CN116669769A

CN116669769A - Piperidinyl small molecule degradants of HELIOS and methods of use

Info

Publication number: CN116669769A
Application number: CN202180067159.3A
Authority: CN
Inventors: B·贝尔; W·佩特里; H·刘; T·张; L·琼斯; J·车
Original assignee: New Variant Co; Dana Farber Cancer Institute Inc
Current assignee: New Variant Co; Dana Farber Cancer Institute Inc
Priority date: 2020-10-16
Filing date: 2021-10-15
Publication date: 2023-08-29

Abstract

Compounds and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof which cause degradation of various proteins such as IKZF2 (Helios) are disclosed. Pharmaceutical compositions containing the compounds, and methods of making and using the compounds to treat diseases and conditions associated with Helios and that may benefit from degradation of Helios are also disclosed.

Description

Piperidinyl small molecule degradants of HELIOS and methods of use

RELATED APPLICATIONS

The present application claims priority from U.S. c. ≡119 (e) to U.S. provisional application No. 63/092,610 filed on day 16 of 10 and 10 of 2020 and U.S. provisional application No. 63/153,599 filed on day 25 of 2 of 2021, each of which is incorporated herein by reference in its entirety.

Background

Imide molecules such as thalidomide (thalidomide) and analogs thereof bind to Cereblon (CRBN), a substrate adapter for ubiquitously expressed kulin (cullin) cycloligase 4 (cull 4) -RBX1-DDB1-CRBN (cull 4 CRBN) E3 ligase (Kronke et al, science 343:301-305 (2014); ito et al, science 327:1345-1350 (2010)). This leads to recruitment, ubiquitination and subsequent proteasome degradation of new substrates, i.e., ikaros (IKZF 1) and Aiolos (IKZF 3), but not any other member of the IKZF zinc finger transcription factor family. CC-885 (an imide analog) is predicted to have some activity in inducing Helios degradation, but also induces GSPT1 (a key translation termination factor) degradation (Matyskiela et al, nature 535:252-257 (2016)).

Helios (IKZF 2) (a member of the IKZF family) are key regulators of T cell activity and function. The gene deletion of Helios resulted in an enhancement of the anti-tumor immune response (Kim et al, science 350:334-339 (2015)). Notably, helios is highly expressed in regulatory T cells (Elkord et al, expert Opin. Biol. Ther.12:1423-1425 (2012)), which are a subset of T cells that limit effector T cell activity. Selective deletion of Helios in regulatory T cells results in both loss of inhibitory activity and acquisition of effector T cell function (Najagawa et al, proc. Natl. Acad. Sci. USA 113:6248-6253 (2016); yates et al, proc. Natl. Acad. Sci. USA 115:2162-2167 (2018)). Thus, helios is a key factor limiting T cell effector function in tregs.

It has been reported that in both cases of chronic viral infection (Crawford et al, immunity 40:289-302 (2014), doering et al, immunity 371130-1144 (2012), scott-Browne et al, immunity45:1327-1340 (2016)) and tumors (Martinez et al, immunity 42:265-278 (2015), mongnol et al, proc.Natl. Acad. Sci. USA114:E2776-E2785 (2017), pereira et al, J.Leukoc. Biol.102:601-615 (2017), singer et al, cell 166:1500-1511 (2016), schietininger et al, immunity 45:389-401 (2016)), and in dysfunctional chimeric antigen receptor (CAR et al, nat. Med. 21:581590 (2016)), helios expression is also "up-regulated". Helios and various splice subtypes have been reported to be overexpressed or aberrantly expressed in several hematological malignancies, including T-cell leukemia and lymphoma (Nakase et al, exp. Hematol.30:313-317 (2002); tabayashi et al, cancer Sci.98:182-188 (2007); asanum et al, cancer Sci.104:1097-1106 (2013)). Furthermore, knocking down Helios in Mixed Lineage Leukemia (MLL) driven myeloid leukemia models effectively suppressed proliferation and increased Cell death (Park et al, J.Clin.Invest.125:1286-1298 (2015); park et al, cell Stem Cell 24:153-165 (2019)).

Disclosure of Invention

A first aspect of the present invention relates to a compound having a structure represented by formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof:

wherein R is _1a 、R _1b 、R _1a ’、R _1b ’、R ₂ 、R ₃ 、R ₄ 、R ₄ ’、R ₅ 、R ₅ ’、R ₆ And n ₁ As defined herein.

A second aspect of the present invention relates to a compound having a structure represented by formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof:

wherein R is _1a 、R _1b 、R _1a ’、R _1b ’、R ₂ 、R ₄ 、R ₄ ’、R ₅ 、R ₅ ’、R ₂₁ And n ₁ As defined herein.

Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a co-crystal of a compound of formula (I) or (II).

Yet another aspect of the invention relates to methods of treating diseases or conditions that would benefit from IKZF2 (Helios) degradation.

In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is T-cell leukemia, T-cell lymphoma, hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple Negative Breast Cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stabilized colorectal cancer (mssccr), thymoma, or carcinoid.

As demonstrated in the working examples, the compounds of the invention exhibit potent degradation of IKZF2 (Helios).

While not intending to be bound by any particular theory of operation, it is believed that the compounds of the invention can enhance an anti-tumor immune response by converting regulatory T cells into effector T cells and by rescuing effector T cell function in depleted T cells or CAR-T cells.

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. As used in the specification and the appended claims, the following terms have the indicated meanings, unless indicated to the contrary, in order to facilitate an understanding of the present invention.

As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes a mixture of two or more such compositions, reference to "an inhibitor" includes a mixture of two or more such inhibitors, and the like.

Unless otherwise indicated, the term "about" refers to within 10% (e.g., within 5%, 2%, or 1%) of a particular value modified by the term "about".

The transitional term "comprising" synonymous with "including," "containing," or "characterized by" is inclusive or open-ended and does not exclude additional unrecited elements or method steps. When used in the context of the number of heteroatoms in a heterocyclic structure, it means a heterocyclic group containing the least number of heteroatoms. In contrast, the transitional phrase "consisting of … …" does not include any element, step, or component not specified in the claims. The transitional phrase "consisting essentially of" defines the scope of the claims as a specified material or step, "as well as a material or step that does not materially affect one or more of the basic and novel characteristics of the claimed invention.

To the extent that the following terms are used herein to further describe the compounds of the present invention, the following definitions apply.

As used herein, the term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon group. In one embodiment, alkyl is C ₁ -C ₁₈ A group. In other embodiments, alkyl is C ₀ -C ₆ 、C ₀ -C ₅ 、C ₀ -C ₃ 、C ₁ -C ₁₂ 、C ₁ -C ₈ 、C ₁ -C ₆ 、C ₁ -C ₅ 、C ₁ -C ₄ Or C ₁ -C ₃ A group (wherein C ₀ Alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, isopropyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. In some embodiments, alkyl is C ₁ -C ₃ An alkyl group. In some embodiments, alkyl is C ₁ -C ₂ Alkyl or methyl.

As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain consisting of only carbon and hydrogen, free of unsaturation, and having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like, connecting the remainder of the molecule to a group. The alkylene chain may be attached to the remainder of the molecule by a single bond and to the group by a single bond. In some embodiments, the alkylene group contains 1 to 8 carbon atoms (C ₁ -C ₈ An alkylene group). In other embodiments, the alkylene group contains 1 to 5 carbon atoms (C ₁ -C ₅ An alkylene group). In other embodiments, the alkylene group contains 1 to 4 carbon atoms (C ₁ -C ₄ An alkylene group). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (C ₁ -C ₃ An alkylene group). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (C ₁ -C ₂ An alkylene group). In other embodiments, the alkylene group contains one carbon atom (C ₁ An alkylene group).

As used herein, the term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl groups include those having "cis" and "trans"oriented, or alternatively" E "and" Z "oriented groups. In one example, alkenyl is C ₂ -C ₁₈ A group. In other embodiments, alkenyl is C ₂ -C ₁₂ 、C ₂ -C ₁₀ 、C ₂ -C ₈ 、C ₂ -C ₆ Or C ₂ -C ₃ A group. Examples include vinyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methylbut-1, 3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1, 3-dienyl.

As used herein, the term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. In one example, alkynyl is C ₂ -C ₁₈ A group. In other examples, alkynyl is C ₂ -C ₁₂ 、C ₂ -C ₁₀ 、C ₂ -C ₈ 、C ₂ -C ₆ Or C ₂ -C ₃ . Examples include ethynyl prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl.

The term "alkoxy" as used herein refers to an alkyl group as defined above having an oxy group attached thereto and the oxy group being the point of attachment. Representative alkoxy groups include methoxy, ethoxy, propoxy, t-butoxy, and the like. An "ether" is two hydrocarbon groups covalently linked by oxygen. Thus, the substituent of the alkyl group that renders the alkyl group an ether is or is analogous to an alkoxy group, such as may be represented by one of-O-alkyl, -O-alkenyl, and-O-alkynyl.

As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine or iodine.

As used herein, the term "cyclic group" refers broadly to any group containing a saturated, partially saturated, or aromatic ring system, used alone or as part of a larger moiety, for example, carbocycles (cycloalkyl, cycloalkenyl), heterocycles (heterocycloalkyl, heterocycloalkenyl), aryl, and heteroaryl. The cyclic group may have one or more (e.g., fused) ring systems. Thus, for example, a cyclic group may contain one or more carbocyclyl, heterocyclyl, aryl, or heteroaryl groups.

As used herein, the term "carbocycle" (also referred to as "carbocyclyl") refers to a group, used alone or as part of a larger moiety, that contains a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms that is part of a separate or larger moiety (e.g., an alkyl carbocyclyl group). The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In one embodiment, the carbocyclyl group contains 3 to 15 carbon atoms (C ₃ -C ₁₅ ). In one embodiment, the carbocyclyl group contains 3 to 12 carbon atoms (C ₃ -C ₁₂ ). In another embodiment, the carbocyclyl group comprises C ₃ -C ₈ 、C ₃ -C ₁₀ Or C ₅ -C ₁₀ . In another embodiment, the carbocyclyl as a single ring comprises C ₃ -C ₈ 、C ₃ -C ₆ Or C ₅ -C ₆ . In some embodiments, the carbocyclyl group as a bicyclic ring comprises C ₇ -C ₁₂ . In another embodiment, the carbocyclyl group as the spiro system comprises C ₅ -C ₁₂ . Representative examples of monocyclic carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuterated cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl and cyclododecyl; bicyclic carbocyclyl groups having 7 to 12 ring atoms include [4,3 ]]、[4,4]、[4,5]、[5,5]、[5,6]Or [6,6 ]]Ring systems, such as, for example, bicyclo [2.2.1 ]]Heptane, bicyclo [2.2.2]Octane, naphthalene and bicyclo [3.2.2]Nonane. Representative examples of spirocarbocyclyl groups include spiro [2.2 ]]Pentane, spiro [2.3 ]]Hexane, spiro [2.4 ]]Heptane, spiro [2.5 ]]Octane and spiro [4.5 ]]Decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated mono-, di-, or spiro carbocycles). The term carbocyclic group also includes groups fused to one or more (e.g., 1, 2, or 3) different cyclic groups Carbocycles of groups (e.g., aryl rings or heterocycles) in which the linking group or point of attachment is on the carbocycle.

Thus, the term carbocycle also encompasses carbocyclylalkyl, which as used herein refers to the formula- -R ^c -carbocyclyl group, wherein R ^c Is an alkylene chain. The term carbocycle also encompasses carbocyclylalkoxy groups, which, as used herein, refers to groups of the formula- -O- -R ^c -a radical bonded to an oxygen atom of a carbocyclyl group, wherein R ^c Is an alkylene chain.

As used herein, the term "aryl" used alone or as part of a larger moiety (e.g., "aralkyl" wherein the terminal carbon atom on the alkyl group is the point of attachment, e.g., benzyl; "aralkoxy" wherein the oxygen atom is the point of attachment, or "aryloxyalkyl" wherein the point of attachment is on an aryl group) refers to a group comprising a monocyclic, bicyclic, or tricyclic carbocyclic ring system (which includes fused rings), wherein at least one ring in the system is aromatic. In some embodiments, the aralkoxy is benzyloxy. The term "aryl" may be used interchangeably with the term "aryl ring". In one embodiment, aryl groups include groups having 6 to 18 carbon atoms. In another embodiment, aryl groups include groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, phenanthryl, naphthacene, 1,2,3, 4-tetrahydronaphthyl, 1H-indenyl, 2, 3-dihydro-1H-indenyl, naphthyridinyl, and the like, which may be substituted with one or more substituents described herein or independently. A particular aryl group is phenyl. In some embodiments, an aryl group comprises an aryl ring fused to one or more (e.g., 1,2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic), wherein the linking group or point of attachment is on the aryl ring. The structure of any aryl group capable of having differently positioned double bonds is considered to encompass any and all such resonating structures.

Thus, the term aryl embraces aralkyl (e.g., benzyl), as disclosed above, which refers to the formula- -R ^c -aryl groups, wherein R ^c Is an alkylene chain such as methylene or ethylene. In some embodiments, the aralkyl is an optionally substituted benzyl. The term aryl also encompasses aralkoxy groupsAs used herein, it refers to the formula- -O- -R ^c -an oxygen atom-bonded group of an aryl group, wherein R ^c Is an alkylene chain such as methylene or ethylene.

As used herein, the term "heterocyclyl" refers to a "carbocyclyl" containing a saturated, partially unsaturated, or aromatic ring system, alone or as part of a larger moiety, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced by heteroatoms (e.g., O, N, N (O), S, S (O), or S (O) ₂ ) Instead of this. The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In some embodiments, heterocyclyl refers to a 3 to 15 membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a 3 to 12 membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3 to 12 membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaryl ring system, such as a 5 to 14 membered heteroaryl ring system. The term heterocyclyl also includes C ₃ -C ₈ Heterocycloalkyl, which is a saturated or partially unsaturated mono-, di-or spiro-ring system containing 3-8 carbons and one or more (1, 2, 3 or 4) heteroatoms.

In some embodiments, heterocyclyl includes 3-12 ring atoms and includes monocyclic, bicyclic, tricyclic, and spiro ring systems, wherein ring atoms are carbon, and 1 to 5 ring atoms are heteroatoms, such as nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl includes 3 to 7 membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocyclyl includes a 4 to 6 membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocyclyl includes a 3-membered monocyclic ring. In some embodiments, the heterocyclyl includes a 4-membered monocyclic ring. In some embodiments, the heterocyclyl comprises a 5-6 membered monocyclic ring. In some embodiments, the heterocyclyl contains 0 to 3 double bonds. In any of the preceding embodiments, the heterocyclyl comprises 1,2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO ₂ ) And any nitrogen heteroatoms may optionally be quaternized (e.g., [ N ]R ₄ ] ⁺ Cl-、[NR ₄ ] ⁺ OH-). Representative examples of heterocyclyl groups include oxiranyl, aziridinyl, thietanyl, azetidinyl, oxetanyl, thietanyl, 1, 2-dithiatanyl, 1, 3-dithiatanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, Oxazinyl, thiazinyl, thia->Alkyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepinyl, thiepanyl, oxazepine->Group, oxazepanyl, diazepinyl, 1, 4-diazepinyl, diazepinyl +.>Radical, thiazal->Radical, thiazepanyl, tetrahydrothiopyranyl,/radical>Oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1-dioxoisothiazolidinonyl,/->Oxazolidone, imidazolonyl, 4,5,6, 7-tetrahydro [2H ]]Indazolyl, tetrahydrobenzimidazolyl, 4,5,6, 7-tetrahydrobenzo [ d ]]Imidazolyl, 1, 6-dihydroimidazo l [4,5-d ]]Pyrrolo [2,3-b]Pyridyl, thiazinyl, thienyl, < ->Oxazinyl, thiadiazinyl,>diazinyl, dithiazinyl, di +.>Oxazinyl, (-) and>thiazinyl, thiatriazinyl, < >>Triazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, di->Alkyl, 1, 3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithiolanyl, pyrimidinonyl, pyrimidindione, pyrimidine-2, 4-dione, piperazinonyl, piperazindione, pyrazolidinimidazolinyl, 3-azabicyclo [3.1.0 ]Hexalkyl, 3, 6-diazabicyclo [3.1.1]Heptyl, 6-azabicyclo [3.1.1]Heptyl, 3-azabicyclo [3.1.1]Heptyl, 3-azabicyclo [4.1.0]Heptyl and azabicyclo [2.2.2]Hexalkyl, 2-azabicyclo [3.2.1]Octyl, 8-azabicyclo [3.2.1]Octyl, 2-azabicyclo [2.2.2]Octyl, 8-azabicyclo [2.2.2]Octyl, 7-oxabicyclo [2.2.1]Heptane, azaspiro [3.5 ]]Nonylalkyl, azaspiro [2.5]Octyl, azaspiro [4.5 ]]Heptyl, 1-azaspiro [4.5 ]]Decan-2-one, azaspiro [5.5 ]]Undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1-dioxo-hexahydrothiopyranyl. Examples of 5-membered heterocyclic groups containing sulfur or oxygen atoms and 1 to 3 nitrogen atoms are thiazolyl groups, includingThiazol-2-yl and thiazol-2-yl N-oxides, thiadiazolyl, including 1,3, 4-thiadiazol-5-yl and 1,2, 4-thiadiazol-5-yl,/-and->Azolyl radicals, e.g.)>Azol-2-yl and->Diazolyl groups such as 1,3,4->Diazol-5-yl and 1,2,4->Diazol-5-yl. Exemplary 5-membered ring heterocyclyl groups containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl such as 1,3, 4-triazol-5-yl, 1,2, 3-triazol-5-yl, 1,2, 4-triazol-5-yl; and tetrazolyl, such as 1H-tetrazol-5-yl. Representative examples of benzo-fused 5-membered heterocyclyl groups are benzo +. >Oxazol-2-yl, benzothiazol-2-yl and benzimidazol-2-yl. Exemplary 6 membered heterocyclyl groups contain 1 to 3 nitrogen atoms and optionally sulfur or oxygen atoms, for example pyridinyl, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; pyrimidinyl such as pyrimidin-2-yl and pyrimidin-4-yl; triazinyl groups such as 1,3, 4-triazin-2-yl and 1,3, 5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl and pyrazinyl. Pyridine N-oxide and pyridazine N-oxide, and other examples of pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazinyl and 1,3, 4-triazin-2-yl are heterocyclyl groups. In some embodiments, a heterocyclic group includes a heterocycle fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocycle or heterocycle), wherein the linking group or point of attachment is on the heterocycle, and in some embodiments, wherein the point of attachment is contained in the heterocycleIs a heteroatom of (2).

Thus, the term heterocycle encompasses N-heterocyclyl, which as used herein refers to a heterocyclyl containing at least one nitrogen, and wherein the point at which the heterocyclyl is attached to the remainder of the molecule passes through the nitrogen atom in the heterocyclyl. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. The term heterocycle also encompasses C-heterocyclyl, as used herein, which refers to a heterocyclyl containing at least one heteroatom, and wherein the point at which the heterocyclyl is attached to the remainder of the molecule passes through a carbon atom in the heterocyclyl. Representative examples of C-heterocyclyl include 2-morpholinyl, 2-or 3-or 4-piperidinyl, 2-piperazinyl, and 2-or 3-pyrrolidinyl. The term heterocycle also encompasses heterocyclylalkyl groups, as disclosed hereinabove, which refers to the formula- -R ^c -a heterocyclyl group, wherein R ^c Is an alkylene chain. The term heterocycle also encompasses heterocyclylalkoxy groups, which, as used herein, refers to the group represented by the formula- -O- -R ^c -a radical to which the oxygen atom of the heterocyclic radical is bonded, wherein R ^c Is an alkylene chain.

As used herein, the term "heteroaryl", alone or as part of a larger moiety (e.g., a "heteroarylalkyl" (also referred to as "heteroarylalkyl") or "heteroarylalkoxy" (also referred to as "heteroarylalkoxy"), refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 ring atoms, at least one of which is aromatic and contains at least one heteroatomAzolyl, iso->Oxazolyl, triazolyl, thiadiazolyl,/-yl>Diazolyl, tetrazolyl, thiatriazolyl, < ->Triazolyl, pyridyl, pyrimidinyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo [1,5-b ]]Pyridazinyl, purinyl, deazapurine, benzo +.>Oxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1, 3-thiazol-2-yl, 1,3, 4-triazol-5-yl, 1,3- >Oxazol-2-yl, 1,3,4->Diazol-5-yl, 1,2,4->Diazole-5-yl, 1,3, 4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2, 3-triazol-5-yl and pyridin-2-yl N-oxide. The term "heteroaryl" also includes groups in which the heteroaryl group is fused to one or more cyclic (e.g., carbocyclyl or heterocyclyl) rings, wherein the linking group or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl (benzothiophenyl), methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodiol>Oxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, pheno->Oxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl and pyrido [2,3-b ]]-1,4-/>Oxazin-3 (4H) -one. Heteroaryl groups may be monocyclic, bicyclic or tricyclic. In some embodiments, heteroaryl groups include heteroaryl rings fused to one or more (e.g., 1,2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic), wherein the linking group or point of attachment is on the heteroaryl ring, and in some embodiments, wherein the point of attachment is a heteroatom contained in the heterocyclic ring. The structure of any heteroaryl group capable of having differently positioned double bonds is considered to encompass any and all such resonating structures.

Thus, the term heteroaryl encompasses N-heteroaryl, which as used herein refers to a heteroaryl as defined above containing at least one nitrogen, and wherein the point at which the heteroaryl is attached to the remainder of the molecule passes through a nitrogen atom in the heteroaryl. The term heteroaryl also encompasses C-heteroaryl, as used herein, which refers to heteroaryl as defined above, and wherein the point at which the heteroaryl is attached to the remainder of the molecule passes through a carbon atom in the heteroaryl. The term heteroaryl also encompasses heteroarylalkyl groups, as disclosed above, which refers to the formula- -R ^c -heteroaryl groups, wherein R ^c Are alkylene chains as defined above. The term heteroaryl also encompasses heteroarylalkoxy (or heteroarylalkoxy), which, as used herein, means a compound represented by the formula- -O- -R ^c -an oxygen atom-bonded group of heteroaryl, wherein R ^c Is an alkylene group as defined above.

Any group described herein may be substituted or unsubstituted, unless otherwise indicated, and to the extent that any one or more specific groups are not further defined. The term "substituted" as used herein refers broadly to all permissible substituents, provided that such substitutions are consistent with the permissible valences of the atoms and substituents to be substituted, and that the substitution results in stable compounds, i.e., compounds which do not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, and the like. Representative substituents include halogen, hydroxyl, and any other organic group grouped in a linear, branched, or cyclic structure containing any number of carbon atoms (e.g., 1-14 carbon atoms) and may contain one or more or (e.g., 1, 2, 3, or 4) heteroatoms such as oxygen, sulfur, and nitrogen.

Representative examples of substituents for any one or more particular groups may include alkyl, substituted alkyl (e.g., C ₁ -C ₆ 、C ₁ -C ₅ 、C ₁ -C ₄ 、C ₁ -C ₃ 、C ₁ -C ₂ 、C ₁ ) Alkoxy (e.g., C ₁ -C ₆ 、C ₁ -C ₅ 、C ₁ -C ₄ 、C ₁ -C ₃ 、C ₁ -C ₂ 、C ₁ ) Substituted alkoxy (e.g., C ₁ -C ₆ 、C ₁ -C ₅ 、C ₁ -C ₄ 、C ₁ -C ₃ 、C ₁ -C ₂ 、C ₁ ) Haloalkyl (e.g., CF) ₃ ) Alkenyl (e.g., C ₂ -C ₆ 、C ₂ -C ₅ 、C ₂ -C ₄ 、C ₂ -C ₃ 、C ₂ ) Substituted alkenyl (e.g., C ₂ -C ₆ 、C ₂ -C ₅ 、C ₂ -C ₄ 、C ₂ -C ₃ 、C ₂ ) Alkynyl (e.g., C ₂ -C ₆ 、C ₂ -C ₅ 、C ₂ -C ₄ 、C ₂ -C ₃ 、C ₂ ) Substituted alkynyl (e.g., C ₂ -C ₆ 、C ₂ -C ₅ 、C ₂ -C ₄ 、C ₂ -C ₃ 、C ₂ ) Ring (e.g. C ₃ -C ₁₂ 、C ₅ -C ₆ ) Substituted cyclic (e.g., C ₃ -C ₁₂ 、C ₅ -C ₆ ) Carbocycles (e.g. C ₃ -C ₁₂ 、C ₅ -C ₆ ) Substituted carbocycles (e.g., C ₃ -C ₁₂ 、C ₅ -C ₆ ) Heterocycles (e.g. C ₃ -C ₁₂ 、C ₅ -C ₆ ) SubstitutedHeterocycles (e.g. C ₃ -C ₁₂ 、C ₅ -C ₆ ) Aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or phenyl), heteroaryl (e.g., pyridyl or pyrimidinyl), substituted heteroaryl (e.g., substituted pyridyl or pyrimidinyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxy, aryloxy (e.g., C) ₆ -C ₁₂ 、C ₆ ) Substituted aryloxy (e.g., C ₆ -C ₁₂ 、C ₆ ) Alkylthio (e.g., C ₁ -C ₆ ) Substituted alkylthio (e.g., C ₁ -C ₆ ) Arylthio (e.g., C ₆ -C ₁₂ 、C ₆ ) Substituted arylthio (e.g., C ₆ -C ₁₂ 、C ₆ ) Cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinylamino, substituted sulfinylamino, sulfonamide, substituted sulfonamide, ureido, substituted ureido, carbamate, substituted carbamate, amino acid, and peptide.

In one aspect, the compounds of the present invention are represented by formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof,

wherein:

each R _1a 、R _1b 、R _1a ' and R _1b ' independently hydrogen or (C) ₁ -C ₆ ) Alkyl, or

R _1a And R is _1a ' together with the same carbon atom to which they are attached form a spiro (C) ₃ -C ₇ ) Cycloalkyl or 4-to 7-membered heterocycloalkyl, or

R, when on different carbon atoms _1a And R is _1a ' together with the carbon atom to which they are attached form (C ₃ -C ₇ ) Cycloalkyl or 4-to 7-membered heterocycloalkyl, or

R _1b And R is _1b ' Forming screw (C) ₃ -C ₇ ) Cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the alkyl, cycloalkyl, or heterocycloalkyl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

each R ₂ Independently selected from the group consisting of: hydrogen, hydroxy, amino, cyano, halo, (C) ₁ -C ₆ ) Alkyl and (C) ₁ -C ₆ ) A haloalkyl group;

R ₃ selected from the group consisting of: hydrogen, amino, hydroxy, cyano, halogen, (C) ₁ -C ₆ ) Alkyl and (C) ₁ -C ₆ ) Haloalkyl wherein said alkyl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Substituted by radicals, or

R ₃ And R is ₄ Together with the carbon atoms to which they are attached form (C ₃ -C ₇ ) Cycloalkyl or 4-to 7-membered heterocycloalkyl, or

R ₂ And R is ₃ Together with the carbon atoms to which they are attached form (C ₃ -C ₇ ) Cycloalkyl or 4-to 7-membered heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl are further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

each R ₄ And R is ₄ ' independently selected from the group consisting of: hydrogen, hydroxy, amino, amido, carbonyl, cyano, halogen, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₁ -C ₆ ) Hydroxyalkyl (C) ₃ -C ₇ ) Cycloalkyl, 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl, monocyclic and bicyclic 5 to 10 membered heteroaryl, (C) ₂ -C ₆ ) Alkenyl group sum (C) ₂ -C ₆ ) Alkynyl; wherein the alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionallyAnd independently by one or more of the same or different R ₁₅ Substituted by radicals, or

R ₄ And R is ₄ ' together with the same carbon atom to which they are attached form a spiro (C) ₃ -C ₇ ) Cycloalkyl or 4-to 7-membered heterocycloalkyl, or

R ₄ And R is ₄ ' together with the same carbon atom to which they are attached form c= (O), or

R, when on different carbon atoms ₄ And R is ₄ ' together with the carbon atom to which they are attached form (C ₃ -C ₇ ) Cycloalkyl or 4-to 7-membered heterocycloalkyl, or

R ₄ And R is ₄ ' together with the carbon atom to which they are attached form (C ₆ -C ₁₀ ) Aryl or 5 or 6 membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

R ₅ and R is ₅ ' independently selected from the group consisting of: hydrogen, (C) ₁ -C ₆ ) Alkyl, (C) ₂ -C ₆ ) Alkenyl group (C) ₂ -C ₆ ) Alkynyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₁ -C ₆ ) Hydroxyalkyl (C) ₃ -C ₇ ) Cycloalkyl, 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl and monocyclic and bicyclic 5 to 10 membered heteroaryl groups; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

R ₆ is R ₇ Substituted aryl or R ₇ Substituted heteroaryl; wherein the aryl or heteroaryl groups are further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Substituted by radicals, or

R ₆ The method comprises the following steps:

R ₇ selected from the group consisting of:

R ₈ selected from (C) ₆ -C ₁₀ ) Aryl and monocyclic and bicyclic 5 to 10 membered heteroaryl groups; wherein the aryl or heteroaryl groups are further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

each R ₉ Independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₇ ) Cycloalkyl, 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl and monocyclic and bicyclic 5 to 10 membered heteroaryl groups; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

each R ₁₁ And R is ₁₁ ' independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₇ ) Cycloalkyl, 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl, monocyclic and bicyclic 5-to 10-membered heteroaryl, halo, cyano, -N (R) ₉ ) ₂ 、-OR ₉ 、(C ₁ -C ₆ ) Alkoxy, (C) ₁ -C ₆ ) Haloalkoxy, (C) ₂ -C ₆ ) Alkenyl group sum (C) ₂ -C ₆ ) Alkynyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution; or (b)

R ₁₁ And R is ₁₁ ' together with the same carbon atom to which they are attached form a spiro (C) ₃ -C ₇ ) Cycloalkyl or 4-to 7-membered heterocycloalkyl, or

R ₁₁ And R is ₁₁ ' together with the same carbon atom to which they are attached form c= (O), or

R, when on different carbon atoms ₁₁ And R is ₁₁ ' together with the carbon atom to which they are attached form (C ₃ -C ₇ ) Cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

R ₁₂ and R is ₁₃ Together with the carbon atoms to which they are attached form (C ₆ -C ₁₀ ) Aryl, or monocyclic or bicyclic 5-to 10-membered heteroaryl, wherein said aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

each R ₁₄ And R is ₁₄ ' independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₇ ) Cycloalkyl, 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl, monocyclic and bicyclic 5-to 10-membered heteroaryl, halo, cyano, -N (R) ₉ ) ₂ 、-OR ₉ 、(C ₁ -C ₆ ) Alkoxy, (C) ₁ -C ₆ ) Haloalkoxy, (C) ₂ -C ₆ ) Alkenyl group sum (C) ₂ -C ₆ ) Alkynyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution; or (b)

R ₁₄ And R is ₁₄ ' together with the same carbon atom to which they are attached form a spiro (C) ₃ -C ₇ ) Cycloalkyl or 4-to 7-membered heterocycloalkyl, or

R ₁₄ And R is ₁₄ ' together with the same carbon atom to which they are attached form c= (O), or

R, when on different carbon atoms ₁₄ And R is ₁₄ ' together with the carbon atom to which they are attached form (C ₃ -C ₇ ) Cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

provided that at least one R ₁₄ And at least one R ₁₄ ' together with the same carbon atom to which they are attached form c= (O);

each R ₁₅ Independently selected from the group consisting of: alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkoxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl arylaminoculfonyl, heteroarylsulfamoyl, N-alkyl-N-arylaminoculfonyl, N-alkyl-N-heteroarylsulfamoyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, aralkylsulfonylamino, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-aryl An alkylaminocarbonyl group, an N-alkyl-N-heteroarylaminocarbonyl group, a cyano group, a nitro group, an azido group, a phosphino group, a phosphoryl group including a phosphino group and a phosphonate group, a cyclic acetal group, a 4-to 7-membered heterocycloalkyl group containing at least one nitrogen atom and linked via said nitrogen atom, an aryl group, a heteroaryl group, and wherein two adjacent R ₁₅ Together with the corresponding atom to which each is bound form aryl, heteroaryl, 5-to 8-membered cycloalkyl or 5-to 8-membered heterocycloalkyl;

R ₁₆ independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₇ ) Cycloalkyl, 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl, monocyclic and bicyclic 5-to 10-membered heteroaryl, halo, cyano, -N (R) ₉ ) ₂ 、-OR ₉ 、(C ₁ -C ₆ ) Alkoxy, (C) ₁ -C ₆ ) Haloalkoxy, (C) ₂ -C ₆ ) Alkenyl group (C) ₂ -C ₆ ) Alkynyl groups and free radicals involved in single bond formation; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

each G is independently selected from C (R ₁₁ )(R ₁₁ ’)、NR ₁₁ And O, provided that at least one G is NR ₁₁ Or O;

W ₁ selected from the group consisting of: -O-, -S-and-NR ₉ -；

W ₂ Selected from the group consisting of: -O-, -S-, -SO ₂ -, -C= (O) -and-NR ₉ -；

Each W is ₃ Is nitrogen or CR ₁₆ ；

Y is-SO ₂ -or-c= (O) -;

each Q is independently selected from C, C (R ₁₆ ) C= (O), O, S, N and NR ₁₆ ；

n ₁ 0, 1 or 2;

n ₃ independently 1, 2 or 3;

n ₄ independently 1 or 2; and is also provided with

n ₅ And independently 0 or 1.

In some embodiments, the compound is represented by formula I, wherein:

each R _1a 、R _1b 、R _1a ' and R _1b ' is hydrogen;

each R ₂ Independently selected from the group consisting of hydrogen, halo, and (C) ₁ -C ₆ ) Alkyl groups;

R ₃ selected from the group consisting of: hydrogen, amino, hydroxy, cyano, halogen, (C) ₁ -C ₆ ) Alkyl and (C) ₁ -C ₆ ) Haloalkyl wherein said alkyl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

each R ₄ And R is ₄ ' independently selected from the group consisting of: hydrogen, hydroxy, halogen, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl and (C) ₁ -C ₆ ) Hydroxyalkyl, wherein said alkyl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Substituted by radicals, or

R, when on different carbon atoms ₄ And R is ₄ ' together with the carbon atom to which they are attached form (C ₃ -C ₇ ) Cycloalkyl or 4 to 7 membered heterocycloalkyl;

R ₅ And R is ₅ ' independently hydrogen or (C) ₁ -C ₆ ) An alkyl group; wherein the alkyl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

R ₆ The method comprises the following steps:

R ₇ selected from the group consisting of:

/>

R, when on different carbon atoms ₁₄ And R is ₁₄ ' together with the carbon atom to which they are attached form (C ₃ -C ₇ ) Cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ The substitution of the groups is carried out,

each R ₁₅ Independently selected from the group consisting of: alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkoxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocyclylalkylaminosulfonyl, arylaminoculfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminoculfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylamino Carbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido, phosphino, phosphoryl including phosphino and phosphonate, cyclic acetal, 4 to 7 membered heterocycloalkyl containing at least one nitrogen atom and linked via said nitrogen atom, aryl, heteroaryl, and wherein two adjacent R ₁₅ Together with the corresponding atom to which each is bound form aryl, heteroaryl, 5-to 8-membered cycloalkyl or 5-to 8-membered heterocycloalkyl;

W ₁ selected from the group consisting of: -O-, -S-and-NR ₉ -；

Each W is ₃ Is nitrogen or CR ₁₆ ；

Y is-SO ₂ -or-c= (O) -;

each Q is independently selected from C, C (R ₁₆ ) C= (O), O, S, N and NR ₁₆ ，

n ₁ 0, 1 or 2;

n ₃ independently 1, 2 or 3;

n ₄ independently 1 or 2; and is also provided with

n ₅ And independently 0 or 1.

In some embodiments, the compound is represented by formula I, wherein:

each R ₂ Is hydrogen;

R ₃ is hydrogen or hydroxy;

each R ₄ And R is ₄ ' independently hydrogen or (C) ₁ -C ₆ ) An alkyl group;

R ₅ and R is ₅ ' independently selected from hydrogen or (C) ₁ -C ₆ ) An alkyl group;

R ₆ is that

Each R ₁₁ And R is ₁₁ ' independently hydrogen or (C) _1- C ₆ ) An alkyl group, wherein the alkyl group is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution; or (b)

R ₁₆ independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, halo, cyano, -N (R) ₉ ) ₂ 、-OR ₉ 、(C ₁ -C ₆ ) Alkoxy, (C) ₁ -C ₆ ) Haloalkoxy and radicals involved in the formation of single bonds; wherein the alkyl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution; and is also provided with

n ₁ 1.

In some embodiments, the compound is represented by formula I, wherein R ₆ Is thatWherein R is ₆ Further optionally and independently substituted with one or more groups selected from: (C) _1- C ₆ ) Alkyl, halo, and cyano; and is also provided with

Each R ₁₁ And R is ₁₁ ' independently hydrogen or (C) _1- C ₆ ) An alkyl group.

In some embodiments, the compound is represented by formula I, R ₈ Selected from:

wherein R is ₈ Further optionally and independently is one or more R ₁₅ And (3) substitution.

In some embodiments, the compound is represented by formula I, R ₈ Selected from:/>

A second aspect of the present invention relates to a compound having a structure represented by formula (II):

wherein:

each R ₄ And R is ₄ ' independently selected from the group consisting of: hydrogen, hydroxy, amino, amido, carbonyl, cyano, halogen, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₁ -C ₆ ) Hydroxyalkyl (C) ₃ -C ₇ ) Cycloalkyl, 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl, monocyclic and bicyclic 5 to 10 membered heteroaryl, (C) ₂ -C ₆ ) Alkenyl group sum (C) ₂ -C ₆ ) Alkynyl; wherein the alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Substituted by radicals, or

each R ₁₅ Independently selected from the group consisting of: alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, Heteroaryloxy, aralkoxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminoculfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminoculfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido, phosphinyl, phosphoryl groups including phosphinyl and phosphonyl, cyclic acetals, 4-to 7-membered heterocycloalkyl, aryl, heteroaryl groups containing at least one nitrogen atom and being linked via said nitrogen atom, and wherein two adjacent R ₁₅ Together with the corresponding atom to which each is bound form aryl, heteroaryl, 5-to 8-membered cycloalkyl or 5-to 8-membered heterocycloalkyl;

R ₂₁ is substituted C ₆ -aryl, provided that said aryl is substituted with at least two R ₁₅ Substituted, with the proviso that when on adjacent carbon atoms, the R ₁₅ Form a 5-or 6-membered heteroaryl group, said 5-or 6-membered heteroaryl group being substituted with at least one (C ₆ -C ₁₀ ) Aryl group,Or a monocyclic or bicyclic 5 to 10 membered heteroaryl substitution; wherein the aryl and heteroaryl groups are further optionally and independently substituted with one or more R ₁₅ Substituted or

R ₂₁ Is a substituted 5-or 6-membered heteroaryl, provided that the heteroaryl is substituted with at least two R ₁₅ Substituted, with the proviso that when on adjacent atoms, the R ₁₅ Two of which form C ₆ -aryl, or 5 or 6 membered heteroaryl, said C ₆ -aryl, or 5-or 6-membered heteroaryl, substituted with at least one (C ₆ -C ₁₀ ) Aryl, or monocyclic or bicyclic 5 to 10 membered heteroaryl substitution; wherein the aryl and heteroaryl groups are further optionally and independently substituted with one or more R ₁₅ Substituted or

R ₂₁ Is that

W ₁ selected from the group consisting of: -O-, -S-and-NR ₉ -；

R ₉ Independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₇ ) Cycloalkyl, 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl and monocyclic and bicyclic 5 to 10 membered heteroaryl groups; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

y is-SO ₂ -or-c= (O) -;

R ₁₆ Independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₇ ) Cycloalkyl, one or more 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl, monocyclic and bicyclic 5-to 10-membered heteroaryl, halo, cyano, -N (R) ₉ ) ₂ 、-OR ₉ 、(C ₁ -C ₆ ) Alkoxy, (C) ₁ -C ₆ ) Haloalkoxy, (C) ₂ -C ₆ ) Alkenyl group (C) ₂ -C ₆ ) Alkynyl groups and free radicals involved in single bond formation; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

n ₁ 0, 1 or 2; and is also provided with

n ₅ And independently 0 or 1.

In some embodiments, the compound is represented by formula II, wherein:

each R _1a 、R _1b 、R _1a ' and R _1b ' is hydrogen;

each R ₂ Is hydrogen;

R ₅ and R is ₅ ' each is hydrogen or (C) ₁ -C ₆ ) An alkyl group;

R ₂₁ is that

Each Q ₁ Independently selected from C, C (R) ₁₆ ) C= (O), O, S, N and NR ₁₆ Provided that at least one Q ₁ Is N;

R ₁₆ independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, halo, cyano, -N (R) ₉ ) ₂ 、-OR ₉ 、(C ₁ -C ₆ ) Alkoxy, (C) ₁ -C ₆ ) Haloalkoxy and radicals involved in the formation of single bonds; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution; and is also provided with

n ₁ 1.

In some embodiments, the compound is represented by formula II, wherein R ₂₁ Selected from:

/>

and wherein R is ₂₁ Optionally and independently is/are substituted with one or more (C _1- C ₆ ) Alkyl, halo, and cyano substitutions.

In some embodiments, the compound is represented by formula II, R ₈ Selected from:

In some embodiments, the compounds of the invention are represented by formula IIa, IIb, IIc, IId or IIe:

wherein,,

each R ₂ Independently selected from the group consisting of hydrogen and halo;

each R ₁₅ Independently selected from the group consisting of: alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkoxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkyl Sulfamoyl, cycloalkylsulfamoyl, heterocyclylalkylsulfamoyl, arylaminoculfonyl, heteroarylsulfamoyl, N-alkyl-N-arylaminoculfonyl, N-alkyl-N-heteroarylsulfamoyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-heteroarylaminocarbonyl, cyano, nitro, aza, phosphino, phosphonyl, cyclic acetal including phosphonyl and phosphonyl, and where the cyclic acetal groups containing at least one and at least 7R atoms adjacent to two heteroatoms are attached via at least one atom of the heteroaryl groups of the two atoms ₁₅ Together with the corresponding atom to which each is bound form aryl, heteroaryl, 5-to 8-membered cycloalkyl or 5-to 8-membered heterocycloalkyl; and is also provided with

Each R ₁₆ Independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl and halo.

In some embodiments, R ₈ Selected from:

wherein the method comprises the steps of

R ₈ Further optionally and independently is/are substituted with one or more (C ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₁ -C ₆ ) Alkoxy, cyano, halo and one or more groups selected from R ₁₅ Is substituted by a group of (2); and is also provided with

R ₁₆ ' selected from hydrogen and (C) _1- C ₆ ) Alkyl groups.

Representative compounds of the present invention have the following structure:

/>

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Formula I encompasses compounds 1-26, 32-34 and 45-52. Formula II encompasses compounds 27-31, 35-44 and 53-99.

The compounds of the invention (compounds of formula (I) and (II)) may be in the form of the free acid or the free base or a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable" in the context of salts refers to salts of a compound that do not abrogate the biological activity or properties of the compound, and that are relatively non-toxic, i.e., the compound in salt form may be administered to a subject without causing undesirable biological effects (such as dizziness or gastric discomfort) or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The term "pharmaceutically acceptable salt" refers to the product obtained by reacting a compound of the invention with a suitable acid or base. Examples of pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic bases, such as Li salts, na salts, K salts, ca salts, mg salts, fe salts, cu salts, al salts, zn salts, and Mn salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, mesylate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate, p-toluenesulfonate and the like. Certain compounds of the invention may form pharmaceutically acceptable salts with various organic bases, such as lysine, arginine, guanidine, diethanolamine, or metformin. Suitable base salts include aluminum, calcium, lithium, magnesium, potassium, sodium or zinc salts.

The compounds of the invention may have at least one chiral center and thus may be in the form of stereoisomers, which as used herein encompass all isomers of a single compound that differ only in the orientation of its atoms in space. The term stereoisomers includes mirror image isomers (including enantiomers of the (R-) or (S-) configuration of the compounds), mirror image isomer mixtures of the compounds (physical mixtures of enantiomers and racemates or racemic mixtures), geometric (cis/trans or E/Z, R/S) isomers of the compounds and isomers of the compounds (diastereomers) which have more than one chiral center and are not mirror images of each other. Chiral centers of compounds may undergo epimerization in vivo; thus, for these compounds, administration of a compound in its (R-) form is considered equivalent to administration of a compound in its (S-) form. Thus, the compounds of the present invention may be made and used in the form of individual isomers and substantially free of other isomers, or in the form of mixtures of various isomers (e.g., racemic mixtures of stereoisomers).

In some embodiments, the compound is an isotopic derivative in that it has at least one desired isotopic substitution of an atom in an amount higher than the natural abundance, i.e., enrichment, of the isotope. In one embodiment, the compound comprises deuterium or multiple deuterium atoms. With a chemical compound such as deuterium (i.e., ² H) Substitution of heavier isotopes of (i) may afford certain therapeutic advantages resulting from greater metabolic stability, for example,an increased in vivo half-life or reduced dosage requirements, and thus may be advantageous in some circumstances.

The compounds of the invention may also be in the form of N-oxides, crystalline forms (also known as polymorphs), active metabolites, prodrugs, tautomers and unsolvated forms of the compounds as well as solvated (e.g., hydrated) forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, of the compounds having the same type of activity.

The compounds of the present invention may be prepared by crystallization under different conditions and may exist as one polymorph or a combination of polymorphs of the compound. For example, different polymorphs can be identified and/or prepared by performing crystallization at different temperatures, or by performing recrystallization using different solvents or different solvent mixtures during crystallization using various cooling modes ranging from very fast to very slow cooling. Polymorphs can also be obtained by heating or melting the compound followed by gradual or rapid cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction patterns, and/or other known techniques.

In some embodiments, the pharmaceutical composition comprises a co-crystal of the inventive compound. The term "co-crystal" as used herein refers to a stoichiometric multicomponent system comprising a compound of the invention and a co-crystal former, wherein the compound of the invention and the co-crystal former are linked by a non-covalent interaction. The term "co-crystal former" as used herein refers to a compound that can form intermolecular interactions with the compounds of the present invention and co-crystallize therewith. Representative examples of co-crystal formers include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2, 5-dihydroxybenzoic acid, glycolic acid, trans-2-hexanoic acid, 2-hydroxycaproic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4' -bipyridine para-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl 4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, pyrogallol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone (phenozone), etoxytheophylline (etofyline), and phenobarbital.

Synthesis method

In another aspect, the invention relates to a process for preparing a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In a broad sense, the compounds of the present invention, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, may be prepared by any method known to be suitable for preparing chemically related compounds. The compounds of the present invention will be better understood in conjunction with the synthetic schemes described in the various working examples, which illustrate non-limiting methods by which the compounds of the present invention can be prepared.

Pharmaceutical composition

Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as known in the art refers to a pharmaceutically acceptable material, composition or vehicle suitable for administration of the compounds of the present invention to a mammal. Suitable carriers can include, for example, liquids (aqueous and non-aqueous analogs, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids) and gases that function to carry or transport the compounds from one organ or portion of the body to another organ or portion of the body. The carrier is "acceptable" in the sense of being physiologically inert to the other ingredients of the formulation, compatible with the other ingredients of the formulation, and not deleterious to the subject or patient. Depending on the type of formulation, the composition may also comprise one or more pharmaceutically acceptable excipients.

Broadly, the compounds of the present invention and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof may be formulated into a given type of composition according to conventional pharmaceutical practice, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, and compressing processes (see, for example, remington: pharmaceutical science and practice (The Science and Practice of Pharmacy) (20 th edition), editions of a.r.gennaro, lippincott Williams & Wilkins,2000 and encyclopedia of pharmaceutical technology (Encyclopedia of Pharmaceutical Technology), editions of j.swarbrick and j.c. boylan, 1988-1999,Marcel Dekker,New York). The type of formulation depends on the mode of administration, which may include enteral (e.g., oral, buccal, sublingual, and rectal), parenteral (e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), and intrasternal injection, or infusion techniques, intraocular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation), and topical (e.g., transdermal). Generally, the most appropriate route of administration will depend on a variety of factors including, for example, the nature of the agent (e.g., its stability in the gastrointestinal environment) and/or the condition of the subject (e.g., whether the subject is capable of tolerating oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous because the compounds may be administered relatively quickly, such as in the case of single dose therapies and/or acute conditions.

In some embodiments, the compounds are formulated for oral or intravenous administration (e.g., systemic intravenous injection).

Thus, the compounds of the present invention may be formulated as solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which the compound solid particles are dispersed, emulsions, and solutions containing liposomes, micelles, or nanoparticles, syrups, and elixirs); semisolid compositions (e.g., gels, suspensions, and creams); and gases (e.g., propellants for aerosol compositions). The compounds may also be formulated for rapid, immediate or extended release.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with a carrier such as sodium citrate or dicalcium phosphate and additional carriers or excipients such as the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia (acacia), c) wetting agents such as glycerol, d) disintegrants such as crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethylcellulose (crosslinked sodium carboxymethylcellulose), sodium starch glycolate, agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Similar types of solid compositions can also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings. They may further contain opacifying agents.

In some embodiments, the compounds of the present invention may be formulated into hard or soft gelatin capsules. Representative excipients that may be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, lactose anhydrous, microcrystalline cellulose, and croscarmellose sodium. The gelatin shell may comprise gelatin, titanium dioxide, iron oxide, and a colorant.

Liquid dosage forms for oral administration include solutions, emulsions, microemulsions, syrups and elixirs. In addition to the compounds, liquid dosage forms may contain aqueous or non-aqueous carriers commonly used in the art (depending on the solubility of the compound), such as, for example, water or other solvents; solubilizing agents and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. The oral compositions may also contain excipients such as wetting agents, suspending agents, coloring agents, sweetening, flavoring and perfuming agents.

Injectable formulations for parenteral administration may include sterile aqueous solutions or oily suspensions. They may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be employed include water, ringer's solution (u.s.p.) and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The injectable formulation may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. The action of the compound can be prolonged by slowing its absorption, which can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. Absorption of the compound from a parenterally administered formulation may also be prolonged by suspending the compound in an oily vehicle.

In certain embodiments, the compounds of the invention may be administered in a local rather than systemic manner, for example, via direct injection of the conjugate into the organ, typically in the form of a depot (depot) formulation or a sustained release formulation. In particular embodiments, the depot formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Injectable depot forms are made by forming a matrix of microcapsules of a compound in biodegradable polymers, such as polylactide-polyglycolide, poly (orthoesters) and poly (anhydrides). The release rate of the compound can be controlled by varying the ratio of compound to polymer and the nature of the particular polymer used. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compounds are delivered in targeted drug delivery systems, e.g., in liposomes coated with organ-specific antibodies. In such embodiments, the liposome targets and is selectively absorbed by the organ.

The compositions may be formulated for buccal or sublingual administration, examples of which include tablets, troches and gels.

The compounds of the invention may be formulated for administration by inhalation. Various forms suitable for inhaled administration include aerosols, foggers or powders. The pharmaceutical composition may be delivered from a pressurized package or nebulizer in the form of an aerosol spray presentation using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In some embodiments, the dosage unit of the pressurized aerosol may be determined by providing a valve that delivers a metered amount. In some embodiments, capsules and cartridges containing, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds of the invention may be formulated for topical administration, as used herein, which refers to intradermal administration of the formulations to the epidermis by the invention. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.

Representative examples of carriers that can be used to formulate the compounds for topical application include solvents (e.g., alcohols, polyols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffer solutions (e.g., hypotonic or buffered saline). For example, saturated or unsaturated fatty acids (such as stearic, palmitic, oleic, palmitoleic, cetyl or oleyl alcohol) may be used to formulate a cream. The cream may also contain nonionic surfactants such as polyoxy-40-stearate (polyoxy-40-stearate).

In some embodiments, the topical formulation may further comprise an excipient, an example of which is a penetration enhancer. These agents are capable of transporting the pharmacologically active compound across the stratum corneum and preferably into the epidermis or dermis with little or no systemic absorption. Numerous compounds have been evaluated for their effectiveness in increasing the permeation rate of drugs through the skin. See, e.g., transdermal penetration enhancers (Percutaneous Penetration Enhancers), mailach h.i. and Smith h.e. (editions), CRC Press company, boca Raton, fla (1995), which examined the use and testing of various skin penetration enhancers; and Buyuktimkin et al, chemical means for transdermal drug permeation enhancement in transdermal and topical drug delivery systems (Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems), gosh T.K., pfister W.R., yum S.I. (eds.), interferon Press, buffalo Grove, ill. (1997). Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethanol, isopropanol, octylphenyl polyethylene glycol (octolyphenylpolyethylene glycol), oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methyl pyrrolidone.

Representative examples of other excipients that may be included in topical formulations, as well as other types of formulations (to the extent they are compatible), include preservatives, antioxidants, moisturizers, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulphite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols and chelating agents such as EDTA and citric acid. Suitable humectants include glycerin, sorbitol, polyethylene glycol, urea and propylene glycol. Suitable buffers include citric acid, hydrochloric acid and lactic acid buffers. Suitable solubilizing agents include quaternary ammonium chloride, cyclodextrin, benzyl formate, lecithin and polysorbate. Suitable skin protectants include vitamin E oil, allantoin, dimethicone, glycerin, petrolatum, and zinc oxide.

Transdermal formulations generally employ transdermal delivery devices and transdermal delivery patches in which the compounds are formulated as lipophilic emulsions or buffered aqueous solutions, dissolved and/or dispersed in a polymer or adhesive. The patch may be configured for continuous, pulsatile, or on-demand delivery of the agent. Transdermal delivery of the compounds may be achieved by means of iontophoretic patches. Transdermal patches can provide controlled delivery of compounds, where the rate of absorption is slowed by the use of a rate controlling membrane or by entrapment of the compound within a polymer matrix or gel. Absorption enhancers may be used to increase absorption, examples of which include absorbable pharmaceutically acceptable solvents that aid in passage through the skin.

Ophthalmic formulations include eye drops.

Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG and the like. Compositions for rectal or vaginal administration may also be formulated as suppositories, which may be prepared by mixing the compound with suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycols, suppository waxes and combinations thereof, which are both solid at the ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.

Dosage amount

As used herein, the term "therapeutically effective amount" refers to the following amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof: which produces the desired therapeutic response in patients suffering from diseases or conditions involving IKZF2 (Helios) and would benefit from IKZF2 degradation. Thus, the term "therapeutically effective amount" includes the following amounts of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof: which when administered induces a positive change in the disease or disorder to be treated in the subject, or is sufficient to prevent the development or progression of the disease or disorder, or to alleviate to some extent one or more symptoms of the disease or disorder being treated, or simply kills or inhibits the growth of diseased cells or reduces the amount of IKZF2 in the diseased cells.

The total daily dose of the compound and its use may be determined according to standard medical practice, for example, by the attending physician using sound medical judgment. The specific therapeutically effective dose for any particular subject will depend on a variety of factors, including the following: the disease or disorder being treated and its severity (e.g., its status); the activity of the compound employed; the specific composition employed; age, weight, general health, sex, and diet of the subject; the time of administration, route of administration and rate of excretion of the compound employed; duration of treatment; a medicament for use in combination or simultaneously with the particular compound employed; and similar factors well known in the medical arts (see, e.g., hardman et al, editors, goodman and Gilman, pharmacological basis for therapeutics (The Pharmacological Basis of Therapeutics), 10 th edition, mcGraw-Hill Press,155-173, 2001).

The compounds of the present invention may be effective over a wide dosage range. In some embodiments, the total daily dose (e.g., for an adult) may range from about 0.001 to about 1600mg per day, 0.01 to about 1000mg per day, 0.01 to about 500mg per day, about 0.01 to about 100mg per day, about 0.5 to about 100mg per day, 1 to about 100-400mg per day, about 1 to about 50mg per day, about 5 to about 40mg per day, and in other embodiments about 10 to about 30mg per day. Depending on the number of daily administrations of the compound, a single dose may be formulated to contain the desired dose. For example, capsules may be formulated with about 1 to about 200mg (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg) of the compound. In some embodiments, the compound may be administered at a dose in the range of about 0.01mg to about 200mg per kg body weight per day. In some embodiments, a dose of 0.1 to 100mg/kg per day (e.g., 1 to 30mg/kg per day) may be effective in one or more doses per day. For example, a suitable dose for oral administration may be in the range of 1-30mg/kg body weight per day, and a suitable dose for intravenous administration may be in the range of 1-10mg/kg body weight per day.

Application method

In some aspects, the invention relates to methods of treating diseases or conditions involving IKZF2 in need thereof by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Broadly, diseases or conditions that may be amenable to treatment with the compounds of the present invention involve IKZF2 or IKZF2 activity that is otherwise dysfunctional relative to non-pathological conditions. A "disease" is generally considered to be a state of health of a subject, wherein the subject is unable to maintain homeostasis, and wherein the subject's health continues to deteriorate if the disease is not improved. In contrast, a "steady state" of a subject is a state of health in which the subject is able to maintain steady state, but in which the subject's state of health is less favorable than in the absence of the disorder. If left untreated, the condition does not necessarily lead to a further decline in the health of the subject. In some embodiments, the compounds of formulas (I) and (II) are useful in the treatment of cell proliferative diseases and disorders (e.g., cancer or benign neoplasms). As used herein, the term "cell proliferative disease or disorder" refers to conditions characterized by deregulation or abnormal cell growth or both, including non-cancerous conditions (such as neoplasms, pre-cancerous conditions, benign tumors) and cancers.

The term "subject" (or "patient") as used herein includes all members of the animal kingdom that are susceptible to or suffering from the indicated disease or condition. In some embodiments, the subject is a mammal, e.g., a human or non-human mammal. The method is also applicable to companion animals such as dogs and cats, as well as livestock such as cows, horses, sheep, goats, pigs, and other domesticated and wild animals. A subject "in need of" treatment according to the invention may be "suffering from or suspected of suffering from" a particular disease or disorder, may have been diagnosed or otherwise presented with a sufficient number of risk factors or a sufficient number of signs or symptoms or combination of signs or symptoms such that a medical professional may diagnose or suspected the subject to suffer from the disease or disorder. Thus, subjects suffering from and suspected of suffering from a particular disease or disorder are not necessarily two distinct populations.

Exemplary types of non-cancerous (e.g., cell proliferative) diseases or conditions that can be treated with the compounds of the invention include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, heart diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, and allergic and genetic diseases.

Representative examples of specific non-cancerous diseases and conditions include rheumatoid arthritis, alopecia areata, lymphoproliferative conditions, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, anhidrotic ectodermal dysplasia, simple erythrocyte anemia, and idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryocystitis, crypto-thermal protein related periodic syndrome (CAPS), endotoxic shock, endometritis, gram-negative sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammation, chronic graft rejection, suppurative sweat gland, inflammatory bowel disease Crohn's disease, behcet's syndrome, systemic lupus erythematosus, glomerulonephritis, multiple sclerosis, juvenile onset diabetes, autoimmune uveitis, autoimmune vasculitis, thyroiditis, edison's disease, lichen planus, appendicitis, bullous pemphigoid, leaf-type pemphigoid, paraneoplastic pemphigoid, myasthenia gravis, immunoglobulin A kidney disease, hashimoto's disease, sjogren's syndrome, white spots, wegener's granulomatosis (Wegener granulomatosis), granulomatous orchitis, autoimmune ovaritis, sarcoidosis, rheumatic heart disease, ankylosing spondylitis, graves disease, autoimmune thrombocytopenic purpura, psoriasis, psoriatic arthritis, eczema, dermatitis herpetiformis, ulcerative colitis, pancreatic fibrosis, hepatitis, liver fibrosis, CD 14-mediated sepsis, non-CD 14-mediated sepsis, acute and chronic kidney disease, irritable bowel syndrome, heartburn (pyresis), restenosis, cervicitis, stroke and ischemic injury, neurotrauma, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, congestive heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, lyme disease (Lyme disease), reiter's syndrome (Reiter's ssyndrome), acute synovitis, muscle degeneration, bursitis, tendinitis, tenosynovitis, dysenteriae, congestive heart failure, chronic coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, lyme disease, and the like disc herniation, rupture or prolapse syndrome, osteosclerosis, rhinosinusitis, thrombosis, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, fibromyalgia, AIDS and other viral diseases such as shingles, herpes simplex I or II, influenza virus and cytomegalovirus, diabetes type I and type II, obesity, insulin resistance and diabetic retinopathy, 22q11.2 deficiency syndrome, angleman syndrome (Angelman syndrome), kanavan disease, celiac disease, charcot-mare-posi disease (Charcot-Marie-toolh disease), color blindness, cat cry like crying (cridu chat, down syndrome), cystic fibrosis, duchenne muscular dystrophy (Duchenne muscular dystrophy), hemophilia, kerter's syndrome (klineiter' ssyne), hemophilia, neurofibromatosis, phenylketonuria, prader-Willi syndrome (Prader-Willi syndrome), sickle cell disease, tay-Sachs disease, turner syndrome (urea circulatory disorder, thalassemia, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, uveitis, polymyositis, proctitis, interstitial pulmonary fibrosis, dermatomyositis, atherosclerosis, arteriosclerosis, amyotrophic lateral sclerosis, nonsocial, varicose veins, vaginitis, depression, and sudden infant death syndrome.

In other embodiments, the methods are directed to treating a subject having cancer. In a broad sense, the compounds of the invention are effective in the treatment of cancers (solid tumors, including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers (cancers affecting the blood including lymphocytes, bone marrow, and/or lymph nodes), such as leukemia, lymphoma, and multiple myeloma. Including adult tumors/cancers and pediatric tumors/cancers. The cancer may be a vascularized, or not yet substantially vascularized, or non-vascularized tumor.

Representative examples of cancers include adrenal cortical cancer, AIDS-related cancers (e.g., kaposi's (Kaposi ') and AIDS-related lymphomas), appendiceal cancer, childhood cancer (e.g., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), cholangiocarcinoma, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, bladder cancer, urinary bladder cancer, brain cancer (e.g., glioma and glioblastoma such as brain stem glioma, gestational trophoblastoma glioma, cerebellar glioma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supracurtain primary neuroectodermal tumor, visual pathway and hypothalamic glioma), breast cancer, bronchial adenoma/carcinoid, carcinoid tumor, nervous system cancer (e.g., central nervous system cancers, central nervous system lymphomas), cervical cancer, chronic myeloproliferative disorders, colorectal cancer (e.g., colon cancer, rectal cancer), polycythemia vera, lymphoid neoplasms, mycosis fungoides, szerni Syndrome (Sezary syncrome), endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic cholangiocarcinomas, ocular cancer, intraocular melanoma, retinoblastomas, gall bladder cancer, gastrointestinal cancer (e.g., gastric cancer, small intestine cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST)), germ cell tumors, ovarian germ cell tumors, head and neck cancer, hodgkin's lymphoma, leukemia, lymphoma, multiple myeloma, hepatocellular carcinoma, hypopharyngeal carcinoma, intraocular melanoma Eye cancer, islet cell Tumor (endocrine pancreas), kidney cancer (e.g., wilms's Tumor), clear cell renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), waldenstem's macroglobulinemia (Waldenstrom's macroglobulinema), melanoma, intraocular (eye) melanoma, meckel cell carcinoma (merkel cell carcinoma), mesothelioma, occult primary metastatic squamous neck cancer, multiple Endocrine Neoplasia (MEN), myelodysplastic syndrome, idiopathic thrombocythemia, myelodysplastic/myeloproliferative diseases, nasopharyngeal carcinoma, neuroblastoma, oral cancer (e.g., oral cancer, lip cancer, oral cancer (oral cavity cancer), tongue cancer, oropharyngeal cancer, laryngeal carcinoma (throat cancer), laryngeal cancer), ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell Tumor, ovarian low malignant potential Tumor), pancreatic cancer, pancreatic islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma, pituitary Tumor, plasma cell neoplasm, pleural pneumoblastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial uterine cancer, uterine sarcoma, uterine body cancer), squamous cell carcinoma, testicular cancer, thymoma (thymoma), thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, urethral cancer, trophoblastoma, vaginal cancer, and vulval cancer.

Sarcomas which can be treated with the compounds of the invention also include both soft tissue and bone cancers, representative examples of which include osteosarcoma or osteogenic sarcoma (bone) (e.g., ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelioma or mesothelioma (membranous lining of the body cavity), fibrosarcoma (fibrous tissue), angiosarcoma or vascular endothelial tumor (blood vessel), liposarcoma (adipose tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primary embryonal connective tissue) and mesothelioma (mesenchymous tumor) or mixed mesoblastoma (mixed connective tissue type).

In some embodiments, the methods of the invention entail treating a subject suffering from a cell proliferative disease or disorder of the blood system, liver, brain, lung, colon, pancreas, prostate, ovary, breast, skin, and endometrium.

As used herein, "cell proliferative disease or disorder of the blood system" includes lymphomas, leukemias, myeloid neoplasms, mast cell neoplasms, myelodysplasias, benign monoclonal gammaglobulosis, lymphomatoid papulosis, polycythemia vera, chronic myelogenous leukemia, myelodysplastic causes, and idiopathic thrombocythemia. Representative examples of hematological cancers may thus include multiple myeloma, lymphoma (including T-cell lymphoma, hodgkin's lymphoma, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular Lymphoma (FL), mantle Cell Lymphoma (MCL), and ALK+ anaplastic large cell lymphoma (e.g., B-cell non-Hodgkin's lymphoma), selected from diffuse large B-cell lymphoma (e.g., germinal center B-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma), burkitt's lymphoma (Burkitt's lymphoma)/leukemia, mantle cell lymphoma, mediastinal (thymus) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic/Fahrenheit, metastatic pancreatic adenocarcinoma, refractory B-cell non-hodgkin lymphoma, and recurrent B-cell non-hodgkin lymphoma, childhood lymphoma, and lymphomas of both cell and cutaneous origin, for example, small lymphocytic lymphomas, leukemias, including childhood leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphoblastic leukemia, chronic myelogenous leukemia and mast cell leukemia, myeloid neoplasms and mast cell neoplasms.

As used herein, "cell proliferative disease or disorder of the liver" includes all forms of cell proliferative disorders affecting the liver. Cell proliferative disorders of the liver may include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and hepatoblastoma), precancerous or precancerous conditions of the liver, benign growth or lesions of the liver, malignant growth or lesions of the liver, and metastatic lesions in body tissues and organs other than the liver. Cell proliferative disorders of the brain may include hyperplasia, metaplasia, dysplasia, hepatocellular carcinoma, intrahepatic cholangiocarcinoma (cholangiocarcinoma), angiosarcoma, hepatoblastoma, and secondary liver cancer (metastatic liver cancer).

As used herein, a "cell proliferative disease or disorder of the brain" includes all forms of cell proliferative disorders affecting the brain. Cell proliferative disorders of the brain may include brain cancers (e.g., glioma, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, and primitive neuroectodermal tumors (medulloblastoma)), precancerous or precancerous conditions of the brain, benign growth or lesions of the brain, malignant growth or lesions of the brain, and metastatic lesions in body tissues and organs other than the brain. Cell proliferative disorders of the brain may include hyperplasia, metaplasia and dysplasia of the brain.

As used herein, "cell proliferative disease or disorder of the lung" includes all forms of cell proliferative disorders affecting lung cells. Cell proliferative disorders of the lung include lung cancer, precancers and precancerous conditions of the lung, benign growth or lesions of the lung, hyperplasia, metaplasias and dysplasia of the lung, and metastatic lesions in body tissues and organs other than the lung. Lung cancer includes all forms of lung cancer, e.g., malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer includes small cell lung cancer ("SLCL"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, squamous cell carcinoma, and mesothelioma. Lung cancer may include "scar cancer," bronchoalveolar cancer, giant cell cancer, spindle cell cancer, and large cell neuroendocrine cancer. Lung cancer also includes lung neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cell types). In some embodiments, the compounds of the invention are useful for treating non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC carrying ROS1 rearrangement, lung adenocarcinoma, and squamous cell lung carcinoma).

As used herein, a "cell proliferative disease or disorder of the colon" includes all forms of cell proliferative disorders affecting the cells of the colon, including colon cancer, precancers or precancerous conditions of the colon, adenomatous polyps of the colon, and heterotemporal lesions of the colon. Colon cancer includes sporadic and hereditary colon cancer, malignant colon neoplasms, carcinoma in situ, typical and atypical carcinoid tumors, adenocarcinomas, squamous cell carcinomas and squamous cell carcinomas. Colon cancer may be associated with hereditary syndromes such as: hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, MYH-related polyposis, gardner's syndrome, peutz-Jeghers syndrome, peclet's syndrome, and juvenile polyposis. Cell proliferative disorders of the colon may also be characterized by hyperplasia, metaplasia or dysplasia of the colon.

As used herein, "cell proliferative disease or disorder of the pancreas" includes all forms of cell proliferative disorders that affect pancreatic cells. Cell proliferative disorders of the pancreas can include pancreatic cancer, precancerous or precancerous conditions of the pancreas, hyperplasia of the pancreas, dysplasia of the pancreas, benign growth or lesions of the pancreas, and malignant growth or lesions of the pancreas, as well as metastatic lesions in body tissues and organs other than the pancreas. Pancreatic cancer includes all forms of pancreatic cancer, including ductal adenocarcinoma, adenosquamous carcinoma, polymorphous giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, bursa adenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatic blastoma, papillary neoplasms, bursa adenoma, papillary cystic neoplasms, and serous cystic adenoma, as well as pancreatic neoplasms having histological and ultrastructural heterogeneity (e.g., mixed cell types).

As used herein, "cell proliferative disease or disorder of the prostate" includes all forms of cell proliferative disorders affecting the prostate. Cell proliferative disorders of the prostate may include prostate cancer, precancers or precancerous conditions of the prostate, benign growths or lesions of the prostate and malignant growths or lesions of the prostate, as well as metastatic lesions in body tissues and organs other than the prostate. Cell proliferative disorders of the prostate may include hyperplasia, metaplasia and dysplasia of the prostate.

As used herein, "cell proliferative disease or disorder of the ovary" includes all forms of cell proliferative disorders affecting ovarian cells. Cell proliferative disorders of the ovary can include precancerous or precancerous conditions of the ovary, benign growth or lesions of the ovary, ovarian cancer, and metastatic lesions in body tissues and organs other than the ovary. Cell proliferative disorders of the ovary can include hyperplasia, metaplasia and dysplasia of the ovary.

As used herein, "cell proliferative disease or disorder of the breast" includes all forms of cell proliferative disorders affecting breast cells. Cell proliferative disorders of the breast may include breast cancer, precancerous or precancerous conditions of the breast, benign growth or lesions of the breast, and metastatic lesions in body tissues and organs other than the breast. Cell proliferative disorders of the breast may include hyperplasia, metaplasia and dysplasia of the breast.

As used herein, "cell proliferative disease or disorder of the skin" includes all forms of cell proliferative disorders that affect skin cells. Cell proliferative disorders of the skin may include precancerous or precancerous conditions of the skin, benign growth or lesions of the skin, melanoma, malignant melanoma or other malignant growth or lesions of the skin, and metastatic lesions in body tissues and organs other than the skin. Cell proliferative disorders of the skin may include hyperplasia, metaplasia and dysplasia of the skin.

As used herein, "cell proliferative disease or disorder of the endometrium" includes all forms of cell proliferative disorders affecting endometrial cells. Cell proliferative disorders of the endometrium may include precancerous or precancerous conditions of the endometrium, benign growth or lesions of the endometrium, endometrial cancer, and metastatic lesions in body tissues and organs other than the endometrium. Cell proliferative disorders of the endometrium may include hyperplasia, metaplasia and dysplasia of the endometrium.

In some embodiments, the compounds of the invention are useful for treating T cell leukemia or T cell lymphoma.

In some embodiments, the compounds of the invention are useful for treating hodgkin's lymphoma or non-hodgkin's lymphoma.

In some embodiments, the compounds of the invention are useful for treating myeloid leukemia.

In some embodiments, the compounds of the invention are useful for treating non-small cell lung cancer (NSCLC).

In some embodiments, the compounds of the invention are useful for treating melanoma.

In some embodiments, the compounds of the invention are useful for treating Triple Negative Breast Cancer (TNBC).

In some embodiments, the compounds of the invention are useful for treating nasopharyngeal carcinoma (NPC).

In some embodiments, the compounds of the invention are useful for treating microsatellite stabilized colorectal cancer (mssCRC).

In some embodiments, the compounds of the invention are useful for treating thymoma.

In some embodiments, the compounds of the invention are useful for treating carcinoid.

In some embodiments, the compounds of the invention are useful for treating gastrointestinal stromal tumors (GIST).

The compounds of the invention, as well as their pharmaceutically acceptable salts and stereoisomers, may be administered to a patient, e.g., a cancer patient, as monotherapy or by combination therapy. The therapy may be "front line/first line", i.e., as an initial treatment of a patient who has not undergone a prior anti-cancer treatment regimen, alone or in combination with other treatments; or "two-line" as a treatment for a patient who has undergone past anti-cancer treatment regimens, alone or in combination with other treatments; either as "three-wire", "four-wire" or the like therapy, alone or in combination with other therapies. Therapy may also be administered to patients who have previously received unsuccessful or partially successful treatment, but who have not responded or are intolerant to the particular treatment. The therapy may also be administered as an adjuvant therapy, i.e., to prevent recurrence of cancer in patients who currently have no detectable disease or after surgical removal of the tumor. Thus, in some embodiments, the compound may be administered to a patient who has received prior therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy, or any combination thereof.

The methods of the invention may entail administering the compounds of the invention or pharmaceutical compositions thereof to a patient in a single dose or in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses). For example, the frequency of administration may range from once daily up to about once every eight weeks. In some embodiments, the frequency of administration is in the range of about once daily for 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments at least one 28 day period is required, including daily administration for 3 weeks (21 days), followed by a 7 day off period. In other embodiments, the compound may be administered twice daily (BID) for a half-and-half-day time period (5 doses total) or once daily (QD) for a two-day time period (2 doses total). In other embodiments, the compound may be administered once daily (QD) over a five day period.

Combination therapy

The compounds of the invention and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers may be combined with at least one other active agent (e.g., anti-cancer agent) or regimen or used simultaneously in the treatment of diseases and conditions. The terms "in combination with … …" and "simultaneously" herein mean co-administration of agents, including substantially contemporaneous administration by the same or separate dosage forms and by the same or different modes of administration, or sequential administration, e.g., as part of the same therapeutic regimen, or by a sequential therapeutic regimen. Thus, if administered sequentially, at the beginning of administration of the second agent, the first of the two agents may still, in some cases, detect an effective concentration at the treatment site. The order and time intervals may be determined such that they may act together (e.g., synergistically to provide increased benefits over otherwise applied). For example, the agents may be administered simultaneously or sequentially in any order at different time points; however, if not administered simultaneously, they may be administered at a time sufficiently close to provide the desired therapeutic effect, which administration may be performed in a synergistic manner. Thus, the term is not limited to the administration of the active agent at exactly the same time.

In some embodiments, a therapeutic regimen may comprise administering a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in combination with one or more additional therapeutic agents known to be useful in treating a disease or disorder (e.g., cancer). The dosage of the additional anti-cancer therapeutic agent may be the same as or even lower than the known or recommended dosage. See Hardman et al, editors, goodman and Gilman's therapeutic basis pharmacological basis (The Pharmacological Basis Of Basis Of Therapeutics), 10 th edition, mcGraw-Hill, new York,2001; physician Desk Reference (Physician's Desk Reference), 60 th edition, 2006. For example, anticancer agents that may be used in combination with the compounds of the present invention are known in the art. See, for example, U.S. patent 9,101,622 (section 5.2 thereof) and U.S. patent 9,345,705B2 (columns 12-18 thereof). Representative examples of additional anti-cancer agents and treatment regimens include radiation therapy, chemotherapeutic agents (e.g., mitotic inhibitors, angiogenesis inhibitors, anti-hormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, anti-microtubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulatory agents, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapies.

In some embodiments, the compounds of the invention and the additional anti-cancer therapeutic agent may be administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 1 to about 2 hours apart, about 2 to about 3 hours apart, about 3 to about 4 hours apart, about 4 to about 5 hours apart, about 5 to about 6 hours apart, about 6 to about 7 hours apart, about 7 to about 8 hours apart, about 8 to about 9 hours apart, about 9 to about 10 hours apart, about 10 to about 11 hours apart, about 11 to about 12 hours apart, about 12 to 18 hours apart, 18 to 24 hours apart, 24 to 36 hours apart, 36 to 48 hours apart, 48 to 52 hours apart, 52 to 60 hours apart, 60 to 72 hours apart, 72 to 84 hours apart, 96 to 96 hours apart, or 120 hours apart. Two or more anticancer therapeutic agents may be administered within the same patient visit.

In some embodiments, the compounds of the invention and additional therapeutic agents (e.g., anti-cancer therapeutic agents) are administered periodically. For example, in the context of cancer treatment, cyclic therapy involves administering one anticancer therapeutic for a period of time followed by a second anticancer therapeutic for a period of time and repeating the sequential administration, i.e., cycling, in order to reduce resistance to one or both anticancer therapeutic, to avoid or reduce side effects of one or both anticancer therapeutic, and/or to improve efficacy of the therapy. In one example, the circulatory therapy involves administering a first anticancer therapeutic for a period of time, followed by a second anticancer therapeutic for a period of time, optionally followed by a third anticancer therapeutic for a period of time, and so forth, and repeating the sequential administration, i.e., circulatory, so as to reduce resistance to one anticancer therapeutic, to avoid or reduce side effects of one anticancer therapeutic, and/or to improve the efficacy of an anticancer therapeutic.

In some embodiments, and depending on the particular cancer being treated, the compounds of the invention may be used in combination with at least one other anti-cancer agent such as: paclitaxel (e.g., ovarian cancer, breast cancer, lung cancer, kaposi's sarcoma, cervical cancer, and pancreatic cancer), topotecan (e.g., ovarian cancer and lung cancer), irinotecan (Irinotecan) (e.g., colon cancer and small cell lung cancer), etoposide (Etoposide) (e.g., testicular cancer, lung cancer, lymphoma, and non-lymphocytic leukemia), vincristine (e.g., leukemia), leucovorin (e.g., colon cancer), altretamine (e.g., ovarian cancer), daunorubicin (e.g., acute Myelogenous Leukemia (AML), acute Lymphocytic Leukemia (ALL), chronic Myelogenous Leukemia (CML), and kaposi's sarcoma), trastuzumab (e.g., trastuzumab), breast cancer, gastric cancer, and esophageal cancer), rituximab (Rituximab) (e.g., non-hodgkin's lymphoma), cetuximab (Cetuximab) (e.g., colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer), pertuzumab (Pertuzumab) (e.g., metastatic HER2 positive breast cancer), alemtuzumab (Alemtuzumab) (e.g., chronic Lymphocytic Leukemia (CLL), cutaneous T-cell lymphoma (CTCL), and T-cell lymphoma), panitumumab (Panitumumab) (e.g., colon cancer and rectal cancer), tamoxifen (Tamoxifen) (e.g., breast cancer), fulvestrant (e.g., fulvestrant), breast cancer), letrozole (letrozole) (e.g., breast cancer), exemestane (Exemestane) (e.g., breast cancer), azacytidine (azacytodine) (e.g., myelodysplastic syndrome), mitomycin C (Mitomycin C) (e.g., gastrointestinal cancer, anal cancer, and breast cancer), dactinomycin (Dactinomycin) (e.g., wilms ' tumor, rhabdomyosarcoma, ewing's sarcoma, trophoblastoma, testicular cancer, and ovarian cancer), erlotinib (Erlotinib) (e.g., non-small cell lung cancer and pancreatic cancer), sorafenib (Sorafenib) (e.g., kidney cancer and liver cancer), temsirolimus (Temsirolimus) (e.g., kidney cancer), bortezomib (Bortezomib) (e.g., multiple myeloma and mantle cell lymphoma), pessanase (e.g., mantle cell lymphoma), acute lymphoblastic leukemia), cabometyb (Cabometyx) (e.g., hepatocellular carcinoma, medullary thyroid carcinoma, and renal cell carcinoma), pembrolizumab (e.g., cervical cancer, gastric cancer, hepatocellular carcinoma, hodgkin's lymphoma, melanoma, meckerr cell carcinoma, non-small cell lung carcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck), nivolumab (Nivolumab) (e.g., colorectal cancer, hepatocellular carcinoma, melanoma, non-small cell lung carcinoma, renal cell carcinoma, small cell lung carcinoma, and urothelial carcinoma), regorafenib (e.g., colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma), cimip Li Shan anti (cemiplist) (e.g., squamous cell carcinoma of the skin (CSCC)), avistuzumab (Avelumab) (e.g., merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma), devaluzumab (Durvalumab) (e.g., bladder carcinoma and lung carcinoma), aletuzumab (Atezolizumab) (e.g., urothelial carcinoma, non-small cell lung carcinoma (NSCLC), triple Negative Breast Carcinoma (TNBC), small Cell Lung Carcinoma (SCLC), and hepatocellular carcinoma (HCC)), and Ipilimumab (Ipilimumab) (e.g., melanoma, non-small cell lung carcinoma (NSCLC), small Cell Lung Carcinoma (SCLC), bladder carcinoma, and prostate carcinoma).

Pharmaceutical kit

The present compositions may be assembled into kits or pharmaceutical systems. A kit or pharmaceutical system according to this aspect of the invention comprises a carrier or package, such as a box, carton, tube or the like, having enclosed therein one or more containers, such as vials, tubes, ampoules or bottles, containing a compound of the invention or a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier, wherein the compound and carrier may be provided in the same or separate containers. The kits or pharmaceutical systems of the invention may also include printed instructions for using the compounds and compositions.

These and other aspects of the invention will be further appreciated upon consideration of the following examples, which are intended to illustrate certain specific embodiments of the invention, but are not intended to limit the scope of the invention as defined by the claims.

Examples

Example 1: synthesis of 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione

4- (2, 6-Dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

3- (6-bromo-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione (3.0 g,9.3 mmol), tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (11.5 g,37.3 mmol), potassium phosphate (2.0 g,9.3 mmol) and [1,1 "-bis (diphenylphosphino) ferrocene]A mixture of palladium (II) dichloride (0.7 g,1.9 mmol) in N, N-dimethylformamide (20 mL) was stirred at 90℃for 4 hours. The reaction mixture was then concentrated to give a residue, which was dissolved in ethyl acetate (500 mL). Water (500 mL) was added and the layers separated. Solid NaCl was added to the aqueous layer with vigorous stirring until NaCl saturation was reached. Undissolved NaCl was removed by filtration and the aqueous phase was further extracted with tetrahydrofuran (500 ml×2). The combined organic layers were dried and concentrated to give the crude product which was purified using silica gel column chromatography (petroleum ether/ethyl acetate=1:1 to 100% ethyl acetate) to give the title compound (1.1 g, 36%) as a yellow solid. MS [ M+H ]] ⁺ ＝426.3。

4- (2, 6-Dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidine-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl 4- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (1.0 g,2.4 mmol) and 10% Pd/C (400 mg) was added N, N-dimethylformamide (10 mL). The suspension was stirred at room temperature (rt) under hydrogen atmosphere for 16 hours. The reaction mixture was then diluted with dichloromethane, filtered and concentrated to give the title compound (1.0 g, 91%) as a yellow solid, which was used without further purification. MS [ M+H ]] ⁺ ＝428.3。

3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione

To 4- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidine-1-carboxylic acid tert-butyl ester (1.0 g,2.3 mmol) was added 4.0M HCl/diAlkane (6 mL) and the reaction vessel was closed and the reaction stirred at room temperature for 5 hours. The reaction mixture is reacted in the presence ofConcentration in vacuo afforded the title compound (1.0 g, 100%) as a yellow solid, which was used without further purification. MS [ M+H ]] ⁺ ＝328.3。

Example 2: 5-oxo-4-phenyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazas Synthesis of 7-Formaldehyde />

7-vinyl-3, 4-dihydrobenzo [ f][1,4]Oxazas5 (2H) -ones

7-bromo-3, 4-dihydrobenzo [ f][1,4]Oxazas-5 (2H) -one (4.5 g,18.7 mmol), potassium trifluorol (vinyl) -borane (5.0 g,37.3 mmol), N-cyclohexyl-N-methylcyclohexylamine (7.3 g,37.3 mmol), [1,1 "-bis (diphenylphosphino) ferrocene ]Palladium (II) dichloride (1.4 g,1.9 mmol) in 1, 4-di->The mixture in alkane (30 mL) was stirred at 90℃for 16 h. The reaction mixture was concentrated, then diluted with ethyl acetate (500 mL). The organic layer was washed with water (500 mL). The layers were separated and NaCl was added to the aqueous layer until a saturated solution was formed. The aqueous layer was then extracted with tetrahydrofuran (500 mL. Times.2). The organics were laminated and dried over MgSO ₄ Dried and then filtered. The filtrate was concentrated to give the crude product which was purified by column on silica gel (petroleum ether/ethyl acetate=10:1 to 5:1 elution) to give the title compound (2.5 g, 71%) as a yellow solid. MS [ M+H ]] ⁺ ＝190.2。

4-phenyl-7-vinyl-3, 4-dihydrobenzo [ f][1,4]Oxazas5 (2H) -ones

7-vinyl-3, 4-dihydrobenzo [ f][1,4]OxazasA mixture of 5 (2H) -one (2.4 g,12.7 mmol), iodobenzene (2.6 g,12.7 mmol), potassium phosphate (0.7 g,3.2 mmol), 1, 10-phenanthroline (0.9 g,5.1 mmol) and copper (I) iodide (1.0 g,5.1 mmol) in toluene (20 mL) was stirred at 110℃for 16H. The reaction mixture was concentrated, then diluted with ethyl acetate (500 mL). The organic phase was washed with water (500 mL). NaCl was added to the aqueous layer until a saturated solution was formed and extracted with tetrahydrofuran (500 mL. Times.2). The combined organic layers were dried and concentrated. The crude product was purified by column on silica gel (petroleum ether/ethyl acetate=10:1 to 5:1 elution) to give the title compound (1.9 g, 56%) as a yellow solid. MS [ M+H ] ] ⁺ ＝266.2。

5-oxo-4-phenyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazas7-Formaldehyde

4-phenyl-7-vinyl-3, 4-dihydrobenzo [ f ] at room temperature][1,4]OxazasTo a solution of 5 (2H) -one (600 mg,2.3 mmol), 4-methylmorpholine N-oxide (796 mg,6.8 mmol) and sodium periodate (963 mg,4.5 mmol) in acetone/water (15 mL, 3:2) was added potassium osmium (VI) dihydrate (40 mg,0.1 mmol). The reaction mixture was stirred at room temperature for 16 hours. Ethyl acetate (500 mL) was then added and the organic layer was washed with water (500 mL). NaCl was added to the aqueous layer until a saturated solution was formed. The aqueous layer was extracted with THF (500 mL. Times.2). The combined organic layers were dried and concentrated. The crude product was purified by column on silica gel (petroleum ether/ethyl acetate=5:1 to 3:1) to give the title compound (300 mg, 50%) as a yellow solid. MS [ M+H ]] ⁺ ＝268.2。

Example 3:3- (1-oxo-5- (1- ((5-oxo-4-phenyl-2, 3,4, 5-tetrahydrobenzene)And [ f ]][1,4]Oxazas Synthesis of (7-yl) methyl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (1) />

5-oxo-4-phenyl-2, 3,4, 5-tetrahydrobenzo [ f ]][1,4]OxazasA mixture of 7-formaldehyde (80 mg,0.3 mmol), 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (98 mg,0.3 mmol) and sodium triacetoxyborohydride (191 mg,0.9 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The suspension was concentrated and purified by preparative HPLC to give the title compound as a white solid (29.9 mg, 17%). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.98(s,1H),7.69-7.62(m,2H),7.55-7.39(m,8H),7.37-7.28(m,1H),7.09(d,J＝8.4Hz,1H),5.11(dd,J＝13.3,5.2Hz,1H),4.49-4.39(m,3H),4.30(d,J＝17.2Hz,1H),3.92(t,J＝5.2Hz,2H),3.56(s,2H),2.97(dd,J＝8.4,5.5Hz,2H),2.94-2.87(m,1H),2.73-2.57(m,2H),2.48-2.34(m,1H),2.13(t,J＝11.0Hz,2H),2.05-1.95(m,1H),1.84-1.67(m,4H)。MS[M+H] ⁺ ＝579.8。

Example 4: 4-oxo-5-phenyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Synthesis of pyrazine-2-carbaldehyde

1- (2- ((tert-Butoxycarbonyl) amino) ethyl) -1H-pyrazole-3, 5-dicarboxylic acid diethyl ester

To a stirred solution of diethyl 1H-pyrazole-3, 5-dicarboxylate (2.0 g,9.43 mmol) and tert-butyl (2-bromoethyl) carbamate (2.7 g,12.2 mmol) in DMF (20 mL) was added K ₂ CO ₃ (2.6g,18.8mmol)。The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (50 mL. Times.3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give the title compound (2.6 g, 78%) as a white solid. MS [ M+H ]] ⁺ ＝356.17。

4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine-2-carboxylic acid ethyl ester

To 1- (2- ((tert-Butoxycarbonyl) amino) ethyl) -1H-pyrazole-3, 5-dicarboxylic acid diethyl ester (2.6 g,7.3 mmol) in CH ₃ To a solution in CN (20 mL) was added aqueous HCl (3N, 5 mL) and the reaction was stirred at 80℃for 1.5 h. The reaction was then treated with NaHCO ₃ The aqueous solution was neutralized to ph=7 and diluted with water (50 mL). The aqueous layer was extracted with dichloromethane (50 mL. Times.3). The organics were combined and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give the title compound (1.15 g, 62%) as a white solid. MS [ M+H ] ] ⁺ ＝210.08。

4-oxo-5-phenyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine-2-carboxylic acid ethyl ester

4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] under nitrogen]Pyrazine-2-carboxylic acid ethyl ester (1.15 g,5.5 mmol), phenylboronic acid (1.05 g,8.25 mmol), cu (OAc) ₂ A solution of (995 mg,5.5 mmol) and triethylamine (1.1 g,11.0 mmol) in Dichloromethane (DCM) (10 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (50 mL) and the organic layer was washed with water (50 ml×3). The organic layer was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give the title compound (700 mg, 44.6%) as a white solid. MS [ M+H ]] ⁺ ＝286.10。

2- (hydroxymethyl) -5-phenyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one

4-oxo-5-phenyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a]Pyrazine-2-carboxylic acid ethyl ester (700 mg,2.45 mmol) and CaCl ₂ A solution of (430 mg,3.8 mmol) in EtOH (10 mL) was stirred at 0deg.C for 10 min. Addition of solid NaBH ₄ (280 mg,7.4 mmol) and combining the reaction mixtureStirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 ml×3). The organic layers were combined, taken over Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by a silica gel column to give the title compound (250 mg, 84%) as a white solid. MS [ M+H ] ] ⁺ ＝244.10。

4-oxo-5-phenyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine-2-carbaldehyde

2- (hydroxymethyl) -5-phenyl-6, 7-dihydropyrazolo [1,5-a]Pyrazin-4 (5H) -one (250 mg,1.0 mmol), naHCO ₃ A suspension of (864 mg,10 mmol) and Dess-Martin periodate (Dess-Martin periodinane) (DMP, 875mg,2.0 mmol) in DCM (25 mL) was stirred at room temperature for 1 h. Water (20 mL) was then added and the aqueous phase extracted with ethyl acetate (20 mL. Times.3). The organic layers were combined, taken over Na ₂ SO ₄ Drying and concentration gave a residue which was purified by column on silica gel (dichloromethane/methanol=15:1) to give the title compound (150 mg, 62%) as a white solid. MS [ M+H ]] ⁺ ＝242.10。

Example 5:3- (1-oxo-5- (1- ((4-oxo-5-phenyl-4, 5,6, 7-tetrahydropyrazolo [1,5 a)]Pyrazine-like compound Synthesis of 2-yl-methyl) piperidin-4-yl-isoindolin-2-yl) piperidine-2, 6-dione (8)

4-oxo-5-phenyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a]Pyrazine-2-carbaldehyde (150 mg,0.62 mmol), 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (203 mg,0.62 mmol) and NaBH (OAc) ₃ A solution of (254 mg,1.2 mmol) in DMF (5 mL) was stirred at rt for 16 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL. Times.3). The organic layers were laminated and passed over Na ₂ SO ₄ And (5) drying. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound (12 mg, 3.5%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.97(s,1H),8.17(s,1H),7.64(s,1H),7.51-7.37(m,5H),7.29(d,J＝7.2Hz,1H),6.75(s,1H),5.09(s,1H),4.54-4.14(m,7H),3.09-2.85(m,3H),2.65(d,J＝15.0Hz,1H),2.44-2.33(m,1H),2.23-1.94(m,3H),1.91-1.59(m,4H)。MS[M+H] ⁺ ＝553.20。

Example 6:3- (5- (1- (3- ((1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) benzyl) piperidine) Synthesis of 4-yl) -1-oxo-isoindolin-2-yl-piperidine-2, 6-dione (12)

3- ((3- (hydroxymethyl) phenyl) amino) -1-methylpyridin-2 (1H) -one

Under nitrogen, with (3-aminophenyl) methanol (320 mg,2.6 mmol), pd (OAc) ₂ (24 mg,0.11 mmol), xantphos (64 mg,0.11 mmol) and K ₃ PO ₄ (552 mg,2.6 mmol) A solution of 3-bromo-1-methylpyridin-2 (1H) -one (400 mg,2.2 mmol) in 10mL anhydrous DMF was treated and the reaction mixture stirred at 120℃for 16H. After completion, the reaction mixture was extracted with ethyl acetate (EtOAc) (50 mL) and the layers were separated. The organic phase was concentrated to give the crude product, which was purified by preparative High Performance Liquid Chromatography (HPLC) to give the title compound (30 mg, 6%) as a yellow solid. MS [ M+H ]] ⁺ ＝231.0。

3- ((1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) benzaldehyde

To a solution of 3- ((3- (hydroxymethyl) phenyl) amino) -1-methylpyridin-2 (1H) -one (20 mg,0.09 mmol) in DCM (2 mL) was added dess-Martin periodate (74 mg,0.17 mmol) and NaHCO ₃ (34 mg,0.40 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was then filtered and the filtrate concentrated to give the crude title compound (10 mg, 49%) as a yellow solid, which was used without further purification. ¹ H NMR(400MHz,CDCl ₃ )δ9.98(s,1H),7.71(dt,J＝2.3,1.0Hz,1H),7.48-7.45(m,2H),7.39-7.36(m,1H),7.27(s,1H),7.14(dd,J＝7.4,1.8Hz,1H),6.83(dd,J＝6.8,1.6Hz,1H),6.18(t,J＝7.2Hz,1H),3.63(s,3H)。

3- (5- (1- (3- ((1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) benzyl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (12)

To a solution of 3- ((1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) benzaldehyde (10 mg,0.04 mmol) and 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (14 mg,0.04 mmol) in DMF (1 mL) was added Na (OAc) ₃ BH (17 mg,0.08 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was then filtered and the filtrate concentrated to give a crude residue which was purified by preparative HPLC to give compound 12 (3.3 mg, 15%) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.96(s,1H),7.67-7.58(m,2H),7.49(s,1H),7.40(d,J＝8.0Hz,1H),7.26-7.19(m,2H),7.13-7.06(m,3H),6.88(d,J＝7.6Hz,1H),6.17(t,J＝7.2Hz,1H),5.09(dd,J＝13.4,5.0Hz,1H),4.42(dd,J＝17.2,2.6Hz,1H),4.29(dd,J＝17.4,2.8Hz,1H),3.80(d,J＝13.0Hz,1H),3.52(s,3H),3.48(s,2H),3.21-3.11(m,1H),2.99-2.87(m,3H),2.67-2.56(m,2H),2.44-2.33(m,1H),2.13-2.04(m,2H),2.01-1.96(m,1H),1.87-1.68(m,4H)。MS[M+H] ⁺ ＝540.3。

Example 7:3- [ 1-oxo-5- [1- [ (2-oxo-1-phenyl-indolin-6-yl) methyl]-4-piperidinyl]Different species Indol-2-yl]Synthesis of piperidine-2, 6-dione (18)

6-bromo-1-phenyl-indolin-2-one

Iodobenzene (5.53 g,27.12 mmol) was added to a suspension of 6-bromoindolin-2-one (5 g,23.58 mmol) in acetonitrile (ACN, 75 mL) under nitrogen. While heating the suspension to 40 ℃ and stirring for 30 minutes, a steady stream of nitrogen was bubbled through the suspension. Adding K ₂ CO ₃ (7.17 g,51.88 mmol), cuI (449.08 mg,2.36 mmol) and N, N' -dimethylethane-1, 2-diamine (415.72 mg,4.72 mmol) and the reaction mixture was heated to 80℃under nitrogen for 5 hours. After the reaction was completed, it was cooled to room temperature, 1M HCl (100 mL) was added, and the solution was extracted with EtOAc (100 mL. Times.3). The combined organic extracts were subjected to Na ₂ SO ₄ Dried and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (eluent: 0 to 50% ethyl acetate/petroleum ether) to give the title compound (3.3 g,49% yield) as an orange solid. MS [ M+H ]] ⁺ ＝288.0。

Phenyl-6-vinyl-indolin-2-one

To 6-bromo-1-phenyl-indolin-2-one (2.8 g,9.72 mmol) in twoAlkane (32 mL) and H ₂ To a solution of O (4 mL) was added potassium vinyltrifluoroborate (2.60 g,19.44 mmol), pd (dppf) Cl ₂ (711.04 mg,0.972 mmol) and K ₂ CO ₃ (4.03 g,29.15 mmol). The mixture was stirred at 110℃for 12 hours. After the reaction was completed, it was cooled to room temperature and poured into H ₂ O (40 mL) and extracted with EtOAc (40 mL. Times.3). The combined organic layers were washed with brine (40 mL. Times.2), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by MPLC (SiO ₂ Petroleum ether: etoac=10/1 to 1/1) to give the title compound (1.5 g,66% yield) as a red solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.54-7.42(m,2H),7.40-7.28(m,3H),7.23-7.13(m,1H),7.08-6.97(m,1H),6.79-6.69(m,1H),6.63-6.48(m,1H),5.63-5.49(m,1H),5.14(d,J＝10.9Hz,1H),3.63(s,2H)。

2-oxo-1-phenyl-indoline-6-carbaldehyde

Ozone was bubbled into a solution of 1-phenyl-6-vinyl-indolin-2-one (1.5 g,6.38 mmol) in DCM (30 mL) at-78 ℃ for 30 min. In the process of passing through N ₂ Purging excessive O ₃ After that, me is added at-78 DEG C ₂ S (7.92 g,127.51 mmol). The reaction was stirred at 20℃for 12 hours. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by MPLC (SiO ₂ Petroleum ether: etOAc=10/1 to 1/1) to afford the title compound (370 mg,25% yield) as a red solid. MS [ M+H ]] ⁺ ＝238.1。

3- [ 1-oxo-5- [1- [ (2-oxo-1-phenyl-indolin-6-yl) methyl ] -4-piperidinyl ] isoindolin-2-yl ] piperidine-2, 6-dione (18)

Compound 18 was prepared similarly to compound 12 in example 6. ¹ H NMR:(400MHz,DMSO-d ₆ )δ11.07-10.93(m,1H),8.23(s,0.5H),7.64-7.53(m,3H),7.50-7.22(m,6H),7.05-6.99(m,1H),6.71-6.65(m,1H),5.14-5.04(m,1H),4.47-4.20(m,2H),3.77-3.70(m,2H),3.44(br s,2H),2.89(br d,J＝11.9Hz,2H),2.66-2.55(m,2H),2.46-2.34(m,2H),2.07-1.93(m,3H),1.78-1.69(m,2H),1.68-1.56(m,2H)。MS[M+H] ⁺ ＝549.1。

Example 8:3- (1-oxo-5- (1- ((4-oxo-3- (pyridin-2-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of (yl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (31)

5-bromo-2-nitro-N- (pyridin-2-yl) benzamide

To a solution of 5-bromo-2-nitrobenzoic acid (5 g,20.32 mmol), pyridin-2-amine (1.91 g,20.32 mmol) and N, N-diisopropylethylamine (7.88 g,60.97 mmol) in 50mL of DMF was added HATU (9.3 g,24.38 mmol). The mixture was stirred at room temperature for 16 hours. Adding H ₂ O (200 mL) and the aqueous phase was extracted with DCM (2X 200 mL). The organic phases were combined, concentrated and purified by silica gel column chromatography (methanol (MeOH): dcm=1/100 to 3/100) to give the title compound (3.6 g, 55%).

2-amino-5-bromo-N- (pyridin-2-yl) benzamide

5-bromo-2-nitro-N- (pyridin-2-yl) benzamide (2.60 g,8.07 mmol), NH ₄ Cl (2.16 g,40.36 mmol) in ethanol (EtOH)/H ₂ A solution in O (30 mL, v: v=7/3) at 50℃under N ₂ Stirring for 30 minutes under an atmosphere. Fe (2.25 g,40.36 mmol) was added and the reaction stirred for an additional 2 hours. The suspension was filtered to give a clear organic phase which was concentrated and purified by silica gel column chromatography (MeOH: dcm=1/100 to 5/100) to give the title compound (0.8 g, 33.9%).

6-bromo-3- (pyridin-2-yl) quinazolin-4 (3H) -one

A solution of 2-amino-5-bromo-N- (pyridin-2-yl) benzamide (1.1 g,3.77 mmol) in triethyl orthoformate (22 mL) was stirred at 140℃for 2 hours. The mixture was then concentrated to give the crude product, which was purified by silica gel column chromatography (MeOH: dcm=1/100 to 3/100) to give the title compound (800 mg, 70%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.69(ddd,J＝4.9,1.9,0.8Hz,1H),8.64(s,1H),8.33(d,J＝2.3Hz,1H),8.11(dd,J＝8.0,1.9Hz,0H),8.10-8.06(m,1H),7.86(dt,J＝8.1,0.9Hz,1H),7.75(d,J＝8.7Hz,1H),7.60(ddd,J＝7.5,4.9,1.0Hz,1H)。

3- (pyridin-2-yl) -6-vinylquinazolin-4 (3H) -one

To 6-bromo-3- (pyridin-2-yl) quinazolin-4 (3H) -one (300 mg,1.33 mmol), potassium vinyltrifluoroborate (357.13 mg,2.67 mmol) and N-cyclohexyl-N-methylcyclohexylamine (520.83 mg,2.67 mmol) in 1, 4-di [1,1' -bis (diphenylphosphino) ferrocene was added to a solution in alkane (6 mL)]Palladium (II) dichloride (97.1 mg,0.13 mmol). The mixture was stirred at 70℃under N ₂ Stirring is carried out for 16 hours under an atmosphere. The mixture was then concentrated and purified by silica gel column chromatography (MeOH: dcm=1/100 to 3/100) to give the title compound (180 mg, 73%).

4-oxo-3- (pyridin-2-yl) -3, 4-dihydro-quinazoline-6-carbaldehyde

A solution of 3- (pyridin-2-yl) -6-vinylquinazolin-4 (3H) -one (150 mg,0.6 mmol) in 6mL MeOH was stirred at-78℃for 5 min, then O was added ₃ Bubbling through for 10 minutes. The mixture was then concentrated to give the crude product, which was purified by preparative HPLC to give the title compound (60 mg, 40%). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.19(s,1H),8.79(d,J＝1.8Hz,1H),8.73(s,1H),8.70-8.66(m,2H),8.32(dd,J＝8.4,1.9Hz,1H),8.10(td,J＝7.8,1.9Hz,1H),7.92(d,J＝8.4Hz,1H),7.87(d,J＝8.1Hz,1H),7.60(dd,J＝7.0,5.3Hz,1H)。

3- (1-oxo-5- (1- ((4-oxo-3- (pyridin-2-yl) -3, 4-dihydro-quinazolin-6-yl) methyl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (31)

Compound 31 was prepared in analogy to compound 12 in example 6 in 13% yield. ¹ HNMR(400MHz,DMSO-d ₆ )δ10.97(s,1H),8.67(dd,J＝4.9,1.1Hz,1H),8.55(s,1H),8.18(d,J＝1.7Hz,1H),8.08(td,J＝7.8,1.9Hz,1H),7.88(dd,J＝8.3,1.9Hz,1H),7.84(d,J＝8.1Hz,1H),7.75(d,J＝8.3Hz,1H),7.64(d,J＝7.8Hz,1H),7.57(ddd,J＝7.5,4.9,1.0Hz,1H),7.51(s,1H),7.41(d,J＝7.9Hz,1H),5.09(dd,J＝13.3,5.1Hz,1H),4.42(d,J＝17.3Hz,1H),4.28(d,J＝17.4Hz,1H),3.70(s,2H),2.97(d,J＝11.3Hz,3H),2.94-2.82(m,1H),2.70-2.54(m,1H),2.46-2.29(m,1H),2.16(t,J＝10.0Hz,2H),2.05-1.93(m,1H),1.82-1.69(m,3H)。MS[M+H] ⁺ ＝563.0。

Example 9:3- [ 1-oxo-5- [1- [ (2-phenylpyrazolo [1, 5-a)]Pyridin-6-yl) methyl]-4-piperidinyl] Isoindolin-2-yl]Synthesis of piperidine-2, 6-dione (38)

1-aminopyridineSalt

To a mixture of amino 2,4, 6-trimethylbenzenesulfonate (17.06 g,79.27 mmol) in DCM (200 mL) was added dropwise a solution of 3-bromopyridine (12 g,75.95 mmol) in DCM (150 mL) at 0 ℃. The mixture was stirred at 20℃for 12 hours. The white solid was collected by filtration and washed with EtOAc (100 mL). The filter cake was dried in vacuo to give the title compound as a white solid (23.3 g, 78.7%), which was used without further purification.

6-bromo-2-phenyl-pyrazolo [1,5-a ]]Pyridine-3-carboxylic acid methyl ester at 0℃to 1-aminopyridineSalt (23.30 g,62.43 mmol) to a solution in Dimethylformamide (DMF) (100 mL) was added K ₂ CO ₃ (21.57 g,156.09 mmol) and 3-benzeneMethyl propyl-2-alkynoate (6.25 g,39.02 mmol). The mixture was then stirred at 20℃for 16 hours. To the reaction was added water (300 mL) and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic phases were taken up in Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1 to 4/1) to give the title compound (5.2 g, 32%) as a pale yellow solid.

6-bromo-2-phenyl-pyrazolo [1,5-a ] pyridine-3-carboxylic acid

To 6-bromo-2-phenyl-pyrazolo [1,5-a ]]Pyridine-3-carboxylic acid methyl ester (5.2 g,15.70 mmol) in H ₂ KOH (4.41 g,78.51 mmol) was added in one portion to a solution of O (26 mL) and MeOH (50 mL). The mixture was stirred at 60℃for 3 hours. The mixture was concentrated in vacuo. The aqueous phase was acidified to ph=3 with 1N HCl and the white solid formed was filtered and washed with water (20 mL). The filter cake was dried in vacuo to give the title compound (4.6 g) as a white solid, which was used without further purification.

6-bromo-2-phenyl-pyrazolo [1,5-a ] pyridine

To the 6-bromo-2-phenyl-pyrazolo [1,5-a ]]A suspension of pyridine-3-carboxylic acid (4.6 g,14.50 mmol) in 1, 2-dichlorobenzene (30 mL) was degassed and N ₂ Three purges and then the mixture was purged at 170 ℃ under N ₂ Stirred for 3 hours. The reaction was then cooled to room temperature and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/0 to 10/1) to give the title compound (2.1 g, 53%) as a white solid. ¹ H NMR:(400MHz,CDCl ₃ )δ8.63(d,J＝0.4Hz,1H),7.95(d,J＝7.2Hz,2H),7.37-7.49(m,4H),7.15-7.18(m,1H),6.82(s,1H)。

2-phenyl-6-vinyl-pyrazolo [1,5-a ] pyridines

To 6-bromo-2-phenyl-pyrazolo [1,5-a ]]Pyridine (200 mg,0.73 mmol) in dimethoxyethane (1.6 mL) and H ₂ To a solution of 4, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolan (169.17 mg,1.10 mmol), na were added in O (0.8 mL) ₂ CO ₃ (256.12 mg,2.42 mmol) and Pd (PPh) ₃ ) ₂ Cl ₂ (51.40 mg, 73. Mu. Mol). The mixture was stirred at 70℃under N ₂ Stirred for 12 hours. The mixture was then diluted with water (15 mL) and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were taken up in Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexane: etoac=4:1) to give the title compound (130 mg, 81%) as a brown solid. ¹ H NMR:(400MHz,CDCl ₃ )δ8.42(s,1H),7.97(d,J＝7.2Hz,2H),7.44-7.51(m,3H),7.36-7.40(m,1H),7.33-7.34(m,1H),6.79(s,1H),6.64-6.72(m,1H),5.76(d,J＝17.6Hz,1H),5.33(d,J＝11.2Hz,1H)。

2-phenylpyrazolo [1,5-a ] pyridine-6-carbaldehyde

NaIO at 20 ℃ ₄ (1.77 g,8.29 mmol) and OsO ₄ (42.13 mg, 166. Mu. Mol) 2-phenyl-6-vinyl-pyrazolo [1, 5-a)]Pyridine (730 mg,3.31 mmol) in twoAlkane (20 mL) and H ₂ The solution in O (10 mL) was treated for 12 hours. The mixture was taken up in saturated Na ₂ SO ₃ The aqueous solution (20 mL) was quenched and the aqueous phase extracted with EtOAc (2X 10 mL). The combined organic phases were taken up in Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/0 to 0/1) to give the title compound (200 mg, 27%) as a yellow solid.

3- [ 1-oxo-5- [1- [ (2-phenylpyrazolo [1,5-a ] pyridin-6-yl) methyl ] -4-piperidinyl ] isoindolin-2-yl ] piperidine-2, 6-dione (38)

Compound 38 was prepared in analogy to compound 12 in example 6 in 18% yield as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.00(s,1H),10.71(s,1H),8.67(s,1H),9.00(s,1H),8.01(d,J＝7.2Hz,2H),7.79(d,J＝8.8Hz,1H),7.70(d,J＝8.0Hz,1H),7.45-7.52(m,4H),7.37-7.43(m,2H),7.16(s,1H),5.08-5.13(m,1H),4.47(s,1H),4.40-4.43(m,2H),4.28-4.33(m,1H),3.06-3.15(m,3H),2.86-3.01(m,3H),2.35-2.40(m,1H),1.69-2.12(m,6H)。MS[M+H] ⁺ ＝534.3。

Example 10:3- [ 1-oxo-5- [1- [ [ 4-oxo-3- (2-pyridinyl) phthalazin-6-yl]Methyl group]-4-piperidines Base group]Isoindolin-2-yl]Synthesis of piperidine-2, 6-dione (43)

3, 6-dibromo-3H-isobenzofuran-1-one

To 6-bromo-3H-isobenzofuran-1-one (5.7 g,26.76 mmol) in CHCl ₃ To a solution of (60 mL) was added NBS (5.24 g,29.46 mmol) and AIBN (439.37 mg,2.68 mmol). The mixture was stirred at 80℃for 2 hours. The reaction was then filtered and the filtrate concentrated in vacuo to give the title compound (10 g) as a white solid, which was used without further purification. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.92-7.90(m,1H),7.56(d,J＝7.9Hz,1H),6.58(s,1H)。

6-bromo-3-hydroxy-3H-isobenzofuran-1-one

3, 6-dibromo-3H-isobenzofuran-1-one (5.7 g,19.53 mmol) in H ₂ The suspension in O (30 mL) was degassed and further treated with N ₂ Three purges and then the mixture was purged at 100 ℃ under N ₂ Stirring is carried out for 1 hour under an atmosphere. The reaction mixture was poured onto H ₂ O (20 mL) and the aqueous phase was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (2X 50 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the title compound (6.87 g) as a white solid, which was used without further purification. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.32(br s,1H),8.11-7.98(m,3H),7.70(d,J＝8.0Hz,1H),6.71(br s,1H)。

7-bromo-2- (2-pyridinyl) phthalazin-1-one

To a solution of 6-bromo-3-hydroxy-3H-isobenzofuran-1-one (1 g,4.37 mmol) in AcOH (30 mL) was added 2-pyridylhydrazine (476.49 mg,4.37 mmol). The reaction was stirred at 100deg.C for 12 hours and then concentrated in vacuo to give a crude residue which was suspended in H ₂ O (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2X 50 mL). The combined organic layers were washed with brine (2X 50 mL), and dried over Na ₂ SO ₄ Drying, filtering and concentrating in vacuo to give a yellow solidThe title compound (0.94 g) was used without further purification. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.62-8.58(m,1H),8.57(s,1H),8.38(d,J＝2.0Hz,1H),8.19(dd,J＝2.0,8.3Hz,1H),8.05-7.95(m,2H),7.67-7.60(m,1H),7.55-7.48(m,1H)。

2- (2-pyridinyl) -7-vinyl-phthalazin-1-one

7-bromo-2- (2-pyridinyl) phthalazin-1-one (0.84 g,2.78 mmol), potassium vinyltrifluoroborate (558.63 mg,4.17 mmol), iron bis-tert-butyl (cyclopentyl) phosphine dichloropalladium (181.20 mg, 278. Mu. Mol) and K ₃ PO ₄ (1.18 g,5.56 mmol) in THF (16 mL) and H ₂ The mixture in O (4 mL) was degassed and N ₂ Purging three times. The reaction was quenched at 80℃under N ₂ Stirring is carried out for 1 hour under an atmosphere. The reaction mixture was poured onto H ₂ O (50 mL) and extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (2X 50 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound (0.5 g, 72%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.63(dd,J＝1.1,4.8Hz,1H),8.54(s,1H),8.31(s,1H),8.19(dd,J＝1.6,8.2Hz,1H),8.07-7.98(m,2H),7.65(d,J＝8.0Hz,1H),7.53(dd,J＝4.9,7.3Hz,1H),7.02(dd,J＝11.0,17.6Hz,1H),6.15(d,J＝17.6Hz,1H),5.53(d,J＝11.0Hz,1H)。MS[M+H] ⁺ ＝250.2。

7- (1, 2-dihydroxyethyl) -2- (2-pyridinyl) phthalazin-1-one

To 2- (2-pyridinyl) -7-vinyl-phthalazin-1-one (0.3 g,1.20 mmol) in THF (3 mL) and H ₂ K was added to a solution in O (0.3 mL) ₂ OsO ₄ .2H ₂ O (44.35 mg, 120. Mu. Mol) and NMO (422.98 mg,3.61 mmol). The mixture was stirred at 20℃for 12 hours. The reaction was taken up in saturated Na ₂ SO ₃ The aqueous solution (20 mL) was quenched and the aqueous phase extracted with EtOAc (2X 10 mL). The combined organic phases were taken up in Na ₂ SO ₄ Drying, filtration and concentration gave the title compound (0.27 g) as a yellow liquid which was used without further purification.

4-oxo-3- (2-pyridinyl) phthalazine-6-carbaldehyde

To 7- (1, 2-dihydroxyethyl) -2- (2-pyridinyl) phthalazin-1-one (0.27 g,0.95 mmol) in two Alkane (4 mL) and H ₂ NaIO was added to the solution in O (0.4 mL) ₄ (407.72 mg,1.91 mmol). The mixture was stirred at 20℃for 2 hours. The reaction mixture was poured onto H ₂ O (10 mL) and extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (2X 10 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound (0.05 g, 21%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.25(s,1H),8.83(s,1H),8.68(s,1H),8.64(dd,J＝1.1,4.7Hz,1H),8.66-8.60(m,1H),8.41(dd,J＝1.4,8.1Hz,1H),8.21(d,J＝8.1Hz,1H),8.06(dt,J＝1.9,7.8Hz,1H),7.69(d,J＝7.9Hz,1H),7.55(dd,J＝5.0,6.8Hz,1H)。MS[M+H] ⁺ ＝252.1。

3- [ 1-oxo-5- [1- [ [ 4-oxo-3- (2-pyridinyl) phthalazin-6-yl ] methyl ] -4-piperidinyl ] isoindolin-2-yl ] piperidine-2, 6-dione (43)

Compound 43 was prepared in analogy to compound 12 in example 6 in 27% yield. ¹ HNMR(400MHz,DMSO-d ₆ )δ11.18(br s,1H),10.98(s,1H),8.66-8.59(m,2H),8.57(s,1H),8.36(dd,J＝1.5,8.1Hz,1H),8.15(d,J＝8.1Hz,1H),8.06(dt,J＝1.9,7.8Hz,1H),7.68(dd,J＝7.9,13.1Hz,2H),7.58-7.52(m,1H),7.45(s,1H),7.39(d,J＝7.9Hz,1H),5.10(dd,J＝5.0,13.3Hz,1H),4.61(br d,J＝4.8Hz,2H),4.49-4.27(m,2H),3.48(br d,J＝11.4Hz,2H),3.21-3.06(m,2H),3.00-2.85(m,2H),2.59(br d,J＝16.9Hz,1H),2.44-2.34(m,1H),2.15(br d,J＝12.9Hz,2H),2.00(br d,J＝11.1Hz,3H)。MS[M+H] ⁺ ＝563.1。

Example 11:3- (4-fluoro-1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione hydrochloride Synthesis of salts

5-bromo-4-fluoro-3-hydroxyisobenzofuran-1 (3H) -one

To a solution of 2, 6-tetramethylpiperidine (48.4 g, 348 mmol) in THF (150 mL) was added n-BuLi (2M in cyclohexane, 137mL,274 mmol) dropwise at-75 ℃ and the mixture was warmed to 0 ℃ and stirred at that temperature for 20min. The reaction mixture was then cooled to-75 ℃ and a solution of 4-bromo-3-fluorobenzoic acid (15.0 g,68.5 mmol) in THF (30 mL) was added dropwise. The reaction mixture was stirred for 40min, then DMF (10.0 g,137 mmol) was added dropwise to THF (15 mL) at-75℃and the resulting mixture was stirred for an additional 2h. The reaction mixture was quenched with 5M HCl (10 mL) and diluted with brine solution (50 mL). The resulting mixture was extracted with DCM (2X 100 mL) and the combined organic extracts were taken over anhydrous Na ₂ SO ₄ Drying and filtering. The solvent was removed under reduced pressure and the crude material was purified by column chromatography on silica gel using EtOAc in hexanes (60-80%) as eluent to give the title compound as an off-white solid (14.0 g, 71%). MS [ M-H ]] ⁺ ＝244.8。

3- (5-bromo-4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione

At 25 ℃ at N ₂ To a solution of 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1 (3H) -one (2.00 g,8.10 mmol) in 1, 2-dichloroethane (DCE, 20 mL) was added 3-aminopiperidine-2, 6-dione hydrochloride (2.00 g,12.1 mmol) under an atmosphere. The reaction mixture was stirred for 30min, then sodium triacetoxyborohydride (5.15 g,24.3 mmol) was added and the resulting mixture was stirred at room temperature for 18h. The reaction mixture was quenched with brine (15 mL) and the aqueous layer extracted with EtOAc (2X 100 mL). The combined organic extracts were subjected to anhydrous Na ₂ SO ₄ Drying and filtering. The solvent was removed under reduced pressure to give a crude residue which was dissolved in ACN (5 mL)/methyl tert-butyl ether (MTBE, 5 mL) and stirred for 10min to give the title compound as a pale blue solid (1.32 g, 48%), which was isolated by filtration, washed with excess MTBE, and dried by vacuum. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.20-10.76(m,1H),7.88(dd,J＝6.1,7.9Hz,1H),7.55(d,J＝8.0Hz,1H),5.13(dd,J＝5.1,13.4Hz,1H),4.67-4.59(m,1H),4.50-4.43(m,1H),2.98-2.86(m,1H),2.66-2.56(m,1H),2.44(dd,J＝4.4,12.9Hz,1H),2.01(dtd,J＝2.3,5.2,12.7Hz,1H)。MS[M+H] ⁺ ＝340.9。

4- (2, 6-Dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

At room temperature under continuous N ₂ 3- (5-bromo-4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (1.32 g,3.87 mmol) was bubbled for 20min into the di-phaseTo a stirred solution of 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (2.39 g,7.74 mmol), N-diisopropylethylamine (DIPEA, 1.00g,7.74 mmol) and Pd (tBu) in alkane (20 mL)/water (2.2 mL) was added ₃ P) ₂ (0.198 g,0.387 mmol). The reaction mixture was stirred at 100℃for 15h. The excess solvent was removed under reduced pressure to give a crude residue which was dissolved in ACN (5 mL)/MTBE (5 mL) and stirred for 10min to give the title compound (1.30 g, 72%) as a white solid, which was isolated by filtration, washed with excess MTBE, and dried by vacuum. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.01(s,1H),7.80-7.35(m,2H),6.11(brs,1H),5.12(dd,J＝5.1,13.3Hz,1H),4.62-4.49(m,1H),4.46-4.25(m,1H),4.03(brs,2H),3.56(t,J＝5.5Hz,2H),2.98-2.81(m,1H),2.73-2.56(m,1H),2.49-2.41(m,2H),2.4(m,1H),2.08-1.89(m,1H),1.44(s,9H)。MS[M+H] ⁺ ＝444.2。

4- (2, 6-Dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) piperidine-1-carboxylic acid tert-butyl ester

At room temperature at N ₂ To a solution of tert-butyl 4- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (0.500 g,1.13 mmol) in DMF (10 mL) was added Pd/C (10-50% wet, 0.120g,0.113 mmol) under an atmosphere and the mixture was stirred under hydrogen atmosphere for 60H. Passing the reaction mixture throughFiltered and washed with THF (50 mL x 2). The solvent was removed under reduced pressure to give a crude residue which was dissolved in ACN (5 mL)/MTBE (5 mL) and stirred for 10min to give the title compound as a white solid (0.380 g, 73%), which was isolated by filtration, washed with excess MTBE, and dried by vacuum. ¹ HNMR(400MHz,DMSO-d ₆ )δ11.00(s,1H),7.55-7.50(m,2H),5.14-5.08(m,1H),4.55(d,J＝17.4Hz,1H),4.42-4.34(m,1H),4.10(d,J＝11.0Hz,2H),3.16-3.06(m,1H),2.98-2.78(m,3H),2.66-2.55(m,1H),2.44(dd,J＝4.6,13.1Hz,1H),2.05-1.95(m,1H),1.81-1.69(m,2H),1.67-1.54(m,2H),1.43(s,9H)。MS[M-H] ⁺ ＝444.

3- (4-fluoro-1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione hydrochloride

To 4- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) piperidine-1-carboxylic acid tert-butyl ester (0.45 g,1.0 mmol) at 0deg.C in 1, 4-diHCl (4M in 1, 4-di +.>In alkane, 5.0mL,20 mmol) and the mixture was stirred for 10min, then warmed to room temperature and held for 12h. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was dissolved in ACN (5 mL)/MTBE (5 mL) and stirred for 10min to give the title compound as an off-white solid (0.32 g, 91%), which was isolated by filtration, washed with excess MTBE, and dried by vacuum. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.35-10.61(m,1H),8.37(s,1H),7.59(d,J＝7.9Hz,1H),7.52-7.45(m,1H),5.16-5.07(m,1H),4.61-4.51(m,1H),4.43-4.33(m,1H),3.19(brs,3H),2.83(brs,3H),2.64-2.58(m,1H),2.47-2.37(m,2H),2.05-1.94(m,1H),1.84-1.74(m,3H)。MS[M+H] ⁺ ＝346。

Example 12: synthesis of 6-methyl-3- (6- (trifluoromethyl) pyridin-2-yl) quinazolin-4 (3H) -one

To 6-methylquinazolin-4 (3H) -one (0.500 g,3.12 mmol) at 25℃in 1, 4-diTo a stirred solution of 2-bromo-6- (trifluoromethyl) pyridine (1.13 g,4.99 mmol), cesium carbonate (3.05 g,9.36 mmol) and 1, 2-dimethylethylenediamine (DMEDA, 0.549g,6.24 mmol) in alkane (10 mL) were added. The reaction mixture was taken up in N ₂ Deaeration for 10min, then copper (I) iodide (0.294 g,1.56 mmol) was added at room temperature and the reaction mixture was heated at 120℃for 24h. The reaction mixture was cooled to room temperature and the volatiles were evaporated under reduced pressure. The crude material was purified by reverse phase chromatography (using 10mM ammonium acetate in water and ACN) followed by lyophilization to give the title compound as an off-white solid (130 mg, 33%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.53(s,1H),8.38(t,J＝7.9Hz,1H),8.23-7.99(m,3H),7.77-7.58(m,2H),2.51(br s,3H)。MS[M+H] ⁺ ＝306。/>

Example 13: synthesis of 3- (6-methyl-4-oxoquinazolin-3 (4H) -yl) benzonitrile

To a solution of 6-methylquinazolin-4 (3H) -one (1.00 g,6.24 mmol) in DCM (20 mL) at 25deg.C was addedMolecular sieves (2.00 g,6.24 mmol), (3-cyanophenyl) boronic acid (1.84 g,12.5 mmol), pyridine (1.01 ml,12.5 mmol) and copper (II) acetate (1.13 g,6.24 mmol). The reaction mixture was stirred at room temperature under an air filled balloon for 14h. The reaction mixture was passed through->The pad was filtered and washed with ethyl acetate (50 mL). The filtrate was evaporated under reduced pressure to give a solid (1.5 g), which was then passed throughPurification by silica gel column chromatography (using ethyl acetate-hexane) afforded the title compound (0.300 g, 17%) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.44-8.30(m,1H),8.15(t,J＝1.7Hz,1H),8.05-7.99(m,2H),7.95(ddd,J＝1.1,2.1,8.1Hz,1H),7.85-7.71(m,2H),7.70-7.62(m,1H),2.53(d,J＝2.0Hz,3H)。MS[M+H] ⁺ ＝262.1。

Example 14: synthesis of 5-fluoro-6-methyl-3- (pyridin-2-yl) quinazolin-4 (3H) -one

To a solution of 6-amino-2-fluoro-3-methylbenzoic acid (0.500 g,2.96 mmol) in triethyl orthoformate (5 mL) was added pyridin-2-amine (0.278 g,2.96 mmol) at room temperature. The resulting reaction mixture was stirred at 140℃for 24h. The reaction mixture was concentrated under reduced pressure to give a crude material which was purified by silica gel column chromatography (EtOAc in hexanes (30%) as eluent) to give the title compound as an off-white solid (0.150 g, 19%). MS [ M+H ] ] ⁺ ＝256.4。

Example 15:3- (1-oxo-5- (1- ((4-oxo-3- (6- (trifluoromethyl) pyridin-2-yl) -3, 4-dihydroquin-ol) Synthesis of azolin-6-yl-methyl) piperidin-4-yl-isoindolin-2-yl) piperidine-2, 6-dione (64)

6- (bromomethyl) -3- (6- (trifluoromethyl) pyridin-2-yl) quinazolin-4 (3H) -one

To a stirred solution of 6-methyl-3- (6- (trifluoromethyl) pyridin-2-yl) quinazolin-4 (3H) -one (0.250 g,0.819 mmol) in ACN (10 mL) was added N-bromosuccinimide (NBS, 0.292g,1.64 mmol) and azobisisobutyronitrile (AIBN, 0.067g,0.41 mmol) at 25 ℃. The reaction mixture was heated at reflux for 24h. The reaction mixture was evaporated under reduced pressure to give a crude material which was purified by silica gel column chromatography (using15% ethyl acetate in hexanes) to give the title compound as a pale yellow solid (100 mg, 25%). MS [ M+H ]] ⁺ ＝384.2。

3- (1-oxo-5- (1- ((4-oxo-3- (6- (trifluoromethyl) pyridin-2-yl) -3, 4-dihydroquinazolin-6-yl) methyl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione

To a solution of 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione hydrochloride (90.0 mg,0.246 mmol) in DMF (2 mL) was added DIPEA (0.209 mL,1.23 mmol) at 0deg.C and the mixture was stirred for 10min. 6- (bromomethyl) -3- (6- (trifluoromethyl) pyridin-2-yl) quinazolin-4 (3H) -one (95.0 mg,0.246 mmol) was added and the reaction mixture stirred at room temperature for 12H. The reaction mixture was evaporated under reduced pressure to give a crude solid which was purified by preparative HPLC [ method information: column: x select (150 mm. Times.19) 5 μm,0.1% HCOOH H ₂ ACN, flow rate: 15mL/min]And (5) purifying. The pure fractions were lyophilized to give the title compound as an off-white solid (5.8 mg, 4%). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.98(s,1H),8.59(brs,1H),8.46-8.34(m,1H),8.19(d,J＝8.1Hz,1H),8.15-8.09(m,1H),8.01-7.74(m,2H),7.66(d,J＝7.8Hz,1H),7.56-7.36(m,2H),6.53(s,1H),5.11(dd,J＝5.1,13.3Hz,1H),4.49-4.38(m,1H),4.33-4.24(m,1H),3.92-3.64(m,1H),3.17-2.84(m,3H),2.71(m,1H),2.66-2.56(m,3H),2.39(dd,J＝4.3,12.9Hz,2H),2.14(m,1H),2.06-1.95(m,1H),1.91-1.74(m,3H)。MS[M+H] ⁺ ＝631.1。

Example 16: synthesis of 6-bromo-3- (pyridin-3-yl) quinazolin-4 (3H) -one

A solution of 2-amino-5-bromobenzoic acid (10.0 g,46.3 mmol) and pyridin-3-amine (4.36 g,46.3 mmol) in triethyl orthoformate (100 mL,600 mmol) was heated at 140℃for 48h. The reaction mixture was concentrated under reduced pressure to give a crude solid. The crude solid was washed with 2-propanol and the solid was filtered to give the title compound (9.00 g, 52%) as a pale brown solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.78(d,J＝2.0Hz,1H),8.72(dd,J＝1.6,3.6Hz,1H),8.48(s,1H),8.30(d,J＝2.4Hz,1H),8.08-8.04(m,2H),7.74(d,J＝8.8Hz,1H),8.66-8.63(m,1H)。MS[M+H,M+2H] ⁺ ＝302.0,304.0.

Example 17: synthesis of 6-bromo-2-methyl-3- (pyridin-2-yl) quinazolin-4 (3H) -one

By reacting 6-bromo-2H-benzo [ d ]][1,3]A mixture of oxazine-2, 4 (1H) -dione (3.00 g,12.4 mmol), 2-aminopyridine (1.28 g,13.6 mmol) and triethyl orthoacetate (3.02 g,18.6 mmol) was reacted under N ₂ Stirred at 140℃for 24h. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (using 50-90% EtOAc in hexanes as eluent) to give the title compound (1.80 g, 46%) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.76-8.64(m,1H),8.20(d,J＝2.3Hz,1H),8.12(dt,J＝1.9,7.7Hz,1H),8.03(dd,J＝2.4,8.6Hz,1H),7.71-7.60(m,3H),2.11(s,3H)。MS[M+H,M+2H] ⁺ ＝316.2,318.2.

Example 18:3- (1-oxo-5- (1- ((4-oxo-3- (pyridin-3-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of (yl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (67)

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3- (pyridin-3-yl) -6-vinylquinazolin-4 (3H) -one

At room temperature under continuous N ₂ Bubbling 6-bromo-3- (pyridin-3-yl) quinazolin-4 (3H) -one (700 mg,2.32 mmol) into 1, 4-diPotassium vinyltrifluoroborate (310 mg,2.32 mmol) was added to a solution in alkane (8 mL), followed by cesium carbonate solution (2M in water, 1.16mL,2.32 mmol) and PdCl ₂ (dppf) ₂ -CH ₂ Cl ₂ Adducts (1.89 g,2.32 mmol). The reaction mixture was stirred at 85℃for 18h. Ethyl acetate (50 mL) was added to the reaction mixture and passed throughThe mixture was filtered through a pad. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (using ethyl acetate and hexane as eluent) to give the title compound (470 mg, 71%) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.79(d,J＝2.0Hz,1H),8.71(dd,J＝1.2,4.8Hz,1H),8.41(s,1H),8.16(d,J＝2.0Hz,1H),8.11-8.05(m,2H),7.75(d,J＝8.4Hz,1H),8.66-8.63(m,1H),6.96(dd,J＝11.0,17.6Hz,1H),6.02(d,J＝17.6Hz,1H),5.42(d,J＝11.0Hz,1H)。MS[M+H] ⁺ ＝250.3。

4-oxo-3- (pyridin-3-yl) -3, 4-dihydro-quinazoline-6-carbaldehyde

To 3- (pyridin-3-yl) -6-vinylquinazolin-4 (3H) -one (470 mg,1.91 mmol) in 1, 4-di-at 0deg.CTo a solution of alkane (7 mL) and water (0.2 mL) was added sodium periodate (815 mg,3.81 mmol) and 4-methylmorpholine (0.105 mL,0.953 mmol), followed by dropwise addition of osmium (VIII) oxide (4 wt.%) in water, 1.50mL,0.191 mmol) at 0deg.C. The reaction mixture was warmed to 25 ℃ and stirred for 3h. During the reaction, substantial solids formation was observed. The reaction mixture was filtered and the solid residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (ethyl acetate in hexane (45-95%) as eluent) to give the title compound (225 mg, 45%) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.19(s,1H),8.82(d,J＝2.0Hz,1H),8.78(d,J＝2.0Hz,1H),8.73(dd,J＝1.6,4.8Hz,1H),8.59(s,1H),8.32(dd,J＝2.0,4.4Hz,1H),8.11-8.07(m,1H),7.92(d,J＝8.4Hz,1H),6.68-6.65(m,1H)。MS[M+H] ⁺ ＝252.1。

3- (1-oxo-5- (1- ((4-oxo-3- (pyridin-3-yl) -3, 4-dihydro-quinazolin-6-yl) methyl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione

A solution of 4-oxo-3- (pyridin-3-yl) -3, 4-dihydroquinazoline-6-carbaldehyde (121 mg,0.481 mmol) and 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione, HCl (175 mg,0.481 mmol) in DMF (3 mL) was stirred at room temperature for 15min. At room temperature at N ₂ Sodium triacetoxyborohydride (255 mg,1.20 mmol) was added to the reaction mixture and the reaction mixture was stirred for 15h. The reaction mixture was concentrated under reduced pressure to give a crude solid which was dissolved in ACN: water (1:1) and purified by reverse phase column chromatography using a C-18 column (eluting with 10-50% acetonitrile in water containing 0.1% formic acid). The fractions were lyophilized to give the title compound as an off-white solid (40 mg, 14%). A portion of the solid (6.3 mg, 11. Mu. Mol) was taken up in acetonitrile (0.50 mL) and water (0.50 mL). Formic acid (5.0 μl,0.13 mmol) was added to the suspension at room temperature. The resulting solution was stirred at room temperature for 10min, then lyophilized to give 3- (1-oxo-5- (1- ((4-oxo-3- (pyridin-3-yl) -3, 4-dihydro-quinazolin-6-yl) methyl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione formate (6.0 mg,9.9 μmol) as an off-white solid. ¹ H NMR(500MHz,DMSO-d ₆ )δ10.97(s,1H)8.78(br s,1H)8.70(br d,J＝4.4Hz,1H)8.39(s,1H)8.16(br s,1H)8.05(br d,J＝7.7Hz,1H)7.87(br d,J＝8.2Hz,1H)7.75(br d,J＝8.2Hz,1H)7.63(br d,J＝7.1Hz,2H)7.51(br s,1H)7.41(br d,J＝7.7Hz,1H)5.09(br s,1H)4.24-4.51(m,2H)3.70(br s,1H)3.32(br s,3H)2.84-3.04(m,3H)2.56-2.72(m,2H)2.33-2.45(m,1H)2.15(br t,J＝10.4Hz,2H)1.93-2.06(m,1H)1.67-1.85(m,3H)。MS[M+H] ⁺ ＝563.2。

Example 19:3- (1-oxo-5- (1- ((2-phenylimidazo [1, 2-a))]Pyridin-6-yl) methyl) piperidin-4- Synthesis of base) isoindolin-2-yl piperidine-2, 6-dione (54)

6-iodo-2-phenylimidazo [1,2-a ] pyridine

A mixture of 2-bromo-1-phenylethan-1-one (5.00 g,25.1 mmol) and 5-iodopyridin-2-amine (5.53 g,25.1 mmol) in ethanol (100 mL) was stirred at reflux for 2h. Sodium bicarbonate (4.64 g,55.3 mmol) was added to the reaction mixture at room temperature and the mixture was heated at reflux for 5h. The reaction mixture was diluted with EtOAc (300 mL) and the mixture was washed with water (2X 150 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was triturated with hexane, filtered and dried under vacuum to give the title compound as a pale brown solid (5.70 g, 67%). ¹ H NMR(400MHz,CDCl ₃ )δ8.42(dd,J＝0.9,1.7Hz,1H),7.96(dd,J＝1.3,8.3Hz,2H),7.84(d,J＝0.6Hz,1H),7.52-7.42(m,3H),7.41-7.33(m,2H)。MS[M+H] ⁺ ＝321。

2-phenyl-6-vinylimidazo [1,2-a ] pyridine

At room temperature under continuous N ₂ Bubbling down 6-iodo-2-phenylimidazo [1,2-a ]]Pyridine (5.70 g,17.8 mmol) in 1, 4-diTo a stirred solution of potassium vinyltrifluoroborate (2.39 g,17.8 mmol) in alkane (57 mL), cs in water (26.7 mL) was added ₂ CO ₃ (17.4 g,53.4 mmol) followed by addition of PdCl ₂ (dppf)-CH ₂ Cl ₂ Adducts (1.45 g,1.78 mmol). The reaction mixture was stirred at 85℃for 14h. The reaction mixture was passed through- >The pad was filtered and washed with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na ₂ SO ₄ Washed and filtered. The solvent was removed under reduced pressure to give the title compound (3.50 g, 79%) as a pale brown solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.09(s,1H),8.02-7.95(m,1H),7.86(s,1H),7.68(s,1H),7.53-7.41(m,5H),6.68(dd,J＝11.0,17.4Hz,1H),5.79(d,J＝17.4Hz,1H),5.38(d,J＝11.0Hz,1H)。MS[M+H] ⁺ ＝221。

2-phenylimidazo [1,2-a ] pyridine-6-carboxaldehyde

2-phenyl-6-vinylimidazo [1,2-a ]]Pyridine (1.00 g,4.54 mmol) in 1, 4-diA solution of alkane (12.5 mL)/water (1.3 mL) was cooled to 0deg.C, then sodium periodate (1.94 g,9.08 mmol) and N-methylmorpholine (0.230 g,2.27 mmol) were added followed by dropwise addition of osmium tetroxide (4 wt.%) in water, 2.89g,0.454 mmol) at the same temperature. The reaction mixture was stirred at 25℃for 3h. The reaction mixture was quenched with ice-cold brine (100 mL) and then extracted with EtOAc (3X 200 mL). The combined organic extracts were subjected to anhydrous Na ₂ SO ₄ Drying and filtering. The solvent was removed under reduced pressure to give a crude residue which was purified by silica gel column chromatography (using 40-60% ethyl acetate in hexanes as eluent) to give the title compound as a yellow solid (250 mg, 25%). ¹ H NMR(400MHz,CDCl ₃ )δ9.98(s,1H),8.70(s,1H),8.04-7.94(m,3H),7.77-7.64(m,2H),7.54-7.46(m,2H),7.45-7.35(m,1H)。MS[M+H] ⁺ ＝223。

3- (1-oxo-5- (1- ((2-phenylimidazo [1,2-a ] pyridin-6-yl) methyl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione

2-phenylimidazo [1,2-a ] s at room temperature ]To a stirred solution of pyridine-6-carbaldehyde (100 mg,0.450 mmol) in DMF (2 mL) was added 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione hydrochloride (180 mg, 0.495mmol). The reaction mixture was stirred at room temperature for 30min, then sodium triacetoxyborohydride (238 mg,1.13 mmol) was added at room temperature and the mixture was stirred for 15h. The reaction mixture was diluted with cold water (2X 30 mL) and extracted with 10% MeOH/DCM (2X 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a crude residue which was purified by preparative HPLC [ (column: X select (150 mm. Times.19) ] 5 μm, mobile phase A:0.1% over H ₂ HCOOH in O, mobile phase B: acetonitrile, flow rate: 15 mL/min)]And (5) purifying. Removal by lyophilizationThe title compound (51 mg, 21%) was obtained as a white solid, except ACN/water. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.98(s,1H),8.46(s,1H),8.37(s,1H),8.00-7.92(m,2H),7.65(d,J＝7.9Hz,1H),7.59-7.48(m,2H),7.47-7.39(m,3H),7.35-7.29(m,1H),7.26(dd,J＝1.6,9.3Hz,1H),5.10(dd,J＝5.1,13.3Hz,1H),4.47-4.38(m,1H),4.33-4.25(m,1H),3.54(s,2H),3.06-2.84(m,3H),2.66-2.55(m,2H),2.48-2.36(m,1H),2.20-2.08(m,2H),2.04-1.95(m,1H),1.86-1.68(m,4H)。MS[M+H] ⁺ ＝534.2。

Example 20:3- (1-oxo-5- (1- ((2-phenyl- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) methyl Synthesis of piperidin-4-yl) isoindolin-2-yl piperidine-2, 6-dione (55)

N- (5-bromopyridin-2-yl) benzamidines

To a stirred solution of 5-bromopyridin-2-amine (2.00 g,11.6 mmol) in DMF (6 mL) was added sodium hydride (0.555 g,13.9 mmol) at 0deg.C. The resulting reaction mixture was stirred at 0deg.C for 30min, then benzonitrile (1.43 g,13.9 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 2h. Aqueous sodium bicarbonate (5%, 20.0 mL) was added and the mixture extracted with ethyl acetate (2×30 mL). The organic layer was purified by Na ₂ SO ₄ Drying and evaporation under reduced pressure gave a crude residue which was purified by silica gel column chromatography (ethyl acetate in hexanes (8-10%) as eluent) to give the title compound (1.00 g, 23%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.44(dd,J＝0.4,2.8Hz,1H),8.04(dd,J＝1.6,8.4Hz,2H),7.88(dd,J＝2.4,8.8Hz,1H),7.53-7.47(m,3H),7.06(d,J＝8.8Hz,1H)。MS[M+H,M+2H] ⁺ ＝276.0,278.0.

6-bromo-2-phenyl- [1,2,4] triazolo [1,5-a ] pyridine

A mixture of potassium iodide (0.812 g,4.89 mmol) and iodine (0.993 g,3.91 mmol) in DMSO (15 mL) was stirred at room temperature for 10min. N- (5-bromopyridin-2-yl) benzamidine (0.900 g,3.26 mmol) and K were combined at room temperature ₂ CO ₃ (1.35 g,9.78 mmol) was added to the mixture. The mixture was heated at 100 ℃ under nitrogen atmosphere for 2h. To the reaction mixture was added 5% Na ₂ S ₂ O ₃ Aqueous (5 mL) and brine (50 mL). The mixture was extracted with ethyl acetate (2X 40 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Drying and concentration under reduced pressure gave a crude residue which was purified by silica gel column chromatography (ethyl acetate in hexanes (4-6%) as eluent) to give the title compound (0.580 g, 61%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(dd,J＝0.8,1.6Hz,1H),8.29-8.27(m,2H),7.68(d,J＝9.2Hz,1H),7.61(dd,J＝2.0,9.2Hz,1H),7.54-7.50(m,3H)。MS[M+H,M+2H] ⁺ ＝273.8,275.8.

2-phenyl-6-vinyl- [1,2,4] triazolo [1,5-a ] pyridine

At room temperature under continuous N ₂ Bubbling down 6-bromo-2-phenyl- [1,2,4]Triazolo [1,5-a ]]Pyridine (0.580 g,2.12 mmol) in 1, 4-diTo a stirred solution of alkane (8 mL) was added potassium vinyltrifluoroborate (0.850 g,6.35 mmol), cesium carbonate (2M, 1.06mL,2.12 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ Adducts (0.173 g,0.212 mmol). The resulting mixture was stirred at 85℃for 18h. The mixture was concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (ethyl acetate in hexane (9-10%) as eluent) to give the title compound (0.340 g, 72%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.56(s,1H),8.31-8.28(m,2H),7.74-7.71(m,2H),7.55-7.48(m,3H),6.75(dd,J＝11.2,17.6Hz,1H),5.85(d,J＝17.6Hz,1H),5.46(d,J＝11.2Hz,1H)。MS[M+H] ⁺ ＝222.3.

2-phenyl- [1,2,4] triazolo [1,5-a ] pyridine-6-carbaldehyde

To 2-phenyl-6-vinyl- [1,2,4] at 0 DEG C]Triazolo [1,5-a ]]Pyridine (0.340 g,1.54 mmol) in 1, 4-diAlkane (6 mL) sodium periodate (0.657 g,3.07 mmol) and N-methylmorpholine (0.084 mL,0.768 mmol) were added to a stirred solution in water (0.2 mL), followed by dropwise addition of osmium tetroxide (4 wt% water, 1.21mL,0.154 mmol). The resulting reaction mixture was stirred at room temperature for 3h. The reaction mixture was quenched with ice-cold brine (20 mL) and extracted with EtOAc (3X 30 mL). The combined organic extracts were subjected to anhydrous Na ₂ SO ₄ Drying and filtering. The solvent was removed under reduced pressure to give a crude residue which was purified by silica gel column chromatography (ethyl acetate in hexanes (25-28%) as eluent) to give the title compound (0.120 g, 32%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.07(s,1H),9.77(dd,J＝0.8,1.6Hz,1H),8.27-8.25(m,2H),8.04-7.96(m,2H),7.61-7.56(m,3H)。MS[M+H] ⁺ ＝224.2。

3- (1-oxo-5- (1- ((2-phenyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) methyl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione

To a stirred solution of 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione hydrochloride (0.160 g,0.440 mmol) in DMF (4 mL) at room temperature was added 2-phenyl- [1,2,4]Triazolo [1,5-a ]]Pyridine-6-carbaldehyde (0.118 g,0.528 mmol). The reaction mixture was stirred at room temperature for 30min, then cooled to 0deg.C and sodium triacetoxyborohydride (0.242 g,1.143 mmol) was added in portions. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 20h. The reaction mixture was concentrated under reduced pressure to give a crude residue which was purified using reverse phase column chromatography (eluting with 0.1% HCOOH in water: acetonitrile). Acetonitrile/water was removed by freeze drying to give the title compound (0.074 g, 30%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.98(br s,1H),8.92(s,1H),8.20(dd,J＝1.6,4.0Hz,2H),7.84(d,J＝9.2Hz,1H),7.71-7.63(m,2H),7.57-7.51(m,4H),7.43-7.41(m,1H),5.10(dd,J＝5.2,13.2Hz,2H),4.43(d,J＝17.2Hz,2H),4.29(d,J＝17.2Hz,2H),3.65(s,2H),3.02-2.87(m,3H),2.68-2.62(m,1H),2.428-2.37(m,1H),2.20-2.15(m,2H),2.00-1.98(m,1H),1.79-1.74(m,2H)。MS[M+H] ⁺ ＝535.2。

Example 21:3- (5- (1- ((6-bromoimidazo [1 ]),2-a]Pyridin-2-yl) methyl) piperidin-4-yl) -1-oxo Synthesis of isoindolin-2-yl) piperidine-2, 6-dione

To a stirred solution of 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione hydrochloride (0.6278 g,1.73 mmol) in DMF (5 mL) was added 6-bromoindole-2-carbaldehyde (0.300 g,1.15 mmol) and DIPEA (0.603 mL,3.45 mmol) at 25deg.C. The mixture was stirred for 10min. Sodium triacetoxyborohydride (1.22 g,5.76 mmol) was added in portions at 0 ℃. The reaction mixture was stirred under nitrogen at 25 ℃ for 18h. The reaction mixture was then concentrated under reduced pressure to give a crude residue which was purified by normal phase column chromatography (using a gradient of 12% IPA in DCM as eluent) to give the title compound (0.240 g) as a pale yellow solid. A portion of the isolated compound (70 mg,0.124 mmol) was further purified by preparative HPLC [ method information: column: xselect (150 mm. Times.19) 5 μm,0.1% at H ₂ HCl in O and ACN, flow rate: 15mL/min]And (5) purifying. The collected fractions were lyophilized to give the title compound as an off-white solid (17 mg, 11%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.0(s,1H),10.65(brs,1H),9.10(s,1H),8.20(s,1H),7.80-7.60(m,2H),7.55-7.50(m,1H),7.5-7.4(m,1H),7.40-7.30(m,1H),5.15-5.05(m,1H),4.55-4.35(m,3H),4.32(d,J＝17.6Hz,1H),3.60-3.50(m,2H),3.25-3.10(m,2H),3.00-2.85(m,2H),2.65-2.50(m,1H),2.34-2.20(m,1H),2.15-1.90(m,5H)。MS[M+2H] ⁺ ＝538.1.

Example 22:3- (1-oxo-5- (1- ((6-phenylimidazo [1, 2-a))]Pyridin-2-yl) methyl) piperidin-4- Synthesis of base) isoindolin-2-yl piperidine-2, 6-dione (96)

In succession N ₂ Bubbling for 10min followed by 3- (5- (1- ((6-bromoimidazo) amino)[1,2-a]Pyridin-2-yl) methyl piperidin-4-yl) -1-oxoisoindolin-2-yl piperidine-2, 6-dione (100 mg,0.186 mmol) in 1, 4-diTo a stirred solution of alkane (3 mL)/water (0.15 mL) was added phenylboronic acid (34.1 mg,0.280 mmol) and H ₂ K in O ₃ PO ₄ (4M, 0.140mL,0.559 mmol) followed by PdCl ₂ (dppf)-CH ₂ Cl ₂ Adduct (15 mg,0.019 mmol). The reaction mixture was taken up in N ₂ Stirring is carried out for 12h at 100℃under an atmosphere. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by normal phase column chromatography (using a gradient of 16% IPA in DCM as eluent) to give the title compound (80 mg) as a pale brown solid. The material was further purified by preparative HPLC [ method information: column: x select (150 mm. Times.19) 5 μm,0.1% at H ₂ HCl in O and ACN, flow rate: 15mL/min]And (5) purifying. The collected fractions were lyophilized to give 3- (1-oxo-5- (1- ((6-phenylimidazo [1, 2-a)) as an off-white solid ]Pyridin-2-yl) methyl) piperidin-4-yl) isoindolin-2-yl piperidine-2, 6-dione hydrochloride (6.5 mg, 6.4%). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.99(s,1H),10.55(brs,1H),9.12(s,1H),8.26(s,1H),7.90-7.65(m,5H),7.60-7.50(m,2H),7.50-7.32(m,3H),5.20-5.05(m,1H),4.60-4.51(m,2H),4.45(d,J＝17.2Hz,1H),4.32(d,J＝17.6Hz,1H),3.64-3.61(m,2H),3.31-3.11(m,2H),3.05-2.85(m,2H),2.65-2.55(m,1H),2.44-2.35(m,1H),2.10-1.90(m,5H)。MS[M+H] ⁺ ＝534.2。

Example 23:3- (1-oxo-5- (1- ((6- (pyridin-3-yl) imidazo [1, 2-a))]Pyridin-2-yl) methyl) piperaquine Synthesis of pyridin-4-yl) isoindolin-2-yl piperidine-2, 6-dione (97)

In succession N ₂ Bubbling for 10min followed by 3- (5- (1- ((6-bromoimidazo [1, 2-a))]Pyridin-2-yl) methyl) piperidin-4-yl) -1-oxoisoindolin-2-yl) pipa-dePyridine-2, 6-dione (0.100 g,0.186 mmol) in 1, 4-dioneTo a stirred solution of 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.057 g,0.28 mmol) and DIPEA (0.072 g,0.56 mmol) in alkane (3 mL)/water (0.15 mL) was added followed by bis (tri-t-butylphosphine) palladium (0) (9.50 mg,0.019 mmol). The reaction mixture was irradiated under microwaves at 140℃for 4h. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by reverse phase column chromatography (4% ACN in water as eluent) to give the title compound (30 mg). The isolated compound was further purified by preparative HPLC [ method information: column: x select (150 mm. Times.19) 5 μm,0.1% at H ₂ HCl in O and ACN, flow rate: 15mL/min]And (5) purifying. The collected fractions were lyophilized to give 3- (1-oxo-5- (1- ((6- (pyridin-3-yl) imidazo [1, 2-a)) as a pale yellow solid ]Pyridin-2-yl) methyl) piperidin-4-yl) isoindolin-2-yl piperidine-2, 6-dione hydrochloride (6.1 mg, 6%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.28(brs,1H),11.0(s,1H),9.42(s,1H),9.21(s,1H),8.84(s,1H),8.69-8.58(m,1H),8.12-8.01(m,1H),7.95-7.87(m,2H),7.79-7.67(m,1H),7.48(s,1H),7.41-7.33(m,1H),5.19-5.06(m,1H),4.65-4.50(m,2H),4.46(d,J＝17.6Hz,1H),4.32(d,J＝17.6Hz,1H),3.68-3.55(m,2H),3.30-3.11(m,2H),3.05-2.85(m,2H),2.65-2.55(m,1H),2.45-2.35(m,1H),2.23-1.90(m,5H)。MS[M+H] ⁺ ＝535.3。

Example 24:3- (1-oxo-5- (1- ((2- (pyridin-3-yl) -2H-indazol-6-yl) methyl) piperidin-4-yl) Synthesis of isoindolin-2-yl) piperidine-2, 6-dione (95)

2- (pyridin-3-yl) -2H-indazole-6-carboxylic acid methyl ester

To a vial containing 4- (methoxycarbonyl) -2-nitrobenzaldehyde (500 mg,2.39 mmol) was added isopropanol (6.0 mL) followed by 3-aminopyridine (247 mg,2.63 mmol). Will be smallThe bottle was flushed with nitrogen and then heated at 80 ℃. After 4 hours, the mixture was cooled to room temperature, followed by the addition of tri-n-butylphosphine (1.77 mL,7.17 mmol). The resulting mixture was heated at 80℃for 16hr overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (4 mL) and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography on a C18 reverse phase column eluting with 20-100% acetonitrile in water containing 0.1% formic acid. The product containing fractions were combined and lyophilized to give methyl 2- (pyridin-3-yl) -2H-indazole-6-carboxylate formate (255 mg, 42%) as a tan solid. ¹ H NMR(500MHz,CDCl ₃ )δ9.14-9.30(m,1H)8.70(dd,J＝1.0,4.8Hz,1H)8.58(s,1H)8.52(s,1H)8.31-8.43(m,1H)8.11(s,1H)7.77(s,2H)7.57(dd,J＝4.8,8.4Hz,1H)3.98(s,3H)。MS[M+H] ⁺ ＝254.1。

(2- (pyridin-3-yl) -2H-indazol-6-yl) methanol

A solution of methyl 2- (pyridin-3-yl) -2H-indazole-6-carboxylate (255 mg,1.01 mmol) in THF (10 mL) was cooled to 0deg.C. Addition of LiAlH to solution ₄ (1M in THF, 3.00mL,3.00 mmol) and the mixture was slowly warmed to room temperature. The mixture was quenched with MeOH (added dropwise) and the solution was stirred at room temperature for 30min. The mixture was diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate x 2. The combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give a crude residue which was purified by column chromatography on silica gel (eluting with 40-100% ethyl acetate in hexanes then until 10% methanol in ethyl acetate) to give the title compound as a yellow solid (78 mg, 34%). ¹ HNMR (500 MHz, methanol-d) ₄ )δ9.18-9.29(m,1H)8.86(s,1H)8.61(d,J＝4.9Hz,1H)8.45(dd,J＝1.4,8.5Hz,1H)7.75(d,J＝8.8Hz,1H)7.68(s,1H)7.65(dd,J＝4.9,8.2Hz,1H)7.14(d,J＝8.8Hz,1H)4.72(s,2H)。MS[M+H] ⁺ ＝226.1。

2- (pyridin-3-yl) -2H-indazole-6-carbaldehyde

To a solution of (2- (pyridin-3-yl) -2H-indazol-6-yl) methanol (75 mg,0.33 mmol) in DCM (1.7 mL) was added at room temperatureDMP (0.17 g,0.40 mmol). After the addition of DMP, the mixture became an orange homogeneous solution. After stirring for 30min, the solution was passed through a syringe filter and purified by column chromatography on silica gel (eluting with 30-100% ethyl acetate in hexanes). The fractions containing the product were combined and concentrated to give the title compound (43 mg, 58%). ¹ H NMR(500MHz,CDCl ₃ )δ10.07-10.17(m,1H)9.22(d,J＝2.2Hz,1H)8.72(d,J＝3.8Hz,1H)8.54(s,1H)8.27-8.36(m,2H)7.83(d,J＝8.8Hz,1H)7.68(dd,J＝1.1,8.8Hz,1H)7.54(dd,J＝4.7,8.2Hz,1H)。MS[M+H] ⁺ ＝224.1。

3- (1-oxo-5- (1- ((2- (pyridin-3-yl) -2H-indazol-6-yl) methyl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione

To a solution of 3- (1-oxo-5- (piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (40 mg,0.12 mmol) and 2- (pyridin-3-yl) -2H-indazole-6-carbaldehyde (40 mg,0.18 mmol) in dimethylacetamide (DMA, 4 mL) was added sodium triacetoxyborohydride (78 mg,0.37 mmol) at room temperature, followed by DIPEA (64 μl,0.37 mmol). After stirring for 18h, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3X 10 mL). The combined organics were washed with brine (2×30 mL), dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography on a C18 column (eluting with 10-100% acetonitrile in water containing 0.1% formic acid) to give the title compound as a white solid. MS [ M+H ]] ⁺ ＝535.3。

Example 25:3- (5- (1- ((3- (3-fluorophenyl) -4-oxo-3, 4-dihydro-quinazolin-6-yl) methyl) piperidine) Synthesis of 4-yl) -1-oxo-isoindolin-2-yl-piperidine-2, 6-dione (28)

Compound 28 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝580.2。

Example 26:3- (1-oxo-5- (1- ((4-oxo-3- (3- (trifluoromethyl) phenyl) -3, 4-dihydroquinazoline) Synthesis of 6-yl-methyl) piperidin-4-yl-isoindolin-2-yl) piperidine-2, 6-dione (60)

Compound 60 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝630.1。

Example 27:3- (6- ((4- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidine) Synthesis of 1-yl) methyl) -4-oxoquinazolin-3 (4H) -yl benzonitrile (61)

Compound 61 was prepared according to a similar procedure as described in examples 13 and 15. MS [ M+H ]] ⁺ ＝587.2。

Example 28:3- (5- (1- ((3- (6-methylpyridin-2-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of (yl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (62)

Compound 62 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝577.1。

Example 29:3- (5- (1- ((3- (6-isopropylpyridin-2-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) Synthesis of methyl) piperidin-4-yl) -1-oxoisoindolin-2-yl piperidine-2, 6-dione (63)

Compound 63 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝605.1。

Example 30:3- (5- (1- ((3- (6-methoxypyridin-2-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) Synthesis of methyl) piperidin-4-yl) -1-oxoisoindolin-2-yl piperidine-2, 6-dione (65)

Compound 65 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝593.1。

Example 31:3- (1-oxo-5- (1- ((4-oxo-3- (thiazol-5-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Base) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (66) synthesis

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Compound 66 was prepared according to a similar procedure as described in examples 16 and 18.

Example 32:3- (5- (1- ((3- (2-methylpyridin-3-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of (yl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (68)

Compound 68 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝577.4。

Example 33:3- (5- (1- ((3- (6-methylpyridin-3-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) methyl) Phenyl) piperidin-4-yl) -1-oxo-isoindolin-2-yl-piperidine-2, 6-dione (69) synthesis

Compound 69 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝577.3。

Example 34:3- (5- (1- ((3- (2, 6-dimethylpyridin-3-yl) -4-oxo-3, 4-dihydroquinazolin-6) one) Methyl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (70) synthesis

Compound 70 was prepared according to a similar procedure as described in examples 16 and 18.

Example 35:3- (5- (1- ((3- (6-isopropylpyridin-3-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) Synthesis of methyl) piperidin-4-yl) -1-oxoisoindolin-2-yl piperidine-2, 6-dione (71)

Compound 71 was prepared according to a similar procedure as described in examples 16 and 18.

Example 36:3- (5- (1- ((3- (2-isopropylpyridin-3-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) Synthesis of methyl) piperidin-4-yl) -1-oxoisoindolin-2-yl piperidine-2, 6-dione (72)

Compound 72 was prepared according to a similar procedure as described in examples 16 and 18.

Example 37:3- (1-oxo-5)- (1- ((4-oxo-3- (6- (trifluoromethyl) pyridin-3-yl) -3, 4-dihydroquinazolin) Synthesis of azolin-6-yl-methyl) piperidin-4-yl-isoindolin-2-yl) piperidine-2, 6-dione (73)

Compound 73 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝631.1。

Example 38:3- (5- (1- ((3- (6-methoxypyridin-3-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) Synthesis of methyl) piperidin-4-yl) -1-oxoisoindolin-2-yl piperidine-2, 6-dione (74)

Compound 74 was prepared according to a similar procedure as described in examples 16 and 18.

Example 39:3- (5- (1- ((3- (5-fluoropyridin-3-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of piperidin-4-yl) -1-oxoisoindolin-2-yl piperidine-2, 6-dione (75)

Compound 75 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝581.3。

Example 40:3- (1-oxo-5- (1- ((4-oxo-3- (pyridazin-3-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of (yl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (76)

Compound 76 was prepared according to a similar procedure as described in examples 16 and 18.

Example 41:3- (1-oxo-5- (1- ((4-oxo-3- (pyrazin-2-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of (yl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (77)

Compound 77 was prepared according to a similar procedure as described in examples 16 and 18.

Example 42:3- (1-oxo-5- (1- ((4-oxo-3- (pyridin-4-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of (yl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (78)

Compound 78 was prepared according to a similar procedure as described in examples 16 and 18.

Example 43:3- (1-oxo-5- (1- ((4-oxo-3- (2-oxo-1, 2-dihydropyridin-3-yl) -3, 4-di-n-e) Synthesis of hydroquinazolin-6-yl) methyl) piperidin-4-yl isoindolin-2-yl) piperidine-2, 6-dione (79)

Compound 79 was prepared according to a similar procedure as described in examples 16 and 18.

Example 44:3- (1-oxo-5- (1- ((4-oxo-3- (6-oxo-1, 6-dihydropyridin-2-yl) -3, 4-di-n) Synthesis of hydroquinazolin-6-yl) methyl) piperidin-4-yl isoindolin-2-yl) piperidine-2, 6-dione (80)

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Compound 80 was prepared according to a similar procedure as described in examples 16 and 18.

Example 45:3- (5- (1- ((3- (1-methyl-1H-imidazol-5-yl) -4-oxo-3, 4-dihydroquinazolin-6) one) Methyl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (81) synthesis

Compound 81 was prepared according to a similar procedure as described in example 8.

Example 46:3- (5- (1- ((3- (1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-6) one) Methyl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (82) synthesis

Compound 82 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝566.2。

Example 47:3- (5- (1- ((2-methyl-4-oxo-3-phenyl-3, 4-dihydroquinazolin-6-yl) methyl) methylphenidate Synthesis of pyridin-4-yl) -1-oxo-isoindolin-2-yl-piperidine-2, 6-dione (83)

Compound 83 was prepared according to a similar procedure as described in examples 17 and 18. MS [ M+H ]] ⁺ ＝576.8。

Example 48:3- (5- (1- ((2-methyl-4-oxo-3- (pyridine))-2-yl) -3, 4-dihydroquinazolin-6-yl-methyl Group) Synthesis of piperidin-4-yl) -1-oxoisoindolin-2-yl-piperidine-2, 6-dione (84)

Compound 84 was prepared according to a similar procedure as described in examples 17 and 18. MS [ M+H ]] ⁺ ＝577.3。

Example 49:3- (4-fluoro-1-oxo-5- (1- ((4-oxo-3- (pyridin-2-yl) -3, 4-dihydroquinazolin-6- Methyl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (85) synthesis

Compound 85 was prepared according to a similar procedure as described in examples 11, 16 and 18. MS [ M+H ]] ⁺ ＝581.7。

Example 50:3- (5- (1- ((8-fluoro-4-oxo-3- (pyridin-2-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of (yl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (86)

Compound 86 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝581.0。

Example 51:3- (5- (1- ((7-fluoro-4-oxo-3- (pyridin-2-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of (yl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (87)

Compound 87 was prepared according to a similar procedure as described in examples 16 and 18. MS [ M+H ]] ⁺ ＝581.4。

Example 52:3- (5- (1- ((5-fluoro-4-oxo-3- (pyridin-2-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of (yl) piperidin-4-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (88)

Compound 88 was prepared according to a similar procedure as described in examples 14 and 15. MS [ M+H ] ] ⁺ ＝581.2。

Example 53:3- (4-fluoro-1-oxo-5- (1- ((4-oxo-3- (pyridin-3-yl) -3, 4-dihydroquinazolin-6- Methyl) piperidin-4-yl) isoindolin-2-yl) piperidine-2, 6-dione (89) synthesis

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Compound 89 was prepared according to a similar procedure as described in examples 11, 16 and 18. MS [ M+H ]] ⁺ ＝581.2。

Example 54:3- (5- (1- ((7-fluoro-4-oxo-3- (pyridin-3-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Synthesis of 1-oxo-isoindolin-2-yl) -piperidin-2, 6-dione (90)

Compound 90 was prepared according to a similar procedure as described in examples 16 and 18.

Example 55:3- (5- (1- ((5-fluoro-4-oxo-3- (pyridin-3-yl) -3, 4-dihydroquinazolin-6-yl) methyl) Group) piperidin-4-yl) -1-oxoisoindolesSynthesis of lin-2-yl) piperidine-2, 6-dione (91)

Compound 91 was prepared according to a similar procedure as described in examples 16 and 18.

Example 56:3- (1-oxo-5- (1- ((2- (pyridin-2-yl) pyrazolo [1, 5-a))]Pyridin-6-yl) methyl) piperazine Synthesis of pyridin-4-yl) isoindolin-2-yl piperidine-2, 6-dione (92)

Compound 92 was prepared according to a similar procedure as described in example 9.MS [ M+H ]] ⁺ ＝535.4。

Example 57:3- (1-oxo-5- (1- ((2- (pyridin-3-yl) pyrazolo [1, 5-a))]Pyridin-6-yl) methyl) piperazine Synthesis of pyridin-4-yl) isoindolin-2-yl piperidine-2, 6-dione (93)

Compound 93 was prepared according to an analogous procedure as described in example 9.

Example 58:3- (1-oxo-5- (1- ((2- (pyridin-2-yl) -2H-indazol-6-yl) methyl) piperidin-4-yl) Synthesis of isoindolin-2-yl) piperidine-2, 6-dione (94)

/>

Compound 94 was prepared according to a similar procedure as described in example 24.

Example 59:3- (1-oxo-5- (1- ((7-phenylimidazo [1, 2))-a]Pyridin-2-yl) methyl) piperidin-4- Synthesis of base) isoindolin-2-yl piperidine-2, 6-dione (98)

Compound 98 was prepared according to a similar procedure as described in examples 21 and 22. MS [ M+H ]] ⁺ ＝534.2。

Example 60:3- (1-oxo-5- (1- ((7- (pyridin-3-yl) imidazo [1, 2-a))]Pyridin-2-yl) methyl) piperaquine Synthesis of pyridin-4-yl) isoindolin-2-yl piperidine-2, 6-dione (99)

Compound 99 was prepared according to a similar procedure as described in examples 21 and 23. MS [ M+H ]] ⁺ ＝535.3。

Example 61: liquid Chromatography Mass Spectrometry (LCMS) data

Using a device withThe Shimadzu LC-20AD series (binary pump and diode array detector) of C18 column (3 μm,2.0×30 mm) was subjected to reaction monitoring and final compound characterization. Mobile phase: a:0.04% trifluoroacetic acid in water (v/v), B:0.02% trifluoroacetic acid (v/v) in MeCN. Flow rate: 1mL/min (0.00-1.80 min) and 1.2mL/min (1.81-2.00 min), 25 ℃. MS:2020, quadrupole LC/MS, ion source: API-ESI, TIC: 100-1000 m/z; drying gas flow rate: 15L/min; sprayer pressure: 1.5L/min; drying gas temperature: capillary voltage (Vcap) at 250 ℃): 1400V.

TABLE 1 LCMS data for inventive compounds

Example 62: additional LCMS data

Reaction monitoring and final compound characterization were collected using Shimadzu N-series UPLC-MS system (LCMS-2020). Unless otherwise noted, all masses reported are m/z of the protonated parent ion. The sample is dissolved in a suitable solvent (such as methanol, acetonitrile or DMSO) and injected directly into the column using an automated sample processor. The analysis was performed on the following equipment:acquity UPLC CSH C18 1.7 μm, 2.1X10 mm: flow rate: 1.0mL/min;40 ℃ (column temperature) solvent a:0.1% formic acid in water, solvent B:0.1% formic acid in acetonitrile, gradient: solvent a:0.01min-3.0%,1.5-1.9min-97.0%,2.0min-3.0%. Agilent Zorbax eclipse plus C18 2.1X105 mm 1.8 μm: flow rate: 0.8mL/Min:40 ℃ (column temperature) solvent a:0.1% formic acid in water, solvent B:0.1% formic acid in acetonitrile, gradient: solvent a:0.01-0.25min-5.0%,2.5-3.0min-100.0%,3.1-4.0min-5.0%. Waters X-Bridge C8 (50X 4.6) mm,3.5 μm: flow rate: 0.8mL/min;40 ℃ (column temperature): solvent a:10mM ammonium bicarbonate in water, solvent B: acetonitrile, gradient: solvent a:0.01min-5.0%,1.5-3.0min-95.0%,3.5-4.0min-5.0%. Waters X-Bridge C8 (50X 4.6) mm,3.5 μm: flow rate: 0.8mL/min;40 ℃ (column temperature): solvent a:10mm ammonium acetate in water, solvent B: acetonitrile, gradient: solvent a:0.01min-5.0%,1.5-3.0min-95.0%,3.5-4.0min-5.0%.

TABLE 2 LCMS data for inventive compounds

Example 63: hiBiT scheme

HiBiT peptide tags mediated via CRISPR/Cas (Promega ^TM ) Insertion intoTo the N-terminus of the IKZF2 locus (Neon ^TM Transfection system), the HiBiT protein labelling system was applied to MOLT4 cells. The resulting HiBiT-Helios stable cell lines were treated in triplicate with the following inventive compounds according to a 13-point concentration protocol ranging from 10. Mu.M to 0.00026. Mu.M. At the indicated point in time, use is made ofHiBiT cleavage detection System (Promega ^TM ) Detecting bioluminescence of the HiBiT tag in the treated cells: the abundance of the tag is proportional to the luminescence level. After normalization to DMSO, a dose response curve (GraphPad Prism) was drawn to determine the concentration points at which each compound achieved 50% HiBiT-Helios degradation. The degradation degree (light emission range) from the highest concentration point to the lowest concentration point is calculated to determine Dmax. The results are shown in Table 3.

TABLE 3 degradation Activity of inventive Compounds after 6 hours treatment (HiBiT-IKZF 2 assay)

"+" is greater than 25 to less than 100×10 ^-9 M; "++" is greater than 5 to less than 25×10 ^-9 M; "+ ++ +" Small "at 5X 10 ^- ⁹ M

Example 64: MOLT4 IKZF2 HiBit assay protocol

This protocol uses MOLT4 cells engineered with CRISPR/Cas9 mediated genomic insertion of HiBit, which is tagged to the N-terminus of the IKZF2 coding sequence. Day 1. Tecan D300e was used to establish a 10-point dose response starting from 30. Mu.M down to 1 nM. Next, MOLT4 IKZF2 HiBit cells of 8,000 cells/well were added to the compound plates. Incubate for 24 hours. Day 2. Will be HiBit lysis buffer-HiBit cleavage substrate/LgBit protein mixture was added to each well and incubated for 15 min. Finally, BMG Labtech>FSX reads the luminescence signal. Data were normalized to DMSO and plotted using GraphPad Prism to determine the concentration points at which each compound achieved 50% HiBiT-Helios degradation. The degradation degree (light emission range) from the highest concentration point to the lowest concentration point is calculated to determine Dmax. Data for selected compounds are provided in table 4.

Table 4: degradation Activity of inventive Compounds after 6 hours treatment (HiBiT-IKZF 2 assay)

All patent publications and non-patent publications are indicative of the level of skill of those skilled in the art to which this invention pertains. All such publications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

1. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, having a structure represented by formula (I):

wherein:

R ₆ The method comprises the following steps:

R ₇ selected from the group consisting of:

each R ₁₅ Independently selected from the group consisting of: alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkoxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoAlkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminoculfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminoculfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino heteroaryl sulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido, phosphino, phosphoryl including phosphino and phosphonyl, cyclic acetal, 4 to 7 membered heterocycloalkyl containing at least one nitrogen atom and linked via said nitrogen atom, aryl, heteroaryl, and wherein two adjacent R ₁₅ Together with the corresponding atom to which each is bound form aryl, heteroaryl, 5-to 8-membered cycloalkyl or 5-to 8-membered heterocycloalkyl;

R ₁₆ independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₇ ) Cycloalkyl, 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl, monocyclic and bicyclic 5-to 10-membered heteroaryl, halo, cyano, -N (R) ₉ ) ₂ 、-OR ₉ 、(C ₁ -C ₆ ) Alkoxy, (C) ₁ -C ₆ ) Haloalkoxy, (C) ₂ -C ₆ ) Alkenyl group (C) ₂ -C ₆ ) Alkynyl groups and free radicals involved in single bond formation; wherein said alkaneThe radicals, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

W ₁ selected from the group consisting of: -O-, -S-and-NR ₉ -；

Each W is ₃ Is nitrogen or CR ₁₆ ；

Y is-SO ₂ -or-c= (O) -;

n ₁ 0, 1 or 2;

n ₃ independently 1, 2 or 3;

n ₄ independently 1 or 2; and is also provided with

n ₅ And independently 0 or 1.

2. A compound according to claim 1, wherein:

each R _1a 、R _1b 、R _1a ' and R _1b ' is hydrogen;

each R ₄ And R is ₄ ' independently selected from the group consisting of: hydrogen, hydroxy, halogen, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl and (C) ₁ -C ₆ ) A hydroxyalkyl group; wherein the alkyl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Substituted by radicals, or

R ₆ The method comprises the following steps:

R ₇ selected from the group consisting of:

R ₁₂ and R is ₁₃ Together with the carbon atoms to which they are attached form (C ₆ -C ₁₀ ) Aryl, or monocyclic or bicyclic 5-to 10-membered heteroarylA radical, wherein the aryl or heteroaryl radical is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

each R ₁₅ Independently selected from the group consisting of: alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkoxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heteroCycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminoculfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminoculfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido, phosphino, phosphoryl including phosphino and phosphonate, cyclic acetal groups, 4 to 7 membered heterocycloalkyl groups containing at least one nitrogen atom and being linked via said nitrogen atom, aryl, heteroaryl groups, and wherein two adjacent R ₁₅ Together with the corresponding atom to which each is bound form aryl, heteroaryl, 5-to 8-membered cycloalkyl or 5-to 8-membered heterocycloalkyl;

R ₁₆ independently selected from the group consisting of: hydrogen, (C) _1- C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₇ ) Cycloalkyl, 4-to 7-membered heterocycloalkyl, (C) ₆ -C ₁₀ ) Aryl, monocyclic and bicyclic 5-to 10-membered heteroaryl, halo, cyano, -N (R) ₉ ) ₂ 、-OR ₉ 、(C ₁ -C ₆ ) Alkoxy group、(C ₁ -C ₆ ) Haloalkoxy, (C) ₂ -C ₆ ) Alkenyl group (C) ₂ -C ₆ ) Alkynyl groups and free radicals involved in single bond formation; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted with one or more R's, which may be the same or different ₁₅ Group substitution;

each G is independently selected from C (R ₁₁ )(R ₁₁ ’)、NR ₁₁ And O, provided that at least one G is NR ₁₁ Or (b) O is added to the mixture of the two,

W ₁ selected from the group consisting of: -O-, -S-and-NR ₉ -；

Each W is ₃ Is nitrogen or CR ₁₆ ；

Y is-SO ₂ -or-c= (O) -;

n ₁ 0, 1 or 2;

n ₃ independently 1, 2 or 3;

n ₄ independently 1 or 2; and is also provided with

n ₅ And independently 0 or 1.

3. The compound according to claim 2, wherein:

each R ₂ Is hydrogen;

R ₃ is hydrogen or hydroxy;

R ₆ is that

n ₁ 1.

4. A compound according to claim 3, wherein R ₆ Is thatWherein R is ₆ Further optionally and independently is/are selected from (C) _1- C ₆ ) Alkyl, halo, and cyano groups; and is also provided with

5. The compound of claim 3 or 4, wherein R ₈ Selected from: wherein R is ₈ Further optionally and independently is one or more R ₁₅ And (3) substitution.

6. The compound of claim 5, wherein R ₈ Selected from: wherein R is ₈ Further optionally and independently is one or more R ₁₅ And (3) substitution.

7. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, having a structure represented by formula (II):

wherein:

R _1a And R is _1a 'Lian' for connectingTogether with the same carbon atom to which they are attached form a spiro (C) ₃ -C ₇ ) Cycloalkyl or 4-to 7-membered heterocycloalkyl, or

each R ₁₅ Independently selected from the group consisting of: alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkoxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl cycloalkyl sulfonyl, heterocycloalkyl sulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminoculfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminoculfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkyl Sulfonylamino, heterocyclylalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocyclylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido, phosphino, phosphoryl including phosphine oxide and phosphonate, cyclic acetal, 4 to 7 membered heterocycloalkyl containing at least one nitrogen atom and attached via the nitrogen atom, aryl, heteroaryl, and wherein two adjacent R ₁₅ Together with the corresponding atom to which each is bound form aryl, heteroaryl, 5-to 8-membered cycloalkyl or 5-to 8-membered heterocycloalkyl;

R ₂₁ is substituted C ₆ -aryl, provided that said aryl is substituted with at least two R ₁₅ Substituted, with the proviso that when on adjacent carbon atoms, the R ₁₅ Form a 5-or 6-membered heteroaryl group, said 5-or 6-membered heteroaryl group being substituted with at least one (C ₆ -C ₁₀ ) Aryl, or monocyclic or bicyclic 5 to 10 membered heteroaryl substitution; wherein the aryl and heteroaryl groups are further optionally and independently substituted with one or more R ₁₅ Substituted or

R ₂₁ Is that

W ₁ selected from the group consisting of: -O-, -S-and-NR ₉ -；

y is-SO ₂ -or-c= (O) -;

n ₁ 0, 1 or 2; and is also provided with

n ₅ And independently 0 or 1.

8. A compound according to claim 7, wherein:

each R _1a 、R _1b 、R _1a ' and R _1b ' is hydrogen;

each R ₂ Is hydrogen;

R ₅ and R is ₅ ' each is hydrogen or (C) ₁ -C ₆ ) An alkyl group;

R ₂₁ is that

n ₁ 1.

9. The compound of claim 8, wherein R ₂₁ Selected from:

/>

wherein R is ₂₁ Optionally and independently is/are substituted with one or more (C _1- C ₆ ) Alkyl, halo, and cyano substitutions.

10. The compound according to claim 8 or 9, wherein R ₈ Selected from: wherein R is ₈ Further optionally and independently is one or more R ₁₅ And (3) substitution. />

11. The compound of claim 10, wherein R ₈ Selected from: wherein R is ₈ Further optionally and independently is one or more R ₁₅ And (3) substitution.

12. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which is:

/>

13. the compound of claim 7, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, represented by formula IIa, IIb, IIc, IId or IIe:

wherein,,

each R ₂ Independently selected from the group consisting of hydrogen and halo; and is also provided with

14. The compound of claim 13, wherein R ₈ Selected from: /> Wherein R is ₈ Further optionally and independently is one or more R ₁₅ And (3) substitution.

15. The compound of claim 14, wherein R ₈ Selected from:

wherein the method comprises the steps of

R ₁₆ ' selected from hydrogen and (C) _1- C ₆ ) Alkyl groups.

16. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which is:

/>

17. the compound of any one of claims 1-16, in the form of the pharmaceutically acceptable salt.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-16, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 18, wherein the compound is in a co-crystal form.

20. A method of treating a disease or disorder associated with IKZF2 (Helios) and which would benefit from IKZF2 degradation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-16, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

21. The method of claim 20, wherein the disease or disorder is cancer.

22. The method of claim 21, wherein the cancer is a T cell leukemia or a T cell lymphoma.

23. The method of claim 21, wherein the cancer is hodgkin's lymphoma or non-hodgkin's lymphoma.

24. The method of claim 21, wherein the cancer is myeloid leukemia.

25. The method of claim 21, wherein the cancer is non-small cell lung cancer (NSCLC).

26. The method of claim 21, wherein the cancer is melanoma.

27. The method of claim 21, wherein the cancer is Triple Negative Breast Cancer (TNBC).

28. The method of claim 21, wherein the cancer is nasopharyngeal carcinoma (NPC).

29. The method of claim 21, wherein the cancer is microsatellite stabilized colorectal cancer (mssCRC).

30. The method of claim 21, wherein the cancer is a thymoma.

31. The method of claim 21, wherein the cancer is a carcinoid.

32. The method of claim 21, wherein the cancer is gastrointestinal stromal tumor (GIST).