Degradation inducers of cyclin-dependent kinase 7 (CDK7) and uses thereof

Abstract

Bispecific compounds that target CDK7 for degradation (degradation inducers) are disclosed. Pharmaceutical compositions containing the degradation inducers and methods of using the compounds to treat disease are also disclosed.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 882,958, filed August 5, 2019, which is incorporated herein by reference in its entirety.

[0002] Government Licensing Rights This invention was made with Government support under Grant No. W81XWH-16-1-0252 awarded by the U.S. Army Medical Research Command. The Government has certain rights in this invention. [Background technology]

[0003] Cyclin-dependent kinase 7 (CDK7) is a master regulator of cell cycle progression and gene transcription. It has been reported that CDK7 inhibition reduces proliferation and increases cell death in various tumor models (Kwiatkowski et al., Nature 511(7511):616-620(2014); Olson et al., Cell Chem. Biol. 26(6):792-803.e10(2019). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Kwiatkowski et al.,Nature 511(7511):616-620(2014) [Non-Patent Document 2] Olson et al.,Cell Chem.Biol.26(6):792-803.e10(2019) Summary of the Invention [Means for solving the problem]

[0005] A first aspect of the present invention provides a bispecific compound comprising a targeting ligand that binds to cyclin-dependent kinase 7 (CDK7) and a degron, covalently linked to each other by a linker, the bispecific compound having the formula (I):

[0006] [ka] (In the formula, R1, R2, R3, R4, R5, L1, L2, A and B are as defined herein; Degrons represent the moiety that binds to E3 ubiquitin ligases. or a pharma- ceutically acceptable salt or stereoisomer thereof. A targeting ligand (TL) is attached to a linker (L) via the R2 group of TL.

[0007] Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a bispecific compound of Formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof and a pharma- ceutically acceptable carrier.

[0008] A further aspect of the present invention relates to a method of preparing a bispecific compound of formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0009] A further aspect of the present invention relates to a method of treating a disease or disorder associated with aberrant (e.g., dysfunctional or dysregulated) CDK7 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a bispecific compound of Formula (I) or a pharma- ceutical acceptable salt or stereoisomer thereof.

[0010] In some embodiments, the disease or disorder is cancer.

[0011] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is breast cancer, brain cancer, lung cancer, colorectal cancer, neuroblastoma, osteosarcoma, or lymphoma.

[0012] In some embodiments, the cancer is a hematological cancer. In some embodiments, the hematological cancer is leukemia, lymphoma, or multiple myeloma.

[0013] In some embodiments, the disease or disorder is an autoimmune disease or disorder.

[0014] Without intending to be bound by any particular theory of operation, it is believed that the bispecific compounds of formula (I) of the present invention cause the degradation of CDK7 by recruiting the cellular ubiquitin / proteasome system, whose function is to routinely identify and remove damaged proteins, to the vicinity of CDK7 as a result of the binding between CDK7 and the targeting ligand. After the CDK7 protein is destroyed, the degradation inducer is released and remains active. The applicant has recently identified a CDK7 inhibitor with low nanomolar potency. By conjugating this potent CDK7 ligand with an E3 ligase binder, the bispecific degradation inducer molecule of the present invention is found to be able to recruit E3 ligase and thus promote the degradation of CDK7. Thus, the bispecific compounds of the present invention may be a potential improvement to current small molecule inhibitors of CDK7 by engaging and utilizing the body's own natural protein processing system, and may overcome one or more limitations of their use. Thus, the effective intracellular concentration of the degradation inducer may be significantly lower than that of small molecule CDK7 inhibitors. In summary, the bispecific compounds of the present invention may be a new set of chemical tools for CDK7 knockdown, providing a potential therapeutic modality for CDK7-related cancers and autoimmune disorders. [Brief description of the drawings]

[0015] [Figure 1A] FIG. 1A is an immunoblot showing CDK7 degradation following treatment of Jurkat cells with bispecific compounds 1-10 of the invention and DMSO (negative control) for 6 hours. [Figure 1B]FIG. 1B is an immunoblot showing CDK7 degradation following treatment of Jurkat cells with bispecific compounds of the invention 11-20, 3 (positive control) and DMSO (negative control) for 6 hours. [Figure 1C] FIG. 1C is an immunoblot showing CDK7 degradation after treatment of Jurkat cells with bispecific compounds 21-26 of the invention and DMSO (negative control) for 6 hours. [Figure 2A] FIG. 2A is an immunoblot showing CDK7 degradation after treatment of Jurkat cells with the selective CDK7 inhibitor YKL-5-124, compound DGY-05-180, the proteasome inhibitor bortezomib or the neddylation inhibitor MLN4924 for 2 hours followed by addition of bispecific compound 3 for 4 hours. [Figure 2B] FIG. 2B is an immunoblot showing CDK7 degradation after treatment of Jurkat cells with YKL-5-124, compound DGY-05-180, bortezomib or MLN4924 for 2 hours followed by addition of bispecific compound 20 for 4 hours. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Unless otherwise defined, 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 of this specification belongs. As used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings set forth to facilitate understanding of the invention.

[0017] 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 mixtures of two or more such compositions, reference to "an inhibitor" includes mixtures of two or more such inhibitors, etc.

[0018] Unless otherwise specified, the term "about" means within 10% (eg, within 5%, 2%, or 1%) of the particular value that is modified by the term "about."

[0019] The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. In contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of the claim to the materials or steps specified and those that do not "materially affect the basic and novel characteristics" of the claimed invention.

[0020] With respect to the compounds of the present invention, and to the extent that the following terms are used herein to further describe them, the following definitions apply.

[0021] As used herein, the term "alkyl" refers to a saturated, straight or branched chain, monovalent hydrocarbon group. In one embodiment, an alkyl group is a C1-C 18 In another embodiment, the alkyl group is a C0-C6, C0-C5, C0-C3, C1-C 12, C1-C8, C1-C6, C1-C5, C1-C4 or C1-C3 groups (CO alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 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-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-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. In some embodiments, the alkyl group is a C1 to C3 alkyl group, In some embodiments, the alkyl group is a C1 to C2 alkyl group.

[0022] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain, e.g., methylene, ethylene, propylene, n-butylene, etc., linking the remainder of the molecule to a radical group consisting only of carbon and hydrogen, containing no unsaturation, and having 1 to 12 carbon atoms. The alkylene chain may be attached to the remainder of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene). In other embodiments, the alkylene group contains 1 to 5 carbon atoms (C1-C5 alkylene). In other embodiments, the alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene group contains 1 carbon atom (C1 alkylene).

[0023] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted with one or more (eg, 1, 2, 3 or 4) halo groups.

[0024] 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 includes radicals having "cis" and "trans" orientations, alternatively "E" and "Z" orientations. In one example, an alkenyl group is a C2-C 18 In another embodiment, the alkenyl group is a C2-C 12 , C2~C 10 , C2-C8, C2-C6 or C2-C3 groups. Examples include ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

[0025] As used herein, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In one example, an alkynyl group is a C2-C 18 In another example, the alkynyl group is a C2-C 12 , C2~C 10 , C2-C8, C2-C6 or C2-C3. Examples include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl.

[0026] The term "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen group attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. An "ether" is two hydrocarbyl groups covalently linked by an oxygen. Thus, the substituent of an alkyl that makes it an ether is or resembles an alkoxyl, as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0027] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine, or iodine.

[0028] As used herein, the term "carbocyclic" (also referred to as "carbocyclyl"), used alone or as part of a larger moiety, refers to a group containing a saturated, partially unsaturated, or aromatic ring system having from 3 to 20 carbon atoms, alone or as part of a larger moiety (e.g., an alkcarbocyclic group). The term carbocyclyl includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof. In one embodiment, a carbocyclyl is a ring system having from 3 to 15 carbon atoms (C 15 In one embodiment, the carbocyclyl contains 3 to 12 carbon atoms (C 12 In another embodiment, carbocyclyl is C3-C8, C3-C 10 Or C5~C 10 In another embodiment, the carbocyclyl as a monocycle includes C3-C8, C3-C6, or C5-C6. In some embodiments, the carbocyclyl as a bicycle includes C7-C 12 In another embodiment, the carbocyclyl as a spiro system is a C5-C 12Includes. Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclyls 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 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-, bi- or spiro-carbocycles). The term carbocyclic group also includes carbocyclic rings fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., aryl or heterocyclic rings) where the group or point of attachment is on the carbocyclic ring.

[0029] Thus, the term carbocyclic, as used herein, also refers to a ring of the formula -R c -carbocyclyl (wherein R c is an alkylene chain). The term carbocyclic, as used herein, also includes carbocyclylalkyl groups, which refer to groups of the formula -OR c -carbocyclyl (wherein R c is an alkylene chain).

[0030] As used herein, the term "heterocyclyl" used alone or as part of a larger moiety refers to a "carbocyclyl" containing a saturated, partially unsaturated, or aromatic ring system in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., O, N, N(O), S, S(O), or S(O)2). The term heterocyclyl includes mono-, di-, tri-, 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 C3-C8 heterocycloalkyl, which are saturated or partially unsaturated mono-, bi- or spiro-ring systems containing 3 to 8 carbons and one or more (1, 2, 3 or 4) heteroatoms.

[0031] In some embodiments, heterocyclyl groups contain 3-12 ring atoms, including monocyclic, bicyclic, tricyclic, and spirocyclic systems in which the ring atoms are carbon and 1-5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyls contain 3-7 membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyls contain 4-6 membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyls contain 3 membered monocyclic rings. In some embodiments, heterocyclyls contain 4 membered monocyclic rings. In some embodiments, heterocyclyls contain 5-6 membered monocyclic rings. In some embodiments, heterocyclyls contain 0-3 double bonds. In any of the foregoing embodiments, heterocyclyls contain 1, 2, 3, or 4 heteroatoms. The nitrogen or sulfur heteroatoms may be optionally oxidized (e.g., NO, SO, SO2), and the nitrogen heteroatoms may be optionally quaternized (e.g., [NR4] + Cl - , [NR4] + OH -Representative examples of heterocyclyl include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxaziridinyl, hexahydrothiopyranyl, hexahydropyrimidinyl, hexahydrothiopyranyl, hexahydrothiopyrimidin ... Nanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo [d]imidazolyl, 1,6-dihydroimidazole[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, thiophenyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrimidine, pyrimidine Lazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidine-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decane-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls containing sulfur or oxygen atoms and 1 to 3 nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, such as oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Examples of 5-membered heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyls such as imidazol-2-yl, triazolyls such as 1,3,4-triazol-5-yl, and tetrazolyls such as 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and 1H-tetrazol-5-yl. Representative examples of benzo-fused 5-membered heterocyclyls are benzoxazol-2-yl, benzothiazol-2-yl, and benzimidazol-2-yl. Examples of 6-membered heterocyclyls contain 1 to 3 nitrogen atoms and optionally sulfur or oxygen atoms, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, especially pyridazin-3-yl, and pyrazinyl. Pyridine N-oxide and pyridazine N-oxide and pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and 1,3,4-triazin-2-yl groups are further examples of heterocyclyl groups. In some embodiments, heterocyclic groups comprise a heterocyclic ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic rings) where the group or point of attachment is on the heterocyclic ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0032] Thus, the term heterocyclic, as used herein, refers to a heterocyclyl group that contains at least one nitrogen, and includes N-heterocyclyl groups, where the attachment point of the heterocyclyl group to the rest of the molecule is through the nitrogen atom of the heterocyclyl group. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl. The term heterocyclic, as used herein, also refers to a heterocyclyl group that contains at least one heteroatom, and includes C-heterocyclyl groups, where the attachment point of the heterocyclyl group to the rest of the molecule is through the carbon atom of the heterocyclyl group. Representative examples of C-heterocyclyl groups include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term heterocyclic also refers to a group of the formula -R c -heterocyclyl (wherein R c is an alkylene chain). The term heterocyclic as used herein also refers to a group of the formula -OR c -heterocyclyl (wherein R c Also included are heterocyclylalkoxy groups, which refer to groups attached through an oxygen atom of a heterocyclic ring (wherein is an alkylene chain).

[0033] As used herein, the term "aryl" used alone or as part of a larger moiety (e.g., "aralkyl" where the terminal carbon atom of the alkyl group is the point of attachment, e.g., a benzyl group, "aralkoxy" where an oxygen atom is the point of attachment, or "aroxyalkyl" where the point of attachment is on the aryl group) refers to a group containing a monocyclic, bicyclic, or tricyclic carbon ring system, including fused rings, in which at least one ring of the system is aromatic. In some embodiments, an aralkoxy group is a benzoxy group. The term "aryl" may be used interchangeably with the term "aryl ring." In one embodiment, aryl includes groups having 6 to 18 carbon atoms. In another embodiment, aryl includes groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, naphthyridinyl, and the like, which may be substituted or independently substituted with one or more substituents described herein. A particular aryl is phenyl. In some embodiments, aryl groups include an aryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic rings) where the group or point of attachment is on the aryl ring.

[0034] Thus, the term aryl refers to a group of the formula -R c -aryl (wherein R c is an alkylene chain such as methylene or ethylene), and includes aralkyl groups (e.g., benzyl). In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl, as used herein, refers to a group of the formula -OR c -aryl (wherein R c Also included are aralkoxy groups, which refer to groups attached through an oxygen atom of a alkylene chain such as methylene or ethylene.

[0035] As used herein, the term "heteroaryl," used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also referred to as "heteroaralkyl") or "heteroarylalkoxy" (also referred to as "heteroaralkoxy"), refers to a monocyclic, bicyclic, or tricyclic system having 5 to 14 ring atoms in which at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes a 4-6 membered monocyclic aromatic group in which one or more ring atoms are independently, optionally substituted nitrogen, sulfur, or oxygen. In another embodiment, heteroaryl includes a 5-6 membered monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetra ... lazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidinyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,5-triazol-2-yl, 1,3,6-triazol-2-yl, 1,3,7-triazol-2-yl, 1,3,8-triazol-2-yl, 1,3,9-triazol-2-yl, 1,3,1 ... -yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl and pyrid-2-yl N-oxide. The term "heteroaryl" also includes groups where the heteroaryl is fused to one or more cyclic (e.g., carbocyclyl or heterocyclyl) rings, where the group or point of attachment is on the heteroaryl ring.Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, or tricyclic. In some embodiments, heteroaryl groups comprise a heteroaryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic rings) where the group or point of attachment is on the heteroaryl ring, and in some embodiments the point of attachment is a heteroatom contained in the heterocyclic ring.

[0036] The term heteroaryl, as used herein, also refers to a heteroaryl group as defined above that contains at least one nitrogen atom, and includes N-heteroaryl groups, where the attachment point of the N-heteroaryl group to the rest of the molecule is through a nitrogen atom of the heteroaryl group. The term heteroaryl, as used herein, further refers to a heteroaryl group as defined above, and includes C-heteroaryl groups, where the attachment point of the heteroaryl group to the rest of the molecule is through a carbon atom of the heteroaryl group. The term heteroaryl, as disclosed herein, further includes heteroarylalkyl groups, which refer to groups of the formula -Rc-heteroaryl, where Rc is an alkylene chain, as defined above. The term heteroaryl, as used herein, further includes heteroaralkoxy (or heteroarylalkoxy) groups, which refer to groups attached through an oxygen atom of the formula -O-Rc-heteroaryl, where Rc is an alkylene group, as defined above.

[0037] Unless otherwise specified and unless further defined for any particular group, any of the groups described herein may be substituted or unsubstituted. As used herein, the term "substituted" refers broadly to all permissible substituents, with the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like. Representative substituents include halogens, hydroxyl groups, and any other organic group that contains any number of carbon atoms, e.g., 1-14 carbon atoms, and may include one or more (e.g., 1, 2, 3, or 4) heteroatoms, such as oxygen, sulfur, and nitrogen atoms, grouped in a linear, branched, or cyclic structural format.

[0038] Thus, unless any particular group is disclosed, representative examples of substituents include alkyl, substituted alkyl (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), haloalkyl, aryl ... alkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), cyclic (e.g., C3-C 12 , C5-C6), substituted cyclic (e.g., C3-C 12 , C5-C6), carbocyclic (e.g., C3-C 12 , C5-C6), substituted carbocyclic (e.g., C3-C 12 , C5-C6), heterocyclic (e.g., C3-C 12 , C5-C6), substituted heterocyclic (e.g., C3-C 12, C5-C6), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or phenyl), heteroaryl (e.g., pyridyl or pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C 12 , C6), substituted aryloxy (e.g., C6-C 12 , C6), alkylthio (e.g., C1-C6), substituted alkylthio (e.g., C1-C6), arylthio (e.g., C6-C 12 , C6), substituted arylthio (e.g., C6-C 12 , C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid and peptide groups.

[0039] The substituent may be a "nitrogen protecting group" (also called an amino protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , -N(R bb )2, -C(=O)R aa , -C(=O)N(R bb )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -SO2N(R bb )2, -SO2R bb , -SO2OR bb , -SOR aa , -C(=S)N(R bb )2, -C(=O)SR bb , -C(=S)SR bb , C 1~10Alkyl (e.g., aralkyl, heteroaralkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~4 Aryl and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R cc substituted with R aa , R bb and R cc Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3 rd This includes those described in detail in the following publication, John Wiley & Sons, 1999.

[0040] Amide groups (e.g., -C(=O)R aa Representative examples of protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0041] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as, but not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate, 5-methoxyphenyl carbamate, 6-methoxyphenyl carbamate, 7-methoxyphenyl carbamate, 8-methoxyphenyl carbamate, 9-methoxyphenyl carbamate, 10-methoxyphenyl carbamate, 11-methoxyphenyl carbamate, 12-methoxyphenyl carbamate, 13-methoxyphenyl carbamate, 14-methoxyphenyl carbamate, 15-methoxyphenyl carbamate, 16-methoxyphenyl carbamate, 17-methoxyphenyl carbamate, 18-methoxyphenyl carbamate, 19-methoxyphenyl carbamate, 20-methoxyphenyl carbamate, 21-methoxyphenyl carbamate, 22-methoxyphenyl carbamate, 23-methoxyphenyl carbamate, 24-methoxyphenyl carbamate, 25-methoxyphenyl carbamate, 26-methoxyphenyl carbamate, 27-methoxyphenyl carbamate, 28-methoxyphenyl carbamate, 29-methoxyphenyl carbamate, 30-methoxyphenyl carbamate, 31-methoxyphenyl carbamate, 32-methoxyphenyl carbamate, 33-methoxyphenyl carbamate, 34-methoxyphenyl carbamate, 35-methoxyphenyl carbamate, 36-methoxyphenyl carbamate, 37-methoxyphenyl carbamate, 38-methoxyphenyl carbamate, 39-methoxyphenyl carbamate, 40-methoxyphenyl carbamate, 41-methoxyphenyl carbamate, methylethylcarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Trot), 2-trimethylsilylethylcarbamate (Teoc), 2-phenylethylcarbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate 1-Methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (N oc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrile benzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-0,3-Dithianylmethylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromo Nylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2 -Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1 -methylcyclohexyl carbamate, 1-methyl-l-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate and 2,4,Contains 6-trimethylbenzyl carbamate.

[0042] Sulfonamide groups (e.g., -S(=O)R aa Nitrogen protecting groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethyl ...tb), 4-methoxybenzenesulfonamide (Mtb), 4-methoxybenzenesulfonamide (Mtb), 4-methoxybenzenesulfonamide (Mtb), 4-methoxybenzenesulfonamide (Mtb), 4-methoxybenzenesulfonamide (Mtb), 4-methoxybenzenesulfonamide (Mtb), 4-methoxybenzenesulfonamide ( These include anthracene sulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), 13-trimethylsilylethanesulfonamide (SES), 9-anthracene sulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and phenacylsulfonamide.

[0043] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adducts. STABASE, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololine-3-yl)amine (N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololine-3-yl)amine tro-2-oxo-3-pyroolin-3-yDamine), quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxy , N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-Dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide and 3-nitropyridine sulfenamide (NPY).

[0044] The substituent may be an "oxygen protecting group" (also called a hydroxyl protecting group). Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference. rdExemplary oxygen protecting groups include, but are not limited to, methyl, t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl (2,2,2-trichloroethoxymethyl), ... Methyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyltetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7 a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-l-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenylmethyl) , 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl dimethylsilyl (DRIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate Acetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Trot), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formyl Benzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate These include alkyl esters such as ethyl ester, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate and tosylate (Ts).

[0045] The term "leaving group" is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or group that can be displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. Exemplary leaving groups include, but are not limited to, activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2 and -OP(=O)(NR bb )2(wherein, R aa , R bb and R ccare as defined herein). In some cases, the leaving group is a sulfonate ester, such as toluenesulfonate (tosylate, -OT), methanesulfonate (mesylate, -OM), p-bromobenzenesulfonyloxy (brosylate, -OB), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. The leaving group can also be a phosphine oxide (e.g., formed during the Mitsunobu reaction) or an internal leaving group, such as an epoxide or a cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohol, ether moiety, thioether moiety, zinc halide, magnesium moiety, diazonium salt, and copper moiety.

[0046] The term "binding", when referring to the interaction between a targeting ligand and a targeting protein, which for purposes of the present invention is CDK7 and its mutant forms (collectively "CDK7"), typically refers to an intermolecular interaction that may be preferential or substantially specific (also referred to herein as "selective"), in that the binding of the targeting ligand to other proteinaceous entities present within the cell is not of functional importance. The bispecific compounds of the present invention are capable of preferentially binding to and recruiting CDK7 and its mutant forms for targeted degradation.

[0047] The term "binding," when referring to the interaction between a degron and an E3 ubiquitin ligase, typically refers to an intermolecular interaction that may or may not exhibit an affinity level equal to or greater than the affinity between a targeting ligand and a target protein, but which affinity is nevertheless sufficient to achieve recruitment of the ligase for targeted degradation and selective degradation of the targeted protein.

[0048] In general, a bispecific compound comprises one moiety that binds to cyclin-dependent kinase 7 (CDK7) (referred to herein as a targeting ligand) and a second moiety that binds to an E3 ubiquitin ligase, referred to as a "degron," linked via a linker. The compound has the formula (I):

[0049] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof (In the formula, R1 is -NR a R b , -CHR a R b -OR a R a and R b each is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom, or R a and R b together with the atoms to which they are attached form an optionally substituted carbocyclic ring, an optionally substituted heterocyclic ring, an optionally substituted aryl ring, or an optionally substituted heteroaryl ring; Each of R3 and R4 independently represents hydrogen, halogen, optionally substituted C1-C6 alkyl, or optionally substituted aryl, or R3 and R4 together with the atom to which they are attached form an optionally substituted C3-C6 carbocyclyl ring; R5 independently represents hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group; L1, -NR L1 -, -NR L1 C(=O)-, -C(=O)NR L1 -, -O-, or -S-, RL1 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group; A represents optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L2 is a bond, absent, -C(=O)-, or -C(=O)NR L2 -, -NR L2 C(=O)-, -O-, or -S-; R L2 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group; B is a bond or absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R2 is absent or has one of the following structures:

[0050] [ka]

[0051] [ka]

[0052] [ka] (In the formula, asterisk( * ) represents the point of attachment to B, and the squiggle represents

[0053] [ka] represents the attachment point to; L3 is a bond or an absent or optionally substituted C 1~4 a hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently -C(=O)-, -O-, -S-, -NR L3a , -NR L3aC(=O)-, -C(=O)NR L3a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L3a C(=S)-, -C(=S)NR L3a -, Trans-CR L3b =CR L3b -, cis-CR L3b =CR L3b -, -CS(=O)-, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L3a -, -NR L3a S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NR L3a -, or -NR L3a S(=O)2- is replaced by R L3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group; R L3b each occurrence of is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b groups, together with the atoms to which they are attached, form an optionally substituted carbocyclic or an optionally substituted heterocyclic ring; L4 is a bond or an optionally substituted branched or unbranched C 1~6 is a hydrocarbon chain; R EI , R E2 , and R E3 each independently represents hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -CHOR EE , -CH2N(R EE )2, -CH2SR EE , -OR EE, -N(R EE )2, -Si(R EE )3, and -SR EE and R EE each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups, together with the atoms to which they are attached, form an optionally substituted heterocyclic ring; or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 together with the atoms to which they are attached form an optionally substituted carbocyclic or an optionally substituted heterocyclic ring; R E4 is a leaving group; R E6 is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group; Each instance of Y is independently O, S or NR E7 and R E7 is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group; a is 1 or 2; Each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, valence permitting. The compound has a structure represented by:

[0054] With respect to the compounds of the present invention, the targeting ligand has the following structure:

[0055] [ka] (In the formula, the squiggly line is

[0056] [ka] represents the attachment point to It is represented by:

[0057] In some embodiments, R1 is

[0058] [ka] (In the formula, R 1’ and R 1’’ each is independently hydrogen, an optionally substituted C1-C6 alkyl, or a nitrogen protecting group; R 1a is hydrogen, C1-C6 alkyl, or optionally substituted aryl; R 2a is hydrogen, -OR 1N or -NR 1N R 2N and R 1N and R 2N each is independently hydrogen, C1-C6 alkyl, or a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom. It is.

[0059] In some embodiments, R 1’’ is hydrogen, Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0060] In some embodiments, R1 is

[0061] [ka] In some embodiments, R1 is

[0062] [ka] It is.

[0063] In some embodiments, R 1a is hydrogen, methyl, ethyl, propyl or phenyl.

[0064] In certain embodiments, R 2a is hydrogen. In some embodiments, R 2a -OR IN and R 1N is hydrogen, C1-C6 alkyl, or an oxygen protecting group. 2a is —OH. In certain embodiments, R 2a Ga-NR 1N R 2N and R IN and R 2N Each of R is independently hydrogen, C1-C6 alkyl, or a nitrogen protecting group. 1N and R 2N and R are both hydrogen, methyl, ethyl, propyl, or a nitrogen protecting group. 1N and R 2N At least one of R is hydrogen, methyl, ethyl, propyl, or a nitrogen protecting group. IN is methyl and R 2N is hydrogen. In some embodiments, R 1N is ethyl, and R 2N is hydrogen. In some embodiments, R 1N is propyl, and R 2N is hydrogen. In some embodiments, R 1N is a nitrogen protecting group, and R 2N is hydrogen. In some embodiments, R 1N is methyl and R 2N is a nitrogen protecting group. In some embodiments, R 1N is ethyl, and R 2N is a nitrogen protecting group. In some embodiments, R 1N is propyl, and R 2N is a nitrogen protecting group.

[0065] In some embodiments, R1 is

[0066] [ka]

[0067] [ka] It is.

[0068] In some embodiments, R2 is a bond.

[0069] [ka] It is.

[0070] In some embodiments, R3 and R4 are independently methyl, isopropyl, or phenyl, or R3 and R4 together with the atom to which they are attached form an optionally substituted C3-C6 carbocyclyl ring, in some embodiments, R3 and R4 are both methyl.

[0071] In some embodiments, R5 is hydrogen or methyl.

[0072] In some embodiments, A is a 6-membered carbocyclyl or a 6-membered heterocyclyl.

[0073] In some embodiments, B is a bond, a 6-membered carbocyclyl, or a 6-membered heterocyclyl.

[0074] In some embodiments, L1 is NH or -NHC(O)-.

[0075] In some embodiments, L2 is a bond, NH, or -NHC(O)-.

[0076] In some embodiments where L1 is NH or -NHC(O)-, R3 and R4 are methyl, and R5 is H, the compound of formula (I) may be represented by formulas (I-1a) and (I-1b):

[0077] [ka] and

[0078] [ka] or any one of its pharma- ceutically acceptable salts or stereoisomers.

[0079] In some embodiments where A is a 6-membered carbocyclyl, R3 and R4 are methyl, and R5 is H, the compound of formula (I) has the formulas (I-2a)-(I-2f):

[0080] [ka]

[0081] [ka]

[0082] [ka] or any one of its pharma- ceutically acceptable salts or stereoisomers.

[0083] L1 is NH or -NHC(O)- and R1 is

[0084] [ka] In some embodiments where R3 and R4 are methyl and R5 is H, the compound of formula (I) has the formula (I-3a)-(I-3d):

[0085] [ka]

[0086] [ka] or any one of its pharma- ceutically acceptable salts or stereoisomers.

[0087] A is a 6-membered carbocyclyl and R1 is

[0088] [ka] In some embodiments where R3 and R4 are methyl and R5 is H, the compound of formula (I) has the formula (I-4a)-(I-4l):

[0089] [ka]

[0090] [ka]

[0091] [ka]

[0092] [ka]

[0093] [ka] or any one of its pharma- ceutically acceptable salts or stereoisomers.

[0094] L1 is NH or -NHC(O)- and R1 is

[0095] [ka] In some embodiments where R and R are methyl and R is H, the compound of formula (I) is represented by formulas (I-5a) and (I-5b):

[0096] [ka]

[0097] [ka] or any one of its pharma- ceutically acceptable salts or stereoisomers.

[0098] A is a 6-membered carbocyclyl and R1 is

[0099] [ka] In some embodiments where R3 and R4 are methyl and R5 is H, the compound of formula (I) has the formula (I-6a)-(I-6l):

[0100] [ka]

[0101] [ka]

[0102] [ka]

[0103] [ka]

[0104] [ka] or any one of its pharma- ceutically acceptable salts or stereoisomers.

[0105] In some embodiments, the compound of formula (I) is represented by formulas (I-7) to (I-57):

[0106] [ka]

[0107] [ka]

[0108] [ka]

[0109] [ka]

[0110] [ka]

[0111] [ka]

[0112] [ka]

[0113] [ka]

[0114] [ka]

[0115] [ka]

[0116] [ka]

[0117] [ka]

[0118] [ka] or any one of its pharma- ceutically acceptable salts or stereoisomers.

[0119] L1 is -NHC(O)-, A is a 6-membered carbocyclyl, B, L2 and R2 are each a bond (or absent), and R1 is

[0120] [ka] and both R and R are methyl, in some embodiments, the compound of formula (I) is represented by formula (I-58):

[0121] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0122] Linker The linker ("L") provides a covalent bond to the targeting ligand and the degron. The structure of the linker may not be important as long as it does not substantially interfere with the activity of the targeting ligand or the degron. In some embodiments, the linker comprises an alkylene chain (e.g., having 2-20 alkylene units). In other embodiments, the linker is any one of -O-, -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR') -, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2- , -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, C3~C 12 It may comprise an alkylene chain or a divalent alkylene chain which may be interrupted and / or terminated (at either or both ends) by at least one of a carbocyclene, a 3- to 12-membered heterocyclene, a 5- to 12-membered heteroarylene, or any combination thereof (wherein R' is H or C1-C6 alkyl), and the interrupting group and one or both end groups may be the same or different.

[0123] In some embodiments, the linker is a C1-C 12 It may contain an alkylene chain, the nitrogen of which is also attached to a degron.

[0124] In some embodiments, the linker has 1 to 10 alkylene units.

[0125] [ka] The term "alkylene chain" includes alkylene chains interrupted or terminated by:

[0126] "Carbocyclene" refers to an optionally substituted divalent carbocyclic group.

[0127] "Heterocyclene" refers to an optionally substituted divalent heterocyclyl group.

[0128] "Heteroarylene" refers to an optionally substituted divalent heteroaryl group.

[0129] Representative examples of alkylene linkers that may be suitable for use in the present invention include the following:

[0130] [ka] (In the formula, n is an integer from 1 to 12 ("of" means inclusive), for example, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5 , 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, 9-10, and 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10), examples of which are:

[0131] R: [ka] Alkylene chains terminated with various functional groups (as described above), examples of which are:

[0132] [ka] Alkylene chains interrupted by various functional groups (as above), examples of which are:

[0133] [ka] An alkylene chain interrupted or terminated by a heterocyclene group, e.g.

[0134] [ka] (wherein m and n are independently an integer of 0 to 10), examples thereof include the following:

[0135] [ka] Alkylene chains interrupted by amide, heterocyclene and / or aryl groups, examples of which include:

[0136] [ka] Heterocyclene and aryl groups and alkylene chains interrupted by heteroatoms, examples of which include:

[0137] [ka] And Alkylene chains interrupted by heteroatoms such as N, O or B, e.g.

[0138] [ka] wherein each n is independently an integer from 1 to 10, e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, 9-10, and 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and R is H, or C1-C4 alkyl.

[0139] [ka] is Examples include:

[0140] In some embodiments, the linker is -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2- , -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, C 3~12 It may comprise a polyethylene glycol chain which may be terminated (at either or both ends) by at least one of a carbocyclene, a 3- to 12-membered heterocyclene, a 5- to 12-membered heteroarylene, or any combination thereof (wherein R' is H or a C1-C6 alkyl), and one or both end groups may be the same or different.

[0141] In some embodiments, the linker has 2-8 PEG units.

[0142] [ka] The polyethylene glycol chain includes a terminating

[0143] Examples of linkers containing polyethylene glycol chains include:

[0144] [ka] (wherein n is an integer of 2 to 10), examples of which include:

[0145] [ka] Examples include:

[0146] In some embodiments, the polyethylene glycol linker may terminate in a functional group, examples of which are as follows:

[0147] [ka]

[0148] In some embodiments, the compound of formula (I) has the structure (L10):

[0149] [ka] (Wherein, Q is CH2 or O; Y is CH2, CH2CH2 or absent, provided that when X is O, then Y is CH2CH2; n is an integer from 0 to 6. The linker is represented by:

[0150] In some embodiments, the linker has the structures L11-L23:

[0151] [ka] . It is represented by one of the following:

[0152] In some embodiments, the bispecific compound of formula (I) has the formulas (I-59) to (I-71):

[0153] [ka]

[0154] [ka]

[0155] [ka]

[0156] [ka] or any one of its pharma- ceutically acceptable salts or stereoisomers.

[0157] Degron A degron ("D") is a functional moiety that binds to an E3 ubiquitin ligase. In some embodiments, the degron binds to cereblon (CRBN).

[0158] Representative examples of degrons that bind to cereblon and may be suitable for use in the present invention are described in U.S. Patent Application Publication No. 2018 / 0015085 (e.g., indolinones such as isoindolinones and isoindoline-1,3-diones encompassed by formulas IA and IA' therein, and bridged cycloalkyl compounds encompassed by formulas IB and IB' therein).

[0159] In some embodiments, the compound of formula (I) has the structure (D1-a)-(D1-h):

[0160] [ka]

[0161] [ka] The present invention includes a cereblon-binding degron represented by any one of the following:

[0162] In some embodiments, the compound of Formula (I) has the formula (I-72a)-(I-72h):

[0163] [ka]

[0164] [ka]

[0165] [ka] or any one of its pharma- ceutically acceptable salts or stereoisomers.

[0166] In some embodiments, the degron binds to the von Hippel-Lindau (VHL) tumor suppressor. Representative examples of degrons that bind to VHL are as follows:

[0167] [ka] (wherein Y' is a bond, N, O or C);

[0168] [ka] (wherein Z is a C5-C6 carbocyclic group or a C5-C6 heterocyclic group), and

[0169] [ka] In some embodiments, Z is

[0170] [ka] It is.

[0171] Still other degrons that bind to VHL and may be suitable for use as degrons in the present invention are disclosed in US Patent Application Publication No. 2017 / 0121321.

[0172] In some embodiments, the compound of Formula (I) has the formula (I-73a)-(I-73e):

[0173] [ka]

[0174] [ka] (wherein R represents H, methyl, ethyl, isopropyl, or CF3; Y' is a bond, N, O, or C; and Z is a C5-C6 carbocyclic or heterocyclic group), or any one of its pharma- ceutically acceptable salts or stereoisomers.

[0175] In some embodiments, the compound of formula (I) has the structure (1)-(26):

[0176] [ka]

[0177] [ka]

[0178] [ka]

[0179] [ka]

[0180] [ka]

[0181] [ka]

[0182] [ka]

[0183] [ka] or any one of its pharma- ceutically acceptable salts and stereoisomers.

[0184] The bispecific compounds of formula (I) may be in the form of a free acid or free base, or a pharma- ceutically acceptable salt. As used herein, the term "pharma-ceutically acceptable" in the context of a salt refers to a salt of a compound that does not abolish the biological activity or properties of the compound and is 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 stomach upset) or interacting in a harmful manner with any of the other components of the composition in which it is contained. The term "pharma-ceutically acceptable salt" refers to the product obtained by reacting a compound of the present invention with a suitable acid or base. Examples of pharma-ceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples of pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate, etc. Certain compounds of the present invention can form pharma- ceutically acceptable salts with various organic bases, such as lysine, arginine, guanidine, diethanolamine or metformin.

[0185] The bispecific compounds of formula (I) may have at least one chiral center. Thus, they may be in the form of stereoisomers. As used herein, the term "stereoisomers" encompasses all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomers includes enantiomers (enantiomers containing the (R-) or (S-) configuration of a compound), mixtures of enantiomers of a compound (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of a compound, and isomers of a compound that have two or more chiral centers that are not mirror images of each other (diastereoisomers). The chiral centers of a compound may undergo epimerization in vivo, so for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Thus, the compounds of the invention can be prepared and used in the form of individual isomers, substantially free of other isomers, or in the form of mixtures of various isomers, e.g., racemic mixtures of stereoisomers.

[0186] In some embodiments, the bispecific compounds of formula (I) are isotopic derivatives in that they have at least one desired isotopic substitution of an atom at a level greater than the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound contains deuterium or multiple deuterium atoms. Deuterium, i.e. 2 Substitution with heavier isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be advantageous in some circumstances.

[0187] In addition to isotopic derivatives, the term "bispecific compounds of Formula (I)" encompasses N-oxides, crystalline forms (also known as polymorphs), active metabolites of the compounds having the same type of activity, tautomers, and unsolvated forms of the compounds as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the conjugates presented herein are also considered to be disclosed herein.

[0188] Synthesis method In some embodiments, the present invention relates to a method for preparing a bispecific compound of formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof. In a broad sense, the compounds of the present invention, or a pharma- ceutically acceptable salt or stereoisomer thereof, can be prepared by any method known to be applicable to the preparation of chemically related compounds. Representative synthetic schemes are described in the various examples, illustrating non-limiting methods by which the compounds of the present invention can be prepared.

[0189] Pharmaceutical Compositions Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a bispecific compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof and a pharma- ceutically acceptable carrier. The term "pharma- ceutically acceptable carrier" as known in the art refers to a pharma- ceutically acceptable material, composition or vehicle suitable for administering the compound of the present invention to a mammal. Suitable carriers may include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), and gases that function to carry or transport the compound from one organ or part of the body to another. A 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 harmful to the subject or patient. Depending on the type of formulation, the composition may include one or more pharma- ceutically acceptable excipients.

[0190] In general, the bispecific compounds of formula (I) and their pharma- ceutically acceptable salts and stereoisomers can be formulated into a given type of composition according to conventional pharmaceutical practice, such as conventional mixing, dissolving, granulating, dragee-making, wet-milling, emulsifying, encapsulating, entrapping and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. 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 (sc), intravenous (iv), intramuscular (im) and intrasternal injection, or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intracerebroventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation) and topical (e.g., transdermal). In general, 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 environment of the gastrointestinal tract) and / or the condition of the subject (whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous in that the compound may be administered relatively quickly, such as in the case of single dose treatments and / or acute conditions.

[0191] In some embodiments, the compounds are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0192] Thus, the bispecific compounds of the present invention may be formulated into 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 solid particles of the compound are dispersed, emulsions, and solutions containing liposomes, micelles or nanoparticles, syrups and elixirs); semi-solid compositions (e.g., gels, suspensions and creams); and gases (e.g., propellants for aerosol compositions). The compounds may also be formulated for rapid, intermediate or extended release.

[0193] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with a carrier such as sodium citrate or dicalcium phosphate, as well as a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrants, such as crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone (crospovidone), crosslinked carboxymethylcellulose, The glycerol may be mixed with additional carriers or excipients such as sodium (croscarmellose sodium), sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells such as enteric coatings and other coatings. They may further contain an opacifying agent.

[0194] In some embodiments, the bispecific 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, anhydrous lactose, microcrystalline cellulose, and croscarmellose sodium. The gelatin shell may contain gelatin, titanium dioxide, iron oxide, and colorants.

[0195] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups and elixirs.In addition to the compound, liquid dosage forms can contain aqueous or non-aqueous carriers (depending on the solubility of the compound), such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.Oral compositions can also contain excipients such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents and aromatic agents.

[0196] Injectable preparations may include sterile aqueous or oily suspensions. These may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable preparations may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. The effect of the compound can be prolonged by slowing its absorption, which can be accomplished by using liquid suspensions or crystalline or amorphous material with poor water solubility. Prolonged absorption of a compound from a parenterally administered formulation can also be accomplished by suspending the compound in an oil vehicle.

[0197] In certain embodiments, the bispecific compounds of formula (I) may be administered locally rather than systemically, for example, via direct injection of the conjugate into an organ, often in a depot or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Injectable depot forms are made by forming microencapsule matrices of the 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 encapsulating the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and taken up selectively by the organ.

[0198] The bispecific compounds may be formulated for buccal or sublingual administration and examples include tablets, lozenges and gels.

[0199] The bispecific compound may be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosol, mist or powder. The pharmaceutical composition may be delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer 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 to deliver a metered amount. In some embodiments, capsules and cartridges, including, for example, gelatin, for use in an inhaler or insufflator, may be formulated containing the compound and a suitable powder base, such as lactose or starch, and a powder mixture.

[0200] The bispecific compounds of formula (I) may be formulated for topical administration, which as used herein refers to intradermal administration by application of the formulation to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.

[0201] Representative examples of carriers useful for formulating compositions for topical application include solvents (e.g., alcohol, polyalcohol, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffers (e.g., hypotonic or buffered saline).Creams can be formulated using saturated or unsaturated fatty acids, such as, for example, stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl or oleyl alcohol.Creams can also contain non-ionic surfactants, such as polyoxy-40-stearate.

[0202] In some embodiments, topical formulations can also include excipients, examples of which are penetration enhancers.These agents can transport pharmacologically active compounds through the stratum corneum to the epidermis or dermis, preferably with little or no systemic absorption.A wide variety of compounds have been evaluated for their effectiveness in increasing the penetration rate of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum SI (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997), which review the use and testing of various skin penetration enhancers. Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glyceryl monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0203] Representative examples of further excipients that may be included in topical and other types of formulations (to the extent that 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 bisulfite, butylhydroxytoluene, butylhydroxyanisole, tocopherol, and chelating agents such as EDTA and citric acid. Suitable moisturizers include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citric acid, hydrochloric acid, and lactic acid buffers. Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0204] Transdermal formulations typically use transdermal delivery devices and transdermal delivery patches in which the compound is formulated in a lipophilic emulsion or buffered aqueous solution and dissolved and / or dispersed in a polymer or adhesive. Patches can be configured for continuous, pulsatile or on-demand delivery of pharmaceuticals. Transdermal delivery of compounds can be achieved by iontophoretic patches. Transdermal patches can provide controlled delivery of compounds with slow absorption rates by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Absorption enhancers can be used to increase absorption, examples of which include absorbable pharmacologic acceptable solvents that aid in passage through the skin.

[0205] Ophthalmic preparations include eye drops.

[0206] 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, etc. Compositions for rectal or vaginal administration may also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients, such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the compound.

[0207] Dosage As used herein, the term "therapeutically effective amount" refers to an amount of a bispecific compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof that is effective to bring about a desired therapeutic response in a particular patient suffering from a disease or disorder characterized or mediated by aberrant CDK7 activity. Thus, the term "therapeutically effective amount" includes an amount of a compound of the present invention or a pharma- ceutically acceptable salt or stereoisomer thereof that, when administered, is sufficient to induce a positive modification (e.g., selectively inhibit / degrade CDK7) in the disease or disorder being treated, or to prevent the onset or progression of the disease or disorder, or to alleviate to some extent one or more of the symptoms of the disease or disorder being treated in the subject, or to simply kill or inhibit the proliferation of diseased (e.g., neuroblastoma) cells, or to reduce the amount of CDK7 in diseased cells.

[0208] The total daily dosage of the bispecific compound and its use can be determined by the attending physician according to standard medical practice, for example, using sound medical judgment.The specific therapeutically effective dose for any particular subject can depend on a variety of factors, including the disease or disorder being treated and its severity (e.g., its current condition); the subject's age, weight, general health, sex and diet; the time of administration, the route of administration, and the excretion rate of the specific compound used; the duration of treatment; the drugs used in combination or simultaneously with the bispecific compound, etc., as are well known in the medical field (see, for example, Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 10th Edition, A.Gilman, J.Hardman and L.Limbird, eds., McGraw-Hill Press, 155-173, 2001).

[0209] The bispecific compounds of formula (I) and their pharma- ceutically acceptable salts and stereoisomers may be effective over a wide dosage range. In some embodiments, the total daily dosage (e.g., for an adult) may range from about 0.001 to about 1600 mg, 0.01 to about 1600 mg, 0.01 to about 500 mg, about 0.01 to about 100 mg, about 0.5 to about 100 mg, 1 to about 100 to about 400 mg / day, about 1 to about 50 mg / day, and about 5 to about 40 mg / day, and in still other embodiments, about 10 to about 30 mg / day. Individual dosages may be formulated to contain the desired dosage depending on the number of times the compound is administered per day. By way of example, capsules may be formulated with about 1 to about 200 mg of a bispecific compound of Formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg).Some embodiments may be formulated such that individual doses contain the desired dosage depending on the number of times the compound is to be administered per day.

[0210] How to use In some aspects, the present invention relates to a method of treating a disease or disorder associated with aberrant (e.g., dysfunctional or dysregulated) CDK7 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a bispecific compound of Formula (I) or a pharma- ceutical acceptable salt or stereoisomer thereof.

[0211] A disease or disorder can be said to be characterized by or mediated by abnormal (e.g., dysfunctional or dysregulated) CDK7 activity (e.g., elevated levels of protein or functionally abnormal compared to non-pathological conditions). A "disease" is generally considered to be a state of health of a subject in which the subject is unable to maintain homeostasis and in which the subject's health continues to deteriorate if the disease is not ameliorated. In contrast, a "disorder" of a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject's health is less favorable than it would be in the absence of the disorder. If left untreated, a disorder does not necessarily result in further deterioration of the animal's health.

[0212] The term "subject" (or "patient") as used herein includes all members of the animal kingdom susceptible to or suffering from the indicated disease or disorder. 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 domestic and wild animals. A subject "in need" of treatment according to the present invention may be "suffering or suspected of suffering from" a particular disease or disorder, or may have been positively diagnosed with or exhibit a sufficient number of risk factors or a sufficient number or combination of signs or symptoms that allow a medical professional to diagnose or suspect that the subject suffers from the disease or disorder. Thus, subjects suffering from and suspected of suffering from a particular disease or disorder are not necessarily two distinct groups.

[0213] Exemplary types of non-cancerous (e.g., cell proliferative) diseases or disorders that can be treated with the compounds of the invention include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, cardiac diseases, viral diseases, chronic and acute renal diseases or injuries, metabolic diseases, and allergic and genetic diseases.

[0214] Representative examples of specific non-cancerous diseases and disorders include lymphoproliferative conditions, autoimmune diseases, cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, sepsis, septic shock, dacryoadenitis, cryopyrin-associated periodic syndromes (CAPS), endotoxin shock, endometritis, gram-negative bacterial sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammation, chronic graft rejection, hidradenitis suppurativa, inflammatory bowel disease, Crohn's disease, Behcet's syndrome, glomerulonephritis, multiple sclerosis, young adulthood, and the like. Year-onset diabetes, thyroiditis, Addison's disease, appendicitis, testicular sarcoidosis, eczema, pancreatic fibrosis, hepatitis, liver fibrosis, CD14-mediated sepsis, non-CD14-mediated sepsis, acute and chronic kidney disease, irritable bowel syndrome, heartburn, 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, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendonitis, tendonitis, hernia, rupture or or herniated disc syndrome, osteoporosis, sinusitis, thrombosis, silicosis, pulmonary sarcosis, bone resorption diseases such as osteoporosis, fibromyalgia, AIDS and other viral diseases such as shingles, herpes simplex type I or II, influenza virus and cytomegalovirus, diabetes mellitus type I and II, obesity, insulin resistance and diabetic retinopathy, 22q11.2 deletion syndrome, Angelman syndrome, Canavan disease, Charcot-Marie-Tooth disease, color blindness, cri-de-chat syndrome, Down syndrome, cystic fibrosis, fibrosis, Duchenne muscular dystrophy, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome, urea cycle disorders, thalassemia, otitis media, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, uveitis, polymyositis, proctitis, interstitial pulmonary fibrosis, dermatomyositis, arteriosclerosis, atherosclerosis, amyotrophic lateral sclerosis, asocial disorders, varicose veins, vaginitis, depression, and sudden infant death syndrome.

[0215] Examples of autoimmune diseases include autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, anhidrotic ectodermal dysplasia, true erythrocytic anemia, and idiopathic thrombocytopenia), alopecia areata, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune uveoretinitis, autoimmune vasculitis, lichen planus, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, myasthenia gravis, immunoglobulin A nephropathy, Hashimoto's disease, Sjogren's syndrome, vitiligo, Wegener's granulomatosis, autoimmune oophoritis, sarcoidosis, rheumatic carditis, ankylosing spondylitis, Graves' disease, autoimmune thrombocytopenic purpura, psoriasis, psoriatic arthritis, dermatitis herpetiformis, ulcerative colitis, and celiac disease.

[0216] In other embodiments, the methods are directed to treating a subject with cancer. In general, the bispecific compounds of the present invention may be effective in treating carcinomas (solid tumors, including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers (cancers that originate in the blood, including lymphocytes, bone marrow, and / or lymph nodes), such as leukemia, lymphoma, and multiple myeloma. Adult tumors / cancers and pediatric tumors / cancers are included. The cancer may be a vascularized tumor, a tumor that is not yet substantially vascularized, or a non-vascularized tumor.

[0217] Representative examples of cancer include adrenal cortical carcinoma, AIDS-related cancer (e.g., Kaposi's and AIDS-related lymphoma), appendix cancer, childhood cancer (e.g., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, and urinary bladder cancer. cancer), brain cancer (e.g., gliomas and glioblastomas, e.g., brain stem glioma, gestational trophoblastic tumor glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma), breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, nervous system cancer (e.g., central nervous system cancer, central nervous system lymphoma), cervical cancer, chronic myeloproliferative disorder, colorectal cancer (e.g., colon cancer, rectal cancer), lymphoid neoplasia Mycosis fungoides, Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g., gastric cancer, small intestine cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST)), cholangiocarcinoma, germ cell tumors, ovarian germ cell tumors, head and neck cancer, neuroendocrine tumors, Hodgkin lymphoma, Ann Arbor stage III and stage IV pediatric non-Hodgkin lymphoma, ROS1-positive refractory non-Hodgkin lymphoma Cancer, leukemia, lymphoma, multiple myeloma, hypopharyngeal cancer, intraocular melanoma, eye cancer, pancreatic islet cell tumors (endocrine pancreas), kidney cancer (e.g., Wilms' tumor, renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), ALK-positive anaplastic large cell lymphoma, ALK-positive advanced malignant solid neoplasms, Waldenström's macroglobulinemia, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of unknown primary site, multiple endocrine gland Neoplasms (MEN), myelodysplastic syndromes, myelodysplastic / myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cavity cancer (e.g., oral cavity, lip, oral cavity, tongue, oropharyngeal, pharyngeal, laryngeal), ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell tumors, ovarian low malignant potential tumors), pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma, metastatic anaplastic thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer,These include pituitary tumors, plasma cell neoplasms / multiple myeloma, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial carcinoma, uterine sarcoma, endometrial carcinoma), squamous cell carcinoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, juvenile xanthogranuloma, transitional cell carcinoma of the renal pelvis and ureter and other urinary tracts, urethral cancer, gestational trophoblastic tumor, vaginal cancer, vulvar cancer, hepatoblastoma, rhabdoid tumor, and Wilms' tumor.

[0218] Sarcomas that may be treatable with the compounds of the invention include both soft tissue and bone cancers alike, 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 (membrane lining of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (fatty tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), mesenchymal or mixed mesodermal tumor (mixed connective tissue types), and histiocytic sarcoma (immune cancer).

[0219] In some embodiments, methods of the invention involve treatment of subjects with cell proliferative diseases or disorders of the blood system, liver, brain, lung, colon, pancreas, prostate, ovaries, breast, skin and endometrium.

[0220] As used herein, "cell proliferative diseases or disorders of the blood system" (also referred to as "blood cancers") include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, myeloid metaplasia of cryptogenic origin, and essential thrombocythemia. Thus, representative examples of hematological cancers include multiple myeloma, lymphomas (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. diffuse large B-cell lymphoma (e.g. germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma), Burkitt's lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, bladder cancer ... lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, metastatic pancreatic adenocarcinoma, B-cell non-Hodgkin's lymphoma selected from refractory B-cell non-Hodgkin's lymphoma and relapsed B-cell non-Hodgkin's lymphoma, childhood lymphoma, and lymphomas of lymphocytic and cutaneous origin, including small lymphocytic lymphoma), leukemia (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms, and mast cell neoplasms.

[0221] As used herein, "hepatic cell proliferation disease or disorder" includes all forms of cell proliferation disorder that occur in the liver.Hepatic cell proliferation disorder can include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma and hepatoblastoma), pre-cancer or pre-cancerous condition of the liver, benign growth or lesion of the liver, and malignant growth or lesion of the liver, as well as metastatic lesion of body tissues and organs other than the liver.Hepatic cell proliferation disorder can include liver hyperplasia, metaplasia and dysplasia.

[0222] As used herein, "brain cell proliferation disease or disorder" includes all forms of cell proliferation disorder that occur in the brain.Brain cell proliferation disorder can include brain cancer (e.g., glioma, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma and primitive neuroectodermal tumor (medulloblastoma)), brain precancer or precancerous condition, brain benign growth or lesion, and brain malignant growth or lesion, and metastatic lesion of body tissue and organ other than brain.Brain cell proliferation disorder can include brain hyperplasia, metaplasia and dysplasia.

[0223] As used herein, "pulmonary cell proliferative disease or disorder" includes all forms of cell proliferative disorders that affect lung cells. Pulmonary cell proliferative disorders include lung cancer, pre-cancer and pre-cancerous conditions of the lung, benign growths or lesions of the lung, hyperplasia, metaplasia and dysplasia of the lung, and metastatic lesions of body tissues and organs other than the lung. Lung cancer includes all forms of cancer of the lung, such as 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, and mesothelioma. Lung cancer can include "scar carcinoma", bronchioveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer also includes lung neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cell types). In some embodiments, the compounds of the present invention can be used to treat non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC with ROS1 rearrangement, lung adenocarcinoma, and squamous cell carcinoma).

[0224] As used herein, "colon cell proliferation disease or disorder" includes all forms of cell proliferation disorder that occur in colon cells, including colon cancer, colon precancer or precancerous conditions, colon adenomatous polyps and colon metachronous lesions.Colon cancer includes sporadic and hereditary colon cancer, malignant colon neoplasms, intraepithelial carcinoma, typical and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma and squamous cell carcinoma.Colon cancer can be associated with hereditary syndromes such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MYH-associated polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome and juvenile polyposis.Colon cell proliferation disorder can also be characterized by colon hyperplasia, metaplasia or dysplasia.

[0225] As used herein, "pancreatic cell proliferative disease or disorder" includes all forms of cell proliferative disorder that occur in pancreatic cells.Pancreatic cell proliferative disorder can include pancreatic cancer, precancer or precancerous conditions of pancreas, pancreatic hyperplasia, pancreatic dysplasia, benign growth or lesion of pancreas, and malignant growth or lesion of pancreas, as well as metastatic lesions of body tissues and organs other than pancreas.Pancreatic cancer includes all forms of pancreatic cancer, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma, as well as pancreatic neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cells).

[0226] As used herein, "prostate cell proliferation disease or disorder" includes all forms of prostate cell proliferation disorder.Prostate cell proliferation disorder can include prostate cancer, prostate precancer or precancerous condition, prostate benign growth or lesion, prostate malignant growth or lesion, and metastatic lesion of body tissue and organ other than prostate.Prostate cell proliferation disorder can include prostate hyperplasia, metaplasia and dysplasia.

[0227] As used herein, "cell proliferative disease or disorder of the ovary" includes all forms of cell proliferative disorders affecting cells of the ovary. Cell proliferative disorders of the ovary may include precancer or precancerous conditions of the ovary, benign ovarian growths or lesions, ovarian cancer, and metastatic lesions of body tissues and organs other than the ovary. Cell proliferative disorders of the ovary may include ovarian hyperplasia, metaplasia, and dysplasia.

[0228] As used herein, "cell proliferative disease or disorder of the breast" includes all forms of cell proliferative disorders that affect breast cells. Cell proliferative disorders of the breast can include breast cancer, precancer or precancerous conditions of the breast, benign growths or lesions of the breast, and metastatic lesions of body tissues and organs other than the breast. Cell proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

[0229] 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 growths or lesions of the skin, melanoma, malignant melanoma or other malignant growths or lesions of the skin, and metastatic lesions of body tissues and organs other than the skin. Cell proliferative disorders of the skin may include hyperplasia, metaplasia and dysplasia of the skin.

[0230] As used herein, "endometrial cell proliferative disease or disorder" includes all forms of cell proliferative disorder that affect endometrial cells.Endometrial cell proliferative disorder may include endometrial precancer or precancerous conditions, endometrial benign proliferation or lesions, endometrial cancer, and metastatic lesions of body tissues and organs other than endometrium.Endometrial cell proliferative disorder may include endometrial hyperplasia, metaplasia, and dysplasia.

[0231] In some embodiments, the bispecific compound or pharma- ceutically acceptable salt or stereoisomer of the invention is used in the treatment of a disease or disorder where the disease or disorder is high-risk neuroblastoma (NB).

[0232] In some embodiments, the disease or disorder treatable with the bispecific compounds of the invention is acute myeloid leukemia (AML), multiple myeloma (MM), melanoma, rhabdomyosarcoma, or diffuse large B-cell lymphoma. In other embodiments, the disease or disorder is a small solid tumor. In other embodiments, the disease or disorder is colon cancer, rectal cancer, gastric cancer, breast cancer, or pancreatic cancer.

[0233] The bispecific compounds of formula (I) can be administered to patients, such as cancer patients, as monotherapy or in combination therapy. The therapy can be a "first line", i.e., as an initial treatment in patients who have not previously received an anti-cancer treatment regimen, alone or in combination with other treatments; or a "second line", i.e., as a treatment in patients who have previously received an anti-cancer treatment regimen, alone or in combination with other treatments; or a "third line", "fourth line", etc. treatment, alone or in combination with other treatments. The therapy can also be given to patients who have received previous treatments that have been unsuccessful or partially successful but have become unresponsive or intolerant to a particular treatment. The therapy can also be given as an adjuvant treatment, i.e., in patients who currently have no detectable disease or to prevent recurrence of cancer after surgical removal of a tumor. Thus, in some embodiments, the compound can be administered to patients who have received another therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy, or any combination thereof.

[0234] The methods of the invention may involve administering a bispecific compound of formula (I) or a pharmaceutical composition thereof to a patient in a single dose or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 or more doses). For example, the dosing frequency may range from once per day to about once every 8 weeks. In some embodiments, the dosing frequency ranges from about once per day for 1, 2, 3, 4, 5 or 6 weeks, and in other embodiments involves a 28-day cycle including daily dosing for 3 weeks (21 days). In other embodiments, the bispecific compound may be administered twice daily (BID) for a course of 2 1 / 2 days (5 doses total), or once daily (QD) for a course of 2 days (2 doses total). In other embodiments, the bispecific compound may be administered once daily (QD) for a course of 5 days.

[0235] Combination therapy The bispecific compounds of formula (I) may be used in combination or simultaneously with at least one other active agent, such as an anti-cancer agent or regimen, in the treatment of diseases and disorders. The terms "in combination" and "simultaneously" in this context mean that the agents are administered simultaneously, including substantially contemporaneous administration, as the same or separate dosage forms and by the same or different modes of administration, or sequentially, such as as part of the same treatment regimen or as a consecutive treatment regimen. Thus, when given sequentially, at the start of administration of the second compound, the first compound of the two compounds may still be detectable at effective concentrations at the treatment site, in some cases. The order and time intervals may be determined so that they can act together (e.g., synergistically to provide increased benefits than if they were administered otherwise). For example, the therapeutic agents may be administered sequentially in any order at the same time or at different times; however, if not administered simultaneously, they may be administered close enough in time to provide the desired therapeutic effect, which may be in a synergistic manner. Thus, these terms are not limited to administering the active agents at exactly the same time.

[0236] In some embodiments, the treatment regimen may include administering the bispecific compound of formula (I) in combination with one or more additional therapeutic agents known for use in treating a disease or condition (e.g., cancer). The dosage of the additional anti-cancer therapeutic agent may be the same as or even less than the known or recommended dose. See Hardman et al., eds., Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician's Desk Reference 60th ed., 2006. For example, anti-cancer agents that may be suitable for use in combination with the bispecific compounds of the present invention are known in the art. See, for example, U.S. Pat. No. 9,101,622 (section 5.2 therein) and U.S. Pat. No. 9,345,705 (columns 12-18). Representative examples of additional active agents and treatment regimens include radiation therapy, chemotherapeutic agents (e.g., mitotic inhibitors, angiogenesis inhibitors, antihormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, antiandrogens, signal transduction pathway inhibitors, microtubule inhibitors, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors and topoisomerase inhibitors), immunomodulatory agents, therapeutic antibodies (e.g., monospecific and bispecific antibodies) and CAR-T therapy.

[0237] In some embodiments, the bispecific compound of Formula (I) and the additional (e.g., anti-cancer) therapeutic agent may be administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 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, 84 to 96 hours apart, or 96 to 120 hours apart. Two or more (eg, anti-cancer) therapeutic agents may be administered within the same patient visit.

[0238] In some embodiments involving cancer treatment, the bispecific compound of formula (I) and the additional anti-cancer or therapeutic agent are administered cyclically. Cycling therapy involves the administration of one anti-cancer therapeutic agent for a period of time, followed by the administration of a second anti-cancer therapeutic agent for a period of time, and repeating this sequential administration, i.e., cycle, to reduce the development of resistance to one or both of the anti-cancer therapeutic agents, to avoid or reduce the side effects of one or both of the anti-cancer therapeutic agents, and / or to improve the efficacy of the therapy. In one example, cycling therapy involves the administration of a first anti-cancer therapeutic agent for a period of time, followed by the administration of a second anti-cancer therapeutic agent for a period of time, optionally followed by the administration of a third anti-cancer therapeutic agent for a period of time, etc., and repeating this sequential administration, i.e., cycle, to reduce the development of resistance to one of the anti-cancer therapeutic agents, to avoid or reduce the side effects of one of the anti-cancer therapeutic agents, and / or to improve the efficacy of the anti-cancer therapeutic agents.

[0239] Medicine Kit The bispecific compounds and / or compositions containing them may be assembled into kits or pharmaceutical systems. The kits or pharmaceutical systems according to this aspect of the invention include a carrier or package such as a box, carton, tube, etc. having in close confinement therein one or more containers such as vials, tubes, ampoules or bottles containing the bispecific compounds of Formula (I) or pharmaceutical compositions thereof. The kits or pharmaceutical systems of the invention may also include printed instructions for using the compounds and compositions.

[0240] These and other aspects of the present invention will be further understood in light of the following examples, which are intended to illustrate certain specific embodiments of the invention, but are not intended to limit its scope, which is defined by the claims. EXAMPLES

[0241] Example 1: Synthesis of N1-(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)terephthalamide (1)

[0242] [ka]

[0243] 5-(tert-butyl) 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate To a solution of tert-butyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (4 g, 16 mmol) and N,N-diisopropylethylamine (DIEA) (5.2 mL, 32 mmol) in THF (160 mL) was added ethyl chloroformate (1.5 mL, 16 mmol, dissolved in 40 mL THF) dropwise at 0° C. for 30 min. The mixture was then stirred at room temperature for 1 h. After the reaction was complete, the mixture was concentrated and then diluted with some water. The mixture was extracted with ethyl acetate (EA). The organic layer was concentrated in vacuum and then purified by silica gel column chromatography (EA / Hexane, 40%) to give the desired compound (1.6 g, 33%) as a white solid.

[0244] LCMS: 325 [M+H] + .

[0245] [ka]

[0246] 5-(tert-butyl) 1-ethyl 3-(4-(methoxycarbonyl)benzamido)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate To a solution of 5-(tert-butyl)1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (972 mg, 3 mmol) and DIEA (990 μL, 6 mmol) in dry DCM (20 mL) was added methyl 4-(chlorocarbonyl)benzoate (713 mg, 3.6 mmol) at 0° C. The mixture was stirred at 40° C. overnight. After the reaction was completed, the mixture was concentrated in vacuo and then purified by silica gel column chromatography (EA / hexane, 40%) to give the desired compound (1.28 g, 87%).

[0247] LCMS: 487[M+H] + .

[0248] [ka]

[0249] Ethyl 3-(4-(methoxycarbonyl)benzamido)-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate To a solution of 5-(tert-butyl)1-ethyl 3-(4-(methoxycarbonyl)benzamido)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (1275 mg, 2.6 mmol) in DCM (8 mL) was added TFA (2 mL) at 0° C. Then the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with some water. Et3N (2 mL) was added to the mixture, which was then extracted with isopropanol (IPA) / chloroform (v / v=1 / 3). The organic layer was collected, concentrated in vacuum, and purified by silica gel column chromatography (MeOH / DCM, 16%) to give the desired compound (940 mg, 72%).

[0250] 1 H NMR(500MHz,DMSO-d6)δ 11.03(s,1H),9.78(s,1H),8.19(d,J=8.5Hz,2H),8.06(d,J=8.5Hz,2H),4.63( s,2H),4.49(q,J=7.1Hz,2H),3.92(s,3H),1.68(s,6H),1.38(t,J=7.1Hz,3H).

[0251] LCMS: 387 [M+H] + .

[0252] [ka]

[0253] Ethyl (S)-5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-3-(4-(methoxycarbonyl)benzamido)-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (S)-N 1 ,N 1 To a solution of 4-dimethyl-2-phenylethane-1,2-diamine (401 mg, 2.45 mmol) and DIEA (808 μL, 4.9 mmol) in dry THF (20 mL) was added 4-nitrophenyl chloroformate (542 mg, 2.69 mmol) at 0° C. After the mixture was stirred at room temperature for 1 h, ethyl 3-(4-(methoxycarbonyl)benzamido)-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (850 mg, 2.2 mmol) was added. The mixture was stirred at 60° C. overnight. After the reaction was completed, the mixture was concentrated and then purified by silica gel column chromatography (MeOH / DCM, 5%) to give the desired compound (498 mg, 39%).

[0254] LCMS: 577 [M+H] + .

[0255] [ka]

[0256] (S)-4-((5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)carbamoyl)benzoic acid To a solution of ethyl (S)-5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-3-(4-(methoxycarbonyl)benzamido)-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (498 mg, 0.86 mmol) in MeOH / THF (4 mL, 1:1) was added LiOH (1 M aqueous solution, 4.3 mL, 4.3 mmol). The mixture was stirred for 0.5 h. After the reaction was complete, HCl (2 M aqueous solution, 2 mL) was added and the mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (0.5% TFA in MeOH / DCM, 40%) to give the desired compound (407 mg, 78%) as a TFA salt.

[0257] 1 H NMR(500MHz,DMSO-d6)δ 12.75(s,1H),11.09(s,1H),10.23(s,1H),8.15-7.93(m,4H),7.51-7.41(m,2H),7.36(t,J=7.7Hz,2H),7.31-7.20(m,1H),6.87(s,1 H),5.19-5.04(m,1H),4.62(q,J=12.1Hz,2H),3.13(d,J=14.8Hz,1H),2.79(d,J=12.0Hz,1H),2.49(s,6H),1.65(s,3H),1.58(s,3H).

[0258] LCMS: 491 [M+H] + .

[0259] [ka]

[0260] To a solution of (S)-4-((5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)carbamoyl)benzoic acid (22 mg, 0.036 mmol) and DIEA (60 μL, 0.36 mmol) in anhydrous DCM (2 mL) was added propanephosphonic anhydride (T3P®) (50 wt % in EA, 115 μL, 0.18 mmol). The reaction was stirred for 10 min before the addition of 4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (16 mg, 0.036 mmol). The mixture was stirred for 30 min and then concentrated in vacuo. The crude product was purified by preparative HPLC to give compound 1 (2.6 mg, 7%) as a TFA salt.

[0261] 1 H NMR(500MHz,DMSO-d6)δ 12.47(s,1H),11.10(s,1H),11.02(s,1H),8.66(s,1H),8.09(d,J=8.1Hz,2H),7.95(d,J=8.1Hz,2H),7.58(dd,J=8.6,7.1Hz,1H),7.3 8(d,J=7.2Hz,2H),7.30(t,J=7.5Hz,2H),7.20(t,J=7.3Hz,1H),7.14(d,J=8.6Hz,1H),7.04(d,J=7.0Hz,1H),6.60(t,J=5.8Hz,1H),6. 27(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.90(s,1H),4.57(s,2H),3.61(t,J=5.4Hz,2H),3.54(d,J=3.5Hz,9H),3.45(dt,J=11.2,5.6H z,4H),3.33(s,6H),2.88(ddd,J=16.7,13.7,5.4Hz,1H),2.62-2.53(m,1H),2.22(s,5H),2.10-1.98(m,1H),1.66(s,3H),1.58(s,3H).

[0262] LCMS: 921 [M+H] + .

[0263] Example 2: Synthesis of N1-(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)terephthalamide (2)

[0264] [ka]

[0265] Following the synthetic route of compound 1 in Example 1, compound 2 (20.4 mg, 65%) was obtained using 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0266] 1 H NMR(500MHz,DMSO-d6)δ 11.09(d,J=6.4Hz,2H),9.05(s,1H),8.86(t,J=5.3Hz,1H),8.10(d,J=8.5Hz,2H),7.96(d,J=8.5Hz,2H),7.59(dd,J=8.6,7.0Hz,1H),7.48-7 .43(m,2H),7.40(t,J=7.7Hz,2H),7.34-7.28(m,1H),7.26(d,J=8.7Hz,1H),7.04(d,J=7.0Hz,1H),6.86(s,1H),6.77(d,J=9.2Hz,1H),5.36(d dd,J=12.6,9.2,3.9Hz,1H),5.06(dd,J=12.8,5.5Hz,1H),4.78(d,J=11.8Hz,1H),4.58(d,J=11.9Hz,1H),3.62-3.47(m,5H),3.36(ddd,1H), 2.89(d,J=4.7Hz,3H),2.85(d,J=4.8Hz,3H),2.60(dt,J=17.6,3.5Hz,1H),2.03(dtd,J=11.3,6.3,5.6,3.0Hz,1H),1.69(s,3H),1.60(s,3H).

[0267] LCMS: 789 [M+H] + .

[0268] Example 3: Synthesis of N1-(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N4-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)terephthalamide (3)

[0269] [ka]

[0270] Compound 3 (13.2 mg, 35%) was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-2-(4-aminobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0271] 1H NMR (500MHz, DMSO-d6) δ 11.08(s,1H),9.00(s,2H),8.64(t,J=5.5Hz,1H),8.38(d,J=7.8Hz,1H),8.22 -8.05(m,2H),8.04-7.94(m,2H),7.90(d,J=9.3Hz,1H),7.44(dd,J=8.5,2.0Hz ,4H),7.40(td,J=8.3,7.9,2.8Hz,4H),7.36-7.27(m,1H),6.77(d,J=9.1Hz,1H ),5.40-5.31(m,2H),4.93(t,J=7.2Hz,1H),4.79(d,J=11.8Hz,1H),4.56(dd,J =17.6,10.6Hz,2H),4.44(t,J=8.0Hz,1H),4.30(s,1H),3.67-3.51(m,4H),3. 39-3.26(m,4H),2.89(d,J=4.8Hz,3H),2.85(d,J=4.8Hz,3H),2.46(s,3H),2.3 4(dt,J=14.8,7.8Hz,1H),2.22(dt,J=14.5,7.3Hz,1H),2.01(d,J=14.5Hz,1H) ,1.79(tdd,3H),1.69(s,3H),1.60(s,3H),1.38(d,J=6.9Hz,3H),0.96(s,9H).

[0272] LCMS: 1002 [M+H] + .

[0273] Example 4: Synthesis of N1-(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)terephthalamide (4)

[0274] [ka]

[0275] Following the synthetic route of compound 1 in Example 1, compound 4 (11 mg, 38%) was obtained using 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0276] 1 H NMR(500MHz,DMSO-d6)δ 12.55(s,1H),11.07(d,J=21.1Hz,2H),8.64(t,J=5.6Hz,1H),8.13-8.05(m,2H),7.97(d,J=8.0Hz,2H),7.58(dd,J=8.6,7.1Hz,1H),7.43(d,J =7.2Hz,2H),7.37(t,J=7.6Hz,2H),7.27(t,J=7.3Hz,1H),7.10(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.61(s,1H),6.55(t,J=5.9Hz,1H),5. 21(s,1H),5.06(dd,J=12.7,5.5Hz,1H),4.74(d,J=12.0Hz,1H),4.57(d,J=11.8Hz,1H),3.34(s,6H),3.29(p,J=6.6Hz,4H),2.89(ddd,J=16.8 ,13.7,5.4Hz,1H),2.72-2.55(m,6H),2.03(dtd,J=13.1,5.3,2.2Hz,1 H),1.68(s,3H),1.60(s,3H),1.55(m,2H),1.39(dt,J=7.0,3.7Hz,4H).

[0277] LCMS: 845 [M+H] + .

[0278] Example 5: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)terephthalamide (5)

[0279] [ka]

[0280] Compound 5 (5 mg, 17%) was obtained according to the synthetic route of compound 1 in Example 1 using 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0281] 1 H NMR(500MHz,DMSO-d6)δ 12.49(s,1H),11.10(s,1H),11.03(s,1H),8.67(s,1H),8.09(d,J=8.1Hz,2H),7.96(d,J=8.1Hz,2H),7.58(dd,J=8.6,7.0Hz,1H),7.39 (d,J=7.2Hz,2H),7.32(t,J=7.5Hz,2H),7.22(t,J=7.3Hz,1H),7.14(d,J=8.6Hz,1H),7.04(d,J=7.0Hz,1H),6.60(t,J=5.8Hz,1H),6.3 5(s,1H),5.06(dd,J=12.7,5.4Hz,1H),4.98(s,1H),4.58(s,2H),3.62(t,J=5.4Hz,2H),3.57-3.49(m,12H),3.46(dt,J=12.0,5.8Hz,5 H),2.89(ddd,J=16.9,13.7,5.4Hz,1H),2.63-2.54(m,2H),2.31(s,1H),2.03(ddd,J=11.7,6.4,3.9Hz,1H),1.66(s,3H),1.59(s,3H).

[0282] LCMS: 965 [M+H] + .

[0283] Example 6: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4Synthesis of -(2-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethoxy)ethyl)terephthalamide (6)

[0284] [ka]

[0285] Compound 6 (6.5 mg, 20%) was obtained by following the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-2-(3-(2-(2-aminoethoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0286] 1H NMR(500MHz,DMSO-d6)δ 11.08(s,1H),9.05(s,1H),8.99(s,1H),8.69(t,J=5.6Hz,1H),8.38(d,J=7.8Hz,1H), 8.10(d,J=8.5Hz,2H),7.98(d,J=8.5Hz,2H),7.87(d,J=9.3Hz,1H),7.46-7.42(m,4H) ,7.42-7.35(m,4H),7.33-7.29(m,1H),6.77(d,J=9.1Hz,1H),5.36(ddd,J=12.4,9.1, 4.0Hz,2H),4.91(p,J=7.3Hz,2H),4.79(d,J=11.9Hz,1H),4.55(dd,J=19.3,10.6Hz,2 H),4.43(t,J=8.1Hz,1H),4.29(dd,J=4.7,2.4Hz,1H),3.67-3.47(m,11H),3.45(q,J= 6.8,6.3Hz,2H),3.36(ddt,J=12.6,8.9,4.4Hz,1H),2.89(d,J=4.8Hz,3H),2.84(d,J= 4.8Hz,3H),2.46(s,3H),2.36(dt,J=14.6,6.1Hz,1H),2.07-1.99(m,1H),1.80(ddd,J =12.9,8.5,4.6Hz,1H),1.69(s,3H),1.60(s,3H),1.37(d,J=7.0Hz,3H),0.94(s,9H).

[0287] LCMS: 1076 [M+H] + .

[0288] Example 7: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hex-5-yn-1-yl)terephthalamide (7)

[0289] [ka]

[0290] Following the synthetic route of compound 1 in Example 1, compound 7 (3.3 mg, 12%) was obtained using 4-(6-aminohex-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0291] 1 H NMR(500MHz,DMSO-d6)δ 12.61(s,1H),11.13(s,1H),11.04(s,1H),9.71(s,1H),8.73(s,1H),8.11(d,J=8.1Hz,2H),7.98(d,J=8.1Hz,2H),7.9 0-7.85(m,1H),7.84-7.81(m,2H),7.45(d,J=7.7Hz,2H),7.38(t,J=7.6Hz,2H),7.29(t,J=7.3Hz,1H),6.73(s,1H),5. 32(s,1H),5.14(dd,J=12.8,5.5Hz,1H),4.81(d,J=12.1Hz,1H),4.57(d,J=11.8Hz,1H),2.93-2.70(m,4H),2.60(t,J= 7.0Hz,4H),2.09-2.00(m,1H),1.76(q,J=7.4,6.7Hz,2H),1.68(d,J=6.3Hz,4H),1.60(s,3H),1.21(d,J=29.7Hz,2H).

[0292] LCMS: 826 [M+H] + .

[0293] Example 8: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentyl)terephthalamide (8)

[0294] [ka]

[0295] Following the synthetic route of compound 1 in Example 1, compound 8 (7.2 mg, 29%) was obtained using 4-((5-aminopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0296] 1 H NMR(500MHz,DMSO-d6)δ 11.04(d,J=18.1Hz,2H),8.59(t,J=5.7Hz,1H),8.04(d,J=8.3Hz,2H),7.91(d,J=8.1Hz,2H),7.76(dd,J=8.5,7.2Hz,1H),7.48(d,J=8.6Hz,1H ),7.38(dd,J=14.5,7.4Hz,3H),7.30(t,J=7.6Hz,2H),7.21(t,J=7.2Hz,1H),6.51(s,1H),5.03(dd,J=12.8,5.5Hz,1H),4.64(s,1H),4.52(d,J =11.9Hz,1H),4.18(t,J=6.4Hz,1H),3.55(s,1H),3.31-3.26(m,6H),3.07(s,1H),3.01(q,J=7.2Hz,3H),2.83(ddd,J=17.0,13.8,5.5Hz,2H), 2.59-2.49(m,3H),2.01-1.95(m,1H),1.77(p,J=6.6Hz,2H),1.62(s,3H ),1.58(t,J=7.4Hz,2H),1.54(s,3H),1.48(qd,J=9.9,9.0,6.0Hz,2H).

[0297] LCMS: 832 [M+H] + .

[0298] Example 9: 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)octyl)terephthalamide (9)

[0299] [ka]

[0300] Compound 9 (15 mg, 52%) was obtained following the synthetic route of compound 1 in Example 1 using 4-((8-aminooctyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0301] 1 H NMR(500MHz,DMSO-d6)δ 12.49(s,1H),11.11(s,1H),11.02(s,1H),8.60(t,J=5.7Hz,1H),8.09(d,J=8.1Hz,2H),7.95(d,J=8.1Hz,2H),7.81(dd,J=8.5,7.3Hz, 1H),7.52(d,J=8.5Hz,1H),7.44(d,J=7.2Hz,1H),7.32(t,J=7.6Hz,2H),7.22(t,J=7.3Hz,1H),6.33(s,1H),5.09(dd,J=12.8,5.5Hz,1H ),4.95(s,1H),4.59(s,2H),4.21(t,J=6.4Hz,2H),3.33(s,6H),2.89(ddd,J=16.8,13.8,5.4Hz,1H),2.64-2.54(m,1H),2.33-2.18(m,5 H),2.03(dtd,J=13.0,5.3,2.2Hz,1H),1.83-1.71(m,2H),1.66(s,3H),1.63-1.53(m,5H),1.48(t,J=7.8Hz,2H),1.35(d,J=4.1Hz,6H).

[0302] LCMS: 874 [M+H] + .

[0303] Example 10: Synthesis of N-((S)-2-(dimethylamino)-1-phenylethyl)-3-(4-(11-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)undecanamido)benzamido)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (10)

[0304] [ka]

[0305] 5-(tert-butyl) 1-ethyl 6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate To a solution of 5-(tert-butyl) 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (875 mg, 2.7 mmol) and DIEA (1.34 mL, 8.1 mmol) in DCM (40 mL) was added 4-nitrobenzoyl chloride (600 mg, 3.24 mmol) at 0° C. The reaction was stirred at room temperature overnight. The mixture was concentrated in vacuo and then purified by silica gel column chromatography (EA / Hexane, 30%) to give the desired compound (822 mg, 64%).

[0306] LCMS: 474 [M+H] + .

[0307] [ka]

[0308] Ethyl 6,6-dimethyl-3-(4-nitrobenzamido)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate To a solution of 5-(tert-butyl) 1-ethyl 6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (822 mg, 1.74 mmol) in DCM (8 mL) was added TFA (2 mL) at 0° C. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The crude product was used in the next step without further purification.

[0309] LCMS: 374 [M+H] + .

[0310] [ka]

[0311] Ethyl (S)-5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-3-(4-nitrobenzamido)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate To a solution of ethyl 6,6-dimethyl-3-(4-nitrobenzamido)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (633 mg, 1.3 mmol) and DIEA (130 μL, 0.78 mmol) in DCM (10 mL) was added triphosgene (194 mg, 0.65 mmol, dissolved in 2 mL of DCM) dropwise at 0° C. The mixture was stirred at 0° C. for 30 min. Then, the (S)-N 1 ,N 1 -Dimethyl-2-phenylethane-1,2-diamine (256 mg, 1.56 mmol) and DIEA (320 μL, 1.95 mmol) were added. The mixture was stirred at 40° C. overnight. After the reaction was completed, the mixture was concentrated in vacuo and then purified by silica gel column chromatography (MeOH / DCM, 6%) to give the desired compound (232 mg, 32%).

[0312] LCMS: 564 [M+H] + .

[0313] [ka]

[0314] (S)-3-(4-aminobenzamido)-N-(2-(dimethylamino)-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide To a solution of ethyl (S)-5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-3-(4-nitrobenzamido)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (232 mg, 0.41 mmol) in isopropanol (2 mL) was added LiOH (1N aqueous solution, 2 mL). The reaction was stirred at room temperature for 10 min and then extracted with IPA / chloroform (v / v=1 / 3). The pooled organic layers were concentrated in vacuo. The resulting product was then redissolved in MeOH (20 mL). Palladium (10% on activated carbon, 30 mg) was added and the mixture was stirred under H2 atmosphere for 3 h. After the reaction was complete, the mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (1.75N NH3 in MeOH / DCM, 30%) to give the desired compound (153 mg, 81% for two steps).

[0315] 1 H NMR(500MHz,DMSO-d6)δ 12.33(s,0H),10.33(s,0H),9.19(s,0H),7.77(d,J=8.3Hz,1H),7.41(d,J=7.5Hz,1H),6.57(d,J=8.3Hz,1H),5.88(s,0H) ,5.75(s,1H),4.63(s,1H),4.53(d,J=11.9Hz,2H),3.17(d,J=5.2Hz,1H),2.64(p,J=1.8Hz,1H),1.66(s,3H),1.58(s,3H).

[0316] LCMS: 462 [M+H] + .

[0317] [ka]

[0318] To a solution of 11-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)undecanoic acid (14 mg, 0.03 mmol) and DIEA (50 μL, 0.3 mmol) in dry DCM (2 mL) was added T3P (50 wt% in EA, 90 μL, 0.15 mmol). The reaction was stirred for 10 min before (S)-3-(4-aminobenzamido)-N-(2-(dimethylamino)-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (14 mg, 0.03 mmol). The mixture was stirred for 30 min and then concentrated in vacuo. The crude product was purified by preparative HPLC to give compound 10 (7.6 mg, 25%) as a TFA salt.

[0319] 1H NMR(500MHz,DMSO-d6)δ 11.10(s,1H),10.79(s,1H),10.16(s,1H),9.00(s,1H),7.98(d,J=8.7Hz,2H),7.81(d d,J=8.5,7.2Hz,1H),7.72(d,J=8.6Hz,2H),7.51(d,J=8.5Hz,1H),7.44(d,J=7.4Hz,3 H),7.42-7.38(m,2H),7.34-7.28(m,1H),6.76(d,J=9.1Hz,1H),5.35(ddd,J=12.4,9. 0,3.9Hz,1H),5.08(dd,J=12.8,5.5Hz,1H),4.76(d,J=11.9Hz,1H),4.55(d,J=11.8Hz, 1H),4.20(t,J=6.4Hz,2H),3.59-3.51(m,1H),3.35(ddt,J=17.1,12.3,6.2Hz,1H),3. 18-3.13(m,1H),2.89(d,J=4.8Hz,3H),2.84(d,J=4.9Hz,3H),2.59(dt,J=17.4,3.4Hz ,1H),2.34(t,J=7.4Hz,2H),2.03(dtd,J=13.0,5.2,2.2Hz,1H),1.75(q,J=6.9,6.4Hz ,2H),1.68(s,3H),1.59(s,3H),1.46(dq,J=15.1,7.3,6.7Hz,2H),1.38-1.22(m,12H).

[0320] LCMS: 902 [M+H] + .

[0321] Example 11: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)octyl)terephthalamide (11)

[0322] [ka]

[0323] Compound 9 (15 mg, 52%) was obtained following the synthetic route of compound 1 in Example 1 using 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0324] LCMS: 817 [M+H] + .

[0325] Example 12: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)terephthalamide (12)

[0326] [ka]

[0327] Compound 12 (8.6 mg, 28%) was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-2-(6-aminohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0328] 1H NMR(500MHz,DMSO-d6)δ 11.08(s,1H),9.00(s,1H),8.60(t,J=5.6Hz,1H),8.38(d,J=7.8Hz,1H),8.09(d,J=8.5Hz, 2H),7.96(d,J=8.5Hz,2H),7.80(d,J=9.3Hz,1H),7.65(s,1H),7.48-7.42(m,4H),7.42-7.3 8(m,4H),7.34-7.28(m,1H),6.77(d,J=9.2Hz,1H),5.36(ddd,J=12.5,9.1,3.9Hz,2H),4.92 (t,J=7.2Hz,1H),4.78(d,J=11.8Hz,1H),4.58(d,J=11.9Hz,2H),4.53(d,J=9.3Hz,1H),4.4 3(t,J=8.0Hz,1H),4.29(t,J=3.6Hz,1H),3.66-3.50(m,5H),3.35(td,J=8.6,4.2Hz,1H),3. 27(q,J=6.5Hz,2H),2.89(d,J=4.8Hz,3H),2.85(d,J=4.8Hz,3H),2.46(s,3H),2.27(dq,J=1 3.3,6.9,6.1Hz,1H),2.15(tdd,J=14.3,8.2,5.5Hz,2H),2.02(ddd,J=11.1,7.8,2.7Hz,1H) ,1.80(td,J=8.4,4.2Hz,1H),1.69(s,3H),1.60(s,3H),1.38(d,J=7.0Hz,3H),0.94(s,9H).

[0329] LCMS: 1030 [M+H] + .

[0330] Example 13: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexyl)terephthalamide (13)

[0331] [ka]

[0332] Compound 13 (12 mg, 48%) was obtained according to the synthetic route of compound 1 in Example 1 using 4-(6-aminohexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0333] 1 H NMR (500MHz, DMSO-d6) δ 11.12(s,1H),11.08(s,1H),9.05(s,1H),8.60(t,J=5.6Hz,1H),8.09(d,J=8 .5Hz,2H),7.96(d,J=8.5Hz,2H),7.80-7.74(m,2H),7.71(dd,J=6.9,1.9Hz,1 H),7.45(d,J=7.3Hz,2H),7.40(t,J=7.7Hz,2H),7.35-7.29(m,1H),6.77(d,J =9.1Hz,1H),5.36(ddd,J=12.6,9.1,3.9Hz,1H),5.13(dd,J=12.7,5.5Hz,1H) ,4.78(d,J=11.9Hz,1H),4.58(d,J=11.9Hz,1H),3.56(td,J=12.9,2.7Hz,1H ),3.36(ddd,J=12.8,8.8,4.0Hz,1H),3.27(q,J=6.6Hz,2H),3.09-2.99(m,2H ),2.89(d,J=4.7Hz,3H),2.86(s,3H),2.65-2.52(m,2H),2.06(dp,J=10.5,3. 3Hz, 1H), 1.69 (s, 3H), 1.60 (s, 5H), 1.55 (t, J=7.0Hz, 2H), 1.42-1.33 (m, 4H).

[0334] LCMS: 830 [M+H] + .

[0335] Example 14: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4Synthesis of -(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)terephthalamide (14)

[0336] [ka]

[0337] Compound 14 (5 mg, 16%) was obtained following the synthetic route of compound 1 in Example 1 using 4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione.

[0338] 1 H NMR(500MHz,DMSO-d6)δ 11.07(s,1H),11.02(s,1H),9.01(s,1H),8.67(t,J=5.6Hz,1H),8.46 -8.26(m,2H),8.14-8.06(m,2H),8.03-7.93(m,4H),7.84(dt,J=11.0, 7.8Hz,1H),7.48-7.37(m,4H),7.33-7.26(m,1H),6.76(d,J=9.2Hz,1H),5.83(dt,J=11.9,6.0Hz,1H),5.36(td,J=10.6,9.1,3.9Hz,1H),4.7 8(d,J=11.8Hz,1H),4.57(d,J=11.8Hz,1H),4.40-4.21(m,2H),3.85(d,J=4.2Hz,2H),3.63(dt,J=5.7,2.5Hz,2H),3.56(dt,J=8.2,5.1Hz,10 H),3.44(t,J=5.8Hz,2H),2.89(d,J=4.7Hz,3H),2.84(d,J=4.7Hz,3H),2.65-2.54(m,2H),2.06(d,J=19.3Hz,1H),1.69(s,3H),1.60(s,3H).

[0339] LCMS: 972 [M+H] + .

[0340] Example 15: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethyl)terephthalamide (15)

[0341] [ka]

[0342] Compound 15 (11.7 mg, 33%) was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-2-(3-(2-aminoethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0343] 1H NMR (500MHz, DMSO-d6) δ 11.09(s,1H),8.99(s,2H),8.66(t,J=5.7Hz,1H),8.39(d,J=7.8Hz,1H),8.10(d ,J=8.5Hz,2H),7.99(d,J=8.5Hz,2H),7.90(d,J=9.3Hz,1H),7.47-7.42(m,4H), 7.42-7.35(m,4H),7.32-7.27(m,1H),6.77(d,J=9.1Hz,1H),5.36(ddd,J=12.6, 9.1,3.9Hz,1H),4.91(p,J=7.0Hz,1H),4.78(d,J=11.9Hz,1H),4.56(dd,J=19.3 ,10.6Hz,2H),4.44(t,J=8.1Hz,1H),4.29(dd,J=4.7,2.4Hz,1H),3.72-3.50(m, 8H),3.45(q,J=5.5Hz,2H),2.89(d,J=4.8Hz,3H),2.84(d,J=4.8Hz,3H),2.61-2 .53(m,1H),2.46(s,3H),2.42-2.35(m,1H),2.11-1.99(m,1H),1.79(ddd,J=13. 0,8.6,4.5Hz,1H),1.69(s,3H),1.60(s,3H),1.36(d,J=7.0Hz,3H),0.93(s,9H).

[0344] LCMS: 1032 [M+H] + .

[0345] Example 16: Synthesis of N-((S)-2-(dimethylamino)-1-phenylethyl)-3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanamido)benzamido)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (16)

[0346] [ka]

[0347] Following the synthetic route of compound 10 in Example 10, compound 16 (9.5 mg, 35%) was obtained using 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoic acid.

[0348] LCMS: 803 [M+H] + .

[0349] Example 17: Synthesis of N-((S)-2-(dimethylamino)-1-phenylethyl)-3-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-ylamido)benzamido)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (17)

[0350] [ka]

[0351] Compound 17 (5.2 mg, 19%) was obtained by following the synthetic route of compound 10 in Example 10 using 6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-ynoic acid.

[0352] 1H NMR(500MHz,DMSO-d6)δ 12.42(s,1H),11.00(s,1H),10.76(s,1H),10.26(s,1H),7.98(d,J=8.4Hz,2H),7.72(dd,J=7.9,3.5Hz,3H),7.65(t, J=9.1Hz,2H),7.53(t,J=7.6Hz,1H),7.40(d,J=7.6Hz,2H),7.33(t,J=7.5Hz,2H),7.24(d,J=8.3Hz,1H),5.14(dd,J= 13.3,5.1Hz,1H),5.01(s,1H),4.63-4.53(m,1H),4.49(d,J=17.9Hz,1H),4.35(d,J=7.7Hz,1H),2.92(ddd,J=17.3,1 3.6,5.4Hz,1H),2.58(q,J=7.3Hz,7H),2.04-1.98(m,1H),1.93(td,J=8.4,7.2,4.9Hz,3H),1.66(s,3H),1.58(s,3H).

[0353] LCMS: 798 [M+H] + .

[0354] Example 18: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropyl)terephthalamide (18)

[0355] [ka]

[0356] Compound 18 (3.6 mg) was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-2-(3-aminopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0357] 1 H NMR(500MHz,DMSO-d6)δ 12.61(s,1H),11.05(s,1H),8.99(s,1H),8.68(s,1H),8.42(d,J=7.8Hz,1H),8.11(d,J=7.9Hz,2H),7.98(d,J=8.7Hz,2H),7.50-7. 20(m,9H),6.75(s,1H),5.33(s,1H),5.17(s,1H),4.91(q,J=7.4Hz,1H),4.82(d,J=11.8Hz,1H),4.55(dd,J=14.4,10.4Hz,2H),4.45 (t,J=8.0Hz,1H),4.29(s,1H),3.63(d,J=4.4Hz,2H),3.50(ddd,J=29.3,13.5,6.6Hz,2H),2.79(s,6H),2.59(dt,J=14.7,7.4Hz,1H ),2.46(s,3H),2.09-1.98(m,1H),1.80(ddd,J=12.9,8.5,4.7Hz,1H),1.69(s,3H),1.61(s,3H),1.38(d,J=7.0Hz,3H),0.94(s,9H).

[0358] LCMS: 988 [M+H] + .

[0359] Example 19: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)terephthalamide (19)

[0360] [ka]

[0361] Compound 19 (5.9 mg, 21%) was obtained following the synthetic route of compound 1 in Example 1 using 4-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0362] 1 H NMR(500MHz,DMSO-d6)δ 12.52(s,1H),11.09(d,J=20.2Hz,2H),9.12(s,1H),8.69(t,J=5.6Hz,1 H),8.47(s,1H),8.08(d,J=8.3Hz,2H),7.96(d,J=8.0Hz,2H),7.57(dd,J =8.6,7.1Hz,1H),7.43(d,J=7.5Hz,2H),7.37(t,J=7.6Hz,2H),7.29(d,J=7.4Hz,1H),7.17(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.64(t,J=5.8 Hz,1H),5.24(s,1H),5.05(dd,J=12.8,5.5Hz,1H),4.72(s,1H),4.58(d,J=11.8Hz,1H),3.64(dt,J=26.2,5.6Hz,4H),3.49(dq,J=12.0,5.7Hz,4 H),3.16(d,J=16.7Hz,2H),2.89(ddd,J=17.0,13.9,5.4Hz,2H),2.65-2. 53(m,1H),2.02(dtd,J=12.6,5.2,2.2Hz,1H),1.68(s,3H),1.60(s,3H).

[0363] LCMS: 833 [M+H] + .

[0364] Example 20: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4Synthesis of -(5-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)terephthalamide (20)

[0365] [ka]

[0366] Compound 20 (9.1 mg, 28%) was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-2-(5-aminopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0367] 1 H NMR(500MHz,DMSO-d6)δ 12.49(s,1H),11.03(s,1H),8.99(s,1H),8.62(s,0H),8.38(d,J=7.8Hz ,1H),8.10(d,J=8.1Hz,2H),7.95(d,J=8.0Hz,2H),7.82(d,J=9.3Hz,1H ),7.46-7.42(m,2H),7.41-7.36(m,4H),7.32(t,J=7.7Hz,2H),7.22(t, J=7.3Hz,1H),6.34(s,1H),5.11(d,J=3.6Hz,1H),4.93(q,J=7.2Hz,1H), 4.59(s,2H),4.53(d,J=9.3Hz,1H),4.43(t,J=8.0Hz,1H),4.29(s,1H), 3.70-3.54(m,2H),2.46(s,3H),2.30(q,J=14.3,7.8Hz,4H),2.17(dd,J =14.0,7.5Hz,2H),2.02(td,J=8.9,4.4Hz,1H),1.81(td,J=8.4,4.2Hz, 1H),1.66(s,3H),1.60-1.48(m,7H),1.38(d,J=7.0Hz,3H),0.95(s,9H).

[0368] LCMS: 1016 [M+H] + .

[0369] Example 21: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)terephthalamide (21)

[0370] [ka]

[0371] Compound 21 (8.5 mg, 30%) was obtained according to the synthetic route of compound 1 in Example 1 using 5-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0372] 1H NMR(500MHz,DMSO-d6)δ 11.07(d,J=3.8Hz,2H),9.01(s,1H),8.63(t,J=5.7Hz,1H),8.09(d,J=8.2Hz,2H),7.96(d,J=8.5Hz,2H),7.57(d,J=8.4Hz,1H),7.45(d,J=7.4 Hz,2H),7.40(t,J=7.7Hz,2H),7.34-7.27(m,1H),6.96(d,J=2.1Hz,1H),6.86(dd,J=8.4,2.2Hz,1H),6.77(d,J=9.2Hz,1H),5.36(ddd,J=12.5 ,9.1,3.9Hz,1H),5.03(dd,J=12.7,5.5Hz,1H),4.78(d,J=11.9Hz,1H),4.58(d,J=11.9Hz,1H),3.64-3.42(m,10H),3.21-3.15(m,2H),2.89(d ,J=4.9Hz,3H),2.85(d,J=4.8Hz,3H),2.58(dt,J=20.4,4.2Hz,1H),2.06-1.95(m,1H),1.69(s,3H),1.60(s,3H),1.45(td,J=8.4,4.2Hz,2H).

[0373] LCMS: 831 [M+H] + .

[0374] Example 22: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)terephthalamide (22)

[0375] [ka]

[0376] Compound 22 (6.9 mg, 20%) was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-2-(7-aminoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0377] 1 H NMR (500MHz, DMSO-d6) δ 12.47(s,1H),11.02(s,1H),8.99(s,1H),8.59(s,1H),8.37(d,J=7.8Hz,1H),8 .09(d,J=8.0Hz,2H),7.95(d,J=8.0Hz,2H),7.80(d,J=9.3Hz,1H),7.46-7.42(m ,2H),7.38(d,J=8.1Hz,4H),7.30(t,J=7.6Hz,2H),7.20(t,J=7.3Hz,1H),6.27 (s,1H),5.10(d,J=3.5Hz,1H),4.92(p,J=8.9,8.1Hz,2H),4.57(s,1H),4.53(d, J=9.3Hz,1H),4.43(t,J=8.0Hz,1H),4.29(s,1H),3.62(d,J=4.1Hz,2H),3.27( d,J=6.9Hz,2H),2.46(s,3H),2.27(dd,J=14.3,7.5Hz,1H),2.16-2.11(m,1H),2 .05-1.96(m,1H),1.80(ddd,J=12.8,8.5,4.6Hz,1H),1.66(s,3H),1.58(s,3H) ,1.51(tt,J=14.5,7.2Hz,4H),1.37(d,J=7.0Hz,3H),1.31(s,4H),0.94(s,9H).

[0378] LCMS: 1044 [M+H] + .

[0379] Example 23:N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4Synthesis of -(8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl)terephthalamide (23)

[0380] [ka]

[0381] Compound 23 (12.3 mg, 36%) was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-2-(8-aminooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0382] 1H NMR(500MHz,DMSO-d6)δ 12.53(s,1H),11.09(s,1H),9.20(s,1H),8.99(s,1H),8.62(t,J=5.7Hz,1H),8.38(d,J=7.8Hz,1H ),8.10(d,J=8.4Hz,2H),7.96(d,J=8.1Hz,2H),7.79(d,J=9.3Hz,1H),7.44(dd,J=7.8,5.7Hz,4H), 7.42-7.36(m,4H),7.33-7.27(m,1H),6.77(d,J=9.1Hz,1H),5.36(ddd,J=12.5,9.1,3.9Hz,1H),5. 11(d,J=3.6Hz,1H),4.98-4.88(m,1H),4.80(d,J=11.8Hz,1H),4.57(d,J=11.9Hz,1H),4.52(d,J=9 .3Hz,1H),4.43(t,J=8.0Hz,1H),4.31-4.24(m,1H),3.61(t,J=3.9Hz,2H),3.55(t,J=12.5Hz,1H), 3.27(q,J=6.7Hz,2H),2.86(d,J=19.3Hz,6H),2.46(s,3H),2.27(dd,J=14.3,7.4Hz,1H),2.12(ddd ,J=14.0,7.9,6.1Hz,1H),2.02(ddd,J=10.8,7.4,2.7Hz,1H),1.80(ddd,J=12.9,8.4,4.6Hz,1H),1 .69(s,3H),1.60(s,3H),1.57-1.45(m,4H),1.38(d,J=7.0Hz,3H),1.34-1.23(m,4H),0.94(s,9H).

[0383] LCMS: 1058 [M+H] + .

[0384] Example 24: Synthesis of N-((S)-2-(dimethylamino)-1-phenylethyl)-3-(4-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbonyl)benzamido)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (24)

[0385] [ka]

[0386] Compound 24 (3.6 mg) was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0387] 1 H NMR(500MHz,DMSO-d6)δ 12.49(s,1H),11.05(s,1H),8.99(s,1H),8.51(d,J=7.8Hz,1H),8.10(d,J=8.0Hz,2H),7.68(d,J=7.7Hz,2 H),7.45(d,J=8.3Hz,2H),7.43-7.37(m,4H),7.33(t,J=7.2Hz,2H),7.29-7.20(m,1H),5.05(s,1H),4.99(q ,J=7.2Hz,1H),4.68-4.48(m,2H),4.26(s,1H),3.73(dd,J=10.9,3.7Hz,1H),3.27(d,J=11.0Hz,1H),2.46( s,3H),2.44(s,1H),2.22-2.15(m,1H),1.93-1.81(m,1H),1.67(s,3H),1.59(s,3H),1.43(d,J=7.0Hz,3H).

[0388] LCMS:804[M+H] + .

[0389] Example 25: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4Synthesis of -((S)-14-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbonyl)-15,15-dimethyl-12-oxo-3,6,9-trioxa-13-azahexadecyl)terephthalamide (25)

[0390] [ka]

[0391] Compound 25 (7.2 mg, 19%) was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-1-amino-14-(tert-butyl)-12-oxo-3,6,9-trioxa-13-azapentadecan-15-oyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0392] 1H NMR(500MHz,DMSO-d6)δ 11.08(s,1H),9.13-8.92(m,2H),8.69(t,J=5.6Hz,1H),8.38(d,J=7.8Hz ,1H),8.21-8.06(m,3H),8.00-7.96(m,2H),7.86(d,J=9.3Hz,1H),7.49- 7.36(m,9H),7.30(td,J=6.8,6.4,1.5Hz,1H),6.77(d,J=9.2Hz,1H),5.4 1-5.29(m,2H),4.92(t,J=7.3Hz,1H),4.78(d,J=11.9Hz,1H),4.63-4.48 (m,2H),4.43(t,J=8.0Hz,1H),4.28(s,1H),3.69-3.41(m,16H),3.38-3. 32(m,1H),2.89(d,J=4.8Hz,3H),2.85(d,J=4.8Hz,3H),2.46(s,3H),2.3 5(dt,J=14.5,6.1Hz,1H),2.02(dd,J=12.1,8.7Hz,1H),1.80(td,J=8.4, 4.3Hz,1H),1.69(s,3H),1.60(s,3H),1.38(d,J=7.0Hz,3H),0.94(s,9H).

[0393] LCMS: 1120 [M+H] + .

[0394] Example 26: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)terephthalamide (26)

[0395] [ka]

[0396] Compound 26 (14.7 mg, 49%) was obtained following the synthetic route of compound 1 in Example 1 using 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0397] 1 H NMR(500MHz,DMSO-d6)δ 11.09(d,J=9.6Hz,2H),9.04(s,1H),8.66(t,J=5.6Hz,1H),8.09(d,J=8.5H z,2H),7.97(d,J=8.5Hz,2H),7.58(dd,J=8.6,7.0Hz,1H),7.47-7.43(m,2H) ,7.40(dd,J=8.5,6.8Hz,2H),7.34-7.29(m,1H),7.13(d,J=8.6Hz,1H),7.0 4(d,J=7.0Hz,1H),6.77(d,J=9.2Hz,1H),6.61(t,J=5.9Hz,1H),5.36(ddd,J =12.5,9.2,3.8Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.78(d,J=11.9Hz,1H ),4.57(d,J=11.9Hz,1H),3.66-3.51(m,10H),3.48-3.37(m,4H),3.36(ddd, J=12.6,8.6,4.0Hz,1H),2.89(d,J=4.6Hz,3H),2.85(d,J=4.7Hz,3H),2.63 -2.53(m,2H),2.03(ddd,J=10.6,5.5,3.0Hz,1H),1.69(s,3H),1.60(s,3H).

[0398] LCMS: 877 [M+H] + .

[0399] Example 27: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4Synthesis of -(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl)oxy)propyl)terephthalamide (27)

[0400] [ka]

[0401] Compound 27 (7.5 mg) was obtained according to the synthetic route of compound 1 in Example 1 using 5-(3-aminopropoxy)-2-(2,6-dioxopiperidin-3-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione.

[0402] 1 H NMR(500MHz,DMSO-d6)δ 11.00(s,1H),10.95(s,1H),8.96(s,1H),8.70(q,J=5.5Hz,1H),8.36-8.20(m,2H),8.07-7.99(m,3H),7.97-7.88(m,4H),7.78(dt, J=10.3,7.8Hz,1H),7.39-7.29(m,4H),7.27-7.20(m,1H),6.69(d,J=9.2Hz,1H),5.76(dt,J=12.2,6.0Hz,1H),5.28(ddd,J=12.6,9. 1,3.9Hz,1H),4.71(d,J=11.9Hz,1H),4.50(d,J=11.9Hz,1H),4.25(q,J=5.8Hz,2H),3.51-3.44(m,4H),3.31-3.22(m,1H),2.81(d,J =4.8Hz,3H),2.77(d,J=4.8Hz,3H),2.57-2.47(m,2H),2.05(q,J=6.3Hz,2H),1.98(td,J=9.4,4.1Hz,1H),1.61(s,3H),1.53(s,3H).

[0403] LCMS: 854 [M+H] + .

[0404] Example 28: N 1-(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl)oxy)hexyl)terephthalamide (28)

[0405] [ka]

[0406] Compound 28 (6.9 mg) was obtained according to the synthetic route of compound 1 in Example 1 using 5-((6-aminohexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione.

[0407] 1 H NMR(500MHz,DMSO-d6)δ 10.99(s,1H),10.94(s,1H),8.96(s,1H),8.55(s,1H),8.37-8.20(m,2H),8.06-7.98(m,3H),7.97-7.83(m,4H),7.77(q,J=8.5Hz, 1H),7.41-7.29(m,4H),7.28-7.19(m,1H),6.69(d,J=9.1Hz,1H),5.75(dt,J=11.7,5.9Hz,1H),5.28(ddd,J=12.6,9.1,3.9Hz,1H), 4.71(d,J=11.9Hz,1H),4.50(d,J=11.9Hz,1H),4.16(q,J=6.4Hz,2H),3.52-3.45(m,1H),3.26(d,J=22.8Hz,5H),2.82(d,J=4.7Hz) ,3H),2.77(d,J=4.8Hz,3H),2.59-2.47(m,2H),2.03-1.90(m,1H),1.84-1.71(m,2H),1.61(s,3H),1.56-1.42(m,5H),1.37(s,2H).

[0408] LCMS: 896 [M+H]+ .

[0409] Example 29: N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4 Synthesis of -(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl)oxy)ethoxy)ethoxy)ethyl)terephthalamide (29)

[0410] [ka]

[0411] Compound 29 (4.5 mg) was obtained according to the synthetic route of compound 1 in Example 1 using 5-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione.

[0412] 1H NMR(500MHz,DMSO-d6)δ 10.98(s,1H),10.94(s,1H),8.98(s,1H),8.61(t,J=5.6Hz,1H),8.38-8.16(m,2H),8.08-7.86(m,7H),7.75(dt,J=10.5,7. 8Hz,1H),7.45-7.28(m,4H),7.23(t,J=7.2Hz,1H),6.68(d,J=9.2Hz,1H),5.75(dt,J=11.7,5.9Hz,1H),5.28(ddd,J=12.2,9 .2,3.9Hz,1H),4.69(d,J=11.8Hz,1H),4.54-4.40(m,1H),4.27(q,J=5.5Hz,2H),3.79(q,J=5.2Hz,2H),3.64-3.43(m,9H), 3.41-3.35(m,2H),2.79(dd,J=22.8,4.7Hz,6H),2.61-2.46(m,2H),1.97(dd,J=11.9,6.2Hz,1H),1.61(s,3H),1.53(s,3H).

[0413] LCMS:928[M+H] + .

[0414] Example 30:N 1 Synthesis of -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)terephthalamide (30)

[0415] [ka]

[0416] Compound 30 (7.1 mg) was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0417] 1 H NMR(500MHz,DMSO-d6)δ 12.50(s,1H),11.07(s,1H),8.99(s,1H),8.42(d,J=7.8Hz,1H),8.20-8.14(m,1H),8.10(d,J=8.2Hz,2H),8.00(d,J=8.1Hz,2H),7.48-7.43 (m,2H),7.42-7.38(m,4H),7.33(t,J=7.6Hz,2H),7.23(t,J=7.3Hz,1H),6.38(s,1H),5.15(d,J=3.5Hz,1H),5.06-4.90(m,2H),4.79(d,J=9. 1Hz,1H),4.58(t,J=12.1Hz,2H),4.47(t,J=8.1Hz,1H),4.33(s,1H),3.69(d,J=3.1Hz,2H),2.86(d,J=19.3Hz,6H),2.47(s,3H),2.42-2.27( m,1H),2.05(ddd,J=12.6,7.6,2.7Hz,1H),1.82(ddd,J=12.9,8.6,4.5Hz,1H),1.66(s,3H),1.59(s,3H),1.39(d,J=7.0Hz,3H),1.06(s,9H).

[0418] LCMS: 917 [M+H] + .

[0419] Example 31:N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4Synthesis of -(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)terephthalamide (31)

[0420] [ka]

[0421] Compound 31 was obtained according to the synthetic route of compound 1 in Example 1 using (2S,4R)-1-((S)-2-(2-aminoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0422] LCMS: 974 [M+H] + .

[0423] Example 32: Synthesis of 8-(4-((5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)carbamoyl)benzoyl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-8-azaspiro[4.5]decane-2-carboxamide (32)

[0424] [ka]

[0425] Compound 32 (11.3 mg) was obtained by using N-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-8-azaspiro[4.5]decane-2-carboxamide according to the synthetic route of compound 1 in Example 1.

[0426] 1 H NMR(500MHz,DMSO-d6)δ 12.51(s,1H),11.02(s,1H),8.99(s,1H),8.39(d,J=7.8Hz,1H),8.07(d,J=7.9Hz,2H),7.74(s,1H),7.51(d,J=7.8Hz,2H),7 .47-7.31(m,9H),7.25(t,J=7.3Hz,1H),6.48(s,1H),5.12(s,2H),4.92(p,J=7.1Hz,1H),4.65(s,1H),4.54(dd,J=24.8,10.4 Hz,2H),4.43(t,J=8.1Hz,1H),4.29(s,1H),3.60(s,4H),3.29(s,2H),2.99(d,J=14.4Hz,6H),2.46(s,3H),2.02(t,J=10.4Hz) ,1H),1.84-1.75(m,4H),1.67(s,3H),1.59(s,3H),1.55-1.44(m,8H),1.38(d,J=7.0Hz,3H),0.94(s,9H),0.89-0.79(m,1H).

[0427] LCMS: 1082 [M+H] + .

[0428] Example 33:N 1 -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N 4Synthesis of -(3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)phenyl)terephthalamide (33)

[0429] [ka] (S)-3-(4-((5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)carbamoyl)benzamido)benzoic acid

[0430] To a solution of (S)-4-((5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)carbamoyl)benzoic acid (15 mg, 0.025 mmol) and DIEA (12.9 mg, 0.1 mmol) in anhydrous DCM (1 mL) was added propanephosphonic anhydride (T3P®) (50 wt % in EA, 32 μL, 0.05 mmol). The reaction was stirred for 10 min before tert-butyl 3-aminobenzoate (4.8 mg, 0.025 mmol) was added. The mixture was stirred for 30 min and then concentrated in vacuo. The crude product was dissolved in DCM (1 mL) before TFA (0.5 mL) was added. After 1 h, the solvent was removed in vacuo to give the crude product without further purification.

[0431] LCMS: 666[M+H]+.

[0432] [ka]

[0433] To a solution of (S)-3-(4-((5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)carbamoyl)benzamido)benzoic acid (15 mg, 0.025 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide HCl salt (13 mg, 0.025 mmol) and DIEA (13 mg, 0.098 mmol) in DMF (1 mL) was added HATU (18 mg, 0.049 mmol). The mixture was stirred at room temperature for 10 min and then purified by reverse HPLC to give compound 33 as a TFA salt (1.8 mg, 6%).

[0434] LCMS: 1036 [M+H] + .

[0435] Example 34: N 1 Synthesis of -(5-(((S)-2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N4-(3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)terephthalamide (34)

[0436] [ka] (S)-3-(4-((5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)carbamoyl)benzamido)bicyclo[1.1.1]pentane-1-carboxylic acid

[0437] To a solution of (S)-4-((5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)carbamoyl)benzoic acid (20 mg, 0.040 mmol) and DIEA (21 mg, 0.16 mmol) in anhydrous DCM (1 mL) was added propanephosphonic anhydride (T3P®) (50 wt % in EA, 52 μL, 0.08 mmol). The reaction was stirred for 10 min before adding methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate (8.4 mg, 0.060 mmol). The mixture was stirred for 30 min and then concentrated in vacuo. The crude product was dissolved in THF (1 mL) before adding LiOH (0.5 mL, 1 M aqueous solution). After 1 h, the reaction was acidified with aqueous HCl. The mixture was extracted with EA. The organic layer was collected and concentrated in vacuo. The resulting residue was purified by reverse HPLC to give the title compound (29.8 mg, 0.04 mmol).

[0438] LCMS: 600 [M+H] + .

[0439] [ka]

[0440] To a solution of (S)-3-(4-((5-((2-(dimethylamino)-1-phenylethyl)carbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)carbamoyl)benzamido)bicyclo[1.1.1]pentane-1-carboxylic acid (29 mg, 0.04 mmol) and DIEA (31 mg, 0.24 mmol) in anhydrous DCM (1 mL) was added propanephosphonic anhydride (T3P®) (50 wt % in EA, 62 μL, 0.096 mmol). The reaction was stirred for 10 min before (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide HCl salt (25 mg, 0.048 mmol) was added. The mixture was stirred for 30 min and then concentrated in vacuo. The residue was purified by reverse HPLC to give compound 34 as a TFA salt (11 mg, 0.0096 mmol, 24%).

[0441] 1H NMR (500 MHz, DMSO-d6)δ 12.57(s,1H),11.09(s,1H),9.30(s,1H),9.23(s,1H),8.99(s,1H),8.43(dd ,J=7.8,1.7Hz,1H),8.10(dd,J=8.5,6.1Hz,2H),7.99(t,J=10.9Hz,2H),7.45 (dq,J=8.3,1.7Hz,4H),7.42-7.37(m,4H),7.33-7.26(m,2H),6.77(d,J=8.9H z,1H),5.37(d,J=11.2Hz,1H),5.17(d,J=3.5Hz,1H),4.97-4.89(m,1H),4.80 (dd,J=11.2,7.9Hz,1H),4.62-4.54(m,2H),4.46(q,J=8.5Hz,1H),4.30(s,1H ),3.69(s,1H),3.65-3.52(m,2H),2.86(d,J=19.5Hz,6H),2.46(s,3H),2.33( s,4H),2.10-2.01(m,1H),1.86-1.76(m,1H),1.69(s,3H),1.60(s,3H),1.39( dd,J=7.0,1.7Hz,3H),1.32-1.23(m,1H),1.19(t,J=7.3Hz,1H),0.96(s,9H).

[0442] LCMS: 1026 [M+H] + .

[0443] Example 35: Decomposition of the present dual-specific compound 1~26 and CDK7

[0444] Jurkat cells were treated with DMSO or 1 μM of compounds 1–26 for 6 h. Cells were then lysed in radioimmunoprecipitation (RIPA) buffer (Sigma® Life Science) containing a protease / phosphatase inhibitor cocktail (Roche). Protein concentrations were measured by bicinchoninic acid assay (BCA) analysis (Pierce®). Equal amounts of protein were separated by 4–12% Tris-Base gels (Invitrogen®) and then transferred to immunoblotted polyvinylidene difluoride (PVDF) membranes (BioRad) and immunoblotted with primary antibodies against CDK7 (Cell Signaling) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (Cell Signaling Technology®), followed by IRDye® 800-labeled goat anti-rabbit immunoglobulin G (IgG) and IRDye® 680-labeled goat anti-mouse IgG (LI-COR®) secondary antibodies. Membranes were detected with an Odyssey® CLx system.

[0445] The results, shown in FIG. 1A, show that bispecific compounds 1, 3, 6, 7, 8, 9 and 10 induced degradation of CDK7 after 6 hours.

[0446] The results shown in Figure 2A show that bispecific compounds 3, 11, 12, 13, 15, 16 and 20 induced degradation of CDK7 after 6 hours.

[0447] The results shown in FIG. 1C show that bispecific compounds 21, 22, 23, 25 and 26 induced the degradation of CDK7 after 6 hours.

[0448] Example 36: Degradation of CDK7 is ligand- and proteasome-dependent

[0449] Jurkat cells were pretreated with 10 μM YKL-5-124 (parent compound and known CDK7 inhibitor), 10 μM DGY-05-180 (VHL ligand), 0.2 μM bortezomib (e.g., a proteasome inhibitor available from Millipore Sigma, catalog number 179324-69-7, Burlington, Mass.) and 1 μM MLN4924 (e.g., a NEDDylation inhibitor available from MedChemExpress (MCE®), catalog number HY-70062, Monmouth Junction, NJ) for 2 hours, then treated with 1 μM compound 3 or 20 for 4 hours. Cells were lysed and immunoblotted with antibodies against CDK7 and GAPDH as described in Example 27. The structures of YKL-5-124, DGY-05-180, bortezomib and MLN4924 are shown below.

[0450] [ka]

[0451] The results are shown in Figures 2A and 2B, which show that YKL-5-124, DGY-05-180, bortezomib and MLN4924 rescued CDK7 degradation induced by bispecific compounds 3 and 20. These results indicate that CDK7 degradation is ligand- and proteasome-dependent.

[0452] All patent 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 are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0453] Although the invention has been described herein 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 can be made to the illustrative embodiments and other arrangements can be devised without departing from the spirit and scope of the invention as defined by the appended claims. The present invention includes the following embodiments. [1] 1. A bispecific compound comprising a moiety that binds to cyclin-dependent kinase 7 (CDK7) and a degron, covalently linked to each other by a linker, the bispecific compound having formula (I): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof (In the formula, R 1 -NR a R b , -CHR a R b -OR a R a and R b each is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom, or R a and R b together with the atoms to which they are attached form an optionally substituted carbocyclic ring, an optionally substituted heterocyclic ring, an optionally substituted aryl ring, or an optionally substituted heteroaryl ring; R 3 and R 4 Each of the groups is independently selected from hydrogen, halogen, optionally substituted C 1 ~C 6 represents alkyl, or optionally substituted aryl, or R 3 and R 4 together with the atoms to which they are attached, optionally substituted C 3 ~C 6 Forming a carbocyclyl ring; R 5 are independently hydrogen, optionally substituted C 1 ~C 6 represents an alkyl, or nitrogen protecting group; L 1 -NR L1 -, -NR L1 C(=O)-, -C(=O)NR L1 -, -O-, or -S-, R L1 is hydrogen, optionally substituted C 1 ~C 6 alkyl, or a nitrogen protecting group; A represents optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L 2 is a bond or nothing, -C(=O)-, -C(=O)NR L2 -, -NR L2 C(=O)-, -O-, or -S-; R L2 is hydrogen, optionally substituted C 1 ~C 6 alkyl, or a nitrogen protecting group; B represents a bond or absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 2 is non-existent, or:

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[10] R 3 and R 4 and wherein both are methyl.

[11] R 5 is hydrogen or methyl.

[12] The bispecific compound of [1], wherein A is a 6-membered carbocyclyl or a 6-membered heterocyclyl.

[13] The bispecific compound of [1], wherein B is a bond, a 6-membered carbocyclyl, or a 6-membered heterocyclyl.

[14] L 1 is NH or -NHC(O)-.

[15] L 2 is a bond, NH, or -NHC(O)-.

[16] L 1 is NH or -NHC(O)-, and R 3 and R 4 is methyl and R 5 is H, and the compound represented by formula (I-1a) and (I-1b):

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[17] A is a 6-membered carbocyclyl and R 3 and R 4 is methyl and R 5 is H, and the formulas (I-2a) to (I-2f):

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[18] L 1 is NH or -NHC(O)-, and R 1 but

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[19] A is a 6-membered carbocyclyl and R 1 but

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[20] L 1 is NH or -NHC(O)-, and R 1 but

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[21] R 1 but

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[22] Formulas (I-7) to (I-57):

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[23] L 1 is -NHC(O)-, A is 6-membered carbocyclyl, B, L 2 and R 2 is a bond or absent, and R 1 but

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[24] R 5 The bispecific compound of

[23] , wherein

[25] The linker has the structures (L11) to (L23):

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[24] , wherein the bispecific compound is represented by any one of the following:

[26] Formulas (I-59) to (I-71):

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[27] The bispecific compound according to any one of [1] to

[26] , wherein the degron binds to an E3 ubiquitin ligase that is cereblon.

[28] The degron has the structures (D1-a) to (D1-h):

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[27] , wherein the bispecific compound is represented by any one of the following:

[29] Formula (I-72a)~(I-72h):

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[30] The bispecific compound according to any one of [1] to

[26] , wherein the degron binds to an E3 ubiquitin ligase that is a von Hippel-Lindau tumor suppressor.

[31] The degron has the structures (D2-a) to (D2-e):

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[30] , wherein the bispecific compound is represented by any one of the following:

[32] Z

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[31] ,

[33] Formulas (I-73a) to (I-73e):

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[34] Structures (1) to (26):

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[35] A pharmaceutical composition comprising a therapeutically effective amount of the bispecific compound according to any one of [1] to

[34] , or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[36] A method for treating a disease or disorder mediated by abnormal CDK7 activity, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a bispecific compound described in any one of [1] to

[34] , or a pharma- ceutical acceptable salt or stereoisomer thereof.

[37] The method according to

[36] , wherein the disease is cancer.

[38] The method according to

[37] , wherein the cancer is a solid tumor.

[39] The method according to

[38] , wherein the solid tumor is breast cancer, brain cancer, lung cancer, colorectal cancer, neuroblastoma, or osteosarcoma.

[40] The method according to

[37] , wherein the cancer is a blood cancer.

[41] The method according to

[40] , wherein the blood cancer is leukemia, lymphoma or multiple myeloma.

[42] The method according to

[36] , wherein the disease is an autoimmune disease.

Claims

1. A bispecific compound comprising a moiety that binds to cyclin-dependent kinase 7 (CDK7) and a degron (D), covalently linked to each other by a linker (L), said compound having formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt or stereoisomer thereof (In the formula, R １ is -NR ａ R ｂ , -CHR ａ R ｂ Or -OR ａ represents R ａ and R ｂ each is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom, or R ａ and R ｂ together with the atoms to which they are attached form an optionally substituted carbocyclic ring, an optionally substituted heterocyclic ring, an optionally substituted aryl ring, or an optionally substituted heteroaryl ring; R ３ and R ４ Each of the is independently hydrogen, halogen, optionally substituted C １ ~C ６ represents an alkyl or an optionally substituted aryl, or R ３ and R ４ together with the atoms to which they are attached, optionally substituted C ３ ~C ６ forming a carbocyclyl ring; R ５ are independently hydrogen, optionally substituted C １ ~C ６ represents an alkyl, or nitrogen protecting group; L １ is -NR Ｌ１ --, --NR Ｌ１ C(=O)-, -C(=O)NR Ｌ１ represents -, -O-, or -S-; R Ｌ１ is hydrogen, optionally substituted C １ ~C ６ alkyl, or a nitrogen protecting group; A represents optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L ２ is absent, -C(=O)-, -C(=O)NR Ｌ２ --, --NR Ｌ２ C(═O)—, —O—, or —S—; R Ｌ２ is hydrogen, optionally substituted C １ ~C ６ alkyl, or a nitrogen protecting group; B represents absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R ２ is non-existent Any of the linkers may be —O—, —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, or —C(O)N(R′)C(O)N(R′)—. , -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR') -, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O) an alkylene chain or polyethylene glycol chain which may be interrupted by and / or terminated (at either or both ends) by at least one of: -2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O) 2 -, -S(O) 2 O-, -N(R')S(O) 2 -, -S(O) 2 N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O) 2 N(R')-, -N(R')S(O)N(R')-, C 3 -C 12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene, or any combination thereof, where R' is H or C 1 -C 6 alkyl; The degrons have the structures (D1-a) to (D1-h) and (D2-a) to (D2-e): 【Chemistry 52】 【Chemistry 56】 【Chemistry 57】 where Y' is a bond, N, O or C; 【Chemistry 58】 wherein Z is a C 5 -C 6 carbocyclic group or a C 5 -C 6 heterocyclic group; and 【Chemistry 59】 and The nitrogen protecting groups include formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide and o-(benzoyloxymethyl) ) benzamide, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phen oc), 2,2,2-trichloroethyl carbamate (Trot), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (M oz), p-nitrile benzyl carbamate, p-bromo benzyl carbamate, p-chloro benzyl carbamate, 2,4-dichloro benzyl carbamate, 4-methylsulfinyl benzyl carbamate (Msz), 9-anthryl methyl carbamate, diphenyl methyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonyl ethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-0,3-dithianyl methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethythio ethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrophenylcarbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylphenyl)methyl ...N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-l-cyclopropyl methyl carbamate carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate, Carbamate, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mt s), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), 13-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide or phenacylsulfonamide; The oxygen protecting group is methyl, t-butyloxycarbonyl (BOC), methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxymethyl), methyl ... 2-(trimethylsilyl)ethoxymethyltetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7 a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-l-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenylmethyl) , 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzoisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl silyl (DRIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate Acetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Trotto), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formyl Benzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate , (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate or tosylate (Ts); A bispecific compound having a structure represented by:

2. R １ but 【Chemistry 5】 and R １’ and R １’’ Each of is independently hydrogen, optionally substituted C １ ~C ６ alkyl, or nitrogen protecting group; R １ａ is hydrogen, C １ ~C ６ alkyl, or optionally substituted aryl; R ２ａ is hydrogen, -OR １Ｎ Or -NR １Ｎ R ２Ｎ and R １Ｎ and R ２Ｎ Each of the groups is independently hydrogen, C １ ~C ６ 2. The bispecific compound of claim 1, which is an alkyl, or a nitrogen protecting group if attached to a nitrogen, or an oxygen protecting group if attached to an oxygen atom.

3. R １’’ is hydrogen, Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl or Ts, or R １ but 【Chemistry 6】 and optionally, R １ but 【Chemistry 7】 or R １ａ The bispecific compound of claim 2 , wherein is hydrogen, methyl, ethyl, propyl or phenyl.

4. R １ but 【Chemistry 8】 【Chemistry 9】 or R ３ and R ４ is independently methyl, isopropyl or phenyl, or R ３ and R ４ together with the atoms to which they are attached, optionally substituted C ３ ~C ６ forming a carbocyclyl ring, or R ３ and R ４ are both methyl, or R ５ is hydrogen or methyl, or A is a 6-membered carbocyclyl or a 6-membered heterocyclyl; or B is a 6-membered carbocyclyl or a 6-membered heterocyclyl; or L １ is NH or -NHC(O)-, or L ２ The bispecific compound of claim 1 , wherein is NH or -NHC(O)-.

5. L １ is NH or -NHC(O)-, and R ３ and R ４ is methyl, R ５ is H, and the bispecific compound has the formula (I-1a) and (I-1b): 【Chemistry 11】 or a pharma- ceutically acceptable salt or stereoisomer thereof; or A is a 6-membered carbocyclyl; R ３ and R ４ is methyl, R ５ is H, and the bispecific compound has the formula (I-2a) to (I-2f): 【Chemistry 12】 【Chemistry 13】 or a pharma- ceutically acceptable salt or stereoisomer thereof; or L １ is NH or -NHC(O)-, and R １ but 【Chemistry 14】 and R ３ and R ４ is methyl, R ５ is H, and the bispecific compound has the formula (I-3a) to (I-3d): 【Chemistry 15】 【Chemistry 16】 2. The bispecific compound of claim 1, having a structure represented by any one of:

6. A is a 6-membered carbocyclyl; R １ but 【Chemistry 17】 and R ３ and R ４ is methyl, R ５ is H, and the bispecific compound has the formula (I-4a) to (I-4l): 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 or a pharma- ceutically acceptable salt or stereoisomer thereof; or L １ is NH or -NHC(O)-, and R １ but 【Chemistry 23】 and R ３ and R ４ is methyl, R ５ is H, and the bispecific compound has the formula (I-5a) to (I-5d): 【Chemistry 24】 【Chemistry 25】 or a pharma- ceutically acceptable salt or stereoisomer thereof; or R １ but 【Chemistry 26】 and R ３ and R ４ is methyl, R ５ is H, and the bispecific compound has the formula (I-6a) to (I-6l): 【Chemistry 27】 【Chemistry 28】 【Chemical 29】 【Chemistry 30】 【Chemistry 31】 2. The bispecific compound of claim 1, having a structure represented by any one of:

7. The bispecific compound has the formula (I-7) to (I-57): 【Chemistry 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 or a pharma- ceutically acceptable salt or stereoisomer thereof; or L １ is -NHC(O)-, A is 6-membered carbocyclyl, B, L ２ and R ２ each of which is absent, and R １ but 【Chemistry 45】 and R ３ and R ４ are methyl, and said bispecific compound has the formula (I-58): 【Chemistry 46】 or a pharma- ceutically acceptable salt or stereoisomer thereof, optionally comprising R ５ is H, The bispecific compound of claim 1.

8. The linker has the structures (L11) to (L28): 【Chemistry 47】 【Chemistry 48】 8. The bispecific compound of claim 1, wherein the bispecific compound is represented by any one of the following formulas:

9. Formulae (I-59) to (I-71): 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 2. The bispecific compound of claim 1, represented by any one of:

10. The degron of claim 1, wherein the degron has the structure (D1-a) to (D1-h): 【Chemistry 52】 and optionally the bispecific compound is represented by any one of: Formulas (I-72a) to (I-72h): 【Chemistry 53】 【Chemical 54】 【Chemistry 55】 10. The bispecific compound of any one of claims 1 to 9, represented by any one of:

11. The degron of claim 1, wherein the degron has the structure (D2-a) to (D2-e): 【Chemistry 56】 【Chemistry 57】 where Y' is a bond, N, O or C; 【Chemistry 58】 where Z is C ５ ~C ６ Carbocyclic group or C ５ ~C ６ A heterocyclic group, optionally wherein Z is 【Chemistry 60】 and 【Chemistry 59】 and optionally the bispecific compound is represented by any one of formulas (I-73a) to (I-73e): 【Chemistry 61】 【Chemistry 62】 where Y' is a bond, N, O or C; and Z is a C5-C6 carbocyclic or heterocyclic group.

10. The bispecific compound of any one of claims 1 to 9, represented by any one of:

12. 【Chemical 63】 【Chemistry 64】 【Chemistry 65】 【Chemistry 66】 【Chemistry 67】 【Chemistry 68】 【Chemistry 69】 【Chemistry 70】 【Chemistry 71】 2. The bispecific compound of claim 1, which is:

13. 13. A pharmaceutical composition comprising a therapeutically effective amount of a bispecific compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

14. 14. A pharmaceutical composition according to claim 13 for use in a method for treating a disease or disorder mediated by aberrant CDK7 activity, said method comprising administering to a patient in need thereof a therapeutically effective amount of said pharmaceutical composition, The pharmaceutical composition, wherein the disease is cancer or an autoimmune disease.

15. 15. The pharmaceutical composition of claim 14, wherein the cancer is a solid tumor or a hematological cancer, optionally wherein the solid tumor is breast cancer, brain cancer, lung cancer, colorectal cancer, neuroblastoma, or osteosarcoma, and optionally wherein the hematological cancer is leukemia, lymphoma, or multiple myeloma.

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