffuse large B-cell lymphoma.

[0250] In certain embodiments, the NSD2-mediated disease or condition is myeloma.

[0251] In certain embodiments, the NSD2-mediated disease or condition is thyroid cancer. In certain embodiments, the NSD2-mediated disease or condition is colon cancer.

[0252] In certain embodiments, the cancer overexpresses NSD2. In certain embodiments, the cancer has a mutation in NSD2. In certain embodiments, the cancer has an activating mutation in NSD2. In certain embodiments, the cancer has a t(4;14)(p16.3;q32.3) translocation in NSD2. In certain embodiments, the cancer has an E1099K mutation in NSD2. In certain embodiments, the cancer has a T1150A mutation in NSD2.

[0253] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a child. In certain embodiments, the subject is an elderly person.

[0254] Another aspect of the invention provides the use of a compound described herein (such as a compound of Formula I or II, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease or condition described herein, such as cancer.

[0255] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula I or II, or other compound in Section I) for treating a disease or condition, such as a disease or condition described herein (e.g., cancer).

[0256] Furthermore, the compounds described herein, such as compounds of formula I or II, or other compounds of Section I, inhibit the activity of nuclear SET domain-containing protein 2 (NSD2). Accordingly, 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 deuterium-enriched piperidinyl-methyl-purinamine or related compound described herein, such as compounds of formula I or II, or other compounds of Section I, to inhibit the activity of said NSD2. In certain embodiments, the compound is a compound of formula I or II as defined by one of the embodiments described above.

[0257] Compounds can be tested for their ability to bind to and / or inhibit NSD2 activity according to any of a variety of assays known in the art, including, for example, LC-MS / MS enzyme assays that monitor SAH production, cellular FRET assays, cellular ELISA assays, methyltransferase enzyme luminescence assays that monitor SAH production, and radiometric assays using tritium-labeled SAMs. Such assays are described, for example, in WO2021 / 028854 and Coussens, NP et al. J.Biol.Chem.(2018) Vol.293, No.35, pp.13750-13755, each of which is incorporated herein by reference in its entirety.

[0258] The advantages of the deuterium-enriched compounds described herein may include increased metabolic stability. Such increased metabolic stability may result in a longer half-life of the deuterium-enriched compound in the patient's circulatory system and / or a higher Cmax value in the patient's plasma. The longer half-life of the deuterium-enriched compound may allow for less frequent administration of the deuterium-enriched compound to the patient while still achieving a desired level of efficacy. The higher Cmax value of the deuterium-enriched compound may provide greater efficacy when using the deuterium-enriched compound to treat a disease. The increased metabolic stability of the compound may also allow for a lower dose of the compound to be administered to the patient, which may reduce the frequency and / or magnitude of any adverse side effects.

[0259] The metabolic stability of deuterium-enriched compounds can be evaluated using procedures described in the literature for measuring metabolic stability of compounds. For example, the test deuterium-enriched compounds can be incubated at 37°C in a solution containing hepatocytes obtained from a subject (e.g., mouse, rat, dog, monkey, or human). Aliquots of the solution are taken at several time points (e.g., 0, 15, 30, 60, 120, and 180 minutes), and the aliquots are evaluated by analytical methods (e.g., HPLC and / or HPLC-MS techniques) to determine the amount of the original deuterium-enriched compound and / or the presence of any metabolites and / or degradation products of the original deuterium-enriched compound. A control article (e.g., verapamil) can be used as an internal standard during the experiment.

[0260] In a more specific embodiment, the metabolic stability of deuterium-enriched compounds can be assessed by the following procedure: (i) preparing an appropriate substrate (e.g., nucleosomes) for a specific methyltransferase (e.g., NSD2) in a freshly prepared reaction buffer; (ii) delivering the appropriate methyltransferase into the substrate solution and gently mixing; (iii) delivering a deuterium-enriched test compound in DMSO into the methyltransferase reaction mixture, e.g., by using acoustic technology in the nanoliter range (Echo 550, LabCyte Inc. Sunnyvale, Calif.) and incubating for 20 minutes at room temperature; (iv) adding 1 μM of deuterium-enriched test compound into the reaction mixture. 3 H-SAM (methyl donor) is delivered to initiate the reaction; (v) the reaction mixture is incubated at 30° C. for 1 hour; (vi) the reaction mixture is delivered to filter paper for detection; (vii) the data is analyzed using Excel and GraphPad Prism software.

[0261] III. Combination Therapy Another aspect of the present invention provides combination therapy. The deuterium-enriched piperidinyl-methyl-purine amine or related compounds described herein (e.g., compounds of formula I or II, or other compounds of Section I), or pharma- ceutically acceptable salts thereof, can be used in combination with additional therapeutic agents to treat diseases or conditions, such as cancer.

[0262] Thus, in some embodiments, the present invention provides a method of treating a disclosed disease or condition, comprising administering to a patient in need of treatment an effective amount of a compound disclosed herein and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents.

[0263] One or more other therapeutic agents may be administered separately from the compound or composition of the present invention as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compound of the present invention in a single composition. When administered as a multiple dose regimen, one or more other therapeutic agents and the compound or composition of the present invention may be administered simultaneously, sequentially, or within a period of each other.

[0264] In certain embodiments, the additional therapeutic agent is an anti-cancer agent, an anti-allergy agent, an anti-emetic agent (or anti-emetic agent), an analgesic agent, a cytoprotective agent, or a combination thereof. In certain embodiments, the additional therapeutic agent is an anti-cancer agent, an analgesic agent, an anti-inflammatory agent, or a combination thereof.

[0265] In certain embodiments, the additional therapeutic agent is an anti-cancer or chemotherapeutic agent. Examples of anti-cancer agents contemplated for use in the combination therapy of the present invention include erlotinib, bortezomib, fulvestrant, sunitib, imatinib mesylate, letrozole, finasunate, platins such as oxaliplatin, carboplatin, and cisplatin, finasunate, fluorouracil, rapamycin, leucovorin, lapatinib, lonafamib, sorafenib, gefitinib, camptothecin, topotecan, bryostatin, adezelin, anthracyclines, and the like. Other agents include, but are not limited to, cyclophosphamide, doxorubicin, vincristine, prednisone or prednisolone, other alkylating agents such as mechlorethamine, chlorambucil, and ifosfamide, antimetabolites such as azathioprine or mercaptopurine, other microtubule inhibitors (vinca alkaloids such as vincristine, vinblastine, vinorelbine, and vindesine, as well as taxol ... Sun), podophyllotoxins (etoposide, teniposide, etoposide phosphate, and epipodophyllotoxin), topoisomerase inhibitors, other cytotoxins such as actinomycin, daunorubicin, valrubicin, idarubicin, edrecolomab, epirubicin, bleomycin, plicamycin, and mitomycin, as well as other anti-cancer antibodies (cetuximab, bevacizumab, ibritumomab, abagovomab, adecatumumab, afutuzumab, alacizumab, alemtuzumab, anatumomab, apolizumab, bavituximab, belim Mab, bivatuzumab mertansine, blinatumomab, brentuximab vedotin, cantuzumab mertansine, catemashomab, cetuximab, sitatuzumab bogatox, cixutumumab, clivatuzumab tetraxetan, conatumumab, dacetuzumab, daclizumab, detumomab, ecromeximab, edrecolomab, elotuzumab, epratuzumab, ertumaxomab, etaracizumab, faretuzumab, figitumumab, frezolimumab, galiximab, gembatumumab vedotin, gemtuzumab, ibritumomab tiuxetan,Inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lucatumumab, rumilicimab, mapatumumab, matuzumab, milatuzumab, mitumomab, nacolomab butafenatox, naptumomab estafenatox, necitumumab, nimotuzumab, ofatumumab, olarab tuzumab, oportuzumab monatox, oregovomab, panitumumab, pemtumomab, pertuzumab, pintumomab, pritumumab, ramucirumab, rilotumumab, lobatumumab, rituximab, sibrotuzumab, tacatuzumab tetraxetan, taplitumomab paptox, tenatumomab, ticilimumab, tigatuzumab, tositumomab, or 131 I-tositumomab, trastuzumab, tremelimumab, tuocuzumab celmoleukin, veltuzumab, visilizumab, volociximab, votumumab, zalutumumab, zanolimumab, IGN-101, MDX-010, ABX-EGR, EMD72000, ior-t1, MDX-220, MRA, H-11 scFv, huJ591, TriGem, TriAb, R3, MT-201, G-250, ACA-125, Onyvax-105, CD:-960, Cea-Vac, BrevaRex AR54, IMC-1C11, GlioMab-H, ING-1, anti-LCG MAbs, MT-103, KSB-303, Therex, KW2871, anti-HMI.24, anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-RI MAb, prostate cancer antibody, H22xKi-r, ABX-Mai, Imuteran, Monopharm-C), and antibody drug conjugates comprising any of the above agents (particularly the auristatins MMAE and MMAF, maytansinoids such as DM-1, calicheamicin, or various cytotoxins).

[0266] In certain embodiments, the additional therapeutic agent is anastrozole (ARIMIDEX®), bicalutamide (CASODEX®), bleomycin sulfate (BLENOXANE®), busulfan (MYLERAN®), busulfan injection (BUSULFEX®), capecitabine (XELODA®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (PARAPLATIN®), carmustine (BiCNU®), chlorambucil ( LEUKERAN®), cisplatin (PLATINOL®), cladribine (LEUSTATIN®), cyclophosphamide (CYTOXAN® or NEOSAR®), cytarabine, cytosine arabinoside (CYTOSAR-U®), cytarabine liposome injection (DEPOCYT®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, COSMEGAN®), daunorubicin hydrochloride (CERUBIDINE®), )), Daunorubicin Citrate Liposomal Injection (DAUNOXOME®), Dexamethasone, Docetaxel (TAXOTERE®), Doxorubicin Hydrochloride (ADRIAMYCIN®, RUBEX®), Etoposide (VEPESID®), Fludarabine Phosphate (FLUDARA®), 5-Fluorouracil (ADRUCIL®, EFUDEX®), Flutamide (EULEXIN®), Tezacitibine, Gemcitabine (Difluorodeoxycytidine), Hydroxypropyl 1,2-Difluorouracil (Hydroxypropyl 1,2-Difluorouracil ... roxiurea (HYDREA®), idarubicin (IDAMYCIN®), ifosfamide (IFEX®), irinotecan (CAMPTOSAR®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (ALKERAN®), 6-mercaptopurine (PURINETHOL®), methotrexate (FOLEX®), mitoxantrone (NOVANTRONE®), gemtuzumab ozogamicin (MYLOTARG™),Selected from paclitaxel (TAXOL®), nab-paclitaxel (ABRAXANE®), Phoenix (Yttrium 90 / MX-DTPA), pentostatin, polipheprosan 20 with carmustine implant (GLIADEL®), tamoxifen citrate (NOLVADEX®), teniposide (VUMON®), 6-thioguanine, thiotepa, tirapazamine (TIRAZONE®), topotecan hydrochloride for injection (HYCAMPTIN®), vinblastine (VELBAN®), vincristine (ONCOVIN®), and vinorelbine (NAVELBINE®).

[0267] In certain embodiments, the additional therapeutic agent is capable of inhibiting BRAF, MEK, CDK4 / 6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or a combination thereof. In certain embodiments, the compound of the present invention is combined with another therapeutic agent selected from vemurafinib, debrafinib, LGX818, trametinib, MEK162, LEE011, PD-0332991, panobinostat, belinostat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib, panitumumab, vandetanib, INC280, everolimus, simolimus, BMK120, BYL719 or CLR457, or a combination thereof.

[0268] In certain embodiments, the additional therapeutic agent is selected based on the disease or condition being treated. For example, in the treatment of melanoma, the additional therapeutic agent is selected from aldesleukin (e.g., PROLEUKIN®), dabrafenib (e.g., TAFINLAR®), dacarbazine, recombinant interferon alpha-2b (e.g., INTRON® A), ipilimumab, trametinib (e.g., MEKINIST®), pegylated interferon alpha-2b (e.g., PEGINTRON®, SYLATRON™), vemurafenib (e.g., ZELBORAF®), and ipilimumab (e.g., YERVOY®).

[0269] For the treatment of ovarian cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), carboplatin (PARAPLATIN®), cyclophosphamide (CYTOXAN®, NEOSAR®), cisplatin (PLATINOL®, PLATINOL-AQ®), doxorubicin hydrochloride liposomal (DOXIL®, DOX-SL®, EVACET®, LIPODOX®), gemcitabine hydrochloride (GEMZAR®), topotecan hydrochloride (HYCAMTIN®), and paclitaxel (TAXOL®).

[0270] For the treatment of thyroid cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), cabozantinib-S-malate (COMETRIQ®), and vandetanib (CAPRELSA®).

[0271] For the treatment of colon cancer, the additional therapeutic agent is selected from fluorouracil (e.g., ADRUCIL®, EFUDEX®, FLUOROPLEX®), bevacizumab (AVASTIN®), irinotecan hydrochloride (CAMPTOSTAR®), capecitabine (XELODA®), cetuximab (ERBITUX®), oxaliplatin (ELOXATIN®), leucovorin calcium (WELLCOVORIN®), regorafenib (STIVARGA®), panitumumab (VECTIBIX®), and ziv-aflibercept (ZALTRAP®).

[0272] For the treatment of lung cancer, the additional therapeutic agent may be methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX and selected from PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), paclitaxel (TAXOL®), paclitaxel albumin-stabilized nanoparticle formulation (ABRAXANE®), afatinib maleate (GILOTRIF®), pemetrexed disodium (ALIMTA®), bevacizumab (AVASTIN®), carboplatin (PARAPLATIN®), cisplatin (PLATINOL®, PLATINOL-AQ®), crizotinib (XALKORI®), erlotinib hydrochloride (TARCEVA®), gefitinib (IRESSA®), and gemcitabine hydrochloride (GEMZAR®).

[0273] For the treatment of pancreatic cancer, the other therapeutic agent may be selected from fluorouracil (ADRUCIL®, EFUDEX®, FLUOROPLEX®), erlotinib hydrochloride (TARCEVA®), gemcitabine hydrochloride (GEMZAR®), and mitomycin or mitomycin C (MITOZYTREXTM, MUTAMYCIN®).

[0274] For the treatment of cervical cancer, the additional therapeutic agent is selected from bleomycin (BLENOXANE®), cisplatin (PLATINOL®, PLATINOL-AQ®), and topotecan hydrochloride (HYCAMTIN®).

[0275] For the treatment of head and neck cancer, the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), fluorouracil (ADRUCIL®, EFUDEX®, FLUOROPLEX®), bleomycin (BLENOXANE®), cetuximab (ERBITUX®), cisplatin (PLATINOL®, PLATINOL-AQ®), and docetaxel (TAXOTERE®).

[0276] For the treatment of leukemia, including chronic myelomonocytic leukemia (CMML), the additional therapeutic agent is selected from bosutinib (BOSULIF®), cyclophosphamide (CYTOXAN®, NEOSAR®), cytarabine (CYTOSAR-U®, TARABINE PFS®), dasatinib (SPRYCEL®), imatinib mesylate (GLEEVEC®), ponatinib (ICLUSIG®), nilotinib (TASIGNA®), and omacetaxine mepesuxinate (SYNRIBO®).

[0277] In some cases, patients may experience allergic reactions to the compounds of the present invention and / or other anti-cancer drug(s) during or after administration. Therefore, anti-allergic agents may be administered to minimize the risk of allergic reactions. Suitable anti-allergic agents include corticosteroids such as dexamethasone (e.g., DECADRON®), beclomethasone (e.g., BECLOVENT®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, e.g., ALA-CORT®, hydrocortisone phosphate, Solu-CORTEF®, HYDROCORT Acetate®, and LANACORT®), prednisolone (e.g., DELTA-Cortel®, ORAPRED®, PEDIAPRED®, and PRELONE®), prednisone (e.g., DELTASONE®, LIQUID RED ... antihistamines such as RED®, METICORTEN®, and ORASONE®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, e.g., DURALONE®, MEDRALONE®, MEDROL®, M-PREDNISOL®, and SOLU-MEDROL®), diphenhydramine (e.g., BENADRYL®), hydroxyzone, and cyproheptadine, and bronchodilators such as beta-adrenergic receptor antagonists, albuterol (e.g., PROVENTIL®), and terbutaline (e.g., BRETHINE®).

[0278] In other cases, patients may experience nausea during and after administration of the compounds of the present invention and / or other anticancer drug(s). Therefore, antiemetics may be administered to prevent nausea (upper stomach) and vomiting. Suitable antiemetics include aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HCl (KYTRIL®), lorazepam (ATIVAN®), dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and Zunrisa®), and combinations thereof.

[0279] In still other cases, medications to reduce the pain experienced during treatment are prescribed to make the patient more comfortable. Common over-the-counter painkillers such as TYLENOL® are often used. Opioid painkillers such as hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphone hydrochloride (OPANA®), and fentanyl (e.g., DURAGESIC®) are also useful for moderate or severe pain.

[0280] In addition, cytoprotectants (e.g., neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, etc.) may be used as adjunctive therapy to protect normal cells from treatment toxicity and limit organ toxicity. Suitable cytoprotectants include amifostine (ETHYOL®), glutamine, dimesna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor, and folinic acid).

[0281] In yet another aspect, the compounds of the present invention can be used in combination with known therapeutic processes, for example with the administration of hormones or with radiation therapy. In certain cases, the compounds of the present invention can be used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0282] The dose and dosing schedule of the active ingredients used in the combination therapy can be determined by the attending clinician. In certain embodiments, the compound described herein (e.g., a compound of Formula I or II, or other compounds of Section I) and the additional therapeutic agent(s) are administered at a dose that is generally employed when such agents are used as monotherapy to treat a disease or condition. In other embodiments, the compound described herein (e.g., a compound of Formula I or II, or other compounds of Section I) and the additional therapeutic agent(s) are administered at a dose that is lower than the dose that is generally employed when such agents are used as monotherapy to treat a disease or condition. In certain embodiments, the compound described herein (e.g., a compound of Formula I or II, or other compounds of Section I) and the additional therapeutic agent(s) are present in the same composition that is suitable for oral administration.

[0283] In certain embodiments, the compounds described herein (e.g., compounds of Formula I or II, or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow for the use of lower dosages of one or more agents of the combination therapy and / or less frequent administration of one or more agents. Lower dosages or less frequent administration of one or more agents may reduce the toxicity of the therapy without reducing the efficacy of the therapy.

[0284] Another aspect of the present invention is a kit comprising a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I or II, or other compounds of Section I), a pharma- ceutically acceptable carrier, vehicle, or diluent, and, optionally, at least one additional therapeutic agent as listed above. In certain embodiments, the kit further comprises instructions, such as instructions for treating a disease described herein.

[0285] IV. Pharmaceutical Compositions and Dosage Considerations As indicated above, the present invention provides pharmaceutical compositions comprising one or more of the compounds described above in a therapeutically effective amount, formulated with one or more pharma- ceutical acceptable carriers (additives) and / or diluents.The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or as a sustained release formulation; (3) topical application, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin; (4) intravaginally or rectally, e.g., as a pessary, cream, or foam; (5) sublingually; (6) intraocularly; (7) transdermally; or (8) intranasally. In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein (eg, a compound of Formula I or II) and a pharma- ceutically acceptable carrier.

[0286] The phrase "therapeutically effective amount" as used herein means an amount of a compound, material, or composition, including a compound of the invention, that is effective to produce a desired therapeutic effect in at least a subpopulation of cells in an animal, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0287] The phrase "pharmacologically acceptable" is employed herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0288] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0289] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0290] The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may be conveniently presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0291] In certain embodiments, the formulations of the invention comprise an additive selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides, and a compound of the invention. In certain embodiments, the above formulations render the compounds of the invention orally bioavailable.

[0292] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0293] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powder, granules, each containing a predetermined amount of a compound of the present invention as the active ingredient, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0294] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) excipients or fillers, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) disintegrating agents such as paraffin, (6) absorption enhancers such as quaternary ammonium compounds, and surfactants such as poloxamers and sodium lauryl sulfate, (7) wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof, (10) coloring agents, and (11) controlled release agents such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be employed as excipients in soft and hard shell gelatin capsules using additives such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0295] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0296] Tablets and other solid dosage forms of the pharmaceutical composition of the present invention, such as dragees, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in various proportions to provide the desired release profile. They can be formulated for rapid release, for example, lyophilized. They can also be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be compositions that release the active ingredient(s) only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0297] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form can contain inert diluent commonly used in the art, such as water or other solvent, solubilizer, emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0298] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0299] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0300] Formulations of pharmaceutical compositions of the invention for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0301] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

[0302] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0303] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0304] Powders and sprays can contain, in addition to the compounds of the invention, additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0305] Transdermal patch has the added advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be made by dissolving or dispersing the compound in suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0306] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0307] Pharmaceutical compositions of the invention suitable for parenteral administration contain one or more compounds of the invention in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0308] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0309] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action on the subject compounds may be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0310] In some cases, it is desirable to slow down the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of drugs.This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility.The absorption rate of drugs then depends on their dissolution rate, which in turn depends on crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0311] Injectable depot forms are prepared by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0312] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be administered by themselves or, for example, in combination with a pharma- ceutical acceptable carrier, as a pharmaceutical composition containing 0.1 to 99% (more preferably, 10 to 30%) of the active ingredient.

[0313] The preparations of the present invention can be administered orally, parenterally, topically or rectally.They are naturally administered in a form suitable for each administration route.For example, they are administered in tablet or capsule form, by injection, inhalation, eye drops, ointments, suppositories, etc., by administration by injection, infusion or inhalation, topically by lotion or ointment, rectally by suppositories.Oral administration is preferred.

[0314] The phrases "parenteral administration" and "administered parenterally", as used herein, mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0315] The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally," as used herein, refer to administration of a compound, drug, or other material other than directly into the central nervous system, e.g., subcutaneous administration, so that it enters the patient's system and thus is subject to metabolic and other similar processes.

[0316] These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally, e.g., by spray, rectally, intravaginally, parenterally, intracisternally, and topically, including buccal and sublingually, such as by powders, ointments, or drops.

[0317] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention are formulated into pharma- ceutical acceptable dosage forms by conventional methods known to those skilled in the art.

[0318] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0319] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention, or esters, salts, or amides thereof, employed, the route of administration, the timing of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical arts.

[0320] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0321] In general, a suitable daily dose of the compound of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Preferably, the compound is administered at about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compound described herein is co-administered with another agent (e.g., as a sensitizer), the effective amount may be less than when the agent is used alone.

[0322] If desired, the effective daily amount of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. The preferred dosage is a single administration per day.

[0323] The present invention further provides unit dosage forms (such as tablets or capsules) comprising deuterium-enriched piperidinyl-methyl-purinamine or related compounds as described herein in a therapeutically effective amount for the treatment of the diseases or conditions described herein. EXAMPLES

[0324] The invention generally described herein will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to be limiting of the invention.

[0325] Example 1 - Synthesis of methyl 5-((R)-3-(benzylamino)-3-((S)-2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2,5-difluoro-4-(methoxy-d3)phenyl)isonicotinate [ka] The title compound was prepared using the following procedure. [ka]

[0326] Part 1: Preparation of compound B To a solution of compound A (200 g, 1.00 equiv.) and K2CO3 (330 g, 2.50 equiv.) in DMF (2.0 L) was added CD3I (208 g, 1.50 equiv.) at 0° C. The mixture was stirred at 20° C. for 16 h. The reaction mixture was then quenched by the addition of H2O (1.00 L) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (500 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound B (190 g, crude) as a white solid. 1 H NMR: (CDCl3, 400 MHz) δ 7.27 (dd, J = 10.0, 6.4 Hz, 1H), 6.78 (dd, J = 9.6, 7.2 Hz, 1H).

[0327] Part 2: Preparation of compound C To a solution of compound B (150 g, 1.00 equiv.) and BPD (337 g, 2.00 equiv.) in dioxane (1.05 L) was added AcOK (97.7 g, 1.50 equiv.) and Pd(dppf)Cl2 (48.5 g, 0.10 equiv.) under N2 atmosphere. The resulting mixture was stirred at 90° C. for 16 h. The reaction mixture was then cooled to 20° C., quenched by addition of H2O (500 mL), and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (500 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound C (200 g, crude) as a white solid. 1 H NMR: (CDCl3, 400 MHz) δ 7.38 (dd, J = 11.2, 5.6 Hz, 1H), 6.64 (dd, J = 10.0, 6.8 Hz, 1H), 1.26 (s, 12H).

[0328] Part 3: Preparation of compound E Compound C (200 g, 1.00 equiv.) and compound D (136.8 g, 0.85 equiv.) were mixed in dioxane (1.6 L) and water (400 mL). To the resulting mixture, K2CO3 (202 g, 2.00 equiv.) and Pd(dppf)Cl2 (53.6 g, 0.05 equiv.) were added under N2 atmosphere. The mixture was then stirred at 80° C. for 16 h. The reaction mixture was then cooled to 20° C., quenched by addition of H2O (500 mL), and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (500 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound E (390 g, crude) as a white solid. 1 H NMR: (D2O, 400 MHz) δ 8.45 (s, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.39 (dd, J = 12.0, 7.2 Hz, 1H), 6.98 (dd, J = 12.4, 7.2 Hz, 1H).

[0329] Part 4: Preparation of compound F To a solution of compound E (390 g, 1.00 equiv.) in DMF (2.34 L) was added Me2SO4 (105.8 g, 0.70 equiv.). The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then poured into H2O (1.00 L) and filtered to remove solids. The filtrate was concentrated under reduced pressure to yield compound F (128 g, crude) as a white solid. 1 H NMR: (CDCl3, 400 MHz) δ 8.65 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.81 (dd, J = 12.0, 7.2 Hz, 1H), 6.79 (dd, J = 12.4, 6.8 Hz, 1H), 4.01 (s, 3H).LCMS: ESI MS+1=301.0)

[0330] Part 5: Preparation of compound H, having the chemical name methyl 5-((R)-3-(benzylamino)-3-((S)-2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2,5-difluoro-4-(methoxy-d3)phenyl)isonicotinate To a solution of compound F (50.0 g, 1.00 equiv.) in NMP (300 mL), DIEA (172 g, 8.00 equiv.) and compound G (102 g, 1.00 equiv.) were added. The resulting mixture was stirred at 100 °C for 12 h. The reaction mixture was then cooled to 20 °C, quenched by the addition of H2O (500 mL), and extracted with EtOAc (100 mL x 2). To the combined organic layers, H2O (300 mL) was added and 35% HCl was added dropwise to adjust the pH to about 1-2 at 20 °C to provide a suspension. The suspension was filtered, and the resulting filter cake was dissolved by 2-MeTHF (500 mL). To the solution, a 20% mixed solvent of KHCO3 / H2O (500 mL) was added and extracted by 2-MeTHF (200 mL x 3). The 2-MeTHF phase was washed with brine (500 mL×3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give compound H (85.0 g) as a yellow oil. 1 H NMR: (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.85 (s, 1H), 7.69(dd, J = 12.4, 7.6 Hz, 1H), 7.28-7.17 (m, 5H), 6.65 (dd, J = 12.0, 6.8 Hz, 1H), 5.92 (td, J = 55.2, 3.6 Hz, 1H), 3.71-3.55 (m, 6H), 3.20-3.17 (m, 2H), 2.96 (d, J = 11.6 Hz, 1H), 2.85-2.77 (m, 1H), 2.05-2.01 (m, 1H), 1.68-1.64 (m, 1H).LCMS: ESI MS+1=550.3.

[0331] Example 2 – Synthesis of Compound I-1 [ka] The title compound was prepared using the following procedure. [ka]

[0332] Part 1: Preparation of compound O To a solution of compound H (33.0 g, 1.00 equiv.) in THF (297 mL) and MeOH (33.0 mL) was added LiBH4 (2.00 M, 59.9 mL, 2.00 equiv.) at 20° C., and the reaction mixture was then stirred at 40° C. for 3 h. The reaction was then quenched by the addition of water (100 mL), and the resulting mixture was extracted with EtOAc (50.0 mL×3). The organic phase of the mixture was isolated, washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to provide compound O (29.0 g) as a white solid. 1 HNMR: (DMSO-d, 400 MHz) δ 8.35 (s, 1H), 7.90 (s, 1H), 7.75-7.73 (m, 1H), 7.38-7.30 (m, 4H), 7.24-7.22 (m, 2H), 6.26 (t, J = 55.2 Hz, 1H), 5.72-7.71 (d, J = 6.4 Hz, 1H), 5.41 (t, J = 6.4 Hz, 1H), 4.59-4.57 (d, J = 5.6 Hz, 2H), 3.80-3.76 (m, 2H), 3.66-3.64 (m, 1H), 3.12 (d, J = 11.6 Hz, 1H), 2.93 (d, J = 10.8 Hz, 1H), 2.71-2.69 (m, 1H), 2.22-2.21 (m, 1H), 1.84-1.69 (m, 4H).LCMS: ESI MS+1=523.2.

[0333] Part 2: Preparation of compound P To a solution of compound O (28.0 g, 1.00 equiv.) in DCM (280 mL), SOCl2 (10.96 g, 1.60 equiv.) was added in portions at 0° C., and then the reaction mixture was stirred at 0° C. for 2 h. H2O (20.0 mL) was added to the reaction mixture, and the resulting mixture was stirred at 25° C. for 16 h. Then the reaction mixture was slowly quenched by the addition of aqueous Na2CO3 (100 mL, 10%). The resulting mixture was extracted with DCM (100 mL×2). The combined organic layers were washed with brine (200 mL×2), dried over Na2SO4, and concentrated under vacuum to provide compound P (29.0 g) as a yellow solid. 1 H NMR: (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.75 (s, 1H), 7.70 (dd, J = 12.4, 7.6 Hz, 2H), 7.28-7.18 (m, 5H), 6.67 (dd, J = 12.4, 7.2 Hz, 1H), 5.95 (td, J = 55.2, 3.2 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 3.74-3.62 (m, 3H), 3.06-3.05 (m, 3H), 2.81-2.79 (m, 1H), 2.06-2.02 (m, 1H),1.92 (s, 1H), 1.84-1.80 (m, 2H), 1.74-1.71 (m, 1H).LCMS: ESI MS+1=541.2

[0334] Part 3: Preparation of compound Q To a solution of compound P (29.0 g, 1.00 equiv.) and compound K (18.0 g, 1.30 equiv.) in DMA (174 mL) was added K2CO3 (14.8 g, 2.00 equiv.). The resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was then quenched by the addition of H2O (200 mL) at 0-5 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 4), dried over Na2SO4, filtered and concentrated under vacuum to provide a residue. The residue was purified by column chromatography to provide compound Q (19.8 g) as a yellow solid.

[0335] Part 4: Preparation of compound R A solution of compound Q (19.8 g, 1.00 equiv.) in TFA (59.4 mL) and DCM (118 mL) was stirred at 40° C. for 16 h. The reaction mixture was then concentrated under reduced pressure to remove TFA and DCM. The resulting residue was diluted with MeOH (40.0 mL) and then poured into aqueous Na2CO3 (50.0 mL). A solid precipitated from the mixture, and the solid was collected by filtration. The filter cake was washed with MeOH and dried under vacuum to provide compound R (16.0 g, crude) as a white solid. 1 H NMR: (DMSO-d, 400 MHz) δ 8.84-8.79 (br s, 1H), 8.55 (s, 1H), 8.23 ​​(s, 1H), 8.06 (s, 1H), 7.69 (dd, J = 12.4, 7.6 Hz, 1H), 7.54-7.53 (m, , 2H), 7.36-7.25 (m, 5H), 7.13 (dd, J = 12.8, 7.6 Hz, 1H), 7.00 (s, 1H), 6.46 (m, 1H), 5.81-5.74 (m, 1H), 5.57-5.53 (br d, J = 16.0Hz, 2H), 4.42-4.30 (m, 3H), 3.50-3.45 (m, 2H), 3.00 (m, 2H), 2.82 (m, 1H), 2.05-1.90 (m, 4H), 1.75 (m, 1H).LCMS: ESI MS+1=640.4

[0336] Part 5: Preparation of compound I-1 To a solution of compound R (14.00 g, 1.00 equiv.) in THF (70.0 mL) was added Pd(OH)2 (1.40 g, 10%) and TFA (7.48 g, 3.00 equiv.) under N2 atmosphere. The resulting suspension was degassed and purged with H2 three times. The resulting mixture was stirred under H2 (15 Psi) at 20°C for 16 h. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC to provide compound I-1 (6.70 g) as an off-white solid. 1 H NMR: (DMSO-d, 400 MHz) δ 8.49 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.71-7.66 (m, 1H), 7.29 (s, 1H), 7.13-7.08 (m, 1H), 6.92 (s, 1H), 6.18 (t, J = 56.4 Hz, 1H), 5.71 (d, J = 4.8 Hz, 1H), 5.56-5.43 (m, 2H), 3.78 (br s, 1H), 3.10 (d, J = 10.8 Hz, 2H), 3.08 (br s, 1H), 2.91 (br s, 1H), 2.77 (d, J = 7.6 Hz, 1H), 1.89-1.72 (m, 4 H), 1.47 (s, 1H).MS(ES API+), 550.0, calculated 550.2 (M+H+).

[0337] Example 3 – Synthesis of Compound I-2 [ka] The title compound was prepared using the following procedure. [ka]

[0338] Part 1: Preparation of Compound I To a solution of compound H (70.0 g, 1.00 equiv.) in THF (490 mL) was added LiAlD4 (7.24 g, 1.50 equiv.) at 20-30 °C and the reaction was stirred at 40 °C for 3 h. The reaction was then quenched with D2O (200 mL) and extracted with EtOAc (100 mL x 3). The organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to provide compound I (63.0 g, crude) as a yellow solid. 1 HNMR: (CDCl3, 400 MHz δ 8.36 (s, 1H), 7.73 (s, 1H), 7.69 (dd, J = 14.8, 7.6 Hz, 1H), 7.28-7.19 (m, 6H), 6.67 (dd, J = 12.0, 6.8 Hz, 1H), 5.96 (td, J = 56.0, 4.0 Hz, 1H), 3.72-3.64 (m, 2H), 3.10-3.07 (m, 1H), 3.03-2.96 (m, 2H), 2.83-2.81 (m, 1H), 1.97-1.95 (m, 1H), 1.84-1.74(m, 3H).LCMS: ESI MS+1=525.2)

[0339] Part 2: Preparation of compound J To a solution of compound I (54.0 g, 1.00 equiv.) in DCM (540 mL) was added SOCl2 (18.00 g, 1.50 equiv.) in portions at 0° C. The reaction mixture was then stirred at 0° C. for 2 h. Water (60.0 mL) was then added to the reaction mixture, and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then slowly quenched with aqueous Na2CO3 (200 mL, 10%) and extracted with DCM (100 mL×3). The combined organic layers were washed with brine (200 mL×2), dried over Na2SO4, and concentrated under vacuum to provide compound J (55.0 g, crude) as a yellow solid. 1H NMR: (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.74 (s, 1H), 7.71 (dd, J = 14.4, 6.8 Hz, 1H), 7.28-7.18 (m, 5H), 6.68 (dd, J = 12.0, 6.8 Hz, 1H), 5.97 (td, J = 55.2, 3.2 Hz, 1H), 3.77-3.61 (m, 3H), 3.06-3.05 (m, 3H), 2.82-2.79 (m, 1H), 2.05-2.01 (m, 1H), 1.82-1.75 (m, 3H).LCMS: ESI MS+1=543.1

[0340] Part 3: Preparation of compound L To a solution of compound J (50.0 g, 1.00 equiv.) and compound K (40.0 g, 1.30 equiv.) in DMA (300 mL) was added K2CO3 (25.4 g, 2.00 equiv.). The resulting mixture was stirred at 20° C. for 12 h. The reaction mixture was then quenched by the addition of D2O (500 mL) and then extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (200 mL×4), dried over Na2SO4, and filtered. The resulting residue was purified by column chromatography to provide compound L (60.0 g) as a yellow solid. 1 H NMR: (CDCl3, 400 MHz) δ 8.69 (s, 1H), 8.48 (s, 1H), 7.95 (s, 1H), 7.66 (dd, J = 12.4, 7.2 Hz, 1H), 7.29-7.15 (m, 6H), 6.55 (dd, J = 12.4, 7.2 Hz, 1H), 6.02 (t, J = 56.0 Hz, 1H), 3.80-3.71 (m, 2H), 3.31-3.30 (m, 1H), 3.00-2.88 (m, 3H), 1.85-1.78 (m, 4H), 1.36 (s, 18H).

[0341] Part 4: Preparation of Compound M Compound L (30.0 g, 1.00 equiv.) was mixed with DCM (180 mL) and then TFA (90.0 mL) was added. The resulting mixture was stirred at 40° C. for 16 h. The reaction mixture was then concentrated under reduced pressure to remove TFA and DCM. The resulting residue was diluted with MeOD (100 mL) and then poured into aqueous Na2CO3 (200 mL). A solid precipitated and was collected by filtration. The filter cake was washed with MeOH and dried under vacuum to provide compound M (27.0 g, crude) as a white solid. 1 H NMR: (DMSO-d, 400 MHz) δ 8.52 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.68 (dd, J = 12.4, 7.2 Hz, 1H), 7.40-7.11 (m, 8H), 6.96 (s, 1H), 6.28 (t, J = 54.8 Hz, 1H), 5.84 (br s, 1H), 4.01-3.95 (m, 2H), 3.86-3.72 (m, 1H), 3.06-3.02 (m, 2H), 2.85-2.83 (m, 1H), 2.44-2.43 (m, 1H), 1.75-1.73 (m, 4H).LCMS: ESI MS+1=642.4)

[0342] Part 5: Preparation of compound I-2 To a solution of compound M (27.0 g crude, 1.00 equiv.) in THF (135 mL) was added Pd(OH)2 (6.00 g, 10.0%) and TFA (14.4 g, 3.00 equiv.) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 20°C for 16 h. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to provide a residue. The residue was dissolved by EtOH (40.0 mL) and then a solution of lower alkyl dicarboxylic acid in D2O (7.50 mL) was added dropwise. The mixture was stirred at 50°C for 16 h. The mixture was then filtered and the filter cake was concentrated. The filter cake was neutralized using Na2CO3 (50.0 mL) and then filtered to provide compound I-2 as a white solid. 1H NMR: (DMSO-d, 400 MHz) δ 8.50 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.71-7.66 (m, 1H), 7.32 (s, 1H), 7.14-7.09 (m, 1H), 6.98 (s, 1H), 6.21 (td, J = 55.6, 3.6 Hz, 1H), 3.88-3.81 (m, 2H), 3.12 (d, J = 12.0 Hz, 1H), 3.04-3.02 (m, 1H), 2.93-2.85 (m, 2H), 1.89-1.72 (m, 3H), 1.58-1.56 (m, 1H).MS(TOF ES+), 552.2495.552.2507 calculated (M+H+).

[0343] Incorporation by Reference The entire disclosure of each of the patent documents and scientific articles referenced herein is incorporated by reference for all purposes.

[0344] Equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. The scope of the present invention is therefore indicated by the appended claims rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A compound represented by formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , and R ２１ is independently H or Z; Z is H or D, provided that the abundance of deuterium in Z is at least 75%; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , and R ２１ or a pharmaceutically acceptable salt thereof, provided that at least one of:

2. The compound is represented by formula IA: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein: R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , and R ２１ is independently H or Z; Z is H or D, provided that the abundance of deuterium in Z is at least 75%; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , and R ２１ is Z.

3. The compound of claim 2, wherein the compound is a compound of formula IA.

4. A compound represented by formula II: 【Transformation 3】 or a pharmaceutically acceptable salt thereof, wherein: R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , and R ２０ is independently H or Z; The compound or a pharmaceutically acceptable salt thereof, wherein Z is H or D, provided that the abundance of deuterium in Z is at least 75%.

5. R １ , R ２ , and R ３ The compound according to any one of claims 1 to 4, wherein is Z.

6. R ４ , R ５ , R ６ , and R ７ The compound of claim 5 , wherein is H.

7. R ８ and R ９ The compound of claim 6, wherein is H, and R 10 and R 11 are H.

8. 6. The compound of claim 5, wherein the abundance of deuterium in Z is at least 90%.

9. 6. The compound of claim 5, wherein the abundance of deuterium in Z is at least 95%.

10. 6. The compound of claim 5, wherein the compound has an enantiomeric excess of at least 95%. Claim 11: The compound of Table 1 Table 1-1 Table 1-2 Table 1-3 Table 1-4 10. The compound of claim 1, wherein the compound is:

12. The compound of claim 1, 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, 【Transformation 5】 2. The compound of claim 1, wherein:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising the compound of claim 12 and a pharmaceutically acceptable carrier.

16. 16. The pharmaceutical composition of claim 15 for treating cancer mediated by nuclear SET domain-containing protein 2 (NSD2).

17. 17. The pharmaceutical composition of claim 16, wherein the cancer is selected from a solid tumor, leukemia, myeloma, and lymphoma.

18. 17. The pharmaceutical composition of claim 16, wherein the cancer 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, or non-Hodgkin's lymphomatosis.

19. The pharmaceutical composition described in claim 16, wherein the cancer is prostate cancer.

20. The pharmaceutical composition described in claim 16, wherein the cancer is lung cancer.

21. The pharmaceutical composition described in claim 16, wherein the cancer is non-small cell lung cancer.

22. 16. The pharmaceutical composition of claim 15 for inhibiting the activity of nuclear SET domain-containing protein 2 (NSD2).

23. The pharmaceutical composition of claim 14 for treating cancer mediated by nuclear SET domain-containing protein 2 (NSD2).

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