WO2024099441A1 - Bromodomain and extra-terminal (bet) protein degrader - Google Patents

Bromodomain and extra-terminal (bet) protein degrader Download PDF

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WO2024099441A1
WO2024099441A1 PCT/CN2023/131058 CN2023131058W WO2024099441A1 WO 2024099441 A1 WO2024099441 A1 WO 2024099441A1 CN 2023131058 W CN2023131058 W CN 2023131058W WO 2024099441 A1 WO2024099441 A1 WO 2024099441A1
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optionally substituted
group
compound
alkyl
cycloalkyl
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PCT/CN2023/131058
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French (fr)
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Ying Han
Dapeng Li
Yao-Ling Qiu
Meng HAN
Sidney Yu
Dongdong HAN
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Jingrui Biopharma (Shandong) Co., Ltd.
Jingrui Biopharma (Suzhou) Co., Ltd.
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Publication of WO2024099441A1 publication Critical patent/WO2024099441A1/en

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  • the present invention is directed to novel compounds, their use and compositions thereof.
  • Such compounds comprise a target protein binding moiety and an E3 ubiquitin ligase binding moiety via a linker.
  • such compounds are useful as modulators to degrade and/or inhibit targeted ubiquitination of Bromodomain and Extra-terminal (BET) Protein.
  • Bromodomain and extraterminal domain (BET) proteins are epigenetic readers characterized by the presence of two tandem bromodomains (BD1 and BD2) , an extraterminal domain (ET) , and a C-terminal domain (CTD) . They comprise the ubiquitously expressed BRD2, BRD3, and BRD4 and the testis-restricted BRDT, and mainly recognize acetylated lysine of histone 4 (5, 6) . BET proteins also recognize acetylated nonhistone proteins, including different transcription factors.
  • BRD4 examples are the binding of BRD4 to the acetylated transcription factor TWIST, involved in mesoderm formation; to acetylated RelA, regulating the transcriptional activity of NFkappaB; or to acetylated ERG in acute myeloid leukemia (AML) cells.
  • BET proteins can also bind other proteins, including transcription factors, in a bromodomain-independent manner, such as the binding of BRD4 to FLI1, MYB, SPI1 (PU. 1) , CEBPA, CEBPB, or p53.
  • BET can also have kinase activity, a function not yet fully understood.
  • BET proteins play an essential role in increasing the overall transcriptional activity in cancer cells and, in particular, driving the overexpression of c-Myc, an oncogene that is most frequently overexpressed in various tumors. Therefore, targeting BET proteins and subsequently reducing c-Myc expression, is a plausible stretagy for anti-cancer therapy.
  • some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al., Cell, 2004 117 (3) : 349-60) .
  • the proteasome recognizes and degrades cellular proteins that are conjugated with ubiquintin. This conjugation step is mediated by a family of ubiquitin ligases, among which are the E3 ligases. Increasingly, utilizing the ubiquitin E3 ligase to direct ubiquitin conjugation of a pathological protein target, leading to subsequent removal of such protein by intrinsic protein degradation machinery, is a viable approach of therapeutic intervention.
  • proteolysis targeting chimeras involves designing a bifunctional chemical compound that links up the intended protein target and an E3 ligase, and by so doing, brings the target protein close to the proteasome and induces protein degradation of the target, and thus removing the pathological enzymatic activity of the target protein within the affected cells.
  • the PROTAC bifunctional chemical compound is composed of a moiety that binds to the intended target, a linker, and a moiety that binds to an E3 ligase (or a subunit of it) .
  • the E3 ligase used in this disclosure is the Von Hippel Lindau (VHL) .
  • VHL is the substrate recognition subunit of an E3 ligase complex called VCB.
  • a small chemical molecule that binds to VHL has been incorporated in various PROTAC designs.
  • Other E3 ligases should also be effective if they are expressed in the tumor cells of intended treatment.
  • ARV-771, ZBC-260, AT-1 and ZXH-3-26 have been demonstrated in vitro as well as in vivo efficacy in various cancer cells and a prostate cancer animal model.
  • BET protein degraders have not entered the stage of early clinical trial testing. Therefore, there remains a need to provide novel compounds which can intervene the function of BET proteins in cancer. The compounds of the present help meet this need.
  • the present invention relates to novel hetero-bifunctional compounds that function to recruit BET proteins to an E3 ubiquitin ligase for targeted ubiquitination and subsequent proteasomal degradation, and pharmaceutical compositions comprising such compounds, as well as methods of making and using the same.
  • the description provides methods of using an effective amount of a compound of the present invention for treatment or ameliorationb of a disease condition, such as BET-related disease or disorder, e.g., accumulation or overactivity of a BET protein or gain-of function of a BET protein, and various cancers.
  • the present invention provides a bifunctional compound, which comprises an E3 ubiquitin ligase binding moiety, such that the target BET proteins are thereby placed in proximity to the ubiquitin ligase to effect ubiquitination and subsequent degradation and/or inhibition of the BET protein.
  • the structure of the bifunctional compound can be depicted as:
  • T is a BET protein binding moiety (i.e. a ligand for BET proteins) , -is a bond, and U is an E3 ubiquitin ligase binding moiety (i.e. a ligand for an E3 ubiquitin ligase) ; L is a linker, such as a bond or a bivalent chemical linking group connected to groups T and U.
  • the compound as described herein comprises multiple independently selected T groups, multiple U groups, multiple chemical L groups or a combination thereof.
  • T is a small molecule moiety that binds to a BET protein.
  • T is a small molecule moiety that broadly binds to one, some or all of BRD2 (BD1 and BD2) , BRD3 (BD1 and BD2) , BRD4 (BD1 and BD2) and BRDT (BD1 and BD2) .
  • T is a small molecule moiety that selectively binds to BRD2 (BD1 or BD2) , BRD3 (BD1 or BD2) , BRD4 (BD1 or BD2) or BRDT (BD1 or BD2) .
  • U is a small molecule moiety that binds to E3 ubiquitin ligase.
  • U is a small molecule moiety that binds to E3 ubiquitin ligase Cereblon (CRBN) .
  • U is derived from optionally substituted 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione.
  • U is derived from 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione, wherein nitrogen and phenyl ring may be optionally substituted.
  • U is derived from optionally substituted 3- (1-oxoisoindolin-2-yl) piperidine-2, 6-dione.
  • U is derived from 3- (1-oxoisoindolin-2-yl) piperidine-2, 6-dione, wherein nitrogen and phenyl ring can be optionally substituted.
  • L is a bond
  • L is a connector with a linear non-hydrogen atom number in the range from 1 to 45 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 or 45) .
  • L can contain one or more functional groups including, but not limited to ether, amide, amine, CN, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, ester, urea, carbamate, thioether, sulfoxide, and sulfone.
  • L can contain an aromatic group, aheteroaromatic group, a heterocyclic group, a C 3 -C 12 cycloalkyl group, or a combination thereof, each optionally substituted with one or more groups selected from the group consisting of halogen, CN, OH, protected OH, amino, optionally substituted amino, protected amino, and optionally substituted C 1 -C 4 alkyl.
  • L can contain one or more aliphatic groups optionally substituted with one or more groups selected from the group consisting of halogen, CN, OH, protected OH, amino, optionally substituted amino, protected amino, and optionally substituted C 1 -C 4 alkyl.
  • a pharmaceutical composition comprising an effective amount of the bifunctional compound as described herein, or a salt form thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition can be used to trigger targeted degradation of one, some, or all of the BET proteins (BRD2, BRD3, BRD4 and BRDT, each with BD1 and BD2) ) , in a patient or subject, for example, an animal such as a human, and can be used for treating or ameliorating one or more disease states, conditions, or symptoms causally related to BET protein thereof, which treatment is accomplished through degradation or inhibition of the BET protein thereof, or controlling or lowering BET protein levels thereof, in a patient or subject.
  • BET proteins BET2, BRD3, BRD4 and BRDT, each with BD1 and BD2
  • the pharmaceutical compositions as described herein may be used to effectuate the degradation of BET protein thereof, for the treatment or amelioration of a disease such as, e.g., accumulation, aggregation, or overeactivity of a BET protein, a mis-folded, or a mutated form thereof (such as pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, breast cancer and brain cancer) .
  • a disease such as, e.g., accumulation, aggregation, or overeactivity of a BET protein, a mis-folded, or a mutated form thereof (such as pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, breast cancer and brain cancer)
  • Also provided herein is a method of ubiquitinating BET protein thereof in a cell (e.g., in vitro or in vivo) .
  • the method comprises administering the bifunctional compound as described herein, to effectuate degradation of the BET protein thereof.
  • Also provided herein is a description provides methods for identifying the effects of the degradation of BET protein in a biological system using the compound according to the present disclosure.
  • FIG. 1 is a Western Blot image of the degradation of BET proteins effect of example compounds 1, 3, 4, and 5 in colorectal carcinoma cell HCT-116.
  • FIG. 2 shows the degradation of BET proteins effect of example 1, 3, 4 and 5 in colorectal carcinoma cell HCT-116.
  • FIG. 3 is a Western Blot image of the degradation of BET proteins effect of example compounds 1, 3, 4, and 5 in colorectal carcinoma cell HCC1806.
  • FIG. 4 shows the degradation of BET proteins effect of example compounds1, 3, 4 and 5 in colorectal carcinoma cell HCC1806.
  • FIG. 5 is a Western Blot image of time-dependent degradation of BRD2 and BRD4 by Example 1, 3, and 5.
  • FIG. 6 shows the effect of degradation of BET proteins by example compounds 1 and 2 in colorectal carcinoma cell HCT 116 and breast cancer cell HCC1806.
  • FIG. 7 shows the effect of degradation of BET proteins by example compounds 3 and 4 in colorectal carcinoma cell HCT 116 and breast cancer cell HCC1806.
  • FIG. 8 shows the effect of degradation of BET proteins by example compound 5 in colorectal carcinoma cell HCT 116 and breast cancer cell HCC1806.
  • U is a small molecule moiety that binds to E3 ubiquitin ligase Cereblon (CRBN) .
  • U is a small molecule moiety that binds to other E3 ubiquitin ligase.
  • the present invention provide a bifunctional compound as shown by formula (A) :
  • T is a BET protein binding moiety, -is a bond
  • U is a CRBN E3 ubiquitin ligase binding moiety
  • L is a linker, such as a bond or a bivalent chemical linking group connected to groups T and U.
  • a compound of Formula (A) described above or a pharmaceutically acceptable salt thereof, stereoisomer thereof, deuterated derivatives thereof.
  • the compound as described herein comprises multiple independently selected T groups, multiple U groups, multiple chemical L groups or a combination thereof.
  • T is a small molecule moiety that binds to a BET protein.
  • T is a small molecule moiety that broadly binds to one, some or all of BRD2 (BD1 and BD2) , BRD3 (BD1 and BD2) , BRD4 (BD1 and BD2) and BRDT (BD1 and BD2) .
  • T is a small molecule moiety that selectively binds to BRD2 (BD1 or BD2) , BRD3 (BD1 or BD2) , BRD4 (BD1 or BD2) or BRDT (BD1 or BD2) .
  • U is derived from optionally substituted 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione.
  • U is derived from 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione, wherein nitrogen and phenyl ring may be optionally substituted.
  • U is derived from optionally substituted 3- (1-oxoisoindolin-2-yl) piperidine-2, 6-dione.
  • U is derived from 3- (1-oxoisoindolin-2-yl) piperidine-2, 6-dione, wherein nitrogen and phenyl ring can be optionally substituted.
  • L is a bond
  • L is a connector with a linear non-hydrogen atom number in the range from 1 to 45 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 or 45) .
  • L can contain one or more functional groups including, but not limited to ether, amide, amine, CN, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, ester, urea, carbamate, thioether, sulfoxide, and sulfone.
  • L can contain an aromatic group, aheteroaromatic group, a heterocyclic group, and a C 3 -C 12 cycloalkyl, or a combination thereof, each optionally substituted with one or more groups selected from the group consisting of halogen, CN, OH, protected OH, amino, optionally substituted amino, protected amino, and optionally substituted C 1 -C 4 alkyl.
  • L can contain an aliphatic group optionally substituted with one or more groups selected from the group consisting of halogen, CN, OH, protected OH, amino, optionally substituted amino, protected amino, and optionally substituted C 1 -C 4 alkyl.
  • T is represented by the chemical structure (I) :
  • ring A and Q are each independently selected from the group consisting of optionally substituted 3-to 12-membered aryl, optionally substituted heteroaryl or optionally substituted heterocyclic group; and W is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted 3-to 12-membered aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic group.
  • W is hydrogen or optionally substituted C 1 -C 6 alkyl.
  • W is C 1 -C 6 alkyl optionally substituted with C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, 3-to 12-membered heterocyclic group, 3-to 12-membered aryl, or optionally substituted heteroaryl; wherein the C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, 3-to 12-membered heterocyclic group, 3-to 12-membered aryl, and optionally substituted heteroaryl may be further substituted.
  • W is C 1 -C 6 alkyl optionally substituted with C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, or 3-to 12-membered heterocyclic group; wherein the C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, and 3-to 12-membered heterocyclic group may be further substituted.
  • W is C 1 -C 6 alkyl optionally substituted with 3-to 12-membered aryl or heteroaryl; wherein the 3-to 12-membered aryl and heteroaryl may be further substituted.
  • W is C 1 -C 6 alkyl substituted with a group selected from optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, and optionally substituted 3-to 12-membered heterocyclic group; and a group selected from optionally substituted 3-to 12-membered aryl and optionally substituted heteroaryl.
  • W is C 1 -C 6 alkyl substituted with an optionally substituted 3-to 12-membered heterocyclic group and an optionally substituted heteroaryl.
  • W is C 1 -C 4 alkyl substituted with an optionally substituted 3-to 12-membered heterocyclic group and an optionally substituted heteroaryl.
  • W is a methyl substituted with an optionally substituted 3-to 12-membered heterocyclic group and an optionally substituted heteroaryl.
  • W is a methyl substituted with tetrahydro-2H-pyran-4-yl and 3-fluoropyridin-2-yl or 2-pyridyl.
  • T is selected from the following chemical structures (I-1 to I-5) :
  • R 1 is selected from the group consisting of H, CN, optionally substituted C 1 -C 6 alkyl, and optionally substituted with C 3 -C 8 cycloalkyl.
  • R 1 is selected from the group consisting ofH, Me, CD 3 , Et, i-Pr, CF 3 , CHF 2 , CN, cyclopropyl, and C 1 -C 6 -alkyl optionally substituted with C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, or 3-to 12-membered heterocyclic group;
  • Q is selected from the group consisting of
  • W is selected from the group consisting of H, Me, Et, and
  • T is selected from the following chemical structures (II-1 to II-8) :
  • U is a CRBN ligand selected from the following chemical structures (III-1 to III-4) :
  • R 2 is hydrogen or optionally substituted C 1 -C 6 alkyl
  • R 3 at each occurrence is independently selected from the group consisting of hydrogen, halogen, CN, -NR 4 R 5 , -PR 4 R 5 , -P (O) R 4 R 5 , -S (O) 2 R 4 R 5 , -S (O) R 4 R 5 , -BR 4 R 5 , and optionally substituted C 1 -C 6 alkyl
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen or optionally substituted C 1 -C 6 -alkyl
  • m is 0, 1, 2 or 3.
  • L is selected from the following chemical structure:
  • M 1 and V 2 are each independently selected from the group consisting of a single bond, optionally substituted C 1 -C 4 alkyl, -N (R 6 ) -, O, S, -S (O) -, -S (O) 2 -, -OC (O) -, -N (R 6 ) C (O) -, -S (O) 2 N (R 6 ) -, -N (R 6 ) C (O) N (R 6 ) -, -N (R 6 ) C (O) O-, a double bond and a triple bond; wherein R 6 at each occurrence is independently hydrogen or optionally substituted C 1 -C 6 alkyl;
  • M 2 and V 1 are each independently selected from the group consisting of a bond, optionally substituted C 1 -C 4 alkyl, a double bond, a triple bond, optionally substituted C 3 -C 12 cycloalkyl optionally substituted heteroaryl, optionally substituted phenyl, optionally substituted heterocyclic group; wherein R 6 at each occurrence is as previously defined;
  • X at each occurrence is independently selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -N (R 6 ) -, O, S, -S (O) -, -S (O) 2 -, -OC (O) -, -N (R 6 ) C (O) -, -S (O) 2 N (R 6 ) -, -N (R 6 ) C (O) N (R 6 ) -, -N (R 6 ) C (O) O-, a double bond, a triple bond, optionally substituted 3-to 12-membered aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic group; wherein R 6 at each occurrence is as previously defined; and
  • n 1 or 2.
  • M 2 and V 1 are each independently a bond, optionally substituted heterocyclic or optionally substituted C 3 -C 12 cycloalkyl; wherein the heterocyclic group and cycloalkyl may contain a fused or spiro polycyclic system.
  • X is optionally substituted heterocyclic group or optionally substituted C 3 -C 12 cycloalkyl; wherein the heterocyclic and cycloalkyl may contain a fused or spiro polycyclic system.
  • M 2 , V 1 and X are independently selected from the following structures:
  • Y is selected from the group consisting of-C (R 6 ) 2 -, O, S, -N (R 6 ) -, and-C (O) N (R 6 ) -;
  • Z is O, -NH-, – (CH 2 ) m1 –, -OCH 2 –, or-CH 2 OCH 2 –;
  • m1 is 1, 2 or 3;
  • n1, n2, n3, n4, n5, and n6 are each independently 0, 1 or 2;
  • R 6 is as previously defined; and wherein the listed ring structures may be optionally substituted with 1 to 4 substituents selected from the group consisting of hydrogen, halogen, CN, hydroxyl, and optionally substituted C 1 -C 6 -alkyl.
  • L is selected from the following chemical structures:
  • a pharmaceutical composition comprising a compound of Formula T-U or T-L-U, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
  • a method of treating a cancer disease in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula T-U or T-L-U, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of degrading the BET protein comprising contacting the oncoprotein with an effective amount of a compound of Formula T-U or T-L-U, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.
  • the compounds of the invention are useful in cancer treatment by degrade the BET protein.
  • alleviate and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition.
  • the terms can also refer to reducing adverse effects associated with an active ingredient.
  • the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
  • aryl refers to a mono-or polycyclic carbocyclic system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
  • a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
  • Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
  • the aryl has from 6 to 20 (C 6 -C 20 ) , from 6 to 15 (C 6 -C 15 ) , or from 6 to 10 (C 6 -C 10 ) ring carbon atoms.
  • aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • the aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl) .
  • the aryl group is not bonded to the rest of a molecule through its nonaromatic ring.
  • the aryl is monocyclic.
  • the aryl is bicyclic.
  • the aryl is tricyclic.
  • the aryl is polycyclic.
  • heteroaryl refers to a mono-or polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring; wherein any N or S contained within the ring may be optionally oxidized.
  • heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl.
  • a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
  • aromatic groups can be substituted or unsubstituted.
  • bicyclic aryl or “bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and the two rings can be fused or covalently attached.
  • alkyl refers to saturated, straight-or branched-chain hydrocarbon radicals.
  • C 1 -C 3 alkyl, ” ” C 1 -C 6 alkyl, ” “C 1 -C 10 alkyl, ” “C 2 -C 4 alkyl, ” or “C 3 -C 6 alkyl, ” refer to alkyl groups containing from one to three, one to six, one to ten carbon atoms, 2 to 4 and 3 to 6 carbon atoms respectively.
  • C 1 -C 8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
  • alkenyl refers to straight-or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • C 2 -C 10 alkenyl, ” “C 2 -C 8 alkenyl, ” “C 2 -C 4 alkenyl, ” or “C 3 -C 6 alkenyl, ” refer to alkenyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • alkynyl refers to straight-or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • C 2 -C 10 alkynyl, ” “C 2 -C 8 alkynyl, ” “C 2 -C 4 alkynyl, ” or “C 3 -C 6 alkynyl, ” refer to alkynyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring or a bi-or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond.
  • Preferred cycloalkyl groups include C 3 -C 12 cycloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 8 cycloalkyl and C 4 -C 7 cycloalkyl.
  • C 3 -C 12 cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.0] hexyl, spiro [2.5] octyl, 3-methylenebicyclo [3.2.1] octyl, spiro [4.4] nonanyl, and the like.
  • cycloalkenyl refers to monocyclic or polycyclic carbocyclic ring or a bi-or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond.
  • Preferred cycloalkenyl groups include C 3 -C 12 cycloalkenyl, C 3 -C 8 cycloalkenyl or C 5 -C 7 cycloalkenyl groups.
  • C 3 -C 12 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [2.2.1] hept-2-enyl, bicyclo [3.1.0] hex-2-enyl, spiro [2.5] oct-4-enyl, spiro [4.4] non-1-enyl, bicyclo [4.2.1] non-3-en-9-yl, and the like.
  • arylalkyl means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CH 2 CH 2 -phenyl.
  • substituted arylalkyl means an arylalkyl functional group in which the aryl group is substituted.
  • heteroarylalkyl means a functional group wherein an alkylene chain is attached to a heteroaryl group.
  • substituted heteroarylalkyl means a heteroarylalkyl functional group in which the heteroaryl group is substituted.
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
  • Preferred alkoxy are (C 1 -C 3 ) alkoxy.
  • any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
  • An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds.
  • aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH 2 , C (O) , S (O) 2 , C (O) O, C (O) NH, OC (O) O, OC (O) NH, OC (O) NH 2 , S (O) 2 NH, S (O) 2 NH 2 , NHC (O) NH 2 , NHC (O) C (O) NH, NHS (O) 2 NH, NHS (O) 2 NH 2 , C (O) NHS (O) 2, C (O) NHS (O) 2 NH or C (O) NHS (O) 2 NH 2 , and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted) , and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group.
  • Carbon atoms of an aliphatic group can be optionally oxo-substituted.
  • An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.
  • heterocyclic or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic monocyclic ring or a bi-or tri-cyclic group fused, bridged or spiro ring system that contain at least one non-aromatic ring, where (i) one or more non-aromatic ring contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system
  • Representative heterocycloalkyl groups include, but are not limited to, 1, 3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo [2.2.1] -heptyl, 8-azabicyclo [3.2.1] octyl, 5-azaspiro [2.5] octyl, 1- oxa-7-azaspiro [4.4] nonanyl, 7-oxooxepan-4-yl, and te
  • heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible) .
  • any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom (s) .
  • One of skill in the art can readily determine the valence of any such group from the context in which it occurs.
  • substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, C 1 -C 12 -alkyl; C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, protected hydroxy, -NO 2 , -N 3 , -CN, -NH 2 , protected amino, oxo, thioxo, -NH-C 1 -C 12 -alkyl, -NH-C 2 -C 8 -alkenyl, -NH-C 2 -C 8 -alkynyl, -NH-C 3 -C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diary
  • the substituents are independently selected from halo, preferably Cl and F; C 1 -C 4 -alkyl, preferably methyl and ethyl; C 2 -C 4 -alkenyl; halo-C 1 -C 4 -alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; halo-C 2 -C 4 -alkenyl; C 3 -C 6 -cycloalkyl, such as cyclopropyl; -CN; -OH; NH 2 ; C 1 -C 4 -alkylamino; di (C 1 -C 4 -alkyl) amino; and NO 2 .
  • halo preferably Cl and F
  • C 1 -C 4 -alkyl preferably methyl and ethyl
  • C 2 -C 4 -alkenyl halo-C 1 -C 4 -alkyl, such as fluoromethyl, difluoromethyl,
  • each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from C 1 -C 4 -alkyl; CF 3 , C 1 -C 4 -alkoxy; -OCF 3 , -F, -Cl, -Br, -I, -OH, -NO 2 , -CN, and-NH 2 .
  • aryls, heteroaryls, alkyls, cycloalkyls and the like can be further substituted.
  • halo or halogen alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.
  • the term “optionally substituted” means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group (s) individually and independently selected from groups described herein.
  • hydrox includes hydrogen and deuterium.
  • recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.
  • the compounds of each formula herein are defined to include isotopically labelled compounds.
  • An “isotopically labelled compound” is a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope.
  • an isotopically labelled compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H) , deuterium ( 2 H) , tritium ( 3 H) , carbon-11 ( 11 C) , carbon-12 ( 12 C) , carbon-13 ( 13 C) , carbon-14 ( 14 C) , nitrogen-13 ( 13 N) , nitrogen-14 ( 14 N) , nitrogen-15 ( 15 N) , oxygen-14 ( 14 O) , oxygen-15 ( 15 O) , oxygen-16 ( 16 O) , oxygen-17 ( 17 O) , oxygen-18 ( 18 O) , fluorine-17 ( 17 F) , fluorine-18 ( 18 F) , phosphorus-31 ( 31 P) , phosphorus-32 ( 32 P) , phosphorus-33 ( 33 P) , sulfur-32 ( 32 S) , sulfur-33 ( 33 S) , sulfur-34 ( 34 S) , sulfur-35 ( 35 S) , sulfur-36 ( 36 S) , chlorine
  • an isotopically enriched compound is in a stable form, that is, non-radioactive.
  • one or more hydrogen atom positions in a compound can be enriched with deuterium to a level which is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20%or at least 50%.
  • a deuterated compound may, for example, be metabolized more slowly than its non-deuterated analog, and therefore exhibit a longer half-life when administered to a subject.
  • Such compounds can synthesize using methods known in the art, for example by employing deuterated starting materials. Unless stated to the contrary, isotopically labelled compounds are pharmaceutically acceptable.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
  • hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate and the like.
  • activated hydroxyl refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure (s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis , 3rd edition, John Wiley & Sons, New York (1999) .
  • hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2, 2, 2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl-methyl (trityl) , methoxymethyl, methylthiomethyl, benzyloxymethyl, 2- (trimethylsilyl) -ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • hydroxy prodrug group refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure (s) , the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery , (Drugs and the Pharmaceutical Sciences; Volume 53) , Marcel Dekker, Inc., New York (1992) and in “Prodrugs of Alcohols and Phenols” by S.S.
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure (s) the amino protecting group as described herein may be selectively removed.
  • Amino protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis , 3rd edition, John Wiley & Sons, New York (1999) .
  • Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • amino acid refers to naturally occurring and synthetic ⁇ , ⁇ , ⁇ , or ⁇ amino acids, and includes but is not limited to, amino acids found in proteins or intermediates in metabolism of amino acids or proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, citrulline, arginine and histidine.
  • the amino acid is in the L-configuration.
  • the amino acid is in the D-configuration.
  • the amino acid is provided as a substituent of a compound described herein, wherein the amino acid is a residue selected from the group consisting of alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, ⁇ -alanyl, ⁇ -valinyl, ⁇ -leucinyl, ⁇ -isoleuccinyl, ⁇ -prolinyl, ⁇ -phenylalaninyl, ⁇ -tryptophanyl, ⁇ -methioninyl, ⁇ -glycinyl
  • amino acid derivative refers to a group derivable from a naturally or non-naturally occurring amino acid, as described and exemplified herein.
  • Amino acid derivatives are apparent to those of skill in the art and include, but are not limited to, ester, amino alcohol, amino aldehyde, amino lactone, and N-methyl derivatives of naturally and non-naturally occurring amino acids.
  • an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is–NR u -G (S c ) -C (O) -Q 1 , wherein Q 1 is–SR v , -NR v R v or alkoxyl, R v is hydrogen or alkyl, S c is a side-chain of a naturally occurring or non-naturally occurring amino acid, G is C l -C 2 alkyl, and R u is hydrogen; or R u and S c are taken together with the atoms to which they are attached to form a five-membered heterocyclic ring.
  • an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is-O-C (O) -G (S c ) -NH-Q 2 , wherein Q 2 is hydrogen or alkoxyl, S c is a side-chain of a naturally occurring or non-naturally occurring amino acid and G is C 1 -C 2 alkyl.
  • Q 2 and S c are taken together with the atoms to which they are attached to form a five-membered heterocyclic ring.
  • G is an optionally substituted methylene and S c is selected from the group consisting of hydrogen, alkyl, arylalkyl, heterocycloalkyl, carboxylalkyl, heteroarylalkyl, aminoalkyl, hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl, sulfanylalkyl, carbamoylalkyl, alkylsulfanylalkyl and hydroxylarylalkyl.
  • an amino acid derivative is provided as a substituent of a compound described herein, wherein the amino acid derivative is in the D-configuration.
  • an amino acid derivative is provided as a substituent of a compound described herein, wherein the amino acid derivative is in the L-configuration.
  • leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • protic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject) .
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the Formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations , 2 nd Ed. Wiley-VCH (1999) ; T.W. Greene and P.G.M.
  • subject refers to an animal.
  • the animal is a mammal. More preferably, the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
  • treat, ” “treating, ” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause (s) of the disorder, disease, or condition itself.
  • the disease is a cancer.
  • alleviate and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition.
  • the terms can also refer to reducing adverse effects associated with an active ingredient.
  • the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
  • the term “inhibitor” refers to biological or chemical substance that interferes with or otherwise reduces the physiological and/or biochemical action of another biological or chemical molecule. In some embodiments, the inhibitor or antagonist specifically binds to the other molecule.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system) , increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R) -or (S) -, or as (D) -or (L) -for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus, a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of these compounds and mixtures thereof.
  • the term "pharmaceutically acceptable salt, " refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977) .
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, esters of C 1 -C 6 -alkanoic acids, such as acetate, propionate, butyrate and pivalate esters.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
  • the term "pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid;
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents,
  • compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • the pharmaceutical composition provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectable.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly (orthoesters) and poly (anhydrides) .
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the pharmaceutical composition provided herein can be administered topically to the skin, orifices, or mucosa.
  • the topical administration includes (intra) dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system.
  • Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs.
  • Delivery of aerosolized therapeutics, particularly aerosolized antibiotics is known in the art (see, for example U.S. Pat. No. 5,767,068 to Van Devanter et al., U.S. Pat. No. 5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of which are incorporated herein by reference) .
  • compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release
  • provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by compounds of the present invention in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (A) , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula (A) , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an is
  • the subject is a mammal. In certain embodiments, the subject is a human.
  • conditions are treated or prevented in a patient such as a human or another animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • the "therapeutically effective amount” or “effective amount” of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA) , cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • the therapeutic effect or biological or medical response may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect) .
  • an effective amount of the compound described above may range from about 0.001 mg/kg to about 500 mg/kg, preferably from about 0.01 to about 50 mg/kg, more preferably from about 0.1 to about 25 mg/kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05%of a given value or range.
  • the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from about 0.01 to about 50 mg/kg body weight or more usually from about 0.1 to about 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 1 mg to about 2000 mg of the compound (s) of this invention per day in single or multiple doses.
  • the administered dose can also be expressed in units other than mg/kg/day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m 2 /day to given either the height or weight of a subject or both. For example, a dose of 1 mg/m 2 /day for a 65 kg human is approximately equal to 58 mg/kg/day.
  • the compounds of the present invention described herein can, for example, be administered by injection, intravenously, intra-arterial, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.01 to about 500 mg/kg of body weight, alternatively dosages between about 1 mg and about 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
  • Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with pharmaceutically excipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 1%to about 95%active compound (w/w) .
  • such preparations may contain from about 20%to about 80%active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • a compound provided herein can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID) , and three times daily (TID) .
  • the administration can be continuous, i.e., every day, or intermittently.
  • the term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals.
  • intermittent administration of a compound provided herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) , or administration on alternate days.
  • a compound provided herein is cyclically administered to a subject. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
  • a compound provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a condition, disorder, or disease described herein.
  • the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents) .
  • the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound provided herein
  • a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) , concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject.
  • a second therapy e.g., a prophylactic or therapeutic agent
  • a compound provided herein is administered orally.
  • a compound provided herein is administered intravenously.
  • the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • acompound provided herein and a second therapy are administered by the same mode of administration, orally or by IV.
  • a compound provided herein is administered by one mode of administration, e.g., by IV, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., orally.
  • compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95%of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • the synthetic realization and optimization of the bifunctional molecules as described herein may be approached in a stepwise or modular fashion.
  • identification of compounds that bind to the target protein i.e., BET can involve high or medium throughput screening campaigns if no suitable ligands immediately available. It is not unusual for initial ligands to require iterative design and optimization cycles to improve suboptimal aspects as identified by data from suitable in vitro and pharmacological and/or ADMET assays. Part of the optimization/SAR campaign would be to probe positions of the ligand that are tolerant of substitution and that might be suitable places on which to attach the chemical linking group previously referred to herein. Where crystallographic or NMR structural data are available, these can be used to focus such a synthetic effort.
  • bifunctional molecules can be synthesized with a range of compositions, lengths and flexibility and functionalized such that the a BET protein binding moiety T and the E3 ubiquitin ligase binding moiety U can be attached sequentially to distal ends of the linker.
  • a library of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET/PK studies.
  • the final bifunctional molecules can be subject to iterative design and optimization cycles in order to identify molecules with desirable properties.
  • protecting group strategies and/or functional group interconversions may be required to facilitate the preparation of the desired materials.
  • FGIs functional group interconversions
  • R 2 , R 3 , m, n, M 1 , M 2 , X, V 1 , V 2 are as previously defined.
  • R 2 , R 3 , LG, m, n, M 1 , M 2 , X, V 1 , V 2 are as previously defined.
  • n, A, W, Q are as previously defined.
  • Step 4 Methyl 3- (5-bromo-3-nitropyridin-2-yl) -1- (methyl-d3) -1H-pyrazole-5-carboxylate
  • Step 6 Methyl 1- (methyl-d3) -3- (5- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -3-nitropyridin-2-yl) -1H-pyrazole-5-carboxylate
  • Step 7 Methyl 4-iodo-1- (methyl-d3) -3- (5- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -3-nitropyridin-2-yl) -1H-pyrazole-5-carboxylate
  • Step 8 Methyl 3- (3-amino-5- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) pyridin-2-yl) -4-iodo-1- (methyl-d3) -1H-pyrazole-5-carboxylate
  • Step 9 Methyl 2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4-dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate
  • Step 10 Methyl 4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate
  • Step 11 4- ( (3-Fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4-dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylic acid
  • Step 1 A solution of methyl 4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate (52.5 mg, 0.1 mmol) and LiAlH 4 (16 mg, 0.4 mmol) in THF (2 mL) was stirred at 25°Cover night. The reaction was quenched by water (20 mL) .
  • Step 1 To a solution of compound 2.1 (500 mg, 2.0 mmol) and TsCl (421 mg, 2.2 mmol) in DCM(5mL) was added TEA (406 mg, 4.0 mmol) , and the solution was stirred at 25°Cfor 2 h. Then the mixture was concentrated. To the residue was added EtOAc (50 mL) , and the organic phase was washed with water (10 mL) , brine (10 mL) and dried over sodium sulfate. The organic layer was concentrated to afford comound 2.2 (830 mg, crude) as yellow oil. LCMS (ESI) m/z: 404.3 [M+H] + . Chemical Formula: C 18 H 29 NO 7 S; Molecular Weight: 403.5.
  • Step 2 To a solution of 2- (2, 6-dioxopiperidin-3-yl) -4-hydroxyisoindoline-1, 3-dione (200 mg, 0.73 mmol) and compound 2.2 (323.7 mg, 0.80 mmol) in DMF (5 mL) was added NaHCO 3 (91.9 mg, 1.1 mmol) and KI (12.1 mg, 0.073 mmol) at 25°C. The reaction mixture was stirred at 80°C over night. The reaction mixture was cooled to room temperature and quenched with water (50 mL) . The aqueous layer was extracted with EtOAc (50 mL x 3) . The combined organic phase was dried over sodium sulfate and concentrated.
  • Step 3 A solution of compound 2.3 (400 mg, 0.79 mmol) in HCl/1, 4-dioxane (4 M, 2 mL) was stirred at room temperature for 2 h. The solution was concentrated to afford compound 2.4 (390 mg) as a yellow oil.
  • Step 4 To a solution of compound 2.4 (39.7 mg, 0.098 mmol) and intermediate 1 (50 mg, 0.098 mmol) in DMF (2 mL) was added HATU (112 mg, 0.29 mmol) and DIPEA (50.6 mg, 392 mmol) at 25°C. The reaction mixture was stirred at 25°C for 2 h. The reaction was quenched with water (10 mL) . The aqueous layer was extracted with EtOAc (50 mL x 3) . The combined organic layer was washed with brine (10 mL) , dried over sodium sulfate and concentrated. The residue was purified by prep-HPLC to afford Example 2 (15.2 mg, 17.3%yield) as a yellow solid.
  • Step 1 To a solution of 3- (7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (104 mg, 0.37 mmol) and compound 3.1 (92 mg, 0.37 mmol) in NMP (2 mL) was added DIPEA (96.5 mg, 0.74 mmol) at 25°C. The reaction mixture was stirred at 90°C for 2 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL) . The aqueous layer was extracted with EtOAc (50 mL x 3) . The combined organic phase was dried over sodium sulfate, filtered, and filtrate concentrated.
  • Step 2 To a solution of compound 3.2 (63.5 mg, 0.13 mmol) in DCM (5 mL) was added TFA (1 mL) , and the mixture was stirred at room temperature for 1 h. The solution was concentrated to afford compound 3.3 (45.6 mg, 89.7%yield, HCl salt) as a yellow oil.
  • Step 3 To a solution of compound 3.3 (40 mg, 0.10 mmol) and intermediate 1 (50 mg, 0.098 mmol) in DMF (3 mL) was added HATU (114 mg, 0.30 mmol) and DIPEA (38.7 mg, 0.30 mmol) at 25°C. The reaction mixture was stirred at 25°C for 16 h. The reaction was quenched with water (10 mL) . The aqueous layer was extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over sodium sulfate and concentrated. The crude product was purified by prep-HPLC to afford Example 3 (12.2 mg, 13.9%yield) as a yellow solid.
  • BET proteins including BRD2, BRD3, BRD4 and BRDT
  • cMyc protein expression induced by example compounds
  • HCT-116 and HCC1806 cells were seeded into 96-well plate and chemical compounds for growth inhibition were added at 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, 1 uM, 300 nM, 100 nM, 30 nM, 10 nM, and DMSO (vehicle solvent) .
  • the IC50 of the tested compounds were derived from fitting non-linear regression equation:
  • logIC50 same log units as X
  • Results are shown in Tables 1-3 and FIGs 1-8.
  • DC 50 Compound concentrations that reduce BET proteins, BRD2, BRD3, BRD4 and BRDT, by 50%relative to no drug control (DC 50 ) are reported.
  • DC 50 ranges are as follows: A ⁇ 0.05 ⁇ M; B 0.05-0.1 ⁇ M; C 0.1 ⁇ M-0.5 ⁇ M; D>0.5 ⁇ M.
  • N.D. Value not determined
  • EC 50 compound concentrations that reduce cell proliferation by 50%relative to no drug controls
  • EC 50 compound concentrations that reduce cell proliferation by 50%relative to no drug controls

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Abstract

Provided are compounds of Formula (A), or pharmaceutically acceptable salts, esters, or prodrugs thereof: T-L-U, wherein T is a BET protein binding moiety (i.e. a ligand for BET proteins), -is a bond, and U is an E3 ubiquitin ligase binding moiety (i.e. a ligand for an E3 ubiquitin ligase); L is a linker, such as a bond or a bivalent chemical linking group connected to groups T and U.

Description

BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN DEGRADER TECHNICAL FIELD
The present invention is directed to novel compounds, their use and compositions thereof. Such compounds comprise a target protein binding moiety and an E3 ubiquitin ligase binding moiety via a linker. Specifically, such compounds are useful as modulators to degrade and/or inhibit targeted ubiquitination of Bromodomain and Extra-terminal (BET) Protein.
BACKGROUND OF THE INVENTION
Bromodomain and extraterminal domain (BET) proteins are epigenetic readers characterized by the presence of two tandem bromodomains (BD1 and BD2) , an extraterminal domain (ET) , and a C-terminal domain (CTD) . They comprise the ubiquitously expressed BRD2, BRD3, and BRD4 and the testis-restricted BRDT, and mainly recognize acetylated lysine of histone 4 (5, 6) . BET proteins also recognize acetylated nonhistone proteins, including different transcription factors. Examples are the binding of BRD4 to the acetylated transcription factor TWIST, involved in mesoderm formation; to acetylated RelA, regulating the transcriptional activity of NFkappaB; or to acetylated ERG in acute myeloid leukemia (AML) cells. BET proteins can also bind other proteins, including transcription factors, in a bromodomain-independent manner, such as the binding of BRD4 to FLI1, MYB, SPI1 (PU. 1) , CEBPA, CEBPB, or p53. Finally, BET can also have kinase activity, a function not yet fully understood. All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division-suggesting a role in the maintenance of epigenetic memory. During oncogenesis, BET proteins play an essential role in increasing the overall transcriptional activity in cancer cells and, in particular, driving the overexpression of c-Myc, an oncogene that is most frequently overexpressed in various tumors. Therefore, targeting BET proteins and subsequently reducing c-Myc expression, is a plausible stretagy for anti-cancer therapy. In addition, some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al., Cell, 2004 117 (3) : 349-60) .
The proteasome recognizes and degrades cellular proteins that are conjugated with ubiquintin. This conjugation step is mediated by a family of ubiquitin ligases, among which are the E3 ligases. Increasingly, utilizing the ubiquitin E3 ligase to direct ubiquitin conjugation of a pathological protein target, leading to subsequent removal of such protein by intrinsic protein degradation machinery, is a viable approach of therapeutic intervention. Such approach, called proteolysis targeting chimeras (PROTACs) , involves designing a bifunctional chemical compound that links up the intended protein target and an E3 ligase, and by so doing, brings the target protein close to the proteasome and induces protein degradation of the target, and thus removing the pathological enzymatic activity of the target protein within the affected cells. The PROTAC bifunctional chemical compound is composed of a moiety that binds to the intended target, a linker, and a moiety that binds to an E3 ligase (or a subunit of it) . The E3 ligase used in this disclosure is the Von Hippel Lindau (VHL) . VHL is the substrate recognition subunit of an E3 ligase complex called VCB. A small chemical molecule that binds to VHL has been incorporated in various PROTAC designs. Other E3 ligases should also be effective if they are expressed in the tumor cells of intended treatment.
Although ARV-771, ZBC-260, AT-1 and ZXH-3-26 have been demonstrated in vitro as well as in vivo efficacy in various cancer cells and a prostate cancer animal model. BET protein degraders have not entered the stage of early clinical trial testing. Therefore, there remains a need to provide novel compounds which can intervene the function of BET proteins in cancer. The compounds of the present help meet this need.
SUMMARY OF THE INVENTION
The present invention relates to novel hetero-bifunctional compounds that function to recruit BET proteins to an E3 ubiquitin ligase for targeted ubiquitination and subsequent proteasomal degradation, and pharmaceutical compositions comprising such compounds, as well as methods of making and using the same. In addition, the description provides methods of using an effective amount of a compound of the present invention for treatment or ameliorationb of a disease condition, such as BET-related disease or disorder, e.g., accumulation or overactivity of a BET protein or gain-of function of a BET protein, and various cancers.
In a first aspect, the present invention provides a bifunctional compound, which comprises an E3 ubiquitin ligase binding moiety, such that the target BET proteins are thereby placed in proximity to the ubiquitin ligase to effect ubiquitination and subsequent degradation and/or inhibition of the BET protein. The structure of the bifunctional compound can be depicted as:
T-L-U
wherein T is a BET protein binding moiety (i.e. a ligand for BET proteins) , -is a bond, and U is an E3 ubiquitin ligase binding moiety (i.e. a ligand for an E3 ubiquitin ligase) ; L is a linker, such as a bond or a bivalent chemical linking group connected to groups T and U.
In certain embodiments of the present invention, the compound as described herein comprises multiple independently selected T groups, multiple U groups, multiple chemical L groups or a combination thereof.
In any of the aspects or embodiments of the present invention, T is a small molecule moiety that binds to a BET protein.
In certain embodiments of the present invention, T is a small molecule moiety that broadly binds to one, some or all of BRD2 (BD1 and BD2) , BRD3 (BD1 and BD2) , BRD4 (BD1 and BD2) and BRDT (BD1 and BD2) .
In certain embodiments of the present invention, T is a small molecule moiety that selectively binds to BRD2 (BD1 or BD2) , BRD3 (BD1 or BD2) , BRD4 (BD1 or BD2) or BRDT (BD1 or BD2) .
In any of the aspects or embodiments of the present invention, U is a small molecule moiety that binds to E3 ubiquitin ligase.
In certain embodiments of the present invention, U is a small molecule moiety that binds to E3 ubiquitin ligase Cereblon (CRBN) .
In certain embodiments of the present invention, U is derived from optionally substituted 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione.
In certain embodiments of the present invention, U is derived from 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione, wherein nitrogen and phenyl ring may be optionally substituted.
In certain embodiments of the present invention, U is derived from optionally substituted 3- (1-oxoisoindolin-2-yl) piperidine-2, 6-dione.
In certain embodiments of the present invention, U is derived from 3- (1-oxoisoindolin-2-yl) piperidine-2, 6-dione, wherein nitrogen and phenyl ring can be optionally substituted.
In certain embodiments of the present invention, L is a bond.
In certain embodiments of the present invention, L is a connector with a linear non-hydrogen atom number in the range from 1 to 45 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 or 45) .
In certain embodiments of the present invention, L can contain one or more functional groups including, but not limited to ether, amide, amine, CN, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, ester, urea, carbamate, thioether, sulfoxide, and sulfone.
In certain embodiments of the present invention, L can contain an aromatic group, aheteroaromatic group, a heterocyclic group, a C3-C12 cycloalkyl group, or a combination thereof, each optionally substituted with one or more groups selected from the group consisting of halogen, CN, OH, protected OH, amino, optionally substituted amino, protected amino, and optionally substituted C1-C4 alkyl.
In certain embodiments of the present invention, L can contain one or more aliphatic groups optionally substituted with one or more groups selected from the group consisting of halogen, CN, OH, protected OH, amino, optionally substituted amino, protected amino, and optionally substituted C1-C4 alkyl.
Also provided herein is a pharmaceutical composition comprising an effective amount of the bifunctional compound as described herein, or a salt form thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition can be used to trigger targeted degradation of one, some, or all of the BET proteins (BRD2, BRD3, BRD4 and BRDT, each with BD1 and BD2) ) , in a patient or subject, for example, an animal such as a human, and can be used for treating or ameliorating one or more disease states, conditions, or symptoms causally related to BET protein thereof, which treatment is accomplished through degradation or inhibition of the BET protein thereof, or controlling or lowering BET protein levels thereof, in a patient or subject. In certain embodiments, the pharmaceutical compositions as described herein may be used to effectuate the degradation of BET protein thereof, for the treatment or amelioration of a disease such as, e.g., accumulation, aggregation,  or overeactivity of a BET protein, a mis-folded, or a mutated form thereof (such as pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, breast cancer and brain cancer) .
Also provided herein is a method of ubiquitinating BET protein thereof in a cell (e.g., in vitro or in vivo) . In any aspect or embodiment described herein, the method comprises administering the bifunctional compound as described herein, to effectuate degradation of the BET protein thereof.
Also provided herein is a description provides methods for identifying the effects of the degradation of BET protein in a biological system using the compound according to the present disclosure.
Additionally provided herein is processes and intermediates for making the bifunctional compound of the present disclosure capable of targeted ubiquitination and degradation of the BET protein in a cell (e.g., in vivo or in vitro) .
These and other features of the invention will be set forth in expanded form as the disclosure continues.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a Western Blot image of the degradation of BET proteins effect of example compounds 1, 3, 4, and 5 in colorectal carcinoma cell HCT-116.
FIG. 2 shows the degradation of BET proteins effect of example 1, 3, 4 and 5 in colorectal carcinoma cell HCT-116.
FIG. 3 is a Western Blot image of the degradation of BET proteins effect of example compounds 1, 3, 4, and 5 in colorectal carcinoma cell HCC1806.
FIG. 4 shows the degradation of BET proteins effect of example compounds1, 3, 4 and 5 in colorectal carcinoma cell HCC1806.
FIG. 5 is a Western Blot image of time-dependent degradation of BRD2 and BRD4 by Example 1, 3, and 5.
FIG. 6 shows the effect of degradation of BET proteins by example compounds 1 and 2 in colorectal carcinoma cell HCT 116 and breast cancer cell HCC1806.
FIG. 7 shows the effect of degradation of BET proteins by example compounds 3 and 4 in colorectal carcinoma cell HCT 116 and breast cancer cell HCC1806.
FIG. 8 shows the effect of degradation of BET proteins by example compound 5 in colorectal carcinoma cell HCT 116 and breast cancer cell HCC1806.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, U is a small molecule moiety that binds to E3 ubiquitin ligase Cereblon (CRBN) . In another aspect, U is a small molecule moiety that binds to other E3 ubiquitin ligase.
In one aspect, the present invention provide a bifunctional compound as shown by formula (A) :
T-L-U    (A)
wherein T is a BET protein binding moiety, -is a bond, U is a CRBN E3 ubiquitin ligase binding moiety, and L is a linker, such as a bond or a bivalent chemical linking group connected to groups T and U.
In one embodiment of the present invention, provided is a compound of Formula (A) described above, or a pharmaceutically acceptable salt thereof, stereoisomer thereof, deuterated derivatives thereof.
In certain embodiments of the present invention, the compound as described herein comprises multiple independently selected T groups, multiple U groups, multiple chemical L groups or a combination thereof.
In any of the aspects or embodiments of the present invention, T is a small molecule moiety that binds to a BET protein.
In certain embodiments of the present invention, T is a small molecule moiety that broadly binds to one, some or all of BRD2 (BD1 and BD2) , BRD3 (BD1 and BD2) , BRD4 (BD1 and BD2) and BRDT (BD1 and BD2) .
In certain embodiments of the present invention, T is a small molecule moiety that selectively binds to BRD2 (BD1 or BD2) , BRD3 (BD1 or BD2) , BRD4 (BD1 or BD2) or BRDT (BD1 or BD2) .
In certain embodiments of the present invention, U is derived from optionally substituted 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione.
In certain embodiments of the present invention, U is derived from 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione, wherein nitrogen and phenyl ring may be optionally substituted.
In certain embodiments of the present invention, U is derived from optionally substituted 3- (1-oxoisoindolin-2-yl) piperidine-2, 6-dione.
In certain embodiments of the present invention, U is derived from 3- (1-oxoisoindolin-2-yl) piperidine-2, 6-dione, wherein nitrogen and phenyl ring can be optionally substituted.
In certain embodiments of the present invention, L is a bond.
In certain embodiments of the present invention, L is a connector with a linear non-hydrogen atom number in the range from 1 to 45 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 or 45) .
In certain embodiments of the present invention, L can contain one or more functional groups including, but not limited to ether, amide, amine, CN, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, ester, urea, carbamate, thioether, sulfoxide, and sulfone.
In certain embodiments of the present invention, L can contain an aromatic group, aheteroaromatic group, a heterocyclic group, and a C3-C12 cycloalkyl, or a combination thereof, each optionally substituted with one or more groups selected from the group consisting of halogen, CN, OH, protected OH, amino, optionally substituted amino, protected amino, and optionally substituted C1-C4 alkyl.
In certain embodiments of the present invention, L can contain an aliphatic group optionally substituted with one or more groups selected from the group consisting of halogen, CN, OH, protected OH, amino, optionally substituted amino, protected amino, and optionally substituted C1-C4 alkyl.
In certain embodiments of the present invention, T is represented by the chemical structure (I) :
wherein ring A and Q are each independently selected from the group consisting of optionally substituted 3-to 12-membered aryl, optionally substituted heteroaryl or optionally substituted heterocyclic group; and W is selected from the group consisting of hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted 3-to 12-membered aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic group.
In certain embodiments of the present invention, W is hydrogen or optionally substituted C1-C6alkyl.
In certain embodiments of the present invention, W is C1-C6alkyl optionally substituted with C3-C12cycloalkyl, C3-C12cycloalkenyl, 3-to 12-membered heterocyclic group, 3-to 12-membered aryl, or optionally substituted heteroaryl; wherein the C3-C12 cycloalkyl, C3-C12cycloalkenyl, 3-to 12-membered heterocyclic group, 3-to 12-membered aryl, and optionally substituted heteroaryl may be further substituted.
In certain embodiments of the present invention, W is C1-C6alkyl optionally substituted with C3-C12cycloalkyl, C3-C12cycloalkenyl, or 3-to 12-membered heterocyclic group; wherein the C3-C12cycloalkyl, C3-C12cycloalkenyl, and 3-to 12-membered heterocyclic group may be further substituted.
In certain embodiments of the present invention, W is C1-C6alkyl optionally substituted with 3-to 12-membered aryl or heteroaryl; wherein the 3-to 12-membered aryl and heteroaryl may be further substituted.
In certain embodiments of the present invention, W is C1-C6 alkyl substituted with a group selected from optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, and optionally substituted 3-to 12-membered heterocyclic group; and a group selected from optionally substituted 3-to 12-membered aryl and optionally substituted heteroaryl.
In certain embodiments of the present invention, W is C1-C6 alkyl substituted with an optionally substituted 3-to 12-membered heterocyclic group and an optionally substituted heteroaryl.
In certain embodiments of the present invention, W is C1-C4 alkyl substituted with an optionally substituted 3-to 12-membered heterocyclic group and an optionally substituted heteroaryl.
In certain embodiments of the present invention, W is a methyl substituted with an optionally substituted 3-to 12-membered heterocyclic group and an optionally substituted heteroaryl.
In certain embodiments of the present invention, W is a methyl substituted with tetrahydro-2H-pyran-4-yl and 3-fluoropyridin-2-yl or 2-pyridyl.
In some embodiments of the present invention, T is selected from the following chemical structures (I-1 to I-5) :
wherein R1 is selected from the group consisting of H, CN, optionally substituted C1-C6 alkyl, and optionally substituted with C3-C8cycloalkyl. Preferably, R1 is selected from the group consisting ofH, Me, CD3, Et, i-Pr, CF3, CHF2, CN, cyclopropyl, and C1-C6-alkyl optionally substituted with C3-C12cycloalkyl, C3-C12cycloalkenyl, or 3-to 12-membered heterocyclic group;
Q is selected from the group consisting of
and
W is selected from the group consisting of H, Me, Et, and
In some embodiments of the present invention, T is selected from the following chemical structures (II-1 to II-8) :
In some embodiments of the present invention, U is a CRBN ligand selected from the following chemical structures (III-1 to III-4) :
wherein R2 is hydrogen or optionally substituted C1-C6alkyl; R3 at each occurrence is independently selected from the group consisting of hydrogen, halogen, CN, -NR4R5, -PR4R5, -P (O) R4R5, -S (O) 2R4R5, -S (O) R4R5, -BR4R5, and optionally substituted C1-C6alkyl; R4 and R5  are each independently selected from the group consisting of hydrogen or optionally substituted C1-C6-alkyl; and m is 0, 1, 2 or 3.
In some embodiments of the present invention, L is selected from the following chemical structure:
wherein M1 and V2 are each independently selected from the group consisting of a single bond, optionally substituted C1-C4alkyl, -N (R6) -, O, S, -S (O) -, -S (O) 2-, -OC (O) -, -N (R6) C (O) -, -S (O) 2N (R6) -, -N (R6) C (O) N (R6) -, -N (R6) C (O) O-, a double bond and a triple bond; wherein R6 at each occurrence is independently hydrogen or optionally substituted C1-C6alkyl;
M2 and V1 are each independently selected from the group consisting of a bond, optionally substituted C1-C4alkyl, a double bond, a triple bond, optionally substituted C3-C12 cycloalkyl optionally substituted heteroaryl, optionally substituted phenyl, optionally substituted heterocyclic group; wherein R6 at each occurrence is as previously defined;
X at each occurrence is independently selected from the group consisting of optionally substituted C1-C4alkyl, -N (R6) -, O, S, -S (O) -, -S (O) 2-, -OC (O) -, -N (R6) C (O) -, -S (O) 2N (R6) -, -N (R6) C (O) N (R6) -, -N (R6) C (O) O-, a double bond, a triple bond, optionally substituted 3-to 12-membered aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic group; wherein R6 at each occurrence is as previously defined; and
n is 1 or 2.
In some embodiments of the present invention, M2 and V1 are each independently a bond, optionally substituted heterocyclic or optionally substituted C3-C12 cycloalkyl; wherein the heterocyclic group and cycloalkyl may contain a fused or spiro polycyclic system.
In some embodiments of the present invention, X is optionally substituted heterocyclic group or optionally substituted C3-C12 cycloalkyl; wherein the heterocyclic and cycloalkyl may contain a fused or spiro polycyclic system.
In some embodiments of the present invention, M2, V1 and X are independently selected from the following structures:
wherein Y is selected from the group consisting of-C (R6) 2-, O, S, -N (R6) -, and-C (O) N (R6) -; Z is O, -NH-, – (CH2) m1–, -OCH2–, or-CH2OCH2–; m1 is 1, 2 or 3; n1, n2, n3, n4, n5, and n6 are each independently 0, 1 or 2; R6 is as previously defined; and wherein the listed ring structures may be optionally substituted with 1 to 4 substituents selected from the group consisting of hydrogen, halogen, CN, hydroxyl, and optionally substituted C1-C6-alkyl.
In some embodiments of the present invention, L is selected from the following chemical structures:

Each preferred group stated above can be taken in combination with one, any or all other preferred groups.
Also provided herein is a pharmaceutical composition comprising a compound of Formula T-U or T-L-U, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an  isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
Additionally provided herein is a method of treating a cancer disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula T-U or T-L-U, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
Provided herein is a method of degrading the BET protein, comprising contacting the oncoprotein with an effective amount of a compound of Formula T-U or T-L-U, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
It will be appreciated that the description of the present invention herein should be construed in congruity with the laws and principles of chemical bonding. In some instances, it may be necessary to remove a hydrogen atom in order to accommodate a substituent at any given location.
It will be yet appreciated that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.
In one aspect, the compounds of the invention are useful in cancer treatment by degrade the BET protein.
It should be understood that the compounds encompassed by the present invention are those that are suitably stable for use as pharmaceutical agent.
DEFINITIONS
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.
Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
The terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
The term "aryl, " as used herein, refers to a mono-or polycyclic carbocyclic system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring. Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof. In certain embodiments, the aryl has from 6 to 20 (C6-C20) , from 6 to 15 (C6-C15) , or from 6 to 10 (C6-C10) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl) . For an aryl group containing an aromatic ring and a nonaromatic heterocyclic ring, the aryl group is not bonded to the rest of a molecule through its nonaromatic ring. In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In still another embodiment, the aryl is polycyclic.
The term "heteroaryl, " as used herein, refers to a mono-or polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring; wherein any N or S contained within the ring may be optionally oxidized. For a heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring. In certain embodiments, the  heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
In accordance with the invention, aromatic groups can be substituted or unsubstituted.
The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and the two rings can be fused or covalently attached.
The term “alkyl” as used herein, refers to saturated, straight-or branched-chain hydrocarbon radicals. “C1-C3 alkyl, ” ” C1-C6 alkyl, ” “C1-C10 alkyl, ” “C2-C4 alkyl, ” or “C3-C6 alkyl, ” refer to alkyl groups containing from one to three, one to six, one to ten carbon atoms, 2 to 4 and 3 to 6 carbon atoms respectively. Examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
The term “alkenyl” as used herein, refers to straight-or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom. “C2-C10 alkenyl, ” “C2-C8 alkenyl, ” “C2-C4 alkenyl, ” or “C3-C6 alkenyl, ” refer to alkenyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
The term “alkynyl” as used herein, refers to straight-or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. “C2-C10 alkynyl, ” “C2-C8 alkynyl, ” “C2-C4 alkynyl, ” or “C3-C6 alkynyl, ” refer to alkynyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
The term “cycloalkyl” , as used herein, refers to a monocyclic or polycyclic saturated carbocyclic ring or a bi-or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond. Preferred cycloalkyl groups include C3-C12 cycloalkyl, C3-C6  cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl. Examples of C3-C12cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.0] hexyl, spiro [2.5] octyl, 3-methylenebicyclo [3.2.1] octyl, spiro [4.4] nonanyl, and the like.
The term “cycloalkenyl” , as used herein, refers to monocyclic or polycyclic carbocyclic ring or a bi-or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond. Preferred cycloalkenyl groups include C3-C12 cycloalkenyl, C3-C8cycloalkenyl or C5-C7cycloalkenyl groups. Examples of C3-C12cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [2.2.1] hept-2-enyl, bicyclo [3.1.0] hex-2-enyl, spiro [2.5] oct-4-enyl, spiro [4.4] non-1-enyl, bicyclo [4.2.1] non-3-en-9-yl, and the like.
As used herein, the term “arylalkyl” means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CH2CH2-phenyl. The term “substituted arylalkyl” means an arylalkyl functional group in which the aryl group is substituted. Similarly, the term “heteroarylalkyl” means a functional group wherein an alkylene chain is attached to a heteroaryl group. The tem “substituted heteroarylalkyl” means a heteroarylalkyl functional group in which the heteroaryl group is substituted.
As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred alkoxy are (C1-C3) alkoxy.
It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds. Examples of aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C (O) , S (O) 2, C (O) O, C (O) NH, OC (O) O, OC (O) NH, OC (O) NH2, S (O) 2NH,  S (O) 2NH2, NHC (O) NH2, NHC (O) C (O) NH, NHS (O) 2NH, NHS (O) 2NH2, C (O) NHS (O) 2, C (O) NHS (O) 2NH or C (O) NHS (O) 2NH2, and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted) , and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group. Carbon atoms of an aliphatic group can be optionally oxo-substituted. An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.
The terms “heterocyclic” or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic monocyclic ring or a bi-or tri-cyclic group fused, bridged or spiro ring system that contain at least one non-aromatic ring, where (i) one or more non-aromatic ring contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. For a heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, Representative heterocycloalkyl groups include, but are not limited to, 1, 3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo [2.2.1] -heptyl, 8-azabicyclo [3.2.1] octyl, 5-azaspiro [2.5] octyl, 1- oxa-7-azaspiro [4.4] nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted.
In certain embodiments, heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible) .
It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom (s) . One of skill in the art can readily determine the valence of any such group from the context in which it occurs.
In certain embodiments, when a bond to a substituent is shown to cross a bond connecting two atoms in a ring, it is understood that such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term “substituted” refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, C1-C12-alkyl; C2-C12-alkenyl, C2-C12-alkynyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NH-C1-C12-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C12-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1-C12-alkyl, -O-C2-C8-alkenyl, -O-C2-C8-alkynyl, -O-C3-C12-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C (O) -C1-C12-alkyl, -C (O) -C2-C8-alkenyl, -C (O) -C2-C8-alkynyl, -C (O) -C3-C12-cycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) -heterocycloalkyl, -CONH2, -CONH-C1-C12-alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C12-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C12-alkyl, -OCO2-C2-C8-alkenyl, -OCO2-C2-C8-alkynyl, -OCO2-C3-C12-cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C1-C12 alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2-C3-C12-cycloalkyl, -CO2-aryl, CO2-heteroaryl, CO2-heterocyloalkyl, -OCONH2, -OCONH-C1-C12-alkyl, -OCONH-C2-C8-alkenyl, -OCONH-C2-C8-alkynyl, -OCONH-C3-C12-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclo-alkyl, -NHC (O) H, -NHC (O) -C1-C12-alkyl, -NHC (O) -C2-C8-alkenyl, - NHC (O) -C2-C8-alkynyl, -NHC (O) -C3-C12-cycloalkyl, -NHC (O) -aryl, -NHC (O) -heteroaryl, -NHC (O) -heterocyclo-alkyl, -NHCO2-C1-C12-alkyl, -NHCO2-C2-C8-alkenyl, -NHCO2-C2-C8-alkynyl, -NHCO2-C3-C12-cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, -NHC (O) NH2, -NHC (O) NH-C1-C12-alkyl, -NHC (O) NH-C2-C8-alkenyl, -NHC (O) NH-C2-C8-alkynyl, -NHC (O) NH-C3-C12-cycloalkyl, -NHC (O) NH-aryl, -NHC (O) NH-heteroaryl, -NHC (O) NH-heterocycloalkyl, NHC (S) NH2, -NHC (S) NH-C1-C12-alkyl, -NHC (S) NH-C2-C8-alkenyl, -NHC (S) NH-C2-C8-alkynyl, -NHC (S) NH-C3-C12-cycloalkyl, -NHC (S) NH-aryl, -NHC (S) NH-heteroaryl, -NHC (S) NH-heterocycloalkyl, -NHC (NH) NH2, -NHC (NH) NH-C1-C12-alkyl, -NHC (NH) NH-C2-C8-alkenyl, -NHC (NH) NH-C2-C8-alkynyl, -NHC (NH) NH-C3-C12-cycloalkyl, -NHC (NH) NH-aryl, -NHC (NH) NH-heteroaryl, -NHC (NH) NH-heterocycloalkyl, -NHC (NH) -C1-C12-alkyl, -NHC (NH) -C2-C8-alkenyl, -NHC (NH) -C2-C8-alkynyl, -NHC (NH) -C3-C12-cycloalkyl, -NHC (NH) -aryl, -NHC (NH) -heteroaryl, -NHC (NH) -heterocycloalkyl, -C (NH) NH-C1-C12-alkyl, -C (NH) NH-C2-C8-alkenyl, -C (NH) NH-C2-C8-alkynyl, -C (NH) NH-C3-C12-cycloalkyl, -C (NH) NH-aryl, -C (NH) NH-heteroaryl, -C (NH) NH-heterocycloalkyl, -S (O) -C1-C12-alkyl, -S (O) -C2-C8-alkenyl, -S (O) -C2-C8-alkynyl, -S (O) -C3-C12-cycloalkyl, -S (O) -aryl, -S (O) -heteroaryl, -S (O) -heterocycloalkyl, -SO2NH2, -SO2NH-C1-C12-alkyl, -SO2NH-C2-C8-alkenyl, -SO2NH-C2-C8-alkynyl, -SO2NH-C3-C12-cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1-C12-alkyl, -NHSO2-C2-C8-alkenyl, -NHSO2-C2-C8-alkynyl, -NHSO2-C3-C12-cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -P (O) (C1-C6-alkyl) 2, -P (O) (aryl) (C1-C6-alkyl) , -P (O) (aryl) 2, -P (O) (OC1-C6-alkyl) 2, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C12-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C12-alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-C12-cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthio-methyl. In certain embodiments, the substituents are independently selected from halo, preferably Cl and F; C1-C4-alkyl, preferably methyl and ethyl; C2-C4-alkenyl; halo-C1-C4-alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; halo-C2-C4-alkenyl; C3-C6-cycloalkyl, such as cyclopropyl; -CN; -OH; NH2; C1-C4-alkylamino; di (C1-C4-alkyl) amino; and NO2. It is understood that the substituents, such as the aryls, heteroaryls, alkyls, and the like, are optionally further substituted. In some cases, each substituent in a substituted moiety is additionally optionally substituted with one or more  groups, each group being independently selected from C1-C4-alkyl; CF3, C1-C4-alkoxy; -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN, and-NH2.
It is understood that the aryls, heteroaryls, alkyls, cycloalkyls and the like can be further substituted.
The term “halo” or halogen” alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.
The term “optionally substituted” , as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group (s) individually and independently selected from groups described herein.
The term “hydrogen” includes hydrogen and deuterium. In addition, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.
In certain embodiments, the compounds of each formula herein are defined to include isotopically labelled compounds. An “isotopically labelled compound” is a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope. In certain embodiments, an isotopically labelled compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H) , deuterium (2H) , tritium (3H) , carbon-11 (11C) , carbon-12 (12C) , carbon-13 (13C) , carbon-14 (14C) , nitrogen-13 (13N) , nitrogen-14 (14N) , nitrogen-15 (15N) , oxygen-14 (14O) , oxygen-15 (15O) , oxygen-16 (16O) , oxygen-17 (17O) , oxygen-18 (18O) , fluorine-17 (17F) , fluorine-18 (18F) , phosphorus-31 (31P) , phosphorus-32 (32P) , phosphorus-33 (33P) , sulfur-32 (32S) , sulfur-33 (33S) , sulfur-34 (34S) , sulfur-35 (35S) , sulfur-36 (36S) , chlorine-35 (35Cl) , chlorine-36 (36Cl) , chlorine-37 (37Cl) , bromine-79 (79Br) , bromine-81 (81Br) , iodine-123 (123I) , iodine-125 (125I) , iodine-127 (127I) , iodine-129 (129I) , and iodine-131 (131I) . In certain embodiments, an isotopically enriched compound is in a stable form, that is, non-radioactive. For example, one or more hydrogen atom positions in a compound can be enriched with deuterium to a level which is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20%or at least 50%. Such a deuterated compound may, for example,  be metabolized more slowly than its non-deuterated analog, and therefore exhibit a longer half-life when administered to a subject. Such compounds can synthesize using methods known in the art, for example by employing deuterated starting materials. Unless stated to the contrary, isotopically labelled compounds are pharmaceutically acceptable.
The term “hydroxy activating group, ” as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction. Examples of hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate and the like.
The term “activated hydroxyl, ” as used herein, refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
The term “hydroxy protecting group, ” as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure (s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic  Synthesis, 3rd edition, John Wiley & Sons, New York (1999) . Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2, 2, 2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl-methyl (trityl) , methoxymethyl, methylthiomethyl, benzyloxymethyl, 2- (trimethylsilyl) -ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
The term "protected hydroxy, " as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
The term “hydroxy prodrug group, ” as used herein, refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure (s) , the hydroxy prodrug group as described herein must be capable of  reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53) , Marcel Dekker, Inc., New York (1992) and in “Prodrugs of Alcohols and Phenols” by S.S. Dhareshwar and V.J. Stella, in Prodrugs  Challenges and Rewards Part-2, (Biotechnology: Pharmaceutical Aspects) , edited by V.J. Stella, et al, Springer and AAPSPress, 2007, pp 31-99.
The term “amino protecting group, ” as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure (s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic  Synthesis, 3rd edition, John Wiley & Sons, New York (1999) . Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.
The term “protected amino, ” as used herein, refers to an amino group protected with an amino protecting group as defined above.
The term "amino acid" refers to naturally occurring and synthetic α, β, γ, or δ amino acids, and includes but is not limited to, amino acids found in proteins or intermediates in metabolism of amino acids or proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, citrulline, arginine and histidine. In certain embodiments, the amino acid is in the L-configuration. In certain embodiments, the amino acid is in the D-configuration. In certain embodiments, the amino acid is provided as a substituent of a compound described herein, wherein the amino acid is a residue selected from the group consisting of alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleuccinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl and β-histidinyl.
The term "amino acid derivative" refers to a group derivable from a naturally or non-naturally occurring amino acid, as described and exemplified herein. Amino acid derivatives are apparent to those of skill in the art and include, but are not limited to, ester, amino alcohol, amino aldehyde, amino lactone, and N-methyl derivatives of naturally and non-naturally occurring amino acids. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is–NRu-G (Sc) -C (O) -Q1, wherein Q1 is–SRv, -NRvRv or alkoxyl, Rv is hydrogen or alkyl, Sc is a side-chain of a naturally occurring or non-naturally occurring amino acid, G is Cl-C2 alkyl, and Ru is hydrogen; or Ru and Sc are taken together with the atoms to which they are attached to form a five-membered heterocyclic ring. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is-O-C (O) -G (Sc) -NH-Q2, wherein Q2 is hydrogen or alkoxyl, Sc is a side-chain of a naturally occurring or non-naturally occurring amino acid and G is C1-C2 alkyl. In certain embodiments, Q2 and Sc are taken together with the atoms to which they are attached to form a five-membered heterocyclic ring. In certain embodiments, G is an optionally substituted methylene and Sc is selected from the group consisting of hydrogen, alkyl, arylalkyl, heterocycloalkyl, carboxylalkyl, heteroarylalkyl, aminoalkyl, hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl, sulfanylalkyl, carbamoylalkyl, alkylsulfanylalkyl and hydroxylarylalkyl. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the amino acid derivative is in the D-configuration. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the amino acid derivative is in the L-configuration.
The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
The term "aprotic solvent, " as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as,  for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents  Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
The term “protic solvent, ” as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of  Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry  Series, John Wiley & Sons, NY, 1986.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable, ” as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject) .
The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the Formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting  group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, 2nd Ed. Wiley-VCH (1999) ; T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999) ; L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994) ; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) , and subsequent editions thereof.
The term “subject, ” as used herein, refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. A subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
The terms “treat, ” “treating, ” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause (s) of the disorder, disease, or condition itself. In one embodiment, the disease is a cancer.
The terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
As used herein, the term “inhibitor” refers to biological or chemical substance that interferes with or otherwise reduces the physiological and/or biochemical action of another biological or chemical molecule. In some embodiments, the inhibitor or antagonist specifically binds to the other molecule.
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system) , increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R) -or (S) -, or as (D) -or (L) -for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981) . When the compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers or cis-and trans-isomers. Likewise, all tautomeric forms are also intended to be included. Tautomers may be in cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus, a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.
As used herein, the term "pharmaceutically acceptable salt, " refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977) . The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of  pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, esters of C1-C6-alkanoic acids, such as acetate, propionate, butyrate and pivalate esters.
PHARMACEUTICAL COMPOSITIONS
The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
As used herein, the term "pharmaceutically acceptable carrier or excipient" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation  auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides  inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
The pharmaceutical composition provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
The pharmaceutical composition provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may  depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides) . Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in  the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
The pharmaceutical composition provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra) dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
For pulmonary delivery, a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system. Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size:  that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No. 5,767,068 to Van Devanter et al., U.S. Pat. No. 5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of which are incorporated herein by reference) .
The pharmaceutical composition provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release
Method of Use
In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by compounds of the present invention in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (A) , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.
According to the methods of treatment of the present invention, conditions are treated or prevented in a patient such as a human or another animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
In certain embodiments, the "therapeutically effective amount" or “effective amount” of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA) , cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.  The therapeutic effect or biological or medical response may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect) .
In certain embodiments, an effective amount of the compound described above may range from about 0.001 mg/kg to about 500 mg/kg, preferably from about 0.01 to about 50 mg/kg, more preferably from about 0.1 to about 25 mg/kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05%of a given value or range.
The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from about 0.01 to about 50 mg/kg body weight or more usually from about 0.1 to about 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 1 mg to about 2000 mg of the compound (s) of this invention per day in single or multiple doses.
It is understood that the administered dose can also be expressed in units other than mg/kg/day. For example, doses for parenteral administration can be expressed as mg/m2/day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to  mg/m2/day to given either the height or weight of a subject or both. For example, a dose of 1 mg/m2/day for a 65 kg human is approximately equal to 58 mg/kg/day.
The compounds of the present invention described herein can, for example, be administered by injection, intravenously, intra-arterial, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.01 to about 500 mg/kg of body weight, alternatively dosages between about 1 mg and about 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with pharmaceutically excipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 1%to about 95%active compound (w/w) . Alternatively, such preparations may contain from about 20%to about 80%active compound.
Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.
Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
A compound provided herein can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID) , and three times daily (TID) . In addition, the  administration can be continuous, i.e., every day, or intermittently. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound provided herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) , or administration on alternate days.
In certain embodiments, a compound provided herein is cyclically administered to a subject. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
A compound provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a condition, disorder, or disease described herein.
As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents) . However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) , concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.
The route of administration of a compound provided herein is independent of the route of administration of a second therapy. In one embodiment, a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered intravenously. Thus, in accordance with these embodiments, a compound provided herein is administered orally or intravenously, and the second therapy can be administered orally,  parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, acompound provided herein and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, a compound provided herein is administered by one mode of administration, e.g., by IV, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., orally.
When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95%of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
ABBREVIATIONS
Abbreviations which may be used in the descriptions of the scheme and the examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBN for azobisisobutyronitrile; BINAP for 2, 2’-bis (diphenylphosphino) -1, 1’-binaphthyl; Boc2O for di-tert-butyl-dicarbonate; Boc for t-butoxycarbonyl; Bpoc for 1-methyl-1- (4-biphenylyl) ethyl carbonyl; Bz for benzoyl; Bn for benzyl; BocNHOH for tert-butyl N-hydroxycarbamate; t-BuOK for potassium tert-butoxide; Bu3SnH for tributyltin hydride; BOP for (benzotriazol-1-yloxy) tris (dimethylamino) phospho-nium Hexafluorophosphate; Brine for sodium chloride solution in water; BSA for N, O-bis- (trimethylsilyl) acetamide; CDI for carbonyldiimidazole; CH2Cl2 for dichloromethane; CH3 for methyl; CH3CN for acetonitrile; Cs2CO3 for cesium carbonate; CuCl for copper (I) chloride; CuI for copper (I) iodide; dba for dibenzylidene acetone; dppb for diphenylphos-phinobutane; DBU for 1, 8-diazabicyclo [5.4.0] -undec-7-ene; DCC for N, N’-dicyclohexyl-carbodiimide; DEAD for diethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIPEA or (i-Pr) 2EtN for N, N, -diisopropylethyl amine; Dess-Martin periodinane for 1, 1, 1-tris (acetyloxy) -1, 1-dihydro-1, 2-benziodoxol-3- (1H) -one; DMAP for 4-dimethylamino-pyridine; DME for  1, 2-dimethoxyethane; DMF for N, N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT for di (p-methoxyphenyl) -phenylmethyl or dimethoxytrityl; DPPA for diphenylphosphoryl azide; EDC for N- (3-dimethylaminopropyl) -N’-ethylcarbodiimide; EDC HCl for N- (3-dimethylaminopropyl) -N’-ethylcarbodiimide hydrochloride; EtOAc for ethyl acetate; EtOH for ethanol; Et2O for diethyl ether; HATU for O- (7-azabenzotriazol-1-yl) -N, N, N’, N’, -tetramethyluronium Hexafluoro-phosphate; HCl for hydrogen chloride; HOBT for 1-hydroxybenzotriazole; K2CO3 for potassium carbonate; n-BuLi for n-butyl lithium; i-BuLi for i-butyl lithium; t-BuLi for t-butyl lithium; PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP for lithium 2, 2, 6, 6-tetramethyl-piperidinate; MeOH for methanol; Mg for magnesium; MOM for methoxymethyl; Ms for mesyl or-SO2-CH3; Ms2O for methanesulfonic anhydride or mesyl-anhydride; MTBE for t-butyl methyl ether; NaN (TMS) 2 for sodium bis (trimethylsilyl) amide; NaCl for sodium chloride; NaH for sodium hydride; NaHCO3 for sodium bicarbonate or sodium hydrogen carbonate; Na2CO3 for sodium carbonate; NaOH for sodium hydroxide; Na2SO4 for sodium sulfate; NaHSO3 for sodium bisulfite or sodium hydrogen sulfite; Na2S2O3 for sodium thiosulfate; NH2NH2 for hydrazine; NH4HCO3 for ammonium bicarbonate; NH4Cl for ammonium chloride; NMO for N-methyl-morpholine N-oxide; NaIO4 for sodium periodate; Ni for nickel; NSFI for N-fluorobenzene-sulfonimide; OH for hydroxyl; o/n for overnight; OsO4 for osmium tetroxide; PTSA for p-toluenesulfonic acid; PPTS for pyridinium p-toluenesulfonate; TBAF for tetrabutyl-ammonium fluoride; TEA or Et3N for triethylamine; TES for triethylsilyl; TESCl for triethylsilyl chloride; TESOTf for triethylsilyl trifluoro-methanesulfonate; TFA for trifluoroacetic acid; THF for tetrahydro-furan; TMEDA for N, N, N’, N’-tetramethylethylene-diamine; TPP or PPh3 for triphenyl-phosphine; Troc for 2, 2, 2-trichloroethyl carbonyl; Ts for tosyl or–SO2-C6H4CH3; Ts2O for tolylsulfonic anhydride or tosyl-anhydride; TsOH for p-tolylsulfonic acid; Pd for palladium; Ph for phenyl; POPd for dihydrogen dichlorobis (di-tert-butylphosphinito-κP) palladate (II) ; Pd2 (dba) 3 for tris (dibenzylideneacetone) dipalladium (0) ; Pd (PPh3) 4for tetrakis (triphenyl-phosphine) palladium (0) ; PdCl2 (PPh3) 2 for trans-dichlorobis- (triphenylphosphine) palladium (II) ; Pt for platinum; Rh for rhodium; rt for room temperature; Ru for ruthenium; SFC for supercritical fluid chromatography; TBS for tert-butyl dimethylsilyl; TMS for trimethylsilyl; or TMSCl for trimethylsilyl chloride.
GENERAL SYNTHETIC APPROACH
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared. These schemes are of illustrative purpose and are not meant to limit the scope of the invention. Equivalent, similar, or suitable solvents, reagents or reaction conditions may be substituted for those particular solvents, reagents, or reaction conditions described herein without departing from the general scope of the method of synthesis.
The synthetic realization and optimization of the bifunctional molecules as described herein may be approached in a stepwise or modular fashion. For example, identification of compounds that bind to the target protein, i.e., BET can involve high or medium throughput screening campaigns if no suitable ligands immediately available. It is not unusual for initial ligands to require iterative design and optimization cycles to improve suboptimal aspects as identified by data from suitable in vitro and pharmacological and/or ADMET assays. Part of the optimization/SAR campaign would be to probe positions of the ligand that are tolerant of substitution and that might be suitable places on which to attach the chemical linking group previously referred to herein. Where crystallographic or NMR structural data are available, these can be used to focus such a synthetic effort.
In a very analogous way one can identify and optimize ligands for an E3 Ligase.
With compounds that bind to BET protein or E3 ligase (e.g. CRBN) in hand, one skilled in the art can use known synthetic methods for their combination with or without a chemical linking group (s) . Chemical linking group (s) can be synthesized with a range of compositions, lengths and flexibility and functionalized such that the a BET protein binding moiety T and the E3 ubiquitin ligase binding moiety U can be attached sequentially to distal ends of the linker. Thus, a library of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET/PK studies. As with the T and U groups, the final bifunctional molecules can be subject to iterative design and optimization cycles in order to identify molecules with desirable properties.
In some instances, protecting group strategies and/or functional group interconversions (FGIs) may be required to facilitate the preparation of the desired materials. Such chemical processes are well known to the synthetic organic chemist and many of these  may be found in texts such as "Greene's Protective Groups in Organic Synthesis" Peter G. M. Wuts and Theodora W. Greene (Wiley) , and "Organic Synthesis: The Disconnection Approach" Stuart Warren and Paul Wyatt (Wiley) .
General Synthetic Scheme
Scheme 1
In the above scheme 1, R2, R3, m, n, M1, M2, X, V1, V2are as previously defined.
Scheme 2
In the above scheme 2, R2, R3, LG, m, n, M1, M2, X, V1, V2are as previously defined.
Scheme 3
In the above scheme 3, n, A, W, Q are as previously defined.
All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.
Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims.
EXAMPLES
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.





Intermediate 1
4- ( (3-Fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4-dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylic acid
Steps 1, 2, and 3: Methyl 3-bromo-1- (methyl-d3) -1H-pyrazole-5-carboxylate
To a solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (4.0 g, 23.3 mmol) in DMF (28 mL) was added K2CO3 (6.5 g, 46.7 mmol) . The mixture was cooled to 5℃, and CD3I (4.4 g, 30.3 mmol) was added drop-wise. Then the reaction mixture was warmed to room temperature and stirred at room temperature overnight. Water (112 mL) was added into the mixture, and the resulting mixture was extracted with DCM (8 mL x 3) . The organic layer was washed with brine (4 mL x 5) , dried over Na2SO4and evaporated under reduced pressure. The residue was purified by recrystallization in MeOH to afford methyl 1- (methyl-d3) -3-nitro-1H-pyrazole-5-carboxylate (1.6 g, 37%yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H) , 3.94 (s, 3H) .
To a solution of methyl 1- (methyl-d3) -3-nitro-1H-pyrazole-5-carboxylate (4.5 g, 23.9 mmol) in MeOH (90 mL) was added Pd/C (450 mg, 10%wt) . The reaction solution was stirred at room temperature under an atmosphere of hydrogen for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 3-amino-1- (methyl-d3) -1H-pyrazole-5-carboxylate (3.4 g) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.12 (s, 1H) , 3.83 (s, 3H) , 3.134 (s, 2H) .
To a solution of methyl 3-amino-1- (methyl-d3) -1H-pyrazole-5-carboxylate (3.0 g, 18.9 mmol) in MeCN (105 mL) was added CuBr2 (3.6 g, 17.0 mmol) . The mixture was cooled to 0℃, tert-butyl nitrite (3.3 g, 28.5 mmol) was added drop wise at-5 ℃ and the reaction mixture was stirred at 0 ℃ for 2 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4and evaporated under reduced pressure. The residue was purified by silica gel column to afford the title product (2.6 g) as yellow oil and used in the next step directly. 1H NMR (400 MHz, CDCl3) δ 6.08 (s, 1H) , 3.88 (s, 3H) .
Step 4, 5: Methyl 3- (5-bromo-3-nitropyridin-2-yl) -1- (methyl-d3) -1H-pyrazole-5-carboxylate
To a solution of methyl 3-bromo-1- (methyl-d3) -1H-pyrazole-5-carboxylate (5.0 g, 22.5 mmol) in 1, 4-dioxane (60 mL) was added KOAc (6.6 g, 67.6 mmol) and Pin2B2 (8.6 g, 33.8 mmol) . Then purged it by nitrogen 3 times and charged Pd (dppf) Cl2 into the flask under N2. The mixture was stirred at 100℃ for 24 h. The reaction mixture was cooled down to 20～25℃. The mixture was filtered through celit, rinsed the cake with DCM (50 mL x 2) . The combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel column to afford methyl 1- (methyl-d3) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-5-carboxylate (6.0 g) as a waxy solid and used in the next step directly. LCMS (ESI) m/z: 188.1 [M+H] +.
To a solution of methyl 1- (methyl-d3) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-3-carboxylate (2.7 g, 10.0 mmol) in THF (13.5 mL) was added 2, 5-dibromo-3-nitropyridine (2.0 g, 7.0 mmol) and the pre-prapared K3PO4 solution (3.8 g, 18.0 mmol, 3.0 mL) at room temperature. Then charged Pd (dppf) Cl2 into the flask under N2. The mixture was stirred at 90～95℃ for 5 h. The reaction mixture was cooled down to 40～45℃. Then the mixture was filtered through celit and rinsed the cake with DCM (5 mL x 2) . The combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel column to afford the title product (1.4 g) as a light yellow solid and used in the next step directly. LCMS (ESI) m/z: 344.0 [M+H] +.
Step 6: Methyl 1- (methyl-d3) -3- (5- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -3-nitropyridin-2-yl) -1H-pyrazole-5-carboxylate
To a solution of methyl 3- (5-bromo-3-nitropyridin-2-yl) -1- (methyl-d3) -1H-pyrazole-5-carboxylate (2.7 g, 7.8 mmol) and 1-methyl-4- (methyl-d3) -5- (tributylstannyl) -1H-1, 2, 3-triazole (3.7 g, 9.4 mmol) in DMF (40 mL) were added Pd (PPh3) 4 (590 mg, 0.44 mmol) and CuI (224 mg, 1.2 mmol) under N2 atmosphere. The mixture was heated at 95 ℃ for 2 h under N2 atmosphere. The reaction mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (PE/DCM=2/1 and DCM/MeOH=100/1) to afford the title product (2.6 g, 91%yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=1.9 Hz, 1H) , 7.91 (d, J=1.9 Hz, 1H) , 7.43 (s, 1H) , 4.06 (s, 3H) , 3.942 (s, 3H) . LCMS (ESI) m/z: 364.2 [M+H] +.
Step 7: Methyl 4-iodo-1- (methyl-d3) -3- (5- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -3-nitropyridin-2-yl) -1H-pyrazole-5-carboxylate
To solution of methyl 1- (methyl-d3) -3- (5- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -3-nitropyridin-2-yl) -1H-pyrazole-5-carboxylate (2.3 g, 6.4 mmol) in MeCN (120 mL) were added Ce (NH4) 2 (NO3) 6 (2.1 g, 3.8 mmol) and I2 (0.82 g, 3.2 mmol) under N2 atmosphere. The reaction mixture was heated at 80 ℃ for 2 h. Then Ce (NH4) 2 (NO3) 6 (2.1 g, 3.8 mmol) and I2 (0.82 g, 3.2 mmol) were added under N2 atmosphere. The reaction mixture was heated at 80 ℃ for 2 h. The reaction mixture was concentrated. The residue was diluted with DCM and water, the separated aqueous phase was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford the title product (2.6 g, 85%yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=1.3 Hz, 1H) , 8.28 (d, J=1.5 Hz, 1H) , 4.10 (s, 3H) , 4.01 (s, 3H) . LCMS (ESI) m/z: 490.0 [M+H] +.
Step 8: Methyl 3- (3-amino-5- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) pyridin-2-yl) -4-iodo-1- (methyl-d3) -1H-pyrazole-5-carboxylate
To a solution of methyl 4-iodo-1- (methyl-d3) -3- (5- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -3-nitropyridin-2-yl) -1H-pyrazole-5-carboxylate (3.0 g, 6.0 mmol) in EtOH (144 mL) and water (18 mL) were added iron powder (2.5 g, 45 mmol) and NH4Cl (3.7 g, 68.4 mmol) . The reaction mixture was heated at 80 ℃ for 1 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with DCM and water, the separated aqueous phase was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography  (PE/EtOAc=1: 1～DCM/MeOH=50: 1) to afford the title product (2.3 g, 82%yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=1.8 Hz, 1H) , 6.99 (d, J=1.8 Hz, 1H) , 5.15 (s, 2H) , 4.07 (d, J=1.2 Hz, 6H) . LCMS (ESI) m/z: 460.1 [M+H] +.
Step 9: Methyl 2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4-dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate
To a solution of methyl 3- (3-amino-5- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) pyridin-2-yl) -4-iodo-1- (methyl-d3) -1H-pyrazole-5-carboxylate (460 mg, 1.0 mmol) in DME (20 mL) were added CuI (190 mg, 1.0 mmol) , 1, 10-phenaothroline (360 mg, 2.0 mmol) and Cs2CO3 (977.4 mg, 2.5 mmol) . The reaction solution was heated at 90 ℃ for 3 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH=80/1～40/1) to afford the title product (198 mg, 60%yield) as a yellow solid. LCMS (ESI) m/z: 332.1 [M+H] +.
Step 10: Methyl 4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate
To a solution of methyl methyl 2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4-dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate (3.3 g, 10.0 mmol) in toluene (66 mL) were added PPh3 (11.8 g, 45 mmol) and (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (2.5 g, 12.0 mmol) . The mixture was stired at 80 ℃ for 15 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc=1/1～DCM/MeOH=50/1) to afford the title product (4.0 g, 76%yield) as a yellow solid. LCMS (ESI) m/z: 525.3 [M+H] +.
Step 11: 4- ( (3-Fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4-dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylic acid
To a solution of methyl 4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate (218 mg, 0.41 mmol) in THF/H2O (8 mL/2 mL) was added LiOH·H2O (49 mg, 1.18 mmol) , and reaction mixture was stirred at 25℃for 1 h. The solution was adjusted with aq. HCl (1 M) to pH=1～2, and extracted by EtOAc (50 mL x 3) . The organic layer was dried over Na2SO4 and concentrated to give the title product (210 mg,  99%yield) as a white solid. Chemical Formula: C25H19D6FN8O3; Molecular Weight: 510.56. LCMS (ESI) m/z: 511.1 [M+H] +.
Intermediate 2
(4- ( (3-Fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4-dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridin-3-yl) methanol
Step 1: A solution of methyl 4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate (52.5 mg, 0.1 mmol) and LiAlH4 (16 mg, 0.4 mmol) in THF (2 mL) was stirred at 25℃over night. The reaction was quenched by water (20 mL) . The resulting mixture was extracted with EtOAc (20 mL x 3) . The combined organic layer was washed with brine (10 mL) , dried over Na2SO4 and concentrated to afford the title product (57.6 mg, crude) as a grey solid. LCMS (ESI) m/z: =497.5 [M+H] +. Chemical Formula: C25H21D6FN8O2; Molecular Weight: 496.6.
Example 2
N- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) ethoxy) ethyl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4-dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxamide
Step 1: To a solution of compound 2.1 (500 mg, 2.0 mmol) and TsCl (421 mg, 2.2 mmol) in DCM(5mL) was added TEA (406 mg, 4.0 mmol) , and the solution was stirred at 25℃for 2 h. Then the mixture was concentrated. To the residue was added EtOAc (50 mL) , and the organic phase was washed with water (10 mL) , brine (10 mL) and dried over sodium sulfate. The organic layer was concentrated to afford comound 2.2 (830 mg, crude) as yellow oil. LCMS (ESI) m/z: 404.3 [M+H] +. Chemical Formula: C18H29NO7S; Molecular Weight: 403.5.
Step 2: To a solution of 2- (2, 6-dioxopiperidin-3-yl) -4-hydroxyisoindoline-1, 3-dione (200 mg, 0.73 mmol) and compound 2.2 (323.7 mg, 0.80 mmol) in DMF (5 mL) was added NaHCO3 (91.9 mg, 1.1 mmol) and KI (12.1 mg, 0.073 mmol) at 25℃. The reaction mixture was stirred at 80℃ over night. The reaction mixture was cooled to room temperature and quenched with water (50 mL) . The aqueous layer was extracted with EtOAc (50 mL x 3) . The combined organic phase was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel, eluting with petroleum ether/EtOAc (1: 1) to afford compound 2.3 (460 mg, 70%HPLC purity) as yellow oil. LCMS (ESI) m/z: 406.5 [M-Boc] +. Chemical Formula: C24H31N3O9; Molecular Weight: 505.5
Step 3: A solution of compound 2.3 (400 mg, 0.79 mmol) in HCl/1, 4-dioxane (4 M, 2 mL) was stirred at room temperature for 2 h. The solution was concentrated to afford compound 2.4 (390 mg) as a yellow oil. LCMS (ESI) m/z: 406.5 [M+l] +. Chemical Formula: C21H28N4O4; Molecular Weight: 405.4.
Step 4: To a solution of compound 2.4 (39.7 mg, 0.098 mmol) and intermediate 1 (50 mg, 0.098 mmol) in DMF (2 mL) was added HATU (112 mg, 0.29 mmol) and DIPEA (50.6 mg, 392 mmol) at 25℃. The reaction mixture was stirred at 25℃ for 2 h. The reaction was quenched with water (10 mL) . The aqueous layer was extracted with EtOAc (50 mL x 3) . The combined organic layer was washed with brine (10 mL) , dried over sodium sulfate and concentrated. The residue was purified by prep-HPLC to afford Example 2 (15.2 mg, 17.3%yield) as a yellow solid. Chemical Formula: C44H40D6FN11O9; Molecular Weight: 897.96. LCMS (ESI) m/z: 899.0 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H) , 9.09 (s, 1H) , 8.53-8.46 (m, 2H) , 8.28 (s, 1H) , 7.75 (dt, J=27.8, 8.6 Hz, 2H) , 7.56-7.39 (m, 3H) , 6.14 (d, J=11.0 Hz, 1H) , 5.10 (dd, J=12.9, 5.5 Hz, 1H) , 4.36 (d, J=4.3 Hz, 2H) , 4.02 (s, 3H) , 3.87-3.57 (m, 10H) , 3.28 (dt, J=33.1, 11.5 Hz, 4H) , 2.96-2.82 (m, 2H) , 2.78-2.59  (m, 2H) , 2.08-1.97 (m, 1H) , 1.61-1.48 (m, 1H) , 1.46-1.23 (m, 2H) , 1.10 (d, J=12.8 Hz, 1H) .
Example 3
N- (8- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octyl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2- (methyl-d3) -6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -2, 4-dihydropyrazolo [3', 4': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxamide
Step 1: To a solution of 3- (7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (104 mg, 0.37 mmol) and compound 3.1 (92 mg, 0.37 mmol) in NMP (2 mL) was added DIPEA (96.5 mg, 0.74 mmol) at 25℃. The reaction mixture was stirred at 90℃ for 2 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL) . The aqueous layer was extracted with EtOAc (50 mL x 3) . The combined organic phase was dried over sodium sulfate, filtered, and filtrate concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/EtOAc=1/1) to afford compound 3.2 (63.5 mg, 33.8%yield) as a yellow solid. Chemical Formula: C26H36N4O6; Molecular Weight: 500.6. LCMS (ESI) m/z: 501.2 [M+H] +.
Step 2: To a solution of compound 3.2 (63.5 mg, 0.13 mmol) in DCM (5 mL) was added TFA (1 mL) , and the mixture was stirred at room temperature for 1 h. The solution was concentrated to afford compound 3.3 (45.6 mg, 89.7%yield, HCl salt) as a yellow oil. Chemical Formula: C21H28N4O4; Molecular Weight: 400.48. LCMS (ESI) m/z: 401.0 [M+H] +.
Step 3: To a solution of compound 3.3 (40 mg, 0.10 mmol) and intermediate 1 (50 mg, 0.098 mmol) in DMF (3 mL) was added HATU (114 mg, 0.30 mmol) and DIPEA (38.7 mg, 0.30 mmol) at 25℃. The reaction mixture was stirred at 25℃ for 16 h. The reaction was quenched with water (10 mL) . The aqueous layer was extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over sodium sulfate and concentrated. The crude product was purified by prep-HPLC to afford Example 3 (12.2 mg, 13.9%yield) as a yellow solid. Chemical Formula: C46H45D6FN12O6; Molecular Weight: 893.03. LCMS (ESI) m/z: 894.1 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H) , 8.93 (s, 1H) , 8.48 (dd, J=24.8, 2.9 Hz, 2H) , 8.26 (s, 1H) , 7.79-7.67 (m, 2H) , 7.64-7.54 (m, 1H) , 7.46 (dt, J=8.6, 4.6Hz, 1H) , 7.16-6.98 (m, 2H) , 6.54 (s, 1H) , 6.13 (s, 1H) , 5.07 (dd, J= 12.9, 5.1Hz, 1H) , 4.01 (s, 3H) , 3.97-3.71 (m, 2H) , 2.98-2.81 (m, 2H) , 2.69-2.53 (m, 1H) , 2.10-1.93 (m, 2H) , 1.69-1.51 (m, 4H) , 1.48-1.09 (m, 15H) , 1.04-0.79 (m, 2H) .
The following examples were prepared using procedures similar to those described above:

BIOLOGICAL ACTIVITY
General assay procedure:
A. Dose-dependent degradation of BET proteins, including BRD2, BRD3, BRD4 and BRDT, and inhibition of cMyc protein expression induced by example compounds
1. Seed HCC1806 and HCT-116 cells in 6 well plate, incubate overnight at 37℃and 5%CO2.
2. When cells are ready, compounds at final concentrations of 10 uM, 2μM, 400 nM, 80 nM, 16 nM, 1 nM and 0 nM (DMSO only) were applied to the cells. Swirl gently to mix.
3. Incubate for 24 h.
4. At the end of incubation, aspirate away medium and add 200μl of ice-cold lysis buffer. Scrape to collect the lysates into 1.5 ml tube. Vortex briefly and spin in a refrigerated centrifuge for 15 minutes at 12000 rpm.
5. Transfer 150μl of supernatant and add 5X loading buffer, then boil the samples.
6. Load protein into SDS-PAGE gel, then run electrophoresis.
7. Transfer the gel.
8. Block the membrane.
9. Incubate with primary antibody (anti-BET proteins, anti-cMyc, anti-beta-actin) .
10. Wash 3 times in TBS with 0.5‰Tween-20.
11. Incubate with secondary antibody.
12. Wash 3 times in TBS with 0.5‰Tween-20.
13. Expose at Tanon 5200.
B. Time-dependent degradation of BET proteins by compounds Example 1, 3 and 5 in HCT-116 cells.
1. Seed HCT-116 cells in 6 well plate, incubate overnight at 37℃and 5%CO2.
2. When the cells are ready, compounds were added to a final concentration of 100 nM and 0 nM (DMSO only) . Swirl gently to mix
3. Incubate for 1, 3, 6h separately.
4. At the end of incubation, aspirate away medium and add 200μl of ice-cold lysis buffer. Scrape to collect the lysates into 1.5 ml tube. Vortex briefly and spin in a refrigerated centrifuge for 15 minutes at 12000 rpm.
5. Transfer 150μl of supernant to new tube and add 5X loading buffer, then boil the samples.
6. Load protein into SDS-PAGE gel for Western blotting analysis using antibodies specific to BRD2, BRD4 and beta-actin.
C. Cell proliferation assay
1. In day 1, HCT-116 and HCC1806 cells were seeded into 96-well plate and chemical compounds for growth inhibition were added at 30μM, 10μM, 3μM, 1 uM, 300 nM, 100 nM, 30 nM, 10 nM, and DMSO (vehicle solvent) .
2. In day 3, CCK8 Cell Viability Assay reagent were added to each well
3. Signals were recorded using TECAN SPARK
4. Assay robustness was measured by data from DMSO-treated and Medium sample:
H=DMSO, L=Medium;
H, CV% (DMSO) =100* (SD DMSO/ave DMSO)
L, CV% (ref) =100* (SD Medium/ave Medium)
Z’=1-3* (SD DMSO+SD Medium) / (ave DMSO-ave Medium)
Cell viability inhibition, %= (Average_H-Sample) / (Average_H-Average_L) x 100
The IC50 of the tested compounds were derived from fitting non-linear regression equation:
Y=Bottom+ (Top-Bottom) / (1+10^ ( (LogIC50-X) *HillSlope) )
X: Log of compound concentration
Y: Percent inhibition (%inh)
Top and Bottom: Plateaus in same units as Y
logIC50: same log units as X
HillSlope: Slope factor or Hill slope
Results are shown in Tables 1-3 and FIGs 1-8.
Compound concentrations that reduce BET proteins, BRD2, BRD3, BRD4 and BRDT, by 50%relative to no drug control (DC50) are reported. DC50 ranges are as follows: A<0.05 μM; B 0.05-0.1μM; C 0.1μM-0.5μM; D>0.5μM. N.D. =Value not determined
Table 1
Irrespective of readout, compound concentrations that reduce cell proliferation by 50%relative to no drug controls (EC50) are reported; EC50 ranges are as follows: A<0.1μM; B 0.1-0.2μM; C>0.2μM.
Table 2 Summary of Activities
Table 3 Summary of activities for example 3 in difference cancer cell lines
Irrespective of readout, compound concentrations that reduce cell proliferation by 50%relative to no drug controls (EC50) are reported; EC50 ranges are as follows: A<0.1μM; B 0.1-0.2μM; C>0.2μM.
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims (28)

  1. A bifunctional compound as shown by formula (A) or a pharmaceutically acceptable salt thereof, stereoisomer thereof, deuterated derivatives thereof:
    T-L-U   (A)
    wherein T is represented by the chemical structure (I) :
    wherein ring A and Q are each independently selected from the group consisting of optionally substituted 3-to 12-membered aryl, optionally substituted heteroaryl or optionally substituted heterocyclic group; and W is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted 3-to 12-membered aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic group, ,
    U is a CRBN E3 ubiquitin ligase binding moiety, and
    L is a bond or a bivalent chemical linking group connected to groups T and U.
  2. The compound of claim 1, wherein L is a connector with a linear non-hydrogen atom number in the range from 1 to 45 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 or 45) .
  3. The compound of claim 1 or 2, wherein L contains one or more functional groups selected from the group consisting of ether, amide, amine, CN, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, ester, urea, carbamate, thioether, sulfoxide, and sulfone.
  4. The compound of any one of claims 1-3, wherein L contains an aromatic group, a heteroaromatic group, a heterocyclic group, and a C3-C12 cycloalkyl, or a combination thereof,  each optionally substituted with one or more groups selected from the group consisting of halogen, CN, OH, protected OH, amino, optionally substituted amino, protected amino, and optionally substituted C1-C4 alkyl.
  5. The compound of any one of claims 1-4, wherein L can contain an aliphatic group optionally substituted with one or more groups selected from the group consisting of halogen, CN, OH, protected OH, amino, optionally substituted amino, protected amino, and optionally substituted C1-C4 alkyl.
  6. The compound of any one of claims 1-5, wherein W is hydrogen or optionally substituted C1-C6 alkyl.
  7. The compound of any one of claims 1-6, wherein W is C1-C6 alkyl optionally substituted with C3-C12 cycloalkyl, C3-C12 cycloalkenyl, 3-to 12-membered heterocyclic group, 3-to 12-membered aryl, or optionally substituted heteroaryl; wherein the C3-C12 cycloalkyl, C3-C12 cycloalkenyl, 3-to 12-membered heterocyclic group, 3-to 12-membered aryl, and optionally substituted heteroaryl may be further substituted.
  8. The compound of any one of claims 1-7, wherein W is C1-C6 alkyl optionally substituted with C3-C12 cycloalkyl, C3-C12 cycloalkenyl, or 3-to 12-membered heterocyclic group; wherein the C3-C12 cycloalkyl, C3-C12 cycloalkenyl, and 3-to 12-membered heterocyclic group may be further substituted.
  9. The compound of any one of claims 1-8, wherein W is C1-C6 alkyl optionally substituted with 3-to 12-membered aryl or heteroaryl; wherein the 3-to 12-membered aryl and heteroaryl may be further substituted.
  10. The compound of any one of claims 1-9, wherein W is C1-C6 alkyl substituted with a group selected from optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, and optionally substituted 3-to 12-membered heterocyclic group; and a group  selected from optionally substituted 3-to 12-membered aryl and optionally substituted heteroaryl.
  11. The compound of any one of claims 1-10, wherein W is C1-C6 alkyl substituted with an optionally substituted 3-to 12-membered heterocyclic group and an optionally substituted heteroaryl.
  12. The compound of any one of claims 1-11, wherein W is C1-C4 alkyl substituted with an optionally substituted 3-to 12-membered heterocyclic group and an optionally substituted heteroaryl.
  13. The compound of any one of claims 1-12, wherein W is a methyl substituted with an optionally substituted 3-to 12-membered heterocyclic group and an optionally substituted heteroaryl.
  14. The compound of any one of claims 1-13, wherein W is a methyl substituted with tetrahydro-2H-pyran-4-yl and 3-fluoropyridin-2-yl or 2-pyridyl.
  15. The compound of any one of claims 1-14, wherein T is selected from the following chemical structures:
    wherein R1 is selected from the group consisting of H, CN, optionally substituted C1-C6 alkyl, and optionally substituted with C3-C8 cycloalkyl; preferably, R1 is selected from the group consisting of H, Me, CD3, Et, i-Pr, CF3, CHF2, CN, cyclopropyl, and C1-C6-alkyl optionally substituted with C3-C12 cycloalkyl, C3-C12 cycloalkenyl, or 3-to 12-membered heterocyclic group;
    Q is selected from the group consisting of
    W is selected from the group consisting of H, Me, Et, and
  16. The compound of any one of claims 1-15, wherein T is selected from the following chemical structures (II-1 to II-8) :
  17. The compound of any one of claims 1-16, wherein U is a CRBN ligand selected from the following chemical structures (III-1 to III-4) :
    wherein R2 is hydrogen or optionally substituted C1-C6 alkyl; R3 at each occurrence is independently selected from the group consisting of hydrogen, halogen, CN, -NR4R5, -PR4R5,  -P (O) R4R5, -S (O) 2R4R5, -S (O) R4R5, -BR4R5, and optionally substituted C1-C6 alkyl; R4 and R5 are each independently selected from the group consisting of hydrogen or optionally substituted C1-C6-alkyl; and m is 0, 1, 2 or 3.
  18. The compound of any one of claims 1-16, wherein U is a CRBN ligand selected from the following chemical structure III-1:
    wherein R2 is hydrogen or optionally substituted C1-C6 alkyl; R3 at each occurrence is independently selected from the group consisting of hydrogen, halogen, CN, -NR4R5, -PR4R5, -P (O) R4R5, -S (O) 2R4R5, -S (O) R4R5, -BR4R5, and optionally substituted C1-C6 alkyl; R4 and R5 are each independently selected from the group consisting of hydrogen or optionally substituted C1-C6-alkyl; and m is 0, 1, 2 or 3.
  19. The compound of any one of claims 1-18, wherein U is
  20. The compound of any one of claims 1-19, wherein L is selected from the following chemical structure:
    wherein M1 and V2 are each independently selected from the group consisting of a single bond, optionally substituted C1-C4 alkyl, -N (R6) -, O, S, -S (O) -, -S (O) 2-, -OC (O) -, -N (R6) C (O) -,  -S (O) 2N (R6) -, -N (R6) C (O) N (R6) -, -N (R6) C (O) O-, a double bond and a triple bond; wherein R6 at each occurrence is independently hydrogen or optionally substituted C1-C6 alkyl;
    M2 and V1 are each independently selected from the group consisting of a bond, optionally substituted C1-C4 alkyl, a double bond, a triple bond, optionally substituted C3-C12 cycloalkyl optionally substituted heteroaryl, optionally substituted phenyl, optionally substituted heterocyclic group; wherein R6 at each occurrence is as previously defined;
    X at each occurrence is independently selected from the group consisting of optionally substituted C1-C4 alkyl, -N (R6) -, O, S, -S (O) -, -S (O) 2-, -OC (O) -, -N (R6) C (O) -, -S (O) 2N (R6) -, -N (R6) C (O) N (R6) -, -N (R6) C (O) O-, a double bond, a triple bond, optionally substituted 3-to 12-membered aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic group; wherein R6 at each occurrence is as previously defined; and
    n is 1 or 2.
  21. The compound of claim 20, wherein M2 and V1 are each independently a bond, optionally substituted heterocyclic or optionally substituted C3-C12 cycloalkyl; wherein the heterocyclic group and cycloalkyl may contain a fused or spiro polycyclic system.
  22. The compound of claim 20 or 21, wherein X is optionally substituted heterocyclic group or optionally substituted C3-C12 cycloalkyl; wherein the heterocyclic and cycloalkyl may contain a fused or spiro polycyclic system.
  23. The compound of any one of claims 20-22, wherein M2, V1 and X are independently selected from the following structures:
    wherein Y is selected from the group consisting of-C (R6) 2-, O, S, -N (R6) -, and-C (O) N (R6) -; Z is O, -NH-, – (CH2) m1–, -OCH2–, or-CH2OCH2–; m1 is 1, 2 or 3; n1, n2, n3, n4, n5, and n6 are each independently 0, 1 or 2; R6 is as previously defined; and wherein the listed ring structures may be optionally substituted with 1 to 4 substituents selected from the group consisting of hydrogen, halogen, CN, hydroxyl, and optionally substituted C1-C6-alkyl.
  24. The compound of any one of claims 1-23, wherein L is selected from the following chemical structures:

  25. The compound of claim 1, wherein the compound is selected from the group consisting of the following compounds:





  26. A pharmaceutical composition, comprising the compound of any one of claims 1-25, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
  27. A method of treating a cancer disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-25, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  28. A method of degrading the BET protein, comprising contacting an oncoprotein with an effective amount of the compound of any one of claims 1-25, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
PCT/CN2023/131058 2022-11-11 2023-11-10 Bromodomain and extra-terminal (bet) protein degrader WO2024099441A1 (en)

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