Compounds, Compositions, and Methods for Protein Degradation

Abstract

Disclosed herein are compounds that target SMARCA2 and SMARCA4, causing their degradation. Also disclosed herein are compositions and methods for use in treating related disorders and diseases.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 867,642, filed Jun. 27, 2019, the contents of which are hereby incorporated by reference in their entirety.

Background Art

[0002] Targeted proteolysis is a new strategy for eliminating the function of a protein of interest. To date, this process has been achieved using ligands that can bind to and recruit the ligase activity of cereblon (CRBN), von Hippel-Lindau tumor suppressor (VHL), mouse double minute 2 homolog (MDM2), or apoptosis inhibitor (IAP) proteins.

[0003] SMARCA2 and SMARCA4 (also known as the transcriptional activator Brahma-related gene 1 (BRG1) protein) are the catalytic ATPase subunits of the SWItch / Sucrose Non-Fermentable (SWI / SNF) complex, also known as the Brg / Brm-associated (BAF) complex. Together with core and regulatory subunits, SMARCA2 and SMARCA4 cause ATP hydrolysis that disrupts histone-DNA binding. This structural conversion (sculpting) of the nucleosome landscape at the promoter results in access to transcription factors and cognate DNA elements that promote both gene activation and repression.

[0004] Many tumors express mutant forms of SMARCA2 and SMARCA4, and these mutations are involved in several types of cancer. For example, synovial sarcoma (SS) typically affects young adults and teenagers, and the tumor grows in the extremities (often near joints). Standard care is surgical removal of these tumors, often in combination with radiation therapy. However, these treatments can result in significant loss of function in the affected limb, and as a result, a significant decrease in the quality of life of the subject.

[0005] SMARCA4 plays an important role in SS18-SSX, a fusion oncogene present in 95% of subjects with synovial sarcoma. SS18-SSX is formed from the fusion of synovial sarcoma translocation 18 (SS18) and synovial sarcoma breakpoint (SSX). SS18 is a component of the BAF complex, and the interaction between SS18-SSX and BAF results in the loss of function of BAF47, a known tumor suppressor. This leads to the activation of the Sox2 pathway, which is important for the proliferation of malignant SS cells. The degradation of SMARCA4 results in the disruption of the SS18-SSX / BAF complex and, thus, decreases the proliferation of malignant cells such as synovial sarcoma cells.

Summary of the Invention

Problems to be Solved by the Invention

[0006] Therefore, the targeted degradation of SMARCA2 and SMARCA4 is an attractive approach for the inhibition of SS18-SSX and the treatment of synovial sarcoma. However, to date, there are no small molecule therapeutics that target SMARCA2 and SMARCA4 and are approved for use in humans.

Means for Solving the Problems

[0007] Disclosed herein are compounds that selectively degrade SMARCA2 and SMARCA4. Compositions and methods for use in treating related disorders and diseases are also disclosed herein. These diseases include lung cancers such as non-small cell lung cancer, Burkitt lymphoma, pediatric medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial cancer, and melanoma.

[0008] In one aspect, the disclosure provides compounds of formula (I) and formula (II):

Chemical formula

[0009] In certain aspects, the disclosure provides a pharmaceutical composition comprising a compound of Formula I or Formula II and at least one pharma- ceutically acceptable excipient.

[0010] In certain aspects, the disclosure provides a method of treating cancer, comprising administering to a subject in need thereof an amount of a compound of Formula I or Formula II.

Brief Description of the Drawings

[0011]

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[0012] Overview Ubiquitination is a post-translational modification of proteins that is important for many cellular processes including proteasomal protein degradation, cell cycle progression, transcriptional regulation, DNA repair, and signal transduction. Ubiquitination requires the sequential action of three enzymes. E1 or ubiquitin-activating enzyme catalyzes the ATP-dependent activation of ubiquitin and the formation of a thioester bond between the C-terminus of ubiquitin and a catalytic cysteine on E1. The ubiquitin is then transferred to a catalytic cysteine of one of approximately 40 E2s (ubiquitin-conjugating enzymes) and then to the substrate via an E3 (ubiquitin ligase). CRBN interacts with DNA damage-binding protein-1 (DDB1), cullin 4 (Cul4A or Cul4B), and regulator of cullin 1 (RoC1) to form a functional E3 ubiquitin ligase complex. In this complex, CRBN functions as a substrate receptor of the E3 ubiquitin ligase complex and targets proteins for proteolysis via the ubiquitin-proteasome pathway.

[0013] The SMARCA2 and SMARCA4 degraders described herein are a group of synthetic molecules designed to recruit a specific ubiquitin ligase (e.g., cereblon) to a selected target protein (e.g., SMARCA2 or SMARCA4). These degraders act by bringing the target protein and the ligase very close together, enabling facile degradation by the ubiquitination process.

[0014] In one aspect, the degrader consists of two "hooks" linked by a chemical linker. The first hook is a ligase-recruiting ligand (e.g., lenalidomide), and the second hook is a ligand (e.g., PFI-3) that binds to the target protein (e.g., SMARCA2 or SMARCA4).

[0015] In one aspect, the compounds of the disclosure target the SMARCA2 and SMARCA4 proteins and utilize cereblon, an ubiquitinating E3 ligase, for degradation.

[0016] Compound In certain embodiments, the present disclosure provides compounds of formula (I) and formula (II):

Chemical formula

[0017] In certain embodiments, the compound of formula I is a compound of formula Ia or Ib, or the compound of formula II is a compound of formula IIa or IIb: [Chemical formula] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0018] In certain embodiments, X is aryl or heteroaryl; for example, X is phenyl or pyridyl. In certain embodiments, X is phenyl, for example p-phenyl, preferably p-phenyl having no additional substituents. In other embodiments, X is pyridyl, for example 3,6-pyridyl, preferably 3,6-pyridyl having no additional substituents. In still other embodiments, X is a bond.

[0019] In certain embodiments, Z-L is -NH-CH2-L. In other embodiments, Z-L is -O-CH2-L.

[0020] In certain embodiments, L is an alkylene, alkenylene, or alkynylene chain containing from 3 to 35 carbon atoms, such as from 13 to 25 carbon atoms. In certain embodiments, L contains 2 carbon atoms. In other embodiments, L contains 3 carbon atoms. In other embodiments, L contains 4 carbon atoms. In other embodiments, L contains 5 carbon atoms. In yet other embodiments, L contains 6 carbon atoms. In yet other embodiments, L contains 7 carbon atoms. In yet other embodiments, L contains 8 carbon atoms. In yet other embodiments, L contains 9 carbon atoms. In yet other embodiments, L contains 10 carbon atoms. In yet other embodiments, L contains 11 carbon atoms. In yet other embodiments, L contains 12 carbon atoms. In yet other embodiments, L contains 13 carbon atoms. In yet other embodiments, L contains 14 carbon atoms. In yet other embodiments, L contains 15 carbon atoms. In yet other embodiments, L contains 16 carbon atoms. In yet other embodiments, L contains 17 carbon atoms. In yet other embodiments, L contains 18 carbon atoms. In yet other embodiments, L contains 19 carbon atoms. In yet other embodiments, L contains 20 carbon atoms. In yet other embodiments, L contains 21 carbon atoms. In yet other embodiments, L contains 22 carbon atoms. In yet other embodiments, L contains 23 carbon atoms. In yet other embodiments, L contains 24 carbon atoms. In yet other embodiments, L contains 25 carbon atoms.

[0021] In certain embodiments, the invention relates to any one of the compounds described herein, wherein L contains from 1 to 35 -CH2- moieties, and optionally, at least one but no more than 10 of the -CH2- moieties of L are independently replaced by a moiety selected from -C(=O)-, -C(=O)-NR3--NR3-C(=O)-, -C(=O)-O-, -O-C(=O)-, -NR3-C(=O)-NR3-, -O-C(=O)-NR3-, -NR3-C(=O)-O-, -O-, -S-, and -NR3-.

[0022] In one embodiment, the present invention relates to any one of the compounds described herein, wherein at least 1 but no more than 10 -CH2- moieties of L are independently substituted with a moiety selected from -C(=O)-, -C(=O)-NR3--NR3-C(=O)-, -C(=O)-O-, -O-C(=O)-, -NR3-C(=O)-NR3-, -O-C(=O)-NR3-, -NR3-C(=O)-O-, -O-, -S-, and -NR3-.

[0023] In a preferred embodiment, at least 1 but no more than 5 -CH2- moieties of L are substituted with an amide moiety (e.g.,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0024] In certain embodiments, at least one but no more than 10 of the -CH2- moieties of L are replaced by at least one but no more than 10 -O-. In certain embodiments, at least one -CH2- moiety of L is replaced by -O-. In certain embodiments, at least two -CH2- moieties of L are replaced by at least two -O-. In certain embodiments, at least six -CH2- moieties of L are replaced by at least six -O-. In certain embodiments, one, two, or six methylene moieties of L are replaced by -O-. In certain embodiments, L comprises an ethylene glycol moiety, a diethylene glycol moiety, a triethylene glycol moiety, or an oligoethylene glycol moiety, for example, a diethylene glycol moiety.

[0025] In certain embodiments, at least one -CH2- moiety of L is replaced by -NR3-. In certain embodiments, R 3 is H.

[0026] In certain embodiments, at least one -CH2- moiety of L is replaced by -C(=O)-.

[0027] In certain embodiments, R 1 is H.

[0028] In certain embodiments, R 2 is H.

[0029] In certain embodiments, the present invention relates to compounds of formula (I). In other embodiments, the present invention relates to compounds of formula (II).

[0030] In certain embodiments, the compound of formula (I) or formula (II) is: [Table 1] [Table 2]

Table 3

Table 4

Table 5

Table 6

Table 7

[0031] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or formula (II), and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition can be used in treating or preventing a condition or disease as described herein.

[0032] Method of Use In one aspect, the present disclosure provides a method of degrading SMARCA2 or SMARCA4, comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0033] In another aspect, the present disclosure provides a method of treating a disease or disorder, comprising administering a compound of the present disclosure to a subject in need of treatment for the disease or disorder. In certain embodiments, the disease or disorder is cancer. In certain embodiments, the cancer is selected from synovial sarcoma, lung cancer, ovarian cancer, brain cancer, kidney cancer, leukemia, non-small cell lung cancer, Burkitt lymphoma, pediatric medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial cancer, and melanoma.

[0034] In yet another aspect, the present disclosure provides a method of treating a disease or disorder in which degradation of SMARCA2 or SMARCA4 is effective, comprising administering a compound of the present disclosure to a subject in need of treatment for a disease or disorder. In certain embodiments, the disease or disorder is one in which degradation of SMARCA2 is effective. In certain embodiments, the disease or disorder is one in which degradation of SMARCA4 is effective. In certain embodiments, the disease or disorder is cancer. In certain embodiments, the cancer is selected from synovial sarcoma, lung cancer, ovarian cancer, brain cancer, kidney cancer, leukemia, non-small cell lung cancer, Burkitt lymphoma, pediatric medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial cancer, and melanoma.

[0035] In certain embodiments, the methods disclosed herein further comprise co-administering one or more additional chemotherapeutic agents.

[0036] Definitions Unless defined otherwise, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains. The following references provide one of skill with a general definition of many of the terms used in this disclosure. Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless otherwise specified.

[0037] In the present disclosure, terms such as "comprising," "comprising of," "containing," and "having" can have the meanings ascribed to them in United States patent law, can mean "including," "including of," etc., and "consisting essentially of" or "consisting essentially" similarly have the meanings ascribed to them in United States patent law. This term is open-ended and allows for more occurrences than those recited, as long as the basic or novel features of the recited items are not changed by the presence of more occurrences than those recited, except for prior art embodiments.

[0038] As used herein, the term "or" is understood to be inclusive unless specifically stated otherwise or clear from the context. As used herein, the terms "a," "an," and "the" are understood to be either singular or plural unless specifically stated otherwise or clear from the context.

[0039] The term "and / or" is used in the present disclosure to mean either "and" or "or" unless otherwise indicated.

[0040] It is understood that the substituents and substitution patterns of the compounds of the present invention can be selected by those skilled in the art to result in chemically stable compounds that can be readily synthesized from readily available starting materials, by techniques known in the art, as well as by the methods described below. When the substituent itself is substituted with a group having more than 1, it is understood that these multiple groups can be on the same carbon or different carbons as long as a stable structure is obtained.

[0041] As used herein, the term "substituted" refers to the replacement of one to six hydrogen radicals in a given structure by radicals of certain substituents including, but not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2. Preferably, "substituted" refers to the replacement of one to four hydrogen radicals in a given structure with the above substituents. More preferably, one to three hydrogen radicals are substituted by substituents as described above. It is understood that the substituents can be further substituted.

[0042] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0043] The term "acylamino" is recognized in the art and refers to an amino group substituted with an acyl group, and can be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0044] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0045] The term "alkoxy" refers to an alkyl group to which oxygen is attached, preferably a lower alkyl group. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0046] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0047] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl", the latter referring to an alkenyl moiety having substituents that replace one or more hydrogens on one or more carbons of the alkenyl group. Such substituents may be present on one or more carbons that are or are not included in one or more double bonds. Further, such substituents include, except where stability is prohibited, all those contemplated for alkyl groups as discussed below. For example, substitution of an alkenyl group by one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups is contemplated.

[0048] An "alkyl" group or "alkane" is a straight or branched non-aromatic hydrocarbon that is fully saturated. Typically, a straight or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 carbon atoms unless otherwise specified. Examples of straight and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. A straight or branched C1-C6 alkyl group is also referred to as a "lower alkyl" group.

[0049] Furthermore, as used throughout this specification, examples and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl", the latter referring to an alkyl moiety having substituents that replace one or more hydrogens on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that a moiety substituted with a hydrocarbon chain can itself be substituted where appropriate. For example, substituents of substituted alkyl can include amino, azide, imino, amide, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate) and silyl groups, as well as substituted and unsubstituted forms of ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate, and ester), -CF3, -CN, etc. Exemplary substituted alkyls are described below. Cycloalkyl can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc.

[0050] The term "C x-y ", when used in combination with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, means a group containing from x to y carbons in the chain. For example, "C x-yThe term "alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing straight-chain and branched-chain alkyl groups with x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl indicates a hydrogen when the group is at the terminal position or a bond when it is internal. "C 2-y alkenyl" and "C 2-y alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups of similar length and possible substitution as the above alkyl, but each containing at least one double bond or triple bond respectively.

[0051] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0052] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0053] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond, intending to include both "unsubstituted alkynyl" and "substituted alkynyl", and the latter refers to an alkynyl moiety having a substituent that replaces a hydrogen on one or more carbons of the alkynyl group. Such substituents can be present on one or more carbons that are or are not included in one or more triple bonds. Further, such substituents include all that are contemplated for alkyl groups as discussed above, except when stability is prohibited. For example, substitution of an alkynyl group with one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups is contemplated.

[0054] As used herein, the term "amide" refers to the group

Chemical formula

[0055] The terms "amine" and "amino" are recognized in the art and refer to both unsubstituted and substituted amines and their salts, for example,

Chem.

[0056] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0057] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings and at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0058] The term "carbamate" is recognized in the art and refers to the group

Chem.

[0059] As used herein, the terms "carbocyclic" and "carbocyclic ring" refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocyclic ring includes both aromatic carbocyclic rings and non-aromatic carbocyclic rings. Non-aromatic carbocyclic rings include both cycloalkane rings in which all carbon atoms are saturated and cycloalkene rings containing at least one double bond.

[0060] The term "carbocyclic ring" includes monocyclic rings of 5 to 7 members and bicyclic rings of 8 to 12 members. Each ring of a bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. A carbocyclic ring includes bicyclic molecules in which one, two, or more atoms are shared between two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with another ring. Each ring of a fused carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocyclic as long as the valency permits. Exemplary "carbocyclic rings" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocyclic ring" can be substituted at any one or more positions where a hydrogen atom can be retained.

[0061] A "cycloalkyl" group is a completely saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

[0062] As used herein, the term "carbocyclic alkyl" refers to an alkyl group substituted with a carbocyclic group.

[0063] The term "carbonate" is recognized in the art and refers to an -OCO2-R 10 group, where R 10 represents a hydrocarbyl group.

[0064] As used herein, the term "carboxy" refers to a group represented by the formula -CO2H.

[0065] As used herein, the term "ester" refers to a -C(O)OR 10 group, where R 10 represents a hydrocarbyl group.

[0066] As used herein, the term "ether" refers to a hydrocarbyl group bonded to another hydrocarbyl group through an oxygen. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. The ether can be either symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups which can be represented by the general formula alkyl-O-alkyl.

[0067] As used herein, the terms "halo" and "halogen" mean halogen and include chloro, fluoro, bromo, and iodo.

[0068] As used herein, the terms "heteroalkyl" and "heteroarylalkyl" refer to an alkyl group substituted with a heteroaryl group.

[0069] As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, with no two heteroatoms adjacent to each other.

[0070] The terms "heteroaryl" and "heteroaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, the ring structure of which contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "heteroaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings being heteroaromatic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0071] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0072] The terms "heterocyclyl", "heterocyclic", and "heterocyclic ring" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, the ring structure of which contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic ring" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings and at least one of the rings is heterocyclic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like.

[0073] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclic group.

[0074] As used herein, the term "hydrocarbyl" refers to a group that does not have =O or =S substituents, typically has at least one carbon-hydrogen bond and mainly a carbon skeleton, but optionally contains heteroatoms and is bonded through a carbon atom. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for the purposes of this application, but substituents such as acetyl (having an =O substituent on the bonded carbon) and ethoxy (bonded through oxygen rather than carbon) are not hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0075] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0076] The term "lower", when used in combination with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, means a group containing 10 or fewer, preferably 6 or fewer non-hydrogen atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing 10 or fewer, preferably 6 or fewer carbon atoms. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are each lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents such as hydroxyalkyl and aralkyl (in which case, for example, when counting the carbon atoms of the alkyl substituent, the atoms within the aryl group are not counted).

[0077] The terms "polysicyclic", "polycyclic", and "polycyclic ring system" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings". Each ring of the polycyclic ring system can be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring system contains 3 to 10 atoms, preferably 5 to 7 atoms in the ring.

[0078] The term "silyl" refers to a silicon moiety to which three hydrocarbyl moieties are attached.

[0079] The term "substituted" refers to a moiety having a substituent that replaces hydrogen on one or more carbons of the main chain. "Substituted" or "substituted with" includes the implicit condition that such substitution follows the allowed valences of the atoms being substituted and the substituents, and also includes that the substitution results in a stable compound that does not undergo spontaneous transformation, such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents are one or more and may be the same or different for suitable organic compounds. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any permissible substituent of the organic compounds described herein that satisfies the valence of the heteroatom. Substituents can include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thiomethoate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that, where appropriate, substituents themselves may be substituted. Unless specifically stated as "unsubstituted", references herein to chemical moieties are understood to include substituted variants. For example, references to an "aryl" group or moiety implicitly include both substituted and unsubstituted variants.

[0080] The term "sulfate" is recognized in the art and refers to the -OSO3H group, or a pharmaceutically acceptable salt thereof.

[0081] The term "sulfonamide" is recognized in the art and has the general formula [Chemical formula] and refers to a group represented by wherein R 9 and R 10 each independently represents hydrogen or a hydrocarbyl such as alkyl, or R 9 and R 10 together with intervening atom(s) complete a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0082] The term "sulfoxide" is recognized in the art and refers to the -S(O)-R 10 group, where R 10 represents a hydrocarbyl.

[0083] The term "sulfonate" is recognized in the art and refers to the SO3H group or a pharmaceutically acceptable salt thereof.

[0084] The term "sulfone" is recognized in the art and refers to the -S(O)2-R 10 group, where R 10 represents a hydrocarbyl.

[0085] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0086] As used herein, the term "thioester" refers to the -C(O)SR 10 group or the -SC(O)R 10 group, where R 10 represents a hydrocarbyl.

[0087] As used herein, the term "thioether" is equivalent to an ether in which oxygen is replaced by sulfur.

[0088] The term "urea" is recognized in the art and has the general formula [Chemical formula] can be represented by wherein R 9 and R 10 each independently represents hydrogen or a hydrocarbyl such as alkyl, or the presence of either R 10 and R together with intervening atom(s) completes a heterocyclic ring having 4 to 8 atoms in the ring structure. 9

[0089] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group within a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1 - 8, 1971 - 1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert - butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2 - trimethylsilyl - ethanesulfonyl ("TES"), trityl group and substituted trityl groups, allyloxycarbonyl, 9 - fluorenylmethyloxycarbonyl ("FMOC"), nitro - veratryloxycarbonyl ("NVOC"), etc. Representative hydroxyl protecting groups include those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives, and allyl ethers, but are not limited to these.

[0090] The term "prodrug" is intended to encompass compounds (e.g., compounds of formula (I) or formula (II)) that are converted to a therapeutically active agent of the invention under physiological conditions. A common way to make a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the invention. In certain embodiments, some or all of the compounds of formula (I) or formula (II) in the formulations represented above can be replaced with the corresponding appropriate prodrugs, e.g., a hydroxyl in the parent compound is presented as an ester, or a carbonate or carboxylic acid present in the parent compound is presented as an ester.

[0091] The present invention includes all pharmaceutically acceptable isotopically labeled compounds described herein, wherein one or more atoms have the same atomic number but are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. In certain embodiments, the compounds of the invention are enriched in such isotopically labeled substances (e.g., compounds in which the distribution of isotopes in the compound in the composition is different from the natural or typical distribution of isotopes).

[0092] Examples of isotopes suitable for inclusion in the compounds of the invention include hydrogen, e.g., 2 H and 3 H, carbon, e.g., 11 C, 13 C and 14 C, chlorine, e.g., 36 Cl, fluorine, e.g., 18 F, iodine, e.g., 123 I and 125 I, nitrogen, e.g., 13 N and 15 N, oxygen, e.g., 15 O, 17 O and 18 O, phosphorus, e.g.,32 P, and sulfur, for example 35 isotopes of S.

[0093] Certain isotope-labeled compounds disclosed herein, for example, those incorporating radioisotopes, are useful in drug and / or substrate tissue distribution studies. Radioisotope tritium, that is 3 H, and carbon-14, that is 14 C are useful for this purpose from the viewpoints of their ease of incorporation and the ease of means of detection.

[0094] Deuterium, that is, 2 substitution with heavier isotopes such as H may result in certain therapeutic advantages arising from greater metabolic stability, for example, longer in vivo half-life or reduced required dosage, and may therefore be preferred in some situations.

[0095] 11 C, 18 F, 15 O and 13 substitution with positron-emitting isotopes such as N may be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy.

[0096] The compounds of the present invention may have one or more asymmetric carbon atoms and may exist in the form of mixtures of enantiomers such as optically pure enantiomers, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or mixtures of racemates of diastereoisomers. The optically active forms can be obtained, for example, by resolution of racemates, asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, some of the disclosed compounds may exist in various stereoisomeric forms.

[0097] Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly a pair of stereoisomers that cannot be superimposed because they contain an asymmetrically substituted carbon atom that acts as a chiral center. The term "enantiomer" refers to one of a pair of molecules that are mirror images of each other and cannot be superimposed. Diastereomers are most commonly stereoisomers that are not related as mirror images because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of the substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating the enantiomers from a racemate using one or more well-known techniques and methods such as chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating the enantiomers of the compounds described herein from a racemic mixture can be readily determined by those skilled in the art.

[0098] "Geometric isomers" means isomers that differ in the orientation of substituent atoms with respect to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms (other than H) on each side of a carbon-carbon double bond can be in the E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate configurations related to the core molecule. Some of the disclosed compounds may exist in the form of atropisomers. Atropisomers are stereoisomers that result from hindrance to rotation around a single bond, and the steric hindrance to rotation is high enough to allow isolation of the conformers. The compounds of the present invention can be prepared as individual isomers by enantioselective synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming salts of the free bases of each isomer of an isomer pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming salts of the acid form of each isomer of an isomer pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming esters or amides of each isomer of an isomer pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving a mixture of isomers of either the starting material or the final product using various well-known chromatographic methods.

[0099] The diastereomeric purity by weight is the ratio of the weight of one diastereomer or the total weight of all diastereomers. When the stereochemistry of the disclosed compound is named or illustrated by structure, the named or illustrated stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or illustrated by structure, the illustrated or named enantiomer is at least about 60% by weight, about 70% by weight, about 80% by weight, about 90% by weight, about 99% by weight, or about 99.9% optically pure. When a single diastereomer is named or illustrated by structure, the illustrated or named diastereomer is at least about 60% by weight, about 70% by weight, about 80% by weight, about 90% by weight, about 99% by weight, or about 99.9% pure. The percent optical purity is the ratio of the weight of the enantiomer or the weight of the enantiomer plus the weight of its optical isomer.

[0100] The percent purity by mole fraction is the ratio of the number of moles of the enantiomer (or diastereomer) or the number of moles of the enantiomer (or diastereomer) plus the number of moles of its optical isomer. When the stereochemistry of the disclosed compound is named or illustrated by structure, the named or illustrated stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% pure by mole fraction relative to the other stereoisomers. When a single enantiomer is named or illustrated by structure, the illustrated or named enantiomer is at least about 60% pure by mole fraction, about 70% pure by mole fraction, about 80% pure by mole fraction, about 90% pure by mole fraction, about 99% pure by mole fraction, or about 99.9% pure by mole fraction. When a single diastereomer is named or illustrated by structure, the illustrated or named diastereomer is at least about 60% pure by mole fraction, about 70% pure by mole fraction, about 80% pure by mole fraction, about 90% pure by mole fraction, about 99% pure by mole fraction, or about 99.9% pure by mole fraction.

[0101] When the disclosed compounds are named or illustrated by structure without showing stereochemistry and the compound has at least one chiral center, the name or structure should be understood to encompass either the enantiomer of the compound without the corresponding optical isomers, the racemic mixture of the compound, or a mixture enriched in one enantiomer as compared to the corresponding optical isomers. When the disclosed compounds are named or illustrated by structure without showing stereochemistry and have two or more chiral centers, the name or structure should be understood to encompass a diastereomer without other diastereomers, some diastereomers without other diastereomer pairs, a mixture of diastereomers, a mixture of diastereomer pairs, a mixture of diastereomers enriched in one diastereomer as compared to other diastereomer(s), or a mixture of diastereomers enriched in one or more diastereomers as compared to other diastereomers. The present invention encompasses all of these forms.

[0102] As used herein, the term "pharmaceutically acceptable salts" means any pharmaceutically acceptable salts of the compounds of formula (I). For example, any pharmaceutically acceptable salts of the compounds described herein are within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base moiety with a suitable organic acid.

[0103] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts can be acid addition salts containing inorganic or organic acids, or the salts can be prepared from inorganic or organic bases in the case of the acidic form of the compounds of the present invention. In many cases, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases, as well as methods for preparing suitable salts, are well known in the art. The salts can be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.

[0104] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, 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, toluenesulfonate, undecanoate, and valerate. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, and non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0105] The term "subject" to which administration is contemplated includes mammals such as humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or the elderly)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats and / or dogs; and / or birds such as commercially relevant birds such as chickens, ducks, geese and / or turkeys, but is not limited thereto. Preferred subjects are humans.

[0106] As used herein, a therapeutic agent that "prevents" a disorder or symptom is a compound that reduces the occurrence of a disorder or symptom in a treated sample compared to an untreated control sample, or delays or reduces the severity of the onset of one or more signs of a disorder or symptom compared to an untreated control sample, in a statistical sample.

[0107] In "treatment", the goal is to prevent or reduce (alleviate) an undesirable physiological symptom, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms;, reduction in the degree of a symptom, disorder, or disease; a stabilized (i.e., non-worsening) state of a symptom, disorder, or disease; delay or slowing of the onset of progression of a symptom, disorder, or disease; improvement or remission (partial or total) of a symptom, disorder, or disease state, whether detectable or not; improvement of at least one measurable physical parameter not necessarily recognizable by the patient; or enhancement or improvement of a symptom, disorder, or disease. Treatment includes inducing a clinically significant response without undue levels of side effects. Treatment also includes extending survival compared to survival expected in the absence of treatment.

[0108] Pharmaceutical composition The compositions and methods of the present invention can be utilized to treat a subject in need of treatment. In certain embodiments, the subject is a mammal such as a human or a non-human mammal. When administered to a subject such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline, or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters and the like. In a preferred embodiment, when such a pharmaceutical composition is for human administration, particularly for an invasive route of administration (i.e., a route such as injection or implantation that avoids transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide for delayed release of the drug or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in a dosage unit form such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized products for reconstitution, powders, solutions, syrups, suppositories, injections and the like. The composition can also be present in a transdermal delivery system, for example, in a skin patch. The composition can also be present in a solution suitable for topical administration such as eye drops.

[0109] Pharmaceutically acceptable excipients can include, for example, physiologically acceptable agents that act to stabilize, increase the solubility, or increase the absorption of a compound such as a compound of the present invention. Such physiologically acceptable agents can include, for example, carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The selection of a pharmaceutically acceptable excipient that includes a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymeric matrix. This can, for example, incorporate the compound of the present invention therein. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, metabolizable carriers and are relatively easy to manufacture and administer.

[0110] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, or other problems or complications within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0111] As used herein, the phrase "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as carboxymethylcellulose sodium, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0112] The pharmaceutical composition (preparation) can be administered to a subject by any of several routes of administration, including, for example, orally (e.g., aqueous or non-aqueous solution or suspension, tablets, capsules (including sprinkle capsules and gelatin capsules), lozenges for application to the tongue, powders, granules, pastes); absorption through the oral mucosa (e.g., sublingual); anal, rectal or vaginal (e.g., as pessaries, creams or foams); parenterally (e.g., as a sterile solution or suspension, including intramuscular, intravenous, subcutaneous or intrathecal); intranasally; intraperitoneally; subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment or spray applied to the skin or as an eye drop). The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor are described, for example, in U.S. Patent Nos. 6,110,973; 5,763,493; 5,731,000; 5,541,231; 5,427,798; 5,358,970 and 4,172,896 and the patents cited therein.

[0113] The formulations can be presented in convenient unit dosage forms and can be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent of the active ingredient.

[0114] The methods for preparing these formulations or compositions include the step of combining an active compound, such as a compound of the present invention, with a carrier and optionally one or more accessory components. Generally, the formulations are prepared by uniformly and intimately combining the compound of the present invention with a liquid carrier or a finely divided solid carrier, or both, and then shaping the product, if necessary.

[0115] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavor base, usually sucrose and acacia or tragacanth), lyophilized products, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or water-in-oil or oil-in-water liquid emulsions, or elixirs or syrups, or pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia) and / or as mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The composition or compound may also be administered as a bolus, a triturate or a paste.

[0116] To prepare solid dosage forms for oral administration (including capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is combined with sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants such as paraffin; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; (11) coloring agents, etc., and mixed with one or more pharmaceutically acceptable carriers. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also contain a buffering agent. Similar types of solid compositions can also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0117] Tablets can be prepared by compression or molding, optionally using one or more accessory components. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersing agents. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent using a suitable machine.

[0118] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, can be optionally marked or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide slow or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose in various proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and they can be compositions that release the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally with a delayed release. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, where appropriate, with one or more of the above-mentioned excipients.

[0119] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsion, lyophilized matter for reconstitution, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0120] In addition to the inert diluent, the oral composition can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, coloring agents, fragrances and preservatives.

[0121] The suspension can contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxyaluminum, bentonite, agar and tragacanth, and mixtures thereof.

[0122] The formulation of pharmaceutical compositions for rectal, vaginal or urethral administration can be presented as suppositories, which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax or salicylate, which are solid at room temperature but liquid at body temperature, so that they melt in the rectal or vaginal cavity and release the active compound.

[0123] The formulation of pharmaceutical compositions for oral administration can be presented as a mouthwash, or an oral spray, or an oral ointment.

[0124] Alternatively or additionally, the composition can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices can be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0125] Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be suitable in the art.

[0126] Dosage forms for local or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compounds can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as may be required.

[0127] Ointments, pastes, creams, and gels can contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof, in addition to the active compound.

[0128] Powders and sprays can include excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances, in addition to the active compound. Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0129] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can be used to increase the flow of the compound across the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0130] Ophthalmic preparations, eye ointments, powders, solutions, etc. are also contemplated as being within the scope of the present invention. Exemplary ophthalmic preparations are described in U.S. Patent Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074, and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If necessary, liquid ophthalmic preparations have properties similar to those of tears, aqueous humor or vitreous humor, or are compatible with such liquids. A preferred route of administration is topical administration (e.g., topical administration such as eye drops, or administration via an implant).

[0131] As used herein, the terms "parenteral administration" and "administered parenterally" mean a mode of administration other than enteral and topical administration by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subdural, intraspinal and intrasternal injections and infusions. Pharmaceutical compositions suitable for parenteral administration include one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, containing one or more active compounds combined with antioxidants, buffers, bacteriostats, solutes that may render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0132] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0133] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenolsorbic acid and the like. It may also be desirable to include in the composition isotonic agents such as sugars, sodium chloride and the like. Furthermore, the long-term absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0134] In some cases, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of the drug depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of parenterally administered drug forms is achieved by dissolving or suspending the drug in an oily vehicle.

[0135] Injectable depot forms are prepared by forming a microencapsulated matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the drug to the polymer and the nature of the specific polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0136] For use in the method of the present invention, the active compound can be administered as a pharmaceutical composition containing from 0.1 to 99.5% (more preferably from 0.5 to 90%) of the active ingredient, either by itself or in combination with a pharmaceutically acceptable carrier, for example.

[0137] The method of introduction can also be provided by a rechargeable or biodegradable device. In recent years, various sustained-release polymer devices have been developed and tested in vivo for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. Implants for the sustained release of compounds at specific target sites can be formed using various biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers.

[0138] The actual dosage level of the active ingredient in the pharmaceutical composition may vary so that it is not toxic to the subject and an effective amount of the active ingredient is obtained that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration.

[0139] The selected dosage level depends on a variety of factors including the activity of the particular compound or combination of compounds, or its ester, salt or amide, used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) used, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) used, the age, sex, weight, condition, general health and previous medical history of the subject being treated, as well as similar factors well known in the medical arts.

[0140] A physician or veterinarian of ordinary skill in the art can readily determine and prescribe a therapeutically effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can initiate the dosage of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. "Therapeutically effective amount" means a concentration of the compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary depending on the weight, sex, age, and medical history of the subject. Other factors that can affect the effective amount include, but are not limited to, the severity of the subject's symptoms, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered in combination with the compounds of the present invention. Multiple administrations of the agent can deliver a greater total dose. Methods for determining efficacy and dosage are known to those of ordinary skill in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0141] Generally, an appropriate daily dosage of the active compound used in the compositions and methods of the present invention is the amount of the compound that is the lowest dosage effective to produce a therapeutic effect. Such effective dosages generally depend on the factors described above.

[0142] Optionally, the effective daily dosage of the active compound can be administered as 1, 2, 3, 4, 5, 6 or more sub-dosages, which are optionally administered separately in unit dosage forms at appropriate intervals throughout the day. In certain embodiments of the invention, the active compound can be administered 2 or 3 times a day. In a preferred embodiment, the active compound will be administered once a day.

[0143] When used for the indicated effects, the effective dosage of the compounds of the present disclosure ranges from about 0.5 mg to about 5000 mg of the compounds of the present disclosure, as necessary to treat the condition. Compositions for in vivo or in vitro use can contain from about 0.5, about 5, about 20, about 50, about 75, about 100, about 150, about 250, about 500, about 750, about 1000, about 1250, about 2500, about 3500 or about 5000 mg of the disclosed compounds, or in ranges from one amount to another amount in the list of dosages.

[0144] In certain embodiments, the compounds of the invention can be used alone or administered in combination with another type of therapeutic agent. As used herein, the phrase "conjoint administration" refers to any administration form of two or more different therapeutic compounds such that a second compound is administered while a previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in a subject, which can include a synergistic effect of the two compounds). For example, the different therapeutic compounds can be administered simultaneously or sequentially, in the same formulation or in separate formulations. In certain embodiments, the different therapeutic compounds can be administered to each other within 1 hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or 1 week. Thus, for subjects undergoing such treatment, the combined effects of the different therapeutic compounds can be effective.

[0145] In certain embodiments, the combined administration of the compounds of the invention with one or more additional therapeutic agents results in an improvement in efficacy as compared to the separate administration of the compounds of the invention (e.g., compounds of formula (I) or formula (II)) or one or more of its additional therapeutic agents. In certain such embodiments, the combined administration results in an additive effect, which refers to the sum of the individual effects of the compounds of the invention and the individual effects of one or more of its additional therapeutic agents.

[0146] The present invention includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benethamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.

[0147] Pharmaceutically acceptable acid addition salts may also exist as various solvates with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvates can be from the crystallization solvent, inherent to the preparation or crystallization solvent, or indeterminate to such a solvent.

[0148] Wetting agents, emulsifying agents and lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition.

[0149] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0150] Examples Example 1: Synthesis of Exemplary Compounds of the Present Disclosure The compounds of formula (I) and formula (II) can be prepared by methods known in the art of organic synthesis as described in part by the following synthetic schemes. The compounds described herein can be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. NMR data were obtained using 500 MHz NMR with CDCl3 or d6-DMSO as the solvent. Synthesis of Intermediate I1

Chemical formula

[0151] Compound A1 (8.5 g, 0.042 mol), compound A2 (6.3 g, 0.042 mol), and AcOH (100 ml) were heated at reflux for 16 hours, then concentrated to dryness under reduced pressure and stirred in ethanol (150 ml) for 30 minutes. The precipitate was collected and dried to obtain 10 g of the target product as a white solid. MS: m / z (M+1)+: 330.0, 332.0

[0152] Compound A3 (4.5 g, 0.009 mol), Compound A4 (2.97 g, 0.01 mol), BINAP (0.1 equivalent), Pd2(dba)3 (0.05 equivalent) and Cs2CO3 (1.4 equivalents) were suspended in 300 ml of toluene and then stirred at 90 °C for 16 h under N2. After the reaction was completed, the mixture was concentrated and purified by SGC (PE / EA = 5 / 1~EA) to obtain 2.5 g of the target product as a yellow solid. MS: m / z (M+1)+: 448.2

[0153] Compound A5 (2.5 g, 5.59 mmol) was dissolved in 200 ml of ethanol and then 98% NH2NH2.H2O (5 equivalents) was added. The mixture was stirred at 60 °C for 4 h and then filtered. The filtrate was concentrated to obtain 1.7 g of a crude product, which was used in the next step without further purification. MS: m / z (M+1)+: 318.3

[0154] Compound A6 (1.7 g, 5.36 mmol) was dissolved in 300 ml of DCM and then DIPEA (3 equivalents) and FmocCl (1.2 equivalents) were added. The mixture was stirred at room temperature for 16 h. The mixture was washed with H2O (50 ml) and saturated NaCl solution (50 ml), then dried and concentrated to obtain 2.5 g of a crude product, which was used in the next step without further purification. MS: m / z (M+1)+: 540.3

[0155] Compound A7 (2.5 g, 4.63 mmol) was dissolved in 100 ml of DCM and then 30 ml of TFA was added. The mixture was stirred at room temperature for 4 h and then concentrated to obtain a crude product, which was adjusted to pH = 7 with NaHCO3 solution and then concentrated to obtain 2.0 g of a crude product, which was used in the next step without further purification. MS: m / z (M+1)+: 440.2

[0156] Compound A8 (2.0 g, 4.55 mmol) and Compound 9 (2 equivalents) were dissolved in 70 ml of ethanol and stirred at 85 °C for 72 h. The mixture was purified by SGC (PE / EA = 5 / 1~EA) to obtain 500 mg of the target product as a yellow solid. MS: m / z (M+1)+: 586.3

[0157] Compound A10 (500 mg, 0.85 mmol) was dissolved in 20 ml of CH3CN, and then Et2NH (10 equivalents) was added. The mixture was stirred at room temperature for 16 hours, then concentrated and purified by preparative HPLC (NH4HCO3) to obtain 150 mg of I1 as a yellow solid. MS: m / z (M+1)+: 364.2. 1 1H NMR (DMSO-d6, 500 MHz): δ 1.99 - 2.08 (m, 2H), 2.68 - 2.70 (t, 2H, J = 7.0), 3.02 - 3.04 (d, 2H, J = 9.0), 3.62 - 3.64 (d, 2H, J = 7.5), 4.65 (s, 1H), 4.73 (s, 1H), 5.81 - 5.83 (d, 1H, J = 12.0), 6.56 - 6.58 (d, 2H, J = 8.5), 6.77 - 6.79 (m, 2H), 7.01 - 7.03 (d, 2H, J = 8.0), 7.32 - 7.35 (t, 1H, J = 8.0), 7.83 - 7.84 (d, 1H, J = 7.5), 8.21 - 8.23 (d, 1H, J = 12.0), 14.45 (s, 1H). Synthesis of Intermediate I2

Chemical Structure

[0158] Compound B1 (2.2 g, 14.42 mmol), B2 (2.86 g, 14.42 mmol) and Et3N (2.0 equivalents) were dissolved in n-BuOH, and then stirred at 180 °C for 2 hours under microwave conditions. The mixture was concentrated and purified by SGC (PE / EA = 4 / 1) to obtain 800 mg of the target product as a white solid. MS: m / z (M+1)+: 315.1

[0159] A suspension of compound B3 (800 mg, 2.54 mmol) and Ra-Ni (160 mg) in 60 ml of methanol was added with NaBH4 (120 mg) in 20 ml of 8N NaOH solution at 50 °C. The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain a dark red oil, which was stirred with 10 g of KOH for 1 hour, extracted with DCM to obtain 700 mg of a crude product, and used directly in the next step without further purification. MS: m / z(M+1)+: 319.2

[0160] Compound B4 (700 mg, 2.20 mmol) was dissolved in 150 ml of DCM, then DIPEA (3 equivalents) and FmocCl (1.2 equivalents) were added. The mixture was stirred at room temperature for 16 hours. The mixture was washed with H2O (20 ml) and saturated NaCl solution (20 ml), then dried and concentrated to obtain 1.10 g of a crude product, which was used in the next step without further purification. MS: m / z(M+1)+: 541.3

[0161] Compound B5 (1.10 g, 2.03 mmol) was dissolved in 50 ml of DCM, then 15 ml of TFA was added. The mixture was stirred at room temperature for 16 hours, then concentrated to obtain a crude product, which was adjusted to pH = 7 with Et3N, then concentrated to obtain 800 mg of a crude product, and used directly in the next step without further purification. MS: m / z(M+1)+: 441.2

[0162] Compound B6 (800 mg, 1.82 mmol) and compound 7 (3 equivalents) were dissolved in 70 ml of ethanol and stirred at 85 °C for 72 hours. The mixture was purified by SGC (PE / EA = 3 / 1~EA) to obtain 200 mg of the target product as a yellow oil. MS: m / z(M+1)+: 587.2

[0163] Compound B8 (200 mg, 0.34 mmol) was dissolved in 20 ml of CH3CN, and then Et2NH (10 equivalents) was added. The mixture was stirred at room temperature for 16 hours, then concentrated and purified by prep-HPLC (NH4HCO3) to obtain 111 mg of the pure product as a yellow solid. MS: m / z (M+1)+: 365.1. 1 1H NMR (DMSO-d6, 500 MHz): δ 1.99 - 2.07 (m, 2H), 2.67 - 2.70 (t, 2H, J = 7.0), 3.07 - 3.10 (m, 1H), 3.30 - 3.37 (m, 2H), 3.48 - 3.51 (d, 1H, J = 11.0), 3.57 - 3.60 (m, 1H), 4.77 (s, 1H), 4.91 (s, 1H), 5.82 - 5.85 (d, 1H, J = 12.0), 6.50 - 6.52 (d, 2H, J = 8.5), 6.76 - 6.79 (m, 2H), 7.31 - 7.40 (m, 2H), 7.84 - 7.86 (d, 1H, J = 8.0), 7.93 (s, 1H), 8.23 - 8.25 (d, 1H, J = 12.0), 14.44 (s, 1H). Synthesis of L1, L2 and L3

Chemical Structure

[0164] 2-(2,6-Dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione: A mixture of 4-fluoroisobenzofuran-1,3-dione (498.33 mg, 3.00 mmol), 3-aminopiperidine-2,6-dione hydrochloride (493.77 mg, 3.00 mmol) and NaOAc (246.09 mg, 3.00 mmol) in HOAc (10 mL) was stirred at 135 °C overnight, cooled and concentrated in vacuo. The residue was suspended in H2O (100 mL) and stirred at room temperature for 4 hours. The solid was collected by filtration and dried in vacuo to obtain C1 as a white solid (751.43 mg, yield 92%). MS: m / z (M+1) + : 277.25.

[0165] Tert-butyl 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoate To a solution of C1 (320 mg, 1.16 mmol) and tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (321.60 mg, 1.16 mmol) in NMP (6 mL, 0.2 M) was added DIPEA (299.28 mg, 2.32 mmol). The mixture was stirred at 90 °C overnight, cooled to room temperature, diluted with EA (60 mL), and washed with H2O (3 × 20 mL). The organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (EA / PE: 2 / 1, Rf = 0.4) to give C2 (276.10 mg, 45% yield) as a yellow solid. MS: m / z (M+1) + : 534.62.

[0166] 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid To a solution of C2 (54 mg, 0.10 mmol) in DCM (0.2 mL) was added TFA (50 μL). The reaction mixture was stirred at room temperature for 2 h until completion, concentrated, and dried in vacuo to give L1 (50 mg) as a yellow solid. MS: m / z (M+1) + : 478.51.

[0167] Tert-butyl 12-aminododecanoate SOCl2 (10 mL) was slowly added to 12-aminododecanoic acid (960 mg, 6 mmol) at 0 °C. The solid dissolved and turned into a pale yellow solution upon completion of the addition. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to remove excess SOCl2. The residue was tA solution of NaHCO3 (3.57 g, 30 mmol) in BuOH (15 mL) was dissolved at 0 °C and stirred overnight at room temperature. The mixture was concentrated in vacuo to afford C3 as a yellow oil (700 mg).

[0168] Tert-butyl 12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecanoate To a solution of C1 (150 mg, 0.54 mmol) in NMP (3 mL) were added C3 (150 mg, 0.54 mmol) and DIPEA (130 mg, 1.08 mmol). The reaction mixture was stirred at 90 °C for 15 h, cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (20 mL × 2). The organic phase was dried over anhydrous MgSO4, filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane / EA = 4 / 1) to afford C4 as a yellow oil (75 mg, 26%). MS: m / z (M+H) + : 528.23.

[0169] 12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecanoic acid To a solution of C4 (75 mg, 0.14 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 24 h, concentrated, and dried in vacuo to afford L2 as a yellow oil (60 mg). MS: m / z (M+H) + : 472.34.

[0170] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione A mixture of 5-fluoroisobenzofuran-1,3-dione (498.33 mg, 3.00 mmol), 3-aminopiperidine-2,6-dione hydrochloride (493.77 mg, 3.00 mmol) and NaOAc (246.09 mg, 3.00 mmol) in HOAc (10 mL) was stirred at 135 °C overnight, cooled and concentrated in vacuo. The residue was suspended in H2O (100 mL) and stirred at room temperature for 4 h. The solid was collected by filtration and dried in vacuo to give C5 as a white solid (751.43 mg, 92% yield). MS: m / z (M+1) + : 240.55.

[0171] Tert-butyl 12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)dodecanoate To a solution of C5 (150 mg, 0.54 mmol) in NMP (3 mL) were added C3 (150 mg, 0.54 mmol) and DIPEA (130 mg, 1.08 mmol). The reaction mixture was stirred at 90 °C for 15 h, cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with water (20 mL×2). The organic phase was dried over anhydrous MgSO4, filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane / EA = 4 / 1) to give C6 as a yellow oil (51 mg, 18%). MS: m / z (M+H) + : 528.23.

[0172] 12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)dodecanoic acid To a solution of C6 (51 mg, 0.14 mmol) in DCM (4 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 24 h, concentrated and dried in vacuo to give L3 as a yellow oil (43 mg). MS: m / z (M+H) + : 472.45. Synthesis of E1, E2, and E3

Chemical formula

[0173] 3-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)-N-(4-((1S,4S)-5-((E)-3-(2-Hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)ethyl)propanamide: To a solution of L1 (2.62 mg, 0.0055 mmol) and HATU (2.90 mg, 0.0076 mmol) in DMF (0.2 mL) was added DIPEA (7.10 mg, 0.055 mmol) at room temperature. After 2 minutes, (E)-3-((1S,4S)-5-(4-(2-Aminoethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one (1.92 mg, 0.0053 mmol) was added and the mixture was stirred at room temperature for an additional 15 minutes. Monitored by LCMS, the desired product was the major one and the reaction mixture was purified by HPLC (0.1% TFA / MeCN). MS: m / z (M+1) + : 823.92.

[0174] 12-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(4-((1S,4S)-5-((E)-3-(2-Hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)ethyl)dodecanamide To a solution of L2 (2.30 mg, 0.0049 mmol) and HATU (2.23 mg, 0.0058 mmol) in DCM (0.2 mL), DIPEA (6.32 mg, 0.049 mmol) was added at room temperature. After 2 minutes, (E)-3-((1S,4S)-5-(4-(2-aminoethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one (1.80 mg, 0.0049 mmol) was added and the mixture was stirred at room temperature for an additional 15 minutes. Monitoring via LCMS, the desired product was predominant and the reaction mixture was purified via silica gel column chromatography (EA) to afford E3 (5.14 mg, purity 60 - 70%) as a yellow solid. MS: m / z (M+1) + : 818.02.

[0175] 12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(4-((1S,4S)-5-((E)-3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)dodecanamide To a solution of L2 (2.20 mg, 0.0047 mmol) and HATU (2.23 mg, 0.0058 mmol) in DCM (0.2 mL), DIPEA (6.32 mg, 0.049 mmol) was added at room temperature. After 2 minutes, (E)-3-((1S,4S)-5-(4-(2-aminoethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one (1.70 mg, 0.0047 mmol) was added and the mixture was stirred at room temperature for an additional 15 minutes. Monitoring by LCMS, the desired product was predominant and the reaction mixture was purified by silica gel column chromatography (EA) to afford E2 (purity 60 - 70%) as a yellow solid (neutral MeCN). MS: m / z (M+1) + : 818.05.

[0176] Compounds E4 - E13 were synthesized in the same manner as compounds E1 - E3.

[0177] Example 2: Biochemical Assay The inventors incubated the molecules with 0.05 uM His-tagged SMARCA4 protein and 0.015 uM biotinylated probe in alpha assay buffer (50 mM HEPES, 150 mM NaCl, 0.01% Tween-20, 0.1% BSA, pH 7.5) at room temperature for 30 minutes. After incubation, 0.02 mg / ml streptavidin donor beads (Perkin, catalog number #6760002B) and 0.02 mg / ml nickel chelate acceptor beads (Perkin, catalog number #AL108L) were added for an additional 30 minutes. Then, the luminescence signal was read and the protein-molecule interaction was quantified.

[0178] Incorporation by Reference All publications and patents mentioned in this specification are hereby incorporated by reference in their entirety, as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0179] Equivalents Although certain embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Upon review of this specification and the following claims, many variations of the invention will become apparent to those skilled in the art. The full scope of the invention should be determined by reference to the claims, the full scope of their equivalents, the specification, and such variations. The present invention includes the following embodiments 。 [1] A compound of formula I or formula II:

Chemical Formula

Chem.

Chem.

[10] The compound according to any one of [1] to [9], wherein L contains 2 carbon atoms.

[11] The compound according to any one of [1] to [9], wherein L contains 3 carbon atoms.

[12] The compound according to any one of [1] to [9], wherein L contains 4 carbon atoms.

[13] The compound according to any one of [1] to [9], wherein L contains 5 carbon atoms.

[14] The compound according to any one of [1] to [9], wherein L contains 6 carbon atoms.

[15] The compound according to any one of [1] to [9], wherein L contains 7 carbon atoms.

[16] The compound according to any one of [1] to [9], wherein L contains 8 carbon atoms.

[17] The compound according to any one of [1] to [9], wherein L contains 9 carbon atoms.

[18] The compound according to any one of [1] to [9], wherein L contains 10 carbon atoms.

[19] The compound according to any one of [1] to [9], wherein L contains 11 carbon atoms.

[20] The compound according to any one of [1] to [9], wherein L contains 12 carbon atoms.

[21] The compound according to any one of [1] to [9], wherein L contains 13 carbon atoms.

[22] The compound according to any one of [1] to [9], wherein L contains 14 carbon atoms.

[23] The compound according to any one of [1] to [9], wherein L contains 15 carbon atoms.

[24] The compound according to any one of [1] to [9], wherein L contains 16 carbon atoms.

[25] The compound according to any one of [1] to [9], wherein L contains 17 carbon atoms.

[26] The compound according to any one of [1] to [9], wherein L contains 18 carbon atoms.

[27] The compound according to any one of [1] to [9], wherein L contains 19 carbon atoms.

[28] The compound according to any one of [1] to [9], wherein L contains 20 carbon atoms.

[29] The compound according to any one of [1] to [9], wherein L contains 21 carbon atoms.

[30] The compound according to any one of [1] to [9], wherein L contains 22 carbon atoms.

[31] The compound according to any one of [1] to [9], wherein L contains 23 carbon atoms.

[32] The compound according to any one of [1] to [9], wherein L contains 24 carbon atoms.

[33] The compound according to any one of [1] to [9], wherein L contains 25 carbon atoms.

[34] At least 1 but 5 or less, the -CH of L 2 - moiety is replaced by an amide moiety (e.g.,

Chem.

[33] .

[35] At least 1 -CH of L 2 - moiety is replaced by an amide moiety (e.g.,

Chem.

[34] .

[36] At least 2 -CH of L 2 - moieties are replaced by 2 amide moieties (e.g.,

Chem.

[34] .

[37] At least 3 -CH of L 2 - moieties are replaced by 3 amide moieties (e.g.,

Chem.

[34] .

[38] 1, 2, 3, or 6 -CH of L 2 - moieties are replaced by 1, 2, 3, or 6 amide moieties (e.g.,

Chem.

[34] .

[39] The amide moiety is separated by at least 1 carbon atom (e.g., CH 2 unit), a compound according to any one of

[34] to

[38] .

[40] The amide moiety is separated by at least 6 carbon atoms (e.g., CH 2 unit), a compound according to

[39] .

[41] The carbon atom of the amide (e.g., C(=O) unit) is bonded to Z, a compound according to any one of

[34] to

[40] .

[42] The carbon atom of L is bonded to Z, a compound according to any one of [1] to

[41] .

[43] At least 1 but 10 or less, the -CH of L 2 - moiety is replaced by an oxygen atom, a compound according to any one of [1] to

[42] .

[44] At least 1 -CH of L 2 - moiety is replaced by -O-, a compound according to any one of [1] to

[43] .

[45] At least 2 -CH of L 2 - moieties are replaced by at least 2 -O-'s, a compound according to any one of [1] to

[43] .

[46] At least 6 -CH of L 2 - moieties are replaced by at least 6 -O-'s, a compound according to any one of [1] to

[43] .

[47] 1, 2, or 6 -CH of L 2 - moieties are replaced by -O-, a compound according to any one of [1] to

[43] .

[48] The L contains an ethylene glycol moiety, a diethylene glycol moiety, a triethylene glycol moiety, or an oligoethylene glycol moiety, a compound according to any one of [1] to

[43] .

[49] At least 1 -CH of L 2 - moiety is replaced by -NR 3 -, a compound according to any one of [1] to

[48] .

[50] R3 is H, a compound according to

[49] .

[51] At least one -CH of L 2 The compound according to any one of [1] to

[50] , wherein the - moiety is replaced by -C(=O)-.

[52]

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[53] A pharmaceutical composition comprising the compound according to any one of the preceding claims and a pharmaceutically acceptable carrier.

[54] A method of degrading SMARCA2 or SMARCA4, comprising contacting a cell with the compound according to any one of [1] to

[52] or a pharmaceutically acceptable salt thereof.

[55] A method of treating a disease or disorder, comprising administering to a subject in need of treatment for the disease or disorder a compound according to any one of [1] to

[52] .

[56] A method of treating a disease or disorder in which the degradation of SMARCA2 or SMARCA4 is effective, comprising administering to a subject in need of treatment for the disease or disorder a compound according to any one of [1] to

[52] .

[57] The method according to

[56] , wherein the disease or disorder is one in which the degradation of SMARCA2 is effective.

[58] The method according to

[56] , wherein the disease or disorder is one in which the degradation of SMARCA4 is effective.

[59] The method according to any one of

[55] to

[58] , wherein the disease or disorder is cancer.

[60] The method according to

[59] , wherein the cancer is selected from synovial sarcoma, lung cancer, ovarian cancer, brain cancer, kidney cancer, leukemia, non-small cell lung cancer, Burkitt lymphoma, pediatric medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial cancer and melanoma.

[61] The method according to any one of

[55] to

[60] , wherein the method further comprises co-administering one or more additional chemotherapeutic agents.

Claims

1. A compound of formula I or formula II: 【Chemical 1】 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein, X is a bond, phenyl or pyridyl; L is an alkylene chain containing 1 to 25 carbon atoms, optionally with at least 1 but not more than 10 of the -CH ２ - moieties of L being independently replaced by a moiety selected from -C(=O)-, -C(=O)-NR ３ -, -NR ３ -C(=O)-, -O-, and -NR ３ -; provided that the number of -CH - moieties of L is greater than the total number of -C(=O)-, -C(=O)-NR ２ - moieties of L, -C(=O)-, -C(=O)-NR ３ -, -NR ３ -C(=O)-, -O-, and -NR ３ - moieties, provided that there is at least 1 -CH - between each of the -C(=O)-, -C(=O)-NR ３ -, -NR ３ -C(=O)-, -O-, and -NR ３ - moieties; ２ Z-L is -CH -L, -O-CH ２ -L, or -NR ２ -CH ３ -L; and ２ R 1, R １ 2, and R3 are each H, ２ a compound, or a stereoisomer or pharmaceutically acceptable salt thereof.

2. The compound is of formula Ia, Ib, IIa, or IIb: 【Chemical 2】 【Chemical 3】 The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein X is phenyl or pyridyl.

4. Z-L is -NH-CH ２ -L, or -O-CH ２ -L, the compound according to any one of claims 1 to 3.

5. The compound according to any one of claims 1 to 4, wherein L contains 2 to 25 carbon atoms.

6. At least 1 but 5 or less of the -CH ２ - moiety of L is substituted with an amide moiety, or 1, 2, 3, or 6 of the -CH ２ - moieties of L are substituted with 1, 2, 3, or 6 amide moieties, Optionally, the amide moiety is separated by at least 1 carbon atom, or the amide moiety is separated by at least 6 carbon atoms, the compound according to any one of claims 1 to 5.

7. The compound according to claim 6, wherein the C(=O) of the amide is bonded to Z.

8. The compound according to any one of claims 1 to 7, wherein the carbon atom of L is bonded to Z.

9. At least 1 but 10 or less of the -CH ２ - moiety of L is substituted with an oxygen atom, and optionally, L contains an ethylene glycol moiety, a diethylene glycol moiety, a triethylene glycol moiety, or an oligoethylene glycol moiety, the compound according to any one of claims 1 to 8.

10. At least 1 of the -CH ２ - moiety of L is substituted with -NR ３ -, and optionally, R ３The compound according to any one of claims 1 to 9, wherein it is H.

11. At least one -CH of L ２ The compound according to any one of claims 1 to 10, wherein the - moiety is substituted with -C(=O)-.

12. The compound according to any one of claims 1 to 11, wherein R2 is H.

13. 【Chemical formula 9】 【Chemical formula 10】 【Chemical formula 11】 【Chemical formula 12】 【Chemical formula 13】 【Chemical formula 14】 【Chemical formula 15】 The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from

14. A pharmaceutical composition comprising the compound according to claim 12 or 13, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition for treating a disease or disorder in which the degradation of SMARCA2 or SMARCA4 is effective, comprising the compound according to claim 12 or 13, or a stereoisomer or pharmaceutically acceptable salt thereof, a) Optionally, the disease or disorder is cancer, and further optionally, the cancer is selected from synovial sarcoma, lung cancer, ovarian cancer, brain cancer, kidney cancer, leukemia, non-small cell lung cancer, Burkitt lymphoma, pediatric medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial cancer, and melanoma, b) Optionally, comprising co-administering one or more additional chemotherapeutic agents, A pharmaceutical composition.

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