Prmt5 Inhibitors And Uses Thereof

Abstract

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described. ##STR00001##

Description

RELATED APPLICATIONS

[0001] This application is a continuation of and claims priority under 35 U.S.C. .sctn. 120 to U.S. patent application Ser. No. 16/504,910, filed Jul. 8, 2019, which is a continuation of and claims priority under 35 U.S.C. .sctn. 120 to U.S. patent application Ser. No. 15/844,097, filed Dec. 15, 2017, now U.S. Pat. No. 10,391,089, which is a continuation of and claims priority under 35 U.S.C. .sctn. 120 to Ser. No. 15/586,775, filed May 4, 2017; which is a continuation of and claims priority under 35 U.S.C. .sctn. 120 to U.S. patent application Ser. No. 15/054,193, filed Feb. 26, 2016, now U.S. Pat. No. 9,675,614, which is a continuation of U.S. Ser. No. 14/619,371, filed Feb. 11, 2015, now U.S. Pat. No. 9,365,519; which is a continuation of U.S. patent application U.S. Ser. No. 14/136,569, filed Dec. 20, 2013, now U.S. Pat. No. 8,993,555, which claims priority under 35 U.S.C. .sctn. 119(e) to U.S. provisional patent application, U.S. Ser. No. 61/790,525, filed Mar. 15, 2013, and to U.S. provisional patent application, U.S. Ser. No. 61/745,485, filed Dec. 21, 2012, the entire contents of each of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases.

[0003] Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., PRMT5), many of which are associated with specific genetic alterations that can cause human disease.

[0004] Disease-associated chromatin-modifying enzymes (e.g., PRMT5) play a role in diseases such as proliferative disorders, metabolic disorders, and blood disorders. Thus, there is a need for the development of small molecules that are capable of inhibiting the activity of PRMT5.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0005] Protein arginine methyltransferase 5 (PRMT5) catalyzes the addition of two methyl groups to the two co-guanidino nitrogen atoms of arginine, resulting in .omega.-NG, N'G symmetric dimethylation of arginine (sDMA) of the target protein. PRMT5 functions in the nucleus as well as in the cytoplasm, and its substrates include histones, spliceosomal proteins, transcription factors (See e.g., Sun et al., 2011, PNAS 108: 20538-20543). PRMT5 generally functions as part of a molecule weight protein complex. While the protein complexes of PRMT5 can have a variety of components, they generally include the protein MEP50 (methylosome protein 50). In addition, PRMT5 acts in conjunction with cofactor SAM (S-adenosyl methionine).

[0006] PRMT5 is an attractive target for modulation given its role in the regulation of diverse biological processes. It has now been found that compounds described herein, and pharmaceutically acceptable salts and compositions thereof, are effective as inhibitors of PRMT5. Such compounds have the general Formula (I):

##STR00002##

or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.x, n, L, and Ar are as defined herein.

[0007] In some embodiments, pharmaceutical compositions are provided which comprise a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0008] In certain embodiments, compounds described herein inhibit activity of PRMT5. In certain embodiments, methods of inhibiting PRMT5 are provided which comprise contacting PRMT5 with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The PRMT5 may be purified or crude, and may be present in a cell, tissue, or a subject. Thus, such methods encompass inhibition of PRMT5 activity both in vitro and in vivo. In certain embodiments, the PRMT5 is wild-type PRMT5. In certain embodiments, the PRMT5 is overexpressed. In certain embodiments, the PRMT5 is a mutant. In certain embodiments, the PRMT5 is in a cell. In certain embodiments, the PRMT5 is in an animal, e.g., a human. In some embodiments, the PRMT5 is in a subject that is susceptible to normal levels of PRMT5 activity due to one or more mutations associated with a PRMT5 substrate. In some embodiments, the PRMT5 is in a subject known or identified as having abnormal PRMT5 activity (e.g., overexpression). In some embodiments, a provided compound is selective for PRMT5 over other methyltransferases. In certain embodiments, a provided compound is at least about 10-fold selective, at least about 20-fold selective, at least about 30-fold selective, at least about 40-fold selective, at least about 50-fold selective, at least about 60-fold selective, at least about 70-fold selective, at least about 80-fold selective, at least about 90-fold selective, or at least about 100-fold selective relative to one or more other methyltransferases.

[0009] In certain embodiments, methods of altering gene expression in a cell are provided which comprise contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the cell in culture in vitro. In certain embodiments, cell is in an animal, e.g., a human.

[0010] In certain embodiments, methods of altering transcription in a cell are provided which comprise contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the cell in culture in vitro. In certain embodiments, the cell is in an animal, e.g., a human.

[0011] In some embodiments, methods of treating a PRMT5-mediated disorder are provided which comprise administering to a subject suffering from a PRMT5-mediated disorder an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the PRMT5-mediated disorder is a proliferative disorder, a metabolic disorder, or a blood disorder. In certain embodiments, compounds described herein are useful for treating cancer. In certain embodiments, compounds described herein are useful for treating hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer. In certain embodiments, compounds described herein are useful for treating a hemoglobinopathy. In certain embodiments, compounds described herein are useful for treating sickle cell anemia. In certain embodiments, compounds described herein are useful for treating diabetes or obesity.

[0012] Compounds described herein are also useful for the study of PRMT5 in biological and pathological phenomena, the study of intracellular signal transduction pathways mediated by PRMT5, and the comparative evaluation of new PRMT5 inhibitors.

[0013] This application refers to various issued patent, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference.

[0014] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3.sup.rd Edition, Cambridge University Press, Cambridge, 1987.

[0015] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). The present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0016] It is to be understood that the compounds of the present invention may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present invention, and the naming of any compound described herein does not exclude any tautomer form.

##STR00003##

[0017] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of .sup.19F with .sup.18F, or the replacement of a carbon by a .sup.13C- or .sup.14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0018] The term "aliphatic," as used herein, includes both saturated and unsaturated, nonaromatic, straight chain (i.e., unbranched), branched, acyclic, and cyclic (i.e., carbocyclic) hydrocarbons. In some embodiments, an aliphatic group is optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "aliphatic" is intended herein to include alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl moieties.

[0019] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example "C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5, C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4, C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5, and C.sub.5-6 alkyl.

[0020] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C.sub.1-20 alkyl"). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C.sub.1-10 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C.sub.1-9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C.sub.1-8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C.sub.1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C.sub.1-6, alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C.sub.1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C.sub.1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C.sub.1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C.sub.1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C.sub.1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C.sub.2-6 alkyl"). Examples of C.sub.1-6 alkyl groups include methyl (C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl (C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl (C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl (C.sub.5), tertiary amyl (C.sub.5), and n-hexyl (C.sub.6). Additional examples of alkyl groups include n-heptyl (C.sub.7), n-octyl (C.sub.8) and the like. In certain embodiments, each instance of an alkyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is unsubstituted C.sub.1-10 alkyl (e.g., --CH.sub.3). In certain embodiments, the alkyl group is substituted C.sub.1-10 alkyl.

[0021] In some embodiments, an alkyl group is substituted with one or more halogens. "Perhaloalkyl" is a substituted alkyl group as defined herein wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the alkyl moiety has 1 to 8 carbon atoms ("C.sub.1-8 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 6 carbon atoms ("C.sub.1-6 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 4 carbon atoms ("C.sub.1-4 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 3 carbon atoms ("C.sub.1-3 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms ("C.sub.1-2 perhaloalkyl"). In some embodiments, all of the hydrogen atoms are replaced with fluoro. In some embodiments, all of the hydrogen atoms are replaced with chloro. Examples of perhaloalkyl groups include --CF.sub.3, --CF.sub.2CF.sub.3, --CF.sub.2CF.sub.2CF.sub.3, --CCl.sub.3, --CFCl.sub.2, --CF.sub.2Cl, and the like.

[0022] "Alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C.sub.2-20 alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C.sub.2-10 alkenyl"). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C.sub.2-9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C.sub.2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C.sub.2-7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C.sub.2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C.sub.2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C.sub.2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C.sub.2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C.sub.2-4 alkenyl groups include ethenyl (C.sub.2), 1-propenyl (C.sub.3), 2-propenyl (C.sub.3), 1-butenyl (C.sub.4), 2-butenyl (C.sub.4), butadienyl (C.sub.4), and the like. Examples of C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4 alkenyl groups as well as pentenyl (C.sub.5), pentadienyl (C.sub.5), hexenyl (C.sub.6), and the like. Additional examples of alkenyl include heptenyl (C.sub.7), octenyl (C.sub.8), octatrienyl (C.sub.8), and the like. In certain embodiments, each instance of an alkenyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is unsubstituted C.sub.2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C.sub.2-10 alkenyl.

[0023] "Alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C.sub.2-20 alkynyl"). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C.sub.2-10 alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C.sub.2-9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C.sub.2-8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C.sub.2-7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C.sub.2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C.sub.2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C.sub.2-4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C.sub.2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C.sub.2-4 alkynyl groups include, without limitation, ethynyl (C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3), 1-butynyl (C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4 alkynyl groups as well as pentynyl (C.sub.5), hexynyl (C.sub.6), and the like. Additional examples of alkynyl include heptynyl (C.sub.7), octynyl (C.sub.8), and the like. In certain embodiments, each instance of an alkynyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is unsubstituted C.sub.2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C.sub.2-10 alkynyl.

[0024] "Carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C.sub.3-10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C.sub.3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C.sub.5-10 carbocyclyl"). Exemplary C.sub.3-6 carbocyclyl groups include, without limitation, cyclopropyl (C.sub.3), cyclopropenyl (C.sub.3), cyclobutyl (C.sub.4), cyclobutenyl (C.sub.4), cyclopentyl (C.sub.5), cyclopentenyl (C.sub.5), cyclohexyl (C.sub.6), cyclohexenyl (C.sub.6), cyclohexadienyl (C.sub.6), and the like. Exemplary C.sub.3-8 carbocyclyl groups include, without limitation, the aforementioned C.sub.3-6 carbocyclyl groups as well as cycloheptyl (C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl (C.sub.7), cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8), cyclooctenyl (C.sub.8), bicyclo[2.2.1]heptanyl (C.sub.7), bicyclo[2.2.2]octanyl (C.sub.8), and the like. Exemplary C.sub.3-10 carbocyclyl groups include, without limitation, the aforementioned C.sub.3-8 carbocyclyl groups as well as cyclononyl (C.sub.9), cyclononenyl (C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl (C.sub.10), octahydro-1H-indenyl (C.sub.9), decahydronaphthalenyl (C.sub.10), spiro[4.5]decanyl (C.sub.10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contain a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. In certain embodiments, each instance of a carbocyclyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C.sub.3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C.sub.3-10 carbocyclyl.

[0025] In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C.sub.3-10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C.sub.3-8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C.sub.3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C.sub.5-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C.sub.5-10 cycloalkyl"). Examples of C.sub.5-6, cycloalkyl groups include cyclopentyl (C.sub.5) and cyclohexyl (C.sub.5). Examples of C.sub.3-6 cycloalkyl groups include the aforementioned C.sub.5-6 cycloalkyl groups as well as cyclopropyl (C.sub.3) and cyclobutyl (C.sub.4). Examples of C.sub.3-8 cycloalkyl groups include the aforementioned C.sub.3-6 cycloalkyl groups as well as cycloheptyl (C.sub.7) and cyclooctyl (C.sub.8). In certain embodiments, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C.sub.3-10) cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C.sub.3-10 cycloalkyl.

[0026] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-10 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. In certain embodiments, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.

[0027] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0028] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C.sub.6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0029] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 .pi. electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an aryl group has six ring carbon atoms ("C.sub.6 aryl"; e.g, phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C.sub.1-4 aryl", e.g., anthracyl). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. In certain embodiments, each instance of an aryl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is unsubstituted C.sub.6-14 aryl. In certain embodiments, the aryl group is substituted C.sub.6-14 aryl.

[0030] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 .pi. electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g, either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0031] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, each instance of a heteroaryl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.

[0032] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0033] "Partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as herein defined. Likewise, "saturated" refers to a group that does not contain a double or triple bond, i.e., contains all single bonds.

[0034] In some embodiments, aliphatic, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted" or "unsubstituted" aliphatic, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g, a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0035] Exemplary carbon atom substituents include, but are not limited to, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OR.sup.aa, --ON(R.sup.bb).sub.2, --N(R.sup.bb).sub.2, --N(R.sup.bb).sub.3.sup.+X.sup.-, --N(OR.sup.cc)R.sup.bb, --SH, --SR.sup.aa, --SSR.sup.cc, --C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO, --C(OR.sup.cc).sub.2, --CO.sub.2R.sup.aa, --OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa, --C(O)N(R.sup.bb).sub.2, --OC(.dbd.O)N(R.sup.bb).sub.2, --NR.sup.bbC(.dbd.O)R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa, --NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa, --C(.dbd.NR.sup.bb)OR.sup.aa, --OC(.dbd.NR.sup.bb)R.sup.aa, --OC(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa, --SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa, --SO.sub.2OR.sup.aa, --OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa, --OS(.dbd.O)R.sup.aa, --Si(R.sup.aa).sub.3, --OSi(R.sup.aa).sub.3 --C(.dbd.S)N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa, --SC(.dbd.O)SR.sup.aa, --OC(.dbd.O)SR.sup.aa, --SC(.dbd.O)OR.sup.aa, --SC(.dbd.O)R.sup.aa, --P(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(NR.sup.bb).sub.2, --OP(.dbd.O)(R.sup.aa).sub.2, --OP(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2, --OP(.dbd.O).sub.2N(R.sup.bb).sub.2, --P(.dbd.O)(NR.sup.bb).sub.2, --OP(.dbd.O)(NR.sup.bb).sub.2, --NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2, --NR.sup.bbP(.dbd.O)(NR.sup.bb).sub.2, --P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3, --B(R.sup.aa).sub.2, --B(OR.sup.cc).sub.2, --BR.sup.aa(OR.sup.cc), C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups;

[0036] or two geminal hydrogens on a carbon atom are replaced with the group .dbd.O, .dbd.S, .dbd.NN(R.sup.bb).sub.2, .dbd.NNR.sup.bbC(.dbd.O)R.sup.aa, .dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa, .dbd.NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or .dbd.NOR.sup.cc;

[0037] each instance of R.sup.aa is, independently, selected from C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups;

[0038] each instance of R.sup.bb is, independently, selected from hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN, --C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa, --C(.dbd.NR.sup.cc)R.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2, --SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc, --SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2, --C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc, --P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups;

[0039] each instance of R.sup.cc is, independently, selected from hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; [0040] each instance of is, independently, selected from halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OR.sup.ee, --ON(R.sup.ff).sub.2, --N(R.sup.ff).sub.2, --N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff, --SH, --SR.sup.ee, --SSR.sup.ee, --C(.dbd.O)R.sup.ee, --CO.sub.2H, --CO.sub.2R.sup.ee, --OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee, --C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2, --NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee, --NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2, --C(.dbd.NR.sup.ff)OR.sup.ee, --OC(.dbd.NR.sup.ff)R.sup.ee, --OC(.dbd.NR.sup.ff)OR.sup.ee, --C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2, --OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2, --NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2, --NR.sup.ffSO.sub.2R.sup.ee, --SO.sub.2N(R.sup.ff).sub.2, --SO.sub.2R.sup.ee, --SO.sub.2OR.sup.ee, --OSO.sub.2R.sup.ee, --S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi(R.sup.ee).sub.3, --C(.dbd.S)N(R.sup.ff).sub.2, --C(.dbd.O)SR.sup.ee, --C(.dbd.S)SR.sup.ee, --SC(.dbd.S)SR.sup.ee, --P(.dbd.O).sub.2R.sup.ee, --P(.dbd.O)(R.sup.ee).sub.2, --OP(.dbd.O)(R.sup.ee).sub.2, --OP(.dbd.O)(OR.sup.ee).sub.2, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups, or two geminal R.sup.dd substituents can be joined to form .dbd.O or .dbd.S;

[0041] each instance of R.sup.ee is, independently, selected from C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;

[0042] each instance of R.sup.ff is, independently, selected from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl and 5-10 membered heteroaryl, or two R.sup.ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups; and each instance of R.sup.gg is, independently, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1-6 alkyl, --ON(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, --NH(C.sub.1-6 alkyl).sub.2.sup.+X.sup.-, --NH.sub.2(C.sub.1-6 alkyl).sup.+X.sup.-, --NH.sub.3.sup.+X.sup.-, --N(OC.sub.1-6 alkyl)(C.sub.1-6 alkyl), --N(OH)(C.sub.1-6 alkyl), --NH(OH), --SH, --SC.sub.1-6 alkyl, --SS(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-6 alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6 alkyl), --OC(O)(C.sub.1-6 alkyl), --OCO.sub.2(C.sub.1-6 alkyl), --C(.dbd.O)NH.sub.2, --C(.dbd.O)N(C.sub.1-6 alkyl).sub.2, --OC(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl), --N(C.sub.1-6 alkyl)C(.dbd.O)(C.sub.1-6 alkyl), --NHCO.sub.2(C.sub.1-6 alkyl), --NHC(.dbd.O)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl), --OC(.dbd.NH)(C.sub.1-6 alkyl), --OC(.dbd.NH)OC.sub.1-6 alkyl, --C(--NH)N(C.sub.1-6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6 alkyl), --C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2, --NHC(NH)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2, --NHSO.sub.2(C.sub.1-6 alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2, --SO.sub.2NH(C.sub.1-6 alkyl), --SO.sub.2NH.sub.2, --SO.sub.2C.sub.1-6 alkyl, --SO.sub.2OC.sub.1-6 alkyl, --OSO.sub.2C.sub.1-6 alkyl, --SOC.sub.1-6 alkyl, --Si(C.sub.1-6 alkyl).sub.3, --OSi(C.sub.1-6 alkyl).sub.3 --C(.dbd.S)N(C.sub.1-6 alkyl).sub.2, C(.dbd.S)NH(C.sub.1-6 alkyl), C(.dbd.S)NH.sub.2, --C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl, --SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O).sub.2(C.sub.1-6 alkyl), --P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R.sup.gg substituents can be joined to form .dbd.O or .dbd.S; wherein X.sup.- is a counterion. A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F.sup.-, Cl.sup.-, Br.sup.-, I.sup.-), NO.sub.3.sup.-, ClO.sub.4.sup.-, OH.sup.-, H.sub.2PO.sub.4.sup.-, HSO.sub.4.sup.-, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0043] "Halo" or "halogen" refers to fluorine (fluoro, --F), chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine (iodo, --I).

[0044] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN, --C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa, --C(.dbd.NR.sup.bb)R.sup.aa, --C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2, --SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc, --SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2, --C(O)SR.sup.cc, --C(.dbd.S)SR.sup.cc, --P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.cc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups, and wherein R.sup.aa, R.sup.bb, R.sup.cc and R.sup.dd are as defined above.

[0045] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include, but are not limited to, --OH, --OR.sup.aa, --N(R.sup.cc), --C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa, --C(.dbd.NR.sup.cc)R.sup.aa, --C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2, --SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc, --SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2, --C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc, C.sub.1-10 alkyl (e.g., aralkyl, heteroaralkyl), C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups, and wherein R.sup.aa, R.sup.bb, R.sup.cc, and R.sup.dd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0046] Amide nitrogen protecting groups (e.g., --C(.dbd.O)R.sup.aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0047] Carbamate nitrogen protecting groups (e.g., --C(.dbd.O)OR.sup.aa) include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, 5-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenyl ethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0048] Sulfonamide nitrogen protecting groups (e.g., --S(.dbd.O).sub.2R.sup.aa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), p-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8',-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0049] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N'-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N--(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N'-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0050] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa, --C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa, --C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa, --C(.dbd.NR.sup.bb)R.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3, --P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3, --P(.dbd.O)R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2, --P(O).sub.2N(R.sup.bb).sub.2, and --P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and R.sup.cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0051] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, .alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl ally) carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodi phenyl acetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, .alpha.-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzyl sulfonate, and tosylate (Ts).

[0052] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa, --C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa, --C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa, --C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3, --P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3, --P(.dbd.O)R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2, and --P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and R.sup.cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0053] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The present disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.

[0054] "Pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds describe herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group 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 pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, quaternary salts.

[0055] A "subject" to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other non-human animals, for example, non-human mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys), rodents (e.g., rats and/or mice), reptiles, amphibians, and fish. In certain embodiments, the non-human animal is a mammal. The non-human animal may be a male or female at any stage of development. A non-human animal may be a transgenic animal.

[0056] "Condition," "disease," and "disorder" are used interchangeably herein.

[0057] "Treat," "treating" and "treatment" encompasses an action that occurs while a subject is suffering from a condition which reduces the severity of the condition or retards or slows the progression of the condition ("therapeutic treatment"). "Treat," "treating" and "treatment" also encompasses an action that occurs before a subject begins to suffer from the condition and which inhibits or reduces the severity of the condition ("prophylactic treatment").

[0058] An "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., treat the condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0059] A "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0060] A "prophylactically effective amount" of a compound is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0061] As used herein, the term "methyltransferase" represents transferase class enzymes that are able to transfer a methyl group from a donor molecule to an acceptor molecule, e.g., an amino acid residue of a protein or a nucleic base of a DNA molecule. Methytransferases typically use a reactive methyl group bound to sulfur in S-adenosyl methionine (SAM) as the methyl donor. In some embodiments, a methyltransferase described herein is a protein methyltransferase. In some embodiments, a methyltransferase described herein is a histone methyltransferase. Histone methyltransferases (HMT) are histone-modifying enzymes, (including histone-lysine N-methyltransferase and histone-arginine N-methyltransferase), that catalyze the transfer of one or more methyl groups to lysine and arginine residues of histone proteins. In certain embodiments, a methyltransferase described herein is a histone-arginine N-methyltransferase.

[0062] As generally described above, provided herein are compounds useful as PRMT5 inhibitors. In some embodiments, the present disclosure provides a compound of Formula (I).

##STR00004##

or a pharmaceutically acceptable salt thereof, wherein

[0063] represents a single or double bond;

[0064] R.sup.1 is hydrogen, R.sup.z, or --C(O)R.sup.z, wherein R.sup.z is optionally substituted C.sub.1-6 alkyl;

[0065] L is --N(R)C(O)--, --C(O)N(R)--, --N(R)C(O)N(R)--, --N(R)C(O)O--, or --OC(O)N(R)--;

[0066] each R is independently hydrogen or optionally substituted C.sub.1-6 aliphatic;

[0067] Ar is a monocyclic or bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with 0, 1, 2, 3, 4, or 5 R.sup.y groups, as valency permits;

[0068] each R.sup.y is independently selected from the group consisting of halo, --CN, --NO.sub.2, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, --OR.sup.A, --N(R.sup.B).sub.2, --SR.sup.A, --C(.dbd.O)R.sup.A, --C(O)OR.sup.A, --C(O)SR.sup.A, --C(O)N(R.sup.B).sub.2, --C(O)N(R.sup.B)N(R.sup.B).sub.2, --OC(O)R.sup.A, --OC(O)N(R.sup.B).sub.2, --NR.sup.BC(O)R.sup.A, --NR.sup.BC(O)N(R.sup.B).sub.2, --NR.sup.BC(O)N(R.sup.B)N(R.sup.B).sub.2, --NR.sup.BC(O)OR.sup.A, --SC(O)R.sup.A, --C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NNR.sup.B)R.sup.A, --C(.dbd.NOR.sup.A)R.sup.A, --C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --NR.sup.BC(.dbd.NR.sup.B)R.sup.B, --C(.dbd.S)R.sup.A, --C(.dbd.S)N(R.sup.B).sub.2, --NR.sup.BC(.dbd.S)R.sup.A, --S(O)R.sup.A, --OS(O).sub.2R.sup.A, --SO.sub.2R.sup.A, --NR.sup.BSO.sub.2R.sup.A, or --SO.sub.2N(R.sup.B).sub.2;

[0069] each R.sup.A is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0070] each R.sup.B is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;

[0071] R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently hydrogen, halo, or optionally substituted aliphatic;

[0072] each R.sup.x is independently selected from the group consisting of halo, --CN, optionally substituted aliphatic, --OR', and --N(R'').sub.2;

[0073] R' is hydrogen or optionally substituted aliphatic;

[0074] each R'' is independently hydrogen or optionally substituted aliphatic, or two R'' are taken together with their intervening atoms to form a heterocyclic ring; and

[0075] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits.

[0076] In certain embodiments, a provided compound is of Formula (I-a):

##STR00005##

or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.x, n, L, and Ar are as described herein.

[0077] In certain embodiments, a provided compound is of Formula (I-b):

##STR00006##

or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.x, n, L, and Ar are as described herein.

[0078] In certain embodiments, a provided compound is of Formula (I-c):

##STR00007##

or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.x, n, L, and Ar are as described herein.

[0079] In certain embodiments, a provided compound is of Formula (I'):

##STR00008##

or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.x, n, L, and Ar are as described herein.

[0080] In certain embodiments, a provided compound is of Formula (I'-a):

##STR00009##

or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.x, n, L, and Ar are as described herein.

[0081] In certain embodiments, a provided compound is of Formula (I'-b):

##STR00010##

or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.x, n, L, and Ar are as described herein.

[0082] In certain embodiments, a provided compound is of Formula (II).

##STR00011##

or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.x, n, and Ar are as described herein.

[0083] In certain embodiments, a provided compound is of Formula (II-a):

##STR00012##

or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.x, n, and Ar are as described herein.

[0084] In certain embodiments, a provided compound is of Formula (II-b):

##STR00013##

or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.x, n, and Ar are as described herein.

[0085] In certain embodiments, a provided compound is of Formula (III):

##STR00014##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0086] In certain embodiments, a provided compound is of Formula (III-a):

##STR00015##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0087] In certain embodiments, a provided compound is of Formula (III-b):

##STR00016##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0088] In certain embodiments, a provided compound is of Formula (IV):

##STR00017##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0089] In certain embodiments, a provided compound is of Formula (IV-a):

##STR00018##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0090] In certain embodiments, a provided compound is of Formula (I V-b):

##STR00019##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0091] In certain embodiments, a provided compound is of Formula (V):

##STR00020##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0092] In certain embodiments, a provided compound is of Formula (V-a):

##STR00021##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0093] In certain embodiments, a provided compound is of Formula (V-b):

##STR00022##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0094] In certain embodiments, a provided compound is of Formula (VI).

##STR00023##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0095] In certain embodiments, a provided compound is of Formula (VI-a):

##STR00024##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0096] In certain embodiments, a provided compound is of Formula (VI-b):

##STR00025##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0097] In certain embodiments, a provided compound is of Formula (VII):

##STR00026##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0098] In certain embodiments, a provided compound is of Formula (VII-a):

##STR00027##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0099] In certain embodiments, a provided compound is of Formula (VII-b):

##STR00028##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0100] In certain embodiments, a provided compound is of Formula (VIII):

##STR00029##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0101] In certain embodiments, a provided compound is of Formula (VIII-a):

##STR00030##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0102] In certain embodiments, a provided compound is of Formula (VIII-b):

##STR00031##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0103] In certain embodiments, a provided compound is of Formula (IX):

##STR00032##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0104] In certain embodiments, a provided compound is of Formula (IX-a):

##STR00033##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0105] In certain embodiments, a provided compound is of Formula (IX-b):

##STR00034##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0106] In certain embodiments, a provided compound is of Formula (X):

##STR00035##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0107] In certain embodiments, a provided compound is of Formula (X-a):

##STR00036##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0108] In certain embodiments, a provided compound is of Formula (X-b):

##STR00037##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0109] In certain embodiments, a provided compound is of Formula (XI):

##STR00038##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0110] In certain embodiments, a provided compound is of Formula (XI-a):

##STR00039##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0111] In certain embodiments, a provided compound is of Formula (XI-b):

##STR00040##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0112] In certain embodiments, a provided compound is of Formula (XII):

##STR00041##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0113] In certain embodiments, a provided compound is of Formula (XII-a):

##STR00042##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0114] In certain embodiments, a provided compound is of Formula (XII-b):

##STR00043##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0115] In certain embodiments, a provided compound is of Formula (XIII).

##STR00044##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0116] In certain embodiments, a provided compound is of Formula (XIII-a):

##STR00045##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0117] In certain embodiments, a provided compound is of Formula (XIII-b):

##STR00046##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y is as described herein.

[0118] As defined generally above, R.sup.1 is hydrogen, R.sup.z, or --C(O)R.sup.z, wherein R.sup.z is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is hydrogen. In some embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is methyl, ethyl, or propyl. In some embodiments, R.sup.1 is --C(O)R.sup.z, wherein R.sup.z is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is --C(O)R wherein R.sup.z is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is acetyl.

[0119] As defined generally above, L is --N(R)C(O)--, --C(O)N(R)--, --N(R)C(O)N(R)--, --N(R)C(O)O--, or --OC(O)N(R)--, wherein R is as described herein. In some embodiments, L is --N(R)C(O)--. In some embodiments, L is-NHC(O)--. In some embodiments, L is --N(C.sub.1-6 alkyl)C(O)--. In some embodiments, L is --N(CH.sub.3)C(O)--. In some embodiments, L is --C(O)N(R)--. In some embodiments, L is --C(O)NH--. In some embodiments, L is --C(O)N(C.sub.1-6 alkyl)-. In some embodiments, L is --C(O)N(CH.sub.3)--. In some embodiments, L is --N(R)C(O)N(R)--. In some embodiments, L is --NHC(O)NH--. In some embodiments, L is --NHC(O)N(R)--. In some embodiments, L is --N(R)C(O)NH--. In some embodiments, L is --N(CH.sub.3)C(O)N(R)--. In some embodiments, L is --N(R)C(O)N(CH.sub.3)--. In some embodiments, L is --N(CH.sub.3)C(O)N(CH.sub.3)--. In some embodiments, L is --N(R)C(O)O--. In some embodiments, L is --NHC(O)O--. In some embodiments, L is --N(C.sub.1-6 alkyl)C(O)O--. In some embodiments, L is --N(CH.sub.3)C(O)O--. In some embodiments, L is --OC(O)N(R)--. In some embodiments, L is --OC(O)NH--. In some embodiments, L is --OC(O)N(C.sub.1-6 alkyl)-. In some embodiments, L is --OC(O)N(CH.sub.3)--.

[0120] As defined generally above, each R is independently hydrogen or optionally substituted C.sub.1-6 aliphatic. In certain embodiments, R is hydrogen. In some embodiments, R is optionally substituted C.sub.1-6 aliphatic. In some embodiments, R is substituted C.sub.1-6 aliphatic. In some embodiments, R is unsubstituted C.sub.1-6 aliphatic. In some embodiments, R is optionally substituted C.sub.1-6 alkyl. In some embodiments, R is substituted C.sub.1-6 alkyl. In some embodiments, R is unsubstituted C.sub.1-6 alkyl. In some embodiments, R is methyl, ethyl, or propyl.

[0121] As defined generally above, Ar is a monocyclic or bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with 0, 1, 2, 3, 4, or 5 R.sup.y groups, as valency permits. For avoidance of confusion, though Ar is sometimes used to denote the element argon, as used herein it denotes a monocyclic or bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with 0, 1, 2, 3, 4, or 5 R.sup.y groups, as valency permits, and various embodiments thereof as described herein. In certain embodiments, Ar is unsubstituted. In certain embodiments, Ar is substituted with one or two R.sup.y groups. In certain embodiments, Ar is substituted with one R.sup.y group. In certain embodiments, Ar is substituted with two R.sup.y groups. In certain embodiments, Ar is substituted with three R.sup.y groups. In certain embodiments, Ar is substituted with four R.sup.y groups. In certain embodiments, Ar is substituted with five R.sup.y groups.

[0122] In certain embodiments, Ar is phenyl substituted with 0, 1, 2, 3, 4, or 5 R.sup.y groups. In certain embodiments, Ar is phenyl substituted with one or two R.sup.y groups. In certain embodiments, Ar is unsubstituted phenyl. In certain embodiments, Ar is phenyl substituted with one R.sup.y group. In certain embodiments, Ar is phenyl substituted with two R.sup.y groups. In certain embodiments, Ar is phenyl substituted with three R.sup.y groups. In certain embodiments, Ar is phenyl substituted with four R.sup.y groups. In certain embodiments, Ar is phenyl substituted with five R.sup.y groups.

[0123] In certain embodiments, Ar is heteroaryl substituted with 0, 1, 2, 3, 4, or 5 R.sup.y groups, as valency permits. In certain embodiments, Ar is a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with 0, 1, 2, 3, or 4 R.sup.y groups. In certain embodiments, Ar is an unsubstituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ar is a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with one or two R.sup.y groups. In certain embodiments, Ar is a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with one R.sup.y group. In certain embodiments, Ar is a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl), and is substituted with 0, 1, 2, or 3 R.sup.y groups. In certain embodiments, Ar is a 6-membered heteroaryl having 1-3 nitrogens (e.g., pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl), and is substituted with 0, 1, 2, 3, or 4 R.sup.y groups. In certain embodiments, Ar is pyridyl, and is substituted with 0, 1, 2, 3, or 4 R.sup.y groups. In certain embodiments, Ar is pyridyl, and is substituted with one R.sup.y group. In certain embodiments, Ar is pyridyl, and is substituted with two R.sup.y groups. In certain embodiments, Ar is a 6-membered heteroaryl having two nitrogens (e.g., pyrimidyl, pyridazinyl, pyrazinyl), and is substituted with 0, 1, 2, or 3 R.sup.y groups. In certain embodiments, Ar is a 6-membered heteroaryl having two nitrogens (e.g., pyrimidyl, pyridazinyl, pyrazinyl), and is substituted with one R.sup.y group. In certain embodiments, Ar is a 6-membered heteroaryl having two nitrogens (e.g., pyrimidyl, pyridazinyl, pyrazinyl), and is substituted with two R.sup.y groups.

[0124] In certain embodiments, Ar is a bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with 0, 1, 2, 3, or 4 R.sup.y groups. In certain embodiments, Ar is an 8- to 12-membered bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with 0, 1, 2, 3, or 4 R.sup.y groups. In certain embodiments, Ar is an unsubstituted bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ar is a bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with one or two R.sup.y groups. In certain embodiments, Ar is a bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with one R.sup.y group. In certain embodiments, Ar is a bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with two R.sup.y groups. In certain embodiments, Ar is a bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with three R.sup.y groups. In certain embodiments, Ar is a bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with four R.sup.y groups. In certain embodiments, Ar is a bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with five R.sup.y groups. In certain embodiments, Ar is naphthalene substituted with 0, 1, 2, 3, 4, or 5 R.sup.y groups.

[0125] In certain embodiments, Ar is an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with 0, 1, 2, 3, or 4 R.sup.y groups. In certain embodiments, Ar is a 9-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl), wherein Ar is substituted with 0, 1, 2, 3, 4, or 5 R.sup.y groups. In certain embodiments, Ar is a 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., naphthyridinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl), wherein Ar is substituted with 0, 1, 2, 3, 4, or 5 R.sup.y groups. In certain embodiments, Ar is selected from the group consisting of quinoline, benzimidazole, benzopyrazole, quinoxaline, tetrahydroquinoline, tetrahydroisoquinoline, naphthalene, tetrahydronaphthalene, 2,3-dihydrobenzo[b][1,4]dioxine, isoindole, 2H-benzo[b][1,4]oxazin-3(4H)-one, 3,4-dihydro-2H-benzo[b][1,4]oxazine, and quinoxalin-2(1H)-one, wherein Ar is substituted with 0, 1, 2, 3, or 4 R.sup.y groups. In some embodiments, Ar is quinoline, wherein Ar is substituted with 0, 1, 2, 3, or 4 R.sup.y groups.

[0126] As defined generally above, each R.sup.y is independently selected from the group consisting of halo, --CN, --NO.sub.2, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, --OR.sup.A, --N(R.sup.B).sub.2, --SR.sup.A, --C(.dbd.O)R.sup.A, --C(O)OR.sup.A, --C(O)SR.sup.A, --C(O)N(R.sup.B).sub.2, --C(O)N(R.sup.B)N(R.sup.B).sub.2, --OC(O)R.sup.A, --OC(O)N(R.sup.B).sub.2, --NR.sup.BC(O)R.sup.A, --NR.sup.BC(O)N(R.sup.B).sub.2, --NR.sup.BC(O)N(R.sup.B)N(R.sup.B).sub.2, --NR.sup.BC(O)OR.sup.A, --SC(O)R.sup.A, --C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NNR.sup.B)R.sup.A, --C(.dbd.NOR.sup.A)R.sup.A, --C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --NR.sup.BC(.dbd.NR.sup.B)R.sup.B, --C(.dbd.S)R.sup.A, --C(.dbd.S)N(R.sup.B).sub.2, --NR.sup.BC(.dbd.S)R.sup.A, --S(O)R.sup.A, --OS(O).sub.2R.sup.A, --SO.sub.2R.sup.A, --NR.sup.BSO.sub.2R.sup.A, or --SO.sub.2N(R.sup.B).sub.2, wherein R.sup.A and R.sup.B are described herein. In some embodiments, each R.sup.y is independently selected from the group consisting of halo, --CN, --NO.sub.2, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, --OR.sup.A, --N(R.sup.B).sub.2, --SR.sup.A, --C(.dbd.O)R.sup.A, --C(O)OR.sup.A, --C(O)SR.sup.A, --C(O)N(R.sup.B).sub.2, --OC(O)R.sup.A, --NR.sup.BC(O)R.sup.A, --NR.sup.BC(O)N(R.sup.B).sub.2, --SC(O)R.sup.A, --C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --NR.sup.BC(.dbd.NR.sup.B)R.sup.B, --C(.dbd.S)R.sup.A, --C(.dbd.S)N(R.sup.B).sub.2, --NR.sup.BC(.dbd.S)R.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A, --NR.sup.BSO.sub.2R.sup.A, and --SO.sub.2N(R.sup.B).sub.2, wherein R.sup.A and R.sup.B are described herein.

[0127] In some embodiments, at least one R.sup.y is halo. In certain embodiments, at least one R.sup.y is fluoro. In certain embodiments, at least one R.sup.y is chloro. In some embodiments, at least one R.sup.y is --CN. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted aliphatic. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.y is methoxy, ethoxy, or propoxy. In certain embodiments, at least one R.sup.y is methoxy. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.y is --OCH.sub.2CH.sub.2N(CH.sub.3).sub.2. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted heterocyclyl. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is an optionally substituted 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2, wherein each R.sup.B is independently selected from hydrogen or C.sub.1-6 alkyl. In some embodiments, at least one R.sup.y is --NHR.sup.B. In some embodiments, at least one R.sup.y is --N(C.sub.1-6 alkyl).sub.2, --NH(C.sub.1-6 alkyl), or --NH.sub.2. In certain embodiments, at least one R.sup.y is --NH.sub.2. In certain embodiments, at least one R.sup.y is --NHCH.sub.3. In certain embodiments, at least one R.sup.y is --N(CH.sub.3).sub.2. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2 or --NHR.sup.B, wherein at least one R.sup.B is optionally substituted heterocyclyl. In some embodiments, at least one R.sup.y is --N(R.sup.b).sub.2 or --NHR.sup.b, wherein at least one R.sup.B is an optionally substituted 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2 or --NHR.sup.B, wherein at least one R.sup.B is oxetanyl, tetrahydropyranyl, or tetrahydrofuranyl. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2 or --NHR.sup.B, wherein at least one R.sup.B is optionally substituted piperidinyl or optionally substituted piperazinyl.

[0128] In some embodiments, at least one R.sup.y is optionally substituted aliphatic. In certain embodiments, at least one R.sup.y is substituted aliphatic. In certain embodiments, at least one R.sup.y is unsubstituted aliphatic. In some embodiments, at least one R.sup.y is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.y is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.y is substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.y is methyl, ethyl, or propyl. In certain embodiments, at least one R.sup.y is methyl. In certain embodiments, at least one R.sup.y is --CF.sub.3, CHF.sub.2, or CH.sub.2F. In certain embodiments, at least one R.sup.y is C.sub.1-6 alkyl substituted with aryl, heteroaryl, or heterocyclyl. In certain embodiments, at least one R.sup.y is benzyl. In certain embodiments, at least one R.sup.y is --(C.sub.1-6 alkyl)-aryl. In certain embodiments, at least one R.sup.y is --(C.sub.1-6 alkyl)-heteroaryl. In certain embodiments, at least one R.sup.y is --(C.sub.1-6 alkyl)-heterocyclyl. In certain embodiments, at least one R.sup.y is --CH.sub.2-aryl. In certain embodiments, at least one R.sup.y is --CH.sub.2-heteroaryl. In certain embodiments, at least one R.sup.y is --CH.sub.2-heterocyclyl.

[0129] In some embodiments, at least one R.sup.y is --C(O)N(R.sup.B).sub.2. In certain embodiments, at least one R.sup.y is --C(O)NHR.sup.B. In certain embodiments, at least one R.sup.y is --C(O)NH.sub.2. In certain embodiments, at least one R.sup.y is --C(O)N(R.sup.B).sub.2, wherein the R.sup.B groups are taken together with their intervening atoms to form an optionally substituted 5- to 6-membered heterocyclyl. In certain embodiments, at least one R.sup.y is --C(O)N(R.sup.B).sub.2, wherein the R.sup.B groups are taken together with their intervening atoms to form an optionally substituted morpholinyl.

[0130] In some embodiments, at least one R.sup.y is --SO.sub.2N(R.sup.B).sub.2. In certain embodiments, at least one R.sup.y is --SO.sub.2NHR.sup.B. In certain embodiments, at least one R.sup.y is --SO.sub.2NH.sub.2. In certain embodiments, at least one R.sup.y is --SO.sub.2N(R.sup.B).sub.2, wherein neither R.sup.B is hydrogen. In certain embodiments, at least one R.sup.y is --SO.sub.2NH(C.sub.1-6 alkyl) or --SO.sub.2N(C.sub.1-6 alkyl).sub.2. In certain embodiments, at least one R.sup.y is --SO.sub.2N(CH.sub.3).sub.2. In certain embodiments, at least one R.sup.y is --SO.sub.2N(R.sup.b).sub.2, wherein the R.sup.B groups are taken together with their intervening atoms to form an optionally substituted 5- to 6-membered heterocyclyl. In certain embodiments, at least one R.sup.y is --SO.sub.2-morpholinyl. In certain embodiments, at least one R.sup.y is --SO.sub.2-piperidinyl, --SO.sub.2-- piperazinyl, or --SO.sub.2-piperidinyl.

[0131] In some embodiments, at least one R.sup.y is --SO.sub.2R.sup.A In some embodiments, at least one R.sup.y is --SO.sub.2R.sup.A, wherein R.sup.A is optionally substituted aliphatic. In some embodiments, at least one R.sup.y is --SO.sub.2(C.sub.1-6 alkyl). In some embodiments, at least one R.sup.y is --SO.sub.2CH.sub.3. In some embodiments, at least one R.sup.y is --C(O)R.sup.A. In some embodiments, at least one R.sup.y is --C(O)R.sup.A, wherein R.sup.A is optionally substituted aliphatic. In some embodiments, at least one R.sup.y is --C(O)(C.sub.1-6 alkyl). In some embodiments, at least one R.sup.y is --C(O)CH.sub.3.

[0132] In some embodiments, at least one R.sup.y is --N(R.sup.B)C(O)R.sup.A In certain embodiments, at least one R.sup.y is --NHC(O)R.sup.A. In certain embodiments, at least one R.sup.y is --NHC(O)(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.y is --NHC(O)CH.sub.3.

[0133] In some embodiments, at least one R.sup.y is --N(R.sup.B)SO.sub.2R.sup.A. In some embodiments, at least one R.sup.y is --NHSO.sub.2R.sup.A. In some embodiments, at least one R.sup.y is --N(C.sub.1-6 alkyl)SO.sub.2R.sup.A. In certain embodiments, at least one R.sup.y is --NHSO.sub.2(C.sub.1-6 alkyl) or --N(C.sub.1-6 alkyl)SO.sub.2(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.y is --NHSO.sub.2CH.sub.3. In certain embodiments, at least one R.sup.y is --N(CH.sub.3)SO.sub.2CH.sub.3.

[0134] In some embodiments, at least one R.sup.y is optionally substituted heterocyclyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, at least one R.sup.y is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 5-membered heterocyclyl having one heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is optionally substituted pyrrolidinyl. In certain embodiments, at least one R.sup.y is pyrroldinyl, hydroxypyrrolidinyl, or methylpyrrolidinyl. In certain embodiments, at least one R.sup.y is an optionally substituted 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 6-membered heterocyclyl having one heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is optionally substituted piperidinyl. In certain embodiments, at least one R.sup.y is an optionally substituted 6-membered heterocyclyl having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is optionally substituted piperdinyl, optionally substituted piperazinyl, or optionally substituted morpholinyl. In certain embodiments, at least one R.sup.y is morpholinyl, tetrahydropyranyl, piperidinyl, methylpiperidinyl, piperazinyl, methylpiperazinyl, acetylpiperazinyl, methylsulfonylpiperazinyl, aziridinyl, or methylaziridinyl. In some embodiments, at least one R.sup.y is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 5-membered heteroaryl having one heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 5-membered heteroaryl having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 6-membered heteroaryl having 1-3 nitrogens. In certain embodiments, at least one R.sup.y is an optionally substituted pyrazolyl. In certain embodiments, at least one R.sup.y is an optionally substituted imidazolyl. In certain embodiments, at least one R.sup.y is an optionally substituted pyridyl. In certain embodiments, at least one R.sup.y is an optionally substituted pyrimidyl. In certain embodiments, at least one R.sup.y is pyrazolyl, methyl pyrazolyl, imidazolyl, or methylimidazolyl.

[0135] In some embodiments, R.sup.y is --OR.sup.A. In some embodiments, R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted heterocyclyl. In some embodiments, R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted heteroaryl. In some embodiments, R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted cycloalkyl. In some embodiments, R.sup.y is --N(R.sup.B).sub.2. In some embodiments, R.sup.y is --NHR.sup.B In some embodiments, R.sup.y is --NHR.sup.B, wherein R.sup.B is optionally substituted heterocyclyl. In some embodiments, R.sup.y is --NHR.sup.B, wherein R.sup.B is optionally substituted heteroaryl. In some embodiments, R.sup.y is --NHR.sup.B, wherein R.sup.B is optionally substituted cycloalkyl. In some embodiments, R.sup.y is --N(R.sup.B).sub.2, wherein one R.sup.B is optionally substituted heterocyclyl, and the other R.sup.B is C.sub.1-4 alkyl. In some embodiments, R.sup.y is --N(R.sup.B).sub.2, wherein one R.sup.B is optionally substituted heteroaryl, and the other R.sup.B is C.sub.1-4 alkyl. In some embodiments, R.sup.y is --N(R.sup.B).sub.2, wherein one R.sup.B is optionally substituted cycloalkyl, and the other R.sup.B is C.sub.1-4 alkyl.

[0136] In certain embodiments, Ar is selected from the group consisting of:

##STR00047## ##STR00048## ##STR00049## ##STR00050##

[0137] In certain embodiments, Ar is selected from the group consisting of:

##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075##

[0138] As defined generally above, each R.sup.x is independently selected from the group consisting of halo, --CN, optionally substituted aliphatic, --OR', and --N(R'').sub.2. In certain embodiments, at least one R.sup.x is halo. In certain embodiments, at least one R.sup.x is fluoro. In certain embodiments, at least one R.sup.x is --CN. In certain embodiments, at least one R.sup.x is optionally substituted aliphatic. In certain embodiments, at least one R.sup.x is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.x is methyl. In certain embodiments, at least one R.sup.x is --CF.sub.3. In certain embodiments, at least one R.sup.x is --OR' or --N(R'').sub.2. In certain embodiments, R.sup.x is not --OR' or --N(R'').sub.2. In certain embodiments, at least one R.sup.x is --OCH.sub.3. In certain embodiments, R.sup.x is not --OCH.sub.3.

[0139] One of ordinary skill in the art will appreciate that an R.sup.x group can be attached anywhere on the tetrahydroisoquinoline or dihydroisoquinoline ring. In certain embodiments, an R.sup.x group is attached to the benzene portion of the tetrahydroisoquinoline or dihydroisoquinoline ring. In certain embodiments, an R.sup.x group is attached to the tetrahydropyridine or dihydropyridine portion of the tetrahydroisoquinoline or dihydroisoquinoline ring. In certain embodiments, R.sup.x groups are attached to both the benzene portion and the tetrahydropyridine (or dihydropyridine) portion of the tetrahydroisoquinoline (or dihydroisoquinoline) ring. See, for example, the structures shown below:

##STR00076##

[0140] In certain embodiments, a provided compound is of Formula (XIV):

##STR00077##

or a pharmaceutically acceptable salt thereof.

[0141] As defined generally above, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0142] In certain embodiments, a provided compound is of Formula (XV), (XVI), (XVII), or (XVIII)

##STR00078##

or a pharmaceutically acceptable salt thereof, wherein each R.sup.y for Formula (XV), (XVI), (XVII), or (XVIII) is independently as described herein.

[0143] In certain embodiments, a provided compound is of Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a):

##STR00079##

or a pharmaceutically acceptable salt thereof, wherein R.sup.y for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a) is as described herein. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --OR.sup.A. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted heterocyclyl. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted heteroaryl. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted cycloalkyl. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --N(R.sup.B).sub.2. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --NHR.sup.b. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --NHR.sup.b, wherein R.sup.B is optionally substituted heterocyclyl. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --NHR.sup.B, wherein R.sup.B is optionally substituted heteroaryl. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --NHR.sup.b, wherein R.sup.B is optionally substituted cycloalkyl. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --N(R.sup.B).sub.2, wherein one R.sup.B is optionally substituted heterocyclyl, and the other R.sup.B is C.sub.1-4 alkyl. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --N(R.sup.B).sub.2, wherein one R.sup.B is optionally substituted heteroaryl, and the other R.sup.B is C.sub.1-4 alkyl. In some embodiments, e.g. for Formula (XV-a), (XVI-a), (XVII-a), or (XVIII-a), R.sup.y is --N(R.sup.B).sub.2, wherein one R.sup.B is optionally substituted cycloalkyl, and the other R.sup.B is C.sub.1-4 alkyl.

[0144] In certain embodiments, a provided compound is of Formula (XV-b):

##STR00080##

or a pharmaceutically acceptable salt thereof, wherein each R.sup.y is independently as described herein.

[0145] In some embodiments, e.g. for Formula (XV), (XVI), (XVII), (XVIII), (XV-a), (XVI-a), (XVII-a), (XVIII-a), or (XV-b), at least one R.sup.y is halo. In certain embodiments, at least one R.sup.y is fluoro. In certain embodiments, at least one R.sup.y is chloro. In some embodiments, at least one R.sup.y is --CN.

[0146] In some embodiments, e.g. for Formula (XV), (XVI), (XVII), (XVIII), (XV-a), (XVI-a), (XVII-a), (XVIII-a), or (XV-b), at least one R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted aliphatic. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.y is methoxy, ethoxy, or propoxy. In certain embodiments, at least one R.sup.y is methoxy. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.y is --OCH.sub.2CH.sub.2N(CH.sub.3).sub.2. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted heterocyclyl. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is an optionally substituted 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted piperidinyl or optionally substituted piperazinyl. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted heterocyclyl. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted heteroaryl. In some embodiments, at least one R.sup.y is --OR.sup.A, wherein R.sup.A is optionally substituted cycloalkyl.

[0147] In some embodiments, e.g. for Formula (XV), (XVI), (XVII), (XVIII), (XV-a), (XVI-a), (XVII-a), (XVIII-a), or (XV-b), at least one R.sup.y is --N(R.sup.B).sub.2. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2, wherein each R.sup.B is independently selected from hydrogen or C.sub.1-6 alkyl. In some embodiments, at least one R.sup.y is --NHR.sup.B. In some embodiments, at least one R.sup.y is --N(C.sub.1-6 alkyl).sub.2, --NH(C.sub.1-6 alkyl), or --NH.sub.2. In certain embodiments, at least one R.sup.y is --NH.sub.2. In certain embodiments, at least one R.sup.y is --NHCH.sub.3. In certain embodiments, at least one R.sup.y is --N(CH.sub.3).sub.2. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2 or --NHR.sup.B, wherein at least one R.sup.B is optionally substituted heterocyclyl. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2 or --NHR.sup.B, wherein at least one R.sup.B is an optionally substituted 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2 or --NHR.sup.B, wherein at least one R.sup.B is oxetanyl, tetrahydropyranyl, or tetrahydrofuranyl. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2 or --NHR.sup.B, wherein at least one R.sup.B is optionally substituted piperidinyl or optionally substituted piperazinyl. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2, wherein one R.sup.B is optionally substituted heterocyclyl, and the other R.sup.B is C.sub.1-4 alkyl. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2, wherein one R.sup.B is optionally substituted heteroaryl, and the other R.sup.B is C.sub.1-4 alkyl. In some embodiments, at least one R.sup.y is --N(R.sup.B).sub.2, wherein one R.sup.B is optionally substituted cycloalkyl, and the other R.sup.B is C.sub.1-4 alkyl.

[0148] In some embodiments, e.g for Formula (XV), (XVI), (XVII), (XVIII), (XV-a), (XVI-a), (XVII-a), (XVIII-a), or (XV-b), at least one R.sup.y is optionally substituted aliphatic. In certain embodiments, at least one R.sup.y is substituted aliphatic. In certain embodiments, at least one R.sup.y is unsubstituted aliphatic. In some embodiments, at least one R.sup.y is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.y is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.y is substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.y is methyl, ethyl, or propyl. In certain embodiments, at least one R.sup.y is methyl. In certain embodiments, at least one R.sup.y is --CF.sub.3, CHF.sub.2, or CH.sub.2F. In certain embodiments, at least one R.sup.y is C.sub.1-6 alkyl substituted with aryl, heteroaryl, or heterocyclyl. In certain embodiments, at least one R.sup.y is benzyl. In certain embodiments, at least one R.sup.y is --(C.sub.1-6 alkyl)-aryl. In certain embodiments, at least one R.sup.y is --(C.sub.1-6 alkyl)-heteroaryl. In certain embodiments, at least one R.sup.y is --(C.sub.1-6 alkyl)-heterocyclyl. In certain embodiments, at least one R.sup.y is --CH.sub.2-aryl. In certain embodiments, at least one R.sup.y is --CH.sub.2-heteroaryl. In certain embodiments, at least one R.sup.y is --CH.sub.2-heterocyclyl.

[0149] In some embodiments, e.g for Formula (XV), (XVI), (XVII), (XVIII), (XV-a), (XVI-a), (XVII-a), (XVIII-a), or (XV-b), at least one R.sup.y is --C(O)N(R.sup.B).sub.2. In certain embodiments, at least one R.sup.y is --C(O)NHR.sup.B. In certain embodiments, at least one R.sup.y is --C(O)NH.sub.2. In certain embodiments, at least one R.sup.y is --C(O)N(R.sup.B).sub.2, wherein the R.sup.B groups are taken together with their intervening atoms to form an optionally substituted 5- to 6-membered heterocyclyl. In certain embodiments, at least one R.sup.y is --C(O)N(R.sup.B).sub.2, wherein the R.sup.B groups are taken together with their intervening atoms to form an optionally substituted morpholinyl.

[0150] In some embodiments, e.g. for Formula (XV), (XVI), (XVII), (XVIII), (XV-a), (XVI-a), (XVII-a), (XVIII-a), or (XV-b), at least one R.sup.y is --SO.sub.2N(R.sup.B).sub.2. In certain embodiments, at least one R.sup.y is --SO.sub.2NHR.sup.B. In certain embodiments, at least one R.sup.y is --SO.sub.2NH.sub.2. In certain embodiments, at least one R.sup.y is --SO.sub.2N(R.sup.B).sub.2, wherein neither R.sup.B is hydrogen. In certain embodiments, at least one R.sup.y is --SO.sub.2NH(C.sub.1-6 alkyl) or --SO.sub.2N(C.sub.1-6 alkyl).sub.2. In certain embodiments, at least one R.sup.y is --SO.sub.2N(CH.sub.3).sub.2. In certain embodiments, at least one R.sup.y is --SO.sub.2N(R.sup.B).sub.2, wherein the R.sup.B groups are taken together with their intervening atoms to form an optionally substituted 5- to 6-membered heterocyclyl. In certain embodiments, at least one R.sup.y is --SO.sub.2-morpholinyl. In certain embodiments, at least one R.sup.y is --SO.sub.2-piperidinyl, --SO.sub.2-- piperazinyl, or --SO.sub.2-piperidinyl.

[0151] In some embodiments, e.g for Formula (XV), (XVI), (XVII), (XVIII), (XV-a), (XVI-a), (XVII-a), (XVIII-a), or (XV-b), at least one R.sup.y is --SO.sub.2R.sup.A. In some embodiments, at least one R.sup.y is --SO.sub.2R.sup.A, wherein R.sup.A is optionally substituted aliphatic. In some embodiments, at least one R.sup.y is --SO.sub.2(C.sub.1-6 alkyl). In some embodiments, at least one R.sup.y is --SO.sub.2CH.sub.3. In some embodiments, at least one R.sup.y is --C(O)R.sup.A. In some embodiments, at least one R.sup.y is --C(O)R.sup.A, wherein R.sup.A is optionally substituted aliphatic. In some embodiments, at least one R.sup.y is --C(O)(C.sub.1-6 alkyl). In some embodiments, at least one R.sup.y is --C(O)CH.sub.3.

[0152] In some embodiments, e.g for Formula (XV), (XVI), (XVII), (XVIII), (XV-a), (XVI-a), (XVII-a), (XVIII-a), or (XV-b), at least one R.sup.y is --N(R.sup.B)C(O)R.sup.A. In certain embodiments, at least one R.sup.y is --NHC(O)R.sup.A. In certain embodiments, at least one R.sup.y is --NHC(O)(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.y is --NHC(O)CH.sub.3.

[0153] In some embodiments, e.g. for Formula (XV), (XVI), (XVII), (XVIII), (XV-a), (XVI-a), (XVII-a), (XVIII-a), or (XV-b), at least one R.sup.y is --N(R.sup.B)SO.sub.2R.sup.A. In some embodiments, at least one R.sup.y is --NHSO.sub.2R.sup.A In some embodiments, at least one R.sup.y is --N(C.sub.1-6, alkyl)SO.sub.2R.sup.A In certain embodiments, at least one R.sup.y is --NHSO.sub.2(C.sub.1-6 alkyl) or --N(C.sub.1-6 alkyl)SO.sub.2(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.y is --NHSO.sub.2CH.sub.3. In certain embodiments, at least one R.sup.y is --N(CH.sub.3)SO.sub.2CH.sub.3.

[0154] In some embodiments, e.g. for Formula (XV), (XVI), (XVII), (XVIII), (XV-a), (XVI-a), (XVII-a), (XVIII-a), or (XV-b), at least one R.sup.y is optionally substituted heterocyclyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, at least one R.sup.y is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 5-membered heterocyclyl having one heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is optionally substituted pyrrolidinyl. In certain embodiments, at least one R.sup.y is pyrroldinyl, hydroxypyrrolidinyl, or methylpyrrolidinyl. In certain embodiments, at least one R.sup.y is an optionally substituted 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 6-membered heterocyclyl having one heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is optionally substituted piperidinyl. In certain embodiments, at least one R.sup.y is an optionally substituted 6-membered heterocyclyl having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is optionally substituted piperdinyl, optionally substituted piperazinyl, or optionally substituted morpholinyl. In certain embodiments, at least one R.sup.y is morpholinyl, tetrahydropyranyl, piperidinyl, methylpiperidinyl, piperazinyl, methylpiperazinyl, acetylpiperazinyl, methylsulfonylpiperazinyl, aziridinyl, or methylaziridinyl. In some embodiments, at least one R.sup.y is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 5-membered heteroaryl having one heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 5-membered heteroaryl having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, at least one R.sup.y is an optionally substituted 6-membered heteroaryl having 1-3 nitrogens. In certain embodiments, at least one R.sup.y is an optionally substituted pyrazolyl. In certain embodiments, at least one R.sup.y is an optionally substituted imidazolyl. In certain embodiments, at least one R.sup.y is an optionally substituted pyridyl. In certain embodiments, at least one R.sup.y is an optionally substituted pyrimidyl. In certain embodiments, at least one R.sup.y is pyrazolyl, methylpyrazolyl, imidazolyl, or methylimidazolyl.

[0155] In certain embodiments, a provided compound is a compound listed in Table 1, or a pharmaceutically acceptable salt thereof.

TABLE-US-00001 TABLE 1 Exemplary Compounds Cmpd LCMS m/z No Structure Exact Mass (M + H) 1 ##STR00081## 387.1947 388.2 2 ##STR00082## 390.2056 391.2 3 ##STR00083## 310.1681 311.1 4 ##STR00084## 310.1681 311.1 5 ##STR00085## 325.179 326.2 6 ##STR00086## 325.179 326.2 7 ##STR00087## 326.163 327.2 8 ##STR00088## 387.1947 388.2 9 ##STR00089## 387.1947 388.2 10 ##STR00090## 376.1899 377.2 11 ##STR00091## 326.163 327.2 12 ##STR00092## 387.1947 388.2 13 ##STR00093## 387.1947 388.2 14 ##STR00094## 395.2209 396.2 15 ##STR00095## 423.2522 424.2 16 ##STR00096## 409.2365 410.2 17 ##STR00097## 311.1634 312.1 18 ##STR00098## 311.1634 312.2 19 ##STR00099## 387.1947 388.2 20 ##STR00100## 387.1947 388.2 21 ##STR00101## 389.1409 390.1 22 ##STR00102## 353.1739 354.1 23 ##STR00103## 367.1896 368.1 24 ##STR00104## 403.1566 404.1 25 ##STR00105## 353.1739 354.2 26 ##STR00106## 367.1896 368.2 27 ##STR00107## 403.1566 404.2 28 ##STR00108## 397.2365 398.1 29 ##STR00109## 408.2525 409.2 30 ##STR00110## 422.2682 423.2 31 ##STR00111## 403.1566 404.2 32 ##STR00112## 389.1409 390.1 33 ##STR00113## 389.1409 390 34 ##STR00114## 393.2416 394.1 35 ##STR00115## 394.2369 395.2 36 ##STR00116## 408.2525 409.2 37 ##STR00117## 379.226 380.7 38 ##STR00118## 393.2416 394.2 39 ##STR00119## 383.2209 384.2 40 ##STR00120## 423.2522 424.2 41 ##STR00121## 451.2835 452.3 42 ##STR00122## 379.226 380.2 43 ##STR00123## 409.2365 410.2 44 ##STR00124## 409.2365 410.2 45 ##STR00125## 395.2209 396.2 46 ##STR00126## 423.2158 424.2 47 ##STR00127## 437.2678 438.3 48 ##STR00128## 410.2206 411.2 49 ##STR00129## 473.2572 424.1 50 ##STR00130## 381.2052 382.2 51 ##STR00131## 409.2365 4101 52 ##STR00132## 437.2678 438.3 53 ##STR00133## 437.2678 438.3 54 ##STR00134## 410.2318 411.1 55 ##STR00135## 410.2318 411.1 56 ##STR00136## 439.2471 440.1 57 ##STR00137## 427.2271 428.2 58 ##STR00138## 410.2206 411.2 59 ##STR00139## 408.2413 409.1 60 ##STR00140## 409.2365 410.2 61 ##STR00141## 438.2631 439.2 62 ##STR00142## 411.227 412.2 63 ##STR00143## 411.227 412.2 64 ##STR00144## 443.1976 444.1 65 ##STR00145## 427.2271 428 66 ##STR00146## 409.2365 410.1 67 ##STR00147## 439.2471 440.2 68 ##STR00148## 361.179 362.1 69 ##STR00149## 397.2365 398.2 70 ##STR00150## 397.7365 398.2 71 ##STR00151## 423.2522 424.2 72 ##STR00152## 383.2209 384.2 73 ##STR00153## 410.2318 411.1 74 ##STR00154## 410.2318 411.2 75 ##STR00155## 411.227 412.1 76 ##STR00156## 411.227 412.2 77 ##STR00157## 439.2471 440.2 78 ##STR00158## 427.2271 428.2 79 H ##STR00159## 427.2271 428.2 80 ##STR00160## 395.2209 396.2 81 ##STR00161## 395.2209 396.2 82 ##STR00162## 410.2206 411.1 83 ##STR00163## 410.2206 411.1 84 ##STR00164## 375.1947 376 85 ##STR00165## 362.1743 363.1 86 ##STR00166## 406.2005 407.2 87 ##STR00167## 383.2209 384.2 88 ##STR00168## 367.1896 368.1 89 ##STR00169## 381.1689 382.1 90 ##STR00170## 436.2838 437.2 91 ##STR00171## 486.2301 487.2 92 ##STR00172## 490.2556 491.3 93 ##STR00173## 394.2369 395.2 94 ##STR00174## 408.2525 409.3 95 ##STR00175## 423.2522 96 ##STR00176## 409.2365 410.3 97 ##STR00177## 395.2209 98 ##STR00178## 425.2315 426.2 99 ##STR00179## 394.2256 395.2 100 ##STR00180## 450.2631 451.2 101 ##STR00181## 436.2838 437.2 102 ##STR00182## 476.2399 477.2 103 ##STR00183## 450.2995 451.3 104 ##STR00184## 409.2365 410.2 105 ##STR00185## 423.2522 424.2 106 ##STR00186## 451.2835 452.2 107 ##STR00187## 451.2471 452.2 108 ##STR00188## 487.2141 488.2 109 ##STR00189## 491.2396 492.2 110 ##STR00190## 377.1852 378.2 111 ##STR00191## 423.2522 424.2 112 ##STR00192## 376.1899 377.1 113 ##STR00193## 452.2787 453.2 114 ##STR00194## 466.2944 467.2 115 ##STR00195## 452.2787 453.2 116 ##STR00196## 396.2161 397.1 117 ##STR00197## 410.2318 411.1 118 ##STR00198## 424.2474 425.1 119 ##STR00199## 395.2209 396.2 120 ##STR00200## 408.2525 409.2 121 ##STR00201## 436.2474 437.2 122 ##STR00202## 472.2144 473

123 ##STR00203## 422.2682 423.2 124 ##STR00204## 450.2631 451.3 125 ##STR00205## 486.2301 487.2 126 ##STR00206## 490.2556 491.2 127 ##STR00207## 450.2631 451.3 128 ##STR00208## 490.2556 491.2 129 ##STR00209## 395.2209 396.2 130 ##STR00210## 377.1852 378.2 131 ##STR00211## 436.2838 437.2 132 ##STR00212## 422.2682 423.2 133 ##STR00213## 439.7471 440.2 134 ##STR00214## 409.2365 410.3 135 ##STR00215## 437.2678 438.3 136 ##STR00216## 437.2315 438.2 137 ##STR00217## 477.2239 478.3 138 ##STR00218## 408.2525 409.3 139 ##STR00219## 422.2682 423.2 140 ##STR00220## 450.2995 451.2 141 ##STR00221## 486.2301 487.2 142 ##STR00222## 396.2049 397.2 143 ##STR00223## 408.2525 409.3 144 ##STR00224## 409.2365 410.2 145 ##STR00225## 409.2365 410.2 146 ##STR00226## 398.2206 399.2 147 ##STR00227## 451.2947 452.2 148 ##STR00228## 300.1586 315.2 149 ##STR00229## 314.1743 315.1 150 ##STR00230## 314.1743 315.1 151 ##STR00231## 340.1787 341.1 152 ##STR00232## 437.2678 438.3 153 ##STR00233## 437.2678 438.3 154 ##STR00234## 380.21 381.2 155 ##STR00235## 391.1896 392.2 156 ##STR00236## 493.3053 494.2 157 ##STR00237## 466.258 467.2 158 ##STR00238## 494.2893 495.3 159 ##STR00239## 493.3053 494.2 160 ##STR00240## 452.2787 453.3 161 ##STR00241## 436.2838 437.2 162 ##STR00242## 473.1984 474.2 163 ##STR00243## 422.2682 423.3 164 ##STR00244## 443.1879 444.2 165 ##STR00245## 494.2893 495.2 166 ##STR00246## 383.1957 384.1 167 ##STR00247## 423.2522 424.2 168 ##STR00248## 423.2522 424.2 169 ##STR00249## 399.227 400.2 170 ##STR00250## 300.1586 301.1 171 ##STR00251## 314.1743 315.1 172 ##STR00252## 465.274 466.2 173 ##STR00253## 479.2896 480.3 174 ##STR00254## 493.3053 494.4 175 ##STR00255## 507.3209 508.3 176 ##STR00256## 395.2209 396.2 177 ##STR00257## 409.2365 410.2 178 ##STR00258## 411.2522 412.2 179 ##STR00259## 443.1879 444.2 180 ##STR00260## 410.243 411.2 181 ##STR00261## 410.243 411.3 182 ##STR00262## 478.2304 479.3 183 ##STR00263## 411.2158 412.3 184 ##STR00264## 410.2318 411.3 185 ##STR00265## 411.227 412.1 186 ##STR00266## 411.2634 412.3 187 ##STR00267## 380.2212 381.3 188 ##STR00268## 380.2212 381.2 189 ##STR00269## 417.2165 418.2 190 ##STR00270## 417.2165 418.3 191 ##STR00271## 417.2165 418.2 192 ##STR00272## 410.2318 411.3 193 ##STR00273## 411.227 412.2 194 ##STR00274## 521.3366 522.3 195 ##STR00275## 410.2318 411.2 196 ##STR00276## 437.2678 438.3 197 ##STR00277## 437.2315 438.2 198 ##STR00278## 473.1984 474.2 199 ##STR00279## 477.2239 478.3 200 ##STR00280## 409.2478 410.3 201 ##STR00281## 395.2321 396.2 202 ##STR00282## 424.2474 425.3 203 ##STR00283## 492.2348 493.3 204 ##STR00284## 488.2093 489.3 205 ##STR00285## 452.2424 453.3 206 ##STR00286## 424.2587 425.2 207 ##STR00287## 492.2461 493.3 208 ##STR00288## 452.2536 453.3 209 ##STR00289## 396.2274 397.3 210 ##STR00290## 438.2379 439.3 211 ##STR00291## 396.2161 397.1 212 ##STR00292## 423.2522 424.3 213 ##STR00293## 423.2522 424.3 214 ##STR00294## 397.2478 398.2 215 ##STR00295## 450.2631 451.3 216 ##STR00296## 486.2301 487.3 217 ##STR00297## 490.2556 491.3 218 ##STR00298## 361.179 362.1 219 ##STR00299## 375.1947 376.1 220 ##STR00300## 361.179 362.1 221 ##STR00301## 375.1947 376.1 222 ##STR00302## 426.2267 427.1 223 ##STR00303## 423.2634 424.1 224 ##STR00304## 491.2508 492.2 225 ##STR00305## 487.2253 488.3 226 ##STR00306## 477.2352 478.3 227 ##STR00307## 473.2097 474.2 228 ##STR00308## 437.2427 438.3 229 ##STR00309## 410.2318 411.3 230 ##STR00310## 397.2114 398.1 231 ##STR00311## 425.2427 426.1 232 ##STR00312## 425.2427 426.3 233 ##STR00313## 397.2478 398.3 234 ##STR00314## 398.2318 399.3 235 ##STR00315## 423.2634 424.3 236 ##STR00316## 423.2634 424.3 237 ##STR00317## 423.2634 424.3 238 ##STR00318## 425.7427 426.3 239 ##STR00319## 422.2682 423.1 240 ##STR00320## 349.179 350.1 241 ##STR00321## 350.1743 351.1 242 ##STR00322## 350.1743 351.1 243 ##STR00323## 352.1787 353.2 244 ##STR00324## 354.158 355 245 ##STR00325## 362.1743 363.1 246 ##STR00326## 363.1947 364.1 247 ##STR00327## 364.2151 365.1 248 ##STR00328## 366.1402 367

249 ##STR00329## 368.1736 369.1 250 ##STR00330## 380.1736 381.1 251 ##STR00331## 390.1943 391.1 252 ##STR00332## 507.3209 508.2 253 ##STR00333## 452.2787 453.2 254 ##STR00334## 451.2583 452.3 255 ##STR00335## 409.2478 410.3 256 ##STR00336## 412.2111 413.1 257 ##STR00337## 474.2049 475.3 258 ##STR00338## 411.227 412.2 259 ##STR00339## 395.2321 396.1 260 ##STR00340## 410.2318 411,1 261 ##STR00341## 425.2427 426.3 262 ##STR00342## 461.2097 462.3 263 ##STR00343## 475.2253 476.3 264 ##STR00344## 437.2791 438.3 265 ##STR00345## 439.2583 440.3 266 ##STR00346## 436.2474 437.3 267 ##STR00347## 472.2144 473.3 268 ##STR00348## 472.2144 473.3 269 ##STR00349## 349.179 350.2 270 ##STR00350## 349.179 350 271 ##STR00351## 350.163 351 272 ##STR00352## 361.179 362.1 273 ##STR00353## 367.1354 368 274 ##STR00354## 368.1736 369.1 275 ##STR00355## 379.2008 380.1 276 ##STR00356## 383.1401 384.2 277 ##STR00357## 440.2424 441.1 278 ##STR00358## 459.194 460.2 279 ##STR00359## 423.227 424.3 280 ##STR00360## 382.2117 383.1 281 ##STR00361## 396.2274 397.2 282 ##STR00362## 464.2148 465.1 283 ##STR00363## 460.1893 461.2 284 ##STR00364## 424.2223 425.3 285 ##STR00365## 493.2301 494.1 286 ##STR00366## 489.2046 490.3 287 ##STR00367## 453.2376 454.3 288 ##STR00368## 424.2474 425.3 289 ##STR00369## 492.2348 493.3 290 ##STR00370## 488.2093 489.2 291 ##STR00371## 439.2583 440.3 292 ##STR00372## 437.2791 438.3 293 ##STR00373## 436.2474 437.3 294 ##STR00374## 350.1743 351.1 295 ##STR00375## 360.1838 361.1 296 ##STR00376## 367.1696 368.2 297 ##STR00377## 488.2206 489.3 298 ##STR00378## 410.2318 411.1 299 ##STR00379## 382.2005 383.1 300 ##STR00380## 491.2508 492.1 301 ##STR00381## 487.2253 488.1 302 ##STR00382## 451.2583 452.3 303 ##STR00383## 477.2352 478.1 304 ##STR00384## 452.2424 453.3 305 ##STR00385## 351.1695 352.1 306 ##STR00386## 396.2161 397.2 307 ##STR00387## 424.2474 425.1. 308 ##STR00388## 410.2318 411.1 309 ##STR00389## 425.2315 426.1 310 ##STR00390## 409.2478 410.3 311 ##STR00391## 413.2427 414.3 312 ##STR00392## 413.2427 301.1 313 ##STR00393## 439.2583 440.1 314 ##STR00394## 383.2321 384.1 315 ##STR00395## 425.2427 426.1 316 ##STR00396## 451.2195 452.3 317 ##STR00397## 361.179 362.1 318 ##STR00398## 376.1787 377.1 319 ##STR00399## 428.0848 429 320 ##STR00400## 369.2165 370.1 321 ##STR00401## 453.2628 454.2 322 ##STR00402## 493.2941 494.2 323 ##STR00403## 411.2158 412.3 324 ##STR00404## 474.2474 425.1 325 ##STR00405## 406.2117 407.3 326 ##STR00406## 448.2587 449.3 327 ##STR00407## 376.1787 377.2 328 ##STR00408## 381.2052 382.2 329 ##STR00409## 467.2784 468.2 330 ##STR00410## 499.2835 500.2 331 ##STR00411## 500.2787 501.2 332 ##STR00412## 410.2318 411.1 333 ##STR00413## 394.2369 395.3 334 ##STR00414## 394.2369 395.3 335 ##STR00415## 408.2525 409.1 336 ##STR00416## 383.1957

[0156] In certain embodiments, a provided compound inhibits PRMT5. In certain embodiments, a provided compound inhibits wild-type PRMT5. In certain embodiments, a provided compound inhibits a mutant PRMT5. In certain embodiments, a provided compound inhibits PRMT5, e.g., as measured in an assay described herein. In certain embodiments, the PRMT5 is from a human. In certain embodiments, a provided compound inhibits PRMT5 at an IC.sub.50 less than or equal to 10 .mu.M. In certain embodiments, a provided compound inhibits PRMT5 at an IC.sub.50 less than or equal to 1 .mu.M. In certain embodiments, a provided compound inhibits PRMT5 at an IC.sub.50 less than or equal to 0.1 .mu.M. In certain embodiments, a provided compound inhibits PRMT5 in a cell at an EC.sub.50 less than or equal to 10 .mu.M. In certain embodiments, a provided compound inhibits PRMT5 in a cell at an EC.sub.50 less than or equal to 1 .mu.M. In certain embodiments, a provided compound inhibits PRMT5 in a cell at an EC.sub.50 less than or equal to 0.1 .mu.M. In certain embodiments, a provided compound inhibits cell proliferation at an EC.sub.50 less than or equal to 10 .mu.M. In certain embodiments, a provided compound inhibits cell proliferation at an EC.sub.50 less than or equal to 1 .mu.M. In certain embodiments, a provided compound inhibits cell proliferation at an EC so less than or equal to 0.1 .mu.M. In some embodiments, a provided compound is selective for PRMT5 over other methyltransferases. In certain embodiments, a provided compound is at least about 10-fold selective, at least about 20-fold selective, at least about 30-fold selective, at least about 40-fold selective, at least about 50-fold selective, at least about 60-fold selective, at least about 70-fold selective, at least about 80-fold selective, at least about 90-fold selective, or at least about 100-fold selective for PRMT5 relative to one or more other methyltransferases.

[0157] It will be understood by one of ordinary skill in the art that the PRMT5 can be wild-type PRMT5, or any mutant or variant of PRMT5.

[0158] In certain embodiments, the PRMT5 is isoform A (GenBank accession no NP006100) (SEQ ID NO.: 1):

TABLE-US-00002 MAAMAVGGAG GSRVSSGRDL NCVPEIADTL GAVAKQGFDF LCMPVFHPRF KREFIQEPAK NRPGPQTRSD LLLSGRDWNT LTVGKLSPWI RPDSKVEKIR RNSFAAMLQE LNFGAYLGLP AFLLPLNQED NTNLARVLTN HIHTGHHSSM FWMRVPLVAP EDLRDDIIEN APTTHTEEYS GEEKTWMWWH NFRTLCDYSK RIAVALEIGA DLPSNHVIDR WLGEPIKAAI LPTSIFLTNK KGFPVLSKMH QRLIFRLLKL EVQFIITGTN HHSEKEFCSY LQYLEYLSQN RPPPNAYELF AKGYEDYLQS PLQPLMDNLE SQTYEVFEKD PIKYSQYQQA IYKCLLDRVP EEEKDTNVQV LMVLGAGRGP LVNASLRAAK QADRRIKLYA VEKNPNAVVT LENWQFEEWG SQVTVVSSDM REWVAPEKAD IIVSELLGSF ADNELSPECL DGAQHFLKDD GVSIPGEYTS FLAPISSSKL YNEVRACREK DRDPEAQFEM PYVVRLHNFH QLSAPQPCFT FSHPNRDPMI DNNRYCTLEF PVEVNTVLHG FAGYFETVLY QDITLSIRPE THSPGMFSWF PILFPIKQPI TVREGQTICV RFWRCSNSKK VWYEWAVTAP VCSAIHNPTG RSYTIGL

[0159] In certain embodiments, the PRMT5 is isoform B (GenBank accession no. NP001034708) (SEQ ID NO.:2)

TABLE-US-00003 MRGPNSGTEK GRLVIPEKQG FDFLCMPVFH PRFKREFIQE PAKNRPGPQT RSDLLLSGRD WNTLIVGKLS PWIRPDSKVE KIRRNSEAAM LQELNFGAYL GLPAFLLPLN QEDNTNLARV LTNHIHTGHH SSMFWMRVPL VAPEDLRDDI IENAPTTHTE EYSGEEKTWM WWHNFRTLCD YSKRIAVALE IGADLPSNHV IDRWLGEPIK AAILPTSIFL TNKKGFPVLS KMHQRLIFRL LKLEVQFIIT GTNHHSEKEF CSYLQYLEYL SQNRPPPNAY ELFAKGYEDY LQSPLQPLMD NLESQTYEVF EKDPIKYSQY QQAIYKCLLD RVPEEEKDTN VQVLMVLGAG RGPLVNASLR AAKQADRRIK LYAVEKNPNA VVTLENWQFE EWGSQVTVVS SDMREWVAPE KADIIVSELL GSFADNELSP ECLDGAQHFL KDDGVSIPGE YTSFLAPISS SNLYNEVRAC REKDRDPEAQ FEMPYVVRLH NFHQLSAPQP CFTFSHPNRD PMIDNNRYCT LEFPVEVNTV LHGFAGYFET VLYQDITLSI RPETHSPGMF SWFPILFPIK QPITVREGQT ICVRFWRCSN SKKVWYEWAV TAPVCSAIHN PTGRSYTIGL

[0160] In certain embodiments, the PRMT5 is transcript variant 1 (GenBank accession no. NM_006109).

[0161] The present disclosure provides pharmaceutical compositions comprising a compound described herein, e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein, and optionally a pharmaceutically acceptable excipient. It will be understood by one of ordinary skill in the art that the compounds described herein, or salts thereof, may be present in various forms, such as amorphous, hydrates, solvates, or polymorphs. In certain embodiments, a provided composition comprises two or more compounds described herein. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is an amount effective for inhibiting PRMT5. In certain embodiments, the effective amount is an amount effective for treating a PRMT5-mediated disorder. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective to prevent a PRMT5-mediated disorder.

[0162] Pharmaceutically acceptable excipients include any and all solvents, diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. General considerations in formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0163] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing a compound described herein (the "active ingredient") into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.

[0164] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0165] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the present disclosure will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0166] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0167] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0168] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0169] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60], sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor.TM.), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0170] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[0171] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

[0172] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0173] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0174] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0175] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0176] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.

[0177] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0178] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0179] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0180] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the compounds described herein are mixed with solubilizing agents such as Cremophor.TM., alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0181] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0182] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0183] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0184] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0185] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.

[0186] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0187] The active ingredient can be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

[0188] Dosage forms for topical and/or transdermal administration of a provided compound may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any desired preservatives and/or buffers as can be required. Additionally, the present disclosure encompasses the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[0189] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Pat. Nos. 4,886,499, 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. Pat. Nos. 5,480,381, 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851, 5,893,397; 5,466,220; 5,339,163, 5,312,335; 5,503,627; 5,064,413, 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460, and PCT publications WO 97/37705 and WO 97/13537. Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration.

[0190] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions. Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0191] A provided pharmaceutical composition can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0192] Low boiling propellants generally include liquid propellants having a boiling point of below 65.degree. F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0193] Pharmaceutical compositions formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0194] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0195] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A provided pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0196] A provided pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this disclosure.

[0197] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0198] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of provided compositions will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed, the specific composition employed; the age, body weight, general health, sex and diet of the subject, the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0199] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0200] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0201] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0202] In certain embodiments, a compound described herein may be administered at dosage levels sufficient to deliver from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0203] In some embodiments, a compound described herein is administered one or more times per day, for multiple days. In some embodiments, the dosing regimen is continued for days, weeks, months, or years.

[0204] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0205] It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional therapeutically active agents. In certain embodiments, a compound or composition provided herein is administered in combination with one or more additional therapeutically active agents that improve its bioavailability, reduce and/or modify its metabolism, inhibit its excretion, and/or modify its distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.

[0206] The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents. In certain embodiments, the additional therapeutically active agent is a compound of Formula (I). In certain embodiments, the additional therapeutically active agent is not a compound of Formula (I). In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In will further be appreciated that the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of a provided compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved. In general, it is expected that additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0207] Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds (e.g., compounds approved by the U S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0208] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a provided pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a provided pharmaceutical composition or compound. In some embodiments, a provided pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form. In some embodiments, a provided kits further includes instructions for use.

[0209] Compounds and compositions described herein are generally useful for the inhibition of PRMT5. In some embodiments, methods of treating PRMT5-mediated disorder in a subject are provided which comprise administering an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof), to a subject in need of treatment. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the subject is suffering from a PRMT5-mediated disorder. In certain embodiments, the subject is susceptible to a PRMT5-mediated disorder.

[0210] As used herein, the term "PRMT5-mediated disorder" means any disease, disorder, or other pathological condition in which PRMT5 is known to play a role. Accordingly, in some embodiments, the present disclosure relates to treating or lessening the severity of one or more diseases in which PRMT5 is known to play a role.

[0211] In some embodiments, the present disclosure provides a method of inhibiting PRMT5 comprising contacting PRMT5 with an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof. The PRMT5 may be purified or crude, and may be present in a cell, tissue, or subject. Thus, such methods encompass both inhibition of in vitro and in vivo PRMT5 activity. In certain embodiments, the method is an in vitro method, e.g., such as an assay method. It will be understood by one of ordinary skill in the art that inhibition of PRMT5 does not necessarily require that all of the PRMT5 be occupied by an inhibitor at once. Exemplary levels of inhibition of PRMT5 include at least 10% inhibition, about 10% to about 25% inhibition, about 25% to about 50% inhibition, about 50% to about 75% inhibition, at least 50% inhibition, at least 75% inhibition, about 80% inhibition, about 90% inhibition, and greater than 90% inhibition.

[0212] In some embodiments, provided is a method of inhibiting PRMT5 activity in a subject in need thereof comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0213] In certain embodiments, provided is a method of altering gene expression in a cell which comprises contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the cell in culture in vitro. In certain embodiments, the cell is in an animal, e.g., a human. In certain embodiments, the cell is in a subject in need of treatment.

[0214] In certain embodiments, provided is a method of altering transcription in a cell which comprises contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the cell in culture in vitro. In certain embodiments, the cell is in an animal, e.g, a human. In certain embodiments, the cell is in a subject in need of treatment.

[0215] In certain embodiments, a method is provided of selecting a therapy for a subject having a disease associated with PRMT5-mediated disorder or mutation comprising the steps of determining the presence of PRMT5-mediated disorder or gene mutation in the PRMT5 gene or and selecting, based on the presence of PRMT5-mediated disorder a gene mutation in the PRMT5 gene a therapy that includes the administration of a provided compound. In certain embodiments, the disease is cancer.

[0216] In certain embodiments, a method of treatment is provided for a subject in need thereof comprising the steps of determining the presence of PRMT5-mediated disorder or a gene mutation in the PRMT5 gene and treating the subject in need thereof, based on the presence of a PRMT5-mediated disorder or gene mutation in the PRMT5 gene with a therapy that includes the administration of a provided compound. In certain embodiments, the subject is a cancer patient.

[0217] In some embodiments, a provided compound is useful in treating a proliferative disorder, such as cancer, a benign neoplasm, an autoimmune disease, or an inflammatory disease.

[0218] For example, while not being bound to any particular mechanism, PRMT5 has been shown to be involved in cyclin D1 dysregulated cancers. Increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth including CUL4 repression, CDT1 overexpression, and DNA re-replication. Further, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity (Aggarwal et al., Cancer Cell. 2010 18(4):329-40). Additionally, PRMT5 has also been implicated in accelerating cell cycle progression through G1 phase and modulating regulators of G1; for example, PRMT5 may upregulate cyclin-dependent kinase (CDK) 4, CDK6, and cyclins D1, D2 and E1. Moreover, PRMT5 may activate phosphoinositide 3-kinase (PI3K)/AKT signaling (Wei et al., Cancer Sci. 2012 103(9): 1640-50). Thus in some embodiments, the inhibition of PRMT5 by a provided compound is useful in treating the following non-limiting list of cancers: breast cancer, esophageal cancer, bladder cancer, lung cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectum adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumors, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[0219] In some embodiments, the inhibition of PRMT5 by a provided compound is useful in treating prostate cancer and lung cancer, in which PRMT5 has been shown to play a role (Gu et al, PLoS One 2012; 7(8):e44033; Gu et al., Biochem. J. (2012) 446 (235-241)). In some embodiments, a provided compound is useful to delay the onset of, slow the progression of, or ameliorate the symptoms of cancer. In some embodiments, a provided compound is administered in combination with other compounds, drugs, or therapeutics to treat cancer.

[0220] In some embodiments, compounds described herein are useful for treating a cancer including, but not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenstrom's macroglobulinemia"), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g, alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's disease of the vulva).

[0221] In some embodiments, a provided compound is useful in treating a metabolic disorder, such as diabetes or obesity. For example, while not being bound to any particular mechanism, a role for PRMT5 has been recognized in adipogenesis. Inhibition of PRMT5 expression in multiple cell culture models for adipogenesis prevented the activation of adipogenic genes, while overexpression of PRMT5 enhanced adipogenic gene expression and differentiation (LeBlanc et al., Mol Endocrinol. 2012 April; 26(4):583-97). Additionally, it has been shown that adipogenesis plays a pivotal role in the etiology and progression of diabetes and obesity (Camp et al., Trends Mol Med. 2002 September; 8(9):442-7). Thus in some embodiments, the inhibition of PRMT5 by a provided compound is useful in treating diabetes and/or obesity.

[0222] In some embodiments, a provided compound is useful to delay the onset of, slow the progression of, or ameliorate the symptoms of, diabetes. In some embodiments, the diabetes is Type 1 diabetes. In some embodiments, the diabetes is Type 2 diabetes. In some embodiments, a provided compound is useful to delay the onset of, slow the progression of, or ameliorate the symptoms of, obesity. In some embodiments, a provided compound is useful to make a subject lose weight. In some embodiments, a provided compound could be used in combination with other compounds, drugs, or therapeutics, such as metformin and insulin, to treat diabetes and/or obesity.

[0223] In some embodiments, a provided compound is useful in treating a blood disorder, e.g., a hemoglobinopathy, such as sickle cell disease or .beta.-thalassemia. For example, while not being bound to any particular mechanism, PRMT5 is a known repressor of .gamma.-globin gene expression, and increased fetal .gamma.-globin (HbF) levels in adulthood are associated with symptomatic amelioration in sickle cell disease and .beta.-thalassemia (Xu et al., Haematologica. 2012 November; 97(11) 1632-40). Thus in some embodiments, the inhibition of PRMT5 by a provided compound is useful in treating a blood disorder, such as a hemoglobinopathy such as sickle cell disease or .beta.-thalassemia.

[0224] In some embodiments, a provided compound is useful to delay the onset of, slow the progression of, or ameliorate the symptoms of, sickle cell disease. In some embodiments, a provided compound is useful to delay the onset of, slow the progression of, or ameliorate the symptoms of, .beta.-thalassemia. In some embodiments, a provided compound could be used in combination with other compounds, drugs, or therapeutics, to treat a hemoglobinopathy such as sickle cell disease or .beta.-thalassemia.

[0225] In some embodiments, compounds described herein can prepared using methods shown in general Scheme 1. Compound B can be prepared via ring opening of a chiral or racemic epoxide group. This amino alcohol intermediate can be coupled to form an amide via normal amide coupling methodology using a carboxylic acid A wherein Z is hydrogen or via animation of an ester of intermediate A when Z is an optionally substituted aliphatic group.

##STR00417##

[0226] Analogous reactions may be performed to form a carbamate or urea bond using methods known to one of ordinary skill in the art.

[0227] In some embodiments, such couplings can be used to provide a key intermediate for further synthesis, as shown, for example, in exemplary Scheme 2.

##STR00418##

[0228] In other embodiments, an amide coupling step is the final synthetic step as shown in exemplary Scheme 3.

##STR00419##

Examples

[0229] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

Synthetic Methods

Compound 1

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyridin-2-yl)be- nzamide

##STR00420##

[0230] Step 1: Methyl 3-(pyridin-2-yl)benzoate

##STR00421##

[0232] A mixture of (3-(methoxycarbonyl)phenyl)boronic acid (500 mg, 2.78 mmol), 2-bromopyridine (399 mg, 2.53 mmol), K.sub.2CO.sub.3 (1.0 g, 7.6 mmol) and Pd(dppf)Cl.sub.2 (20 mg) in a mixture solution of dioxane (10 mL) and H.sub.2O (2.5 mL) was stirred at 120.degree. C. for 30 min under microwave heating. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography to give the desired product (530 mg, Yield. 90%) and this was used directly in the next step. LCMS (m/z): 214.1.

Step 2: 3-(pyridin-2-yl)benzoic Acid

##STR00422##

[0234] To a solution of methyl 3-(pyridin-2-yl)benzoate (300 mg, 1.40 mmol) in MeOH (3 mL) was added aqueous NaOH (1 mL, 0.4M). The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated and the residue dissolved in water and adjust pH to 5.about.6 with 2N of HCl. The solution was extracted with EtOAc (3.times.20 mL) and the combined organic layers concentrated to give the desired crude product (450 mg, Yield 90%) which was used in the next step without further purification. LCMS (m/z): 200.1 (M+1).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyridin- -2-yl)benzamide

##STR00423##

[0236] To a solution of 3-(pyridin-2-yl)benzoic acid (200 mg, 1.00 mmol) in DCM (6 mL) was added EDCI (383 mg, 2.00 mmol), HOBt (270 mg, 2 mmol), Et.sub.3N (303 mg, 3 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (206 mg, 1.00 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3.times.10 mL). The combined organic layers were then dried and concentrated. The residue was purified by Prep-HPLC to give the product as the formate salt (70 mg, Yield 18%) .sup.1H NMR (400 MHz, MeOD): 8.64 (d, J=4.8 Hz, 1H), 8.46 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.93-7.90 (m. 3H), 7.60 (dd, >8.0 Hz, 1H), 7.40-7.37 (m, 1H), 7.26-7.14 (m, 4H), 4.44 (s, 2H), 4.38 (br.s, 1H), 3.57-3.56 (m, 4H), 3.36-3.16 (m, 4H). LCMS (m/z): 388.2 (M+1).

Compound 2

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(1-methyl-1H-pyr- azol-5-yl)benzamide

##STR00424##

[0237] Step 1: methyl 3-(1-methyl-1H-pyrazol-5-yl)benzoate

##STR00425##

[0239] A mixture of (3-(methoxycarbonyl)phenyl)boronic acid (270 mg, 1.5 mmol), 5-bromo-1-methyl-1H-pyrazole (200 mg, 1.25 mmol), K.sub.2CO.sub.3 (518 mg, 3.75 mmol) and Pd(dppf)C.sub.1-2 (10 mg) in a mixture solution of dioxane (8 mL) and H.sub.2O (2 mL) was stirred at 120.degree. C. for 30 min under microwave heating. The catalyst was filtered and the filtrate concentrated. The residue was then purified by column chromatography to give provide the desired product as a colorless oil (226 mg, Yield 60%). It was used directly in the next step. LCMS (m/z): 217.1.

Step 2: 3-(1-methyl-1H-pyrazol-5-yl)benzoic Acid

##STR00426##

[0241] To a solution of methyl 3-(1-methyl-1H-pyrazol-5-yl)benzoate (200 mg, 0.93 mmol) in MeOH (3 mL) was added aqueous NaOH (1 mL, 0.4M). The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated and the residue was dissolved in water and adjusted pH to 5.about.6 with 2N of HCl. The solution was extracted with EtOAc (2.times.20 mL). The combined organic layers were dried and concentrated to give the target crude product which was used directly in the next step. LCMS (m/z): 203.1 (M+1).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(1-methy- l-1H-pyrazol-5-yl)benzamide

##STR00427##

[0243] To a solution of 3-(1-methyl-1H-pyrazol-5-yl)benzoic acid (130 mg, 0.64 mmol) in DCM (6 mL) was added EDCI (245 mg, 1.28 mmol), HOBt (173 mg, 1.28 mmol), Et.sub.3N (195 mg, 1.93 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (132 mg, 0.64 mmol). The mixture was stirred at room temperature for 16 h until completion of the reaction was indicated by which TLC. The reaction solution was then diluted with water (10 mL) and extracted with DCM (2.times.10 mL) then the combined organic layers were concentrated. The residue was purified by prep-HPLC to give the desired product (60 mg, Yield 25%). .sup.1H NMR (400 MHz, MeOD): 7.55 (s, 1H), 7.52 (s, 1H), 7.24-7.15 (m, 3H), 6.85-6.73 (m, 4H), 6.03 (s, 1H), 4.22 (br.s, 1H), 4.03-3.99 (m, 1H), 3.45 (s, 3H), 3.17-2.73 (m, 7H). LCMS (m/z): 391.2 (M+1).

Compound 3

(S)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide

##STR00428##

[0244] Step 1: (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

##STR00429##

[0246] To a solution of 1,2,3,4-tetrahydroisoquinoline (1 g, 7.52 mmol) in MeOH (40 mL) was added K.sub.2CO.sub.3 (5.19 g, 37.6 mmol) under 0.degree. C. After stirring for 30 minutes, (R)-2-(chloromethyl) oxirane (0.692 g, 7.52 mmol) was added the reaction. The mixture was then stirred at 0.degree. C. overnight before filtration and washing of the solid by with MeOH. The solution was concentrated and the residue purified by column separation to give the title compound as a colorless oil (70% purity). This crude was used directly in the next step. LCMS (m/z): 190.1 (M+1).

Step 2: (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol

##STR00430##

[0248] To a solution of (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (200 mg, 5.2 mmol) in EtOH (20 mL) was added NH.sub.4OH (600 mg, 35.2 mmol) at -78.degree. C. The reaction mixture was then warmed and heated at 100.degree. C. for 3 h in a seal tube. The reaction mixture was concentrated and the crude product was used in next step without further purification. LCMS (m/z): 207.1 (M+1).

Step 3: (S)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzam- ide

##STR00431##

[0250] A solution of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 0.97 mmol), benzoic acid (122.5 mg, 1.07 mmol), HATU (387.6 mg, 1.02 mmol) and TEA (196.1 mg, 1.94 mmol) in DCM (20 mL) was stirred at room temperature for 2 h until completion of the reaction. The reaction mixture was then diluted with water and extracted with DCM (20 ml.times.2). The combined organic layers were dried and concentrated with the residue purified by pre-HPLC and SFC separation to give the desired compound (55 mg, Yield 18%). .sup.1H NMR (400 MHz, MeOD): 7.66 (d, J=8.0 Hz, 2H), 7.36-7.34 (m, 1H), 7.26 (d, J=7.6 Hz, 2H), 6.99-6.89 (m, 4H), 4.01-3.96 (m, 1H), 3.61 (s, 2H), 3.43-3.37 (m, 2H), 2.77-2.72 (m, 4H), 2.56-2.53 (m, 2H). LCMS (m/z): 311.1 (M+1).

Compound 8

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyridin-3-yl)be- nzamide

##STR00432##

[0251] Step 1: methyl 3-(pyridin-3-yl)benzoate

##STR00433##

[0253] A mixture of (3-(methoxycarbonyl)phenyl)boronic acid (600 mg, 3.33 mmol), 3-bromopyridine (479 mg, 3.0 mmol), K.sub.2CO.sub.3 (1.2 g, 9.0 mmol) and Pd(dppf)C.sub.1-2 (50 mg) in a solution of dioxane (10 mL) and H.sub.2O (2.5 mL) was stirred at 120.degree. C. for 30 minutes with microwave heating under N.sub.2. The catalyst was then filtered and the filtrate concentrated. The residue was then purified by column chromatography to give the desired product and used directly in the next step. (630 mg, Yield 90%).

Step 2: 3-(pyridin-3-yl)benzoic acid

##STR00434##

[0255] To a solution of methyl 3-(pyridin-3-yl)benzoate (450 mg, 2.1 mmol) in MeOH (5 mL) was added aqueous of NaOH (1.5 mL, 0.4M). The mixture was stirred at room temperature for 2 h then reaction solution was concentrated and the resulting residue dissolved in water and adjusted pH to 5-6 with 2N HCl. Extracted was then performed using EtOAc with the organic layer dired and concentrated to give the target product which was used without further purification (600 mg, Yield 90%). LCMS (m/z): 200.1 (M+1).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyridin- -3-yl)benzamide

##STR00435##

[0257] To a solution of 3-(pyridin-3-yl)benzoic acid (150 mg, 0.75 mmol) in DCM (6 mL) was added EDCI (215 mg, 1.10 mmol), HOBt (148 mg, 1.10 mmol), Et.sub.3N (228 mg, 2.25 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (185 mg, 0.90 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was then washed with water and extracted with DCM. The organic layer was concentrated, dried and the residue purified by prep-HPLC to give the desired title product (110 mg, Yield 34%). .sup.1H NMR (400 MHz, MeOD) .delta. 8.80 (d, J=2.0 Hz, 1H), 8.52 (dd, J=4.8 Hz, >=3.6 Hz, 1H), 8.10 (s, 1H), 8.09 (dd, J=8.8 Hz, J.sub.2=1.6 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 1.11 (d, J=7.6 Hz, 1H), 7.51-7.46 (m, 2H), 7.06-6.95 (m, 4H), 4.15-4.10 (m, 1H), 3.69 (s, 2H), 3.60-3.47 (m, 2H), 2.85-2.79 (m, 4H), 2.69-2.59 (m, 2H) LCMS (m/z): 388.2 (M+1).

Compound 9

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyridin-4-yl)be- nzamide

##STR00436##

[0258] Step 1: Methyl 3-(pyridin-4-yl)benzoate

##STR00437##

[0260] A mixture of (3-(methoxycarbonyl)phenyl)boronic acid (600 mg, 3.33 mmol), 4-bromopyridine (583.5 mg, 3.0 mmol), K.sub.2CO.sub.3 (1.2 g, 9.0 mmol) and Pd(dppf)Cl.sub.2 (50 mg) in a solution of dioxane (10 mL) and H.sub.2O (2.5 mL) was stirred at 120.degree. C. for 30 min with microwave heating. The catalyst was filtered and the filtrate concentrated. The residue was then purified by column chromatography to give the title product (630 mg, Yield 90%).

Step 2: 3-(pyridin-4-yl)benzoic Acid

##STR00438##

[0262] To a solution of methyl 3-(pyridin-4-yl)benzoate (450 mg, 2.1 mmol) in MeOH (5 mL) was added an aqueous solution of NaOH (1.5 mL, 0.4M). The mixture was stirred at room temperature for 2 h. The reaction solution was then concentrated, the residue was next dissolved in water and adjusted pH to 5-6 with the 2N HCl. After extraction with EtOAc, the organic layers were dried and concentrated to give the product desired (600 mg, Yield 90%). LCMS (m/z): 200.1 (M+1).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyridin- -4-yl)benzamide

##STR00439##

[0264] To a solution of 3-(pyridin-4-yl)benzoic acid (300 mg, 1.5 mmol) in DCM (6 mL) was added EDCI (430 mg, 2.20 mmol), HOBt (296 mg, 2.20 mmol), Et.sub.3N (556 mg, 4.50 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (370 mg, 1.80 mmol). The mixture was stirred at room temperature for 16 h, then the reaction mixture was washed with water and extracted with DCM. The organic layer was then dried, concentrated and the residue purified by prep-HPLC to give the title product (230 mg, Yield 40%). .sup.1H NMR (400 MHz, MeOD) .delta. 8.54 (d, J=4.0 Hz, 2H), 8.16 (s, 1H), 7.85-7.80 (m, 2H), 7.64 (dd 7=4.0 Hz, 2H), 7.48 (dd, J=7.6 Hz, 1H), 7.03-6.95 (m, 4H), 4.13 (br.s, 1H), 3.66 (s, 2H), 3.60-3.48 (m, 2H), 2.80-2.77 (m, 4H), 2.63-2.59 (m, 2H). LCMS (m/z); 388.2 (M+1).

Compound 11

(R)-phenyl (3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamate

##STR00440##

[0265] Step 1: (S)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

##STR00441##

[0267] To a solution of 1,2,3,4-tetrahydroisoquinoline (5 g, 7.52 mmol) in THF (100 mL) was added KF (8.57 g, 150.4 mmol) at 0.degree. C. (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (10.7 g, 41.4 mmol) was added to the reaction in 1 h. The solution was stirred at room temperature overnight. The solid was removed by filtration and washed with THF. The solution was then concentrated and the residue used for next step without further purification (11.3 g Yield 80%). LCMS (m/z): 190.1 (M+1).

Step 2: (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol

##STR00442##

[0269] To a solution of (S)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (2.2 g, 0.012 mol) in EtOH (30 mL), NH.sub.3 was bubbled to the solution under -78.degree. C. The reaction mixture was then sealed and heated at 80.degree. C. for 3 h. After LCMS indicated completion of the reaction, the mixture was concentrated and the crude product was used in next step without further purification (2.2 g, Yield 90%). LCMS (m/z): 207.1 (M+1).

Step 3: (R)-phenyl (3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamate

##STR00443##

[0271] To the stirring solution of (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 0.97 mmol) in 15 mL dry DCM was added TEA (1 mL) and the solution was cooled to 0.degree. C. Phenyl carbonochloridate (151.3 mg, 1.02 mmol) in DCM (10 mL) was then added drop wise to the reaction over 20 minutes and the solution was then stirred at room temperature overnight. The solution was then diluted with water, extracted with DCM, the organic layer was concentrated, purified by pre-HPLC to give the product as formate salt (125 mg, Yield 40%). .sup.1H NMR (400 MHz, MeOD) .delta. 7.35 (dd, J=7.6 Hz, 2H), 7.31-7.18 (m, 5H), 7.08 (d, J=7.6 Hz, 2H), 4.33 (s, 2H), 4.22-4.19 (m, 1H), 3.48 (t, J=6.0 Hz, 2H), 3.27-3.10 (m, 6H). LCMS (m/z): 327.2 (M+1).

Compound 12

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(pyridin-2-yl)be- nzamide

##STR00444##

[0272] Step 1: 2-(pyridin-2-yl)benzoic Acid

##STR00445##

[0274] A mixture of 2-boronobenzoic acid (400 mg, 2.4 mmol), 2-bromopyridine (416 mg, 2.6 mmol), K.sub.2CO.sub.3 (994 mg, 7.2 mmol) and Pd(dppf)C.sub.1-2 (20 mg) in dioxane (8 mL) and H.sub.2O (2 mL) was stirred at 125.degree. C. for 30 min. under microwave heating under N.sub.2. The catalyst was filtered, and the filtrate was acidified with 2N HCl to pH 5.about.6 The solution was concentrated, and the residue was dissolved in MeOH and filtered. The filtrate was concentrated, and the residue was purified by prep-TLC to give the title compound (205 mg, Yield 42.9%). LCMS (m/z): 200.0 (M+1).

Step 2: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(pyridin- -2-yl) Benzamide

##STR00446##

[0276] To a solution of 2-(pyridin-2-yl)benzoic acid (150 mg, 0.75 mmol) in DCM (6 mL) was added EDCI (215 mg, 1.1 mmol), HOBt (148 mg, 1.1 mmol), Et3N (228 mg, 2.25 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (185 mg, 0.9 mmol). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was then concentrated, and the residue was purified by prep-HPLC to give the title compound (80 mg, Yield 27.5%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.60-8.53 (m, 1H), 7.89-7.81 (m, 1H), 7.63-7.51 (m, 4H), 7.48-7.43 (m, 1H), 7.39-7.32 (m, 1H), 7.12-7.05 (m, 3H), 7.05-6.98 (m, 1H), 4.05-3.93 (m, 1H), 3.73-3.63 (s, 2H), 3.46-3.37 (m, 1H), 3.31-3.23 (m, 1H), 2.92-2.75 (m, 4H), 2.56 (s, 2H). LCMS (m/z): 388.2 (M+1).

Compound 13

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4-(pyridin-2-yl)be- nzamide

##STR00447##

[0277] Step 1: 4-(pyridin-2-yl)benzoic Acid

##STR00448##

[0279] A mixture of 4-boronobenzoic acid (200 mg, 1.2 mmol), 2-bromopyridine (208 mg, 1.3 mmol), K.sub.2CO.sub.3 (497 mg, 3.6 mmol) and Pd(dppf)C.sub.1-2 (10 mg) in dioxane (4 mL) and H.sub.2O (1 mL) was stirred at 125.degree. C. for 30 min with microwave heating under N.sub.2. The catalyst was filtered, and the filtrate was acidified with 2N HCl to pH 5.about.6. The solution was concentrated, and the residue was dissolved in MeOH and filtered. The filtrate was concentrated, and the residue was purified by prep-TLC to give the title compound (100 mg, Yield 41.8%). LCMS (m/z): 200.1 (M+1).

Step 2: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4-(pyridin- -2-yl)benzamide

##STR00449##

[0281] To a solution of 4-(pyridin-2-yl)benzoic acid (100 mg, 0.5 mmol) in DCM (5 mL) was added EDCI (144 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), Et.sub.3N (152 mg, 1.5 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (103 mg, 0.5 mmol). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (30 mg, Yield 15.5%) .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.70-8.60 (m, 1H), 8.01-7.84 (m, 6H), 7.45-7.36 (m, 1H), 7.16-6.99 (m, 4H), 4.20-4.10 (m, 1H), 3.79 (s, 2H), 3.62-3.46 (m, 2H), 2.92 (s, 4H), 2.78-2.65 (m, 2H). LCMS (m/z): 388.2 (M+1).

Compound 14

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-morpholinobenzam- ide

##STR00450##

[0282] Step 1: 3-bromo-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) Benzamide

##STR00451##

[0284] To a solution of 3-bromobenzoic acid (200 mg, 1.0 mmol) in DCM (8 mL) was added Et.sub.3N (303 mg, 3.0 mmol), EDCI (383 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (247 mg, 1.2 mmol). The mixture was stirred at 25.degree. C. for 6 h. The mixture was treated with water and extracted with EA. The organic layer was washed with NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and concentrated to give the title compound which was used in next step without further purification (300 mg, Yield 77%). LCMS (m/z): 390.1 (M+1).

Step 2: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-morpholi- no Benzamide

##STR00452##

[0286] A mixture of 3-bromo-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) benzamide (200 mg, 0.51 mmol), morpholine (44 mg, 0.51 mmol), Pd.sub.2(dba).sub.3 (46 mg, 0.05 mmol), BINAP (62 mg, 0.1 mmol) and NaOtBu (73 mg, 0.77 mmol) in toluene (6 mL) was stirred at reflux for 16 h under N.sub.2. The reaction solution was concentrated, and the residue was dissolved in EA and filtered. The filtrate was concentrated, and the residue was purified by prep-HPLC to give the title compound (15 mg, Yield 7.5%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.48 (brs, 1H), 7.42 (s, 1H), 7.37-7.28 (m, 2H), 7.27-7.19 (m, 3H), 7.18-711 (m, 2H), 4.31-4.23 (m, 1H), 4.19 (s, 2H), 3.86 (dd, 0.7=5.1, 4.8 Hz, 4H), 3.61-3.44 (m, 2H), 3.32-3.29 (m, 2H), 3.25-3.16 (m, 4H), 3.14-2.97 (m, 4H). LCMS (m/z): 396.2 (M+1).

Compound 15

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(((tetrahydro-2H- -pyran-4-yl)amino)methyl)benzamide

##STR00453##

[0287] Step 1: methyl 3-(((tetrahydro-2H-pyran-4-yl)amino)methyl)benzoate

##STR00454##

[0289] To a solution of methyl 3-formylbenzoate (492 mg, 3.0 mmol) in MeOH (10 mL) was added tetrahydro-2H-pyran-4-amine (303 mg, 3.0 mmol) and AcOH (0.05 mL). The mixture was stirred at 25.degree. C. for 2 h. NaBH.sub.3CN (945 mg, 15.0 mmol) was added, and the resulting mixture was stirred at 25.degree. C. for 16 h. The reaction solution was concentrated and the residue was dissolved in water and extracted with DCM. The organic layer was concentrated, and the residue was purified by prep-TLC to give the title product (500 mg, Yield 67%). LCMS (m/z): 250.1 (M+1).

Step 2: methyl 3-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)-methyl)benzoate

##STR00455##

[0291] To a solution of methyl 3-(((tetrahydro-2H-pyran-4-yl)amino)methyl)benzoate (400 mg, 1.6 mmol) in a mixture solution of THF (10 mL) and H.sub.2O (1 mL) was added Boc.sub.2O (418 mg, 1.9 mmol) and Et.sub.3N (243 mg, 2.4 mmol). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was concentrated to remove THF, and the residue was dissolved in water and extracted with EA. The organic layer was concentrated, and the residue was purified by column chromatography to give the title product (550 mg, 98%). LCMS (m/z): 350.1 (M+1).

Step 3: 3-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl) Benzoic Acid

##STR00456##

[0293] To a solution of methyl 3-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)benzoate (550 mg, 1.57 mmol) in MeOH (5 mL) was added aqueous of NaOH (2.0 mL, 40% w/w). The mixture was stirred at 25.degree. C. for 4 h. The reaction solution was concentrated, and the residue was dissolved in water and adjusted pH to 5.about.6 with 2N of HCl and extracted with EA. The organic layer was concentrated to give the desired product (300 mg, Yield 57%). LCMS (m/z): 336.1 (M+1).

Step 4: tert-butyl 3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate

##STR00457##

[0295] To a solution of 3-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)benzoic acid (300 mg, 0.89 mmol) in DCM (8 mL) was added EDCI (257 mg, 1.34 mmol), HOBt (181 mg, 1.34 mmol), Et.sub.3N (270 mg, 2.67 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (183 mg, 0.89 mmol). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated to give the title product (350 mg. Yield 65%). LCMS (m/z): 524.3 (M+1).

Step 5: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(((tetra- hydro-2H-pyan-4-yl)amino)methyl)benzamide

##STR00458##

[0297] To a solution of tert-butyl 3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)benzyl(- tetrahydro-2H-pyran-4-yl)carbamate (450 mg, crude) in DCM (6 mL) was added TFA (6 mL). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was concentrated, and the residue was purified by prep-HPLC to give the title product (200 mg, 54.9%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.08 (s, 1H), 8.00-7.89 (m, 1H), 7.81-7.68 (m, 1H), 7.58 (s, 1H), 7.39-7.15 (m, 4H), 4.75-4.47 (m, 2H), 4.46-4.39 (m, 1H), 4.34 (s, 2H), 4.05 (dd, J=11.6, 3.6 Hz, 2H), 3.98-3.70 (brs, 1H), 3.62-3.55 (m, 2H), 3.55-3.45 (m, 4H), 3.45-3.32 (m, 2H), 3.32-3.06 (m, 2H), 2.22-2.07 (m, 2H), 1.89-1.72 (m, 2H). LCMS (m/z): 424.2 (M+1).

Compound 16

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((tetrahydro-2H-- pyran-4-yl)amino)benzamide

##STR00459##

[0298] Step 1: 3-((tert-butoxycarbonyl)amino)benzoic Acid

##STR00460##

[0300] To a solution of 3-aminobenzoic acid (1.37 g, 10 mmol) in a mixture solution of THF (20 mL) and H.sub.2O (2 mL) was added Boc.sub.2O (2.18 g, 10 mmol) and Et.sub.3N (1.52 g, 15 mmol). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was concentrated and the residue was dissolved in water and extracted with EA. The organic layer was concentrated to give the title product (2.3 g, Yield 97%). LCMS (m/z): 260.0 (M+23).

Step 2: tert-butyl (3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)phenyl)carbamate

##STR00461##

[0302] To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (2.5 g, 10.5 mmol) in DCM (25 mL) was added EDCI (3.0 g, 15.7 mmol), HOBt (2.1 g, 15.7 mmol), Et.sub.3N (2.1 g, 21 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (2.2 g, 10.5 mmol). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was washed with water, extracted with DCM and the organic layer was concentrated, and the residue was purified by column chromatography to give the desired product (3.2 g, Yield 71%). LCMS (m/z): 426.3 (M+1).

Step 3: 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) benzamide

##STR00462##

[0304] To a solution of tert-butyl (3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)phenyl- )carbamate (500 mg, 1.18 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was concentrated, and the residue was dissolved in water, pH was adjusted to 7-7.5 with saturated aqueous NaHCO.sub.3 and extracted with EA. The organic layer was concentrated to give the title product (360 mg, Yield 94%). The crude product was used in next step without further purification. LCMS (m/z): 326.2 (M+1).

Step 4: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((tetrah- ydro-2H-pyran-4-yl)amino)benzamide

##STR00463##

[0306] To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (325 mg, 1.0 mmol) in MeOH (10 mL) was added dihydro-2H-pyran-4(3H)-one (88 mg, 1.0 mmol) and AcOH (0.05 mL). The mixture was stirred at 25.degree. C. for 2 h. NaBH.sub.3CN (630 mg, 10.0 mmol) was added, and the resulting mixture was stirred at 25.degree. C. for 16 h. The reaction solution was concentrated, and the residue was dissolved in water, extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (200 mg, Yield 48.9%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.44 (brs, 1H), 7.32-7.20 (m, 3H), 7.20-7.13 (m, 2H), 7.13-7.09 (m, 1H), 7.08-7.00 (m, 1H), 6.86-6.77 (m, 1H), 4.39 (s, 2H), 4.35-4.25 (m, 1H), 4.03-3.89 (m, 2H), 3.63-3.40 (m, 7H), 3.31-3.07 (m, 4H), 2.06-1.92 (m, 2H), 1.55-1.40 (m, 2H). LCMS (m/z): 410.2 (M+1).

Compound 17

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)picolinamide

##STR00464##

[0307] Step 1: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)picolinamide

##STR00465##

[0309] To a solution of picolinic acid (100 mg, 0.81 mmol) in DCM (10 mL), was added EDCI (187 mg, 0.97 mmol) and HOBT (132 mg, 0.98 mmol), which was stirred at 25.degree. C. for 0.5 h before 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (167 mg, 0.81 mmol) was added and the resulting mixture was stirred at 25.degree. C. for 2 h. The solution was concentrated in vacuo and the residue was purified by prep-HPLC to provide the title compound (68 mg, Yield 26.9%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.61 (d, J=3.9 Hz, 1H), 8.49 (brs, 1H), 8.10 (d, J=7.8 Hz, 1H), 8.01-7.92 (m, 1H), 7.56 (dd, J=5.1, 6.8 Hz, 1H), 7.31-7.20 (m, 3H), 7.19-7.13 (m, 1H), 4.44-4.27 (m, 3H), 3.66-3.47 (m, 4H), 3.31-3.12 (m, 4H). LCMS (m/z): 312.1 (M+1).

Compound 21

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4-sulfamoylbenzami- de

##STR00466##

[0310] Step 1: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4-sulfamoylbenzam- ide

##STR00467##

[0312] A solution of 4-sulfamoylbenzoic acid (88.4 mg, 0.44 mmol), HATU (182.4 mg, 0.48 mmol) and TEA (48.48 mg, 0.48 mmol) in DCM (10 mL) was stirred at 22.degree. C. for 10 min. 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (100 mg, 0.48 mmol) was then added and the solution was stirred at 22.degree. C. for another 3 h. The reaction mixture was diluted with water and extracted with DCM. The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (49.5 mg, Yield 29%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.92 (s, 4H), 7.16-7.09 (m, 3H), 7.05-7.02 (m, 1H), 4.14-4.12 (m, 1H), 3.77 (s, 2H), 3.58-3.39 (m, 2H), 2.94-2.91 (m, 2H), 2.90-2.86 (m, 2H), 2.75-2.66 (m, 2H). LCMS (m/z): 390.1 (M+1).

Compound 23

4-acetamido-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzami- de

##STR00468##

[0313] Step 1: 4-acetamido-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzam- ide

##STR00469##

[0314] A solution of 4-acetamidobenzoic acid (100 mg, 0.56 mmol), HATU (234 mg, 0.62 mmol) and TEA (63 mg, 0.62 mmol) in DCM (10 mL) was stirred at 22.degree. C. for 10 min. 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (116 mg, 0.56 mmol) was then added and the solution was stirred at 22.degree. C. for another 3 h. The reaction mixture was then diluted with water and extracted with DCM. The organic layers were combined and dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated and the residue was purified by prep-HPLC to give the title compound (48.5 mg, Yield 24%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.77-7.72 (m, 2H), 7.63-7.57 (m, 2H), 7.17-7.08 (m, 3H), 7.04 (d, J=7.0 Hz, 1H), 4.12 (t, J=6.0 Hz, 1H), 3.75 (s, 2H), 3.58-3.46 (m, 2H), 2.92-2.85 (m, 4H), 2.74-2.63 (m, 2H), 2.16 (s, 3H). LCMS (m/z): 368.1 (M+1).

Compound 28

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(2-(dimethylamin- o)ethoxy)benzamide

##STR00470##

[0315] Step 1: methyl 3-(2-(dimethylamino)ethoxy)benzoate

##STR00471##

[0317] To a stirred mixture of methyl 3-hydroxybenzoate (200 mg, 1.32 mmol), and K.sub.2CO.sub.3 (169 mg, 1.58 mmol) in MeCN (50 mL) was added 2-chloro-N,N-dimethylethanamine (137 mg, 1.58 mmol). The mixture was stirred at 60.degree. C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give the title compound that was used without further purification (300 mg. Yield 98%). .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.61-7.53 (m, 1H), 7.53-7.47 (m, 1H), 7.26-7.23 (m, 1H), 7.06-7.04 (m, 1H), 4.05 (t, J=5.6 Hz, 2H), 3.84 (s, 3H), 2.69 (t, J=5.6 Hz, 2H), 2.28 (s, 6H). LCMS (m/z): 224.2 (M+1).

Step 2: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(2-(dime- thylamino)ethoxy)benzamide

##STR00472##

[0319] A mixture of crude methyl 3-(2-(dimethylamino)ethoxy)benzoate (300 mg, 1.34 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (332 mg, 1.61 mmol) in EtOH (2 mL) was heated at 120.degree. C. in a microwave reactor for 3 h. After evaporation of the solvent, the residue was purified by prep-HPLC to give the title compound (34 mg, Yield 6.4%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.43-7.42 (m, 1H), 7.34-7.29 (m, 2H), 7.12-7.10 (m, 4H), 7.09-7.03 (m, 1H), 4.20-4.10 (m, 3H), 3.75 (brs, 2H), 3.59-3.42 (m, 2H), 2.95-2.85 (m, 4H), 2.82-2.77 (m, 2H), 2.72-2.65 (m, 2H), 2.37 (s, 6H). LCMS (m/z): 398.1 (M+1).

Compound 30

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((4-methylpipera- zin-1-yl)methyl)benzamide

##STR00473##

[0320] Step 1: 3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzoic Acid

##STR00474##

[0322] The solution of 3-formylbenzoic acid (300 mg, 1.83 mmol) and tert-butyl piperazine-1-carboxylate (340 mg, 1.83 mmol) in MeOH (10 mL) was stirred at 27.degree. C. for 1 h. Then NaBH.sub.3CN (138 mg, 2.19 mmol) was added to the solution and stirred at 27.degree. C. for 6 h. The solution was concentrated and the residue was purified by column to give the title product (320 mg, Yield 50%). LCMS (m/z): 321.2 (M+1).

Step 2: tert-butyl 4-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)benzyl)piperazine-1-carboxylate

##STR00475##

[0324] The solution of 3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzoic acid (100 mg, 0.31 mmol) and HATU (119 mg, 0.31 mmol) in DCM (10 mL) was stirred at 28.degree. C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (64.4 mg, 0.31 mmol) and DIPEA (48.4 mg, 0.38 mmol) was added and the resulting solution was stirred at 28.degree. C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give the crude title product (150 mg, Yield 94%). LCMS (m/z): 509.2 (M+1).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(piperaz- in-1-ylmethyl)benzamide

##STR00476##

[0326] The solution of tert-butyl 4-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)benz- yl)piperazine-1-carboxylate (160 mg, 0314 mmol) in DCM (2 mL) and TFA (2 mL) was stirred at 27.degree. C. for 16 h. The solution was concentrated and the residue was purified by prep-HPLC to give the title product (89 mg. Yield 69.0%).sup.LH NMR (D.sub.2O, 400 MHz): .delta. 7.66-7.56 (m, 2H), 7.51-7.44 (m, 1H), 7.44-7.37 (m, 1H), 7.16-7.06 (m, 3H), 7.02 (d, >7.3 Hz, 1H), 4.11 (quin, >5.9 Hz, 1H), 3.73-3.60 (m, 2H), 3.56-3.49 (m, 2H), 3.49-3.42 (m, 1H), 3.41-3.32 (m, 1H), 2.86-2.75 (m, 8H), 2.68-2.58 (m, 2H), 2.56-2.32 (m, 4H). LCMS (m/z); 409.2 (M+1).

Step 4: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((4-meth- yl piperazin-1-yl)methyl)benzamide

##STR00477##

[0328] The solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(piperazin-1-yl- methyl)benzamide (78 mg, 0.19 mmol) and HCHO solution (0.5 mL) in MeOH (10 mL) was stirred at 27.degree. C. for 1 h. Then NaBH.sub.3CN (14.5 mg, 0.23 mmol) was added to the solution and stirred at 27.degree. C. for 4 h. The solution was concentrated and the residue was purified by column chromatography to give the title product (14.1 mg. Yield 17.5%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.79 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.39-7.32 (m, 1H), 7.20-7.07 (m, 3H), 7.06-6.98 (m, 1H), 4.13 (quin, J=6.0 Hz, 1H), 3.75 (s, 2H), 3.63-3.44 (m, 4H), 2.95-2.83 (m, 4H), 2.78-2.62 (m, 3H), 2.62-2.30 (m, 7H), 2.28 (s, 3H). LCMS (m/z): 423.2 (M+1).

Compound 34

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(1-methylpyrroli- din-2-yl) Benzamide

##STR00478##

[0330] To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyrrolidin-2-y- l)benzamide (20 mg, 0.13 mmol) in MeOH (20 mL) was added HCHO (1 mL) and AcOH (0.05 mL). The reaction mixture was stirred at room temperature for 30 min at which time NaBH.sub.3CN (200 mg, 3.22 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and the crude product was purified by prep-HPLC to give the desired product (8.5 mg, Yield 16.8%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.80 (brs, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.35-7.41 (m, 1H), 7.09-7.15 (m, 3H), 7.09-7.15 (m, 1H), 7.02-7.08 (m, 1H), 4.10-4.16 (m, 1H), 3.73-3.81 (m, 2H), 3.49-3.58 (m, 2H), 3.20-3.28 (m, 1H), 3.08-3.16 (m, 1H), 2.84-2.97 (m, 4H), 2.64-2.75 (m, 2H), 2.33-2.40 (m, 1H), 2.20-2.27 (m, 1H), 2.16 (s, 3H), 1.95-2.05 (m, 1H), 1.77-1.93 (m, 2H). LCMS (m/z): 394.1 (M+1).

Compound 35

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(piperazin-1-yl)- benzamide

##STR00479##

[0331] Step 1: 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic Acid

##STR00480##

[0333] The mixture of ethyl 3-bromobenzoate (500 mg, 2.33 mmol), tert-butyl piperazine-1-carboxylate (433 mg, 2.33 mmol) and NaOtBu (268 mg, 2.78 mmol), Pd.sub.2(dba).sub.3 (20 mg, 0.034 mmol) and Xantphos (20 mg, 0,034 mmol) in anhydrous dioxane (10 mL) was heated to 110.degree. C. for 10 h. The mixture was concentrated and the residue was partitioned in water, the solution was adjusted to pH=5, and extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound that was used for next step (300 mg, Yield 42.2%). LCMS (m/z): 307.1 (M+1).

Step 2: tert-butyl 4-(3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl carbamoyl)phenyl)piperazine-1-carboxylate

##STR00481##

[0335] The solution of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (300 mg, 1.0 mmol) and HATU (381 mg, 1.0 mmol) in DCM (10 mL) was stirred at 25.degree. C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 1.0 mmol) and DIPEA (259 mg, 2.00 mmol) was added and the resulting solution was stirred at 25.degree. C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give the title product (140 mg. Yield 28.8%). LCMS (m/z): 495.2 (M+1).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(piperaz- in-1-yl)benzamide

##STR00482##

[0337] To a solution of tert-butyl 4-(3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy propylcarbamoyl)phenyl)piperazine-1-carboxylate (140 mg, 0.28 mmol) in DCM (2 mL) was added TFA (2 mL). The resulting solution was stirred at 27.degree. C. for 4 h. The solution was concentrated and the residue was purified by prep-HPLC to give the title product (64.0 mg, Yield 57%). .sup.1H NMR (CD.sub.3OD, 400 MHZ): .delta. 7.47-7.38 (s, 1H), 7.31-7.21 (m, 2H), 7.19-7.08 (m, 4H), 7.08-7.01 (m, 1H), 4.13 (quin, 6.0 Hz, 1H), 3.77 (s, 2H), 3.62-3.52 (m, 1H), 3.51-3.43 (m, 1H), 3.31-3.19 (m, 4H), 3.15-3.00 (m, 4H), 2.98-2.83 (m, 4H), 2.75-2.62 (m, 2H). LCMS (m/z): 395.2 (M+1).

Compound 38

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(1-methylpyrroli- din-3-yl)benzamide

##STR00483##

[0338] Step 1: tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate

##STR00484##

[0340] A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (5 g 27.0 mmol) in THF (50 ml) was slowly added to a stirring solution of NaHMDS (1M THF, 32.4 ml, 32.4 mmol) at -78.degree. C.

[0341] After 10 min a solution of N-phenyl-O-((trifluoromethyl)sulfonyl)-N-(((trifluoromethyl) sulfonyl)oxy)hydroxylamine (10.6 g, 29.7 mmol) in THF (50 ml) was slowly added. Stirring at -78.degree. C. was continued for 30 min and the cooling bath was removed. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was cooled to 0.degree. C., quenched with sat. NaHCO.sub.3, and extracted with MTBE. The organic layer was washed with 5% citric acid, 1M NaOH, H.sub.2O, brine, dried over Na.sub.2SO.sub.4, concentrated and the residue was purified by flash column chromatography to give the title compound (1.5 g, Yield 17.4%). .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 5.77 (s, 1H), 4.14-4.30 (m, 4H), 1.48 (s, 9H).

Step 2: tert-butyl 3-(3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

##STR00485##

[0343] To a solution of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (300 mg, 0.95 mmol) in dioxane (4 mL) and H.sub.2O (1 mL) was added methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (298 mg, 1.13 mmol), Pd(dppf)C.sub.1-2 (66 mg, 0.09 mmol) and K.sub.2CO.sub.3 (392 mg, 2.84 mmol) at 27.degree. C. The mixture was stirred at 100.degree. C. for 16 h. The catalyst was filtered, the filtrate was concentrated and the residue was purified by column chromatography to give the title compound (213 mg, Yield 74.2%). .sup.1H NMR (CDCl.sub.3, 400 MHz); .delta. 8.03 (d, J=19.6 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.55 (dd, >15.7, 7.8 Hz, 1H), 7.38-7.45 (m, 1H), 6.22 (dt, >16.4, 1.8 Hz, 1H), 4.43-4.58 (m, 2H), 4.24-4.38 (m, 2H), 3.88-3.96 (m, 3H), 1.51 (d, J=7.9 Hz, 9H).

Step 3: tert-butyl 3-(3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate

##STR00486##

[0345] To a solution of tert-butyl 3-(3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (213 mg, 0.7 mmol) in MeOH (10 mL) was added Pd/C (20 mg). The mixture was stirred for 30 min at 30.degree. C. under H.sub.2 atmosphere. The mixture was filtered and the filtrate was concentrated to give the title compound which was used in next step without further purification (210 mg, Yield 98.1%) .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.88-7.97 (m, 2H), 7.36-7.48 (m, 2H), 3.92 (s, 3H), 3.77-3.90 (m, 1H), 3.53-3.72 (m, 1H), 3.25-3.47 (m, 3H), 2.29 (d, J=5.27 Hz, 1H), 2.01 (quin, >10.2 Hz, 1H), 1.42-1.55 (m, 10H).

Step 4: 3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)benzoic Acid

##STR00487##

[0347] To a solution of tert-butyl 3-(3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (210 mg, 0.7 mmol) in EtOH (4 ml) was added a solution of NaOH (56 mg, 1.4 mmol) in H.sub.2O (1 ml) at 29.degree. C. The mixture was stirred for 30 min at 29.degree. C. The mixture was concentrated and the residue was treated with water and extracted with EA. The water layer was treated with 2N HCl until pH=3, extracted with EA and the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the title compound which was used in next step without further purification (200 mg, Yield 98.0%).

Step 5: tert-butyl 3-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl) phenyl)pyrrolidine-1-carboxylate

##STR00488##

[0349] To a solution of 3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)benzoic acid (200 mg, 0.69 mmol) in DMF (4 ml) was added TEA (208 mg, 2.06 mmol), HOBt (139 mg, 1.03 mmol), EDCI (197 mg, 1.03 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (170 mg, 0.82 mmol) at 33.degree. C. The reaction mixture was stirred for 16 h at 31.degree. C. The mixture was treated with water and extracted with EA. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the title compound which was used in next step without further purification (300 mg, Yield 92%).

Step 6: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyrroli- din-3-yl) Benzamide

##STR00489##

[0351] To a solution of tert-butyl 3-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)phenyl)pyrrolidine-1-carboxylate (400 mg, 0.83 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added TFA (1 mL) at 29.degree. C. The mixture was stirred for 2 h at 29.degree. C. The mixture was concentrated and the residue was purified by prep-HPLC to give the title compound (79.1 mg, Yield 25.0%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.75-7.93 (m, 2H), 7.45-7.62 (m, 2H), 7.17-7.37 (m, 4H), 4.45-4.74 (m, 2H), 4.40 (dd, 6.3, 3.3 Hz, 1H), 3.71-4.04 (m, 2H), 3.49-3.70 (m, 5H), 3.35-3.49 (m, 3H), 3.08-3.32 (m, 3H), 2.52 (qd, J=6.6, 4.2 Hz, 1H), 2.09-2.27 (m, 1H). LCMS (m/z): 380.2 (M+1).

Step 7: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(1-methy- lpyrrolidin-3-yl)benzamide

##STR00490##

[0353] To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyrrolidin-3-y- l)benzamide (200 mg, 0.53 mmol) in MeOH (4 ml) was added HCHO (319 mg, 1.05 mmol) and NaBH.sub.3CN (66.1 mg, 1.05 mmol) at 29.degree. C. The mixture was then added AcOH (0.5 ml) at 29.degree. C. and stirred for 16 h. The mixture was purified by prep-HPLC to give the title compound (29.6 mg, Yield 14.3%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.52 (brs, 2H), 7.88 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.53-7.60 (m, 1H), 7.43-7.52 (m, 1H), 7.22-7.33 (m, 3H), 7.15-7.21 (m, 1H), 4.36 (s, 3H), 3.78 (brs, 2H), 3.46-3.67 (m, 6H), 3.41 (brs, 1H), 3.07-3.19 (m, 3H), 3.01 (s, 3H), 2.50-2.64 (m, 1H), 2.19-2.34 (m, 1H). LCMS (m/z): 394.2 (M+1).

Compound 40

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methyl-3-<(te- trahydro-2H-pyran-4-yl)amino)benzamide

##STR00491##

[0354] Step 1: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methyl-3-nitrob- enzamide

##STR00492##

[0356] To a solution of 2-methyl-3-nitrobenzoic acid (1.0 g, 5.5 mmol) in DCM (20 mL) was added EDCI (1.58 g, 8.25 mmol), HOBt (1.11 g, 8.25 mmol), Et.sub.3N (1.11 g, 11.0 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (1.36 g, 6.6 mmol). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography to give the title product (16 g, 78.8%). LCMS (m/z): 370.2 (M+1).

Step 2: 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-- methyl Benzamide

##STR00493##

[0358] To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methyl-3-nitrob- enzamide (1.6 g, 4.3 mmol) in EtOH (15 mL) and H.sub.2O (15 mL) was added Fe powder (1.45 g, 25.8 mmol) and NH.sub.4C.sub.1 (1.38 g, 25.8 mmol). The mixture was stirred at 60.degree. C. for 4 h. The reaction solution was filtered, and the filtrate was concentrated to remove EtOH. The residue was diluted with water and extracted with DCM. The organic layer was concentrated to give the desired product (1.4 g, Yield 95.9%). The crude product was used in next step without further purification. LCMS (m/z): 340.1 (M+H).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methyl-3- -((tetrahydro-2H-pyran-4-yl)amino)benzamide

##STR00494##

[0360] To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methylb- enzamide (200 mg, 0.59 mmol) in MeOH (8 mL) was added AcOH (0.05 mL) and dihydro-2H-pyran-4(3H)-one (118 mg, 1.18 mmol). The mixture was stirred at 25.degree. C. for 2 h. NaBH.sub.3CN (186 mg, 2.95 mmol) was added and the resulting mixture was stirred at 25.degree. C. for 2 h. The reaction solution was concentrated and the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (24 mg, Yield 9.6%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.41 (s, 1H), 7.35-7.23 (m, 3H), 7.20 (d, J=7.0 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.70 (d, J=7.3 Hz, 1H), 4.44 (s, 2H), 4.33 (brs, 1H), 3.99 (d, J=11.5 Hz, 2H), 3.66-3.43 (m, 7H), 3.38-3.16 (m, 4H), 2.15 (s, 3H), 2.01 (d, J=12.8 Hz, 2H), 1.63-1.48 (m, 2H). LCMS (m/z): 424.2 (M+1).

Compound 42

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyrrolidin-2-yl- )benzamide

##STR00495##

[0361] Step 1: tert-butyl 2-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl) phenyl)pyrrolidine-1-carboxylate

##STR00496##

[0363] A mixture of compound 3-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)benzoic acid (100 mg, 0.34 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (70 mg, 0.34 mmol), BOPCl (100 mg, 0.41 mmol) and DIPEA (1 mL) in DCM (10 mL) was stirred at 25.degree. C. for 4 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, concentrated and the residue was purified by prep-TLC to give the title product which was used directly in next step (150 mg, Yield 93%). LCMS (m/z): 480.2 (M+1).

Step 2: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyrroli- din-2-yl) benzamide

##STR00497##

[0365] To a solution of tert-butyl 2-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)phen- yl)pyrrolidine-1-carboxylate (100 mg, 0.11 mmol) in EA (10 mL) was added HCl (1M in EA, 4 mL). The reaction mixture was stirred at 25.degree. C. for 16 h. The solvent was then removed by in vacuo and the crude product was purified by prep-HPLC to give the title compound (39.4 mg, Yield 52%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.80 (brs, 1H), 7.66 (d, J=7. Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.32-7.43 (m, 1H), 7.00-7.17 (m, 4H), 4.05-4.24 (m, 2H), 3.73-3.81 (m, 2H), 3.48-3.60 (m, 2H), 3.17-3.27 (m, 1H), 2.96-3.07 (m, 1H), 2.81-2.95 (m, 4H), 2.64-2.75 (m, 2H), 2.20-2.32 (m, 1H), 1.87-2.05 (m, 2H), 1.70-1.84 (m, 1H). LCMS (m/z): 380.2 (M+1).

Compound 44

(S)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((tetrahydr- o-2H-pyran-4-yl)amino)benzamide

##STR00498##

[0366] Step 1: (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

##STR00499##

[0368] To a solution of 1,2,3,4-tetrahydroisoquinoline (10 g, 0.15 mol) in THF (100 mL) at 0.degree. C. was added KF (22 g, 0.3 mmol). After 1 h, (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (21.4 g, 0.17 mmol) was added and the resulting solution was stirred at 22.degree. C. for 16 h. The solid was removed by filtration and washed with THF. The solution was concentrated and the crude compound was used for next step without further purification (15 g, Yield 53%). LCMS (m/z): 190.1 (M+1).

Step 2: (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol

##STR00500##

[0370] To a solution of (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (15 g, 0.08 mol) in EtOH (100 mL) at -78.degree. C. was slowly bubbled NH.sub.3 (g). The reaction mixture was then sealed and heated at 80.degree. C. for 3 h. The reaction mixture was concentrated and the crude product was used in next step without further purification (15 g, Yield 92%). LCMS (m/z): 207.1 (M+1).

Step 3: Methyl 3-((tert-butoxycarbonyl)amino)benzoate

##STR00501##

[0372] To a solution of methyl 3-aminobenzoate (2.0 g, 13.2 mmol) in THF (20 mL) was added Et.sub.3N (2.67 g, 26.4 mmol) and Boc.sub.2O (3.16 g, 14.5 mmol) at 0.degree. C. The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was concentrated to remove THF, and the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by column chromatography to give the title product (1.6 g, Yield 48.5%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.12 (s, 1H), 7.64-7.60 (m, 2H), 7.37-7.33 (t, J=8 Hz, 1H), 3.89 (s, 3H), 1.52 (s, 9H) LCMS (m/z): 251.1 (M+1).

Step 4: (S)-tert-butyl(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypr- opyl)carbamoyl) phenyl)carbamate

##STR00502##

[0374] A mixture of methyl 3-((tert-butoxycarbonyl)amino)benzoate (500 mg, 2 mmol) and (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (618 mg, 3 mmol) in EtOH (1 mL) was heated at 120.degree. C. for 3 h in a microwave reactor under N.sub.2. The reaction solution was concentrated and the residue was purified by column chromatography to give the title product (500 mg, Yield 58.8%). LCMS (m/z): 426.2 (M+1).

Step 5: (S)-3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl- ) benzamide

##STR00503##

[0376] To a solution of (S)-tert-butyl-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxyl propyl)carbamoyl)phenyl)carbamate (500 mg, 118 mmol) in DCM (8 mL) was added TFA (8 mL). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was concentrated to give the crude title product that was used without further purification (400 mg). LCMS (m/z): 326.2 (M+1).

Step 6: (S)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((t- etrahydro-2H-pyran-4-yl)amino)benzamide

##STR00504##

[0378] To a solution of (S)-3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxylpropyl)benza- mide (400 mg, 1.23 mmol) in MeOH (8 mL) was added AcOH (0.05 mL) and dihydro-2H-pyran-4(3H)-one (123 mg, 1.23 mmol). The mixture was stirred at 25.degree. C. for 2 h NaBH.sub.3CN (387 mg, 6.15 mmol) was added and the resulting mixture was stirred at 25.degree. C. for 2 h. The reaction solution was concentrated, and the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (160 mg, Yield 31.8%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.94-7.76 (m, 2H), 7.63-7.56 (m, 1H), 7.56-7.49 (m, 1H), 7.32-7.24 (m, 3H), 7.21-7.15 (m, 1H), 4.71-4.55 (m, 1H), 4.52-4.28 (m, 2H), 4.05-3.95 (m, 2H), 3.92-3.70 (m, 2H), 3.62-3.46 (m, 3H), 3.46-3.33 (m, 4H), 3.28-3.02 (m, 2H), 1.99-1.85 (m, 2H), 1.82-1.66 (m, 2H). LCMS (m/z): 410.2 (M+1).

Compound 45

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((tetrahydrofura- n-3-yl)amino)benzamide

##STR00505##

[0379] Step 1: 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

##STR00506##

[0381] To a solution of 1,2,3,4-tetrahydroisoquinoline (15 g, 0.11 mol) in MeCN (100 mL) was added K.sub.2CO.sub.3 (30.7 g, 0.23 mol) at 0.degree. C. 2-(bromomethyl)oxirane (17 g, 0.12 mol) was added to the reaction after 1 h. The solution was stirred at 22.degree. C. for 16 h at which time the solids were filtered and washed with MeCN. The solution was concentrated and the residue was used in the next step without further purification (17 g, Yield 78%). LCMS (m/z): 190.1 (M+1).

Step 2: 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol

##STR00507##

[0383] To a solution of 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (17 g, 0.09 mol) in EtOH (300 mL) at -78.degree. C. was slowly bubbled NH.sub.3 (g). The reaction mixture was then sealed and heated at 80.degree. C. for 3 h. The reaction mixture was concentrated and the crude product was used in next step without further purification (18 g, Yield 96%). LCMS (m/z): 207.1 (M+1).

Step 3: tert-butyl (3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)phenyl)carbamate

##STR00508##

[0385] To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (2.5 g, 10.5 mmol) in DCM (25 mL) was added EDCI (3.0 g, 15.7 mmol), HOBt (2.1 g, 15.7 mmol), Et.sub.3N (2.1 g, 21 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (2.2 g, 10.5 mmol). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography to give the title product (3.2 g, 71%). LCMS (m/z): 426.3 (M+1).

Step 5: 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) benzamide

##STR00509##

[0387] To a solution of tert-butyl (3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)phenyl- )carbamate (500 mg, 1.18 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was concentrated, and the residue was dissolved in water, the pH was adjusted to 7.about.7.5 with saturated aqueous of NaHCO.sub.3 and extracted with EA. The organic layer was concentrated to give the title product that was used in the next step without further purification (450 mg). LCMS (m/z): 326.2 (M+1).

Step 6: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((tetrah- ydrofuran-3-yl)amino)benzamide

##STR00510##

[0389] To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (100 mg, 0.31 mmol) in MeOH (5 mL) was added AcOH (0.05 mL) and dihydrofuran-3(2H)-one (27 mg, 0.31 mmol). The mixture was stirred at 22.degree. C. for 2 h. NaBH.sub.3CN (98 mg, 1.55 mmol) was added and the resulting mixture was stirred at 22.degree. C. for 2 h. The reaction solution was concentrated, and the residue was washed with water, extracted with EA, the organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (22 mg, Yield 18.0%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.14-6.95 (m, 7H), 6.80-6.71 (m, 1H), 4.14-4.03 (m, 2H), 3.99-3.89 (m, 2H), 3.87-3.78 (m, 1H), 3.75-3.69 (m, 2H), 3.67-3.61 (m, 1H), 3.55-3.41 (m, 2H), 2.91-2.79 (m, 4H), 2.71-2.57 (m, 2H), 2.32-2.19 (m, 1H), 1.91-1.79 (m, 1H). LCMS (m/z): 396.2 (M+1).

Compound 46

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(morpholine-4-ca- rbonyl)benzamide

##STR00511##

[0390] Step 1: methyl 3-(morpholine-4-carbonyl)benzoate

##STR00512##

[0392] To a solution of 3-(methoxycarbonyl)benzoic acid (200 mg, 1.11 mmol) in DCM (10 mL) were added morpholine (200 mg, 2.30 mmol) and TEA (300 mg, 2.96 mmol) and the resulting solution was stirred for 10 min at 20.degree. C. To the mixture was added HATU (500 mg, 1.31 mmol) and the reaction mixture was stirred at 20.degree. C. for 1 h. The mixture was concentrated and the residue was purified via column chromatography to obtain the title product (250 mg, Yield 90.5%). LCMS (m/z): 250.1 (M+1).

Step 2: 3-(morpholine-4-carbonyl)benzoic Acid

##STR00513##

[0394] To a solution of methyl methyl-3-(morpholine-4-carbonyl)benzoate (300 mg, 1.11 mmol) in MeOH (2 mL) and water (2 mL) was added LiOH (100 mg, 2.38 mmol) at 20.degree. C. The mixture was heated to 60.degree. C. for 1 h under N.sub.2. The reaction solution was concentrated in vacuo and diluted with water. The pH was adjusted to 4 with 2N HCl and the aqueous layer was extracted with DCM. The organic layer was concentrated to dryness and obtained the title product that was used in the next reaction without further purification (250 mg, Yield 96%). LCMS (m/z): 236.2 (M+1).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(morphol- ine-4-carbonyl)benzamide

##STR00514##

[0396] To a solution of 3-(morpholine-4-carbonyl)benzoic acid (300 mg crude, 0.48 mmol) in MeCN (5 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)-propan-2-ol (100 mg, 0.49 mmol), and TEA (250 mg, 2.48 mmol) and the resulting mixture was stirred at 20.degree. C. for 10 min. BOPCl (120 mg, 0.49 mmol) was added and the reaction mixture was stirred at 20.degree. C. for 1 h. After evaporation of the solvent, the residue was purified by prep-HPLC to give the title compound (15.2 mg, Yield 7.5%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.85-7.94 (m, 2H), 7.60 (d, >7.8 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.08-7.16 (m, 3H), 7.01-7.07 (m, 1H), 4.14 (quin, >6.0 Hz, 1H), 3.76 (s, 6H), 3.54-3.68 (m, 3H), 3.47 (dd, >6.8, 13.6 Hz, 3H), 2.80-2.98 (m, 4H), 2.63-2.74 (m, 2H). LCMS (m/z): 424.2 (M+1).

Compound 49

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(methyl(tetrahyd- ro-2H-pyran-4-yl)amino)benzamide

##STR00515##

[0397] Step 1: tert-butyl-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)phenyl)carbamate

##STR00516##

[0399] To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (2.5 g, 10.5 mmol) in DCM (25 mL) was added EDCI (3.0 g, 15.7 mmol), HOBt (2.1 g, 15.7 mmol), Et.sub.3N (2.1 g, 21 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (2.2 g, 10.5 mmol). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography to give the title product (3.2 g, Yield 71%). LCMS (m/z): 426.3 (M+1).

Step 3: 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) Benzamide

##STR00517##

[0401] To a solution of tert-butyl (3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)phenyl)carbamate (500 mg, 1.18 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at 25.degree. C. for 16 h. The reaction solution was concentrated, and the residue was dissolved in water, the pH was adjusted to 7-7.5 with saturated aqueous of NaHCO.sub.3 and extracted with EA. The organic layer was concentrated to give the title product that was used in the next step without further purification (450 mg, crude). LCMS (m/z): 326.2 (M+1).

Step 4. N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(methyl (tetrahydro-2H-pyran-4-yl)amino)benzamide

##STR00518##

[0403] To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((tetrahydro-2H- -pyran-4-yl)amino)benzamide (300 mg, 0.73 mmol) in MeOH (6 mL) was added AcOH (0.05 mL) and HCHO (548 mg, 7.3 mmol, 40% w/w). The mixture was stirred at 20.degree. C. for 2 h. NaBH.sub.3CN (276 mg, 4.38 mmol) was added and the resulting mixture was stirred at 20.degree. C. for 16 h. The reaction solution was concentrated, the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (105 mg, Yield 33.9%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.37-7.29 (m, 1H), 7.23-7.17 (m, 1H), 7.17-6.97 (m, 6H), 4.18-4.08 (m, 1H), 4.07-3.90 (m, 3H), 3.80-3.68 (m, 2H), 3.62-3.51 (m, 3H), 3.51-3.43 (m, 1H), 2.99-2.79 (m, 7H), 2.75-2.58 (m, 2H), 1.94-1.79 (m, 2H), 1.72-1.59 (m, 2H). LCMS (m/z): 424.1 (M+1).

Compound 50

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(oxetan-3-ylamin- o)benzamide

##STR00519##

[0404] Step 1: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(oxetan-3-ylami- no)benzamide

##STR00520##

[0406] To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (100 mg, 0.31 mmol) in MeOH (5 mL) was added AcOH (0.05 mL) and oxetan-3-one (22 mg, 0.31 mmol). The mixture was stirred at 22.degree. C. for 2 h. NaBH.sub.3CN (98 mg, 1.55 mmol) was added, and the resulting mixture was stirred at 22.degree. C. for 2 h. The reaction solution was concentrated, the residue was washed with water, extracted with EA, the organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (17 mg, Yield 14.4%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.17-6.97 (m, 6H), 6.96-6.88 (m, 1H), 6.72-6.62 (m, 1H), 5.03-4.95 (m, 2H), 4.67-4.59 (m, 1H), 4.59-4.49 (m, 2H), 4.15-4.04 (m, 1H), 3.80-3.69 (m, 2H), 3.56-3.40 (m, 2H), 2.96-2.79 (m, 4H), 2.73-2.58 (m, 2H). LCMS (m/z): 382.2 (M+1).

Compound 51

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(morpholinomethy- l)benzamide

##STR00521##

[0407] Step 1: methyl 3-(morpholinomethyl)benzoate

##STR00522##

[0409] To a solution of methyl 3-formylbenzoate (100 mg, 0.61 mmol) in MeOH (5 mL) was added morpholine (100 mg, 1.15 mmol) and the resulting mixture was stirred for 10 min at 20.degree. C. To the mixture was added NaBH.sub.3CN (100 mg, 1.59 mmol) and the reaction mixture was stirred for 30 min at 20.degree. C. The solution was concentrated and the residue was purified by prep-TLC to afford the title compound (130 g, Yield 90.9%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.98-8.05 (m, 1H), 7.92 (td, 0.7=1.4, 7.7 Hz, 1H), 7.57-7.62 (m, 1H), 7.37-7.53 (m, 1H), 3.90 (s, 3H), 3.66-3.71 (m, 4H), 3.57 (s, 2H), 2.41-2.49 (m, 4H).

Step 2: 3-(morpholinomethyl)benzoic Acid

##STR00523##

[0411] To a solution of methyl 3-(morpholinomethyl)benzoate (150 mg, 0.64 mmol) in MeOH (2 mL) and water (2 mL) was added LiOH (55 mg, 1.31 mmol) at 20.degree. C. The mixture was heated to 60.degree. C. for 1 h. The reaction solution was concentrated and purified via prep-HPLC to give the title compound (60 mg. Yield 42.5%). LCMS (m/z): 222 (M+1).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(morphol- inomethyl)benzamide

##STR00524##

[0413] To a solution of 3-(morpholinomethyl)benzoic acid (60 mg, 0.27 mmol) in MeCN (3 mL) were added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (60 mg, 0.29 mmol), TEA (70 mg, 0.69 mmol) and the resulting mixture was stirred at 20.degree. C. for 10 min. BOPCl (70 mg, 0.28 mmol) was added and the reaction mixture was stirred at 20.degree. C. for 16 h. The reaction solution was concentrated and the residue was purified by prep-HPLC to give the title compound (4 mg, Yield 3.6%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.77 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.50 (d, >7.7 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.07-7.14 (m, 3H), 7.00-7.06 (m, 1H), 4.11 (quin, >6.0 Hz, 1H), 3.75 (s, 2H), 3.64-3.72 (m, 4H), 3.43-3.59 (m, 4H), 2.83-2.93 (m, 4H), 2.61-2.74 (m, 2H), 2.44 (brs, 4H). LCMS (m/z): 410.1 (M+1).

Compound 52

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((1-(tetrahydro-- 2H-pyran-4-yl)ethyl)amino)benzamide

##STR00525##

[0414] Step 1: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((1-(tetrahydro- -2H-pyran-4-yl)ethyl)amino)benzamide

##STR00526##

[0416] A solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) benzamide (130 mg, 0.4 mmol), 1-(tetrahydro-2H-pyran-4-yl)ethanone (52 mg, 0.4 mmol) and AcOH (0.1 mL) in MeOH (10 mL). The mixture was stirred at 22.degree. C. for 1 h, then NaBH.sub.3CN (76 mg, 1.2 mmol) was added. The mixture was stirred at 22.degree. C. for 4 h. The reaction mixture was concentrated and quenched with water. The mixture solution was extracted with DCM, the combined organic layers were concentrated and the residue was purified by prep-TLC to give the desired compound (14.0 mg. Yield 8%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 6.90-7.07 (m, 6H), 6.81 (d, J=7.5 Hz, 1H), 6.64 (d, J=8.03 Hz, 1H), 3.98-4.04 (m, 1H), 3.87 (d, J=11.3 Hz, 2H), 3.70 (s, 2H), 3.28-3.45 (m, 5H), 2.82 (brs, 4H), 2.56-2.65 (m, 2H), 1.70 (d, J=13.8 Hz, 1H), 1.57 (brs, 1H), 1.17-1.37 (m, 3H), 1.04 (d, J=6.3 Hz, 3H). LCMS (m/z): 438.3 (M+1).

Compound 53

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((2,2-dimethylte- trahydro-2H-pyran-4-yl)amino)benzamide

##STR00527##

[0417] Step 1: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((2,2-dimethylt- etrahydro-2H-pyran-4-yl)amino)benzamide

##STR00528##

[0419] A solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) benzamide (130 mg, 0.4 mmol), 2,2-dimethyldihydro-2H-pyran-4(3H)-one (52 mg, 0.4 mmol) and AcOH (0.1 mL) in MeOH (10 mL). The mixture was stirred at 22.degree. C. for 12 h, then NaBH.sub.3CN (76 mg, 1.2 mmol) was added and the resulting mixture was stirred at 22.degree. C. for 2 h.

[0420] The reaction mixture was concentrated and quenched with water. The aqueous mixture was extracted with DCM, the combined organic layers were concentrated and the residue was purified by prep-HPLC to give the title compound (5.5 mg, Yield 3.1%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.42 (brs, 1H) 7.00-7.33 (m, 7H) 6.84 (d, J=7.8 Hz, 1H) 4.21-4.41 (m, 3H) 3.40-3.92 (m, 8H) 3.11-3.20 (m, 3H) 1.91-2.07 (m, 2H) 1.18-1.44 (m, 8H). LCMS (m/z): 438.3 (M+1).

Compound 54

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-((tetrahydro-2H-- pyran-4-yl)amino)nicotinamide

##STR00529##

[0421] Step 1. 5-bromo-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)nicotinami- de

##STR00530##

[0423] A solution of 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (326 mg, 1.58 mmol), 5-bromonicotinic acid (300 mg, 1.5 mmol), HATU (627 mg, 1.65 mmol) and TEA (181.8 mg, 1.8 mmol) in DCM (15 mL) was stirred at 22.degree. C. for 2 h, at which time the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried and concentrated and the residue was purified by column chromatography to give title compound that was used in the next step without further purification (200 mg, Yield 34%) LCMS (m/z): 390/392 (M+1/M+2).

Step 2: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-((tetrah- ydro-2H-pyran-4-yl)amino)nicotinamide

##STR00531##

[0425] To a solution of 5-bromo-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) nicotinamide (100 mg, 0.26 mmol) in dioxane (10 mL) were added tetrahydro-2H-pyran-4-amine (39.4 mg, 0.29 mmol), Pd.sub.2(dba).sub.3 (20 mg, 0.02 mmol), NaOtBu (24 mg, 0.52 mmol) and BINAP (26 mg, 0.04 mmol). The reaction mixture was heated at 110.degree. C. for 6 h under N.sub.2. The mixture was concentrated and the residue was dissolved in EA, washed with water, the organic layer was collected, dried, and the residue purified by prep-HPLC to give the title compound (25.9 mg, Yield 24%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.17 (d, 1.5 Hz, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.43-7.35 (m, 1H), 7.13-7.06 (m, 3H), 7.04-6.99 (m, 1H), 4.17-4.07 (m, 1H), 4.02-3.93 (m, 2H), 3.73 (s, 2H), 3.63-3.50 (m, 4H), 3.41 (dd, J=6.8, 13.6 Hz, 1H), 2.94-2.82 (m, 4H), 2.70-2.57 (m, 2H), 2.03-1.93 (m, 2H), 1.57-1.45 (m, 2H). LCMS (m/z): 411.1 (M+1).

Compound 55

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4-((tetrahydro-2H-- pyran-4-yl)amino)picolinamide

##STR00532##

[0426] Step 1: methyl 4-((tetrahydro-2H-pyran-4-yl)amino)picolinate

##STR00533##

[0428] To a solution of compound methyl 4-chloropicolinate (100 mg, 0.59 mmol), tetrahydro-2H-pyran-4-amine hydrochloride (121 mg, 0.88 mmol), Cs.sub.2CO.sub.3 (762 mg, 2.34 mmol), Pd.sub.2(dba).sub.3 (54 mg, 0.059 mmol) and XPhos (28 mg, 0.06 mmol) in toluene (10 mL) was stirred and heated at 110.degree. C. under N.sub.2 for 16 h. The catalyst was filtered and the filtrate was washed with EA, concentrated in vacuo and the residue was purified by prep-TLC to give the title product (50 mg, Yield 36.2%). LCMS (m/z): 237.2 (M+1).

Step 2: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4-((tetrah- ydro-2H-pyran-4-yl)amino)picolinamide

##STR00534##

[0430] To a solution of compound methyl 4-((tetrahydro-2H-pyran-4-yl)amino)picolinate (50 mg, 0.21 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (44 mg, 0.21 mmol) in MeOH (2 mL) was stirred at 100.degree. C. under microwave heating for 3 h. The reaction mixture was purified by prep-HPLC to give the title compound (29.9 mg, Yield 34.4%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.95 (d, J=5.6 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.13-7.05 (m, 3H), 7.03-6.98 (m, 1H), 6.62 (dd, >=2.4, 5.6 Hz, 1H), 4.07 (quin, J=6.0 Hz, 1H), 4.01-3.93 (m, 2H), 3.72 (s, 2H), 3.66-3.60 (m, 1H), 3.60-3.57 (m, 1H), 3.57-3.52 (m, 2H), 3.49-3.42 (m, 1H), 2.95-2.89 (m, 2H), 2.87-2.81 (m, 2H), 2.65 (d, J=6.0 Hz, 2H), 1.97 (d, J=12.8 Hz, 2H), 1.59-1.47 (m, 2H). LCMS (m/z): 411.1 (M+1).

Compound 57

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-fluoro-5-((tetra- hydro-2H-pyran-4-yl)amino)benzamide

##STR00535##

[0431] Step 1: 5-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-fluorob- enzamide

##STR00536##

[0433] The solution of 5-amino-2-fluorobenzoic acid (200 mg, 1.29 mmol) and HATU (490 mg, 1.29 mmol) in DCM (15 mL) was stirred at 17.degree. C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (265 mg, 1.29 mmol) and DIPEA (333 mg, 2.58 mmol) was added and the resulting solution was stirred at 17.degree. C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give desired product (372 mg, Yield 84%).

Step 2: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-fluoro-5- -((tetrahydro-2H-pyran-4-yl)amino)benzamide

##STR00537##

[0435] A solution of 5-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-fluorob- enzamide (372 mg, 1.08 mmol), dihydro-2H-pyran-4(3H)-one (108 mg, 1.08 mmol) and AcOH (0.05 mL) in MeOH (20 mL) was stirred at 17.degree. C. for 2 h. Then NaBH.sub.3CN (109 mg, 1.63 mmol) was added and the resulting solution was stirred at 17.degree. C. for 4 h. The solution was concentrated and the residue was purified by column chromatography to afford the title product (121.5 mg, Yield 17.5%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.16-7.07 (m, 3H), 7.03 (dd, >2.9, 5.9 Hz, 2H), 6.95 (dd, >8.9, 10.7 Hz, 1H), 6.79 (td, >3.6, 8.8 Hz, 1H), 4.11 (quin, >6.0 Hz, 1H), 3.98 (d, J=11.5 Hz, 2H), 3.80-3.69 (m, 2H), 3.64-3.40 (m, 5H), 2.98-2.81 (m, 4H), 2.72-2.60 (m, 2H), 1.99 (d, J=12.8 Hz, 2H), 1.56-1.39 (m, 2H). LCMS (m/z): 428.2 (M+1).

Compound 58

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4-((tetrahydro-2H-- pyran-4-yl)oxy)benzamide

##STR00538##

[0436] Step 1: methyl 4-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

##STR00539##

[0438] To a solution of ethyl 4-hydroxybenzoate (500 mg, 3.0 mmol), tetrahydro-2H-pyran-4-ol (307.3 mg, 3.0 mmol) and PPh.sub.3 (944 mg, 3.6 mmol) in THF (15 mL) was added DEAD (627 mg, 3.6 mmol) at 0.degree. C. The mixture was the warmed to 21.degree. C. and stirred for 16 h. The mixture was treated with water and the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated and the residue was purified by column chromatography to give the title compound (320 mg, Yield 45%). .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.92 (d, J=8.9 Hz, 1H), 6.75-6.94 (m, 1H), 4.44-4.59 (m, 1H), 4.28 (d, J=7.2 Hz, 2H), 3.83-4.00 (m, 2H), 3.46-3.60 (m, 2H), 1.88-2.05 (m, 2H), 1.67-1.83 (m, 2H), 1.31 (t, J=7.2 Hz, 3H).

Step 2: 4-((tetrahydro-2H-pyran-4-yl)oxy)benzoic Acid

##STR00540##

[0440] To a solution of methyl 4-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (400 mg, 1.6 mmol) in MeOH (10 ml) was added a solution of NaOH (128 mg, 3.2 mmol) in H.sub.2O (4 mL) at 22.degree. C. The mixture was stirred at 50.degree. C. for 4 h. The mixture was concentrated and the residue was treated with water and extracted with EA. The water layer was treated with 2N HCl to pH=3. The water layer was then extracted with EA. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the title product which was used in next step without further purification (350 mg, Yield 98.6%). .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 8.08 (d, J=8.9 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 4.64 (tt, J=7.7, 3.8 Hz, 1H), 3.95-4.09 (m, 2H), 3.64 (ddd, J=11.6, 8.2, 3.3 Hz, 2H), 2.01-2.13 (m, 2H), 1.78-1.93 (m, 2H).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4-((tetrah- ydro-2H-pyran-4-yl)oxy)benzamide

##STR00541##

[0442] To a solution of 4-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (150 mg, 0.67 mmol) in DMF (4 mL) was added DIEA (260 mg, 2.01 mmol), HATU (384 mg, 1.01 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (170 mg, 0.81 mmol). The reaction mixture was stirred at 22.degree. C. for 16 h. The mixture was treated with water and extracted with EA. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated and the residue was was purified by prep-HPLC to give the title compound (206.1 mg, Yield 74.9%). .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.84 (d, J=8.8 Hz, 2H), 7.26-7.37 (m, 3H), 7.19-7.25 (m, 1H), 7.05 (d, J=8.8 Hz, 2H), 4.59-4.74 (m, 2H), 4.31-4.49 (m, 2H), 3.93-4.01 (m, 2H), 3.86 (brs, 1H), 3.63 (ddd, J=11.7, 8.8, 3.0 Hz, 2H), 3.53 (qd, J=14.0, 5.7 Hz, 3H), 3.37-3.44 (m, 1H), 3.11-3.32 (m, 3H), 2.02-2.12 (m, 2H), 1.69-1.81 (m, 2H). LCMS (m/z): 411.2 (M+1).

Compound 166

(S)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(oxetan-3-y- lamino)pyrimidine-4-carboxamide

##STR00542##

[0443] Step 1: 6-Hydroxypyrimidine-4-carboxylic Acid

##STR00543##

[0445] To a solution of sodium (Z)-1,4-diethoxy-1,4-dioxobut-2-en-2-olate (55.0 g, 262 mmol) in H.sub.2O (500 mL) was added formimidamide acetate (27.3 g, 262 mmol) and NaOH (10.5 g). After addition, the resulting mixture was stirred at 25.degree. C. for 16 h then concentrated and then acidified by added aqueous HCl (1N) until pH=1. The resulting solid was collected by filtration, washed with H.sub.2O and ether to give 6-hydroxypyrimidine-4-carboxylic acid (6.0 g, yield: 16.3%) .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.89 (s, 1H), 8.24 (s, 1H), 6.83 (s, 1H).

Step 2: 6-chloropyrimidine-4-carboxylic Acid

##STR00544##

[0447] To a solution of 6-hydroxypyrimidine-4-carboxylic acid (6.0 g, 42.8 mmol) in EtOAc (90 mL) was added (COCl).sub.2 (12 mL) dropwise, followed by a few drops of DMF. The mixture was stirred at 75.degree. C. for 3 h, and then at 25.degree. C. for 16 h. The solvent was evaporated to give the crude 6-chloropyrimidine-4-carboxylic acid (6.3 g, yield. 92.9%).sup.LH NMR (400 MHz, DMSO-d.sub.6) .delta. 8.31 (s, 1H), 6.88 (s, 1H).

Step 3: 6-chloropyrimidine-4-carbonyl Chloride

##STR00545##

[0449] A drop of DMF was added to a stirred solution of 6-chloropyrimidine-4-carboxylic acid (5.5 g, 34.7 mmol) and (COCl).sub.2 (12 mL) in DCM (100 mL). The mixture was stirred at 25.degree. C. for 2 h. The solvent was evaporated under reduced pressure to give crude 6-chloropyrimidine-4-carbonyl chloride (6.0 g, yield: 97.7%). NMR (400 MHz, DMSO-d.sub.6) .delta. 9.20 (s, 1H), 8.10 (s, 1H).

Step 4: (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropy- l)pyrimidine-4-carboxamide

##STR00546##

[0451] To a stirred and cooled (0.degree. C.) solution of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl) propan-2-ol (7.15 g, 34.7 mmol) and Et.sub.3N (14.0 g, 138.8 mmol) in DCM (100 mL) was added 6-chloropyrimidine-4-carbonyl chloride (5.5 g, 34.7 mmol). After addition, the resulting mixture was stirred at 25.degree. C. for 16 h, at which time LCMS showed the completion of the reaction. The solvent was evaporated and the residue purified by flash chromatography to give the (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrim- idine-4-carboxamide (7.2 g, yield: 60%). LCMS (m/z): 347.0 [M+H].sup.+

Step 5: (S)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(ox- etan-3-ylamino)pyrimidine-4-carboxamide

##STR00547##

[0453] To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy propyl)pyrimidine-4-carboxamide (347 mg, 1 mmol) in i-PrOH (5 mL) was added oxetan-3-amine (73.1 mg, 1 mmol) and DIPEA (129 mg, 1 mmol). The resulting mixture was stirred at 110.degree. C. for 16 hours, at which time LCMS showed the completion of the reaction. After evaporation of the solvent, the residue was purified by preparative HPLC to give the target compound (S)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(- oxetan-3-ylamino)pyrimidine-4-carboxamide (62.5 mg, yield: 16.3%). .sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta. 8.24 (s, 1H), 7.15-7.05 (m, 4H), 7.02-6.98 (m, 1H), 5.09 (s, 1H), 4.95 (t, J=6.8 Hz, 2H), 4.59 (t, J=6.3 Hz, 2H), 4.10-4.03 (m, 1H), 3.72 (s, 2H), 3.56-3.46 (m, 2H), 2.96-2.91 (m, 2H), 2.87-2.80 (m, 2H), 2.65 (d, J=6.3 Hz, 2H). LCMS (m/z): 384.1 [M+H].sup.+.

Compound 84

N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methylquinoline-- 6-carboxamide

##STR00548##

[0454] Step 1: 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

##STR00549##

[0456] To a stirring solution of 1,2,3,4-tetrahydroisoquinoline (15 g, 0.11 mol) in MeCN (100 mL) at 0.degree. C. was added K.sub.2CO.sub.3 (30.7 g, 0.23 mol), then 2-(bromomethyl) oxirane (17 g, 0.12 mol) added slowly over a period of 1 h. After the addition the solution was stirred at 21.degree. C. for 12 h. The resulting solid was then removed by filtration and washed with MeCN and the combined organic filtrate was concentrated under reduced pressure to give the crude product. This residue was used into next step without further purification (17 g, Yield: 78%). LCMS (m/z): 190.1 (M+1).

Step 2: 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol

##STR00550##

[0458] NH.sub.3 was bubbled into a stirred and cooled (-78.degree. C.) solution of 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (17 g, 0.09 mol) in EtOH (300 mL). After saturation, the reaction mixture was then sealed and heated at 80.degree. C. for 3 h. After LCMS indicated the reaction to be complete, the reaction mixture was concentrated and the crude product used in the next step without further purification (18 g, Yield 96%). LCMS (m/z): 207.1 (M+1).

Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methylqu- inoline-6-carboxamide

##STR00551##

[0460] To a solution of 2-methylquinoline-6-carboxylic acid (100 mg, 0.535 mmol) in DCM (20 mL) was added HATU (244 mg, 0.642 mmol) and TEA (162 mg, 1.604 mmol). The mixture was stirred at 15.degree. C. for 30 minutes before 1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (110 mg, 0.535 mmol) was added. The resulting mixture was stirred for another 16 h at 15.degree. C., at which point LCMS showed the completion of the reaction. The mixture was concentrated and the residue was purified by Preparation HPLC to give the desired title compound (106.2 mg, 53%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) 5=8.32 (d, J=1.9 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.09 (dd, >2.1, 8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.16-7.08 (m, 3H), 7.08-7.03 (m, 1H), 4.18 (quin, >6.1 Hz, 1H), 3.79 (s, 2H), 3.59 (d, J=5.8 Hz, 2H), 2.94-2.88 (m, 4H), 2.79-2.68 (m, 5H). LCMS (m/z): 376.0 (M+1).

Compound 219

(R)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methylquino- line-6-carboxamide

##STR00552##

[0462] To a solution of 2-methylquinoline-6-carboxylic acid (200 mg, 1.070 mmol) in DCM (30 mL), was added HATU (489 mg, 1.283 mmol) and TEA (324 mg, 3.208 mmol). The solution was stirred at 15.degree. C. for 30 minutes before (R)-1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (264 mg, 1.283 mmol) was added. The resulting solution was stirred for another 16 h at 15.degree. C., until the reaction was complete by LCMS analysis. The mixture was then concentrated under vacuum to give the crude material which was purified by Preparative HPLC to give the title compound (118 mg, 29%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.33 (d, J=1.9 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.09 (dd, J=2.1, 8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.15-7.05 (m, 4H), 4.18 (quin, J=6.1 Hz, 1H), 3.79 (s, 2H), 3.63-3.55 (m, 2H), 2.95-2.90 (m, 4H), 2.76 (s, 3H), 2.76-2.68 (m, 2H). LCMS (m/z): 376.1 [M+H].sup.+

Compound 221

(S)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methylquino- line-6-carboxamide

##STR00553##

[0464] To a solution of 2-methylquinoline-6-carboxylic acid (1 g, 5.35 mmol) in DCM (100 mL), was added HATU (2.44 g, 6.42 mmol) and TEA (1620 mg, 16.043 mmol). The solution was stirred at 15.degree. C. for 30 minutes before (S)-1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (1.76 g, 8.55 mmol) was added. The resulting solution was stirred for 16 h at 15.degree. C. until LCMS analysis showed the reaction to be complete. The mixture was then concentrated under vacuum and the residue purified by Preparative HPLC to give the desired title compound (502.1 mg, 25%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.31 (br. s, 1H), 8.08 (d, J=8.8 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.17-7.03 (m, 4H), 4.23-4.11 (m, 1H), 3.78 (br. s., 2H), 3.59 (d, J=5.5 Hz, 2H), 2.91 (br. s., 4H), 2.78-2.69 (m, 5H). LCMS (m/z): 376.1 [M+H].sup.+.

Compound 208

(S)-6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-y- l)-2-hydroxypropyl)pyrimidine-4-carboxamide

##STR00554##

[0465] Step 1: tert-butyl (1-acetylpiperidin-4-yl)carbamate

##STR00555##

[0467] To a solution of tert-butyl piperidin-4-ylcarbamate (200 g, 1 mol) and Et.sub.3N (150 g, 1.5 mol) in DCM (3000 mL) was added Ac.sub.2O (102 g, 1 mol) dropwise over 1 h, while maintained the temperature at 0.degree. C. After addition, the mixture was stirred 0.degree. C. for another 2 h, at which time TLC showed the reaction was completed. The solution was quenched by addition of water (1 L). The organic phase was collected and washed with saturated aqueous NaHCO.sub.3 (1 L), dried (Na.sub.2SO.sub.4) and concentrated to give crude product. Four batches were run in parallel and produced a combined crude product weight of 670 g. This crude was used directly in the step. LCMS (m/z): 243.1 (M+1).

Step 2: 1-(4-aminopiperidin-1-yl)ethanone hydrochloride

##STR00556##

[0469] To a solution of tert-butyl (1-acetylpiperidin-4-yl)carbamate (330 g, 1.36 mol) in MeOH (1000 mL) was added HCl/MeOH (4M, 300 mL) over 30 min to maintain the temperature at 0.degree. C. After addition, the mixture was stirred at 0.degree. C. for another 2 h and then concentrated to give the crude product. Two batches were run in parallel and produced a combined crude product weight of 310 g. This crude was used in next step without further purification .sup.1H NMR (400 MHz, D.sub.2O) .delta. 4.35 (dd, J=2.0, 12.0 Hz, 1H), 3.98-3.85 (m, 1H), 3.44-3.30 (m, 1H), 3.18-3.05 (m, 1H), 2.75-2.58 (m, 1H), 2.06-1.92 (m, 5H), 1.61-1.31 (m, 2H); LCMS (m/z): 143.1 (M+1).

Step 3: 6-chloropyrimidine-4-carbonyl Chloride

##STR00557##

[0471] To a stirred mixture of 6-hydroxypyrimidine-4-carboxylic acid (300 g, 2. Mmol) in EA (3000 mL), oxalyl dichloride (1356 g, 10.68 mol) was dropped slowly to maintain a reaction temperature below 30.degree. C. After addition, the mixture was stirred at 20.degree. C. for 30 min and then 2 mL of DMF was added to the mixture. The mixture was then stirred at 80.degree. C. for 16 hours and concentrated to give the crude product as black solid. Three batches were run in parallel and produced a combined crude product weight of 787 g. This crude was used directly in the next step.

Step 4: (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropy- l)pyrimidine-4-carboxamide

##STR00558##

[0473] To a stirred mixture of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (247 g, 1.20 mol), and TEA (250 g, 2.5 mol) in DCM (3500 mL) was added 6-chloropyrimidine-4-carbonyl chloride (190 g in 100 mL of DCM) slowly at -60.degree. C. over 1 h. After addition, the mixture was then allowed to warm to 10.degree. C. Stirring was continued for 1 h, at which time TLC showed the reaction was completed. The reaction was quenched by addition of water (1.5 L). The organic phase was collected, dried (Na.sub.2SO.sub.4) and evaporated. The residue was purified by flash chromatography (EtOAc.about.DCM:MeOH=10:1) to give the desired product as a pale yellow solid. Four batches were run in parallel and produced a combined crude product weight of 800 g, 49% yield. .sup.1H NMR (400 MHz, MeOD-d4) .delta. 8.73 (d, J=1.0 Hz, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.17-7.06 (m, 3H), 7.00 (d, J=7.0 Hz, 1H), 4.12 (q, J=6.0 Hz, 1H), 3.74 (s, 2H), 3.64-3.53 (m, 2H), 2.94 (q, J=5.5 Hz, 2H), 2.92-2.81 (m, 2H), 2.78-2.64 (m, 2H); LCMS (m/z): 347.2 [M+H].sup.+

Step 5: (S)-6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin- -2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide

##STR00559##

[0475] The solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrim- idine-4-carboxamide (190 g, 0.55 mmol) and 1-(4-aminopiperidin-1-yl)ethanone (78 g), Et.sub.3N (100 g, 1 mol) in i-PrOH (2000 mL) was stirred at 60.degree. C. for 16 h, at which time LCMS showed completed conversion. The mixture was concentrated and the residue was purified by flash chromatography to give the crude product. Four batches were run in parallel and produced a combined crude product weight of 482 g. This crude was further purified on preparative HPLC to give the title compound (325 g, >98% purity, free base form). .sup.1H NMR (400 MHz, MeOD-d4) 8.26 (s, 1H), 7.15-7.02 (m, 5H), 4.46 (m, 1H), 4.15-4.07 (m, 2H), 3.88 (m, 1H), 3.74 (s, 2H), 3.53 (m, 2H), 3.33 (m, 1H), 2.95-2.86 (m, 5H), 2.68 (m, 2H), 2.14-2.01 (m, 5H), 1.48-1.42 (m, 2H), LCMS (m/z): 453.3 [M+H].sup.+

Step 6: (S)-6-((l-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin- -2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide hydrochloride

##STR00560##

[0477] The free base was dissolved in DCM (100 mL) and added dropwise to a stirred and cooled solution of HCl (6N in EtOAc, 1 L) at -30.degree. C. Stirring at -30.degree. C. was continued for another 1 h and the resulting precipitate was collected by filtration. The solid was washed with DCM and EtOAc, dried to give the HCl salt of the target compound (301.4 g, yield: 30.2%) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O) .delta. 8.59 (s, 1H), 7.30-7.17 (m, 3H), 7.17-7.07 (m, 2H), 4.55 (dd, J=6.4, 15.4 Hz, 1H), 4.43-4.19 (m, 4H), 3.88 (d, J=13.8 Hz, 1H), 3.82-3.72 (m, 1H), 3.52-3.33 (m, 4H), 3.31-3.08 (m, 4H), 2.86 (t, J=11.6 Hz, 1H), 2.11-1.94 (m, 5H), 1.67-1.40 (m, 2H); LCMS (m/z): 453.2 [M+H].sup.+.

Compound 254

##STR00561##

[0478] (S)-2-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-- 2(1H)-yl)-2-hydroxypropyl)isonicotinamide

Step 1: methyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)isonicotinate

##STR00562##

[0480] A mixture of methyl 2-bromoisonicotinate (160 g, 0.69 mol) and tert-butyl 4-amino piperidine-1-carboxylate (200 g, 1.0 mol), Pd.sub.2(dba).sub.3 (8 g, 5% w), xantphos (8 g, 5% w), Cs.sub.2CO.sub.3 (326 g, 1.0 mol) in dioxane (2500 mL) was stirred at 80.degree. C. under N.sub.2 for 16 h. After completion of the reaction, the mixture was concentrated and the residue dissolved in water (800 mL) and extracted with DCM (1000 mL.times.3). The combined organic layers were dried and concentrated. The residue was purified by flash chromatography to give the product. Nine batches were run in parallel and produced a combined product weight of 700 g, Yield: 33.4%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.19 (d, J=5.2 Hz, 1H), 7.08 (d, J=5.2 Hz, 1H), 6.96 (s, 1H), 4.62 (d, J=8.0 Hz, 1H), 4.05 (br. s., 2H), 3.92 (s, 3H), 2.97 (t, J=12.0 Hz, 2H), 2.11-1.97 (m, 2H), 1.48 (s, 9H), 1.42-1.35 (m, 2H). LCMS (m/z): 336.1 (M+1).

Step 2: 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)isonicotinic Acid

##STR00563##

[0482] To a solution of methyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)isonicotinate (230 g, 0.69 mol) in MeOH (1500 mL) was added aq. NaOH (56 g, in 200 mL of water) over 20 min at 0.degree. C. After addition, the mixture was stirred at room temperature for 2 h. MeOH was then removed under reduced pressure and the aqueous solution then pH adjusted to pH=6 by acidifying with the addition of 4N HCl. The resulting precipitate was collected by filtration, washed with water and dried to give the crude product. Three batches were run in parallel and produced a combined crude product weight of 590 g, yield: 89.4%. This crude was used in next step without further purification LCMS (m/z): 322.2 (M+1).

Step 3: (S)-tert-butyl 4-((4-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)pyr- idin-2-yl)amino)piperidine-1-carboxylate

##STR00564##

[0484] To a solution of 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)isonicotinic acid (150 g, 0.47 mol) in DCM (1500 mL) was added HATU (178 g, 0.47 mol) and TEA (47 g, 0.47 mol) at 20.degree. C., then the mixture was stirred at the temperature for 2 h. (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (113 g, 0.55 mol) was added to the solution, and the mixture was stirred at 20.degree. C. for another 16 h, at which time TLC showed the completion of the reaction. The mixture washed with water (200 mL) and the combined organic phases were dried and concentrated. The residue was purified by flash chromatography (EtOAc.about.DCM:MeOH=10:1) to give the title compound as yellowish oil. Four batches were run in parallel and produced a combined product weight of 510 g, yield: 53.2%. LCMS (m/z): 510.2 [M+H].sup.+.

Step 4: (S)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(pi- peridin-4-ylamino)isonicotinamide Hydrochloride

##STR00565##

[0486] The mixture of (S)-tert-butyl 4-((4-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)pyridin-2-yl)amino)piperidine-1-carboxylate (510 g, 1.0 mol) in DCM (1000 mL) was dropped slowly into a stirred and cooled (-30.degree. C.) solution of HCl (4M in EtOAc, 2000 mL). After addition, the mixture was stirred at -30.degree. C. for 30 min. The resulting solid was then collected by filtration, washed with DCM and dried under reduced pressure to give the title compound (350 g yield: 85.4%, HCl salt) as a white solid. LCMS (m/z): 410.2 [M+H].sup.+

Step 5: (S)-2-((l-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin- -2(1H)-yl)-2-hydroxypropyl)isonicotinamide

##STR00566##

[0488] To a stirred mixture of (S)--N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(piperidin- -4-ylamino)isonicotinamide (70 g), and Et.sub.3N (40 g) in DCM (2000 mL) was added Ac.sub.2O (17 g) dropwise over 1 h at 0.degree. C. After addition, the mixture was warmed to 20.degree. C. and stirring was continued for another 1 h, at which time TLC showed the reaction was completed.

[0489] The reaction mixture was washed with water (500 mL), and the organic phase dried and concentrated. The residue was then purified by flash chromatography (EtOAc.about.DCM:MeOH=10:1) to give crude product. Five batches were run in parallel and produced a combined crude product weight of 400 g. This crude was further purified by preparative HPLC to give the pure product (310 g, >98% purity, free base form). .sup.1H NMR (400 MHz, MeOD-d4) 7.94-7.92 (d, 7.0 Hz, 1H), 7.14-7.05 (m, 4H), 6.87 (s, 1H), 6.76-6.74 (m, 1H), 4.44 (m, 1H), 4.10 (m, 1H), 3.96-3.94 (m, 2H), 3.75 (s, 2H), 3.52 (m, 2H), 3.33-3.32 (m, 1H), 2.92-2.86 (m, 5H), 2.67 (m, 2H), 2.13-2.00 (m, 5H), 1.44-1.37 (m, 2H); LCMS (m/z): 452.3 [M+H].sup.+

Step 6: (S)-2-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin- -2(1H)-yl)-2-hydroxypropyl)isonicotinamide Hydrochloride

##STR00567##

[0491] The free base was dissolved in DCM (100 mL) and added dropwise to a stirred and cooled solution of HCl (6N in EtOAc, 1 L) at -30.degree. C. Stirring at -30.degree. C. was continued for another 1 h and the resulting precipitate was collected by filtration. The solid was washed with DCM and EtOAc, dried to give the HCl salt of the product (302.2 g, yield: 78.0%) as a white solid. .sup.1H NMR (400 MHz, MeOD-d4) .delta. 8.00 (d, J=6.8 Hz, 1H), 7.64 (br. s., 1H), 7.36-7.18 (m, 5H), 4.70 (d, J=15.4 Hz, 1H), 4.60-4.39 (m, 3H), 4.19 (br. s., 1H), 4.11 (d, J=13.2 Hz, 1H), 3.98-3.85 (m, 1H), 3.63-3.47 (m, 5H), 3.43-3.25 (m, 3H), 3.25-3.11 (m, 2H), 2.33 (s, 3H), 2.22 (t, J=15.2 Hz, 2H), 1.85-1.61 (m, 2H), LCMS (m/z): 452.2 [M+H].sup.+

Compound 284

(S)-6-((1-acetylazetidin-3-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl- )-2-hydroxypropyl)pyrimidine-4-carboxamide

##STR00568##

[0492] Step 1: tert-butyl (1-acetylazetidin-3-yl)carbamate

##STR00569##

[0494] To a solution of tert-butyl azetidin-3-ylcarbamate (100 g, 0.58 mol) and Et.sub.3N (88 g, 0.87 mol) in DCM (1500 mL) was added Ac.sub.2O (59.6 g, 0.88 mol) dropwise at 0.degree. C. The mixture was then stirred at 0.degree. C. for 2 h, at which time TLC showed the completion of the reaction. The reaction was quenched by addition of water (1000 mL) and then stirred at 20.degree. C. for 30 min. The organic phase was separated, dried (Na.sub.2SO.sub.4) and concentrated to give the crude product. Seven batches were run in parallel and produced a combined crude product weight of 530 g. This crude was used in next step without the further purification. LCMS (m/z): 215.1 (M+1).

Step 2: 1-(3-aminoazetidin-1-yl)ethanone

##STR00570##

[0496] To a solution of tert-butyl (1-acetylazetidin-3-yl)carbamate (250 g) in MeOH (1000 mL) was slowly added HCl/MeOH (4M, 300 mL) at 0.degree. C. After addition, the mixture was stirred at 0.degree. C. for 6 h. The mixture was then concentrated under reduced pressure to give the crude product as a white solid. Two batches were run in parallel and produced a combined crude product weight of 186 g. This crude was used in next step without the further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 4.58-4.49 (m, 1H), 4.35-4.19 (m, 2H), 4.19-4.08 (m, 1H), 3.97 (dd, J=4.2, 11.2 Hz, 1H), 1.83 (s, 3H), LCMS (m/z): 115.1 (M+1).

Step 3: 6-chloropyrimidine-4-carbonyl Chloride

##STR00571##

[0498] A stirred mixture of 6-hydroxypyrimidine-4-carboxylic acid (75 g, 0.54 mol) in EtOAc (300 mL) had oxalyl dichloride (226 g, 1.79 mol) dropped slowly to maintain the temperature below 30.degree. C. After addition, the mixture was stirred at 20.degree. C. for 30 min and then DMF (2 mL) was added to the mixture. The mixture was then stirred at 80.degree. C. for 16 hours and concentrated to give the crude product as a black solid. Sixteen batches were run in parallel and produced a combined crude product weight of 1035 g. This crude was used directly in the next step.

Step 4: (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropy- l)pyrimidine-4-carboxamide

##STR00572##

[0500] To a stirred mixture of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (300 g, 1.46 mol), and TEA (300 g, 3 mol) in DCM (4 L) was added 6-chloropyrimidine-4-carbonyl chloride (250 g in 2 L of DCM) slowly at -60.degree. C. over 1 h. After the addition was complete, the mixture was then allowed to warm to 10.degree. C. Stirring was continued for 1 h, at which time TLC showed the reaction was completed. The reaction was quenched by addition of water (2 L). The organic phase was collected, dried (Na.sub.2SO.sub.4) and evaporated. The residue was purified by flash chromatography (EtOAc.about.DCM:MeOH=10:1) to give the desired product as a pale yellow solid. Four batches were run in parallel and produced a combined product weight of 970 g, yield: 49%. .sup.1H NMR (400 MHz, MeOD-d4) .delta. 8.73 (d, J=1.0 Hz, 1H), 8.07 (d, J=1.2 Hz, 1H), 7.17-7.06 (m, 3H), 7.00 (d, J=7.2 Hz, 1H), 5.51 (s, 1H), 4.12 (q, J=6.0 Hz, 1H), 3.74 (s, 2H), 3.64-3.53 (m, 2H), 2.94 (q, J=5.6 Hz, 2H), 2.92-2.81 (m, 2H), 2.78-2.64 (m, 2H); LCMS (m/z): 347.2 [M+H].sup.+

Step 5: (s)-6-((l-acetylazetidin-3-yl)amino)-N-(3-(3,4-dihydroisoquinolin-- 2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide

##STR00573##

[0502] To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) pyrimidine-4-carboxamide (240 g, 0.69 mol) in i-PrOH (2.5 L) was added 1-(3-amino azetidin-1-yl)ethanone (120 g) and TEA (100 g). After addition, the solution was heated at 60.degree. C. for 16 h, at which time LCMS showed completion of the reaction. The mixture was concentrated and the residue was purified by flash chromatography to give the crude product. Four batches were run in parallel and produced a combined crude product weight of 420 g, 90% purity. This crude was further purified on preparative HPLC to give the title compound (330g, >98% purity, free base form). .sup.1H NMR (400 MHz, MeOD-d4) 8.27 (s, 1H), 7.12-6.98 (m, 5H), 4.71 (s, 1H), 4.54 (m, 1H), 4.32 (m, 1H), 4.06 (m, 2H), 3.88 (m, 1H), 3.70 (s, 2H), 3.53-3.50 (m, 2H), 2.91-2.83 (m, 4H), 2.65 (m, 2H), 1.88 (s, 3H), LCMS (m/z): 425.2 [M+H].sup.+

Step 6: (s)-6-((1-acetylazetidin-3-yl)amino)-N-(3-(3,4-dihydroisoquinolin-- 2(1H)-yl)-2-hydroxypropyl) pyrimidine-4-carboxamide Hydrochloride

##STR00574##

[0504] The free base was dissolved in DCM (100 mL) and added dropwise to a stirred and cooled solution of HCl (6N in EtOAc, 1 L) at -30.degree. C. Stirring at -30.degree. C. was continued for another 1 h and the resulting precipitate was collected by filtration. The solid was washed with DCM and EtOAc, dried to give the HCl salt of the product (301 g, yield: 26%) as a white solid. .sup.1H NMR (400 MHz, D.sub.2O) .delta. 8.65 (s, 1H), 7.30-7.19 (m, 4H), 7.13 (d, J=7.5 Hz, 1H), 4.95-4.85 (m, 1H), 4.63-4.50 (m, 2H), 4.41-4.28 (m, 3H), 4.22 (dd, J=4.8, 9.2 Hz, 1H), 3.97 (dd, J=4.6, 10.0 Hz, 1H), 3.77 (dt, J=5.6, 11.3 Hz, 1H), 3.53-3.35 (m, 4H), 3.34-3.26 (m, 1H), 3.22-3.04 (m, 2H), 1.87-1.79 (m, 3H); LCMS (m/z): 425.2 [M+H].sup.+.

Biological Assays

PRMT5 Biochemical Assay

[0505] General Materials. S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), bicine, KCl, Tween20, dimethyl sulfoxide (DMSO), bovine skin gelatin (BSG), and Tris(2-carboxyethyl)phosphine hydrochloride solution (TCEP) were purchased from Sigma-Aldrich at the highest level of purity possible. .sup.3H-SAM was purchase from American Radiolabeled Chemicals with a specific activity of 80 C.sub.1/mmol. 384-well streptavidin Flashplates were purchased from PerkinElmer.

[0506] Substrates. Peptide representative of human histone H4 residues 1-15 was synthesized with a C-terminal linker-affinity tag motif and a C-terminal amide cap by 21.sup.st Century Biochemicals. The peptide was high high-performance liquid chromatography (HPLC) purified to greater than 95% purity and confirmed by liquid chromatography mass spectrometry (LC-MS). The sequence was Ac-SGRGKGGKGLGKGGA[K-Biot]-amide (SEQ ID NO.:3).

[0507] Molecular Biology: Full-length human PRMT5 (NM006109.3) transcript variant 1 clone was amplified from a fetal brain cDNA library, incorporating flanking 5' sequence encoding a FLAG tag (MDYKDDDDK) (SEQ ID NO.:4) fused directly to Ala 2 of PRMT5.

[0508] Full-length human MEP50 (NM_024102) clone was amplified from a human testis cDNA library incorporating a 5' sequence encoding a 6-histidine tag (MHHHHHH) (SEQ ID NO.:5) fused directly to Arg 2 of MEP50. The amplified genes were sublconed into pENTR/D/TEV (Life Technologies) and subsequently transferred by Gateway.TM. attL.times.attK recombination to pDEST8 baculvirus expression vector (Life Technologies).

[0509] Protein Expression. Recombinant baculovirus and Baculovirus-Infected Insect Cells (BIIC) were generated according to Bac-to-Bac kit instructions (Life Technologies) and Wasilko, 2006, respectively. Protein over-expression was accomplished by infecting exponentially growing Spodoptera frugiperda (SF9) cell culture at 1.2.times.10.sup.6 cell/ml with a 5000 fold dilution of BIIC stock. Infections were carried out at 27.degree. C. for 72 hours, harvested by centrifugation, and stored at -80.degree. C. for purification.

[0510] Protein Purification. Expressed full-length human Flag-PRMT5/6His-MeP50 protein complex was purified from cell paste by NiNTA agarose affinity chromatography after a five hour equilibration of the resin with buffer containing 50 mM Tris-HCL, pH 8.0, 25 mM NaCl, and 1 mM TCEP at 4.degree. C., to minimize the adsorption of tubulin impurity by the resin. Flag-PRMT5/6His-MeP50 was eluted with 300 mM Imidazole in the same buffer. The purity of recovered protein was 87%. Reference. Wasilko, D. J. and S. E. Lee: "TIPS: titerless infected-cells preservation and scale-up" Bioprocess J., 5 (2006), pp. 29-32.

[0511] Predicted Translations:

TABLE-US-00004 Flag-PRMT5 (SEQ ID NO.: 6) MDYKDDDDKA AMAVGGAGGS RVSSGRDLNC VPEIADTLGA VAKQGFDFLC MPVFHPRFKR EFIQEPAKNR PGPQTRSDLL LSGRDWNTLI VGKLSPWIRP DSKVEKIRRN SEAAMLQELN FGAYLGLPAF LLPLNQEDNT NLARVLTNHI HTGHHSSMFW MRVPLVAPED LRDDIIENAP TTHTEEYSGE EKTWMWWHNF RTLCDYSKRI AVALEIGADL PSNHVIDRWL GEPIKAAILP TSIFLTNKKG FPVLSKMHQR LIFRLLKLEV QFIITGTNHH SEKEFCSYLQ YLEYLSQNRP PPNAYELFAK GYEDYLQSPL QPLMDNLESQ TYEVFEKDPI KYSQYQQAIY KCLLDRVPEE EKDTNVQVLM VLGAGRGPLV NASLRAAKQA DRRIKLYAVE KNPNAVVTLE NWQFEEWGSQ VTVVSSDMRE WVAPEKADII VSELLGSFAD NELSPECLDG AQHFLKDDGV SIPGEYTSFL APISSSKLYN EVRACREKDR DPEAQFEMPY VVRLHNFHQL SAPQPCFTFS HPNRDPMIDN NRYCTLEFPV EVNTVLHGFA GYFETVLYQD ITLSIRPETH SPGMFSWFPI LFPIKQPITV REGQTICVRF WRCSNSKKVW YEWAVTAPVC SAIHNPTGRS YTIG L 6His-MEP50 (SEQ ID NO.: 7) MHHHHHHRKE TPPPLVPPAA REWNLPPNAP ACMERQLEAA RYRSDGALLL GASSLSGRCW AGSLWLFKDP CAAPNEGFCS AGVQTEAGVA DLTWVGERGI LVASDSGAVE LWELDENETL IVSKFCKYEH DDIVSTVSVL SSGTQAVSGS KDICIKVWDL AQQVVLSSYR AHAAQVTCVA ASPHKDSVFL SCSEDNRILL WDTRCPKPAS QIGCSAPGYL PTSLAWHPQQ SEVFVFGDEN GTVSLVDTKS TSCVLSSAVH SQCVTGLVFS PHSVPFLASL SEDCSLAVLD SSLSELFRSQ AHRDFVRDAT WSPLNHSLLT TVGWDHQVVH HVVPTEPLPA PGPASVTE

[0512] General Procedure for PRMT5/MEP50 Enzyme Assays on Peptide Substrates.

[0513] The assays were all performed in a buffer consisting of 20 mM Bicine (pH=7.6), 1 mM TCEP, 0.005% BSG, and 0.002% Tween20, prepared on the day of use. Compounds in 100% DMSO (1 ul) were spotted into a polypropylene 384-well V-bottom plates (Greiner) using a Platemate Plus outfitted with a 384-channel head (Thermo Scientific). DMSO (1 ul) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 1 ul of SAH, a known product and inhibitor of PRMT5/MEP50, was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control. A cocktail (40 ul) containing the PRMT5/MEP50 enzyme and the peptide was added by Multidrop Combi (Thermo-Fisher). The compounds were allowed to incubate with PRMT5/MEP50 for 30 min at 25 degrees Celsius, then a cocktail (10 ul) containing .sup.3H-SAM was added to initiate the reaction (final volume=51 ul). The final concentrations of the components were as follows: PRMT5/MEP50 was 4 nM, .sup.3H-SAM was 75 nM, peptide was 40 nM, SAH in the minimum signal control wells was 100 uM, and the DMSO concentration was 1%. The assays were stopped by the addition of non-radioactive SAM (10 ul) to a final concentration of 600 uM, which dilutes the .sup.3H-SAM to a level where its incorporation into the peptide substrate is no longer detectable. 50 ul of the reaction in the 384-well polypropylene plate was then transferred to a 384-well Flashplate and the biotinylated peptides were allowed to bind to the streptavidin surface for at least 1 hour before being washed three times with 0.1% Tween20 in a Biotek EL.times.405 plate washer. The plates were then read in a PerkinElmer TopCount plate reader to measure the quantity of .sup.3H-labeled peptide bound to the Flashplate surface, measured as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).

% inhibition calculation

% .times. .times. inh = 100 - ( dpm cmpd - dpm min dpm max - dpm min ) .times. 1 .times. 0 .times. 0 ##EQU00001##

Where dpm=disintegrations per minute, cmpd=signal in assay well, and min and max are the respective minimum and maximum signal controls.

Four-parameter IC50 fit

[0514] Y = Bottom + ( Top - Bottom ) ( 1 + ( X IC 50 ) Hill .times. .times. Coefficient ##EQU00002##

Where top and bottom are the normally allowed to float, but may be fixed at 100 or 0 respectively in a 3-parameter fit. The Hill Coefficient normally allowed to float but may also be fixed at 1 in a 3-parameter fit. Y is the % inhibition and X is the compound concentration.

Z-138 Methylation Assay

[0515] Z-138 suspension cells were purchased from ATCC (American Type Culture Collection, Manassas, Va.). RPMI/Glutamax medium, penicillin-streptomycin, heat inactivated fetal bovine serum, and D-PBS were purchased from Life Technologies, Grand Island, N.Y., USA. Odyssey blocking buffer, 800CW goat anti-rabbit IgG (H+L) antibody, and Licor Odyssey infrared scanner were purchased from Licor Biosciences, Lincoln, Nebr., USA. Symmetric di-methyl arginine antibody was purchased from EMD Millipore, Billerica, Mass., USA. 16% Paraformaldehyde was purchased from Electron Microscopy Sciences, Hatfield, Pa., USA.

[0516] Z-138 suspension cells were maintained in growth medium (RPMI 1640 supplemented with 10% v/v heat inactivated fetal bovine serum and 100 units/mL penicillin-streptomycin) and cultured at 37.degree. C. under 5% CO.sub.2.

[0517] Cell Treatment, In Cell Western (ICW) for detection of Symmetric di-Methyl Arginine and DNA content. Z-138 cells were seeded in assay medium at a concentration of 50,000 cells per mL to a 384-well cell culture plate with 50 .mu.L per well. Compound (100 nL) from 384 well source plates was added directly to 384 well cell plate. Plates were incubated at 37.degree. C. 5% CO.sub.2 for 96 hours. After four days of incubation, 40 .mu.L of cells from incubated plates were added to poly-D-lysine coated 384 well culture plates (BD Biosciences 356697). Plates were incubated at room temperature for 30 minutes then incubated at 37.degree. C. 5% CO.sub.2 for 5 hours. After the incubation, 40 .mu.L per well of 8% paraformaldehyde in PBS (16% paraformaldahyde was diluted to 8% in PBS) was added to each plate and incubated for 30 minutes. Plates were transferred to a Biotek 405 plate washer and washed 5 times with 100 .mu.L per well of wash buffer (1.times.PBS with 0.1% Triton X-100 (v/v)). Next 30 .mu.L per well of Odyssey blocking buffer were added to each plate and incubated 1 hour at room temperature. Blocking buffer was removed and 20 .mu.L per well of primary antibody was added (symmetric di-methyl arginine diluted 1.100 in Odyssey buffer with 0.1% Tween 20 (v/v)) and plates were incubated overnight (16 hours) at 4.degree. C. Plates were washed 5 times with 100 .mu.L per well of wash buffer. Next 20 .mu.L per well of secondary antibody was added (1:200 800CW goat anti-rabbit IgG (H+L) antibody, 1:1000 DRAQ5 (Biostatus limited) in Odyssey buffer with 0.1% Tween 20 (v/v)) and incubated for 1 hour at room temperature. The plates were washed 5 times with 100 .mu.L per well wash buffer then 1 time with 100 .mu.L per well of water. Plates were allowed to dry at room temperature then imaged on the Licor Odyssey machine which measures integrated intensity at 700 nm and 800 nm wavelengths. Both 700 and 800 channels were scanned.

[0518] Calculations: First the ratio for each well was determined by:

( symmetric .times. .times. di .times. - .times. methyl .times. .times. Arginine .times. .times. 800 .times. .times. nm .times. .times. value DRAQ .times. .times. 5 .times. .times. 700 .times. .times. nm .times. .times. value ) ##EQU00003##

[0519] Each plate included fourteen control wells of DMSO only treatment (minimum inhibition) as well as fourteen control wells for maximum inhibition treated with 3 .mu.M of a reference compound (Background wells). The average of the ratio values for each control type was calculated and used to determine the percent inhibition for each test well in the plate. Reference compound was serially diluted three-fold in DMSO for a total of nine test concentrations, beginning at 3 .mu.M. Percent inhibition was determined and IC.sub.50 curves were generated using triplicate wells per concentration of compound.

Percent .times. .times. Inhibition = 100 - ( ( ( Individual .times. .times. Test .times. .times. Sample .times. .times. Ratio ) - ( Background .times. .times. Avg .times. .times. Ratio ) ( Minimum .times. .times. Inhbition .times. .times. Ratio ) - ( Background .times. .times. Average .times. .times. Ratio ) ) * 1 .times. 0 .times. 0 ) ##EQU00004##

Z-138 Proliferation Assay

[0520] Z-138 suspension cells were purchased from ATCC (American Type Culture Collection, Manassas, Va.). RPMI/Glutamax medium, penicillin-streptomycin, heat inactivated fetal bovine serum were purchased from Life Technologies, Grand Island, N.Y., USA. V-bottom polypropylene 384-well plates were purchased from Greiner Bio-One, Monroe, N.C., USA. Cell culture 384-well white opaque plates were purchased from Perkin Elmer, Waltham, Mass., USA. Cell-Titer Glo.RTM. was purchased from Promega Corporation, Madison, Wis., USA. SpectraMax M5 plate reader was purchased from Molecular Devices LLC, Sunnyvale, Calif., USA.

[0521] Z-138 suspension cells were maintained in growth medium (RPMI 1640 supplemented with 10% v/v heat inactivated fetal bovine serum and cultured at 37.degree. C. under 5% CO.sub.2. Under assay conditions, cells were incubated in assay medium (RPMI 1640 supplemented with 10% v/v heat inactivated fetal bovine serum and 100 units/mL penicillin-streptomycin) at 37.degree. C. under 5% CO.sub.2.

[0522] For the assessment of the effect of compounds on the proliferation of the Z-138 cell line, exponentially growing cells were plated in 384-well white opaque plates at a density of 10,000 cells/ml in a final volume of 50 .mu.l of assay medium A compound source plate was prepared by performing triplicate nine-point 3-fold serial dilutions in DMSO, beginning at 10 mM (final top concentration of compound in the assay was 20 .mu.M and the DMSO was 0.2%) A 100 nL aliquot from the compound stock plate was added to its respective well in the cell plate. The 100% inhibition control consisted of cells treated with 200 nM final concentration of staurosporine and the 0% inhibition control consisted of DMSO treated cells. After addition of compounds, assay plates were incubated for 5 days at 37.degree. C. 5% CO.sub.2, relative humidity >90%. Cell viability was measured by quantitation of ATP present in the cell cultures, adding 35 .mu.l of Cell Titer Glo.RTM. reagent to the cell plates. Luminescence was read in the SpectraMax M5 microplate reader. The concentration of compound inhibiting cell viability by 50% was determined using a 4-parametric fit of the normalized dose response curves.

[0523] Results for certain compounds described herein are shown in Table 2

TABLE-US-00005 TABLE 2 Biological Assay Results Cmpd No Biochemical IC.sub.50 ICW EC.sub.50 Proliferation EC.sub.50 1 A A C 2 A A C 3 A A C 4 C -- -- 5 B B ** 6 C -- -- 7 C -- -- 8 A A C 9 A A C 10 A B C 11 A C -- 12 B C ** 13 A A B 14 A B C 15 A B D 16 A A B 17 B B ** 18 B B D 19 A B D 20 A A B 21 B B ** 22 B B ** 23 B B ** 24 A B C 25 B C ** 26 B B D 27 C -- -- 28 A B D 29 A B C 30 A B C 31 B B D 32 B B ** 33 C -- -- 34 A B D 35 A B D 36 A B D 37 A B ** 38 A B D 39 B C ** 40 A A C 41 A A C 42 B C ** 43 B B C 44 A -- B 45 A B -- 46 C -- -- 47 B B -- 48 B B -- 49 B -- -- 50 B -- -- 51 B -- -- 52 B -- -- 53 B -- -- 54 A -- -- 55 A -- -- 56 B -- -- 57 B -- -- 58 A -- -- 59 A A B 60 B B C 61 B B -- 62 A B D 63 A A B 64 A B C 65 A A C 66 A B C 67 B B D 68 A A C 69 B C ** 70 B C ** 71 B B C 72 B C -- 73 A A C 74 A A B 75 B B -- 76 B B -- 77 A B C 78 A A B 79 A A B 80 A A B 81 A B C 82 A A B 83 B B -- 84 A A C 85 B B D 86 B C -- 87 C -- -- 88 B B ** 89 B B ** 90 A B D 91 A A C 92 A A C 93 B C ** 94 A B D 95 B B C 96 A A C 97 A A C 98 A B C 99 A A C 100 A A C 101 A A D 102 A A C 103 A A D 104 A A C 105 A A C 106 A A B 107 A A B 108 A A B 109 A A B 110 A A C 111 A B C 112 B C ** 113 A B D 114 A B D 115 A B ** 116 B B ** 117 B B ** 118 A B ** 119 A B C 120 A B C 121 A A B 122 A A B 123 A B C 124 A A A 125 A A B 126 A A C 127 A A C 128 A A C 129 A A C 130 A B D 131 A B C 132 A B C 133 A A C 134 A B D 135 A A D 136 A A C 137 A A C 138 A B D 139 A A C 140 A A C 141 A A C 142 A A C 143 A A C 144 A A C 145 A A C 146 A A C 147 A B D 148 B C ** 149 B C ** 150 B B ** 151 B B ** 152 A A B 153 A A B 154 A B C 155 B C ** 156 A B C 157 B C ** 158 A -- ** 159 A B C 160 A B D 161 A A C 162 A A C 163 A A C 164 A A C 165 A B C 166 A A B 167 A A B 168 A A B 169 A B C 170 B B ** 171 A B C 172 A A C 173 A A C 174 A A C 175 A B C 176 A A C 177 A A C 178 A A C 179 A A C 180 A B D 181 A B C 182 A A C 183 A A C 184 A A C 185 A B C 186 A A C 187 A A B 188 A A A 189 A A B 190 A A B 191 A A B 192 A A B 193 A A B 194 A B C 195 A B D 196 A A C 197 A A B 198 A A B 199 A A C 200 A B D 201 A B C 202 A A C 203 A A B 204 A A B 205 A A B 206 A B C 207 A A B 208 A A A 209 A A D 210 A A B 211 A A A 212 A A B 213 A A B 214 A A C 215 A A A 216 A A B 217 A A B 218 A B D 219 A B D 220 A A B 221 A A B 222 A B ** 223 A A C 224 A A B 225 A A A 226 A A B 227 A A B 228 A A B 229 A A C 230 A A B 231 A A C 232 B B C 233 A B C 234 A A C 235 A B ** 236 A B C 237 A A C 238 A B D 239 A A C 240 B B ** 241 A B C 242 A B C 243 A B C 244 A B C 245 A B D

246 A B C 247 A B C 248 A B C 249 A B D 250 A A C 251 A A C 252 A B C 253 A B C 254 A A A 255 A A C 256 A A C 257 A A C 258 A B D 259 A B ** 260 A B ** 261 A A C 262 A A B 263 A A C 264 A A C 265 A B C 266 A A B 267 A A B 268 A A B 269 A A C 270 C -- -- 271 A B C 272 A A C 273 A B C 274 A B C 275 B B C 276 A B C 277 A A -- 278 A A -- 279 A A -- 280 A A -- 281 A B -- 282 A A -- 283 A A -- 284 A A -- 285 B B -- 286 A A -- 287 A A -- 288 A B -- 289 B A -- 290 A A -- 291 A A -- 292 A A -- 293 A A -- 294 B B -- 295 B B -- 296 A B -- 297 A A -- 298 A A -- 299 A A -- 300 A A -- 301 A A -- 302 A A -- 303 A A -- 304 A A -- 305 B B -- 306 A -- -- 307 A -- -- 308 A -- -- 309 B -- -- 310 B -- -- 311 A -- -- 312 B -- -- 313 -- -- -- 314 A -- -- 315 A -- -- 316 A -- -- 317 A -- -- 318 A -- -- 319 A -- -- 320 A -- -- 321 A -- -- 322 A -- -- 323 A -- -- 324 A -- -- 325 A -- -- 326 A -- -- 327 B -- -- 328 C -- -- 329 A -- -- 330 A -- -- 331 A -- -- 332 A -- -- 333 A -- -- 334 A -- -- 335 A -- -- For Table 2, "A" indicates an IC.sub.50 or EC.sub.50 <0.100 .mu.M, "B" indicates an IC.sub.50 or EC.sub.50 of 0.101-1.000 .mu.M, "C" indicates an IC.sub.50 or EC.sub.50 of 1.001-10.000 .mu.M, "D" indicates an IC.sub.50 or EC.sub.50 of 10.001-50 .mu.M, and "E" indicates an IC.sub.50 or EC.sub.50 >50 .mu.M. "--" indicates no data. ** indicates an IC.sub.50 or EC.sub.50 >20 .mu.M

OTHER EMBODIMENTS

[0524] The foregoing has been a description of certain non-limiting embodiments of the invention. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Sequence CWU 1

1

71637PRTHomo sapiens 1Met Ala Ala Met Ala Val Gly Gly Ala Gly Gly Ser Arg Val Ser Ser1 5 10 15Gly Arg Asp Leu Asn Cys Val Pro Glu Ile Ala Asp Thr Leu Gly Ala 20 25 30Val Ala Lys Gln Gly Phe Asp Phe Leu Cys Met Pro Val Phe His Pro 35 40 45Arg Phe Lys Arg Glu Phe Ile Gln Glu Pro Ala Lys Asn Arg Pro Gly 50 55 60Pro Gln Thr Arg Ser Asp Leu Leu Leu Ser Gly Arg Asp Trp Asn Thr65 70 75 80Leu Ile Val Gly Lys Leu Ser Pro Trp Ile Arg Pro Asp Ser Lys Val 85 90 95Glu Lys Ile Arg Arg Asn Ser Glu Ala Ala Met Leu Gln Glu Leu Asn 100 105 110Phe Gly Ala Tyr Leu Gly Leu Pro Ala Phe Leu Leu Pro Leu Asn Gln 115 120 125Glu Asp Asn Thr Asn Leu Ala Arg Val Leu Thr Asn His Ile His Thr 130 135 140Gly His His Ser Ser Met Phe Trp Met Arg Val Pro Leu Val Ala Pro145 150 155 160Glu Asp Leu Arg Asp Asp Ile Ile Glu Asn Ala Pro Thr Thr His Thr 165 170 175Glu Glu Tyr Ser Gly Glu Glu Lys Thr Trp Met Trp Trp His Asn Phe 180 185 190Arg Thr Leu Cys Asp Tyr Ser Lys Arg Ile Ala Val Ala Leu Glu Ile 195 200 205Gly Ala Asp Leu Pro Ser Asn His Val Ile Asp Arg Trp Leu Gly Glu 210 215 220Pro Ile Lys Ala Ala Ile Leu Pro Thr Ser Ile Phe Leu Thr Asn Lys225 230 235 240Lys Gly Phe Pro Val Leu Ser Lys Met His Gln Arg Leu Ile Phe Arg 245 250 255Leu Leu Lys Leu Glu Val Gln Phe Ile Ile Thr Gly Thr Asn His His 260 265 270Ser Glu Lys Glu Phe Cys Ser Tyr Leu Gln Tyr Leu Glu Tyr Leu Ser 275 280 285Gln Asn Arg Pro Pro Pro Asn Ala Tyr Glu Leu Phe Ala Lys Gly Tyr 290 295 300Glu Asp Tyr Leu Gln Ser Pro Leu Gln Pro Leu Met Asp Asn Leu Glu305 310 315 320Ser Gln Thr Tyr Glu Val Phe Glu Lys Asp Pro Ile Lys Tyr Ser Gln 325 330 335Tyr Gln Gln Ala Ile Tyr Lys Cys Leu Leu Asp Arg Val Pro Glu Glu 340 345 350Glu Lys Asp Thr Asn Val Gln Val Leu Met Val Leu Gly Ala Gly Arg 355 360 365Gly Pro Leu Val Asn Ala Ser Leu Arg Ala Ala Lys Gln Ala Asp Arg 370 375 380Arg Ile Lys Leu Tyr Ala Val Glu Lys Asn Pro Asn Ala Val Val Thr385 390 395 400Leu Glu Asn Trp Gln Phe Glu Glu Trp Gly Ser Gln Val Thr Val Val 405 410 415Ser Ser Asp Met Arg Glu Trp Val Ala Pro Glu Lys Ala Asp Ile Ile 420 425 430Val Ser Glu Leu Leu Gly Ser Phe Ala Asp Asn Glu Leu Ser Pro Glu 435 440 445Cys Leu Asp Gly Ala Gln His Phe Leu Lys Asp Asp Gly Val Ser Ile 450 455 460Pro Gly Glu Tyr Thr Ser Phe Leu Ala Pro Ile Ser Ser Ser Lys Leu465 470 475 480Tyr Asn Glu Val Arg Ala Cys Arg Glu Lys Asp Arg Asp Pro Glu Ala 485 490 495Gln Phe Glu Met Pro Tyr Val Val Arg Leu His Asn Phe His Gln Leu 500 505 510Ser Ala Pro Gln Pro Cys Phe Thr Phe Ser His Pro Asn Arg Asp Pro 515 520 525Met Ile Asp Asn Asn Arg Tyr Cys Thr Leu Glu Phe Pro Val Glu Val 530 535 540Asn Thr Val Leu His Gly Phe Ala Gly Tyr Phe Glu Thr Val Leu Tyr545 550 555 560Gln Asp Ile Thr Leu Ser Ile Arg Pro Glu Thr His Ser Pro Gly Met 565 570 575Phe Ser Trp Phe Pro Ile Leu Phe Pro Ile Lys Gln Pro Ile Thr Val 580 585 590Arg Glu Gly Gln Thr Ile Cys Val Arg Phe Trp Arg Cys Ser Asn Ser 595 600 605Lys Lys Val Trp Tyr Glu Trp Ala Val Thr Ala Pro Val Cys Ser Ala 610 615 620Ile His Asn Pro Thr Gly Arg Ser Tyr Thr Ile Gly Leu625 630 6352620PRTHomo sapiens 2Met Arg Gly Pro Asn Ser Gly Thr Glu Lys Gly Arg Leu Val Ile Pro1 5 10 15Glu Lys Gln Gly Phe Asp Phe Leu Cys Met Pro Val Phe His Pro Arg 20 25 30Phe Lys Arg Glu Phe Ile Gln Glu Pro Ala Lys Asn Arg Pro Gly Pro 35 40 45Gln Thr Arg Ser Asp Leu Leu Leu Ser Gly Arg Asp Trp Asn Thr Leu 50 55 60Ile Val Gly Lys Leu Ser Pro Trp Ile Arg Pro Asp Ser Lys Val Glu65 70 75 80Lys Ile Arg Arg Asn Ser Glu Ala Ala Met Leu Gln Glu Leu Asn Phe 85 90 95Gly Ala Tyr Leu Gly Leu Pro Ala Phe Leu Leu Pro Leu Asn Gln Glu 100 105 110Asp Asn Thr Asn Leu Ala Arg Val Leu Thr Asn His Ile His Thr Gly 115 120 125His His Ser Ser Met Phe Trp Met Arg Val Pro Leu Val Ala Pro Glu 130 135 140Asp Leu Arg Asp Asp Ile Ile Glu Asn Ala Pro Thr Thr His Thr Glu145 150 155 160Glu Tyr Ser Gly Glu Glu Lys Thr Trp Met Trp Trp His Asn Phe Arg 165 170 175Thr Leu Cys Asp Tyr Ser Lys Arg Ile Ala Val Ala Leu Glu Ile Gly 180 185 190Ala Asp Leu Pro Ser Asn His Val Ile Asp Arg Trp Leu Gly Glu Pro 195 200 205Ile Lys Ala Ala Ile Leu Pro Thr Ser Ile Phe Leu Thr Asn Lys Lys 210 215 220Gly Phe Pro Val Leu Ser Lys Met His Gln Arg Leu Ile Phe Arg Leu225 230 235 240Leu Lys Leu Glu Val Gln Phe Ile Ile Thr Gly Thr Asn His His Ser 245 250 255Glu Lys Glu Phe Cys Ser Tyr Leu Gln Tyr Leu Glu Tyr Leu Ser Gln 260 265 270Asn Arg Pro Pro Pro Asn Ala Tyr Glu Leu Phe Ala Lys Gly Tyr Glu 275 280 285Asp Tyr Leu Gln Ser Pro Leu Gln Pro Leu Met Asp Asn Leu Glu Ser 290 295 300Gln Thr Tyr Glu Val Phe Glu Lys Asp Pro Ile Lys Tyr Ser Gln Tyr305 310 315 320Gln Gln Ala Ile Tyr Lys Cys Leu Leu Asp Arg Val Pro Glu Glu Glu 325 330 335Lys Asp Thr Asn Val Gln Val Leu Met Val Leu Gly Ala Gly Arg Gly 340 345 350Pro Leu Val Asn Ala Ser Leu Arg Ala Ala Lys Gln Ala Asp Arg Arg 355 360 365Ile Lys Leu Tyr Ala Val Glu Lys Asn Pro Asn Ala Val Val Thr Leu 370 375 380Glu Asn Trp Gln Phe Glu Glu Trp Gly Ser Gln Val Thr Val Val Ser385 390 395 400Ser Asp Met Arg Glu Trp Val Ala Pro Glu Lys Ala Asp Ile Ile Val 405 410 415Ser Glu Leu Leu Gly Ser Phe Ala Asp Asn Glu Leu Ser Pro Glu Cys 420 425 430Leu Asp Gly Ala Gln His Phe Leu Lys Asp Asp Gly Val Ser Ile Pro 435 440 445Gly Glu Tyr Thr Ser Phe Leu Ala Pro Ile Ser Ser Ser Lys Leu Tyr 450 455 460Asn Glu Val Arg Ala Cys Arg Glu Lys Asp Arg Asp Pro Glu Ala Gln465 470 475 480Phe Glu Met Pro Tyr Val Val Arg Leu His Asn Phe His Gln Leu Ser 485 490 495Ala Pro Gln Pro Cys Phe Thr Phe Ser His Pro Asn Arg Asp Pro Met 500 505 510Ile Asp Asn Asn Arg Tyr Cys Thr Leu Glu Phe Pro Val Glu Val Asn 515 520 525Thr Val Leu His Gly Phe Ala Gly Tyr Phe Glu Thr Val Leu Tyr Gln 530 535 540Asp Ile Thr Leu Ser Ile Arg Pro Glu Thr His Ser Pro Gly Met Phe545 550 555 560Ser Trp Phe Pro Ile Leu Phe Pro Ile Lys Gln Pro Ile Thr Val Arg 565 570 575Glu Gly Gln Thr Ile Cys Val Arg Phe Trp Arg Cys Ser Asn Ser Lys 580 585 590Lys Val Trp Tyr Glu Trp Ala Val Thr Ala Pro Val Cys Ser Ala Ile 595 600 605His Asn Pro Thr Gly Arg Ser Tyr Thr Ile Gly Leu 610 615 620316PRTArtificial SequenceSynthetic Polypeptide 3Ser Gly Arg Gly Lys Gly Gly Lys Gly Leu Gly Lys Gly Gly Ala Lys1 5 10 1549PRTArtificial SequenceSynthetic Polypeptide 4Met Asp Tyr Lys Asp Asp Asp Asp Lys1 557PRTArtificial SequenceSynthetic Polypeptide 5Met His His His His His His1 56645PRTArtificial SequenceSynthetic Polypeptide 6Met Asp Tyr Lys Asp Asp Asp Asp Lys Ala Ala Met Ala Val Gly Gly1 5 10 15Ala Gly Gly Ser Arg Val Ser Ser Gly Arg Asp Leu Asn Cys Val Pro 20 25 30Glu Ile Ala Asp Thr Leu Gly Ala Val Ala Lys Gln Gly Phe Asp Phe 35 40 45Leu Cys Met Pro Val Phe His Pro Arg Phe Lys Arg Glu Phe Ile Gln 50 55 60Glu Pro Ala Lys Asn Arg Pro Gly Pro Gln Thr Arg Ser Asp Leu Leu65 70 75 80Leu Ser Gly Arg Asp Trp Asn Thr Leu Ile Val Gly Lys Leu Ser Pro 85 90 95Trp Ile Arg Pro Asp Ser Lys Val Glu Lys Ile Arg Arg Asn Ser Glu 100 105 110Ala Ala Met Leu Gln Glu Leu Asn Phe Gly Ala Tyr Leu Gly Leu Pro 115 120 125Ala Phe Leu Leu Pro Leu Asn Gln Glu Asp Asn Thr Asn Leu Ala Arg 130 135 140Val Leu Thr Asn His Ile His Thr Gly His His Ser Ser Met Phe Trp145 150 155 160Met Arg Val Pro Leu Val Ala Pro Glu Asp Leu Arg Asp Asp Ile Ile 165 170 175Glu Asn Ala Pro Thr Thr His Thr Glu Glu Tyr Ser Gly Glu Glu Lys 180 185 190Thr Trp Met Trp Trp His Asn Phe Arg Thr Leu Cys Asp Tyr Ser Lys 195 200 205Arg Ile Ala Val Ala Leu Glu Ile Gly Ala Asp Leu Pro Ser Asn His 210 215 220Val Ile Asp Arg Trp Leu Gly Glu Pro Ile Lys Ala Ala Ile Leu Pro225 230 235 240Thr Ser Ile Phe Leu Thr Asn Lys Lys Gly Phe Pro Val Leu Ser Lys 245 250 255Met His Gln Arg Leu Ile Phe Arg Leu Leu Lys Leu Glu Val Gln Phe 260 265 270Ile Ile Thr Gly Thr Asn His His Ser Glu Lys Glu Phe Cys Ser Tyr 275 280 285Leu Gln Tyr Leu Glu Tyr Leu Ser Gln Asn Arg Pro Pro Pro Asn Ala 290 295 300Tyr Glu Leu Phe Ala Lys Gly Tyr Glu Asp Tyr Leu Gln Ser Pro Leu305 310 315 320Gln Pro Leu Met Asp Asn Leu Glu Ser Gln Thr Tyr Glu Val Phe Glu 325 330 335Lys Asp Pro Ile Lys Tyr Ser Gln Tyr Gln Gln Ala Ile Tyr Lys Cys 340 345 350Leu Leu Asp Arg Val Pro Glu Glu Glu Lys Asp Thr Asn Val Gln Val 355 360 365Leu Met Val Leu Gly Ala Gly Arg Gly Pro Leu Val Asn Ala Ser Leu 370 375 380Arg Ala Ala Lys Gln Ala Asp Arg Arg Ile Lys Leu Tyr Ala Val Glu385 390 395 400Lys Asn Pro Asn Ala Val Val Thr Leu Glu Asn Trp Gln Phe Glu Glu 405 410 415Trp Gly Ser Gln Val Thr Val Val Ser Ser Asp Met Arg Glu Trp Val 420 425 430Ala Pro Glu Lys Ala Asp Ile Ile Val Ser Glu Leu Leu Gly Ser Phe 435 440 445Ala Asp Asn Glu Leu Ser Pro Glu Cys Leu Asp Gly Ala Gln His Phe 450 455 460Leu Lys Asp Asp Gly Val Ser Ile Pro Gly Glu Tyr Thr Ser Phe Leu465 470 475 480Ala Pro Ile Ser Ser Ser Lys Leu Tyr Asn Glu Val Arg Ala Cys Arg 485 490 495Glu Lys Asp Arg Asp Pro Glu Ala Gln Phe Glu Met Pro Tyr Val Val 500 505 510Arg Leu His Asn Phe His Gln Leu Ser Ala Pro Gln Pro Cys Phe Thr 515 520 525Phe Ser His Pro Asn Arg Asp Pro Met Ile Asp Asn Asn Arg Tyr Cys 530 535 540Thr Leu Glu Phe Pro Val Glu Val Asn Thr Val Leu His Gly Phe Ala545 550 555 560Gly Tyr Phe Glu Thr Val Leu Tyr Gln Asp Ile Thr Leu Ser Ile Arg 565 570 575Pro Glu Thr His Ser Pro Gly Met Phe Ser Trp Phe Pro Ile Leu Phe 580 585 590Pro Ile Lys Gln Pro Ile Thr Val Arg Glu Gly Gln Thr Ile Cys Val 595 600 605Arg Phe Trp Arg Cys Ser Asn Ser Lys Lys Val Trp Tyr Glu Trp Ala 610 615 620Val Thr Ala Pro Val Cys Ser Ala Ile His Asn Pro Thr Gly Arg Ser625 630 635 640Tyr Thr Ile Gly Leu 6457348PRTArtificial SequenceSynthetic Polypeptide 7Met His His His His His His Arg Lys Glu Thr Pro Pro Pro Leu Val1 5 10 15Pro Pro Ala Ala Arg Glu Trp Asn Leu Pro Pro Asn Ala Pro Ala Cys 20 25 30Met Glu Arg Gln Leu Glu Ala Ala Arg Tyr Arg Ser Asp Gly Ala Leu 35 40 45Leu Leu Gly Ala Ser Ser Leu Ser Gly Arg Cys Trp Ala Gly Ser Leu 50 55 60Trp Leu Phe Lys Asp Pro Cys Ala Ala Pro Asn Glu Gly Phe Cys Ser65 70 75 80Ala Gly Val Gln Thr Glu Ala Gly Val Ala Asp Leu Thr Trp Val Gly 85 90 95Glu Arg Gly Ile Leu Val Ala Ser Asp Ser Gly Ala Val Glu Leu Trp 100 105 110Glu Leu Asp Glu Asn Glu Thr Leu Ile Val Ser Lys Phe Cys Lys Tyr 115 120 125Glu His Asp Asp Ile Val Ser Thr Val Ser Val Leu Ser Ser Gly Thr 130 135 140Gln Ala Val Ser Gly Ser Lys Asp Ile Cys Ile Lys Val Trp Asp Leu145 150 155 160Ala Gln Gln Val Val Leu Ser Ser Tyr Arg Ala His Ala Ala Gln Val 165 170 175Thr Cys Val Ala Ala Ser Pro His Lys Asp Ser Val Phe Leu Ser Cys 180 185 190Ser Glu Asp Asn Arg Ile Leu Leu Trp Asp Thr Arg Cys Pro Lys Pro 195 200 205Ala Ser Gln Ile Gly Cys Ser Ala Pro Gly Tyr Leu Pro Thr Ser Leu 210 215 220Ala Trp His Pro Gln Gln Ser Glu Val Phe Val Phe Gly Asp Glu Asn225 230 235 240Gly Thr Val Ser Leu Val Asp Thr Lys Ser Thr Ser Cys Val Leu Ser 245 250 255Ser Ala Val His Ser Gln Cys Val Thr Gly Leu Val Phe Ser Pro His 260 265 270Ser Val Pro Phe Leu Ala Ser Leu Ser Glu Asp Cys Ser Leu Ala Val 275 280 285Leu Asp Ser Ser Leu Ser Glu Leu Phe Arg Ser Gln Ala His Arg Asp 290 295 300Phe Val Arg Asp Ala Thr Trp Ser Pro Leu Asn His Ser Leu Leu Thr305 310 315 320Thr Val Gly Trp Asp His Gln Val Val His His Val Val Pro Thr Glu 325 330 335Pro Leu Pro Ala Pro Gly Pro Ala Ser Val Thr Glu 340 345

Claims

1-126. (canceled)

127. A method of treating breast cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound: ##STR00575## or a pharmaceutically acceptable salt thereof.

128. The method of claim 127, comprising administering to the subject in need thereof a therapeutically effective amount of the compound: ##STR00576##

129. The method of claim 127, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the compound: ##STR00577##

130. A method of treating myelodysplastic syndrome (MDS), comprising administering to a subject in need thereof a therapeutically effective amount of a compound: ##STR00578## or a pharmaceutically acceptable salt thereof.

131. The method of claim 130, comprising administering to the subject in need thereof a therapeutically effective amount of the compound: ##STR00579##

132. The method of claim 130, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the compound: ##STR00580##

133. A method of treating acute myelocytic leukemia (AML), comprising administering to a subject in need thereof a therapeutically effective amount of a compound: ##STR00581## or a pharmaceutically acceptable salt thereof.

134. The method of claim 133, comprising administering to the subject in need thereof a therapeutically effective amount of the compound: ##STR00582##

135. The method of claim 133, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the compound: ##STR00583##

136. A method of treating non-Hodgkin lymphoma (NHL), comprising administering to a subject in need thereof a therapeutically effective amount of a compound: ##STR00584## or a pharmaceutically acceptable salt thereof.

137. The method of claim 136, comprising administering to the subject in need thereof a therapeutically effective amount of the compound: ##STR00585##

138. The method of claim 136, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the compound: ##STR00586##