HK40082251A

HK40082251A - Heterobifunctional molecules as tead inhibitors

Info

Publication number: HK40082251A
Application number: HK62023071488.8A
Authority: HK
Inventors: J·R·兹比埃格; E·维拉莫尔; J·鲁道夫; P·P·贝罗扎; J·J·克劳福德
Original assignee: 基因泰克公司
Priority date: 2020-03-04
Filing date: 2021-03-02
Publication date: 2023-06-02

Description

Heterobifunctional molecules as TEAD inhibitors

Cross reference to related patent applications

This application claims benefit and priority from U.S. provisional patent application No. 62/985,256, filed 3, 4, 2020, the disclosure of which is incorporated herein by reference in its entirety.

Sequence listing

This application contains a sequence listing filed by EFS-Web and incorporated herein by reference in its entirety. The ASCII copy was created on 11/2/2021, named P35870-WO _ SL, and has a size of 33,999 bytes.

Technical Field

The present disclosure relates to compounds useful for the treatment and/or prevention of mammals, particularly as inhibitors and/or degradants of TEAD useful for the treatment of cancer.

Background

The Hippo pathway is a signaling pathway that regulates cell proliferation and cell death and determines organ size. This pathway is believed to play a role as a tumor suppressor in mammals, and a disorder of this pathway is often detected in human cancers. This pathway is involved in and/or likely regulates the self-renewal and differentiation of stem and progenitor cells. Furthermore, the Hippo pathway may be involved in wound healing and tissue regeneration. Furthermore, it is believed that as the Hippo pathway interacts with other signaling pathways such as Wnt, notch, hedgehog, and MAPK/ERK crosstalk (cross-talk), it may affect a variety of biological events, and its dysfunction may be involved in many human diseases in addition to cancer. For a review, see, e.g., halder et al, 2011, development 138; zhao et al, 2011, nature Cell Biology 13; bao et al, 2011, J.biochem.149; zhao et al, 2010, j.cell sci.123.

The Hippo signaling pathway is conserved from Drosophila to mammals (Vassilev et al, genes and Development,2001,15,1229-1241, zeng and Hong, cancer Cell,2008,13,188-192). The core of this pathway consists of a kinase cascade (Hippo-MST 1-2 located upstream of Lats 1-2 and NDRI-2) leading to phosphorylation of two transcription coactivators YAP (Yes-associated proteins) and TAZ (a transcription coactivator with a PDZ binding motif or tafazzin; zhao et al, cancer Res.,2009,69,1089-1098 Lei et al, mol.cell.biol.,2008,28,2426-2436).

Because the Hippo signaling pathway is a regulator of animal development, organ size control, and stem cell regulation, it has been implicated in the development of cancer (reviewed in Harvey et al, nat. Rev. Cancer,2013,13,246-257 zhao et al, genes dev.2010,24, 862-874. In vitro, overexpression of YAP or TAZ in mammalian epithelial cells induces cell transformation by the interaction of both proteins with transcription factors of the TEAD family. Increased YAP/TAZ transcriptional activity induces oncogenic properties such as epithelial-mesenchymal transition, and it was also found to confer stem cell properties on breast cancer cells. In vivo, overexpression of YAP or knock-out of its upstream regulatory factor MST1-2 triggered the development of hepatocellular carcinoma in the mouse liver. Furthermore, when the tumor suppressor NF2 in the mouse liver was inactivated, the development of hepatocellular carcinoma could be completely blocked by the co-inactivation of YAP.

<xnotran> , hippo , (NSCLC; zhou , oncogene, 5623 zxft 5623-2186;Wang , cancer Sci.,2010,101,1279-1285), (Chan , cancer Res., 6262 zxft 6262-2598;Lamar , proc.Natl.Acad.Sci, USA,2012;109,E2441-E2250; wang , eur.J.Cancer, 3256 zxft 3256-1234), (Gasparotto , oncotarget., 3456 zxft 3456-1175;Steinmann , oncol.Rep., 3838 zxft 3838-1526), (Angela , hum.Pathol., 5749 zxft 5749-1589;Yuen , PLoS One,2013,8,e54211;Avruch , cell Cycle, 6595 zxft 6595-1096), (Angela , hum.Pathol., 6898 zxft 6898-1589;Chad , cancer Res., 3428 zxft 3428-8525;Hall , cancer Res., 3476 zxft 3476-8525), (Jie , gastroenterol.Res.Pract.,2013,2013,187070;Ahn , mol.Cancer.Res., 3734 zxft 3734-758;Liu , expert.Opin.Ther.Targets, 3757 zxft 3757-247), (Orr , J Neuropathol.Exp.Neurol.2011, 5852 zxft 5852-577;Baia , mol.Cancer Res., 3575 zxft 3575-913;Striedinger , neoplasia, 3625 zxft 3625-1212) (Zhao , genes Dev., 3826 zxft 3826-68;Zhao , genes Dev., 3828 zxft 3828-2761), (Fujii , J.Exp.Med., 3925 zxft 3925-494;Mizuno , oncogene, 5483 zxft 5483-5122;Sekido Y., pathol.Int., 5678 zxft 5678-344), (Seidel , mol.Carcinog., 7439 zxft 7439-871) (Jimenez-Velasco , leukemia, 8624 zxft 8624-2350). </xnotran>

Two central components of the mammalian Hippo pathway are hits 1 and hits 2, which are nuclear Dbf 2-related (NDR) family protein kinases homologous to drosophila Warts (Wts). Lats1/2 protein was activated by binding to the scaffold protein Mob1A/B (Mps is a binding kinase activator like 1A and 1B) homologous to Drosophila Mats. The Lats1/2 protein can also be activated by phosphorylation by STE20 family protein kinases Mst1 and Mst2, which are homologous to Drosophila Hippo. Lats1/2 kinase phosphorylates downstream effectors YAP (Yes-related protein) and TAZ (transcriptional co-activator with PDZ-binding motif; WWTR 1) homologous to Drosophila Yorkie. The phosphorylation of YAP and TAZ by Lats1/2 is a key event in the Hippo signaling pathway. Lats1/2 phosphorylates YAP at multiple sites, but Ser127 phosphorylation is critical for YAP inhibition. Phosphorylation of YAP produces protein binding motifs of the 14-3-3 family of proteins, which upon binding to the 14-3-3 protein, result in retention and/or sequestration of YAP in the cytoplasm. Also, lats1/2 phosphorylates TAZ at multiple sites, but Ser89 phosphorylation is critical for TAZ inhibition. Phosphorylation of TAZ results in retention and/or sequestration of TAZ in the cytoplasm. In addition, it is believed that phosphorylation of YAP and TAZ destabilizes these proteins by activating phosphorylation-dependent degradation catalyzed by YAP or TAZ ubiquitination. Thus, when the Hippo pathway is "on", YAP and/or TAZ are phosphorylated, inactivated and usually sequestered in the cytoplasm; in contrast, when the Hippo pathway is "off," YAP and/or TAZ are unphosphorylated, active and normally present in the nucleus.

Non-phosphorylated activated YAP is transported into the nucleus where its major target transcription factors are four proteins of the TEAD domain-containing family (TEAD 1 to TEAD4, collectively "TEAD"). It has been found that YAP and TEAD (or other transcription factors such as Smad1, RUNX, erbB4 and p 73) together induce the expression of a variety of genes, including Connective Tissue Growth Factor (CTGF), gli2, birc5, birc2, fibroblast growth factor 1 (FGF 1) and Amphiregulin (AREG). Similar to YAP, unphosphorylated TAZ is transported into the nucleus where it interacts with a variety of DNA binding transcription factors such as peroxisome proliferator-activated receptor gamma (PPAR γ), thyroid transcription factor-1 (TTF-1), pax3, TBX5, RUNX, TEAD1 and Smad 2/3/4. Many genes activated by the YAP/TAZ-transcription factor complex mediate cell survival and proliferation. Thus, under some conditions, the YAP and/or TAZ act as oncogenes, while the Hippo pathway acts as a tumor suppressor.

One type of targeted therapy involves heterobifunctional molecules, which utilizes the intracellular ubiquitin-proteasome system to selectively degrade targeted proteins by forming ternary complexes between the targeted protein, the heterobifunctional molecule, and the ubiquitin ligase. This in turn enables ubiquitin ligase to ubiquitinate the targeted protein, labelling the protein for degradation by the proteasome.

There is a need in the art for improved cancer treatment options, i.e. the use of pharmacological targets of TEAD to provide functional alterations of the Hippo cascade. Heterobifunctional molecules may be particularly advantageous.

Disclosure of Invention

In some aspects, there is provided a compound of formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[A] is a ligase ligand;

[B] is a linker moiety;

X ¹ 、X ² and X ³ Each independently is N or C-R ⁵ Wherein each R is ⁵ Independently selected from the group consisting of: H. halo, cyano, C _1-12 Alkyl, O-C _1-12 Alkyl and C _1-12 A haloalkyl group;

L ¹ is a bond or is-C _1-12 Alkyl-, -C _2-12 Alkenyl-, -C _2-12 alkynyl-or-C _3-10 Cycloalkyl-;

R ¹ is H, C _1-12 Alkyl radical, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl, O-C _3-10 Cycloalkyl, O-C _1-12 alkyl-C _3-10 Cycloalkyl or O-C _1-12 A haloalkyl group; and is

R ² Is H, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl, 5-to 20-membered heteroaryl or C _5-13 Spiro ring group, wherein:

R ² c of (A) _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl, 5-to 20-membered heteroaryl or C _5-13 Spiro ring groups are independently optionally substituted with one or more oxo, cyano, halo, C _1-12 Alkyl radical, C _1-12 Haloalkyl, C _3-10 Cycloalkyl radical, C _6-20 Aryl, NO ₂ 、N(R ^x )(R ^y ) And O (R) ^x ) Substitution, wherein:

each R ^x And R ^y Independently selected from the group consisting of: H. c _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl and 5-to 20-membered heteroaryl, wherein:

R ^x and R ^y Each C of _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl and 5-to 20-membered heteroaryl are independently optionally substituted by one or more oxo, cyano, halo, NO ₂ 、NH ₂ Hydroxy, C _1-12 Alkyl radical, C _1-12 Haloalkyl or O-C _l-12 Alkyl substitution.

In some embodiments, the linker moiety has the structure of formula (II):

wherein:

the one of the linker moiety represents the point of attachment to the ligase ligand and the one of the linker moiety represents the point of attachment to the rest of the molecule;

L ² is- (CH) ₂ ) _n -or- (CH) ₂ CH ₂ O) _n -, where n is 1 to 12;

L ³ is a bond or is-C.ident.C-, -CH = CH-, - (CH) ₂ ) _m -, -O-, -NH-orWherein L is ³ Is represented by ² And L is a connection point of ³ Denotes the point of attachment to the ligase ligand;

R ^3a and R ^3b Is H, C _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _6-20 Aryl, 3-to 10-membered heterocyclic group, C _6-20 Aryl or 5-to 20-membered heteroaryl, wherein:

each C _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _6-20 Aryl, 3-to 10-membered heterocyclic group, C _6-20 Aryl or 5-to 20-membered heteroaryl independently optionally substituted by oxo, CN, C _1-12 Alkyl radical, C _1-12 Haloalkyl, halo, NO ₂ 、N(R ^e )(R ^f )、C _1-12 alkyl-C (O) -N (R) ^e )(R ^f ) And OR ^e At least one of, wherein:

each R ^e And R ^f Independently selected from the group consisting of: H. c _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl and 5-to 20-membered heteroaryl, wherein each C _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl independently optionally substituted by one or more oxo, CN, C _1-12 Alkyl radical, C _1-12 Haloalkyl, halo, NO ₂ 、O-C _l-12 Alkyl or OH.

In certain embodiments, the ligase ligand is an E3 ubiquitin ligase ligand.

In some embodiments, the ligase ligand is a cereblon ligand, a VHL ligand, or a XIAP ligand.

In some aspects, the compound of formula (I) is a heterobifunctional molecule.

In some aspects, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

In some aspects, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in pharmaceutical therapy.

In some aspects, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of cancer, mesothelioma, sarcoma or leukemia.

In some aspects, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment or prophylaxis of cancer, mesothelioma, sarcoma or leukemia.

In some aspects, there is provided a method for treating cancer, mesothelioma, sarcoma or leukemia in a mammal, the method comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some aspects, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided for modulating TEAD activity.

In some aspects, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided for use in degrading TEAD proteins. In some aspects, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided for modulating TEAD activity, wherein TEAD activity is modulated by degradation of TEAD protein.

In some aspects, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment or prevention of a disease or condition mediated by TEAD activity.

In some aspects, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by TEAD activity.

In some aspects, there is provided a method for modulating TEAD activity, comprising contacting TEAD with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In some aspects, there is provided a method for treating a disease or condition mediated by TEAD activity in a mammal, the method comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some aspects, provided are ternary complexes comprising: a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof; a TEAD protein; and ubiquitin ligases.

Detailed Description

Definition of

Unless otherwise indicated, the following specific terms and phrases used in the specification and claims are defined as follows.

The term "moiety" refers to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds to form part of a molecule.

The term "substituted" refers to the fact that at least one hydrogen atom of the moiety is replaced with another substituent or moiety.

The term "alkyl" refers to an aliphatic straight or branched chain saturated hydrocarbon moiety having from 1 to 20 carbon atoms, such as from 1 to 12 carbon atoms or from 1 to 6 carbon atoms. The alkyl group may be optionally substituted.

The term "cycloalkyl" means a saturated or partially unsaturated carbocyclic moiety having a monocyclic or bicyclic ring (including bridged bicyclic rings) and 3 to 10 carbon atoms within the ring. In particular aspects, the cycloalkyl group can contain 3 to 8 carbon atoms (i.e., (C) ₃ -C ₈ ) Cycloalkyl groups). In other particular aspects, the cycloalkyl group can contain 3 to 6 carbon atoms (i.e., (C) ₃ -C ₆ ) Cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially unsaturated derivatives thereof (cycloalkenyl) (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl). Cycloalkyl moieties may be attached in a spiro fashion, for example, spirocyclopropyl:

the term "haloalkyl" refers to an alkyl group wherein one or more hydrogen atoms of the alkyl group have been replaced with the same or different halogen atoms, such as fluorine atoms. Examples of haloalkyl include monofluoro-, difluoro-or trifluoro-methyl, -ethyl or-propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl. The haloalkyl group may be optionally substituted.

The term "alkenyl" refers to a straight or branched chain alkyl or substituted alkyl group as defined elsewhere herein having at least one carbon-carbon double bond. The alkenyl group may be optionally substituted.

The term "alkynyl" refers to a straight or branched chain alkyl or substituted alkyl group as defined elsewhere herein having at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted.

The terms "heterocyclyl" and "heterocycle" refer to 4, 5, 6, and 7 membered monocyclic or 7, 8, 9, and 10 membered bicyclic (including bridged bicyclic) heterocyclic moieties that are saturated or partially unsaturated and have one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from oxygen, nitrogen, and sulfur located in the ring, with the remaining ring atoms being carbon. When used to refer to a ring atom of a heterocycle, nitrogen or sulfur may also be in oxidized form, and the nitrogen may be substituted. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocycles include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxacyclohexyl, dioxolanyl, diazepitrienyl, oxepitrienyl, thiepinyl, morpholinyl, and quinuclidinyl. The term heterocycle also includes groups in which the heterocycle is fused to one or more aryl, heteroaryl or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, 2-azabicyclo [2.2.1] heptanyl, octahydroindolyl or tetrahydroquinolinyl. Heterocyclyl groups may be optionally substituted.

The term "aryl" refers to a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic, or tricyclic aromatic ring of 5 to 20 carbon ring atoms. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, benzyl, and the like. The term "aryl" also includes partially hydrogenated derivatives of cyclic aromatic hydrocarbon moieties, provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic, each optionally substituted. In some aspects, monocyclic aryl rings can have 5 or 6 carbon ring atoms. The aryl group may be optionally substituted.

The term "heteroaryl" refers to a 1 to 20 ring atom monocyclic or bicyclic ring system of an aromatic heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl. Heteroaryl groups may be optionally substituted.

The terms "halo" and "halogen" refer to fluoro, chloro, bromo and iodo. In some aspects, halo is fluoro or chloro.

The term "oxo" refers to the = O moiety.

The terms "spirocyclic" and "spirocyclic group" refer to a carbogenic bicyclic ring system containing 5 to 15 carbon atoms with both rings connected by a single atom. The rings may be different in size and nature or may be the same in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spiroketone or spirodecane. One or more carbon atoms in the spiro ring may be substituted with a heteroatom (e.g., O, N, S or P), where in these aspects the spiro ring may contain 3 to 14 carbon atoms. The spiro group may be optionally substituted.

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effects and properties of the free base or free acid, which are not biologically or otherwise undesirable. Salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, N-acetylcysteine and the like. In addition, salts can be prepared by addition of inorganic or organic bases to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts including the following: primary, secondary and tertiary amines, naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like.

The term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical means in an ex vivo environment. For example, a prodrug can be slowly converted to a compound of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical agent.

In some prodrug aspects, prodrugs include compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked through an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of a compound of the disclosure. Amino acid residues include, but are not limited to, the 20 natural amino acids typically represented by three letter symbols, and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, dehydroglucose, isododecane, γ -carboxyglutamic acid, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, methylalanine, p-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and t-butylglycine.

In some other prodrug aspects, the free carboxyl group of a compound of the present disclosure may be derivatized as an amide or alkyl ester. In other prodrug aspects, prodrugs containing free hydroxyl groups may be derivatized to prodrugs by converting the hydroxyl groups to groups such as, but not limited to, phosphate esters, hemisuccinate esters, dimethylaminoacetate or phosphonooxymethyloxycarbonyl, as outlined in Fleisher, D. et al, (1996) Improved organic Drug Delivery, solvent limitations over come by the use of drugs Advanced Drug Delivery Reviews, 19. Also included are carbamate prodrugs of hydroxyl and amino groups, such as carbonate prodrugs of hydroxyl groups, sulfonates, and sulfates. Derivatization of hydroxyl groups as (acyloxy) methyl and (acyloxy) ethyl ethers, in which acyl is also encompassedThe radical group may be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or where the acyl group is an amino acid ester as described above. Such prodrugs are described, for example, in j.med.chem., (1996), 39. More specific examples include substituting the hydrogen atom of an alcohol group with a group such as: (C) _1-6 ) Alkanoyloxymethyl, 1- ((C) _1-6 ) Alkanoyloxy) ethyl, 1-methyl-1- ((C) _1-6 ) Alkanoyloxy) ethyl group, (C) _1-6 ) Alkoxycarbonyloxymethyl, N- (C) _1-6 ) Alkoxycarbonylaminomethyl, succinyl, (C) _1-6 ) Alkanoyl, alpha-amino (C) _1-4 ) Alkanoyl, aryl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl wherein each alpha-aminoacyl group is independently selected from the group consisting of naturally occurring L-amino acids, P (O) (OH) ₂ 、-P(O)(O(C _1-6 ) Alkyl radical) ₂ Or a glycosyl group (a radical generated by removal of the hydroxyl group of the hemiacetal form of a carbohydrate).

For further examples of prodrug derivatives, see, e.g., a) Design of produgs, editions by h.bundgaard (Elsevier, 1985) and Methods in Enzymology, volume 42, pages 309-396, editions by k.widder et al (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, chapter 5 "Design and Application of Prodrugs", pp.113-191 (1991); c) Bundgaard, advanced Drug Delivery Reviews,8:1-38 (1992); d) Bundgaard et al, journal of Pharmaceutical Sciences,77 (1988); and e) n.kakeya et al, chem.pharm.bull, 32 (1984), each of which is specifically incorporated herein by reference.

In addition, the present disclosure provides metabolites of the compounds of the present disclosure. As used herein, "metabolite" refers to a product produced by the metabolism of a particular compound or salt thereof in the body. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound.

Metabolites are typically radiolabeled by preparing compounds of the disclosure (e.g., ¹⁴ c or ³ H) Is/are as followsIsotopes are identified and parenterally administered to an animal (such as a rat, mouse, guinea pig, monkey, or human) in detectable doses (e.g., greater than about 0.5 mg/kg) for sufficient time to metabolize (typically about 30 seconds to 30 hours) and to isolate their conversion products from urine, blood, or other biological samples. Since these products are labeled, they can be easily isolated (by using antibodies that bind to epitopes that survive in the metabolite to isolate other products). The structure of the metabolite is determined in a conventional manner, e.g. by MS, LC/MS or NMR analysis. Typically, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. As long as no metabolites are found in vivo, they can be used in diagnostic assays disclosing therapeutic doses of the compounds.

Certain compounds of the present disclosure may exist in non-solvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be encompassed within the scope of the present disclosure.

Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or in the spatial arrangement of their atoms are referred to as "isomers". Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". Diastereomers are stereoisomers that have opposite configurations at one or more chiral centers but are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, if one carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of one or more of its asymmetric centers, and is described by the R-and S-ordering rules of Cahn, ingold, and Prelog, or by the mode by which the molecule rotates the plane of polarized light and is designated dextrorotatory or levorotatory (i.e., the (+) -or (-) -isomers, respectively). The chiral compounds may exist as individual enantiomers or as mixtures of individual enantiomers. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures". In certain aspects, the compound is enriched in at least about 90% by weight of a single diastereomer or enantiomer. In other aspects, the compound is enriched in at least about 95%, 98%, or 99% by weight of a single diastereomer or enantiomer.

Certain compounds of the present disclosure possess asymmetric carbon atoms (chiral centers) or double bonds; racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separated enantiomers) are all intended to be encompassed within the scope of the present disclosure.

The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconverted through low energy barriers. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by recombination of some of the bonded electrons.

The term "compound of the formula.. Or" compounds of the formula.. Means any compound selected from the group of compounds defined by the formula unless otherwise indicated. In some embodiments or aspects, the term also includes pharmaceutically acceptable salts or esters of any such compounds, as well as stereoisomers, tautomers, of such compounds.

The term "therapeutically effective amount" of a compound means an amount of the compound effective to prevent, alleviate or alleviate the symptoms of a disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill of the art. The therapeutically effective amount or dose of a compound according to the present disclosure may vary within wide ranges and may be determined in a manner known in the art. This dosage will be adjusted according to the individual requirements of each particular case, including the particular compound administered, the route of administration, the condition being treated and the patient being treated. Generally, in the case of oral or parenteral administration to an adult human weighing about 70kg, a daily dose of about 0.1mg to 5,000mg, 1mg to about 1,000mg, or 1mg to 100mg may be suitable, but the lower and upper limits may be exceeded when indicated. The daily dose may be administered as a single dose or divided doses, or for parenteral administration it may be given as a continuous infusion.

The term "pharmaceutically acceptable carrier" is intended to include any and all materials compatible with pharmaceutical administration, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the compounds of the disclosure, its use in the compositions of the disclosure is contemplated. Supplementary active compounds may also be incorporated into the composition.

Compound (I)

In some aspects of the disclosure, a compound, or stereoisomer or pharmaceutically acceptable salt thereof, has the following formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[A] is a ligase ligand;

[B] is a linker moiety;

R ¹ is H, C _1-12 Alkyl radical, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl, O-C _3-10 Cycloalkyl, O-C _1-12 alkyl-C _3-10 Cycloalkyl or O-C _1-12 A haloalkyl group; and is provided with

R ² c of (A) _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl, 5-to 20-membered heteroaryl or C _5-13 Spiro ring groups are independently optionally substituted with one or more oxo, cyano, halo, C _1-12 Alkyl radical, C _1-12 Haloalkyl, C _3-10 Cycloalkyl, C _6-20 Aryl, NO ₂ 、N(R ^x )(R ^y ) And O (R) ^x ) Substitution, wherein:

each R ^x And R ^y Independently selected from the group consisting of: H. c _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl and 5-to 20-membered heteroaryl, wherein:

R ^x and R ^y Each C of _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl and 5-to 20-membered heteroaryl are independently optionally substituted with one or more oxo, cyano, halo, NO ₂ 、NH ₂ Hydroxy, C _1-12 Alkyl radical, C _1-12 Haloalkyl or O-C _l-12 And (3) alkyl substitution.

In some embodiments, the compound of formula (I) is a heterobifunctional molecule. It should be understood that the various components described herein may be combined with other components as if each combination were specifically and individually listed. For example, each description of [ B ] can be combined with each description of [ A ] as if each combination was specifically and individually listed. Further, each such description or combination may apply to formula (I) and other related formulae, as will be apparent to those skilled in the art.

A variety of linker moieties may be present in the compounds of any of the formulae described herein. In some embodiments, one or more portions of the linker moiety may interact with the targeting protein and/or the ligase. In one embodiment, the portion of the linker moiety that interacts with the targeting protein has Such that the part of the compound of formula (I) that interacts with the target protein hasThe structure of (1). In other embodiments, the entire linker moiety may interact with the targeting protein and/or the ligase. In some embodiments, the linker moiety has the structure of formula (II):

wherein the linker moiety represents a point of attachment to the ligase ligand and the linker moiety represents a point of attachment to the remainder of the molecule;

L ² is- (CH) ₂ ) _n -or- (CH) ₂ CH ₂ O) _n -, where n is 1 to 12;

L ³ is a bond or is-C.ident.C-, -CH = CH-, - (CH) ₂ ) _m -, -O-, -NH-orWherein L is ³ Is represented by ² And L is a connection point of ³ Denotes the point of attachment to the ligase ligand; and is provided with

R ^3a And R ^3b Is H, C _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl, C _1-12 alkyl-C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _6-20 Aryl, 3-to 10-membered heterocyclic group, C _6-20 Aryl or 5-to 20-membered heteroaryl, wherein:

each C _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, C _1-12 alkyl-C _6-20 Aryl, 3-to 10-membered heterocyclic group, C _6-20 Aryl or 5-to 20-membered heteroaryl independently optionally substituted by oxo, CN, C _1-12 Alkyl radical, C _1-12 Haloalkyl, halo, NO ₂ 、N(R ^e )(R ^f )、C _1-12 alkyl-C (O) -N (R) ^e )(R ^f ) And OR ^e At least one of, wherein:

Each R ^e And R ^f Independently selected from the group consisting of: H. c _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl and 5-to 20-membered heteroaryl, wherein each C _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl independently optionally substituted by one or more oxo, CN, C _1-12 Alkyl radical, C _1-12 Haloalkyl, halo, NO ₂ 、O-C _l-12 Alkyl or OH.

In some embodiments, R ^3a And R ^3b Each of which is H or C _1-12 An alkyl group. In other embodiments, R ^3a And R ^3b Each of which is H or methyl. In still other embodiments, R ^3a And R ^3b Each of which is H. In a further embodiment, R ^3a Is H and R ^3b Is methyl.

In some embodiments, the ligase ligand is an E3 ubiquitin ligase ligand. In certain embodiments, the E3 ubiquitin ligase ligand is a cereblon ligand. In some embodiments, the cereblon ligand has the structure of formula (III):

wherein: q ¹ And Q ² Is C = O, and Q ¹ And Q ² Is C = O or CH ₂ ；R ^a 、R ^b 、R ^c And R ^d Is L with a linker moiety ³ Is/are as followsA bond, and R ^a 、R ^b 、R ^c And R ^d Each of others in (a) is independently H, halo, C _1-12 Alkyl radical, C _1-12 Haloalkyl or O-C _1-12 An alkyl group; and R is ^e Is H, halo, C _1-12 Alkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl or phenyl.

In some embodiments, wherein the ligase ligand is a cereblon ligand, the compound has the structure of formula (IV):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula (IV) is a compound of formula (V):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (V) is selected from the group consisting of:

or a stereoisomer or pharmaceutically acceptable salt thereof.

In certain embodiments, the E3 ubiquitin ligase ligand is a VHL ligand. In some embodiments, the VHL ligand has the structure of formula (VI):

wherein: w is a group of ¹ Is CH-C _1-12 Alkyl radical, C _6-20 Aryl or 5-to 20-membered heteroaryl; and W ² Is C _6-20 Aryl or 5-to 20-membered heteroaryl, wherein W ¹ Or W ² C of (A) _6-20 Aryl or 5-to 20-membered heteroaryl independently optionally substituted by C _1-12 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl, each of which is further optionally substituted with one or more halo, cyano, hydroxy, N (R) ^x )(R ^y )、C _1-12 Alkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl; and R is ^g And R ^h Each independently selected from the group consisting of: H. halo, cyano, hydroxy, NH ₂ 、C _1-12 Alkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl and 5-to 20-membered heteroaryl.

In some embodiments, wherein the ligase ligand is a VHL ligand, the compound has the structure of formula (VII):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (VII) is a compound of formula (VIII):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula (VIII) is selected from the group consisting of:

or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, the E3 ubiquitin ligand is a XIAP ligand. In certain embodiments, the XIAP ligand has the structure of formula (IX):

wherein: t is a unit of ¹ Is a 3-to 10-membered heterocyclyl or 5-to 20-membered heteroaryl, wherein: 3-to 10-membered heterocyclyl or 5-to 20-membered heteroaryl, independently, optionally substituted with one or more halo, cyano, hydroxy, N (R) ^x )(R ^y )、C _1-12 Alkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl; t is ² Is C (R) ⁱ ) ₂ O or S; t is a unit of ³ 、T ⁴ And T ⁵ Each independently is O or S; each R ⁱ Independently is H, halo, cyano, hydroxy, N (R) ^x )(R ^y )、C _1-12 Alkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl; and each R ^k Independently H, hydroxy, halo, C _1-12 Alkyl radical, C _1-12 Haloalkyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl.

In some embodiments, wherein the ligase ligand is a XIAP ligand, the compound has the structure of formula (X):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (X) is a compound of formula (XI):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (XI) is selected from the group consisting of:

or a stereoisomer or pharmaceutically acceptable salt thereof.

Various ligase ligands may be used in accordance with the present invention. In some embodiments, the ligase ligand is an E3 ubiquitin ligase ligand. In certain embodiments, the ligase ligand is a cereblon ligand. In other embodiments, the ligase ligand is a VHL ligand. In yet other embodiments, the ligase ligand is a XIAP ligand.

It is understood that the scope of the ligase ligands encompassed in the present specification includes, but is not limited to, the specific embodiments and aspects described herein. To this end, certain embodiments and aspects may be modified, while remaining within the scope of the appended claims. For additional embodiments and aspects of ligase ligands, see, e.g., U.S. patent nos. 7,244,851 and 9,694,084 and U.S. patent application publication No. US2016/0272639, each of which is incorporated herein in its entirety.

In some embodiments, there is provided a compound of any one of the formulae as described herein, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L of the linker moiety ² Is- (CH) ₂ ) _n -, where n is 1 to 12. In other embodiments, n is 1 to 10. In still other embodiments, n is 1 to 8. In a further embodiment, n is 1 to 6. In still further embodiments, n is 1 to 4. In other embodiments, n is 1 to 2.

In some embodiments, provided is a compound of any one of the formulae as provided herein, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is ² Is- (CH) ₂ CH ₂ O) _n -, where n is 1 to 12. In other embodiments, n is 1 to 10. In still other embodiments, n is 1 to 8. In a further embodiment, n is 1 to 6. In still further embodiments, n is 1 to 4. In other embodiments, n is 1 to 2.

In some embodiments，L ² Is a group of covalently linked building blocks comprising one or more Y, wherein each Y unit is linked to a ligase ligand, L ³ 、At least one of a moiety, another Y unit, or a combination thereof. In certain embodiments, the Y unit will link the enzyme ligand, L ³ 、The moiety or combination thereof being directly linked to another ligase ligand, L ³ 、Parts or combinations thereof. In other embodiments, the Y unit links the ligase ligand, L, through one or more different Y units ³ 、The moiety or combination thereof is indirectly linked to another ligase ligand, L ³ 、Parts or combinations thereof. In any of the embodiments disclosed herein, one or more covalently linked building blocks of Y may be coupled to L ³ Or a ligase ligand. In certain embodiments, a building block of Y may be connected to L at one or more junctions ³ Or a ligase ligand linkage. In other embodiments, one or more covalently linked building blocks of Y may be coupled toMoiety and also coupled to L ³ Or the ligase ligands of the present disclosure to form heterobifunctional molecules.

In certain embodiments, L ² Is (Y) _q And each Y unit is independently selected from the group consisting of: key, CR ^La R ^Lb 、O、S、SO、SO ₂ 、NR ^Lc 、SO ₂ NR ^Lc 、SONR ^Lc 、CONR ^Lc 、NR ^Lc CONR ^Ld 、NR ^Lc SO ₂ NR ^Ld 、CO、CR ^La ═CR ^Lb 、C≡C、SiR ^La R ^Lb 、P(O)R ^La 、P(O)OR ^La 、NR ^Lc C(＝NCN)NR ^Ld 、NR ^Lc C(＝NCN)、NR ^Lc C(＝CNO ₂ )NR ^Ld 、C _3-10 Cycloalkylene radical, C _3-10 Heterocyclylene, arylene and heteroarylene radicals, in which C _3-10 Cycloalkylene radical, C _3-10 Heterocyclylene, arylene and heteroarylene are independently unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of ^La 、R ^Lb And combinations thereof, wherein each R ^La Or R ^Lb Independently may be linked to other Y groups to form cycloalkylene and/or heterocyclylene moieties, wherein the cycloalkylene and heterocyclylene moieties are independently unsubstituted or substituted with 1, 2, 3 or 4R ^Le Substituted by groups; wherein each R ^La 、R ^Lb 、R ^Lc 、R ^Ld And R ^Le Independently selected from the group consisting of: H. halogen, R ^Lf 、-OR ^Lh 、-SR ^Lh 、-NHR ^Lh 、-N(R ^Lh ) ₂ 、C _3- C ₁₀ Cycloalkyl, aryl, heteroaryl, C _3- C ₁₁ Heterocyclyl, -N (R) ^Lg )(R ^Lf )、-OH、-NH ₂ 、-SH、-SO ₂ R ^Lf 、-P(O)(OR ^Lf )(R ^Lf )、-P(O)(OR ^Lf ) ₂ 、-C≡C-R ^Lf 、-C≡CH、-CH═CH(R ^Lf )、-C(R ^Lf )═CH(R ^Lf )、-C(R ^Lf )═C(R ^Lf ) ₂ 、-Si(OH) ₃ 、-Si(R ^Lf ) ₃ 、-Si(OH)(R ^Lf ) ₂ 、-COR ^Lf 、-CO ₂ H. -halogen, -CN, -CF ₃ 、-CHF ₂ 、-CH ₂ F、-NO ₂ 、-SF ₅ 、-SO ₂ NHR ^Lf 、-SO ₂ N(R ^Lf ) ₂ 、-SONHR ^Lf 、-SON(R ^Lf ) ₂ 、-CONHR ^Lf 、-CON(R ^Lf ) ₂ 、-N(R ^Lf )CONH(R ^Lf )、-N(R ^Lf )CON(R ^Lf ) ₂ 、-NHCONH(R ^Lf )、-NHCON(R ^Lf ) ₂ 、-NHCONH ₂ 、-N(R ^Lf )SO ₂ NH(R ^Lf )、-N(R ^Lf )SO ₂ N(R ^Lf ) ₂ 、-NHSO ₂ NH(R ^Lf )、-NHSO ₂ N(R ^Lf ) ₂ and-NHSO ₂ NH ₂ Wherein R is ^Lf Is substituted or unsubstituted C _1-12 An alkyl group; r is ^Lg Is substituted or unsubstituted C _3-10 A cycloalkyl group; and R is ^Lh Is R ^Lf Or R ^Lg 。

In certain embodiments, q is an integer greater than or equal to 1.

In certain embodiments, q is greater than 2.

In certain embodiments, q is 2.

In certain embodiments, q is 1. In some embodiments, q is 1 and Y is linked to a ligase ligand or L ³ And toA moiety of (a).

In additional embodiments, q is an integer from 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or 1 to 10.

In certain embodiments, L ² Selected from the group consisting of:

in one embodiment, L ² Is selected from the group consisting ofGroup (d) of (a).

In additional embodiments, L ² Is an optionally substituted (poly) ethylene glycol having 1 to about 100 ethylene glycol units, about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units, and 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units, or optionally substituted alkyl groups interdispersed by optionally substituted O, N, S, P or Si atoms. In certain embodiments, L ² Substituted with aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic groups. In certain embodiments, L ² May be asymmetric or symmetric.

In any of the embodiments of compounds described herein, L ² May be any suitable moiety as described herein. In one embodiment, L ² Are substituted or unsubstituted polyethylene glycol groups ranging in size from about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units.

Ligase ligand or L ³ Andthe parts may pass through the butt joint part [ B ]]With L and any group of suitable and stable chemical nature ² And (3) covalent linkage. L is a radical of an alcohol ² Preferably by amides, esters, thioacidsEster, ketone group, carbamate (urethane), carbon or ether are independently covalently bonded to the ligase ligand or L ³ Andmoieties, each group being insertable into a ligase ligand or L ³ Andany position of the moiety to provide a ligase ligand on the ligase and on the target protein to be degradedMaximum binding of the moieties. In thatThe moiety is some aspect of a ligase ligand and the targeting protein for degradation may be the ligase itself. In certain aspects, L ² Can be linked to a ligase ligand and/or L ³ And/orAn optionally substituted alkyl, alkylene, alkenyl or alkynyl group on a moiety, an aryl group or a heterocyclyl group. Note that it may be desirable to ligate the enzyme ligand and/or L ³ And/orPartial derivatization for preparation of L ² Chemical functional groups in the polymer chain. Alternatively, it may be desirable to couple L ² Derivatizing to include a ligand that can be coupled to a ligase and/or L ³ And/orChemical functional groups that are reactive with functional groups found in part.

In some embodiments, L ² Can also be represented by the following formula:

wherein Q is ³ Is to ligate enzyme ligand or L ³ Is connected to Q ⁴ A group of (a); and Q ⁴ Is to be Q ³ Is connected toA moiety of (a).

In some embodiments, Q ³ Absent such that it is a bond. In other embodiments, Q ³ Is- (CH) ₂ ) _j -O、-(CHR ¹⁵ ) _j -O、-[C(R ¹⁵ ) ₂ ] _j -O、-(CH ₂ ) _j -S、-(CH ₂ ) _j -N-R ¹⁵ 、-S、-S(O)、-S(O) ₂ 、-OP(O)OR ¹⁵ 、-Si(R ¹⁵ ) ₂ Or (CH) ₂ ) _j -Q ⁵ Q ⁶ Group, wherein Q ⁵ Q ⁶ Forming amide or carbamate, ester or thioester groups, orWherein each R is ¹⁵ Is H or C ₁ -C ₃ Alkyl, alkanol groups or heterocycles (including water-soluble heterocycles, preferably morpholino, piperidine or piperazine groups that promote water solubility of the linking group); each U is independently a bond, O, S or N-R ¹⁵ (ii) a And each j is independently 0 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5.

In the examples, Q ⁴ Is composed of

Wherein each V is independently a bond,-(CH ₂ ) _m′ -or

j' is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5;

k' is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5; preferably, k is 1, 2, 3, 4 or 5;

m' is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5;

n' is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, l to 8, 1 to 6, 1, 2, 3, 4 or 5;

X ⁴ is O, S or N-R ¹⁵ Preferably O;

u is the same as above;

and, when present in L ² In the middle, CON is Q ³ Is connected to Q ⁴ A linker group (which may be a bond) of (i).

In embodiments, CON is a bond or a heterocycle, including a water-soluble heterocycle, such as piperazinyl or other groups, or a group selected from:

wherein X ⁴ Is cycloalkyl, heterocyclyl, O, S, NR ¹² 、S(O)、S(O) ₂ 、-S(O) ₂ O、-OS(O) ₂ 、OP(O)OR ¹⁵ 、Si(R ¹⁵ ) ₂ Or OS (O) ₂ O；

X ⁵ Is O, S, CHR ¹² 、NR ¹² ；

R ¹² Is H or C optionally substituted by one or two hydroxy groups ₁ -C ₃ An alkyl group, or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof; and is

R ¹⁵ As defined above.

In some embodiments, there is provided a compound of any one of the formulae as described herein, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is substituted for any one of the foregoing ² Combination, L ³ Is a bond. In other embodiments, with any of the aforementioned L ² Combination, L ³ is-O-. In still other embodiments, with any of the aforementioned L ² Combination, L ³ Is that

In some embodiments, there is provided a compound of any one of the formulae as described herein, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L of the linker moiety ² Is- (CH) ₂ ) _n -, where n is 1-12 and L ³ Is a key. In other embodiments, L of the linker moiety ² Is- (CH) ₂ ) _n -, where n is 1 to 12, and L ³ Is a-O-. In still other embodiments, L of the joint portion ² Is (CH) ₂ ) _n -, where n is 1 to 12, and L ³ Is that

In some embodiments, there is provided a compound of any one of the formulae as described herein, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L of the linker moiety ² Is- (CH) ₂ ) _n -, where n is 1 to 6, and L ³ Is a bond. In other embodiments, L of the linker moiety ² Is- (CH) ₂ ) _n -, where n is 1 to 6, and L ³ is-O-. In still other embodiments, L of the joint portion ² Is (CH) ₂ ) _n -, where n is 1-6, and L ³ Is that

In some embodiments, there is provided a compound of any one of the formulae as provided herein, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is ² Is- (CH) ₂ CH ₂ O) _n -, where n is 1 to 12, and L ³ Is a key. In other embodiments, L of the linker moiety ² Is- (CH) ₂ CH ₂ O) _n -, where n is 1 to 12, and L ³ is-O-. In still other embodiments, L of the joint portion ² Is- (CH) ₂ CH ₂ O) _n -, where n is 1 to 12, and L ³ Is that

In some embodiments, there is provided a compound of any one of the formulae as provided herein, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is ² Is- (CH) ₂ CH ₂ O) _n -, where n is 1-6, and L ³ Is a bond. In other embodiments, L of the linker moiety ² Is- (CH) ₂ CH ₂ O) _n -, where n is 1 to 6, and L ³ Is a-O-. In still other embodiments, L of the joint portion ² Is- (CH) ₂ CH ₂ O) _n -, where n is 1-6, and L ³ Is that

In certain embodiments, the linker moiety [ B ]]Is a group of covalently linked building blocks comprising one or more Y, wherein each Y unit is linked to a ligase ligand,At least one of the moiety, the other Y unit, or a combination thereof. In certain embodiments, the Y unit connects the ligase ligand,A moiety or combination thereof directly linked to another ligase ligand, Parts or combinations thereof. In other embodiments, the Y units link the ligase ligand moiety, via one or more different Y units,The moiety or combination thereof is indirectly linked to another ligase ligand moiety,Parts or combinations thereof. In any of the embodiments disclosed herein, one or more covalently linked building blocks of Y may be coupled to a ligase ligand. In certain embodiments, the building block of Y may be linked to a ligase ligand at one or more attachment points. In other embodiments, one or more covalently linked building blocks of Y may be coupled toAnd also coupled to the ligase ligands of the present disclosure to form heterobifunctional molecules.

In certain embodiments, the linker moiety is (Y) _q And each Y unit is independently selected from the group consisting of: key, CR ^La R ^Lb 、O、S、SO、SO ₂ 、NR ^Lc 、SO ₂ NR ^Lc 、SONR ^Lc 、CONR ^Lc 、NR ^Lc CONR ^Ld 、NR ^Lc SO ₂ NR ^Ld 、CO、CR ^La ═CR ^Lb 、C≡C、SiR ^La R ^Lb 、P(O)R ^La 、P(O)OR ^La 、NR ^Lc C(＝NCN)NR ^Ld 、NR ^Lc C(＝NCN)、NR ^Lc C(＝CNO ₂ )NR ^Ld 、C _3-10 Cycloalkylene radical, C _3-10 Heterocyclylene, arylene and heteroarylene radicals, in which C _3-10 Cycloalkylene radical, C _3-10 Heterocyclylene, arylene and heteroarylene are independently unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of ^La 、R ^Lb And combinations thereof, wherein each R ^La Or R ^Lb Independently may be linked to other Y groups to form cycloalkylene and/or heterocyclylene moieties, wherein the cycloalkylene and heterocyclylene moieties are independently unsubstituted or substituted with 1, 2, 3 or 4R ^Le Substituted by groups; wherein each R ^La 、R ^Lb 、R ^Lc 、R ^Ld And R ^Le Independently selected from the group consisting of: H. halogen, R ^Lf 、-OR ^Lh 、-SR ^Lh 、-NHR ^Lh 、-N(R ^Lh ) ₂ 、C _3- C ₁₀ Cycloalkyl, aryl, heteroaryl, C _3- C ₁₁ Heterocyclyl, -N (R) ^Lg )(R ^Lf )、-OH、-NH ₂ 、-SH、-SO ₂ R ^Lf 、-P(O)(OR ^Lf )(R ^Lf )、-P(O)(OR ^Lf ) ₂ 、-C≡C-R ^Lf 、-C≡CH、-CH═CH(R ^Lf )、-C(R ^Lf )═CH(R ^Lf )、-C(R ^Lf )═C(R ^Lf ) ₂ 、-Si(OH) ₃ 、-Si(R ^Lf ) ₃ 、-Si(OH)(R ^Lf ) ₂ 、-COR ^Lf 、-CO ₂ H. -halogen, -CN, -CF ₃ 、-CHF ₂ 、-CH ₂ F、-NO ₂ 、-SF ₅ 、-SO ₂ NHR ^Lf 、-SO ₂ N(R ^Lf ) ₂ 、-SONHR ^Lf 、-SON(R ^Lf ) ₂ 、-CONHR ^Lf 、-CON(R ^Lf ) ₂ 、-N(R ^Lf )CONH(R ^Lf )、-N(R ^Lf )CON(R ^Lf ) ₂ 、-NHCONH(R ^Lf )、-NHCON(R ^Lf ) ₂ 、-NHCONH ₂ 、-N(R ^Lf )SO ₂ NH(R ^Lf )、-N(R ^Lf )SO ₂ N(R ^Lf ) ₂ 、-NHSO ₂ NH(R ^Lf )、-NHSO ₂ N(R ^Lf ) ₂ and-NHSO ₂ NH ₂ Wherein R is ^Lf Is substituted or unsubstituted C _1-12 An alkyl group; r ^Lg Is substituted or unsubstituted C _3-10 A cycloalkyl group; and R is ^Lh Is R ^Lf Or R ^Lg 。

In certain embodiments, q is an integer greater than or equal to 1.

In certain embodiments, q is greater than 2.

In certain embodiments, q is 2.

In certain embodiments, q is 1. In some embodiments, q is 1 and Y is linked to a ligase ligand and up toA moiety of (a).

In additional embodiments, q is an integer of 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or 1 to 10.

In certain embodiments, the linker moiety is selected from the group consisting of:

in one embodiment, the linker is selected from the group consisting ofGroup (d) of (a).

In additional embodiments, the linking group is an optionally substituted (poly) ethylene glycol having from 1 to about 100 ethylene glycol units, from about 1 to about 50 ethylene glycol units, from 1 to about 25 ethylene glycol units, from about 1 to 10 ethylene glycol units, from 1 to about 8 ethylene glycol units, and from 1 to 6 ethylene glycol units, from 2 to 4 ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker may be asymmetric or symmetric.

In any embodiment of the compounds described herein, the linking group can be any suitable moiety described herein. In one embodiment, the linking group is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units.

A ligase ligand andthe moiety may be covalently attached to the linking group through any group that is suitable and stable to the chemical nature of the linking group. The linker is preferably independently covalently bonded to the ligase ligand through an amide, ester, thioester, ketone group, carbamate (urethane), carbon or etherMoieties, each group being insertable into a ligase ligand andany position of the moiety to provide a ligase ligand on the ligase and a target protein to be degradedMaximal binding of the moieties. In thatSome aspects of the ligase ligand are part, and the targeting protein for degradation may be the ligase itself. In certain aspects, the linker may be attached to the ligase ligand and/orAn optionally substituted alkyl, alkylene, alkenyl or alkynyl group on the moiety, an aryl group or a heterocyclyl group. Note that it may be desirable to couple a ligase ligand or Partially derivatized to prepare chemical functional groups that react with the chemical functional groups on the linker. Alternatively, it may be desirable to derivatize the linker to include a ligand that can be conjugated to a ligase and/orChemical functional groups that are reactive with functional groups found in part.

The linker moiety may also be represented by the formula:

wherein Q is ³ Is to link a ligase ligand to Q ⁴ A group of (a); and Q ⁴ Is to be Q ³ Is connected toA moiety of (a).

In the examples, Q ⁴ Is composed of

Wherein each V is independently a bond,-(CH ₂ ) _m′ -or

X ⁴ is O, S or N-R ¹⁵ Preferably O;

u is the same as above;

and, when present in a linker group, CON is such that Q ³ Is connected to Q ⁴ The linking group (which may be a bond) of (a).

X ⁵ Is O, S, CHR ¹² 、NR ¹² ；

R ¹⁵ As defined above.

In an alternative preferred aspect, the linker moiety is a (poly) ethylene glycol having from 1 to about 100 ethylene glycol units, from about 1 to about 50 ethylene glycol units, from 1 to about 25 ethylene glycol units, from about 1 to 10 ethylene glycol units, from 1 to about 8 ethylene glycol units, and from 1 to 6 ethylene glycol units, from 2 to 4 ethylene glycol units. In certain embodiments, the linker is optionally substituted; i.e., containing chemical groups that are interdispersed within or on the PEG linker. In certain embodiments, the PEG linker is substituted with an alkyl, alkylene, aromatic or aryl group (e.g., phenyl), benzyl, or heterocyclic group, or an amino acid side chain, and is optionally interdispersed with the optionally substituted O, N, S, P or Si atoms.

In an embodiment, CON is

Or an amide group.

In some embodiments, the linker is asymmetric. In other embodiments, the joint portion is symmetrical.

Although the ligase ligand andthe moiety may be covalently linked to the linker through any group that is suitable and stable to the chemical nature of the linker, and in preferred aspects the linker is independently linked to the ligase ligand and to the linker through an amide, ester, thioester, keto, carbamate (urethane), or etherMoieties covalently bonded, each group being insertable into a ligase ligand moiety andany position on the moiety such that the ligase ligand binds to the ligase, andthe moiety binds to the target protein to be degraded. In other words, as shown herein, a linker can be designed and linked to a ligase ligand andpart, to minimize, eliminate or neutralize its presence possible to ligase ligands andany effect of binding of the moieties to their respective binding partners. In certain aspects, the targeted protein for degradation may be a ubiquitin ligase. In some embodimentsThe linker moiety may be attached to the ligase ligand and/orAn optionally substituted alkyl, alkylene, alkenyl or alkynyl group on the moiety, an aryl group or a heterocyclyl group.

Additional linker moieties are disclosed in U.S. patent application publication Nos. 2016/0058872, 2016/0045607, 2014/0356322015/0291562, and 2020/0038378; and in WO2014/063061, the contents of each of which are incorporated herein in their entirety.

In some embodiments, there is provided a compound of any one of the formulae as described herein, wherein X is ¹ Is C-R ⁵ Wherein R is ⁵ Is H; x ² Is N; x ³ Is C-R ⁵ Wherein R is ⁵ Is H; and R is ¹ Is O-C _1-12 An alkyl group. In some embodiments, R ¹ Is methoxy. In certain embodiments, the compound has the structure of formula (XII):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In certain embodiments, L ¹ is-CH = CH-. In other embodiments, L ¹ is-C _1-12 An alkyl group-. In a further embodiment, L ¹ is-C _1-6 An alkyl radical. In still other embodiments, L ¹ Is a key.

In some embodiments, L ¹ is-CH = CH-and R ² Is C _3-10 Cycloalkyl radicals, in which C _3-10 Cycloalkyl radicals being interrupted by a C _1-12 Haloalkyl substitution. In certain embodiments, the compound has the structure of formula (XIII):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In other embodiments, L ¹ is-CH = CH-and R ² Is C _3-10 Cycloalkyl radicals, in which C _3-10 Cycloalkyl groups are substituted with one or more halo. In some embodiments, halo is fluoro. In certain embodiments, the compound has the structure of formula (XIV):

Or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, L ¹ is-CH = CH-and R ² Is C _3-10 Cycloalkyl radicals, in which C _3-10 Cycloalkyl is spiro. In certain embodiments, the compound has the structure of formula (XV):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, L ¹ is-CH = CH-and R ² Is C _6-20 Aryl radical, wherein C _6-20 Aryl groups are substituted with one or more halo. In some embodiments, halo is chloro. In certain embodiments, the compounds have the structure of formula (XVI):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, L ¹ Is a bond, and R ² Is C _3-10 Cycloalkyl radicals of which C _3-10 Cycloalkyl quilt C _6-20 Aryl substituted in which C _6-20 Aryl is further substituted with one or more halo. In some embodiments, halo is chloro. In certain embodiments, the compounds have the structure of formula (XVII):

or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, a compound of any of the formulae described herein, or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compounds listed in table 1 below, including racemic mixtures and resolved stereoisomers:

TABLE 1

In some embodiments, a compound of any one of the formulae described herein, or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compounds listed in table 2 below, including racemic mixtures and resolved isomers:

TABLE 2

Provided herein are compounds selected from the group consisting of:

n- (3- (2- ((4- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) butyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (2- ((6- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) hexyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (14- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12-trioxa-3-azatetradecyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (17- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12,15-tetraoxa-3-azedaryl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (2- ((2- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) ethyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

N- (3- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) ethyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (20- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (2- ((3- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) propyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (2- ((7- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) heptyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (2- ((5- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) pentyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

N- (3- (2- ((5- ((1- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -5-oxopentyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (2- ((7- ((1- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobut-2-yl) amino) -7-oxoheptyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (2- ((9- ((1- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -9-oxononyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (13- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -14,14-dimethyl-2,11-dioxo-6,9-dioxa-3,12-diazapentanyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (16- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -17,17-dimethyl-2,14-dioxa-6,9,12-trioxa-3,15-diazadecyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

N- (3- (19- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -20,20-dimethyl-2,17-dioxo-6,9,12,15-tetraoxa-3,18-diaza-heneicosyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (22- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -23,23-dimethyl-2,20-dioxo-6,9,12,15,18-pentaoxa-3,21-diaza-tetracosyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (17- ((5- (1- (2-cyclohexyl-2- (2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (20- ((5- (1- (2-cyclohexyl-2- (2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,20-dioxo-6,9,12,15,18-pentaoxa-3-azaeicosyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

N- (3- (23- ((5- (1- (2-cyclohexyl-2- (2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,23-dioxo-6,9,12,15,18,21-hexaoxa-3-azatricosyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

n- (3- (2- ((4- ((5- (1- (2-cyclohexyl-2- (2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -4-oxobutyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- (2- (4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide;

4- (2- (4,4-difluorocyclohexyl) vinyl) -N- (3- (2- ((4- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) butyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

n- (3- (14- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12-trioxa-3-azatetradecyl) benzyl) -5-methoxy-4- (2- (spiro [2.3] hex-5-yl) vinyl) picolinamide;

4- (4-chlorostyryl) -N- (3- (2- ((7- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) heptyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

4- (3- (4-chlorophenyl) cyclobutyl) -N- (3- (2- ((7- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) heptyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

4- (2- (4,4-difluorocyclohexyl) vinyl) -N- (3- (2- ((5- ((1- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -5-oxopentyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

(3- (13- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -14,14-dimethyl-2,11-dioxo-6,9-dioxa-3,12-diazapentanyl) benzyl) -5-methoxy-4- (2- (spiro [2.3] hex-5-yl) vinyl) picolinamide;

4- (4-chlorostyryl) -N- (3- (19- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -20,20-dimethyl-2,17-dioxo-6,9,12,15-tetraoxa-3,18-diaza-heneicosyl) benzyl) -5-methoxypyridinamide;

4- (2- (3- (4-chlorophenyl) cyclobutyl) vinyl) -N- (3- (2- ((9- ((1- (4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -9-oxononyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

N- (3- (17- ((5- (1- (2-cyclohexyl-2- (2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,17-dioxo-6,9,12,15-tetraoxa-3-azedaryl) benzyl) -4- (2- (4,4-difluorocyclohexyl) vinyl) -5-methoxypyridinamide;

n- (3- (20- ((5- (1- (2-cyclohexyl-2- (2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,20-dioxo-6,9,12,15,18-pentaoxa-3-azaeicosyl) benzyl) -5-methoxy-4- (2- (spiro [2.3] hex-5-yl) vinyl) picolinamide;

4- (4-chlorostyryl) -N- (3- (23- ((5- (1- (2-cyclohexyl-2- (2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,23-dioxo-6,9,12,15,18,21-hexaoxa-3-azaeicosanyl) benzyl) -5-methoxypyridinamide;

4- (2- (3- (4-chlorophenyl) cyclobutyl) vinyl) -N- (3- (2- ((4- ((5- (1- (2-cyclohexyl-2- (2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -4-oxobutyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

(E) -4- (2-cyclohexylvinyl) -N- (3- (2- ((4- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) butyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

(E) -N- (3- (14- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12-trioxa-3-azatetradecyl) benzyl) -5-methoxy-4- (3-phenylprop-1-en-1-yl) picolinamide;

4- (4-cyclopropylphenyl) -N- (3- (2- ((7- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) heptyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

(E) -4- (2-cyclohexylvinyl) -N- (3- (2- ((7- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) heptyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

4- ((E) -2-cyclohexylvinyl) -N- (3- (2- ((5- (((S) -1- ((2s, 4r) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -5-oxopentyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

n- (3- ((S) -13- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -14,14-dimethyl-2,11-dioxo-6,9-dioxa-3,12-diazepidecyl) benzyl) -5-methoxy-4- ((E) -3-phenylprop-1-en-1-yl) picolinamide;

4- (4-cyclopropylphenyl) -N- (3- ((S) -19- ((2s, 4r) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -20,20-dimethyl-2,17-dioxo-6,9,12,15-tetraoxa-3,18-diaza-heneicosyl) benzyl) -5-methoxypyridinamide;

4- ((E) -2-cyclohexylvinyl) -N- (3- (2- ((9- (((S) -1- ((2s, 4r) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -9-oxononyl) amino) -2-oxoethyl) benzyl) -5-methoxypyridinamide;

n- (3- (17- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecyl) benzyl) -4- ((E) -2-cyclohexylvinyl) -5-methoxypyridinamide;

n- (3- (20- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,20-dioxo-6,9,12,15,18-pentaoxa-3-azaeicosyl) benzyl) -5-methoxy-4- ((E) -3-phenylprop-1-en-1-yl) picolinamide;

N- (3- (23- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propanamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,23-dioxo-6,9,12,15,18,21-hexaoxa-3-azaeicosatriyl) benzyl) -4- (4-cyclopropylphenyl) -5-methoxypyridinamide; and

n- (3- (2- ((4- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -4-oxobutyl) (methyl) amino) -2-oxoethyl) benzyl) -4- ((E) -2-cyclohexylvinyl) -5-methoxypyridinamide, or a pharmaceutically acceptable salt thereof. The chemical names of the compounds of tables 1 and 2 were generated using ChemDraw version 18.2. Also provided herein are any and all stereoisomers of the compounds described herein, including geometric isomers (e.g., cis/trans or E/Z isomers), enantiomers, diastereomers, or mixtures thereof in any proportion (including racemic mixtures), where applicable.

In some aspects, the compounds of the present disclosure are isotopically labeled by substituting atoms having different atomic masses or mass numbers for one or more of the atoms therein. Such isotopically-labeled (i.e., radiolabeled) compounds of any one of the formulae as described herein are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of any of the formulae as described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as, but not limited to ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹³ N、 ¹⁵ N、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F、 ³⁶ Cl、 ¹²³ I and ¹²⁵ I. these isotopically labeled compounds will aid in determining or measuring the effectiveness of the compound by characterizing, for example, the site or mode of action, or the binding affinity of the TEAD. Certain isotopically-labeled compounds of any one of the formulae as described herein (e.g., those comprising a radioisotope) are useful in drug and/or matrix tissue distribution studies. Radioisotope tritium (i.e. tritium ³ H) And carbon-14 (i.e. ¹⁴ C) This is particularly useful because they are easily incorporated and the detection means are readily available. For example of any of the formulae as described hereinThe compound may be enriched in 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95% or 99% of a given isotope.

With heavier isotopes such as deuterium, i.e. ² H) Substitution may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

With positron-emitting isotopes (such as ¹¹ C、 ¹⁸ F、 ¹⁵ O and ¹³ n) substitution can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of any one of the formulae as described herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the examples set forth below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously used.

Also provided herein are pharmaceutically acceptable salts or esters of any of the compounds provided herein, as well as stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes or prodrugs of such compounds or pharmaceutically acceptable salts of such compounds.

Pharmaceutical compositions and administration

In addition to one or more compounds provided above (including stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof), the present disclosure also provides compositions and medicaments comprising a compound of the present disclosure, or an embodiment or aspect thereof, and at least one pharmaceutically acceptable carrier. The compositions of the present disclosure are useful for selectively inhibiting TEAD in a patient (e.g., a human).

In one aspect, the present disclosure provides pharmaceutical compositions or medicaments comprising a compound of the present disclosure (or embodiments and aspects thereof including stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts and prodrugs thereof) and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, the present disclosure provides a method for preparing a composition (or medicament) comprising a compound of the present disclosure. In another aspect, the present disclosure provides methods for administering a compound of the present disclosure or a composition comprising a compound of the present disclosure to a patient (e.g., a human patient) in need thereof.

The carrier can be selected from a variety of oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. Water, saline, aqueous dextran solutions and glycols are preferred liquid carriers, particularly for injectable solutions (when isotonic with blood). For example, formulations for intravenous administration comprise a sterile aqueous solution of a compound of the present disclosure prepared by dissolving a solid compound of the present disclosure in water to produce an aqueous solution and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silicon dioxide, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may be subjected to conventional pharmaceutical additives such as preservatives, stabilizers, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like. Suitable Pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, e.w. martin. Regardless, such compositions will comprise an effective amount of a compound of the present disclosure, together with a suitable carrier, to prepare a suitable dosage form for appropriate administration to a subject.

The compositions are formulated, administered and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to the practitioner. The effective amount of the compound to be administered will be determined by these considerations and is the minimum amount required to inhibit TEAD activity to prevent or treat an undesirable disease or condition, such as pain. For example, the amount may be less than that which is toxic to normal cells or the mammal as a whole.

In one example, a therapeutically effective amount of a compound of the present disclosure administered parenterally per dose will be in the range of about 0.01-100mg/kg patient body weight per day, alternatively about, e.g., 0.1 to 20mg/kg patient body weight per day, typically with an initial range of 0.3 to 15 mg/kg/day of the compound used. In certain aspects, the daily dose is administered as a single daily dose or in divided doses from two to six times per day, or in a sustained release form. For a 70kg adult, the total daily dose is usually from about 7mg to about 1,400mg. The dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

The compounds of the present disclosure may be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain components conventional in pharmaceutical formulations, for example, diluents, carriers, pH adjusting agents, sweeteners, fillers and other active agents.

Compositions comprising the compounds of the present disclosure (or embodiments or aspects thereof including stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, and prodrugs thereof) are typically formulated as pharmaceutical compositions according to standard pharmaceutical practice. A typical formulation is prepared by mixing a compound of the present disclosure and a diluent, carrier or excipient. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in, for example, ansel, howard C. Et al, ansel's Pharmaceutical Dosage Forms and Drug Delivery systems, philadelphia, lippincott, williams and Wilkins,2004; gennaro, alfonso R. et al Remington The Science and Practice of pharmacy Philadelphia Lippincott, williams&Wilkins,2000; and Rowe, raymond C.handbook of Pharmaceutical excipients Chicago, pharmaceutical Press, 2005. The formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, flavoring agents, diluents, and other known additives to provide an aesthetically pleasing medicament (i.e., a compound of the present disclosure or a pharmaceutical thereof) Composition) demonstrates or facilitates the preparation of a pharmaceutical product (i.e., a drug). Suitable carriers, diluents and excipients are well known to those skilled in the art and include buffers such as phosphate, citrate and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parabens, such as methyl or propyl parabens; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc protein complexes); and/or nonionic surfactants, such as TWEEN ^TM 、PLURONICS ^TM Or polyethylene glycol (PEG). The active pharmaceutical ingredients of the present disclosure (e.g., a compound of any of the formulae as described herein or embodiments or aspects thereof) may also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly (methylmethacylate) microcapsules, respectively), in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington: the Science and Practice of Pharmacy, remington The Science and Practice of Pharmacy (2005), 21 st edition, lippincott Williams&Wilkins, philadelphia, PA. The particular carrier, diluent or excipient used will depend on the mode and purpose for which the compounds of the present disclosure are to be administered. Solvents are generally selected based on generally recognized as safe solvents (GRAS) for administration to mammals by those skilled in the art. Generally, the safe solvent is a non-toxic aqueous solvent, such as water and othersA non-toxic solvent that is soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), and the like, and mixtures thereof.

Sustained release preparations of the compounds of the disclosure (e.g., a compound of any of the formulae as described herein or an embodiment or aspect thereof) may be prepared. Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of any of the formulae as described herein, or an embodiment or aspect thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (hydroxyethyl 2-methacrylate), or poly (vinyl alcohol)), polylactic acid (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid with γ -ethyl-L-glutamate (Sidman et al, biopolymers 22, 547,1983), non-degradable ethylene-vinyl acetate (Langer et al, j.biomed.mater.res.15:167,1981), degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT 5363 ^TM (injectable microspheres consisting of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D- (-) -3-hydroxybutyric acid (EP 133,988A). Sustained release compositions also include liposome-encapsulated compounds, which can be prepared by methods known per se (Epstein et al, proc. Natl. Acad. Sci. U.S. A.82:3688,1985, hwang et al, proc. Natl. Acad. Sci. U.S. A.77:4030,1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A). Typically, liposomes are small (about 200-800 angstroms) unilamellar liposomes with lipid content greater than about 30mol% cholesterol, the proportions selected being adjusted for optimal treatment.

In one example, a compound of the present disclosure, or an embodiment or aspect thereof, can be formulated for galenic administration by mixing at ambient temperature at an appropriate pH and in a desired purity with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the subject at the dosages and concentrations used). The pH of the formulation depends primarily on the particular use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, a compound of the disclosure (or an embodiment or aspect thereof) is formulated in an acetate buffer at pH 5. In another aspect, the compounds of the present disclosure or embodiments thereof are sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

Formulations of the compounds of the present disclosure suitable for oral administration can be prepared as discrete units, such as pills, capsules, cachets, or tablets, each containing a predetermined amount of a compound of the present disclosure.

Compressed tablets may be prepared by compressing in a suitable machine a compound of the disclosure in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the compound of the present disclosure in powder form moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may optionally be formulated to provide slow or controlled release of the compounds of the present disclosure therefrom.

Tablets, buccal tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules (e.g., gelatin capsules), syrups or elixirs may be prepared for oral administration. Formulations of the compounds of the present disclosure for oral administration may be prepared according to any method known to the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. Tablets comprising a compound of the present disclosure admixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Examples of suitable oral administration forms are tablets containing about 0.1mg, about 1mg, about 5mg, about 10mg, about 25mg, about 30mg, about 50mg, about 80mg, about 100mg, about 150mg, about 250mg, about 300mg and about 500mg of a compound of the present disclosure (or embodiments or aspects thereof) formulated with a filler (e.g., lactose, such as about 90-30mg anhydrous lactose), a disintegrant (e.g., croscarmellose, such as about 5-40mg croscarmellose sodium), a polymer (e.g., polyvinylpyrrolidone (PVP), a cellulose (e.g., hydroxypropylmethylcellulose (HPMC)), and/or a copovidone, such as about 5-30mg PVP, HPMC or copovidone) and a lubricant (e.g., magnesium stearate, such as about 1-10 mg). Wet granulation, dry granulation or dry blending may be used. In one wet granulation aspect, the powdered ingredients are first mixed together and then mixed with a solution or suspension of the polymer (e.g., PVP). The resulting composition may be dried using conventional equipment, granulated, mixed with a lubricant and compressed into tablet form. An example of an aerosol formulation may be prepared by dissolving a compound of the present disclosure (e.g. 5-400 mg) in a suitable buffer solution (e.g. phosphate buffer), if desired with the addition of a penetration enhancer (e.g. a salt such as sodium chloride). The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

For treatment of the eye or other external tissues (e.g., oral cavity and skin), the formulation is preferably administered in the form of a topical ointment or cream containing, for example, 0.075-20% w/w of the compound of the present disclosure. When formulated as an ointment, the compounds of the present disclosure may be used with either a paraffinic or a water-miscible ointment base. Alternatively, the compounds of the present disclosure may be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include polyols, i.e. alcohols having two or more hydroxyl groups, such as propylene glycol, 1,3-butylene glycol, mannitol, sorbitol, glycerol and polyethylene glycols (including PEG 400) and mixtures thereof. Topical formulations may desirably include compounds that enhance absorption or penetration of the compounds of the present disclosure through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

For topical formulations, it is desirable to apply an effective amount of a pharmaceutical composition according to the present disclosure to a target area adjacent to the peripheral neurons to be treated, e.g., a skin surface, a mucosal membrane, etc. Depending on the area to be treated, whether the use is diagnostic, prophylactic or therapeutic, the severity of the symptoms and the nature of the topical vehicle used, the amount will generally be from about 0.0001mg to about 1g of a compound of the disclosure (or an embodiment or aspect thereof) per application. Preferred topical formulations are ointments, wherein from about 0.001mg to about 50mg of a compound of the present disclosure is employed per cubic centimeter of ointment base. The pharmaceutical compositions may be formulated as transdermal compositions or transdermal delivery devices ("patches"). Such compositions include, for example, a backing, a compound reservoir of the present disclosure, a control film, a liner, and a contact adhesive. Such transdermal patches may be used to provide continuous pulsing or on-demand delivery of the compounds of the present disclosure as desired.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier for injections, for example water, prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose of a compound of the present disclosure as described herein above, or an appropriate fraction thereof.

Certain aspects of the present disclosure provide for a compound of the present disclosure (or an embodiment or aspect thereof) to cross the blood-brain barrier when the binding target is located in the brain. Certain neurodegenerative diseases are associated with increased permeability of the blood brain barrier, such that the compounds of the present disclosure (or embodiments or aspects thereof) can be readily introduced into the brain. While the blood-brain barrier remains intact, there are several methods known in the art for transporting molecules across the blood-brain barrier, including but not limited to physical methods, lipid-based methods, and receptor and channel-based methods.

Physical methods of transporting a compound of the present disclosure (or embodiments or aspects thereof) across the blood-brain barrier include, but are not limited to, completely circumventing the blood-brain barrier, or by forming an opening in the blood-brain barrier.

Evasive approaches include, but are not limited to, direct injection into the brain (see, e.g., papanastassiou et al, gene Therapy 9 ^TM ,Guildford Pharmaceutical)。

Methods of forming openings in a Barrier include, but are not limited to, ultrasound (see, e.g., U.S. patent publication No. 2002/0038086), osmotic pressure (e.g., by administration of hypertonic mannitol (Neuwelt, e.a., implantation of the Blood-Brain Barrier and its management, volumes 1 and 2, plenum Press, n.y., 1989)), and permeabilization by, e.g., bradykinin or permeabilizing agent a-7 (see, e.g., U.S. patent nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

Lipid-based methods of delivering a compound of the formula of the present disclosure (or embodiments or aspects thereof) across the blood-brain barrier include, but are not limited to, encapsulating the compound of the present disclosure (or embodiments or aspects thereof) in liposomes coupled to antibody-binding fragments of receptors on the vascular endothelium that bind to the blood-brain barrier (see, e.g., U.S. patent application publication No. 2002/0025313), and coating the compound of the present disclosure (or embodiments or aspects thereof) in low-density lipoprotein particles (see, e.g., U.S. patent application publication No. 2004/0204354) or apolipoprotein E (see, e.g., U.S. patent application publication No. 2004/0131692).

Receptor and channel-based methods of delivering compounds of the present disclosure (or embodiments or aspects thereof) across the blood-brain barrier include, but are not limited to, increasing the permeability of the blood-brain barrier using glucocorticoid blockers (see, e.g., U.S. patent application publication nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g., U.S. patent application publication No. 2005/0089473), inhibiting ABC drug transporter proteins (see, e.g., U.S. patent application publication No. 2003/0073713); the compounds of the present disclosure (or embodiments or aspects thereof) are coated with transferrin and modulate the activity of one or more transferrin receptors (see, e.g., U.S. patent application publication No. 2003/0129186), as well as cationized antibodies (see, e.g., U.S. patent No. 5,004,697).

For intracerebral use, in certain aspects, the compounds may be administered continuously by infusion into a reservoir of the CNS, although a bolus injection may be acceptable. The inhibitor may be administered to the ventricles of the brain or otherwise introduced into the CNS or spinal fluid. Administration may be by continuous administration using an indwelling catheter and such as a pump, or may be by implantation, for example, intracerebral implantation of a slow release vehicle. More specifically, the inhibitor may be injected through a chronically implanted cannula, or chronically with the aid of an osmotic mini-pump. Subcutaneous pumps are available that deliver proteins to the ventricles of the brain through the tubules. The highly complex pump can be refilled through the skin and its delivery rate can be set without surgical intervention. Examples of suitable administration regimens and administration systems involving subcutaneous pump devices or continuous intraventricular infusion via fully implanted drug delivery systems are dosing regimens and administration systems for administering dopamine, dopamine agonists and cholinergic agonists to alzheimer's patients and animal models of parkinson's disease, such as Harbaugh, j.neural trans.suppl.24: 271,1987; and DeYebenes et al, mov.Disord.2:143,1987 said 2.

Indications and treatment methods

In some embodiments, the compound that modulates TEAD activity is a compound of any of the formulae described herein as defined above, or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, the compound that modulates TEAD activity is a degrader of TEAD.

The compounds of the present disclosure (or embodiments or aspects thereof) are useful as pharmaceutical therapies for the treatment of diseases and disorders mediated by TEAD activity. Such diseases and disorders include, but are not limited to, cancer, including acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endotheliosarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, primary thrombocytosis, ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphoblastic leukemia, lymphoma (hodgkin and non-hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, fahrenheit macroglobulinemia, testicular tumor, uterine cancer, and wilms' tumor.

In particular embodiments, the compounds of the present disclosure (or embodiments or aspects thereof) may be administered as a drug therapy to treat proliferative disorders including acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon carcinoma, colorectal carcinoma, craniopharyngeal carcinoma, cystic adenocarcinoma, diffuse large B-cell lymphoma, adverse proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor positive breast cancer, primary thrombocythemia, ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkins and non-hodgkins), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid carcinoma, fahrenheit macroglobulinemia, testicular tumor, uterine cancer and wilms' tumor.

In a particular aspect, the compounds of the disclosure (or embodiments or aspects thereof) may be administered as a drug therapy to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon carcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, adverse proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymal carcinoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor positive breast cancer, primary thrombocythemia, ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular carcinoma, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver carcinoma, hepatocellular carcinoma, hormone-insensitive prostate carcinoma, leiomyosarcoma, leukemia, liposarcoma, lung carcinoma, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphomas (hodgkin and non-hodgkin), bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus malignancies and hyperproliferative disorders, lymphoid malignancies of T-cell or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid carcinoma, fahrenheit macroglobulinemia, testicular tumor, uterine cancer and wilms' tumor.

In another aspect, the present disclosure provides a method for treating acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endotheliosarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, primary thrombocytosis, ewings' tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, smooth muscle sarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (hodgkins and non-hodgkins), malignancies and hyperproliferative diseases of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung carcinoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of the formulae as described herein (or an embodiment or aspect thereof) a therapeutically effective amount of a compound according to any one of the formulae as described herein.

In another aspect, the present disclosure provides a compound of any of the formulae as described herein (or embodiments or aspects thereof) as described elsewhere herein for use in modulating TEAD activity. In some embodiments, the present disclosure provides pharmaceutically acceptable salts of compounds of any of the formulae described herein for modulating TEAD activity.

In another aspect, the present disclosure provides a compound of any one of the formulae described herein, or an embodiment or aspect thereof (such as a pharmaceutically acceptable salt thereof), for use in pharmaceutical therapy.

In another aspect, the present disclosure provides a method for treating or preventing acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, primary thrombocytosis, ewings' tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, smooth muscle sarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkin and non-hodgkin), bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus malignancies and hyperproliferative diseases, lymphoid malignancies of T-or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, fahrenheit macroglobulinemia, testicular tumors, uterine cancer, and wilms' tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the formulae as described herein (or embodiments or aspects thereof).

In another aspect, the present disclosure provides a compound of any one of the formulae as described herein, or an embodiment or aspect thereof (such as a pharmaceutically acceptable salt thereof), for use in the treatment or prophylaxis of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngeal angioma, cystadenocarcinoma, diffuse large B-cell lymphoma, adverse proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor positive breast cancer, primary thrombocythemia, ewings' tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, smooth muscle sarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkin and non-hodgkin), malignant tumors and hyperproliferative diseases of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid carcinoma, fahrenheit macroglobulinemia, testicular tumor, uterine cancer and wilms' tumor.

In another aspect, the present disclosure provides a compound of any one of the formulae as described herein, or an embodiment or aspect thereof (such as a pharmaceutically acceptable salt thereof), for use in the preparation of a medicament for the treatment or prophylaxis of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon carcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplasia and metaplasia) of neoplastic and proliferative changes, embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor positive breast cancer, primary thrombocythemia, ewings' tumor, fibrosarcoma, follicular lymphoma, germ cell testicular carcinoma, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver carcinoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, smooth muscle sarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkin and non-hodgkin), malignant tumors and hyperproliferative diseases of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid carcinoma, fahrenheit macroglobulinemia, testicular tumor, uterine cancer and wilms' tumor.

In another aspect, the present disclosure provides a method for treating acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon carcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable changes in proliferation (dysplasia and metaplasia), embryonal carcinoma in a mammal (e.g., a human), endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, primary thrombocythemia, ewings' tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, smooth muscle sarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkin and non-hodgkin), bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus malignancies and hyperproliferative diseases, lymphoid malignancies of T-cell or B-cell origin, medullary cancers, a medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumor, uterine cancer, and wilms' tumor, comprising administering to a mammal a compound of any of the formulae as described herein, or an embodiment or aspect thereof (such as a pharmaceutically acceptable salt thereof).

In another aspect, the present disclosure provides a method for modulating TEAD activity comprising contacting TEAD with a compound of any one of the formulae as described herein, or an embodiment or aspect thereof (such as a pharmaceutically acceptable salt thereof).

In another aspect, the present disclosure provides a compound of any one of the formulae as described herein, or an embodiment or aspect thereof (such as a pharmaceutically acceptable salt thereof), for use in the treatment or prevention of a disease or condition mediated by TEAD activity. In various aspects of this embodiment, the disease or disorder is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon carcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, primary thrombocytosis, ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphoblastic leukemia, lymphoma (hodgkin and non-hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, fahrenheit macroglobulinemia, testicular tumor, uterine cancer, and wilms' tumor.

In another aspect, the present disclosure provides the use of a compound of any one of the formulae as described herein, or an embodiment or aspect thereof (such as a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by TEAD activity. In various aspects of this embodiment, the disease or disorder is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon carcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, primary thrombocytosis, ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphoblastic leukemia, lymphoma (hodgkins and non-hodgkins), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, fahrenheit macroglobulinemia, testicular tumor, uterine cancer, and wilms' tumor.

In one aspect, the compounds of the present disclosure exhibit greater potency compared to other analogs.

Combination therapy

A compound of any one of the formulae as described herein, or a stereoisomer or pharmaceutically acceptable salt thereof, can be used alone or in combination with other agents for use in therapy. For example, the second agent of a pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of any one of the formulae as described herein such that they do not adversely affect each other. The compounds may be administered together or separately in a single pharmaceutical composition. In one embodiment, the compound or pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

The term "co-administration" refers to the simultaneous administration or separate sequential administration in any manner of a compound of any one of the formulae as described herein or a salt thereof and other active pharmaceutical ingredient(s) (including cytotoxic agents and radiation therapy). If the administration is not simultaneous, the compounds should be administered within a time period close to each other. Furthermore, it is immaterial whether the compounds are administered in the same dosage form, for example one compound may be administered topically and the other orally.

Those other agents may be administered separately from the composition containing the compound of the present invention as part of a multiple dose regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered as part of a multi-dose regimen, the two active agents may be administered simultaneously, sequentially or at intervals from one another (typically within five hours of one another).

As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the invention may be administered with another therapeutic agent, either simultaneously or sequentially, in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of any one of the formulae provided herein (e.g., a compound of any of the formulae described herein), an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of the compound of the invention and other therapeutic agent (in those compositions comprising the other therapeutic agents as described above) that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, the compositions of the present invention are formulated such that a dosage of 0.01 to 100mg/kg body weight/day of the present invention may be administered.

Generally, any agent that is active for the disease or condition being treated may be co-administered. Examples of such drugs can be found in Cancer Principles and Practice of Oncology (v.t. device and s.hellman (ed), 6 th edition (2/15/2001), lippincott Williams & Wilkins publishers, a person of ordinary skill in the art will be able to discern which combination of agents will be useful based on the specific characteristics of the drugs and diseases involved.

In one embodiment, the method of treatment comprises co-administration of a compound of any one of the formulae described herein or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent. As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., at) ²¹¹ 、I ¹³¹ 、I ¹²⁵ 、Y ⁹⁰ 、Re ¹⁸⁶ 、Re ¹⁸⁸ 、Sm ¹⁵³ 、Bi ²¹² 、P ³² 、Pb ²¹² And radioactive isotopes of Lu); a chemotherapeutic agent; raw materialA long-acting inhibitor; enzymes and fragments thereof, such as nucleolytic enzymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.

Exemplary cytotoxic agents may be selected from the group consisting of antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-a inhibitors; inhibitors of fatty acid biosynthesis; inhibitors of cell cycle signaling; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.

"chemotherapeutic agents" include chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (b)Genes of tek/OSI pharm.), bortezomib (Millennium pharmaceuticals (Millennium pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (A)AstraZeneca), shu Niti cloth (AstraZeneca), andPfizer/Sugen) letrozole (C)Novartis (Novartis)), imatinib mesylate (i.e., (ii)) and (ii) pharmaceutically acceptable salts thereofNowa), finafloxacin ester(s) ((s)Norwalk), oxaliplatin: (A)Sirolimus (Sanofi)), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus,wheet (Wyeth)), lapatinib (a), (b), and (c)GSK572016, glan Smith Kline, luo Nafa m (Lonafami) (SCH 66336), sorafenib (R)Bayer Labs (Bayer Labs)), gefitinib (A)Astrazepam), AG1478; alkylating agents such as thiotepa andcyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzotepa, carboquone, meturedpa, and uredpa; ethyleneamines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; annonaceous acetogenins (especially bullatacin and bullatacin); camptothecin (including topotecan and irinotecan); bryostatins; a caristatin (callystatin); CC-1065 (including its adozelesin (adozelesin), carvelesin (carzelesin), and bizelesin (bizelesin) synthetic analogs); cryptophycin (especially cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5 α -reductase (including finasteride and dutasteride); a device Linalostat, romidepsin, pantoprazole, valproic acid, moxistat, dolastatin; aldesleukin, talc, du Ka mycin (including synthetic analogs KW-2189 and CB1-TM 1); eleutherobin (eleutherobin); (ii) coprinus atramentarius alkali; sarcandra glabra alcohol (sarcodictyin); sponge chalone; nitrogen mustards such as chlorambucil, chlorophenylpiperazine, chlorophenylphosphoramide, estramustine, ifosfamide, mechlorethamine hydrochloride, melphalan, neomustard (novembichin), benzene mustard cholesterol, prednimine, trofosfamide (trofosfamide), uramustine (uracil musard); nitrosoureas such as carmustine, chlorourethrine, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ 1I and calicheamicin ω 1I (angelw chem. Intl.ed. Engl.1994 33, 183-186)); daptomycin (dynemicin), including daptomycin a; bisphosphonates such as clodronate; ai Simi star; and a novel carcinostatin (neocarzinostatin) chromophore and related chromoprotein enediyne antibiotic chromophores; aclacinomycin (acacetimycin), actinomycin (actinomycin), anthranilic acid (aurramycin), azaserine (azaserine), bleomycin, actinomycin (cactinomycin), carubicin (carabicin) carminomycin (caminomycin), carzinophilin (carzinophilin), chromomycin (chromomycins), dactinomycin, daunomycin, ditolucin (detorubicin), 6-azido-5-oxo-L-norleucine, (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and doxorubicine, epirubicin, isoxabixin, idarubicin, maccellomycin (marcellomomycin); mitomycins, such as mitomycin C, mycophenolic acid, nogomycin, olivomycin, pelomomycin, methylmitomycin, puromycin, triiron doxorubicin (queamycin), rodoricin (rodorubicin), streptonigrin, streptozotocin, tubercidin, ubenimex, netostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil(5-Fu); folic acid analogs such as denopterin, methotrexate, pteropterin Luo Ling (pteropterin), trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thioguanine (thiamirine), thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as carpoterone, drostandrosterone propionate, epitioandrostanol, meindroxane, testolactone; anti-adrenergic agents such as aminoglutethimide, mitotane, troostitan; folic acid replenisher such as folinic acid; acetic acid glucurolactone; an aldehydic phosphoramide glycoside; (ii) aminolevulinic acid; eniluracil; amsacrine; doubly-branched betuzucil; a bisantrene group; edatrexate (edatraxate); ifosfamide (defofamine); colchicine; imine quinone; ilonidine (elfosmithine); ammonium etiolate; an epothilone; ethydine; gallium nitrate; a hydroxyurea; lentinan; lonidamine (lonidainine); maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol (mopidarnol); diamine nitracridine (nitrarine); pentostatin; methionine mustard (phenamett); pirarubicin; losoxantrone (losoxantrone); podophyllic acid; 2-ethyl hydrazine; (ii) procarbazine; Polysaccharide complex (JHS Natural Products, eugene, oreg., usa); lezoxan; rhizomycin (rhizoxin); schizophyllan (sizofuran); a germanium spiroamine; alternarionic acid; a tri-imine quinone; 2,2',2 "-trichlorotriethylamine; trichothecene toxins (especially T-2 toxin, veracurin a, myrmecin a, and nigella sativa); urethane; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulcitol; pipobroman; gatifloxacin; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes such as TAXOL (paclitaxel; the department of the Buchner Schuibao cancer specialty of Princeton, N.J.), (Bristol-Myers Squibb Oncology, princeton, N.J.)), (see FIGS,(without hydrogenated castor oil (Cremophor)), an albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners Shao Bake, illinois, schaumberg, il.), and(docetaxel, docetaxel; sirolimus-ampheta (Sanofi-Aventis)); chlorambucil;(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); nuntoron (novantrone); (ii) teniposide; edatrexed; daunomycin; aminopterin; capecitabineIbandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agents also include (i) anti-hormonal agents that act to modulate or inhibit the action of hormones on tumors, such as anti-estrogens and Selective Estrogen Receptor Modulators (SERMs), including for example tamoxifen (includingTamoxifen citrate), raloxifene, droloxifene, iodoxifen (iodoxyfene), 4-hydroxytamoxifene, troloxifene, raloxifene (keoxifene), LY117018, onapristone and(toremifene citrate); (ii) Aromatase inhibitors which inhibit the enzyme aromatase, which modulate the production of estrogen by the adrenal glands, for example 4 (5) -imidazoles, aminoglutarimides,(megestrol acetate),Exemestane, pyroxene, formestane, fadrozole,(Fu Luo),(letrozole; noval) and(anastrozole; asricon); (iii) Anti-androgens such as flutamide, nilutamide, bicalutamide, leuprorelin and goserelin; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, bemeili, fluoxymesterone, all trans retinoic acid, fenretinide, and troxacitabine (1,3-dioxolane nucleoside cytosine analogues); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) Antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways implicated by abnormal cell proliferation, such as, for example, PKC- α, ralf, and H-Ras; (vii) Ribozymes, such as VEGF expression inhibitors (e.g., ) And inhibitors of HER2 expression; (viii) Vaccines, such as gene therapy vaccines, e.g.AndrIL-2; topoisomerase 1 inhibitors, such asrmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agents also include antibodies that are capable of binding to the target, such as alemtuzumab (Campath) bevacizumab (Genentech); cetuximab (Imclone); panitumumab (A), (B)Amgen), rituximab (rituximab), (b)Genentech/Biogen Idec), pertuzumab (a: (b) ((b))2C4, genentech), trastuzumab (trastuzumab) (Satsuzumab)Genentech), tositumomab (tositumomab) (Bexxar, corixia) and antibody drug conjugates, gemtuzumab ozogamicin (c: (r)Wyeth). Other humanized monoclonal antibodies with therapeutic potential in combination with the compounds of the invention include: aprezumab (apilizumab), aselizumab, aleizumab, barbiturate, mabbivatuzumab (bivatuzumab mertansine), mo KanTrastuzumab (cantuzumab mertansine), cedelelizumab (Cedellizumab), setuzumab (certolizumab pegol), cefuxinzumab (ciduximab), cedfuzumab (cidfutuzumab), cetuzumab (cidtuzumab), dalizumab (daclizumab), ekulizumab (eculizumab), efalizumab (efalizumab), epapazumab (epratuzumab), erlizumab (erlizumab), uvlizumab (feluzumab), fantuzumab (fentuzumab), glotuzumab (Oxazolimicin), oxotuzumab (Inuzumab), imutazumab ozolozumab (inozozogamumab), lam Bei Zhu monoclonal (Lalautuzumab (Latuzumab), lintuzumab (Lintuzumab), rituzumab, merrilizumab, meipauzumab, 3732 Zuzumab (Latexmuzumab), ravauzumab (La3263), and Mutuzumab (Latex 3763), and Netuzumab (Netuzumab). Nonz Ma Weizhu (numavizumab), ocrelizumab (ocrelizumab), omalizumab, palivizumab (palivizumab), paclobuzumab (pascolizumab), pefuxizumab (pecfuuzumab), pemphizumab (petuuzumab), pexizumab (pexizumab), rillizumab (ralvizumab), ranibizumab (resivizumab), rayleigh mab (resilizumab), resivizumab (resyvivumab), luo Weizhu (rovelizumab), lu Lizhu (ruplizumab), sirolimumab, sibutrumab, matuzumab (Sontuzumab), sontuzumab (Sontuzumab), tizumab (tatuzumab), tezumab (texetan), tamab (tazezumab), tezomab (tazezumab), tezumab (tazezumab), and teuzumab (tezozumab (tezox), and zelizumab), torilizumab, western Mo Bai Interleukin mAb (tucotuzumab celeukin), tukuxizumab (tucusituzumab), wu Mawei Exlizumab (umavuzumab), wu Zhu, ultkumab, vicizumab and anti-Interleukin-12 (ABT-874/J695, whitzerland research and Yapei laboratory) (anti-Interleukin-12 is a recombinant human unique sequence full-length IgG 12 ₁ Lambda antibody, genetically modified to recognize interleukin-12 p40 protein).

Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or directly interact with EGFR and prevent or reduce its signaling activity, and are alternatively referred to as "EGFR antagonists. Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb 579 (ATCC CRL HB)8506 MAb 455 (ATCC CRL HB 8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No. 4,943,533, mendelsohn et al), and variants thereof, such as chimeric 225 (C225 or cetuximab;) And remodeled human 225 (H225) (see, WO96/40210, imclone Systems Inc.); IMC-11F8, a fully human antibody targeting EGFR (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S. patent No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or panitumumab (see WO98/50433, annix (Abgenix)/Amgen); EMD 55900 (Straglitoto et al Eur. J. Cancer 32A 636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody against EGFR, competes with EGF and TGF- α for binding to EGFR (EMD/Merck); human EGFR antibody, huMax-EGFR (GenMab); fully human antibodies, designated E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3, and described in US 6,235,883; MDX-447 (Medarex Inc.); and mAb 806 or humanized mAb 806 (Johns et al, j.biol. Chem.279 (29): 30375-30384 (2004)). An anti-EGFR antibody can be conjugated with a cytotoxic agent to produce an immunoconjugate (see, e.g., EP659,439A2, merck Patent GmbH). EGFR antagonists include small molecules such as U.S. Pat. nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, and PCT publications: the compounds described in WO98/14451, WO98/50038, WO99/09016 and WO 99/24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033,2-acrylamide, N- [4- [ (3-chloro-4-fluorophenyl) amino]-7- [3- (4-morpholinyl) propoxy]-6-quinazolinyl]-, dihydrochloride, feverfew); ZD1839, gefitinib (b)4- (3 '-chloro-4' -fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline, aliskiren); ZM 105180 (6-amino-4- (3-methylphenyl-amino) -quinazoline, jiekang (Zeneca)); BIBX-1382 (N8- (3-chloro-4-fluoro-phenyl) -N2- (1-methyl-piperidin-4-yl) -pyrimidinyl [5,4-d]Pyrimidine-2,8-diamine, boringer Inverghan (Boehringer Ingelheim)); PKI-166 ((R) -4- [4- [ (1-phenylethyl) amino)]-1H-pyrrolidone [2,3-d]Pyrimidin-6-yl]-phenol); (R) -6- (4-hydroxyphenyl) -4- [ (1-phenylethyl) amino group]-7H-pyrrolo [2,3-d]Pyrimidines); CL-387785 (N- [4- [ (3-bromophenyl) amino)]-6-quinazolinyl]-2-butyneamide); EKB-569 (N- [4- [ (3-chloro-4-fluorophenyl) amino group)]-3-cyano-7-ethoxy-6-quinolinyl]-4- (dimethylamino) -2-butenamide) (whelweis); AG1478 (fevered); AG1571 (SU 5271; feverine); dual EGFR/HER2 tyrosine kinase inhibitors, such as lapatinib (R: (R))GSK572016 or N- [ 3-chloro-4- [ (3-fluorophenyl) methoxy ]Phenyl radical]-6[5[ [ [2 (methylsulfonyl) ethyl ] ethyl]Amino group]Methyl radical]-2-furyl radical]-4-quinazolinamines).

Chemotherapeutic agents also include "tyrosine kinase inhibitors" including the EGFR-targeting drugs described in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from the pharmaceutical company martial arts (Takeda); CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (pyroxene and OSI); dual HER inhibitors, such as EKB-569 (available from hewlett-packard), which can preferentially bind EGFR but inhibit both HER2 and EGFR overexpressing cells; lapatinib (GSK 572016; available from Kurarin Schker), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Nowa corporation); pan-HER inhibitors such as canatinib (CI-1033; pharmacia); raf-1 inhibitors, such as the anti-sense agent IS available from ISIS pharmaceutical company for inhibiting Raf-1 signalingIS-5132; non-HER targeted TK inhibitors such as imatinib mesylate (b: (b))Available from glatiramer inc); multi-targeted tyrosine kinase inhibitors, such as sunitinib (C) ((R))Available from pfeiri); VEGF receptor tyrosine kinase inhibitors, such as vartanib (PTK 787/ZK222584, available from Nowa/pioneer company (Schering AG)); CI-1040, a MAPK extracellular regulated kinase I inhibitor (available from Famex corporation); quinazolines, such as PD 153035,4- (3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4- (phenylamino) -7H-pyrrolo [2,3-d ]A pyrimidine; curcumin (diformylmethane, 4,5-bis (4-fluoroanilino) phthalimide); tyrosine containing nitrothiophene moiety; PD-0183805 (Warner-Lambert, inc.); antisense molecules (e.g., molecules that bind to HER-encoding nucleic acids); quinoxalines (U.S. patent No. 5,804,396); tyrphostin (U.S. Pat. No. 5,804,396); ZD6474 (asirizan); PTK-787 (Nowa/Pioneer); pan HER inhibitors such as CI-1033 (pyroxene); affinitac (ISIS 3521; imatinib mesylatePKI 166 (norwa); GW2016 (glatiramer inc); CI-1033 (pfeiffer); EKB-569 (Huishi); sematinib (pyrosorib); ZD6474 (asixicam); PTK-787 (Nowa/Pioneer); INC-1C11 (Imclone), rapamycin (sirolimus,) (ii) a Or in any of the following patent publications: U.S. Pat. Nos. 5,804,396, WO 1999/09016 (American Cyanamid), WO 1998/43960 (American Cyanamid), WO 1997/38983 (Warner Lambert), WO 1999/06378 (Warner Lambert), WO 1999/06396 (Warner Lambert), WO 1996/30347 (Pfizer, inc), WO 1996/33978 (Zeneca), WO 1996/3397 (Zeneca), and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferon, colchicine, chlorpheniramine (metoprine), cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine (amifostine), arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine (clofarabine), darbexatiline alpha (darbebefloetin alfa), dinil interleukin (denileukin), dexrazoxane, epoetin alpha (epoetin alfa), erlotinib (elotinib), filgrastim (filgrastim), histidinerelin acetate (histreetin acetate), ibrinolimumab (ibrinolimumab), telithromycin (ibrutin) interferon alpha-2 a, interferon alpha-2 b, lenalidomide, levamisole, mesna (mesna), methoxsalen, nandrolone (nandrolone), nelarabine (nellabine), norfetimomab (nofetumumab), omprex interleukin (oprelvekin), palifermin (palifermin), pamidronate (pamidronate), or mixtures thereof Pegaselmase, pemetrexed, pefilgrastim, pemetrexed disodium, mithramycin sodium, porfimer sodium, quinacrine, rasburiase, sargrastim, temozolomide, VM-26, and so on, 6-TG, toremifene (toremifene), tretinoin (tretinoin), ATRA, valrubicin (valrubicin), zoledronate (zoledronate), and zoledronic acid (zoledronic acid), and pharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, thiohydrocortisone pivalate, triamcinolone acetonide, mometasone, amcinonide, budesonide, desonide, fluocinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium phosphate, flucolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, alclomethasone dipropionate, betamethasone valerateMethasone, betamethasone dipropionate, prednisone kate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone valerate and fluprednidene acetate; immunoselective anti-inflammatory peptides (imsaids), such as phenylalanine-glutamine-glycine (FEG) and its D-isomer forms (feG) (IMULAN BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine a), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine; tumor necrosis factor alpha (TNF α) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab (Cimzia), golimumab (Simponi); interleukin 1 (IL-1) blockers, such as anakinra (Kineret); t cell co-stimulation blockers, such as abatacept (Orencia); interleukin 6 (IL-6) blockers, such as tollizumab Interleukin 13 (IL-13) blocking agents, such as lerizumab; interferon alpha (IFN) blockers, such as Luo Nazhu monoclonal antibody; β 7 integrin blockers, such as rhuMAb β 7; igE pathway blockers, such as anti-M1 primers; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1/β 2 blockers, such as anti-lymphotoxin alpha (LTa); radioisotope (e.g. At) ²¹¹ 、I ¹³¹ 、I ¹²⁵ 、Y ⁹⁰ 、Re ¹⁸⁶ 、Re ¹⁸⁸ 、Sm ¹⁵³ 、Bi ²¹² 、P ³² 、Pb ²¹² And radioactive isotopes of Lu); various test agents, such as Sulfoplatin, PS-341, phenylbutyrate, ET-18-OCH ₃ Or a farnesyl transferase inhibitor (L-739749, L-744832); polyphenols such as quercetin, resveratrol, picrol, epigallocatechin gallate, theaflavin, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol,) (ii) a Beta-lapachone(ii) a Lappaol; colchicine; betulinic acid; acetyl camptothecin, scopolectin (scopolectin), and 9-aminocamptothecin); podophyllotoxin; tegafurBexaroteneBisphosphonates, such as clodronate (e.g.,or) EtidronateNE-58095, zoledronic acid/zoledronic acid saltAlendronate Pamidronate saltTiluodipine saltOr risedronateAnd epidermal growth factor receptor (EGF-R); vaccines, e.g.A vaccine; pirifosine; a COX-2 inhibitor (e.g., celecoxib or etoxib); proteosome inhibitors (e.g., PS 341); CCI-779; tipifarnib (R11577); olarafinil, ABT510; bcl-2 inhibitors, such as, for example, on Li Meisen sodium (oblimersen sodium)Pixantrone (pixantrone); farnesyl transferase inhibitors, such as lonafarnib (SCH 6636, SARASAR) ^TM ) (ii) a And a pharmaceutically acceptable salt, acid or derivative of any of the above; and combinations of two or more of the above, such as CHOP (abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone); and FOLFOX (oxaliplatin) ^TM ) Abbreviation for treatment regimen in combination with 5-FU and calcium folinate).

Chemotherapeutic agents also include nonsteroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives (e.g., ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin (oxaprozin), and naproxen), acetic acid derivatives (e.g., indomethacin, sulindac, etodolac, diclofenac), enolic acid derivatives (e.g., piroxicam, meloxicam, tenoxicam, droxicam (droxicam), lornoxicam, and isoxicam), fenamic acid derivatives (e.g., mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), and COX-2 inhibitors (e.g., celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib (rofecoxib), rofecoxib, and valdecoxib). NSAIDs may be useful for alleviating symptoms of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthritis, ankylosing spondylitis, psoriatic arthritis, reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, post-operative pain, mild to moderate pain due to inflammation and tissue injury, fever, ileus and renal colic.

In certain embodiments, chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferons, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), podophyllotoxins (e.g., etoposide), cisplatin, mTOR inhibitors (e.g., rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprolol, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, camptothecin (captothececin), cisplatin, metronidazole, and imatinib mesylate, among others. In other embodiments, the compounds of the invention are administered in combination with a biological agent (such as bevacizumab or panitumumab).

In certain embodiments, a compound of the invention or a pharmaceutical composition thereof is administered in combination with an antiproliferative agent or a chemotherapeutic agent selected from any one or more of the following: <xnotran> , , , , , , , , , , , BCG, , , , , , , , , , , , , , , , , , , α, , , , , (), , 5363 zxft 5363 , , , , , , , , , , , , , , , , , , , , , , α -2a, α -2b, , , , , , , , , , , 6-MP, , , , C, , , , , , , , , , , , , , , , , , , , , </xnotran> Labyrinase, rituximab, sargrastim, sorafenib, streptozocin, sunitinib maleate, talcum powder, tamoxifen, temozolomide, teniposide, VM-26, testosterone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, retinoic acid, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate or zoledronic acid.

Chemotherapeutic agents also include those used in the treatment of alzheimer's disease, such as donepezil hydrochloride and rivastigmine; for the treatment of parkinson's disease, such as L-DOPA/carbidopa, entacapone, luo Pingluo L, pramipexole, bromocriptine, pergolide, tripiperidine, and amantadine; agents for treating Multiple Sclerosis (MS), such as interferon-beta (e.g.,and) Glatiramer acetate and mitoxantrone; for the treatment of asthma, such as albuterol and montelukast sodium; agents for treating schizophrenia, such as reptile, visfate, serekan and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-parkinson agents; agents for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for treating liver diseases, such as corticosteroids, cholestyramine, interferon, and antiviral agents; agents for treating blood disorders, such as corticosteroids Alcohols, anti-leukemia agents and growth factors; and agents for treating immunodeficiency disorders, such as gamma globulin.

Additionally, the chemotherapeutic agent includes pharmaceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents described herein, and combinations of two or more thereof.

In another embodiment, there is provided a method of treating cancer using a compound of any of the formulae described herein, or a pharmaceutically acceptable salt thereof, as described elsewhere herein, or an embodiment or aspect thereof, in combination with a PD-1 axis binding antagonist.

The term "PD-1 axis binding antagonist" refers to an agent that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners to eliminate T cell dysfunction caused by signaling on the PD-1 signaling axis, thereby restoring or increasing T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, PD-1 axis binding antagonists include PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists.

The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates, or interferes with signaling resulting from the interaction of PD-1 with one or more of its binding partners (such as PD-L1, PD-L2). In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In particular aspects, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies and antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with signaling resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In one embodiment, the PD-1 binding antagonist can reduce a negative costimulatory signal mediated by or through PD-1 signaling mediated by a cell surface protein expressed on the T lymphocyte, thereby rendering the dysfunctional T cell less dysfunctional (e.g., increasing effector response to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. Specific examples of PD-1 binding antagonists are provided below.

The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates or interferes with signaling resulting from the interaction of PD-L1 with one or more of its binding partners (such as PD-1, B7-1). In some embodiments, the PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In particular aspects, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and/or B7-1. In some embodiments, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with signaling resulting from the interaction of PD-L1 with one or more of its binding partners (such as PD-1, B7-1). In one embodiment, the PD-L1 binding antagonist can reduce a negative costimulatory signal mediated by or through PD-L1 signaling mediated by a cell surface protein expressed on the T lymphocyte, thereby rendering the dysfunctional T cell less dysfunctional (e.g., increasing effector response to antigen recognition). In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody. Specific examples of PD-L1 binding antagonists are provided below.

The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates, or interferes with signaling resulting from the interaction of PD-L2 with its one or more binding partners (such as PD-1). In some embodiments, the PD-L2 binding antagonist is a molecule that inhibits binding of PD-L2 to one or more of its binding partners. In particular aspects, the PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. In some embodiments, PD-L2 antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with signaling resulting from the interaction of PD-L2 with one or more of its binding partners (such as PD-1). In one embodiment, the PD-L2 binding antagonist can reduce a negative costimulatory signal mediated by or through PD-L2 signaling mediated by a cell surface protein expressed on the T lymphocyte, thereby rendering the dysfunctional T cell less dysfunctional (e.g., increasing effector response to antigen recognition). In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

PD-1 axis binding antagonists

Provided herein are methods for treating cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of any one of the formulae described herein or a pharmaceutically acceptable salt thereof. Also provided herein are methods of enhancing immune function or response in an individual (e.g., an individual having cancer) comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of any one of the formulae described herein or a pharmaceutically acceptable salt thereof.

In such methods, the PD-1 axis binding antagonist comprises a PD-1 binding antagonist, a PDL1 binding antagonist, and/or a PDL2 binding antagonist. Alias names for "PD-1" include CD279 and SLEB2. Alias names of "PDL1" include B7-H1, B7-4, CD274, and B7-H. Alias names for "PDL2" include B7-DC, btdc, and CD273. In some embodiments, PD-1, PDL1, and PDL2 are human PD-1, PDL1, and PDL2.

In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand binding partner. In particular aspects, the PD-1 ligand binding partner is PDL1 and/or PDL2. In another embodiment, the PDL1 binding antagonist is a molecule that inhibits the binding of PDL1 to its binding partner. In particular aspects, the PDL1 binding partner is PD-1 and/or B7-1. In another embodiment, the PDL2 binding antagonist is a molecule that inhibits the binding of PDL2 to its binding partner. In a particular aspect, the PDL2 binding partner is PD-1. The antagonist can be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide or a small molecule. If the antagonist is an antibody, in some embodiments, the antibody comprises a human constant region selected from the group consisting of IgG1, igG2, igG3, and IgG 4.

anti-PD-1 antibodies

In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PDL 1 antibodies may be utilized in the methods disclosed herein. In any of the embodiments herein, the PD-1 antibody can bind to human PD-1 or a variant thereof. In some embodiments, the anti-PD-1 antibody is a monoclonal antibody. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of Fab, fab' -SH, fab, and H,Fv, scFv and (Fab') ₂ Antibody fragments of the group consisting of fragments. In some embodiments, the anti-PD-1 antibody is a chimeric or humanized antibody. In other embodiments, the anti-PD-1 antibody is a human antibody.

In some embodiments, the anti-PD-1 antibody is nivolumab (nivolumab) (CAS registry number 946414-94-4). Nivolumab (Bristol-Myers Squibb/Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558 andis an anti-PD-1 antibody as described in WO 2006/121168. Nivolumab comprises heavy and light chain sequences, wherein:

(a) The heavy chain comprises the following amino acid sequence.

QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1), and

(b) The light chain comprises the following amino acid sequence:

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:2)。

in some embodiments, the anti-PD-1 antibody comprises six HVR sequences from SEQ ID NO:1 and SEQ ID NO:2 (e.g., three heavy chain HVRs from SEQ ID NO:1 and three light chain HVRs from SEQ ID NO: 2). In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable domain from SEQ ID NO. 1 and a light chain variable domain from SEQ ID NO. 2.

In some embodiments, the anti-PD-1 antibody is Pembrolizumab (Pembrolizumab) (CAS registry number 1374853-91-4). Pembrolizumab(Merck), also known as MK-3475, merck 3475, pabollizumab, SCH-900475, andis an anti-PD-1 antibody as described in WO 2009/114335. Pembrolizumab comprises heavy and light chain sequences, wherein:

(a) The heavy chain comprises the following amino acid sequence:

QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 3), and

(b) The light chain comprises the following amino acid sequence:

EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:4)。

in some embodiments, the anti-PD-1 antibody comprises six HVR sequences from SEQ ID NO:3 and SEQ ID NO:4 (e.g., three heavy chain HVRs from SEQ ID NO:3 and three light chain HVRs from SEQ ID NO: 4). In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable domain from SEQ ID NO. 3 and a light chain variable domain from SEQ ID NO. 4.

In some embodiments, the anti-PD-1 antibody is MEDI-0680 (AMP-514. MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

In some embodiments, the anti-PD-1 antibody is PDR001 (CAS registry number 1859072-53-9; nowa). PDR001 is a humanized IgG4 anti-PD 1 antibody that blocks binding of PDL1 and PDL2 to PD-1.

In some embodiments, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD 1 antibody.

In some embodiments, the anti-PD-1 antibody is BGB-108 (BeiGene). In some embodiments, the anti-PD-1 antibody is BGB-A317 (BeiGene).

In some embodiments, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD 1 antibody.

In some embodiments, the anti-PD-1 antibody is STI-a1110 (sorento). STI-A1110 is a human anti-PD 1 antibody.

In some embodiments, the anti-PD-1 antibody is incsar-1210 (Incyte). INCSFR-1210 is a human IgG4 anti-PD 1 antibody.

In some embodiments, the anti-PD-1 antibody is PF-06801591 (Pfizer).

In some embodiments, the anti-PD-1 antibody is TSR-042 (also known as ANB011; tesaro/AnaptysBio).

In some embodiments, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

In some embodiments, the anti-PD-1 antibody is ENUM 244C8 (acoustic biological Holdings). ENUM 244C8 is an anti-PD 1 antibody that inhibits the function of PD-1 without preventing binding of PDL1 to PD-1.

In some embodiments, the anti-PD-1 antibody is ENUM 388D4 (acoustic biological Holdings). ENUM 388D4 is an anti-PD 1 antibody that competitively inhibits binding of PDL1 to PD-1.

In some embodiments, the PD-1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and/or a heavy chain variable domain and a light chain variable domain from a PD-1 antibody described in: WO2015/112800 (applicant: regeneron), WO2015/112805 (applicant: regeneron), WO2015/112900 (applicant: novartis), US20150210769 (assigned to Novartis), WO2016/089873 (applicant: celgene), WO2015/035606 (applicant: beigene), WO2015/085847 (applicant: shanghai Hengrui Pharmaceutical/Jianshangsu Hengrui Medicine), WO2014/206107 (applicant: shanghai Junshi Biosciences/Junmence), WO2012/145493 (applicant: amplimMune), US 3262 zxMedmume 62 (applicant 2015/1192016), WO Pf/930 (applicant: sizer/Merck), WO2015/119923 (applicant: pfymek), WO 2015/3264 (applicant: pacif/2014), WO 2015/1192016 (applicant: WO 172016/2014) and WO 2014/2016 (WO 172016: sophor/2016).

anti-PDL 1 antibodies

In some embodiments, the PD-1 axis binding antagonist is an anti-PDL 1 antibody. Various anti-PDL 1 antibodies are contemplated and described herein. In any of the embodiments herein, the isolated anti-PDL 1 antibody may bind to human PDL1, e.g., human PDL1 shown in UniProtKB/Swiss-Prot accession number Q9NZQ7.1, or a variant thereof. In some embodiments, the anti-PDL 1 antibody is capable of inhibiting binding between PDL1 and PD-1 and/or between PDL1 and B7-1. In some embodiments, the anti-PDL 1 antibody is a monoclonal antibody. In some embodiments, the anti-PDL 1 antibody is selected from the group consisting of Fab, fab '-SH, fv, scFv, and (Fab') ₂ Antibody fragments of the group consisting of fragments. In some embodiments, the anti-PDL 1 antibody is a chimeric or humanized antibody. In some embodiments, the anti-PDL 1 antibody is a human antibody. Examples of anti-PDL 1 antibodies useful in the methods of the invention and methods of making the same are described in PCT patent application WO2010/077634 and U.S. patent No. 8,217,149, both of which are incorporated herein by reference.

In some embodiments, the anti-PDL 1 antibody is atelizumab (CAS accession No.: 1422185-06-5). Attrituzumab (Genentech), also known as MPDL3280A, is an anti-PDL 1 antibody.

The atezumab comprises:

(a) The HVR-H1, HVR-H2 and HVR-H3 sequences GFTFSDSWIH (SEQ ID NO: 5), AWISPYGGSTYYADSVKG (SEQ ID NO: 6) and RHWPGGFDY (SEQ ID NO: 7), respectively, and

(b) The HVR-L1, HVR-L2 and HVR-L3 sequences RASQDVSTAVA (SEQ ID NO: 8), SASFLYS (SEQ ID NO: 9) and QQYLYHPAT (SEQ ID NO: 10), respectively.

The atezumab comprises heavy and light chain sequences wherein:

(a) The heavy chain variable region sequence comprises the amino acid sequence:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO:11, and

(b) The light chain variable region sequence comprises the amino acid sequence:

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(SEQ ID NO:12)。

atelizumab comprises heavy and light chain sequences, wherein:

(a) The heavy chain comprises the following amino acid sequence:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 13), and

(b) The light chain comprises the following amino acid sequence:

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:14)。

in some embodiments, the anti-PDL 1 antibody is avilumab (CAS registry No. 1537032-82-8). Avilamumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PDL 1 antibody (Merck KGaA, pfizer). The avilamumab comprises a heavy chain and a light chain sequence, wherein:

(a) The heavy chain comprises the following amino acid sequence:

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 15), and

(b) The light chain comprises the following amino acid sequence:

QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(SEQ ID NO:16)。

in some embodiments, the anti-PDL 1 antibody comprises six HVR sequences from SEQ ID NO:15 and SEQ ID NO:16 (e.g., three heavy chain HVRs from SEQ ID NO:15 and three light chain HVRs from SEQ ID NO: 16). In some embodiments, the anti-PDL 1 antibody comprises a heavy chain variable domain from SEQ ID NO. 15 and a light chain variable domain from SEQ ID NO. 16.

In some embodiments, the anti-PDL 1 antibody is Devolumab (durvalumab) (CAS registry number: 1428935-60-7). Devolumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1 kappa anti-PDL 1 antibody described in WO2011/066389 and US2013/034559 (MedImmune, astraZeneca). Dewaruzumab comprises heavy and light chain sequences, wherein:

(a) The heavy chain comprises the following amino acid sequence:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 17), and

(b) The light chain comprises the following amino acid sequence:

EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:18)。

in some embodiments, the anti-PDL 1 antibody comprises six HVR sequences from SEQ ID NO:17 and SEQ ID NO:18 (e.g., three heavy chain HVRs from SEQ ID NO:17 and three light chain HVRs from SEQ ID NO: 18). In some embodiments, the anti-PDL 1 antibody comprises a heavy chain variable domain from SEQ ID NO 17 and a light chain variable domain from SEQ ID NO 18.

In some embodiments, the anti-PDL 1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PDL 1 antibody described in WO 2007/005874.

In some embodiments, the anti-PDL 1 antibody is LY3300054 (Eli Lilly).

In some embodiments, the anti-PDL 1 antibody is STI-a1014 (sorento). STI-A1014 is a human anti-PDL 1 antibody.

In some embodiments, the anti-PDL 1 antibody is KN035 (Suzhou Alphamab). KN035 is a single domain antibody (dAB) generated from a camelid phage display library.

In some embodiments, the anti-PDL 1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates the antibody antigen-binding domain (e.g., by removing the non-binding steric moiety) to cause it to bind its antigen. In some embodiments, the anti-PDL 1 antibody is CX-072 (cytomX Therapeutics).

In some embodiments, the PDL1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and/or a heavy chain variable domain and a light chain variable domain from a PDL1 antibody described in: US20160108123 (assigned to Novartis), WO2016/000619 (applicant: beigene), WO2012/145493 (applicant: amplimmune), US9205148 (assigned to MedImmune), WO2013/181634 (applicant: sorreno) and WO2016/061142 (applicant: novartis).

In yet another specific aspect, the PD-1 or PDL1 antibody has reduced or minimal effector function. In yet another specific aspect, the minimal effector function is from a "null effector Fc mutation" or aglycosylation mutation. In another embodiment, the null effector Fc mutation is an N297A or D265A/N297A substitution in the constant region. In some embodiments, the isolated anti-PDL 1 antibody is deglycosylated. Glycosylation of antibodies is usually N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline, are recognition sequences for enzymatic attachment of a carbohydrate moiety to the asparagine side chain. Thus, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. The glycosylation sites can be conveniently removed from the antibody by altering the amino acid sequence to remove one of the above-mentioned tripeptide sequences (for N-linked glycosylation sites). Changes can be made by substituting an asparagine, serine, or threonine residue within a glycosylation site for another amino acid residue (e.g., glycine, alanine, or a conservative substitution).

Other PD-1 antagonists

In some embodiments, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PDL1 or PDL2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence)). In some embodiments, the PD-1 binding antagonist is AMP-224.AMP-224 (CAS registry number 1422184-00-6), also known as B7-DCIg, is a PDL2-Fc fusion soluble receptor described in WO2010/027827 and WO 2011/066342.

In some embodiments, the PD-1 binding antagonist is a peptide or small molecule compound. In some embodiments, the PD-1 binding antagonist is AUNP-12 (Pierre Fabre/Aurigene). See, e.g., WO2012/168944, WO2015/036927, WO2015/044900, WO2015/033303, WO2013/144704, WO2013/132317, and WO2011/161699.

In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PD-1. In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL 1. In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits both PDL1 and VISTA. In some embodiments, the PDL1 binding antagonist is CA-170 (also known as AUPM-170). In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits both PDL1 and TIM 3. In some embodiments, the small molecule is a compound described in WO2015/033301 and WO 2015/033299.

As used herein, "combination" refers to any mixture or permutation of one or more compounds of the present disclosure (or embodiments or aspects thereof) with one or more other compounds of the present disclosure or one or more other therapeutic agents. Unless the context clearly indicates otherwise, "combination" may include simultaneous or sequential delivery of a compound of the invention and one or more therapeutic agents. Unless the context clearly indicates otherwise, "combination" may include dosage forms of the compounds of the present disclosure with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" may include the route of administration of a compound of the disclosure with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" may include formulation of a compound of the disclosure with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

Preparation of the Compounds

The following synthetic reaction schemes detailed in the general schemes and examples illustrate only some of the methods that can be used to synthesize the disclosed compounds (or embodiments or aspects thereof). Various modifications to these synthetic reaction schemes are possible and will be suggested to those skilled in the art in view of the disclosure contained herein.

The starting materials and Reagents for preparing these compounds are generally available from commercial suppliers such as Aldrich Chemical Co, or are prepared by methods known to those skilled in the art according to the methods described in the references, such as Fieser and Fieser's Reagents for Organic Synthesis; wiley & Sons, new York,1991, vol.1-15; rodd's chemistry of Carbon Compounds, elsevier Science Publishers,1989, vol.1-5 and suppl.A; and Organic Reactions, wiley & Sons: new York,1991, volumes 1-40.

If desired, starting materials and intermediates of the synthetic reaction schemes can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless stated to the contrary, the reactions described herein are preferably carried out under an inert atmosphere at atmospheric pressure at a temperature in the range of from about-78 ℃ to about 150 ℃, more preferably at a temperature in the range of from about 0 ℃ to about 125 ℃.

Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure (or embodiments or aspects thereof) may be prepared according to the methods generally described herein and/or by methods available to those of ordinary skill in the art using appropriate starting materials.

The intermediates and the final compounds are purified by flash chromatography and/or by reverse-phase preparative HPLC (high performance liquid chromatography) and/or by supercritical fluid chromatography and/or by preparative thin layer chromatography (preparative TLC).

Mass Spectrometry (MS) was performed using: (1) Sciex 15 mass spectrometer, ES + mode; or (2) shimadzu liquid chromatograph-mass spectrometry (LCMS) model 2020 mass spectrometer, ESI + mode. Unless otherwise indicated, mass spectral data is typically only indicative of parent ions. If indicated, MS or HRMS data for the specific intermediate or compound is provided.

Nuclear magnetic resonance spectroscopy (NMR) was performed using the following: (1) a Bruker AV III 300 NMR spectrometer, (2) a Bruker AV III 400 NMR spectrometer, or (3) a Bruker AV III 500 NMR spectrometer, and the internal standard is tetramethylsilane. If indicated, provides NMR data for the particular intermediate or compound.

All reactions involving air sensitive reagents were carried out under an inert atmosphere. Reagents were purchased as received from commercial suppliers unless otherwise indicated.

The following general scheme is used to prepare the disclosed compounds, intermediates and pharmaceutically acceptable salts thereof. The disclosed compounds and intermediates can be prepared using standard organic synthesis techniques and from commercially available starting materials and reagents. It will be appreciated that the synthetic procedures used to prepare the disclosed compounds and intermediates will depend on the specific substituents present in the compounds or intermediates, and may require various protection, deprotection, and conversion steps standard in organic synthesis, but may not be illustrated in the general schemes. It is also understood that any of the steps shown in the following general schemes may be omitted or used in any combination and in any order that is chemically feasible to obtain the desired intermediates or disclosed compounds. In addition, it is to be understood that methods are included and described herein, and that a basis is found for both the general schemes and the specific examples, as if each method were specifically and individually listed for each general scheme and example.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Schemes 1, 2, 3 and 4 describe general synthetic routes for the synthesis of compounds of any of the formulae described herein. [ A ]]、L ¹ 、L ² 、L ³ 、R ² 、R ^3b 、X ¹ 、X ² And X ³ As defined above. Each LG is independently any suitable leaving group, including, for example, OTs (O-SO) ₂ C ₆ H ₄ CH ₃ ). Each PG is independently any suitable protecting group, including, for example, boc (C (O) O- ^t Bu) or Cbz (C (O) OCH) ₂ C ₆ H ₄ ). In scheme 3, R' is any suitable moiety, including, for example, C _1-12 An alkyl group. [ B ]]Is [ B ] as defined above]The remainder of the fractions, not described in scheme 1, 2, 3 or 4, as the case may be. In some embodiments, [ B ] is]Is thatWhereinIs shown andthe connection points of the sections. L is ² * Is L as defined above ² Part of the section, not described in scheme 1, 2, 3 or 4, as the case may be.

Example 1

Preparation of N- (3- (2- ((4- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) butyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide (Compound 1)

The general reaction scheme is as follows:

step 1: 4-Methylbenzenesulfonic acid 4-hydroxybutyl ester

To a solution of butane-1,4-diol (2.0g, 22.19mmol) in DCM (20 mL) at 0 deg.C were added KI (921mg, 5.55mmol) and Ag ₂ O (6.17g, 26.63mmol). Then, a solution of TsCl (5.08g, 26.63mmol) in DCM (20 mL) was added dropwise at 0 ℃. The resulting mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (0-2% MeOH in DCM)The residue was digested to give the title compound (2.3g, 42%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ ):δ7.80(d,J＝8.4Hz,2H),7.36(d,J＝8.0Hz,2H),4.08(t,J＝6.4Hz,2H),3.63(t,J＝6.4Hz,2H),2.46(s,3H),1.78-1.73(m,2H),1.64-1.57(m,2H)。

Step 2:4- (methylamino) butan-1-ol

Adding 33% MeNH to a solution of 4-hydroxybutyl 4-methylbenzenesulfonate (2.1g, 8.6 mmol) in EtOH (5 mL) at room temperature ₂ (in EtOH (5mL, 102.54mmol)). The resulting mixture was stirred at 60 ℃ for 16 hours. Then, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (0-5% meoh in DCM) to give the title compound (886 mg, quantitative) as a colorless oil. ¹ H NMR(400MHz,CD ₃ OD)：δ3.59(t,J＝6.0Hz,2H),3.03-2.98(m,2H),2.69(s,3H),1.77-1.71(m,2H),1.63-1.58(m,2H)。

And step 3: (4-hydroxybutyl) (methyl) carbamic acid tert-butyl ester

At room temperature to Et ₃ Boc was added to a mixture of N (3.23mL, 23.26mmol) and 4- (methylamino) butan-1-ol (800mg, 7.75mmol) in DCM (7.5 mL) ₂ O (2.54g, 11.63mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (0-5% meoh in DCM) to give the title compound (260mg, 16%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ ):δ3.69-3.66(m,2H),3.25(br s,2H),2.81(s,3H),1.56-1.53(m,4H),1.45(s,9H)。

And 4, step 4:4- [ tert-Butoxycarbonyl (methyl) amino ] butyl 4-methylbenzenesulfonate

To a solution of tert-butyl (4-hydroxybutyl) (methyl) carbamate (180mg, 0.89mmol) in DCM (1 mL) at 0 deg.C was added Et ₃ N (0.37mL, 2.66mmol). A solution of TsCl (338mg, 1.77mmol) in DCM (5 mL) was then added dropwise at 0 ℃. The resulting mixture was stirred at room temperature for 16 hours, then concentrated. The residue was purified by silica gel column chromatography (50% etoac in petroleum ether) to give the title compound (200mg, 63%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.80(d,J＝8.4Hz,2H),7.36(d,J＝8.0Hz,2H),4.05(t,J＝6.0Hz,2H),3.18(t,J＝6.4Hz,2H),2.80(s,3H),2.46(s,3H),1.65-1.61(m,2H),1.57-1.50(m,2H),1.44(s,9H)。

And 5: (4- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) butyl) (methyl) carbamic acid tert-butyl ester

KI (19.5mg, 0.12mmol), 2- (2,6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1,3-dione (161mg, 0.59mmol) and Na at room temperature ₂ CO ₃ (125mg, 1.17mmol) to a mixture of 4-methylbenzenesulfonic acid 4- [ tert-butoxycarbonyl (methyl) amino ] in DMF (5 mL) was added]Butyl ester (210mg, 0.59mmol). The resulting mixture was stirred at 80 ℃ for 16 hours. The reaction mixture was then cooled to room temperature, diluted with EtOAc (30 mL), and washed with brine (15 mL × 2). The organic layer is coated with Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (0-50% etoac in petroleum ether) to give the title compound (180mg, 67%) as a yellow oil. LCMS (ESI): m/z 482.1 (M + Na) ⁺ 。

Step 6:2- (2,6-dioxopiperidin-3 yl) -5- (4- (methylamino) butoxy) isoindoline-1,3-dione hydrochloride

To a solution of tert-butyl (4- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) butyl) (methyl) carbamate (180mg, 0.39mmol) in 1,4-dioxane (1 mL) at room temperature was added 4M HCl in 1,4-dioxane (6 mL, 24mmol). The resulting mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated to obtain the title compound (120mg, 77%) as a yellow oil. LCMS (ESI): m/z 360.1 (M + H) ⁺ 。

And 7: n- (3- (2- ((4- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) butyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

To a mixture of 2- (3- ((5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) pyridylamido) methyl) phenyl) acetic acid (50mg, 0.10 mmol) in DMF (2 mL) at room temperature were added DIPEA (68mg, 0.52mmol) and HATU (100mg, 0.26mmol). The resulting mixture was stirred at room temperature for 10 minutes. Then, 2- (2,6-dioxopiperidin-3-yl) -5- (4- (methylamino) butoxy) isoindoline-1,3-dione hydrochloride (45.7 mg, 0.12mmol) was added at room temperature. The reaction mixture was stirred at room temperature for an additional 2 hours. After that, the reaction mixture was concentrated. Using preparative HPLC (YMC Triart C18X 25mM X5 um, water (10 mM NH) ₄ HCO ₃ ) -ACN; 67-97%) to give the title compound (24.1mg, 26%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )：δ8.76(s,1H),8.30(s,1H),8.03(s,1H),7.79(d,J＝8.0Hz,1H),7.35(s,1H),7.30(d,J＝8.0Hz,1H),7.25-7.21(m,1H),7.19-7.17(m,2H),7.10(d,J＝7.2Hz,1H),6.61(d,J＝16.0Hz,2H),6.53(dd,J＝16.0,6.4Hz,1H),5.09-5.04(m,1H),4.48(d,J＝6.0Hz,2H),4.14(s,2H),3.98(s,3H),3.66(s,2H),3.36(t,J＝6.4Hz,2H),3.34-3.14(m,3H),2.96-2.83(m,2H),2.64-2.57(m,2H),2.22-2.19(m,1H),2.08-2.04(m,1H),1.95-1.88(m,4H),1.70-1.59(m,4H),1.37-1.26(m,4H)。LCMS(ESI)：m/z 818.4(M+H) ⁺ 。

Example 2

Preparation of N- (3- (2- ((6- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) hexyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: 4-Methylbenzenesulfonic acid 6-hydroxyhexyl ester

To a solution of hexane-1,6-diol (10.0g, 8.46mmol) in DCM (20 mL) at room temperature was added Et ₃ N (1.76mL, 12.69mmol). A solution of TsCl (1.77g, 9.31mmol) in DCM (5 mL) was then added dropwise at 0 deg.C. The resulting mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL. Times.3). The combined organic layers were washed with brine (30 mL. Times.2) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by silica gel column chromatography (25% etoac in petroleum ether) to give the title compound (800mg, 35%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ ):δ7.78(d,J＝8.4Hz,2H),7.34(d,J＝8.0Hz,2H),4.02(t,J＝6.4Hz,2H),3.60(t,J＝6.4Hz,2H),2.45(s,3H),1.65-1.62(m,2H),1.55-1.49(m,3H),1.35-1.30(m,3H)。

Step 2:6- (methylamino) hexan-1-ol

The title compound (385 mg, quantitative) was provided as a colorless oil. Prepared from 6-hydroxyhexyl 4-methylbenzenesulfonate (800mg, 2.94mmol) following the procedure outlined for example 1, step 2.

And step 3: (6-hydroxyhexyl) (methyl) carbamic acid tert-butyl ester

The title compound (400mg, 59%) was provided as a colorless oil. Prepared from 6- (methylamino) hexan-1-ol (385mg, 2.94mmol) following the procedure outlined for example 1, step 3. ¹ H NMR(400MHz,CDCl ₃ ):δ3.64(t,J＝6.4Hz,2H),3.21(m,2H),2.83(s,3H),1.63-1.50(m,6H),1.46(s,9H),1.42-1.36(m,2H)。

And 4, step 4: 4-Methylbenzenesulfonic acid 6- ((tert-butoxycarbonyl) (methyl) amino) hexyl ester

The title compound (350mg, 52%) was provided as a colorless oil. Prepared from tert-butyl (6-hydroxyhexyl) (methyl) carbamate (400mg, 1.73mmol) following the procedure outlined for example 1, step 4. ¹ H NMR(400MHz,CDCl ₃ ):δ7.79(d,J＝8.4Hz,2H),7.35(d,J＝8.0Hz,2H),4.02(t,J＝6.4Hz,2H),3.16(t,J＝7.2Hz,2H),2.81(s,3H),2.46(s,3H),1.69-1.59(m,4H),1.45(s,9H),1.39-1.30(m,2H),1.28-1.19(m,2H)。

And 5: (6- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) hexyl) (methyl) carbamic acid tert-butyl ester

The title compound (340mg, 77%) was provided as a yellow oil. It was prepared from 4-methylbenzenesulfonic acid 6- [ tert-butoxycarbonyl (methyl) amino group according to the procedure outlined for example 1, step 5]Hexyl ester (350mg, 0.91mmol) was prepared. LCMS (ESI): m/z 432.1(M+H-56) ⁺ 。

Step 6:2- (2,6-dioxopiperidin-3-yl) -5- ((6- (methylamino) hexyl) oxy) isoindoline-1,3-dione hydrochloride

The title compound (174 mg, quantitative) was provided as a yellow oil. Prepared from tert-butyl (6- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) hexyl) (methyl) carbamate (200mg, 0.41mmol) following the procedure outlined for example 1, step 6. LCMS (ESI): m/z 388.1 (M + H) ⁺ 。

And 7: n- (3- (2- ((6- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) hexyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (23.7mg, 26%) was provided as a white solid. Prepared from 2- (2,6-dioxopiperidin-3-yl) -5- ((6- (methylamino) hexyl) oxy) isoindoline-1,3-dione hydrochloride (49mg, 0.12mmol) following the procedure outlined for example 1, step 7. It was purified by preparative HPLC (Welch Xtimate C18 150X 30mm X5 um, water (0.225% FA) -CAN, 55-85%). ¹ H NMR(400MHz,DMSO-d ₆ ): δ 11.13 (s, 1H), 9.10 (t, J =6.4hz, 1h), 8.33 (d, J =3.2hz, 1h), 8.05 (d, J =2.4hz, 1h), 7.82 (d, J =8.4hz, 1h), 7.40-7.39 (m, 1H), 7.34-7.30 (m, 1H), 7.26-7.20 (m, 1H), 7.15 (d, J =9.6hz, 2h), 7.08 (t, J =6.8hz, 1h), 6.61-6.55 (m, 2H), 5.13-5.09 (m, 1H), 4.45 (d, J =6.0hz, 2h), 4.16-4.06 (m, 2H), 3.98 (d, J =3.6hz, 3h), 3.64 (d, J =3.2hz, 2h), 3.25-3.24 (m, 1H), 2.95,2.77 (s, 3H altogether), 2.94-2.92 (m, 1H), 2.68-2.55 (m, 3H), 2.22-2.20 (m, 2H), 2.09-2.00 (m, 1H), 1.91-1.88 (m, 4H), 1.71-1.64 (m, 2H), 1.43-1.18 (m, 10H). LCMS (ESI): m/z 846.4 (M + H) ⁺ 。

Example 3

Preparation of N- (3- (14- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12-trioxa-3-azatetradecyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: 4-Methylbenzenesulfonic acid 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl ester

The title compound (2.1g, 23%) was provided as a colorless oil. Prepared from 2,2' - ((methyl ether (ethane-2,1-diyl)) bis (oxy)) diethanol (5.0 g, 25.74mmol) following the procedure outlined for example 2, step 1. ¹ H NMR(400MHz,CDCl ₃ ):δ7.78(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),4.16-4.11(m,2H),3.69-3.58(m,14H),2.43(s,3H)。

And 2, step: 5,8,11 Trioxa-2-azatridecan-13-ol

The title compound (2.97g, 99%) was provided as a colorless oil. Prepared according to the procedure outlined for example 1, step 2, from 4-methylbenzenesulfonic acid 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl ester (5.0 g, 14.35mmol).

And 3, step 3: (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) (methyl) carbamic acid tert-butyl ester

The title compound (2.1g, 48%) was provided as a colorless oil. Prepared from 5,8,11-trioxa-2-azatridecan-13-ol (2.95g, 14.22mmol) following the procedure outlined for example 1, step 3. ¹ H NMR(400MHz,CDCl ₃ ):δ3.68-3.67(m,2H),3.62-3.55(m,12H),3.34(br,2H),2.86(s,3H),2.67(br,1H),1.40(s,9H)。

And 4, step 4: 4-Methylbenzenesulfonic acid 2,2,5-trimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecyl-16-ester

The title compound (2.0 g, 63%) was provided as a colorless oil. Prepared from tert-butyl (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) (methyl) carbamate (2.1g, 6.83mmol) following the procedure outlined for example 1, step 4. ¹ H NMR(400MHz,CDCl ₃ ):δ7.79(d,J＝8.4Hz,2H),7.33(d,J＝8.0Hz,2H),4.16-4.12(m,2H),3.69-3.66(m,2H),3.58-3.57(m,10H),3.37(br,2H),2.89(s,3H),2.44(s,3H),1.44(s,9H)。

And 5: (2- (2- (2- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) ethyl) (methyl) carbamic acid tert-butyl ester

The title compound (100mg, 41%) was provided as a colorless oil. Prepared from 4-methylbenzenesulfonic acid 2,2,5-trimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecyl-16-ester (200mg, 0.43mmol) following the procedure outlined for example 1, step 5. LCMS (ESI): m/z586.1 (M + Na) ⁺ 。

And 6:5- (5,8,11-trioxa-2-azatridecan-13-yloxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione hydrochloride

The title compound (75mg, 99.5%) was provided as a white solid. Prepared from tert-butyl (2- (2- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) ethyl) (methyl) carbamate (85mg, 0.15mmol) following the procedure outlined for example 1, step 6. LCMS (ESI): m/z 464.5 (M + H) ⁺ 。

And 7: n- (3- (14- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12-trioxa-3-azatetradecyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (17mg, 17%) was provided as a white solid. Prepared from 5- (5,8,11-trioxa-2-azatridecan-13-yloxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione hydrochloride (57.7 mg, 0.12mmol) following the procedure outlined for example 1, step 7. It was purified by preparative HPLC (Xtimate C18X 40mm X10 um, water (0.225% FA) -ACN, 60-90%). ¹ H NMR(400MHz,CD ₃ OD): δ 8.26 (s, 1H), 8.11 (d, J =2.8hz, 1h), 7.75-7.71 (m, 1H), 7.34 (dd, J =2.0,12.4hz, 1h), 7.29-7.23 (m, 4H), 7.13-7.12 (m, 1H), 6.68 (d, J =16.4hz, 1h), 6.53 (dd, J =16.4,6.8hz, 1h), 5.10-5.09 (m, 1H), 4.57 (d, J =3.2hz, 2h), 4.22-4.20 (m, 2H), 4.00 (s, 3H), 3.87-3.77 (m, 3H), 3.72 (s, 1H), 3.69-3.48 (m, 12H), 8978 zzzx (893H), 3.78 (m, 3H), 1.78-5.78 (m, 1H), 2H), 4.78-4.78 (m, 3H), 1H), 2.78, 4.78H, 4.80-4.10-5.09 (m, 1H). LCMS (ESI): m/z 922.5 (M + H) ⁺ 。

Example 4

Preparation of N- (3- (17- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: 4-Methylbenzenesulfonic acid 14-hydroxy-3,6,9,12-tetraoxatetradecyl ester

The title compound (6.1g, 46%) was provided as a colorless oil. Prepared according to the procedure outlined for example 2, step 1, from 3,6,9,12-tetraoxatetradecane-1,14-diol (8.0g, 33.57mmol). ¹ H NMR(400MHz,CDCl ₃ ):δ7.80(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),4.16(t,J＝4.8Hz,,2H),3.72-3.58(m,18H),2.45(s,3H)。

Step 2:5,8,11,14 tetraoxa-2-azahexadecyl-16-ols

The title compound (3.9 g, quantitative) was provided as a colorless oil. Prepared according to the procedure outlined for example 1, step 2, from 4-methylbenzenesulfonic acid 14-hydroxy-3,6,9,12-tetraoxatetradecyl ester (6.1g, 15.54mmol). ¹ H NMR(400MHz,CDCl ₃ ):δ3.78-3.73(m,4H),3.65-3.60(m,12H),3.58-3.55(m,4H),3.27-3.25(m,2H),2.76(s,3H)。

And 3, step 3: (14-hydroxy-3,6,9,12-tetraoxatetradecyl) (methyl) carbamic acid tert-butyl ester

The title compound (2.1g, 39%) was provided as a colorless oil. It was prepared according to the procedure outlined for example 1, step 3, from 5,8,11,14-tetraoxa-2-azadecaHexaalkyl-16-ol (3.9g, 15.52mmol) was prepared. ¹ H NMR(400MHz,CDCl ₃ ):δ3.69-3.64(m,2H),3.62-3.46(m,16H),3.33(br,2H),2.84(s,3H),1.39(s,9H)。

And 4, step 4: 4-Methylbenzenesulfonic acid 2,2,5-trimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecane-19-ester

The title compound (2.0 g, 70%) was provided as a colorless oil. Prepared from tert-butyl (14-hydroxy-3,6,9,12-tetraoxatetradecyl) (methyl) carbamate (2.0 g, 5.69mmol) following the procedure outlined for example 1, step 4. LCMS (ESI): m/z 528.1 (M + Na) ⁺ 。

And 5: (14- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3,6,9,12-tetraoxatetradecyl) (methyl) carbamic acid tert-butyl ester

The title compound (120mg, 46%) was provided as a colorless oil. Prepared from 4-methylbenzenesulfonic acid 2,2,5-trimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecane-19-ester (200mg, 0.43mmol) following the procedure outlined for example 1, step 5. LCMS (ESI): m/z630.3 (M + Na) ⁺ 。

Step 6:5- (5,8,11,14-tetraoxa-2-azahexadecyl-16-yloxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione hydrochloride

The title compound (89mg, 99%) was provided as a white solid. It was prepared from (14- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3,6,9,12-tetraoxatetradecane following the procedure outlined for example 1, step 6Tert-butyl yl) (methyl) carbamate (100mg, 0.16mmol) was prepared. LCMS (ESI): m/z 508.2 (M + H) ⁺ 。

And 7: n- (3- (17- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12,15-tetraoxa-3-azedaryl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (28mg, 20%) was provided as a white solid. Prepared from 5- (5,8,11,14-tetraoxa-2-azahexadecyl-16-yloxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione hydrochloride (88mg, 0.16mmol) following the procedure outlined for example 1, step 7. It was purified by preparative HPLC (Xtimate C18X 40mm X10 um, water (0.225% FA) -ACN, 60-90%). ¹ H NMR(400MHz,CD ₃ OD): δ 8.26 (s, 1H), 8.11 (s, 1H), 7.75 (dd, J =2.8,8.4hz, 1H), 7.37-7.35 (m, 1H), 7.29-7.24 (m, 4H), 7.14 (m, 1H), 6.68 (d, J =16.4hz, 1H), 6.53 (dd, J =16.4,6.8hz, 1H), 5.11-5.06 (m, 1H), 4.58 (s, 3H), 4.26-4.24 (m, 2H), 4.00 (s, 3H), 3.87-3.79 (m, 3H), 3.74 (s, 1H), 3.69-3.47 (m, 15H), 3.06-2.92 (s, 3H total), 2.87-2.79 (m, 1H), 2.91-2.65 (m, 1H), 2.91-5.08 (m, 1H), 1.23.5.5-5.8 (m, 1H). LCMS (ESI): m/z 966.5 (M + H) ⁺ 。

Example 5

Preparation of N- (3- (2- ((2- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) hexyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: 4-Methylbenzenesulfonic acid 2- (2-hydroxyethoxy) ethyl ester

The title compound (7.5g, 61%) was provided as a colorless oil. Prepared according to the procedure outlined for example 1, step 1, from 2,2' -oxydiethanol (5.0g, 47.12mmol). LCMS (ESI): m/z 261.1 (M + H) ⁺ 。

Step 2:2- [2- (methylamino) ethoxy ] ethanol

The title compound (63.2g, 93%) was provided as a colorless oil. Prepared according to the procedure outlined for example 1, step 2, from 2- (2-hydroxyethoxy) ethyl 4-methylbenzenesulfonate (7.5g, 28.81mmol). ¹ H NMR(400MHz,CDCl ₃ ):δ3.78-3.73(m,2H),3.69-3.67(m,2H),3.58-3.57(m,2H),3.18-3.12(m,2H),2.72(s,3H)。

And step 3: (2- (2-Hydroxyethoxy) ethyl) (methyl) carbamic acid tert-butyl ester

The title compound (800mg, 15%) was provided as a yellow oil. Prepared from 2- [2- (methylamino) ethoxy ] ethanol following the procedure outlined for example 1, step 3]Ethanol (3.0 g, 25.18mmol) was prepared. ¹ H NMR(400MHz,CDCl ₃ ):δ3.71-3.70(m,2H),3.58-3.57(m,4H),3.41-3.40(m,2H),2.90(s,3H),1.45(s,9H)。

And 4, step 4: 4-Methylbenzenesulfonic acid 2- (2- ((tert-butoxycarbonyl) (methyl) amino) ethoxy) ethyl ester

The title compound (353mg, 69%) was provided as a colorless oil. It is composed ofPrepared from tert-butyl (2- (2-hydroxyethoxy) ethyl) (methyl) carbamate (300mg, 1.37mmol) following the procedure outlined for example 1, step 4. ¹ H NMR(400MHz,CDCl ₃ ):δ7.78(d,J＝8.4Hz,2H),7.43(d,J＝8.4Hz,2H),4.14-4.10(m,2H),3.65-3.57(m,2H),3.49-3.48(m,2H),3.33-3.29(m,3H),2.83-2.82(m,2H),2.44(s,3H),1.43(s,9H)。LCMS(ESI)：m/z 274.4(M-100+H) ⁺ 。

And 5: (2- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) ethyl) (methyl) carbamic acid tert-butyl ester

The title compound (65mg, 34%) was provided as a yellow oil. Prepared from 2- (2- ((tert-butoxycarbonyl) (methyl) amino) ethoxy) ethyl 4-methylbenzenesulfonate (150mg, 0.40mmol) following the procedure outlined for example 1, step 5. LCMS (ESI): m/z 498.2 (M + Na) ⁺ 。

Step 6:2- (2,6-dioxopiperidin-3-yl) -5- (2- (2- (methylamino) ethoxy) isoindoline-1,3-dione hydrochloride

The title compound (51mg, 91%) was provided as a white oil. Prepared from tert-butyl (2- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) hexyl) (methyl) carbamate (65mg, 0.14mmol) following the procedure outlined for example 1, step 6. LCMS (ESI): m/z 376.1 (M + H) ⁺ 。

And 7: n- (3- (2- ((2- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) hexyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (26mg, 18%) was provided as a white solid. Prepared from 2- (2,6-dioxopiperidin-3-yl) -5- (2- (2- (methylamino) ethoxy) isoindoline-1,3-dione hydrochloride (65mg, 0.17mmol) following the procedure outlined for example 1, step 7. It was purified by preparative HPLC (Xtimate C18X 40mm X10 um, water (0.225% FA) -ACN, 60-80%). ¹ H NMR(400MHz,DMSO-d ₆ ) δ 11.12 (s, 1H), 9.08 to 9.06 (m, 1H), 8.31 (d, J =4.4hz, 1h), 8.03 (d, J =4.4hz, 1h), 7.83 to 7.78 (m, 1H), 7.41 (d, J =2.0hz, 1h), 7.34 to 7.31 (m, 1H), 7.30 to 7.10 (m, 4H), 6.59 to 6.54 (m, 2H), 5.11 to 5.10 (m, 1H), 4.45 to 4.41 (m, 2H), 4.26-4.25 (m, 2H), 3.98 (d, J =3.2hz, 3h), 3.78-3.51 (m, 6H), 2.98,2.81 (s, 3H altogether), 2.85-2.81 (m, 1H), 2.62-2.55 (m, 4H), 2.19-2.18 (m, 2H), 2.02-2.00 (m, 1H), 1.94-1.81 (m, 4H), 1.38-1.22 (m, 4H). LCMS (ESI): m/z 834.5 (M + H) ⁺ 。

Example 6

Preparation of N- (3- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) hexyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: 4-Methylbenzenesulfonic acid 2- (2- (2-hydroxyethoxy) ethoxy) ethyl ester

The title compound (15g, 37%) was provided as a colorless oil. Prepared according to the procedure outlined for example 2, step 1, from 2,2' - (ethane-1,2-diylbis (oxy)) diethanol (20.0 g, 133.18mmol). LCMS (ESI): m/z 304.9 (M + H) ⁺ 。

Step 2:2- (2- (2- (methylamino) ethoxy) ethanol

The title compound (4.5g, 84%) was provided as a colorless oil. Prepared according to the procedure outlined for example 1, step 2, from 4-methylbenzenesulfonic acid 2- (2- (2-hydroxyethoxy) ethoxy) ethyl ester (10g, 32.86mmol). LCMS (ESI): m/z 163.9 (M + H) ⁺ 。

And step 3: (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) (methyl) carbamic acid tert-butyl ester

The title compound (3.6g, 64%) was provided as a colorless oil. Prepared from 2- [2- [2- (methylamino) ethoxy ] ethanol following the procedure outlined for example 1, step 3]Ethoxy radical]Ethanol (3.5g, 21.44mmol) was prepared. ¹ H NMR(400MHz,CDCl ₃ ):δ3.75-3.71(m,2H),3.67-3.60(m,8H),3.40(br s,2H),2.91(s,3H),1.45(s,9H)。

And 4, step 4: 4-Methylbenzenesulfonic acid 2,2,5-trimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-ester

The title compound (4.15g, 73%) was provided as a colorless oil. Prepared from tert-butyl (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) (methyl) carbamate (3.60g, 13.67mmol) following the procedure outlined for example 1, step 4. LCMS (ESI): m/z 440.1 (M + Na) ⁺ 。

And 5: (2- (2- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) ethyl) (methyl) carbamic acid tert-butyl ester

The title compound (139mg, 37%) was provided as a yellow oil. Prepared from 4-methylbenzenesulfonic acid 2,2,5-trimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-ester (300mg, 0.72mmol) following the procedure outlined for example 1, step 5. LCMS (ESI): m/z 542.1 (M + Na) ⁺ 。

Step 6:2- (2,6-dioxopiperidin-3-yl) -5- (2- (2- (methylamino) ethoxy) isoindoline 1,3-dione hydrochloride

The title compound (78.9 mg, quantitative) was provided as a white oil. Prepared from tert-butyl (2- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) hexyl) (methyl) carbamate (90mg, 0.17mmol) following the procedure outlined for example 1, step 6. LCMS (ESI): m/z 420.2 (M + H) ⁺ 。

And 7: n- (3- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) ethoxy) hexyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (21.4 mg, 43%) was provided as a white solid. Prepared from 2- (2,6-dioxopiperidin-3-yl) -5- (2- (2- (methylamino) ethoxy) isoindoline-1,3-dione hydrochloride (90mg, 0.17mmol) following the procedure outlined for example 1, step 7. It was purified by preparative TLC (10% meoh in DCM). ¹ H NMR(400MHz,DMSO-d ₆ )：δ11.09(s,1H),9.03(d,J＝6.0Hz,1H),8.32(s,1H)8.04 (s, 1H), 7.80 (t, J =8.4Hz, 1H), 7.41 (d, J =9.6Hz, 1H), 7.36-7.28 (m, 1H), 7.26-7.18 (m, 1H), 7.17-7.11 (m, 2H), 7.05 (t, J =8.4Hz, 1H), 6.63-6.53 (m, 2H), 5.13-5.10 (m, 1H), 4.45 (d, J =3.2Hz, 2H), 4.27 (d, J =3.6Hz, 2H), 3.99 (s, 3H), 3.76 (s, 2H), 3.68 (s, 1H), 3.64 (s, 1H), 3.59-3.52 (m, 3H), 3.51-3.47 (m, 3H), 2.98,2.86 (s, 3H altogether), 2.64-2.56 (m, 4H), 2.22-2.20 (m, 2H), 2.04-2.02 (m, 1H), 1.93-1.86 (m, 4H), 1.34-1.23 (m, 5H). LCMS (ESI): m/z878.4 (M + H) ⁺ 。

Example 7

Preparation of N- (3- (20- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: 4-Methylbenzenesulfonic acid 17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl ester

The title compound (6.5g, 84%) was provided as a colorless oil. Prepared according to the procedure outlined for example 1, step 1, from 3,6,9,12,15-pentaoxaheptadecane-1,17-diol (5.0g, 17.71mmol). LCMS (ESI): m/z 437.2 (M + H) ⁺ 。

Step 2:5,8,11,14,17-pentaoxa-2-azanonadecane-19-ol

The title compound (4.0 g, 91%) was provided as a colorless oil. Prepared from 4-methylbenzenesulfonic acid 17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl ester (6.5g, 14.89mmol) following the procedure outlined for example 1, step 2And (4) preparing. ¹ H NMR(400MHz,CDCl ₃ ):δ3.83-3.78(m,2H),3.75-3.72(m,2H),3.66-3.61(m,18H),3.59-3.56(m,2H),3.28-3.22(m,2H),2.77(s,3H)。

And step 3: (17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl) (methyl) carbamic acid tert-butyl ester

The title compound (1.9g, 47%) was provided as a yellow oil. Prepared according to the procedure outlined for example 1, step 3, from 5,8,11,14,17-pentaoxa-2-azanonacan-19-ol (3.0 g,10.16 mmol). ¹ H NMR(400MHz,CDCl ₃ ):δ3.74-3.71(m,2H),3.69-3.58(m,20H),3.39(s,2H),2.91(s,3H),1.45(s,9H)。

And 4, step 4: 4-Methylbenzenesulfonic acid 2,2,5-trimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosane-22-ester

The title compound (1.7g, 64%) was provided as a colourless oil. Prepared from tert-butyl (17-hydroxy-3,6,9,12,15-pentaoxaheptadecane) (methyl) carbamate (1.9g, 4.8mmol) following the procedure outlined for example 1, step 4. LCMS (ESI): m/z 450.6 (M-100 + H) ⁺ 。

And 5: (17- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3,6,9,12,15-pentaoxaheptadecane) (methyl) carbamic acid tert-butyl ester

The title compound (260mg, 73%) was provided as a colorless oil. Prepared from 4-methylbenzenesulfonic acid 2,2,5-trimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-ester (300mg, 0.55mmol) following the procedure outlined for example 1, step 5。LCMS(ESI)：m/z 552.2(M-100+H) ⁺ 。

Step 6:5- (5,8,11,14,17-pentaoxa-2-azanonacan-19-yloxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione hydrochloride

The title compound (220mg, 94%) was provided as a yellow solid. Prepared from tert-butyl (17- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3,6,9,12,15-pentaoxaheptadecane) (methyl) carbamate (260mg, 0.40mmol) following the procedure outlined for example 1, step 6. LCMS (ESI): m/z 552.2 (M + H) ⁺ 。

And 7: n- (3- (20- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -3-methyl-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (24mg, 22%) was provided as a white solid. Prepared from 5- (5,8,11,14,17-pentaoxa-2-azanonadecan-19-yloxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione hydrochloride (68mg, 0.12mmol) following the procedure outlined for example 1, step 7. It was purified by preparative HPLC (Boston Green ODS 150X 30mm X5 um; water-ACN, 55-75%). ¹ H NMR(400MHz,DMSO-d ₆ ): δ 11.10 (s, 1H), 9.07 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.78 (d, J =8.4hz, 1h), 7.40 (s, 1H), 7.32 (d, J =8.0hz, 1h), 7.19-7.16 (m, 1H), 7.11 (t, J =7.2hz, 2h), 7.02 (t, J =6.8hz, 1h), 6.58-6.53 (m, 2H), 5.10-5.06 (m, 1H), 4.42 (d, J =6.0hz, 2h), 4.24 (s, 2H), 3.95 (s, 3H), 3.73 (s, 2H), 3.64-3.60 (m, 4H), 3.44-3.41 (m, 16H), 3.37-3.36 (m, 2H), 2.94,2.77 (s, 3H altogether), 2.85-2.82 (m, 1H), 2.57-2.55 (m, 1H), 2.20-2.17 (m, 2H), 2.04-1.99 (m, 1H), 1.86-1.82 (m, 4H), 1.34-1.21 (m,5H)。LCMS(ESI)：m/z 1010.6(M+H) ⁺ 。

example 8

Preparation of N- (3- (2- ((3- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) propyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: (3-hydroxypropyl) (methyl) carbamic acid tert-butyl ester

The title compound (5g, 47%) was provided as a colorless oil. Prepared from 3- (methylamino) propan-1-ol (5g, 56.09mmol) following the procedure outlined for example 1, step 3. ¹ H NMR(400MHz,CDCl ₃ ):δ3.80(br s,1H),3.35(m,2H),3.34(m,2H),2.79(s,3H),1.64(m,2H),1.42(s,9H)。

Step 2: 4-Methylbenzenesulfonic acid 3- ((tert-butoxycarbonyl) (methyl) amino) propyl ester

To a solution of tert-butyl (3-hydroxypropyl) (methyl) carbamate (2g, 10.57mmol) in DCM (7.5 mL) at 0 deg.C were added KI (439mg, 2.64mmol) and Ag ₂ O (3.67g, 15.85mmol). TsCl (2.4 g, 12.68mmol) in DCM (22 mL) was then added dropwise. The resulting reaction mixture was stirred at 40 ℃ for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% meoh in DCM) to give the title compound (630 mg, 17%) as a colorless oil. LCMS (ESI): M/z 244.0 (M-100 + H) ⁺ 。

And 3, step 3: (3- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) propyl) (methyl) carbamic acid tert-butyl ester

The title compound (120mg, 31%) was provided as a colorless oil. Prepared from 3- ((tert-butoxycarbonyl) (methyl) amino) propyl 4-methylbenzenesulfonate (300mg, 0.87mmol) following the procedure outlined for example 1, step 5. ¹ H NMR(400MHz,CDCl ₃ ):δ8.03(s,1H),7.79(d,J＝8.0Hz,1H),7.34(d,J＝2.4Hz,1H),7.20(dd,J＝2.0,8.4Hz,1H),4.97(dd,J＝5.2,12.4Hz,1H),4.11(t,J＝6.0Hz,2H),3.44(t,J＝6.8Hz,2H),2.89(s,3H),2.86-2.79(m,2H),2.20-2.02(m,4H),1.44(s,9H)。

And 4, step 4:2- (2,6-dioxopiperidin-3-yl) -5- (3- (methylamino) propoxy) isoindoline 1,3-dione hydrochloride

The title compound (85mg, 83%) was provided as a yellow oil. Prepared from tert-butyl (3- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) propyl) (methyl) carbamate (120mg, 0.270mmol) following the procedure outlined for example 1, step 6. LCMS (ESI): m/z 346.1 (M + H) ⁺ 。

And 5: n- (3- (2- ((3- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) propyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (29.1mg, 14%) was provided as a yellow solid. It was prepared according to the procedure outlined for example 1, step 7, from 2- (2,6-bisOxopiperidin-3-yl) -5- (3- (methylamino) propoxy) isoindoline-1,3-dione hydrochloride (85mg, 0.22mmol) was prepared. Purification was performed by silica gel column chromatography (100% etoac). ¹ H NMR(400MHz,DMSO-d ₆ ): δ 11.11 (s, 1H), 9.07-9.06 (m, 1H), 8.31 (d, J =6.0Hz, 1H), 8.03 (d, J =7.2Hz, 1H), 7.82-7.80 (m, 1H), 7.41-7.33 (m, 1H), 7.32-7.26 (m, 1H), 7.24-7.18 (m, 1H), 7.16-7.12 (m, 2H), 7.06-7.05 (m, 1H), 6.59-6.54 (m, 2H), 5.12 (dd, J =13.2,5.2Hz, 1H), 4.46-4.41 (m, 2H), 4.14-4.05 (m, 2H), 3.98 (s, 3H), 3.65 (s, 2H), 3.53-3.47 (m, 1H), 3.45-3.39 (m, 2H), 2.96,2.81 (s, 3H altogether), 2.62-2.60 (m, 1H), 2.20-2.18 (s, 2H), 2.08-1.97 (m, 2H), 1.92-1.89 (m, 6H), 1.25-1.23 (m, 4H). LCMS (ESI): m/z 804.2 (M + H) ⁺ 。

Example 9

Preparation of N- (3- (2- ((7- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) heptyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: 4-Methylbenzenesulfonic acid 7-hydroxyheptyl ester

The title compound (6.2g, 57%) was provided as a colorless oil. Prepared from heptane-1,7-diol (5.0 g, 37.82mmol) following the procedure outlined for example 1, step 1. LCMS (ESI): m/z 308.9 (M + Na) ⁺ 。

Step 2:7- (methylamino) hept-1-ol

The title compound (3.1g, 99%) was provided as a colorless oil. It pressesPrepared from 4-methylbenzenesulfonic acid 7-hydroxyheptyl ester (6.2g, 21.65mmol) following the procedure outlined for example 1, step 2. LCMS (ESI): m/z 146.0 (M + H) ⁺ 。

And step 3: (7-Hydroxyheptyl) (methyl) carbamic acid tert-butyl ester

The title compound (400mg, 47%) was provided as a colorless oil. Prepared from 7- (methylamino) heptan-1-ol (500mg, 3.44mmol) following the procedure outlined for example 1, step 3. LCMS (ESI): m/z 146.0 (M-100 + H) ⁺ 。

And 4, step 4: 4-Methylbenzenesulfonic acid 7- ((tert-butoxycarbonyl) (methyl) amino) heptyl ester

The title compound (600mg, 92%) was provided as a colorless oil. Prepared from tert-butyl (7-hydroxyheptyl) (methyl) carbamate (400mg, 1.63mmol) according to the procedure outlined for example 1, step 4. LCMS (ESI): m/z 422.1 (M + Na) ⁺ 。

And 5: (7- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) heptyl) (methyl) carbamic acid tert-butyl ester

The title compound (350mg, 93%) was provided as a yellow oil. Prepared from 7- ((tert-butoxycarbonyl) (methyl) amino) heptyl 4-methylbenzenesulfonate (300mg, 0.75mmol) following the procedure outlined for example 1, step 5. LCMS (ESI): m/z 524.1 (M + Na) ⁺ 。

Step 6:2- (2,6-dioxopiperidin-3-yl) -5- ((7- (methylamino) heptyl) oxy) isoindoline-1,3-dione hydrochloride

The title compound (300mg, 98%) was provided as a yellow oil. Prepared from tert-butyl (7- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) heptyl) (methyl) carbamate (350mg, 0.7 mmol) following the procedure outlined for example 1, step 6. LCMS (ESI): m/z 402.1 (M + H) ⁺ 。

And 7: n- (3- (2- ((7- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) heptyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) ethenyl) picolinamide

The title compound (40.3mg, 42%) was provided as a white solid. Prepared according to the procedure outlined for example 1, step 7, from 2- (2,6-dioxopiperidin-3-yl) -5- ((7- (methylamino) heptyl) oxy) isoindoline-1,3-dione hydrochloride (55mg, 0.13mmol). It was purified by preparative HPLC (Boston Green ODS 150X 30mm X5 um, water-ACN, 70-90%). ¹ H NMR(400MHz,DMSO-d ₆ ): δ 11.12 (s, 1H), 9.09 (t, J =6.0hz, 1h), 8.33 (s, 1H), 8.05 (s, 1H), 7.81 (d, J =8.4hz, 1h), 7.40 (s, 1H), 7.34-7.30 (m, 1H), 7.25-7.20 (m, 1H), 7.15 (d, J =7.2hz, 2h), 7.08 (t, J =6.0hz, 1h), 6.59-6.53 (m, 2H), 5.13-5.09 (m, 1H), 4.45 (d, J =5.2hz, 2h), 4.15-4.10 (m, 2H), 3.99 (s, 3H), 3.63 (s, 2H), 3.27-3.21 (m, 2H), 2.91,2.76 (s, 3H altogether), 2.90-2.84 (m, 1H), 2.61-2.57 (m, 1H), 2.21-2.20 (s, 2H), 2.05-2.02 (m, 1H), 1.94-1.83 (m, 4H), 1.70-1.67 (m, 2H), 1.41-1.23 (m, 11H), 1.17-1.14 (m, 2H). LCMS (ESI): m/z 860.5 (M + H) ⁺ 。

Example 10

Preparation of N- (3- (2- ((5- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) pentyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

Step 1: 4-Methylbenzenesulfonic acid 5-hydroxypentyl ester

The title compound (3g, 61%) was provided as a colorless oil. Prepared from 1,5-pentanediol (2.0 g, 19.2mmol) following the procedure outlined for example 1, step 1. LCMS (ESI): m/z 280.9 (M + Na) ⁺ 。

Step 2:5- (methylamino) pentan-1-ol

The title compound (1.3 g, 96%) was provided as a colorless oil. Prepared according to the procedure outlined for step 2 of example 1 from 5-hydroxypentyl 4-methylbenzenesulfonate (3.0 g, 11.61mmol).

And step 3: (5-Hydroxypentyl) (methyl) carbamic acid tert-butyl ester

The title compound (900mg, 37%) was provided as a colorless oil. Prepared from 5- (methylamino) pentan-1-ol (1.3g, 11.09mmol) following the procedure outlined for example 1, step 3. ¹ H NMR(400MHz,CDCl ₃ ):δ3.63(t,J＝6.4Hz,2H),3.20(br s,2H),2.82(s,3H),1.62-1.49(m,4H),1.44(s,9H),1.38-1.30(m,2H)。

And 4, step 4: 4-Methylbenzenesulfonic acid 5- ((tert-butoxycarbonyl) (methyl) amino) pentyl ester

The title compound (1.34g, 87%) was provided as a colorless oil. Prepared from tert-butyl (5-hydroxypentyl) (methyl) carbamate (900mg, 4.14mmol) following the procedure outlined for example 1, step 4. ¹ H NMR(400MHz,CDCl ₃ )：δ7.78(d,J＝8.4Hz,2H),7.34(d,J＝8.0Hz,2H),4.03-4.00(m,2H),3.17-3.13(m,2H),2.79(s,3H),2.45(s,3H),1.70-1.63(m,2H),1.48-1.46(m,2H),1.43(s,9H),1.33-1.29(m,2H)。LCMS(ESI)：m/z 394.1(M+Na) ⁺ 。

And 5: (5- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) pentyl) (methyl) carbamic acid tert-butyl ester

The title compound (254mg, 66%) was provided as a yellow oil. Prepared according to the procedure outlined for example 1, step 5, from 4-methylbenzenesulfonic acid 5- ((tert-butoxycarbonyl) (methyl) amino) pentyl ester (300mg, 0.81mmol). LCMS (ESI): m/z 496.2 (M + Na) ⁺ 。

Step 6:2- (2,6-dioxopiperidin-3-yl) -5- ((5- (methylamino) pentyl) oxy) isoindoline-1,3-dione hydrochloride

The title compound (200mg, 91%) was provided as a white oil. Prepared from tert-butyl (5- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) pentyl) (methyl) carbamate (254mg, 0.54mmol) following the procedure outlined for example 1, step 6. LCMS (ESI): m/z 374.1 (M + H) ⁺ 。

And 7: n- (3- (2- ((5- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) oxy) pentyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (19mg, 4%) was provided as a white solid. Prepared from 2- (2,6-dioxopiperidin-3-yl) -5- ((5- (methylamino) pentyl) oxy) isoindoline-1,3-dione hydrochloride (200mg, 0.54mmol) following the procedure outlined for example 1, step 7. It was purified by preparative HPLC (Welch XTimate C18X 30mm X5 um, water (0.225% FA) -ACN, 60-80%). ¹ H NMR(400MHz,CDCl ₃ ) δ 8.25 to 8.19 (m, 2H), 8.11 to 8.09 (m, 1H), 8.03 (s, 1H), 7.78 (d, J =8.4Hz, 1H), 7.32 (s, 1H), 7.25 (s, 1H), 7.19 to 7.16 (m, 2H), 6.66 (d, J =16.0Hz, 1H), 6.54 to 6.47 (m, 1H), 4.99 to 4.94 (m, 1H), 4.64 (d, J =6.0Hz, 2H), 4.08 to 4.01 (m, 2H), 3.99-3.97 (m, 3H), 3.74-3.70 (m, 2H), 3.42 (t, J =7.2hz, 1h), 3.34-3.28 (m, 1H), 2.99,2.95 (s, 3H altogether), 2.95-2.73 (m, 4H), 2.24-2.12 (m, 2H), 2.06-1.94 (m, 5H), 1.88-1.76 (m, 2H), 1.53-1.32 (m, 5H), 1.30-1.19 (m, 2H). LCMS (ESI): m/z 832.5 (M + H) ⁺ 。

Example 11

Preparation of N- (3- (2- ((5- (((S) -1- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -5-oxopentyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: (2S, 4R) -1- ((S) -2- (5-Aminopentanamido) -3,3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride

To a solution of (5- (((S) -1- ((2s, 4r) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -5-oxopentyl) carbamic acid tert-butyl ester (300.0 mg, 0.4800mmol) in 1,4-dioxane (1.5 mL) was added 4M HCl in 1,4-dioxane (6ml, 24mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated to give the title compound (200mg, 74%) as a yellow oil. LCMS (ESI): m/z 530.2 (M + H) ⁺ 。

Step 2: n- (3- (2- ((5- (((S) -1- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -5-oxopentyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

To a mixture of (2S, 4R) -1- ((S) -2- (5-Aminopentanamido) -3,3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride (85.6mg, 0.15mmol) and 2- (3- ((5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) pyridinamido) methyl) phenyl) acetic acid (60mg, 0.13mmol) in DCM (2 mL) at room temperature were added DIPEA (0.06mL, 0.38mmol) and T ₃ P (160mg, 0.25mmol). Then, the resulting mixture was stirred at 40 ℃ for 1 hour. The reaction was quenched by addition of water (10 mL) at 0 ℃. The layers were separated and the aqueous solution was extracted with DCM (30 mL. Times.2). The combined organic layers were washed with brine (20 mL. Times.2) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative HPLC (Boston Green ODS 150X 30mm X5 um, water (0.075% TFA) -CAN, 55-75%) to give the title compound (43.1mg, 33%) as a white solid. ¹ H NMR(400MHz,CD ₃ OD)：δ9.08-9.03(m,1H),8.31(s,1H),8.22(d,J＝7.2Hz,1H),7.48(d,J＝8.0Hz,2H),7.42(d,J＝8.0Hz,2H),7.30-7.23(m,3H),7.22-7.18(m,1H),6.73(d,J＝16.4Hz,1H),6.63-6.57(m,1H),4.62-4.57(m,6H),4.37-4.34(m,1H),4.04(s,3H),3.93-3.87(m,1H),3.81-3.78(m,1H),3.48(s,2H),3.16(t,J＝6.8Hz,2H),2.49(s,3H),2.29-2.18(m,4H),2.11-2.07(m,1H),1.99-1.95(m,4H),1.61-1.57(m,2H),1.53-1.40(m,4H),1.39-1.35(m,3H),1.03(s,9H)。LCMS(ESI)：m/z 495.1(M/2+H) ⁺ 。

Example 12

Preparation of N- (3- (2- ((7- (((S) -1- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -7-oxoheptyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: (2S, 4R) -1- ((S) -2- (7-aminoheptanoylamino) -3,3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride

The title compound (140mg, 78%) was provided as a yellow oil. Prepared according to the procedure outlined for example 11, step 1, from tert-butyl (7- (((S) -1- ((2s, 4r) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -7-oxoheptyl) carbamate (200mg, 0.30mmol). LCMS (ESI): m/z 580.2 (M + Na) ⁺ 。

Step 2: n- (3- (2- ((7- (((S) -1- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -7-oxoheptyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (65.3mg, 38%) was provided as a white solid. Prepared from (2s, 4r) -1- ((S) -2- (7-aminoheptanoylamino) -3,3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride (120mg, 0.20mmol) following the procedure outlined for example 11, step 2. It was purified by preparative HPLC (Boston Green ODS 150X 30mm X5 um; water (0.075% TFA) -CAN; 56-76%). ¹ H NMR(400MHz,CD ₃ OD)：δ9.14(s,1H),8.31(s,1H),8.25(s,1H),7.48(d,J＝8.0Hz,2H),7.42(d,J＝8.0Hz,2H),7.30-7.23(m,3H),7.19(d,J＝6.8Hz,1H),6.74(d,J＝16.0Hz,1H),6.63(dd,J＝16.0,6.4Hz,1H),4.63(s,1H),4.95-4.59(m,5H),4.35(d,J＝15.2Hz,1H),4.04(s,3H),3.94-3.89(m,1H),3.83-3.78(m,1H),3.47(s,2H),3.14(t,J＝6.8Hz,2H),2.49(s,3H),2.26-2.18(m,4H),2.11-2.06(m,1H),1.99-1.47(m,4H),1.60-1.53(m,2H),1.47-1.40(m,4H),1.38-1.26(m,7H),1.03(s,9H)。LCMS(ESI)：m/z 1017.0(M+H) ⁺ 。

Example 13

Preparation of N- (3- (2- ((9- (((S) -1- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -9-oxononyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: (2S, 4R) -1- ((S) -2- (9-aminononanamido) -3,3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride

The title compound (270mg, 99%) was provided as a yellow oil. Which was prepared from (9- (((S) -1- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) - 3,3-dimethyl-1-oxobutan-2-yl) amino) -9-oxononyl) carbamic acid tert-butyl ester (300mg, 0.44mmol) was prepared. LCMS (ESI): m/z 586.3 (M + H) ⁺ 。

Step 2: n- (3- (2- ((9- (((S) -1- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -9-oxononyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (23mg, 20%) was provided as a white solid. Prepared from (2s, 4r) -1- ((S) -2- (9-aminononanamido) -3,3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride (78.4mg, 0.13mmol) following the procedure outlined for example 11, step 2. It was purified by preparative HPLC (Boston Green ODS 150X 30mm X5 um; water (0.075% TFA) -CAN; 55-85%). ¹ H NMR(400MHz,CD ₃ OD)：δ9.06(s,1H),8.30(s,1H),8.22(s,1H),7.47(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),7.29-7.23(m,3H),7.20-7.18(m,1H),6.73(d,J＝16.4Hz,1H),6.62(dd,J＝16.4,6.8Hz,1H),4.63-4.49(m,6H),4.33(d,J＝15.6Hz,1H),4.01(s,3H),3.89-3.87(m,1H),3.79-3.75(m,1H),3.45(s,2H),3.11(t,J＝6.8Hz,2H),2.48(s,3H),2.26-2.18(m,4H),2.10-2.05(m,1H),2.02-1.92(m,4H),1.58-1.56(m,2H),1.41-1.39(m,4H),1.31-1.24(m,11H),1.01(s,9H)。LCMS(ESI)：m/z 1044.9(M+H) ⁺ 。

Example 14

Preparation of N- (3- ((S) -13- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -14,14-dimethyl-2,11-dioxo-6,9-dioxa-3,12-diazepidecyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: (2S, 4R) -1- ((S) -2- (2- (2- (2-aminoethoxy) ethoxy) acetylamino) -3,3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride

The title compound (272 mg, quantitative) was provided as a white solid. Prepared according to the procedure outlined for example 11, step 1, from tert-butyl (2- (2- (2- (((S) -1- ((2s, 4r) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethoxy) ethyl) carbamate (300mg, 0.44mmol). LCMS (ESI): m/z 576.3 (M + H) ⁺ 。

Step 2: n- (3- ((S) -13- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -14,14-dimethyl-2,11-dioxo-6,9-dioxa-3,12-diazapentanyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (11.8 mg, 10%) was provided as a white solid. Prepared according to the procedure outlined for example 11, step 2, from (2s, 4r) -1- ((S) -2- (2- (2- (2-aminoethoxy) ethoxy) acetylamino) -3,3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride (77mg, 0.13mmol). It was purified by preparative HPLC (Welch Xtimate C18 150X 30mm X5 um, water (0.225% FA) -CAN, 55-85%). ¹ H NMR(400MHz,DMSO-d ₆ )：δ9.06(t,J＝5.6Hz,1H),8.96(s,1H),8.57(t,J＝5.6Hz,1H),8.32(s,1H),8.15-8.07(m,1H),8.04(s,1H),7.44(d,J＝10.0Hz,1H),7.37-7.35(m,4H),7.23-7.09(m,4H),6.64-6.53(m,2H),5.17(d,J＝3.2Hz,1H),4.58(d,J＝9.2Hz,1H),4.49-4.41(m,3H),4.38-4.29(m,2H),4.28-4.21(m,1H),3.98(s,3H),3.96(s,2H),3.70-3.64(m,1H),3.63-3.57(m,3H),3.52-3.51(m,2H),3.44-3.41(m,4H),3.22-3.11(m,2H),2.45-2.41(m,3H),2.22-2.20(m,2H),2.11-2.01(m,1H),1.96-1.82(m,5H),1.36-1.23(m,4H),0.98-0.89(m,9H)。LCMS(ESI)：m/z 1034.6(M+H) ⁺ 。

Example 15

Preparation of N- (3- ((S) -16- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -17,17-dimethyl-2,14-dioxo-6,9,12-trioxa-3,15-diazacyclooctadecyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: (2S, 4R) -1- ((S) -14-amino-2- (tert-butyl) -4-oxo-6,9,12-trioxa-3-azatetradecane-1-yl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride

The title compound (273 mg, quantitative) was provided as a white solid. Prepared from tert-butyl ((S) -13- ((2s, 4r) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl) carbamate (300mg, 0.42mmol) following the procedure outlined for example 11, step 1. LCMS (ESI): m/z 620.3 (M + H) ⁺ 。

Step 2: n- (3- ((S) -16- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -17,17-dimethyl-2,14-dioxo-6,9,12-trioxa-3,15-diazadecyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (30.4 mg, 27%) was provided as a white solid. Prepared from (2s, 4r) -1- ((S) -14-amino-2- (tert-butyl) -4-oxo-6,9,12-trioxa-3-azatetradecane-1-yl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride (103mg, 0.16mmol) according to the procedure outlined for example 11, step 2. It was purified by preparative HPLC (Welch XTimate C18X 30mm X5 um, water (0.2% FA) -ACN, 53-93%). ¹ H NMR(400MHz,DMSO-d ₆ )：δ9.07(t,J＝6.4Hz,1H),8.99-8.94(m,1H),8.59(t,J＝5.6Hz,1H),8.33(s,1H),8.14-8.05(m,2H),7.45-7.35(m,5H),7.23-7.10(m,4H),6.64-6.53(m,2H),5.16(br s,1H),4.56(d,J＝9.6Hz,1H),4.48-4.40(m,3H),4.40-4.32(m,2H),4.28-4.21(m,1H),3.99(s,3H),3.96(s,2H),3.69-3.65(m,1H),3.63-3.58(m,3H),3.57-3.50(m,6H),3.49-3.46(m,4H),3.16(q,J＝5.6Hz,2H),2.45-2.41(m,3H),2.29-2.15(m,2H),2.10-2.02(m,1H),1.97-1.80(m,5H),1.38-1.21(m,4H),0.97-0.89(m,9H)。LCMS(ESI)：m/z 1078.6(M+H) ⁺ 。

Example 16

Preparation of N- (3- ((S) -19- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -20,20-dimethyl-2,17-dioxo-6,9,12,15-tetraoxa-3,18-diaza-heneicosyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: (2S, 4R) -1- ((S) -17-amino-2- (tert-butyl) -4-oxo-6,9,12,15-tetraoxa-3-azaheptadecane-1-acyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride

The title compound (300mg, 99%) was provided as a yellow solid. Prepared from tert-butyl ((S) -16- ((2s, 4r) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -17,17-dimethyl-14-oxo-3,6,9,12-tetraoxa-15-azaoctadecyl) carbamate (330mg, 0.43mmol) following the procedure outlined for example 11, step 1. LCMS (ESI): m/z664.3 (M + H) ⁺ 。

Step 2: n- (3- ((S) -19- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -20,20-dimethyl-2,17-dioxo-6,9,12,15-tetraoxa-3,18-diaza-heneicosyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (69mg, 57%) was provided as a white solid. Prepared according to the procedure outlined for example 11, step 2, from (2s, 4r) -1- ((S) -17-amino-2- (tert-butyl) -4-oxo-6,9,12,15-tetraoxa-3-azaheptadecane-1-yl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride (88mg, 0.13mmol). It was purified by preparative HPLC (Welch Xtimate C18 150X 30mm X5 um, water (0.235% FA) -ACN, 60-90%). ¹ H NMR(400MHz,CD ₃ OD)：δ8.86(s,1H),8.29(s,1H),8.13(s,1H),7.46-7.38(m,4H),7.29-7.18(m,4H),6.70(d,J＝16.0Hz,1H),6.54(dd,J＝16.0,6.8Hz,1H),4.69(s,1H),4.61-4.55(m,5H),4.50-4.48(m,2H),4.36-4.34(m,1H),4.04-4.00(m,4H),3.91-3.75(m,2H),3.70-3.46(m,17H),2.47(s,3H),2.26-2.20(m,1H),2.09-2.08(m,2H),2.02-1.99(m,4H),1.44-1.27(m,5H),1.01(s,9H)。LCMS(ESI)：m/z 562.1(M/2+H) ⁺ 。

Example 17

Preparation of N- (3- ((S) -22- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -23,23-dimethyl-2,20-dioxo-6,9,12,15,18-pentaoxa-3,21-diaza-tetracosyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1: (2S, 4R) -1- ((S) -20-amino-2- (tert-butyl) -4-oxo-6,9,12,15,18-pentaoxa-3-azaeicosan-1-yl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride

The title compound (270mg, 98%) was provided as a yellow solid. Prepared according to the procedure outlined for example 11, step 1, from tert-butyl ((S) -19- ((2s, 4r) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -20,20-dimethyl-17-oxo-3,6,9,12,15-pentaoxa-18-azaheneicosyl) carbamate (300mg, 0.37mmol). LCMS (ESI): m/z 708.4 (M + H) ⁺ 。

Step 2: n- (3- ((S) -22- ((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -23,23-dimethyl-2,20-dioxo-6,9,12,15,18-pentaoxa-3,21-diaza-tetracosyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (37mg, 22%) was provided as a white solid. It was prepared from (2S, 4R) -1- ((S) -20-amino-2- (tert-butyl) -4-oxo-6,9,12,15,18-pentaoxa-3-azaeicosan- -1-acyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxylic acid ester following the procedure outlined for example 11, step 2Amine hydrochloride (100mg, 0.13mmol) was prepared. It was purified by preparative HPLC (Welch Xtimate C18 150X 30mm X5 um, water (0.225% FA) -ACN, 59-79%). ¹ H NMR(400MHz,CD ₃ OD)：δ8.84(s,1H),8.27(s,1H),8.11(s,1H),7.45-7.37(m,4H),7.29-7.17(m,4H),6.68(d,J＝16.4Hz,1H),6.52(dd,J＝16.4,7.2Hz,1H),4.67(s,1H),4.56(s,1H),4.48-4.46(m,1H),4.33–4.31(m,1H),4.01-3.98(m,4H),3.87-3.82(m,1H),3.80-3.76(m,1H),3.66-3.62(m,4H),3.60(s,2H),3.55-3.51(m,4H),3.49-3.44(m,4H),3.31-3.28(m,12H),2.46-2.43(m,3H),2.23-2.16(m,2H),2.10-2.05(m,1H),2.03-1.92(m,4H),1.45-1.26(m,5H),1.01(s,9H)。LCMS(ESI)：m/z 584.1(M/2+H) ⁺ 。

Example 18

Preparation of N- (3- (17- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

To a solution of 2,2' - ((methyl ether (ethane-2,1-diyl)) bis (oxy)) diethanol (8.0 g, 41.19mmol) in DCM (40 mL) at 0 deg.C were added KI (1.71g, 10.3mmol) and Ag ₂ O (11.45g, 49.43mmol). A solution of TsCl (8.64g, 45.31mmol) in DCM (45 mL) was then added dropwise at 0 deg.C. The resulting mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0-2% MeOH in DCM) to give the title compound (5.6g, 39%) as a colorless oilAnd (4) forming a substance. ¹ H NMR(400MHz,CDCl ₃ ):δ7.80(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,2H),4.19-4.13(m,2H),3.74-3.56(m,14H),2.45(s,3H)。

And 2, step: 5,8,11-trioxa-2-azatridecan-13-ol

To a solution of 4-methylbenzenesulfonic acid 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl ester (5.6 g, 16.07mmol) in EtOH (4 mL) at 0 deg.C was added dropwise 33% MeNH ₂ (in EtOH solution (11.76mL, 241.1mmol)). The reaction was stirred at 60 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (0-10% meoh in DCM) to give the title compound (3.3 g, quantitative) as a colorless oil.

And step 3: benzyl (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) (methyl) carbamate

To a solution of 5,8,11-trioxa-2-azatridecan-13-ol (3.3g, 16.07mmol) in DMF (5 mL) at room temperature were added Cbz-OSu (8.0g, 32.15mmol) and Et ₃ N (3.36mL, 24.11mmol). The resulting mixture was stirred at 40 ℃ for 2 hours. The reaction mixture was then diluted with EtOAc (30 mL), washed with brine (50 mL. Times.3), and over Na ₂ SO ₄ Dried and concentrated. The residue was purified by silica gel column chromatography (0-3% meoh in DCM) to give the title compound (4.1g, 75%) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ ):δ7.39-7.28(m,5H),5.13(s,2H),3.71-3.70(m,2H),3.67-3.56(m,12H),3.48-3.47(m,2H),3.00(s,3H)。

And 4, step 4: ethyl 4-methyl-3-oxo-1-phenyl-2,7,10,13,16-pentaoxa-4-azaoctadecane-18-oic ester

To a suspension of NaH (60% in mineral oil, 576mg, 24.02mmol) in THF (20 mL) at 0 deg.C was added benzyl N- [2- [2- [2- (2-hydroxyethoxy) ethoxy ] ethoxy]Ethoxy radical]Ethyl radical]-N-methyl-carbamate (4.1g, 12.01mmol). The reaction mixture was stirred at 0 ℃ for 30 minutes. Ethyl 2-bromoacetate (4.08mL, 36.03mmol) was added at 0 deg.C, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was then quenched at 0 ℃ by dropwise addition of water (1 mL). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL. Times.2). The combined organic layers were washed with brine (50 mL. Times.2) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by silica gel column chromatography (0-80% etoac in petroleum ether) to give the title compound (3.2g, 62%) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ ):δ7.39-7.27(m,5H),5.13(s,2H),4.21(q,J＝7.2Hz,2H),4.14-4.12(m,2H),3.75-3.67(m,4H),3.66-3.55(m,10H),3.48-3.46(m,2H),3.00(s,3H),1.29-1.26(m,3H)。

And 5: 4-methyl-3-oxo-1-phenyl-2,7,10,13,16-pentaoxa-4-azaoctadecane-18-oic acid

To a solution of ethyl 4-methyl-3-oxo-1-phenyl-2,7,10,13,16-pentaoxa-4-azaoctadecane-18-oate (3.3g, 7.75mmol) in THF (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (929mg, 22.14mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with EtOAc (30 mL) and extracted with water (30 mL. Times.3). The pH of the aqueous layer was adjusted to 3 to 4 with 2MHCl and extracted with EtOAc (30 mL. Times.3). The combined organic layers were passed over Na ₂ SO ₄ Dried and concentrated to give the title compound (2.8g, 91%) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ ):δ7.38-7.28(m,5H),5.13(s,2H),4.16(s,2H),3.76-3.72(m,2H),3.70-3.58(m,12H),3.49-3.48(m,2H),3.00(s,3H)。

Step 6: n- [ (1S) -2- [ [ (1S) -2- [ (2S) -2- [ [2- [ [2- [2- [2- [2- [2- [ benzyloxycarbonyl (methyl) amino ] ethoxy ] acetyl ] amino ] -4-phenyl-thiazol-5-yl ] carbamoyl ] pyrrolidin-1-yl ] -1-cyclohexyl-2-oxo-ethyl ] amino ] -1-methyl-2-oxo-ethyl ] -N-methyl-carbamic acid tert-butyl ester

To a solution of tert-butyl ((S) -1- (((S) -2- ((S) -2- ((2-amino-4-phenylthiazol-5-yl) carbamoyl) pyrrolidin-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxoprop-2-yl) (methyl) carbamate (300mg, 0.49mmol), 4-methyl-3-oxo-1-phenyl-2,7,10,13,16-pentaoxa-4-azaoctadecane-18-oic acid (293mg, 0.73mmol) and DIPEA (316mg, 2.45mmol) in DCM (6 mL) at room temperature was added T ₃ P (623mg, 0.98mmol). The reaction mixture was then stirred at 40 ℃ for 1 hour. The reaction was quenched by addition of water (10 mL) at 0 ℃. The layers were separated and the aqueous solution was extracted with DCM (10 mL. Times.2). The combined organic layers were washed with brine (20 mL. Times.2) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by silica gel column chromatography (0-100% etoac in petroleum ether) to give the title compound (370mg, 76%) as a yellow oil. LCMS (ESI): m/z 994.7 (M + H) ⁺ 。

And 7: (S) -N- (2- (5,8,11,14-tetraoxa-2-azahexadecanoylamino) -4-phenylthiazol-5-yl) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamide Hydrogen bromide

To N- [ (1S) -2- [ [ (1S) -2- [ (2S) -2- [ [2- [ [2- [2- [2- [2- [2- [ benzyloxycarbonyl (methyl) amino group]Ethoxy radical]Ethoxy radical ]Ethoxy radical]Ethoxy radical]Acetyl group]Amino group]-4-phenyl-thiazol-5-yl]Carbamoyl radical]Pyrrolidin-1-yl radical]-1-cyclohexyl-2-oxo-ethyl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid esterA solution of tert-butyl ester (40mg, 0.04mmol) in DCM (1 mL) was added 33% HBr in AcOH (0.1 mL). The resulting mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure to obtain the title compound (30.6 mg, 90%) as a pale yellow solid. LCMS (ESI): m/z 760.5 (M + H) ⁺ 。

And 8: n- (3- (17- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

To a mixture of (S) -N- (2- (5,8,11,14-tetraoxa-2-azahexadecanoylamino) -4-phenylthiazol-5-yl) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamide hydrogen bromide (30.6 mg, 0.04mmol), 2- (3- ((5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) pyridylamido) methyl) phenyl) acetic acid (15mg, 0.03mmol), and DIPEA (0.03mL, 0.16mmol) in DCM (1 mL) at room temperature was added T ₃ P (40mg, 0.06mmol). The reaction mixture was stirred at 40 ℃ for 1 hour. The reaction was quenched by addition of water (4 mL) at 0 ℃. The layers were separated and the aqueous solution was extracted with DCM (5 mL. Times.3). The combined organic layers were washed with brine (20 mL. Times.2) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative HPLC (Welch Xtimate C18X 40mm X10 um, water (0.2% FA) -ACN, 36-66%) to give the title compound (11.9mg, 30%) as a white solid. ¹ H NMR(400MHz,CD ₃ OD): δ =8.28 (s, 1H), 8.13 (s, 1H), 7.75 (d, J =7.2hz, 2H), 7.42 (t, J =7.6hz, 2H), 7.36-7.30 (m, 1H), 7.28-7.18 (m, 3H), 7.12-7.10 (m, 1H), 6.69 (d, J =16.0hz, 1H), 6.53 (dd, J =16.0,6.8hz, 1H), 4.52-4.50 (m, 1H), 4.22 (d, J =14.0hz, 2H), 4.00 (s, 3H), 3.95-3.94 (m, 1H), 3.79 (s, 1H), 3.77-3.62 (m, 10H), 3.56-3.44 (m, 10H), 8978 (zs, 8978), 1H), 89.86 (m, 11H), 1H, 11H, 31.86H), 1H, 11H, 31H, 3.4.4.4.(m,6H),1.44-1.02(m,13H)。LCMS(ESI)：m/z 610.4(M/2+H) ⁺ 。

Example 19

Preparation of N- (3- (20- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,20-dioxo-6,9,12,15,18-pentaoxa-3-azaeicosyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

The title compound (3.06g, 37%) was provided as a colorless oil. Prepared according to the procedure outlined for example 18, step 1, from 3,6,9,12-tetraoxatetradecane-1,14-diol (5.0g, 20.98mmol). LCMS (ESI): m/z 393.2 (M + H) ⁺ 。

Step 2:5,8,11,14 tetraoxa-2-azahexadecyl-16-ols

The title compound (1.96g, 100%) was provided as a colorless oil. Prepared from 4-methylbenzenesulfonic acid 14-hydroxy-3,6,9,12-tetraoxatetradecyl ester (3.06g, 7.8mmol) following the procedure outlined for example 18, step 2.

And step 3: benzyl (14-hydroxy-3,6,9,12-tetraoxatetradecyl) (methyl) carbamate

The title compound (1.12g, 37%) was provided as a colorless oil. Prepared according to the procedure outlined for example 18, step 3, from 5,8,11,14-tetraoxa-2-azahexadecyl-16-ol (1.96g, 7.8mmol). ¹ H NMR(400MHz,CDCl ₃ ):δ7.39-7.28(m,5H),5.13(s,2H),3.75-3.70(m,2H),3.68-3.56(m,16H),3.48(br s,2H),3.00(s,3H)。LCMS(ESI)：m/z 386.2(M+H) ⁺ 。

And 4, step 4: ethyl 4-methyl-3-oxo-1-phenyl-2,7,10,13,16,19-hexaoxa-4-azaheneicosane-21-oate

The title compound (1.06g, 77%) was provided as a yellow oil. Prepared from benzyl (14-hydroxy-3,6,9,12-tetraoxatetradecyl) (methyl) carbamate (1.12g, 2.91mmol) following the procedure outlined for example 18, step 4. ¹ H NMR(400MHz,CDCl ₃ ):δ7.39-7.27(m,5H),5.12(s,2H),4.21(q,J＝7.2Hz,2H),4.16-4.11(m,2H),3.74-3.67(m,4H),3.66-3.56(m,14H),3.51-3.43(m,2H),3.00(s,3H),1.28(t,J＝7.2Hz,3H)。

And 5: 4-methyl-3-oxo-1-phenyl-2,7,10,13,16,19-hexaoxa-4-azaheneicosane-21-oic acid

The title compound (850 mg, 85%) was provided as a yellow oil. Prepared from ethyl 4-methyl-3-oxo-1-phenyl-2,7,10,13,16,19-hexaoxa-4-azaheneicosane-21-oic acid ester (1.06g, 2.25mmol) following the procedure outlined for example 18, step 5. LCMS (ESI): m/z444.3 (M + H) ⁺ 。

And 6: n- [ (1S) -2- [ [ (1S) -2- [ (2S) -2- [ [2- [ [2- [2- [2- [2- [2- [2- [ benzyloxycarbonyl (methyl) amino ] ethoxy ] acetyl ] amino ] -4-phenyl-thiazol-5-yl ] carbamoyl ] pyrrolidin-1-yl ] -1-cyclohexyl-2-oxo-ethyl ] amino ] -1-methyl-2-oxo-ethyl ] -N-methyl-carbamic acid tert-butyl ester

The title compound (340mg, 67%) was provided as a yellow oil. Prepared from 4-methyl-3-oxo-1-phenyl-2,7,10,13,16,19-hexaoxa-4-azaheneicosane-21-oic acid (282mg, 0.64mmol) following the procedure outlined for example 18, step 6. LCMS (ESI): m/z 1038.7 (M + H) ⁺ 。

And 7: (S) -N- (2- (5,8,11,14,17-pentaoxa-2-azanonalkaneamido) -4-phenylthiazol-5-yl) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamide hydrobromide

The title compound (68 mg, quantitative) was provided as a yellow oil. It was prepared from N- [ (1S) -2- [ [ (1S) -2- [ (2S) -2- [ [2- [ [2- [2- [2- [2- [ benzyloxycarbonyl (methyl) amino ] according to the procedure outlined for example 18 step 7]Ethoxy radical]Ethoxy radical]Ethoxy radical]Ethoxy radical]Ethoxy radical]Acetyl group]Amino group]-4-phenyl-thiazol-5-yl]Carbamoyl radical]Pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (80mg, 0.08mmol) was prepared. LCMS (ESI): m/z 804.6 (M + H) ⁺ 。

And 8: n- (3- (20- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,20-dioxo-6,9,12,15,18-pentaoxa-3-azaeicosyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The title compound (17.4mg, 21%) was provided as a white solid. Prepared according to the procedure outlined for example 18, step 8, from (S) -N- (2- (5,8,11,14,17-pentaoxa-2-azanonalkaneamido) -4-phenylthiazol-5-yl) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamide hydrobromide (68mg, 0.08mmol). It was purified by preparative HPLC (Welch Xtimate C18 150X 25mm X5 um, water (0.2% FA) -ACN, 36-66%). ¹ H NMR(400MHz,CD ₃ OD): δ 8.28 (s, 1H), 8.13 (s, 1H), 7.76-7.74 (m, 2H), 7.42 (t, J =6.8Hz, 2H), 7.36-7.30 (m, 1H), 7.29-7.20 (m, 3H), 7.12 (t, J =6.8Hz, 1H), 6.69 (d, J =16.0Hz, 1H), 6.53 (dd, J =16.0,6.8Hz, 1H), 4.52-4.43 (m, 1H), 4.23 (d, J =4.8Hz, 2H), 4.00 (s, 3H), 3.95-3.94 (m, 1H), 3.81 (s, 1H), 3.76-3.64 (m, 10H), 3.57-3.51 (m, 13H), 3.48-3.47 (m, 1H), 3.04,2.91 (s, 3H altogether), 2.44 (s, 3H), 2.29-1.89 (m, 11H), 1.87-1.60 (m, 6H), 1.47-1.00 (m, 13H). LCMS (ESI): m/z 632.1 (M/2+H) ⁺ 。

Example 20

Preparation of the form of N- (3- (23- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -3-methyl-2,23-dioxo-6,9,12,15,18,21-hexaoxa-3-azatricosyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

The title compound (5.0 g, 32%) was provided as a colorless oil. It was prepared from 3,6,9,12,15-pentaoxaheptadecyl-1,17-diol (5363-pentaoxaheptadecyl-1,17-diol, following the procedure outlined for example 18, step 110.0g, 35.42mmol). LCMS (ESI): m/z 437.3 (M + H) ⁺ 。

Step 2:5,8,11,14,17-Pentaoxa-2-azanonadecane-19-ol

The title compound (2.9 g, quantitative) was provided as a colorless oil. Prepared according to the procedure outlined for example 18, step 2, from 4-methylbenzenesulfonic acid 17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl ester (4.4 g, 10.08mmol). LCMS (ESI): m/z 296.1 (M + H) ⁺ 。

And step 3: benzyl (17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl) (methyl) carbamate

The title compound (1.2g, 58%) was provided as a colorless oil. Prepared according to the procedure outlined for example 18, step 3, from 5,8,11,14,17-pentaoxa-2-azanonacan-19-ol (1.0g, 4.82mmol). ¹ H NMR(400MHz,CDCl ₃ ):δ7.35-7.29(m,5H),5.12(s,2H),3.71-3.70(m,2H),3.68-3.57(m,20H),3.47-3.46(m,2H),3.00(s,3H)。

And 4, step 4: ethyl 4-methyl-3-oxo-1-phenyl-2,7,10,13,16,19,22-heptaoxa-4-azatetracosan-24-oate

The title compound (400mg, 28%) was provided as a yellow oil. Prepared from benzyl (17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl) (methyl) carbamate (1.2g, 2.79mmol) following the procedure outlined for example 18, step 4. ¹ H NMR(400MHz,CDCl ₃ )：δ7.38-7.29(m,5H),5.13(s,2H),4.22(q,J＝7.2Hz,2H),4.15(s,2H),3.78-3.72(m,2H),3.71-3.68(m,2H),3.67-3.61(m,16H),3.48-3.47(m,2H),3.00(s,3H),1.72(s,2H),1.29(t,J＝7.2Hz,3H)。

And 5: 4-methyl-3-oxo-1-phenyl-2,7,10,13,16,19,22-heptaoxa-4-azatetracosan-24-oic acid

The title compound (378 mg, quantitative) was provided as a yellow oil. Prepared from ethyl 4-methyl-3-oxo-1-phenyl-2,7,10,13,16,19,22-heptaoxa-4-azatetracosan-24-oate (400mg, 0.780mmol) following the procedure outlined for example 18, step 5. LCMS (ESI): m/z 488.3 (M + H) ⁺ 。

Step 6: <xnotran> N- [ (1S) -2- [ [ (1S) -2- [ (2S) -2- [ [2- [ [2- [2- [2- [2- [2- [2- [2- [ () ] ] ] ] ] ] ] ] ] -4- - -5- ] ] -1- ] -1- -2- - ] ] -1- -2- - ] -N- - </xnotran>

The title compound (205mg, 39%) was provided as a yellow oil. Prepared from 4-methyl-3-oxo-1-phenyl-2,7,10,13,16,19,22-heptaoxa-4-azatetracosane-24-acid (358mg, 0.73mmol) following the procedure outlined for example 18, step 6. LCMS (ESI): m/z1082.7 (M + H) ⁺ 。

Example 21

Preparation of N- (3- (2- ((4- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -4-oxobutyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

The general reaction scheme is as follows:

step 1:4- (methylamino) butanoic acid

1-methyl-2-pyrrolidone (2.0 g,20.18 mmol) in H at room temperature ₂ To a solution of barium hydroxide octahydrate (3.89mg, 12.32mmol) in O (22 mL) was added. Heating the heterogeneous mixture at 110 deg.C for 3 hours, then cooling to 0 deg.C and adding CO ₂ The gas saturates it. The resulting white precipitate was collected by filtration and washed with ice water. The clear filtrate was evaporated to dryness to give the title compound (1.01g, 43%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )：δ2.77-2.68(m,2H),2.39(s,3H),2.22-2.14(m,2H),2.08(s,1H),1.65-1.59(m,2H)。

Step 2:4- (((benzyloxy) carbonyl) (methyl) amino) butanoic acid

Et is added to a solution of 4- (methylamino) butanoic acid (200mg, 1.71mmol) in DMF (5 mL) at room temperature ₃ N (259mg, 2.56mmol) and N- (benzyloxycarbonyloxy) succinimide (511mg, 2.05mmol). The reaction mixture was stirred at room temperature for 16 hours. After that, etOAc (40 mL) was added. The organic layer was washed with water (40 mL. Times.2) and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (0-10% meoh in DCM) to give the title compound (300mg, 70%) as a colorless oil. LCMS (ESI): m/z 252.1 (M + H) ⁺ 。

And step 3: n- [ (1S) -2- [ [ (1S) -2- [ (2S) -2- [ [2- [4- [ benzyloxycarbonyl (methyl) amino ] butyrylamino ] -4-phenyl-thiazol-5-yl ] carbamoyl ] pyrrolidin-1-yl ] -1-cyclohexyl-2-oxo-ethyl ] amino ] -1-methyl-2-oxo-ethyl ] -N-methyl-carbamic acid tert-butyl ester

The title compound (500mg, 37%) was provided as a white solid. Prepared from 4- (((benzyloxy) carbonyl) (methyl) amino) butyric acid (400mg, 1.59mmol) according to the procedure outlined for example 18, step 6. LCMS (ESI): m/z 846.4 (M + H) ⁺ 。

And 4, step 4: ((S) -1- (((S) -1-cyclohexyl-2- ((S) -2- ((2- (4- (methylamino) butanamido) -4-phenylthiazol-5-yl) carbamoyl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxoprop-2-yl) (methyl) carbamic acid tert-butyl ester

To N- [ (1S) -2- [ [ (1S) -2- [ (2S) -2- [ [2- [4- [ benzyloxycarbonyl (methyl) amino group) at room temperature]Butyrylamino group]-4-phenyl-thiazol-5-yl]Carbamoyl radical]Pyrrolidin-1-yl radical]-1-cyclohexyl-2-oxo-ethyl]Amino group]-1-methyl-2-oxo-ethyl]Addition of tert-butyl-N-methyl-carbamate (119mg, 0.14mmol) to MeOH (5 mL) 10% Pd/C (75mg, 0.07mmol). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen (15 psi) for 16 hours. Then, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (10% meoh in DCM) to give the title compound (30mg, 30%) as a white solid. LCMS (ESI): m/z712.4 (M + H) ⁺ 。

And 5: tert-butyl ((S) -1- (((S) -1-cyclohexyl-2- ((S) -2- ((2- (4- (2- (3- ((5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamido) methyl) phenyl) -N-methylacetoacetamido) butyrylamino) -4-phenylthiazol-5-yl) carbamoyl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxoprop-N-2-yl) (methyl) carbamate

To a mixture of ((S) -1- (((S) -1-cyclohexyl-2- ((S) -2- ((2- (4- (methylamino) butyrylamino) -4-phenylthiazol-5-yl) carbamoyl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxoprop-2-yl) (methyl) carbamic acid tert-butyl ester (24.6 mg, 0.03mmol), 2- (3- ((5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) pyridylamido) methyl) phenyl) acetic acid (15mg, 0.03mmol) and DIPEA (0.02mL, 0.09mmol) in DCM (2 mL) was added T ₃ P (40mg, 0.06mmol). The resulting mixture was stirred at 40 ℃ for 1 hour. The reaction mixture was then concentrated. The residue was purified by preparative TLC (10% meoh in DCM) to give the title compound (20mg, 54%) as a white solid. LCMS (ESI): m/z 1170.7 (M + H) ⁺ 。

Step 6: n- (3- (2- ((4- ((5- ((S) -1- ((S) -2-cyclohexyl-2- ((S) -2- (methylamino) propionamido) acetyl) pyrrolidine-2-carboxamido) -4-phenylthiazol-2-yl) amino) -4-oxobutyl) (methyl) amino) -2-oxoethyl) benzyl) -5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide

To a stirred solution of tert-butyl ((S) -1- (((S) -1-cyclohexyl-2- ((S) -2- ((2- (4- (2- (3- ((5-methoxy-4- ((E) -2- (trans-4- (trifluoromethyl) cyclohexyl) vinyl) picolinamide) methyl) phenyl) -N-methylacetamido) butyrylamino) -4-phenylthiazol-5-yl) carbamoyl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxoprop-2-yl) (methyl) carbamate (1695g, 0.01mmol) in 1,4-dioxane (1 mL) was added 4M HCl in 1,4-dioxane (1ml, 4 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated. The residue was purified by HPLC (Welch Xtimate C18X 30mm X5 um, water (0.225% FA) -ACN, 38-58%) to give the title compound (8mg, 50%) as a white solid. ¹ H NMR(400MHz,CD ₃ OD)：δ8.23(d,J＝12.8Hz,1H),8.10(d,J＝8.8Hz,1H),7.72(d,J＝8.0Hz,2H),7.39(t,J＝7.6Hz,2H),7.33-7.28(m,1H),7.21-7.14(m,3H),7.12-7.08(m,1H),6.67-6.59(m,1H) 6.51-6.43 (m, 1H), 4.60-4.52 (m, 6H), 3.97-3.94 (m, 4H), 3.79-3.68 (m, 3H), 3.43-3.36 (m, 3H), 3.00,2.89 (s, 3H altogether), 2.42-2.32 (m, 6H), 2.13 (m, 6H), 1.99-1.86 (m, 4H), 1.79 (m, 6H), 1.38-1.35 (m, 2H), 1.27-1.25 (m, 9H). LCMS (ESI): m/z 1070.7 (M + H) ⁺ 。

Example 22

His-tagged TEAD protein was preincubated with TEAD project compound for 30 min at room temperature. The biotinylated lipid pocket probe was then added to the TEAD/compound mixture and incubated for 60 minutes at room temperature. The lipid pocket probe competes with the test compound for the TEAD lipid pocket until equilibrium is reached. After 60 minutes europium-labeled anti-His (Perkin Elmer # AD 0110) and XL 665-labeled streptavidin (CIS Bio 610 SAXAC) were added to the TEAD/test compound/lipid pocket mixture and incubated for 30 minutes. The TR-FRET values were then measured using an EnVision multi-label microplate reader (Perkin Elmer catalog # 2104-0010A). If the lipid pocket probe binds TEAD as expected, the proximity of anti-His Eu to XL665 will generate a TR-FRET signal. If the TEAD lipid pocket binder such as binds and displaces the lipid pocket probes, disruption of the TEAD: probe interaction will result in a decrease in the TR-FRET signal. IC generated by using non-linear 4-parameter curve fitting ₅₀ The values determine the efficacy of the compounds as TEAD lipid pocket binders. This assay format is able to measure lipid pocket affinity more sensitively than the above-described TEAD lipid pocket FP assay due to the reduced concentration of TEAD protein required for the TR-FRET assay format.

The results for compounds 1 to 21 are shown in table 3 below.

TABLE 3

This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

It is to be understood that the invention is not to be limited to the specific embodiments and aspects disclosed above, as modifications may be made to the specific embodiments and aspects and still fall within the scope of the appended claims. All documents cited or relied upon herein are expressly incorporated by reference.

Claims

1. A compound of formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[A] is a ligase ligand;

[B] is a linker moiety;

R ² Is H, C _3-10 Cycloalkyl, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl, 5-to 20-membered heteroaryl or C _5-13 Spiro ring group, wherein:

R ² said C of _3-10 Cycloalkyl, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl, 5-to 20-membered heteroaryl or C _5-13 Spiro ring groups are independently optionally substituted with one or more oxo, cyano, halo, C _1-12 Alkyl radical, C _1-12 Haloalkyl, C _3-10 Cycloalkyl radical, C _6-20 Aryl, NO ₂ 、N(R ^x )(R ^y ) And O (R) ^x ) Substitution, wherein:

each R ^x And R ^y Independently selected from the group consisting of: H. c _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl and 5-to 2-memberedA 0-membered heteroaryl, wherein:

R ^x and R ^y Each C of _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl and 5-to 20-membered heteroaryl are independently optionally substituted with one or more oxo, cyano, halo, NO ₂ 、NH ₂ Hydroxy, C _1-12 Alkyl radical, C _1-12 Haloalkyl or O-C _l-12 Alkyl substitution.

2. The compound of claim 1, wherein the linker moiety has the structure of formula (II):

wherein:

(ii) the linker moiety represents a point of attachment to the ligase ligand and the linker moiety represents a point of attachment to the remainder of the molecule;

L ² is- (CH) ₂ ) _n -or- (CH) ₂ CH ₂ O) _n -, where n is 1 to 12;

L ³ is a bond or is-C ≡ C-, -CH = CH-, - (CH) ₂ ) _m -, -O-, -NH-orWherein L is ³ Is represented by ² And L is a connection point of ³ Represents a point of attachment to the ligase ligand; and is

R ^3a And R ^3b Is H, C _1-12 Alkyl radical, C _2-12 Alkenyl radical, C _2-12 Alkynyl, C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _3-10 Cycloalkyl radical, C _1-12 alkyl-C _6-20 Aryl, 3-to 10-membered heterocyclic group, C _6-20 Aryl or 5-to 20-membered heteroaryl, wherein：

3. The compound of claim 2, wherein R ^3a And R ^3b Each of which is independently H or C _1-12 An alkyl group.

4. A compound according to claim 3, wherein R ^3a Is H and R ^3b Is H or methyl.

5. The compound of claim 1, wherein the ligase ligand is an E3 ubiquitin ligase ligand.

6. The compound of claim 5, wherein the E3 ubiquitin ligase ligand is a cereblon ligand, a VHL ligand, or a XIAP ligand.

7. The compound of claim 6, wherein the cereblon ligand has the structure of formula (III):

wherein:

Q ¹ and Q ² Is C = O, and Q ¹ And Q ² Is C = O or CH ₂ ；

R ^a 、R ^b 、R ^c And R ^d Is L with the linker moiety ³ Is/are as followsA bond, and R ^a 、R ^b 、R ^c And R ^d Each of others in (a) is independently H, halo, C _1-12 Alkyl radical, C _1-12 Haloalkyl or O-C _1-12 An alkyl group; and is

R ^e Is H, halo, C _1-12 Alkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl or phenyl.

8. The compound of claim 7, wherein the compound has the structure of formula (IV):

or a stereoisomer or pharmaceutically acceptable salt thereof.

9. The compound of claim 8, wherein the compound has the structure of formula (V):

or a stereoisomer or pharmaceutically acceptable salt thereof.

10. The compound of claim 9, wherein the compound of formula (V) is selected from the group consisting of:

or a stereoisomer or pharmaceutically acceptable salt thereof.

11. The compound of claim 6, wherein the VHL ligand has the structure of formula (VI):

wherein:

W ¹ is CH-C _1-12 Alkyl radical, C _6-20 Aryl or 5-to 20-membered heteroaryl;

W ² is C _6-20 Aryl or 5-to 20-membered heteroaryl, wherein:

W ¹ or W ² Said C of _6-20 Aryl or 5-to 20-membered heteroaryl independently optionally substituted by C _1-12 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl, each of which is further optionally substituted with one or more halo, cyano, or a pharmaceutically acceptable salt thereofHydroxy, N (R) ^x )(R ^y )、C _1-12 Alkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl; and is provided with

R ^g And R ^h Each independently selected from the group consisting of: H. halo, cyano, hydroxy, NH ₂ 、C _1-12 Alkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl and 5-to 20-membered heteroaryl.

12. The compound of claim 11, wherein the compound has the structure of formula (VII):

or a stereoisomer or pharmaceutically acceptable salt thereof.

13. The compound of claim 12, wherein the compound has the structure of formula (VIII):

or a stereoisomer or pharmaceutically acceptable salt thereof.

14. The compound of claim 13, wherein the compound of formula (VIII) is selected from the group consisting of:

or a stereoisomer or pharmaceutically acceptable salt thereof.

15. The compound of claim 6, wherein the XIAP ligand has the structure of formula (IX):

wherein:

T ¹ is a 3-to 10-membered heterocyclyl or 5-to 20-membered heteroaryl, wherein:

Said 3-to 10-membered heterocyclyl or 5-to 20-membered heteroaryl is independently optionally substituted with one or more halo, cyano, hydroxy, N (R) ^x )(R ^y )、C _1-12 Alkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl;

T ² is C (R) ⁱ ) ₂ O or S;

T ³ 、T ⁴ and T ⁵ Each independently is O or S;

each R ⁱ Independently is H, halo, cyano, hydroxy, N (R) ^x )(R ^y )、C _1-12 Alkyl radical, C _1-12 Haloalkyl, O-C _1-12 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl; and is

Each R ^k Independently is H, hydroxy, halo, C _1-12 Alkyl radical, C _1-12 Haloalkyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C _6-20 Aryl or 5-to 20-membered heteroaryl.

16. The compound of claim 15, wherein the compound has the structure of formula (X):

or a stereoisomer or pharmaceutically acceptable salt thereof.

17. The compound of claim 16, wherein the compound has the structure of formula (XI):

or a stereoisomer or pharmaceutically acceptable salt thereof.

18. The compound of claim 17, wherein the compound of formula (XI) is selected from the group consisting of:

or a stereoisomer or pharmaceutically acceptable salt thereof.

19. A compound according to claim 1, or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:

X ¹ Is C-R ⁵ Wherein R is ⁵ Is H;

X ² is N;

X ³ is C-R ⁵ Wherein R is ⁵ Is H; and is

R ¹ Is O-C _1-12 An alkyl group.

20. The compound of claim 19, wherein the compound has the structure of formula (XII):

or a stereoisomer or pharmaceutically acceptable salt thereof.

21. A compound according to claim 20, or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein L ¹ is-CH = CH-.

22. The compound of claim 21, or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R ² Is C _3-10 Cycloalkyl, wherein said C _3-10 Cycloalkyl radicals being interrupted by a C _1-12 Haloalkyl substitution.

23. The compound of claim 22, wherein the compound has the structure of formula (XIII):

or a stereoisomer or pharmaceutically acceptable salt thereof.

24. The compound of claim 20, wherein the compound has the structure of formula (XIV):

or a stereoisomer or pharmaceutically acceptable salt thereof.

25. The compound of claim 20, wherein the compound has the structure of formula (XV):

or a stereoisomer or pharmaceutically acceptable salt thereof.

26. The compound of claim 20, wherein the compound has the structure of formula (XVI):

or a stereoisomer or pharmaceutically acceptable salt thereof.

27. The compound of claim 20, wherein the compound has the structure of formula (XVII):

Or a stereoisomer or pharmaceutically acceptable salt thereof.

28. A compound according to claim 2, or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein L ² Is- (CH) ₂ ) _n -, where n is 1 to 12.

29. A compound according to claim 2, or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein L ² Is- (CH) ₂ ) _n -, where n is 1 to 6.

30. A compound according to claim 2, or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein L ² Is- (CH) ₂ CH ₂ O) _n -, where n is 1 to 12.

31. A compound according to claim 2, or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein L ² Is- (CH) ₂ CH ₂ O) _n -, where n is 1 to 6.

32. The compound of claim 2, or a stereoisomer thereofA structure body or a pharmaceutically acceptable salt thereof, wherein L ³ Is a bond.

33. A compound according to claim 2, or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein L ³ is-O-.

34. A compound according to claim 2, or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein L ³ Is composed of

35. A compound selected from the group consisting of:

or a stereoisomer or pharmaceutically acceptable salt thereof.

36. A compound selected from the group consisting of:

or a stereoisomer or pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

38. A compound according to any one of claims 1 to 36, or a stereoisomer or a pharmaceutically acceptable salt thereof, for use in pharmaceutical therapy.

39. A compound according to any one of claims 1 to 36, or a stereoisomer or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon carcinoma, colorectal carcinoma, craniopharyngeal carcinoma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymal carcinoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor positive breast cancer, primary thrombocythemia, ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular carcinoma, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver carcinoma, hepatocellular carcinoma, hormone-insensitive prostate carcinoma, leiomyosarcoma, leukemia, liposarcoma, lung carcinoma, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphomas (hodgkin and non-hodgkin), bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus malignancies and hyperproliferative disorders, lymphoid malignancies of T-cell or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid carcinoma, fahrenheit macroglobulinemia, testicular tumor, uterine cancer and wilms' tumor.

40. A method of treating cancer in a mammal comprising administering to the mammal a compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically acceptable salt thereof.

41. A compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically-acceptable salt thereof, for use in modulating TEAD activity.

42. A compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically-acceptable salt thereof, for use in the treatment and/or prevention of a disease or condition mediated by TEAD activity.

43. The compound for use according to claim 42, wherein the disease or disorder is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (myelogenous) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable proliferative changes (dysplasia and metaplasia), embryonal cancer, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor positive breast cancer, primary thrombocythemia, ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkin and non-hodgkin), bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus malignancies and hyperproliferative disorders, lymphoid malignancies of T-or B-cell origin, myeloid cancers, medulloblastomas, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, fahrenheit macroglobulinemia, testicular tumor, uterine cancer, and wilms' tumor.

44. Use of a compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by TEAD activity.

45. The use of claim 44, wherein the disease or disorder is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable proliferative changes (dysplasia and metaplasia), embryonal cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, primary thrombocytosis, ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkin's and non-hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung carcinoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung carcinoma, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, fahrenheit macroglobulinemia, testicular tumors, uterine cancer and wilms' tumor.

46. A method of modulating TEAD activity comprising contacting TEAD with a compound according to any one of claims 1 to 36, or a salt thereof.

47. A method of treating a disease or condition mediated by TEAD activity in a mammal comprising administering to the mammal a compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically acceptable salt thereof.

48. The method of claim 47, wherein the disease or disorder is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable proliferative changes (dysplasia and metaplasia), embryonal cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, primary thrombocytosis, ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkin's and non-hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal sarcoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, fahrenheit macroglobulinemia, testicular tumors, uterine cancer and wilms' tumor.

49. Use of a compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically-acceptable salt thereof, for modulating TEAD activity.

50. Use of a compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically-acceptable salt thereof, for the treatment and/or prevention of a disease or condition mediated by TEAD activity.

51. The use of claim 50, wherein the disease or disorder is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable proliferative changes (dysplasia and metaplasia), embryonal cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, primary thrombocytosis, ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkin's and non-hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung carcinoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, lung small cell carcinoma, solid tumors (carcinoma and sarcoma), small cell lung carcinoma, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, fahrenheit macroglobulinemia, testicular tumors, uterine cancer and wilms' tumor.

52. A process for preparing a compound according to any one of claims 1 to 36, or a stereoisomer or a pharmaceutically acceptable salt thereof.

53. A compound prepared by the process of claim 52.

54. A method of degrading a TEAD protein comprising contacting the TEAD protein with a compound of any one of claims 1-36.

55. A ternary complex comprising

A compound according to any one of claims 1 to 36;

a TEAD protein; and

ubiquitin ligase.

56. The invention as hereinbefore described.