WO2022221786A2 - Compounds and pharmaceutical compositions that modulate brd4 - Google Patents

Compounds and pharmaceutical compositions that modulate brd4 Download PDF

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Publication number
WO2022221786A2
WO2022221786A2 PCT/US2022/034515 US2022034515W WO2022221786A2 WO 2022221786 A2 WO2022221786 A2 WO 2022221786A2 US 2022034515 W US2022034515 W US 2022034515W WO 2022221786 A2 WO2022221786 A2 WO 2022221786A2
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alkyl
compound
independently
hydrogen
halo
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PCT/US2022/034515
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French (fr)
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WO2022221786A3 (en
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Simon Bailey
Geoffray LERICHE
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Plexium, Inc.
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Priority to PCT/US2022/034515 priority Critical patent/WO2022221786A2/en
Publication of WO2022221786A2 publication Critical patent/WO2022221786A2/en
Publication of WO2022221786A3 publication Critical patent/WO2022221786A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • chromatin DNA and proteins.
  • Histones are the chief protein components of chromatin, acting as spools around which DNA winds.
  • the functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication.
  • the chromatin structure is controlled by a series of post-translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the “histone tails” which extend beyond the core nucleosome structure.
  • Histone tails tend to be free for protein-protein interaction and are also the portion of the histone most prone to post-translational modification. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation. These epigenetic marks are written and erased by specific enzymes that place the tags on specific residues within the histone tail, thereby forming an epigenetic code, which is then interpreted by the cell to allow gene specific regulation of chromatin structure and thereby transcription. [0003] Of all classes of proteins, histones are amongst the most susceptible to post- translational modification. Histone modifications are dynamic, as they can be added or removed in response to specific stimuli, and these modifications direct both structural changes to chromatin and alterations in gene transcription.
  • HATs histone acetyltransferases
  • HDACs histone deacetylases
  • acetylate or de-acetylate specific histone lysine residues Struhl K., Genes Dev., 1989, 12, 5, 599-606.
  • HATs histone acetyltransferases
  • HDACs histone deacetylases
  • acetylate or de-acetylate specific histone lysine residues Struhl K., Genes Dev., 1989, 12, 5, 599-606
  • Bromodomains which are approximately 110 amino acids long, are found in a large number of chromatin-associated proteins and have been identified in approximately 70 human proteins, often adjacent to other protein motifs (Jeanmougin F., et al, Trends Biochem. Sci., 1997, 22, 5,151-153; and Tamkun J. W., et al., Cell, 1992, 7, 3, 561-572).
  • Bromodomain-containing proteins have been implicated in disease processes including cancer, inflammation and viral replication. See, e.g., Prinjha et al, Trends Pharm. Sci., 33(3):146-153 (2012) and Muller et al, Expert Rev., 13(29):1-20 (2011).
  • Cell-type specificity and proper tissue functionality requires the tight control of distinct transcriptional programs that are intimately influenced by their environment. Alterations to this transcriptional homeostasis are directly associated with numerous disease states, most notably cancer, immuno-inflammation, neurological disorders, and metabolic diseases.
  • Bromodomains reside within key chromatin modifying complexes that serve to control distinctive disease-associated transcriptional pathways. This is highlighted by the observation that mutations in bromodomain-containing proteins are linked to cancer, as well as immune and neurologic dysfunction. Moreover, recent findings have demonstrated that small molecule inhibition of the bromodomains of BRD4 may have clinical utility in diverse human diseases, ranging from auto-immunity to cardiac hypertrophy. This is possible because the underlying mechanism resides in transcriptional regulation. Hence, the inhibition of bromodomains across the family creates varied opportunities as novel therapeutic agents in human dysfunction. [0006] Accordingly, the ability to modulate or degrade BRD4 would be a significant advancement in treating cancer and other bromodomain related diseases.
  • an orally deliverable compound that provides for a superior C max and AUC in vivo is desired over compounds that are delivered by parenteral injection.
  • Summary [0008] Disclosed are compounds as well as pharmaceutical compositions comprising said compounds and methods of using said compounds that modulate the activity of or which degrade BRD4. Such compounds are useful in treating diseases mediated, at least in part, by dysfunction of BRD4 including cancers and proliferative disorders.
  • compounds as well as compositions comprising said compounds and methods of using said compounds that degrade BRD4, which in some embodiments these compounds are capable of providing for superior Cmax and AUC values when delivered orally.
  • Such compounds are useful in treating diseases mediated, at least in part, by dysfunction of BRD4, including BRD4 mediated cancers.
  • BRD4 mediated cancers include BRD4 mediated cancers.
  • a compound of formula I-a that binds to or degrades BRD4: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R, R′, R 2 , R 4 , R 5 , T, T 1 , T 2 , T 3 , T 4 , T 5 , and ring A are as described in the detailed description.
  • a compound of formula I-b that binds to and modulates the activity of BRD4: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R 20 , R 20′ , R 22 , R 24 , R 25 , T 20 , T 21 , T 22 , T 23 , T 24 , T 25 , Q 20 , Q 25 , Q 26 , X 20 , Y 20 , ring A 20 , and ring B 20 are as described in the detailed description.
  • a compound of formula I-c that binds to or degrades BRD4: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R 40 , R 40′ , R 42 , R 44 , R 45 , T 40 , T 41 , T 42 , T 43 , T 44 , T 45 , Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , Q 46 , and ring A 40 are as described in the detailed description.
  • a compound of formula IB-d that binds to or degrades BRD4 IB-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R 60 , R 60′ , T 60 , T 61 , T 62 , Q 61 , Q 64 , R 69 and q 60 are as described in the detailed description.
  • IC-d that binds to or degrades BRD4: IC-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R 60 , R 60′ , R 62 , R 64 , R 65 , T 60 , T 61 , T 62 , T 63 , T 64 , T 65 , Q 60 , Q 65 , Q 66 , Y 60 , ring A 60 , and ring B 60 are as described in the detailed description.
  • a compound represented by formula I-e or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof.
  • a compound of formula Ie or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I-a, Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V-a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B- c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof
  • a method for degrading BRD4 which method comprises contacting BRD4 with an effective amount of a compound of formula I-a, Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V-a, I-b, Ia- b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of
  • a method to degrade BRD4 in a subject in need thereof comprises administering to said subject an effective amount of a compound of formula I-a, Ia-a, II-a, II- A-a, II-B-a, III-a, IV-a, V-a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC- d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers,
  • a method for treating a proliferative disorder mediated, at least in part, by BRD4 in a subject in need thereof comprising administering to said subject an effective amount of a compound of formula I-a, Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V-a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI- AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate
  • the proliferative disorder is liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, or Epstein- Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, or diffuse large B-cell lymphoma.
  • the proliferative disorder is prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, or Ewing’s sarcoma.
  • MMS rhabdomyosarcoma
  • the proliferative disorder is non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, or gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma thymoma
  • carcinoid or gastrointestinal stromal tumor
  • the proliferative disorder is non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, or gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • acute myelogenous leukemia or gastrointestinal stromal tumor (GIST).
  • GIST gastrointestinal stromal tumor
  • the proliferative disorder is non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), or microsatellite stable color
  • R is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, -CH 2 C(O)OR 3 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R 3 )2 and -CH2C(O)NR 1 R 1' where R 1 and R 1' are independently hydrogen, C 1 -C 4 alkyl, or R 1 and R 1' together with the nitrogen atom form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR 3 , and S; R 2 and R 2' are
  • V, W, W', R, R 4 , R 5 , R 8 , R 8' , R 10 and R 11 are as defined above
  • R 12 and R 12' together with the carbon atoms to which they are joined form a C 5 -C 8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR 3 and S, or a 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N, NR 3 and S, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one
  • IIIA-a that bind to or degrade BRD4: IIIA-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where W, W', R, R 2 , R 2' , R 4 , R 5 , R 8 , R 8' , R 10 and R 11 are as defined above.
  • IVA-a that bind to or degrade BRD4: IVA-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where W, W', R, R 2 , R 2' , R 4 , R 5 , R 8 , R 8' , R 10 and R 11 are as defined above.
  • VA-a that bind to or degrade BRD4: VA-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where W, W', R, R 2 , R 2' , R 4 , R 5 , R 8 , R 8' , R 9 , R 10 and R 11 are as defined above.
  • W and W' are hydrogen.
  • R is C 1 -C 3 alkylene-N(R 3 ) 2 or -CH 2 C(O)NR 1 R 1' where R 1 and R 1' are independently hydrogen or C 1 -C 4 alkyl.
  • R is -CH 2 C(O)NH 2 or –(CH 2 ) 2 NHCH 3 .
  • R 2 and R 2' are both hydrogen.
  • R 2 and R 2' join together to form a heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR 3 and S or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR 3 and S.
  • the heterocycloalkyl or the heteroaryl has one O or S.
  • R 4 is hydrogen or methyl. In some embodiments R 4 is methyl.
  • R 5 is hydrogen or methyl. In some embodiments R 5 is methyl.
  • R 4 and R 5 are both methyl.
  • R 8 and R 8' are both hydrogen.
  • R 9 is hydrogen.
  • R 10 is hydrogen, methyl or ethyl.
  • R 11 is methyl or difluoromethyl.
  • R 20 is selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR 23 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R 23 )2 and -CH2C(O)NR 21 R 21' where R 21 and R 21' are independently hydrogen, C1-C4 alkyl, or R 21 and R 21' together with the nitrogen atom form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR 23 , and S; R 22 and R
  • the disclosed compounds are as described above, further provided that: i) the total number of N in ring A 20 including Q 25 and Q 26 is from one to three; and further provided that when either Q 25 or Q 26 is N, then neither X 20 or Y 20 can be O, S, or NR 23 ; and ii) when ring A 20 is a 6- or 7-membered heterocycloalkyl and Q 25 is N, then Q 25 is attached to CHR 29 of the 6- or 7-membered heterocycloalkyl.
  • the disclosed compounds are represented by formula IIIA-b: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, where W 20 , W 20' , X 20 , Y 20 , R 20 , R 22 , R 22' , R 24 , R 25 , R 28 , R 28' are as defined above, t 20 is zero, one, or two, and R 32 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, N(R 23 ) 2 , cyano, halo or hydroxyl, provided that the following compounds are excluded:
  • ⁇ in one embodiment, disclosed are compounds of formula IVA-b: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, where W 20 , W 20' , Q 25 , Q 26 , X 20 , Y 20 , R 20 , R 22 , R 22' , R 24 , R 25 , R 28 , R 28' , R 32 and t 20 are as defined above; each of Q 21 , Q 22 , Q 23 and Q 24 are independently N or CR 32 ; further provided that the number of Q 21 -Q 26 that are N is from one to three; and further provided that when either Q 25 or Q 26 is N, then neither X 20 or Y 20 can be O, S or NR 23 ; still further provided that the following compounds are excluded: .
  • the disclosed compounds are represented by formula VA-b: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, where W 20 , W 20' , Q 25 , Q 26 , X 20 , Y 20 , R 20 , R 22 , R 22' , R 24 , R 25 , R 28 , R 28' and R 32 and t 20 are as defined above, v 20 is zero, one, or two, Q 27 and Q 28 are independently CHR 32 or NR 33 where R 33 is selected from hydrogen and C 1 -C 3 alkyl provided that if Q 25 is N, then Q 28 is CHR 32 ; provided that the following compound is excluded: .
  • R 20 is methyl.
  • R 20 is -CH2C(O)OR 23 or a pharmaceutically acceptable salt thereof.
  • R 20 is -CH2C(O)OH.
  • R 20 is -CH2C(O)NR 21 R 21' where R 21 and R 21' are independently hydrogen or C1-C3 alkyl or R 21 and R 21' together with the nitrogen atom form a 4- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, NR 23 , and S where R 23 is hydrogen or C1-C4 alkyl.
  • R 20 is -CH2C(O)NH2.
  • R 22 and R 22' are both hydrogen.
  • R 22 and R 22' join together to form a heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR 23 , and S or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR 23 , and S.
  • the heterocycloalkyl or the heteroaryl has one O or S.
  • R 24 is hydrogen or methyl.
  • R 24 is methyl.
  • R 25 is hydrogen or methyl.
  • R 25 is methyl.
  • R 24 and R 25 are both methyl.
  • R 28 and R 28' are both hydrogen.
  • R 29 is hydrogen, methyl or ethyl.
  • Y 20 is O, S, N, or NH. In some embodiments, Y 20 is O.
  • X 20 is N, NH or CR 27 . In some embodiments, X 20 is CH or C-CH 3 .
  • Y 20 is O and X 20 is CH.
  • Y 20 is S and X 20 is N. In some embodiments, Y 20 is N and X 20 is CH. In some embodiments, Y 20 is N and X 20 is O. In some embodiments, one of X 20 and Y 20 is N and the other is NH. [0064] In some embodiments for the compounds described above, both Q 25 and Q 26 are C. In some embodiments, one of Q 25 and Q 26 is N and the other is C. [0065] In one embodiment for the compounds described above, three of Q 21 , Q 22 , Q 23 , Q 24 , Q 25 , Q 26 are N, provided that only one of Q 25 and Q 26 is N.
  • two of Q 21 , Q 22 , Q 23 , Q 24 , Q 25 , Q 26 are N, provided that only one of Q 25 and Q 26 is N. In some embodiments, one of Q 21 , Q 22 , Q 23 , Q 24 , Q 25 , Q 26 is N. In some embodiments, none of Q 21 , Q 22 , Q 23 , Q 24 , Q 25 , Q 26 is N. [0066] In one embodiment for the compounds described above, W 20 and W 20' are hydrogen.
  • R 40 is selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR 43 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R 43 )2 and -CH2C(O)NR 41 R 41' where R 41 and R 41' are independently hydrogen, C1-C4 alkyl, or R 41 and R 41' together with the nitrogen atom form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR 43 , and S; R 42 and R 42' are independently hydrogen or fluoro, or when R 42 and R 42' are at the 2,2' or
  • a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof Ring A 40 , Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , Q 46 , W 40 , W 40' , R 40 , R 44 , R 45 , R 48 , and R 48' are as defined above, R 51 and R 51' together with the carbon atoms to which they are joined form a C5-C8 cycloalkyl, 5- to 7- membered heterocycloalkyl, phenyl, or a 5- to 6-membered heteroaryl wherein said heterocycloalkyl has up to 2 heteroatoms selected from O, S, N, and NR 43 and said 5-membered heteroaryl has one heteroatom selected from NR 43 , O
  • a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , Q 46 , W 40 , W 40' , R 40 , R 44 , R 45 , R 48 , R 48' , R 50 , R 51 and R 51' are as defined above and u 40 is zero, one or two.
  • a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer thereof where Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , Q 46 , W 40 , W 40' , R 40 , R 44 , R 45 , R 47 , R 48 , R 48' , R 50 , R 51 , and R 51' are as defined above and u 40 is zero, one or two.
  • Y 40 is N, NR 43 , O, S or CR 50 provided that when Q 45 is N, then Y 40 is N;
  • X 40 is NR 43 , N, O, S or CR 50 provided that when Q 46 is N, then X 40 is N; and further provided that when X 40 or Y 40 is NR 43 , O, or S, then Y 40 or X 40 is then N or CR 50 .
  • Y 40 when Q 45 is N, then Y 40 is N or CR 50 . In one embodiment, when Q 46 is N, then Y 40 is N or CR 50 . In one embodiment, when X 40 is NR 43 , O, or S, then Y 40 is CR 50 and when Y 40 is NR 43 , O, or S, then X 40 is CR 50 . [0074] In one embodiment for the compounds described above, W 40 and W 40' are hydrogen. [0075] In one embodiment for the compounds described above, R 40 is C 1 -C 3 alkylene-N(R 43 ) 2 or -CH 2 C(O)NR 41 R 41' where R 41 and R 41' are independently hydrogen or C 1 -C 4 alkyl.
  • R 40 is -CH 2 C(O)NH 2 or –(CH 2 ) 2 NHCH 3 .
  • R 40 is -CH 2 C(O)O(R 43 ).
  • R 40 is -CH 2 C(O)OH.
  • R 42 and R 42' are both hydrogen.
  • R 42 and R 42' join together to form a heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR 43 and S or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR 43 and S.
  • the heterocycloalkyl or the heteroaryl has one O or S.
  • R 44 is hydrogen or methyl. In some embodiments R 44 is methyl.
  • R 45 is hydrogen or methyl. In some embodiments R 45 is methyl.
  • R 44 and R 45 are both methyl.
  • R 48 and R 48' are both hydrogen.
  • R 49 is hydrogen.
  • R 50 is hydrogen, methyl or ethyl.
  • R 51 and R 51' are both hydrogen.
  • four of Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , Q 46 are N.
  • three of Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , Q 46 are N.
  • two of Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , Q 46 are N.
  • one of Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , Q 46 is N.
  • none of Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , Q 46 is N.
  • R 60 is selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR 63 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R 63 )2 and -CH2C(O)NR 61 R 61' where R 61 and R 61' are independently hydrogen, C1-C4 alkyl, or R 61 and R 61' together with the nitrogen atom form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR 63 , and S; R 62 and R 62' are independently
  • the compounds are as described above, wherein Q 61 and Q 62 are independently N or CR 69 provided only one of Q 61 and Q 62 is N.
  • disclosed are compounds represented by formula II-AA-d or II-BA-d that bind to or degrade BRD4: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where p 60 , Q 61 , Q 62 , R 60 , R 64 , R 65 , R 68 , R 68' , and R 69 are as defined above, R 72 and R 72' together with the carbon atoms to which they are joined form a C5-C8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR 63 and S, or a 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N
  • R 60 is C1-3 alkylene-N(R 63 )2 or -CH2C(O)NR 61 R 61' where R 61 and R 61' are independently hydrogen or C1-4 alkyl.
  • R 60 is -CH2C(O)NH2 or –(CH2)2NHCH3.
  • R 62 and R 62’ are both hydrogen.
  • R 62 and R 62' join together to form a heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR 63 and S or a 5- to 6- membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR 63 and S.
  • the heterocycloalkyl or the heteroaryl has one O or S.
  • R 64 is hydrogen or methyl.
  • R 64 is methyl.
  • R 65 is hydrogen or methyl.
  • R 65 is methyl.
  • R 64 and R 65 are both methyl.
  • R 68 and R 68' are both hydrogen.
  • R 69 is hydrogen, methyl or ethyl.
  • one of Q 61 and Q 62 is nitrogen and the other is CR 69 .
  • Q 61 and Q 62 both are carbon or both are nitrogen.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-a.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula II-AA-a or II- BA-a.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IIIA-a.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IVA-a.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula V-a.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-b.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula II-AA-b or II-BA-b.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IIIA-b.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IVA-b.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula VA-b.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-c.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula II-AA-c or II-BA-c.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IIIA-c.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IVA-c.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula V-AA-c or V-BA-c.
  • a method to treat cancer in a subject comprises selecting a subject whose cancer is mediated at least in part by BRD4 and administering to said subject an effective amount of a compound of formula IA-c, II-AA-c, II-BA-c, IIIA-c, IVA-c, V- AA-c or V-BA-c or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-c, II-AA-c, II-BA-c, IIIA-c, IVA-c, V-AA-c or V-BA-c.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-d.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula II-AA-d or II- BB-d.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IIIA-d.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IVA-d.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula VA-d.
  • this disclosure provides for a method for degrading BRD4 which method comprises contacting BRD4 with an effective amount of a compound of Formula IA-a, I-AA-a, I-BA-a, II-AA-a, II-BA-a, IIIA-a, IVA-a, VA-a, IA-b, II-AA-b, II-BA-b, IIIA-b, IVA-b, VA-b, IA-c, II-AA-c, II- BA-c, IIIA-c, IVA-c or V-AA-c, V-BA-c, IA-d, II-AA-d, II-BA-d, IIIA-d, IVA-d, VA-d, I-e, or I-f under conditions wherein BRD4 is degraded.
  • a method to degrade BRD4 in a subject comprises administering to said subject an effective amount of a compound of formula IA-a, I-AA-a, I- BA-a, II-AA-a, II-BA-a, IIIA-a, IVA-a, VA-a, IA-b, II-AA-b, II-BA-b, IIIA-b, IVA-b, VA-b, IA-c, II- AA-c, II-BA-c, IIIA-c, IVA-c or V-AA-c, V-BA-c, IA-d, II-AA-d, II-BA-d, IIIA-d, IVA-d, VA-d, I-e, or I-f, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-a, I-AA-a, I-BA-a, II-AA-a, II-BA-a, IIIA-a,
  • a method to treat cancer in a subject comprises selecting a subject whose cancer is mediated at least in part by BRD4 and administering to said subject an effective amount of a compound of formula IA-a, I-AA-a, I-BA-a, II-AA-a, II-BA-a, IIIA-a, IVA-a, VA-a, IA-b, II-AA-b, II-BA-b, IIIA-b, IVA-b, VA-b, IA-c, II-AA-c, II-BA-c, IIIA-c, IVA-c, V-AA-c, V-BA-c, IA-d, II-AA-d, II-BA-d, IIIA-d, IVA-d, VA-d, I-e, or I-f, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-a, I-AA-a, I-BA-a
  • a dash (“ -”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group.
  • C u-v indicates that the following group has from u to v carbon atoms.
  • C 1-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • the term “about” when used with regard to a dose amount means that the dose may vary by +/- 10%.
  • “Comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure.
  • “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from C 1 -C 6 carbon atoms. In some embodiments, the number of carbon atoms in an alkyl group can be quantified specifically by reciting, e.g., C1-C4 alkyl.
  • This term includes, by way of example only, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2-), neopentyl ((CH3)3CCH2-) and n-hexyl (CH3CH2CH2CH2CH2CH2-).
  • linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH
  • alkylene refers to a divalent alkyl group as described above.
  • Alkoxy refers to -O-alkyl groups where alkyl is defined above. Such alkoxy groups have C1- C6 carbon atoms. In so embodiments, the number of carbon atoms in an alkoxy group can be quantified specifically by reciting, e.g., C1-C4 alkoxy.
  • This term includes, by way of example only, linear and branched alkoxy groups such as methoxy (CH3O-), ethoxy (CH3CH2O-), n-propoxy (CH3CH2CH2O-), isopropoxy ((CH3)2CHO-), n-butoxy (CH3CH2CH2CH2O-), isobutoxy ((CH3)2CHCH2O-), sec-butoxy ((CH3)(CH3CH2)CHO-), t-butoxy ((CH3)3CO-), n-pentyl (CH3CH2CH2CH2O-), neopentyl ((CH3)3CCH2O-) and n-hexyl (CH3CH2CH2CH2CH2O-).
  • alkoxy groups such as methoxy (CH3O-), ethoxy (CH3CH2O-), n-propoxy (CH3CH2CH2O-), isopropoxy ((CH3)2CHO-), n-butoxy (CH3CH
  • alkylene-oxy refers to a divalent alkoxy having the formula: -O-alkylene- where the term alkylene is as described above.
  • Amino refers to the group -NH2.
  • Alkylamino refers to alkyl-NH- and “dialkylamino” refers to (alkyl) 2 N- where alkyl is as defined above.
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
  • aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl.
  • Aryl does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of point of attachment.
  • Halo refers to fluoro, chloro, bromo, and iodo and in one embodiment, fluoro and chloro.
  • Haloalkyl refers to an alkyl group as defined herein wherein at least 1 to up to 6 hydrogen atoms are replaced with halo. In some embodiments, the halo is fluoro.
  • Hydroxy or “hydroxyl” refers to -OH.
  • Hydroxyalkyl refers to an alkyl group as defined herein wherein at least 1 to up to 3 hydrogen atoms are replaced with hydroxy.
  • Heterocycloalkyl or “heterocyclic” refers to a saturated or unsaturated but not heteroaromatic ring system having from 3 to 12 ring members and from 1 to 5 heteroatoms selected from N, O or S. The heteroatoms can also be oxidized, such as, but not limited to, S(O) and S(O)2.
  • Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4 or 3 to 5.
  • the heterocycloalkyl group can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, C6-8, C3-9, C3-10, C3-11, and C3-12.
  • heterocyclyl includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused- heterocyclyl groups, and spiro-heterocyclyl groups.
  • any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).
  • heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • the heterocycloalkyl group can include groups such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, azocanyl, quinuclidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl (1,2-, 1,3- and 1,4-isomers), oxiranyl, oxetanyl, tetrahydrofuranyl, oxanyl (tetrahydropyranyl), oxepanyl, thiiranyl, thietanyl, thiolanyl (tetrahydrothiophenyl), thianyl (tetrahydrothiopyranyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl,
  • heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indolinyl, diazabicycloheptanyl, diazabicyclooctanyl, diazaspirooctanyl or diazaspirononanyl. [0147]
  • the heterocycloalkyl groups can be linked via any position on the ring.
  • aziridinyl can be 1- or 2-aziridinyl
  • azetidinyl can be 1- or 2- azetidinyl
  • pyrrolidinyl can be 1-, 2- or 3-pyrrolidinyl
  • piperidinyl can be 1-, 2-, 3- or 4-piperidinyl
  • pyrazolidinyl can be 1-, 2-, 3-, or 4-pyrazolidinyl
  • imidazolidinyl can be 1-, 2-, 3- or 4-imidazolidinyl
  • piperazinyl can be 1-, 2-, 3- or 4-piperazinyl
  • tetrahydrofuranyl can be 1- or 2-tetrahydrofuranyl
  • oxazolidinyl can be 2-, 3-, 4- or 5-oxazolidinyl
  • isoxazolidinyl can be 2-, 3-, 4- or 5-isoxazolidinyl
  • thiazolidinyl can be 2-, 3-, 4- or 5-thiazolidinyl
  • heterocycloalkyl includes 3 to 8 ring members and 1 to 3 heteroatoms
  • representative members include, but are not limited to, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, oxanyl, tetrahydrothiophenyl, thianyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxzoalidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl and dithianyl.
  • Heterocycloalkyl can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and morpholinyl.
  • 3- to 7-membered heterocycloalkyl refers to a heterocycloalkyl either saturated or partially unsaturated but not heteroaromatic and having at least 1 heteroatom and optionally up to three heteroatoms selected from oxygen, sulfur, N, and NR 3 where R 3 is as defined herein.
  • 3- to 7-membered heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholino, thiomorpholino, N-methylpiperidinyl, and the like.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • the term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring).
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-14 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl).
  • Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.
  • cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.
  • “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • ring carbon atoms i.e., C 1-20 heteroaryl
  • 3 to 12 ring carbon atoms i.e., C 3-12 heteroaryl
  • 3 to 8 carbon ring atoms i.e., C 3-8 heteroaryl
  • 1 to 5 ring heteroatoms 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxide
  • fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings).
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • the heteroaryl groups can be linked via any position on the ring available for such linkage.
  • pyrrole includes 1-, 2- and 3-pyrrolyl
  • pyridinyl includes 2-, 3- and 4-pyridinyl
  • imidazolyl includes 1-, 2-, 4- and 5-imidazolyl
  • pyrazolyl includes 1-, 3-, 4- and 5-pyrazolyl
  • triazolyl includes 1-, 4- and 5-triazolyl
  • tetrazolyl includes 1- and 5-tetrazolyl
  • pyrimidinyl includes 2-, 4-, 5- and 6- pyrimidinyl
  • pyridazinyl includes 3- and 4-pyridazinyl
  • 1,2,3-triazinyl includes 4- and 5-triazinyl
  • 1,2,4-triazinyl includes 3-, 5- and 6-triazinyl
  • 1,3,5-triazinyl includes 2-triazinyl
  • heteroaryl groups include those having from 5 to 9 ring members and from 1 to 3 ring atoms including N, O or S, such as pyrrolyl, pyridinyl, imidazolyl, pyrazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, benzothiophenyl, and benzofuranyl.
  • heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrolyl, pyridinyl, imidazolyl, pyrazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5- isomers), thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl.
  • heteroatoms such as pyrrolyl, pyridinyl, imidazolyl, pyrazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5- isomers), thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazoly
  • bicyclic and tricyclic heteroaryl groups include those having from 9 to 20 ring members and from 1 to 3 heteroatoms, such as indolyl, isoindolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, benzothiophenyl, benzofuranyl and bipyridinyl.
  • heteroaryl groups include those having from 5- to 6- ring members and from 1 to 2 ring atoms including N, O or S, such as pyrrolyl, pyridinyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl.
  • the optional substituents are selected from C 1 -C 10 or C 1 -C 6 alkyl, substituted C 1 -C 10 or C 1 -C 6 alkyl, C 1 -C 10 or C 1 -C 6 alkoxy, substituted C 1 -C 10 or C 1 -C 6 alkoxy, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, C 2 -C 10 heterocyclyl, C 1 -C 10 heteroaryl, substituted C 6 -C 10 aryl, substituted C 3 -C 8 cycloalkyl, substituted C2-C10 heterocyclyl, substituted C 1 -C 10 heteroaryl, -NR 80 R 81 , wherein each R 80 and R 81 is independently hydrogen or C 1 -C 10 or C 1 -C 6 alkyl, halo, cyano, -CO2H or a C 1 -C 6 alky
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent “alkoxycarbonylalkyl” refers to the group (alkoxy)-C(O)-(alkyl)-.
  • polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three.
  • each of the above definitions is constrained by a limitation that, for example, substituted aryl groups are limited to –substituted aryl-(substituted aryl)-substituted aryl.
  • substituted aryl groups are limited to –substituted aryl-(substituted aryl)-substituted aryl.
  • the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable or superimposable.
  • the compounds described herein may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.
  • Compounds described herein may exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.
  • “Prodrug” means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds described herein wherein, for example, a hydroxy, amino or a carboxyl group, in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or a carboxyl group, respectively.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein, and the like.
  • esters e.g., acetate, formate, and benzoate derivatives
  • amides e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N,N-dimethylaminocarbonyl
  • Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B.
  • Subject refers to a mammal.
  • the mammal can be a human or non-human animal mammalian organism.
  • a “patient” refers to a human subject.
  • Treating” or “treatment” of a disease or disorder in a subject refers to 1) preventing the disease or disorder from occurring in a subject that is predisposed or does not yet display symptoms of the disease or disorder; 2) inhibiting the disease or disorder or arresting its development; or 3) ameliorating or causing regression of the disease or disorder.
  • Effective amount refers to the amount of a compound described herein that is sufficient to treat the disease or disorder afflicting a subject or to prevent such a disease or disorder from arising in said subject or patient.
  • administering refers to any art recognized form of administration to a subject including oral (including oral gavage), pulmonary, transdermal, sublingual, injection (e.g., intravenous, intramuscular), transmucosal (e.g., vaginal, nasal, etc.), and the like. The route of administration is selected by the attending clinician and is based on factors such as the age, weight and general health of the patient as well as the severity of the condition. In one embodiment, the compounds and pharmaceutical compositions described herein are administered orally.
  • a BRD4 “modulator” may bind to BRD4, but not degrade BRD4.
  • a BRD4 “degrader” binds to BRD4 and also degrades BRD4.
  • the term “pharmaceutically acceptable salts” of compounds disclosed herein are within the scope of the present disclosure include acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, allergenic, or irritating, and is bioavailable).
  • pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalene sulfonic acid, and p-toluenesolfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid).
  • inorganic acids such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid
  • organic acids e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxa
  • the compound described herein When the compound described herein have an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, trimethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine, and ornithine).
  • alkali and earth alkali metals e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+
  • ammonia or organic amines e.g., dicyclohexylamine, trimethylamine, trimethylamine, pyridine, picoline, ethanolamine,
  • Such salts can be prepared in situ during isolation and purification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed.
  • Compounds [0169] are compounds represented by formula I-a that bind to or degrade BRD4: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A is monocyclic 5-or 6-membered heteroaryl having 1-4 heteroatoms selected from O, N, NR 3 and S, wherein ring A is unsubstituted or substituted with one to four R 14 ; R and R' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR 3 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R 1 )2, or
  • ring A is a monocyclic, nitrogen containing heteroaryl attached to the carbonyl moiety via a ring carbon atom wherein ring A has 0, 1, or 2 additional nitrogen ring atoms and 0 or 1 additional oxygen or sulfur ring atom, wherein ring A is unsubstituted or substituted with one to four R 14 , provided that ring A is not pyrimidine or pyrazine;
  • R is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, -CH 2 C(O)OR 3 , C 1 -C 4 haloalkyl having 1 to 3 halo groups, C 1 -C 3 alkylene-N(R 1 ) 2 , or -CH 2 C(O)N(R 1 ) 2 ,
  • ring A is a monocyclic, nitrogen containing heteroaryl attached to the carbonyl moiety via a ring carbon atom wherein ring A has 0, 1, or 2 additional nitrogen ring atoms and 0 or 1 additional oxygen or sulfur ring atom, wherein ring A is unsubstituted or substituted with one to four R 14 , provided that ring A is not pyrimidine or pyrazine;
  • R is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, -CH 2 C(O)OR 3 , C 1 -C 4 haloalkyl having 1 to 3 halo groups, C 1 -C 3 alkylene-N(R 1 ) 2 , or -CH 2 C(O)N(R 1
  • each of T, T 1 , and T 2 is CH.
  • one of T, T 1 , and T 2 is N.
  • both R and R' are H.
  • R and R' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl.
  • each R 2 is independently hydrogen or fluoro.
  • ring A is , , , V is N or CR 14 ;
  • R 10 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, ethoxy, and C3-C6 cycloalkyl;
  • R 11 is selected from the group consisting of C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, cyano, methoxy, ethoxy, and C3-C6 cycloalkyl;
  • R 12 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, and ethoxy; and h is 0, 1, 2, or 3.
  • the compounds are represented by formula II-A-a or II-B-a: II-A-a II-B-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof.
  • the compounds are represented by formula III-a: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof.
  • the compounds are represented by formula IV-a: IV-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof.
  • the compounds are represented by formula V-a: V-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, mixture of stereoisomers, or tautomer of each thereof.
  • each R 2 is hydrogen.
  • both R 4 and R 5 are methyl.
  • both R 8 are hydrogen.
  • one or both R 8 are fluoro.
  • each R 14 independently is hydrogen, halo, or C 1 -C 4 alkyl.
  • each R 14 is hydrogen.
  • R is hydrogen, CH 3 , CF 3 , -CH 2 C(O)NH 2 , -CH 2 C(O)NHCH 3 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 C(O)OH, -CH 2 C(O)OMe, -CH 2 C(O)NHEt, -CH 2 C(O)N(Et) 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 OH, -CH 2 CH 2 (morpholin-1-yl), -CH 2 CH 2 (pyrrolidin-1-yl), -CH 2 C(O)(morpholin-1-yl), or -CH 2 C(O)(pyrrolidin-1-yl).
  • R is CH 3 , -CH 2 C(O)NHCH 3 , or -CH 2 C(O)N(CH 3 ) 2 .
  • R is -CH 2 C(O)OH, or -CH 2 C(O)OC 1-5 alkyl.
  • ring A 20 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted with one to four R 29 ;
  • R 20 and R 20' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR 23 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R 21 )2, or -CH2C(O)N(R 21 )2, wherein each R 21 is independently hydrogen, C1-C4 alkyl, or both R 21 together with
  • ring A 20 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is substituted with zero to four R 29 ;
  • R 20 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, -CH 2 C(O)OR 23 , C 1 -C 4 haloalkyl having 1 to 3 halo groups, C 1 -C 3 alkylene-N(R 21 ) 2 , or -CH 2 C(O)N(R 21 ) 2 , wherein each
  • ring A 20 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R 29 ;
  • R 20 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR 23 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R 21 )2, or -CH2C(O)N(R 21 )2, wherein
  • each of T 20 , T 21 , and T 22 is CH.
  • one of T 20 , T 21 , and T 22 is N.
  • both R 20 and R 20' are H.
  • R 20 and R 20' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl.
  • R 20 and R 20' together with the carbon atom to which they are attached form a spirocyclopropyl or spirooxetanyl group.
  • each R 22 is independently hydrogen or fluoro.
  • the compounds are represented by formula or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R 20 , R 20′ , R 22 , R 24 , R 25 , R 28 , X 20 , Y 20 , Q 25 , Q 26 , ring A 20 , and ring B 20 are as defined herein.
  • the compounds are represented by formula II-A-b or II-B-b: II-A-b II-B-b or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R 20 , R 20′ , R 22 , R 24 , R 25 , R 28 , X 20 , Y 20 , Q 25 , Q 26 , ring A 20 , and ring B 20 are as defined herein.
  • the compounds are represented by formula III-b: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: t 20 is zero, one, or two; and R 32 is halo, cyano, hydroxy, N(R 27 )2, C1-C4 alkyl, or C1-C4 alkoxy; and R 20 , R 20′ , R 22 , R 24 , R 25 , R 28 , X 20 , Y 20 , and ring B 20 are as defined herein. [0197] In some embodiments of formula I-b or formula Ia-b, the compounds are represented by formula IV-b:
  • each of Q 21 , Q 22 , Q 23 and Q 24 is independently N or CR 32 ; and R 32 is halo, cyano, hydroxy, N(R 27 ) 2 , C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and wherein R 20 , R 20′ , R 22 , R 24 , R 25 , R 28 , X 20 , Y 20 , Q 21 , Q 22 , Q 23 , Q 24 , Q 25 , Q 26 , and ring B 20 are as defined herein.
  • the compounds are represented by formula V-b: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: v 20 is zero, one, or two; Q 27 and Q 28 are independently CHR 32 or NR 33 ; R 32 is halo, cyano, hydroxy, N(R 27 )2, C1-C4 alkyl, or C1-C4 alkoxy; and R 33 is hydrogen or C1-C4 alkyl; and R 20 , R 20′ , R 22 , R 24 , R 25 , R 28 , X 20 , Y 20 , Q 25 , Q 26 , and ring B 20 are as defined herein.
  • each R 22 is hydrogen.
  • both R 24 and R 25 are methyl.
  • both R 28 are hydrogen.
  • one or both R 28 are fluoro.
  • each R 29 independently is hydrogen, halo, or C 1 -C 4 alkyl. In some embodiments of formula I-b or formula Ia-b, each R 29 is hydrogen.
  • R 20 is hydrogen, -CH 3 , -CF 3 , -CH 2 C(O)NH 2 , -CH 2 C(O)NHCH 3 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 C(O)OH, -CH 2 C(O)OMe, -CH 2 C(O)NHEt, -CH 2 C(O)N(Et) 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 OH, -CH 2 CH 2 (morpholin-1-yl), -CH 2 CH 2 (pyrrolidin-1-yl), -CH 2 C(O)(morpholin-1-yl), or -CH 2 C(O)(pyrrolidin-1-yl).
  • R 20 is -CH 3 , -CH 2 C(O)NHCH 3 , or -CH 2 C(O)N(CH 3 ) 2 . In some embodiments of formula I-b or formula Ia-b, R 20 is -CH 2 C(O)OH or -CH 2 C(O)OC 1-5 alkyl.
  • ring A 40 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6- membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R 49 ;
  • R 40 and R 40' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR 43 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R 41 )2, or -CH2C(O)N
  • ring A 40 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6- membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R 49 ;
  • R 40 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR 43 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R 41 )2, or -CH2C(O)N(R 41 )2, wherein each R 41 is independently hydrogen, C
  • ring A 40 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6- membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R 49 ;
  • R 40 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, -CH 2 C(O)OR 43 , C 1 -C 4 haloalkyl having 1 to 3 halo groups, C 1 -C 3 alkylene-N(R 41 ) 2 , or -CH 2 C(O)N(R 41 ) 2 , wherein each R 41 is independently hydrogen, C 1 -C 4 alkyl, or
  • each of T 40 , T 41 , and T 42 is CH.
  • one of T 40 , T 41 , and T 42 is N.
  • both R 40 and R 40' are H.
  • R 40 and R 40' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl.
  • each R 42 is independently hydrogen or fluoro.
  • the compounds are represented by formula II-c: II-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof.
  • the compounds are represented by formula II-A-c or II-B-c: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof; and wherein R 2 , R 4 , R 5 , R 8 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , and ring A are as defined herein.
  • the compounds are represented by formula III-c: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: t 40 is zero, one or two; and R 52 is halo, cyano, hydroxy, N(R 47 )2, C1-C4 alkyl, or C1-C4 alkoxy; and wherein R 42 , R 44 , R 45 , R 48 , Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , Q 46 , and ring A 40 are as defined herein. [0214] In some embodiments of formula I-c or formula Ia-c, the compounds are represented by formula IV-c:
  • IV-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: v 40 is zero, one, or two; and R 52 is halo, cyano, hydroxy, N(R 47 )2, C1-C4 alkyl, or C1-C4 alkoxy; and wherein R 42 , R 44 , R 45 , R 48 , Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , and Q 46 are as defined herein.
  • the compounds are represented by formula V-c: V-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: v 40 is zero, one, or two; and R 52 is halo, cyano, hydroxy, N(R 47 )2, C1-C4 alkyl, or C1-C4 alkoxy; and wherein R 42 , R 44 , R 45 , R 48 , Q 41 , Q 42 , Q 43 , Q 44 , Q 45 , and Q 46 are as defined herein.
  • each R 42 is hydrogen.
  • both R 44 and R 45 are methyl.
  • both R 48 are hydrogen.
  • one or both R 48 are fluoro.
  • each R 49 independently is hydrogen, halo, or C1-C4 alkyl. In some embodiments of formula I-c or formula Ia-c, each R 49 is hydrogen.
  • R 40 is hydrogen, -CH3, -CF3, -CH 2 C(O)NH 2 , -CH 2 C(O)NHCH 3 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 C(O)OH, -CH 2 C(O)OMe, -CH 2 C(O)NHEt, -CH 2 C(O)N(Et) 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 OH, -CH 2 CH 2 (morpholin-1-yl), -CH 2 CH 2 (pyrrolidin-1-yl), -CH 2 C(O)(morpholin-1-yl), or -CH 2 C(O)(pyrrolidin-1-yl).
  • R 40 is -CH 3 , -CH 2 C(O)NHCH 3 , or -CH 2 C(O)N(CH 3 ) 2 . In some embodiments of formula I-c or formula Ia-c, R 40 is -CH 2 C(O)OH or -CH 2 C(O)OC 1-5 alkyl.
  • a compound of formula I-d degrades BRD4 by 30% or more.
  • compounds of formula IB-d which degrade BRD4: IB-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein q 60 is zero, one or two; R 60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR 63 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene- N(R 61 )2 or -CH2C(O)N(R 61 )2, wherein each R 61 is independently hydrogen, C1-C4 alkyl, or both R 61 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl
  • R 60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, or -CH2C(O)N(R 61 )2.
  • R 60′ is hydrogen.
  • R 60 and R 60′ together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl.
  • each R 68 is independently selected from hydrogen and fluoro.
  • said compound is represented by formula IIB-d: IIB-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R 60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, or -CH2C(O)N(R 61 )2, wherein each R 61 is independently hydrogen, C1-C4 alkyl, or both R 61 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR 63 , and S; R 60' is hydrogen; T 62 is N or CH; Q 61 is N or CR 69 ; and R 69 is selected from fluoro, chloro, methyl, and methoxy; and q 60 , R 64 , and R 65 are as defined herein.
  • said compound is represented by formula IIIB-d: IIIB-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R 60 and R 60' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; T 62 is N or CH; Q 61 is N or CR 69 ; and R 69 is selected from fluoro, chloro, methyl, and methoxy; and q 60 , R 64 , R 65 , and Q 61 are as defined herein.
  • R 60 is -CH 3 , -CH 2 C(O)NHCH 3 , or -CH 2 C(O)N(CH 3 ) 2 .
  • ID-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where p 60 is zero, one or two;
  • R 60 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, -CH 2 C(O)OR 63 , C 1 -C 4 haloalkyl having 1 to 3 halo groups, C 1 -C 3 alkylene-N(R 61 ) 2 or -CH 2 C(O)N(R 61 ) 2 , wherein each R 61 is independently hydrogen, C 1 -C 4 alkyl, or both R 61 together with the nitrogen atom to which they
  • a compound of formula ID-d is not a compound of formula IB-d.
  • a compound of formula ID-d is selected from , , , a [0237]
  • ring A 60 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R 69 ;
  • R 60 and R 60' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR 63 , C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R 61 )2, or -CH2C(O)N(R 61 )2, wherein each R 61 is independently hydrogen, C1-C4
  • IC-d IC-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A 60 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R 69 ; R 60 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, -CH 2 C(O)OR 63 , C 1 -C 4 haloalkyl having 1 to 3 halo groups, C 1 -C 3 alkylene-N(R 61 ) 2 , or -CH 2 C(O)N(
  • ring A 60 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R 69 ;
  • R 60 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, -CH 2 C(O)OR 63 , C 1 -C 4 haloalkyl having 1 to 3 halo groups, C 1 -C 3 alkylene-N(R 61 ) 2 , or -CH 2 C(O)N(R 61
  • each of T 60 , T 61 , and T 62 is CH.
  • one of T 60 , T 61 , and T 62 is N.
  • both R 60 and R 60' are H.
  • R 60 and R 60' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl.
  • each R 62 is independently hydrogen or fluoro.
  • the compounds are represented by formula VIC-d: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R 60 , R 60′ , R 62 , R 64 , R 65 , R 68 , Q 60 , Q 65 , Q 66 , Y 60 , and ring A 60 are as defined herein.
  • the compounds are represented by formula VI-AC-d or VI-BC-d: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: q 60 is zero, one or two; Q 61 and Q 64 are independently N or CR 69 ; and two R 62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, or a 5- to 6-membered heteroaryl,wherein each of said cycloalkyl, phenyl, heterocyclyl and heteroaryl are unsubstituted or substituted with one to two R 66 ; and wherein R 60 , R 60′ , R 62 , R 64 , R 65 , R 68 , and R 69 are as defined herein.
  • formula IC-d or formula ICa-d
  • the compounds are represented by formula VIIIC-d: or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein r 60 is zero, one, two, or three; and wherein R 60 , R 60′ , R 62 , R 64 , R 65 , R 68 , and R 69 are as defined herein.
  • the compounds are represented by formula IXC-d:
  • each R 62 is hydrogen.
  • both R 64 and R 65 are methyl.
  • both R 68 are hydrogen.
  • each R 69 independently is hydrogen, halo, or C 1 -C 4 alkyl. In some embodiments of formula IC-d or formula ICa-d, each R 69 is hydrogen.
  • R 60 is hydrogen, -CH3, -CF3, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2C(O)N(CH3)2, -CH2C(O)OH, -CH2C(O)OMe, -CH2C(O)NHEt, -CH2C(O)N(Et)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2(morpholin-1-yl), -CH2CH2(pyrrolidin-1-yl), -CH2C(O)(morpholin-1-yl), or -CH2C(O)(pyrrolidin-1-yl).
  • R 60 is -CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2. In some embodiments of formula IC-d or formula ICa-d, R 60 is -CH2C(O)OH or -CH2C(O)OC1-5alkyl.
  • Scheme 1 illustrates a general method for preparing compounds of formula IA-a, I-b, I-c, or IB-d.
  • substituents W, W', R, R 2 , R 2' , R 4 , R 5 , R 8 , and R 8' are as defined throughout the specification, and are used generally, such that: [0260] LG is a leaving group (including, but not limited to, Br, Cl, I, triflate, and the like) and PG is a protecting group (including, but not limited to, Boc and the like).
  • Ring X is a monocyclic 5- or 6- membered heteroaryl, as in compounds of Formula I-a, a 5,6-bicyclic, as in compounds of Formula I-b, a 6,5- or 6,6-bicyclic, as in compounds of Formula I-c, or a pyrazole-containing bicyclic, as in compounds of Formula IB-d.
  • Scheme 1 [0261] In some embodiments, Scheme 2 illustrates a general method for preparing compounds of formula I-a, I-b, I-c, or IB-d.
  • R is R, R 20 , R 40 , or R 60 ;
  • R’ is R’, R 20’ , R 40’ , or R 60’ ;
  • R 2 is R 2 , R 22 , R 42 , or R 62 ;
  • R 4 is R 4 , R 24 , R 44 , or R 64 ;
  • R 5 is R 5 , R 25 , R 45 , or R 65 ;
  • T is T, T 20 , T 40 , or T 60 ;
  • T 1 is T 1 , T 21 , T 41 , or T 61 ;
  • T 2 is T 2 , T 22 , T 42 , or T 62 ;
  • T 3 is T 3 , T 23 , T 43 , or T 63 ;
  • T 4 is T 4 , T 24 , T 44 , or
  • LG is a leaving group (including, but not limited to, Br, Cl, I, triflate, and the like) and PG is a protecting group (including, but not limited to, Boc and the like).
  • Ring X is a monocyclic 5- or 6- membered heteroaryl, as in compounds of Formula I-a, a 5,6-bicyclic, as in compounds of Formula I-b, a 6,5- or 6,6-bicyclic, as in compounds of Formula I-c, or a pyrazole-containing bicyclic, as in compounds of Formula IB-d.
  • Scheme 3 illustrates one method for preparing compounds of formula I-a, I-b, I-c, or IB-d.
  • Scheme 3 illustrates one method for preparing compounds of formula I-a, I-b, I-c, or IB-d.
  • the specific compound structures are depicted solely for illustrative purposes.
  • the first step is a conventional Suzuki coupling reaction wherein at least a stoichiometric equivalent of 3-(N-Boc-amino) phenyl boronic acid, compound 2, is combined with JQ1, compound 1, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g, palladium diacetate) and a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like.
  • a palladium catalyst e.g, palladium diacetate
  • suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like.
  • Both compound 1 and compound 2 are commercially available from Sigma Aldrich, St. Louis, Missouri, USA.
  • the reaction is typically maintained at from 10° to 65°C until it is substantially complete.
  • Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 3.
  • HPLC high performance liquid chromatography
  • the t-butoxycarbonyl (t-BOC) protecting group is removed by conventional conditions to provide for compound 4.
  • the t-BOC group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like.
  • benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 4.
  • a stoichiometric amount of a suitably substituted carboxylic acid ring X compound, compound 5 is combined with compound 4 under conventional amidation reaction conditions well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC) as an activation agent for the carboxyl group.
  • DCC N,N-dicyclohexylcarbodiimide
  • Other activation agents are well known in the art.
  • the reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N- dimethylformamide, and the like.
  • the reaction is typically conducted at from about 0o to about 30o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • reaction solution Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 6.
  • Other variants of compound 1 are commercially available or can be prepared by conventional reaction conditions well known in the art.
  • the following acid and esters, 7-9 corresponding to the amido starting materials are commercially available from Sigma Aldrich, St. Louis, Missouri, USA.
  • Each of the above compounds, 7, 8 and 9, can be derivatized as desired.
  • the carboxyl group can be amidated as described above.
  • amidation can utilize an amino acid or a diamino acid wherein N-hydroxy succinimide is included in the reaction medium to inhibit racemization.
  • amidation includes an alkylamine, a nitrogen-containing heterocycloalkyl, or cycloalkylamino (e.g.,-NH-cycloalkyl) which provides for compounds 40, 41 and 42: where R 16 is hydrogen or C 1 -C 6 alkyl, g is one, two, three or four; and f is zero, one, two or three.
  • the carboxyl group is reduced under conventional conditions to provide for the corresponding -CH 2 CH 2 OH group.
  • the hydroxyl group can be acylated by conventional methods to provide for -CH 2 CH 2 OC(O)R 16 substituents where R 16 is as defined above.
  • the carboxyl group is reduced under conventional conditions to provide for the corresponding aldehyde, e.g., -CH 2 C(O)H.
  • the aldehyde can then be subjected to conventional reductive amination to provide for the following substituent -CH 2 CH 2 NHR 3 where R 3 is as defined above.
  • the carboxyl group can be subjected to decarboxylation to provide for the methyl substituent.
  • Schemes 4-8 illustrates some embodiments for preparing compounds of formula I-a, I-b, I-c, or IB-d having a tricyclic structure where R 2 and R 2' together with the carbon atoms to which they are joined form a C 5 -C 8 cycloalkenyl, 5- to 7-membered heterocyclic, a C 6 phenyl, or a 5- to 6- heteroaryl wherein said heterocyclic has up to 2 heteroatoms selected from O, S N, and NR 3 and said heteroaryl has one heteroatom selected from O and S and up to two heteroatoms selected from N further wherein each of said cycloalkenyl, heterocyclic, phenyl, and heteroaryl are unsubstituted or substituted with one to two R 6 substituents.
  • the first step is formation of a fluorosulfonate wherein at least a stoichiometric equivalent of sulfuryl difluoride, is combined with 8-nitrophenanthren-2-ol (CAS 935655- 81-5; European Journal of Organic Chemistry, 2021, 810-813), compound 16, in an inert diluent such as dichloromethane, tetrachloromethane and the like in the presence of a suitable base such as triethylamine, diisopropylethylamine, pyridine and the like.
  • the reaction is typically maintained at from 0° to 30°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like.
  • the fluorosulfonate is carbonylated (Tetrahedron Letters, 1992, 33, 1959-62), wherein at least a stoichiometric equivalent of a suitable base triethylamine, diisopropylethylamine or pyridine is combined with the fluorosulfonate in an inert diluent such as DMSO, DMF and the like typically in the presence of a palladium catalyst (e.g, palladium diacetate) under an atmosphere of carbon monoxide.
  • a palladium catalyst e.g, palladium diacetate
  • reaction is typically maintained at from 70° to 100°C until it is substantially complete.
  • Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 17.
  • compound 17 is reduced under conventional hydrogenation reaction conditions well known in the art including the use palladium on carbon as catalyst under a hydrogen atmosphere (Organic Syntheses.; Collective Volume, 5, p.30).
  • Other nitro reducing reagents are well known in the art.
  • the reaction is typically conducted in an inert solvent such as EtOH, ethyl acetate, toluene, and the like.
  • reaction is typically conducted from about 20o to about 60o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 18.
  • Scheme 5 [0277] As to the reactions in Scheme 5, compound 19 (CAS 854395-75-8), is reduced under conventional hydrogenation reaction conditions well known in the art including the use palladium on carbon as catalyst under a hydrogen atmosphere. Other nitro reducing reagents are well known in the art.
  • the reaction is typically conducted in an inert solvent such as EtOH, ethyl acetate, toluene, and the like.
  • the reaction is typically conducted at from about 20o to about 60o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 20.
  • the first step is formation of an alkyl ester wherein compound 21 (Journal of the American Chemical Society 1940, 62, 527-32), is esterified under conventional conditions well known in the art in a suitable solvent such as methanol, ethanol and the like in the presence of a suitable catalyst, such as sulfuric acid.
  • a suitable solvent such as methanol, ethanol and the like
  • a suitable catalyst such as sulfuric acid.
  • the reaction is typically maintained at from 60° to 90°C until it is substantially complete.
  • Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 22.
  • compound 22 is reduced under conventional hydrogenation reaction conditions well known in the art including the use palladium on carbon as catalyst under a hydrogen atmosphere.
  • Other nitro reducing reagents are well known in the art.
  • the reaction is typically conducted in an inert solvent such as EtOH, ethyl acetate, toluene, and the like.
  • the reaction is typically conducted at from about 20o to about 60o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 23.
  • the first step is the hydrogenolysis of the benzyl group of compound 24 (Org. Lett.2003, 5, 761–764) under conventional hydrogenation reaction conditions well known in the art including the use palladium on carbon as catalyst under a hydrogen atmosphere.
  • the reaction is typically conducted in an inert solvent such as EtOH, ethyl acetate, toluene, and the like.
  • the reaction is typically conducted at from about 20o to about 60o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • reaction completion Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 25.
  • the phenol is converted to a fluorosulfonate wherein at least a stoichiometric equivalent of sulfuryl difluoride, is combined with compound 25 (European Journal of Organic Chemistry, 2021, 810-813), in an inert diluent such as dichloromethane, tetrachloromethane and the like in the presence of a suitable base such as triethylamine, diisopropylethylamine or pyridine.
  • a suitable base such as triethylamine, diisopropylethylamine or pyridine.
  • the reaction is typically maintained at from 0° to 30°C until it is substantially complete.
  • Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for the intermediate fluorosulfonate.
  • the fluorosulfonate is carbonylated (Tetrahedron Letters, 1992, 33, 1959-62), wherein at least a stoichiometric equivalent of a suitable base triethylamine, diisopropylethylamine or pyridine is combined with the intermediate fluorosulfonate, in an inert diluent such as DMSO, DMF and the like typically in the presence of a palladium catalyst (e.g, palladium diacetate) under an atmosphere of carbon monoxide.
  • a palladium catalyst e.g, palladium diacetate
  • reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 26.
  • compound 26 is deamidated under standard reaction conditions well known in the art including the use of acid catalysts such as sulfuric acid, hydrochloric acid and the like. Other deamidation conditions are well known in the art.
  • the reaction is typically conducted in an inert solvent such as MeOH, EtOH, and the like.
  • the reaction is typically conducted at from about 60o to about 90o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 27.
  • the reaction is typically conducted at from about 0o to about 30o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 29.
  • the methyl ester is displaced with the anion formed between acetonitrile and a suitable base (Organic Letters, 2006, vol.8, 1161-1163), wherein at least a stoichiometric equivalent of acetonitrile, is combined with compound 29, in an inert diluent such as tetrahydrofuran, toluene, DMF, benzene and the like typically in the presence of a suitable base such as potassium tert-butylate, sodium methylate, sodium hydride, n-butyl lithium and the like.
  • a suitable base such as potassium tert-butylate, sodium methylate, sodium hydride, n-butyl lithium and the like.
  • the reaction is typically maintained at from 20° to 120°C until it is substantially complete.
  • reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 30.
  • a conventional cyclization reaction (Bioorganic and Medicinal Chemistry Letters, 2000, 10, 1953-1957) wherein at least a stoichiometric equivalent of sulfur is combined with compound 30, in a protic diluent such as methanol, ethanol, n-butanol and the like, typically in the presence of a suitable base such as morpholine, triethylamine, pyridine, diisopropylethylamine, and the like.
  • reaction is typically maintained at from 40° to 70°C until it is substantially complete.
  • Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 31.
  • HPLC high performance liquid chromatography
  • at least a stoichiometric amount of a suitably protected amino acid compound, compound 32 is combined with compound 31 under conventional amidation reaction conditions (Angewandte Chemie - International Edition, 2020, 59, 3028-3032) well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC), as an activation agent for the carboxyl group.
  • DCC N,N-dicyclohexylcarbodiimide
  • Other activation agents are well known in the art.
  • the reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like.
  • the reaction is typically conducted at from about 0o to about 30o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 33.
  • the 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group is removed by conventional conditions and cyclization is affected by heating the intermediate in a protic solvent such as ethanol, methanol, 2-propanol and the like in the presence of a mild acid, such as silica to provide for compound 34.
  • a protic solvent such as ethanol, methanol, 2-propanol and the like
  • a mild acid such as silica to provide for compound 34.
  • the Fmoc group is illustrative only and other conventional amino blocking groups such as benzyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like could be used.
  • reaction completion Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 34.
  • isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 34.
  • HPLC high performance liquid chromatography
  • t-Bu tert-butyl ester
  • the t-Bu group is illustrative only and other conventional carboxylic acid blocking groups such as benzyl, methyl, ethyl and the like could be used.
  • the intermediate carboxylic acid is combined with ammonium chloride or ammonium bicarbonate under conventional amidation reaction conditions (WO2020/86858) well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC), as an activation agent for the carboxyl group.
  • DCC N,N-dicyclohexylcarbodiimide
  • Other activation agents are well known in the art.
  • the reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N- dimethylformamide, and the like.
  • the reaction is typically conducted at from about 0o to about 30o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • acetic acid hydrazine is combined with compound 35 under conventional cyclization reaction conditions (Angewandte Chemie - International Edition, 2020, 59, 3028-3032) in an inert diluent such as tetrahydrofuran, toluene, DMF, dichloromethane and the like typically in the presence of a suitable base such as potassium tert-butylate, triethylamine and the like.
  • Schemes 9-11 illustrate additional general methods for preparing compounds of formula I-a, I-b, I-c, or IB-d.
  • substituents R, R', R 2 , R 4 , R 5 , T, T 1 , T 2 , T 3 , T 4 , T 5 and ring X are as defined above.
  • the first step is a photoredox catalyzed carbofluorination reaction (ACS Catal.2019; 9(2): 1558–1563) wherein at least a stoichiometric equivalent of a di-Boc protected amino ester, compound 1a, is combined with an alkyltrifluoroborate salt, in an inert diluent such as DMF, acetonitrile and the like in the presence of Selectfluor and a suitable photocatalyst such as mesityl acridinium.
  • the reaction is typically maintained at from 0° to 40°C until it is substantially complete.
  • reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 2a.
  • Boc protecting groups are removed under conventional conditions.
  • the intermediate amine is combined with Fmoc-OSu or Fmoc-Cl under conventional Fmoc protection reaction conditions well known in the art.
  • the reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like.
  • the reaction is typically conducted at from about 0o to about 30o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • reaction solution Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 3a.
  • PMB protecting group is removed under conventional conditions reaction conditions well known in the art such as the use of DDQ (Tetrahedron Lett.1988, 29, 2459).
  • the PMB group is illustrative only and other conventional alcohol blocking groups such as Methoxymethyl ether, TBDPS, THP and the like could be used.
  • the reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like.
  • the reaction is typically conducted at from about 0o to about 30o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 4a.
  • the alcohol, compound 4a is oxidized to a carboxylic acid wherein at least a stoichiometric equivalent of an oxidizing reagent potassium permanganate (Helvetica Chimica Acta, 1983, 66, 1241-1252), or Dess-Martin reagent/NaClO 2 (Journal of the American Chemical Society, 1999, 121, 6355) is combined with the alcohol in an inert diluent such as acetone, acetic acid, propanol and the like.
  • the reaction is typically maintained at from 0° to 40°C until it is substantially complete.
  • reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 5a.
  • HPLC high performance liquid chromatography
  • at least a stoichiometric amount of compound 5a is combined with carbonic acid amine under conventional amidation reaction conditions well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC) or (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU) as an activation agent for the carboxyl group.
  • DCC N,N-dicyclohexylcarbodiimide
  • HATU 1-oxide hexafluorophosphate
  • the reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like.
  • the reaction is typically conducted at from about 0o to about 30o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 6a.
  • the first step is a H/D exchange of the amino-acid-derived imine (Org. Biomol. Chem., 2011, 9, 7983), wherein at least a stoichiometric equivalent of an imine activated amino ester, compound 8 (Archives of Pharmacal Research, 2012, 35, 1015), is combined with a base, in an inert diluent such as THF, diethyl ether and the reaction is quenched with DBr.
  • the reaction is typically maintained at from 0° to 40°C until it is substantially complete.
  • reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 9a.
  • imine group is removed under conventional conditions such as 1N hydrochloric acid in THF.
  • the intermediate amine is combined with Fmoc-OSu or Fmoc-Cl under conventional Fmoc protection reaction conditions well known in the art.
  • the reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like.
  • the reaction is typically conducted at from about 0o to about 30o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 10a.
  • HPLC high performance liquid chromatography
  • deprotection of the tert-butyl ester group of compound 10a under conventional reaction conditions well known in the art including the use trifluoroacetic acid (Int. J. Pept. Protein Res., 1978, 12, 258).
  • the reaction is typically conducted in an inert solvent such as dichloromethane, chloroform, and the like.
  • the reaction is typically conducted at from about 20o to about 60o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide compound 11a.
  • the reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like.
  • the reaction is typically conducted at from about 0o to about 30o C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 13a.
  • the 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group is removed by conventional conditions and cyclization is affected by heating the intermediate 14a in a protic solvent such as ethanol, methanol, 2-propanol and the like in the presence of a mild acid, such as silica or acetic acid to provide for compound 15a.
  • a protic solvent such as ethanol, methanol, 2-propanol and the like
  • a mild acid such as silica or acetic acid
  • acetic acid hydrazine is combined with compound 15a under conventional cyclization reaction conditions (Angewandte Chemie - International Edition, 2020, 59, 3028) in an inert diluent such as tetrahydrofuran, toluene, DMF, dichloromethane and the like typically in the presence of a suitable base such as potassium tert-butylate, triethylamine and the like.
  • the reaction is typically maintained at from -78° to 0°C until it is substantially complete.
  • Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 16a.
  • a conventional Suzuki coupling reaction wherein at least a stoichiometric equivalent of compound 17a, is combined with compound 16, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g, palladium diacetate, XPhos-Pd-G 2 ) and a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like.
  • a palladium catalyst e.g, palladium diacetate, XPhos-Pd-G 2
  • suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like.
  • the compounds and compositions described herein are useful in methods for treating a BRD4 dependent disease or disorder or a disease or disorder that is mediated, at least in part by, BRD4.
  • the methods comprise administering to a subject suffering from a BRD4 dependent disease or disorder an effective amount of a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein.
  • a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein for use in treating an BRD4 dependent disease or disorder.
  • the method relates a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein for use in manufacture of a medicament for reducing BRD4 protein levels where reduction of such protein levels treats or ameliorates the diseases or disorder.
  • the method relates a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein for use as described herein, wherein the BRD4 degradation at 1 ⁇ M concentration of the compounds described herein is at least 50% or at least 70%.
  • the BRD4 degradation is measured by the assay described in the biological example.
  • BRD4 dependent diseases or disorders such as liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma or diffuse large B-cell lymphoma.
  • the cancer may be selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma.
  • the BRD4-dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple- negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma thymoma
  • carcinoid gastrointestinal stromal tumor
  • the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • the BRD4-dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).
  • the compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
  • methods of using the compounds of the present application comprise administering to a subject in need thereof an effective amount of a compound as described herein.
  • compounds as described herein are useful in the treatment of proliferative disorders (e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases).
  • proliferative disorders e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases.
  • levels of cell proteins of interest e.g., pathogenic and oncogenic proteins are modulated, or their expression is inhibited or the proteins are degraded by contacting said cells with a compound or composition, as described herein.
  • the compounds are useful in treating cancer.
  • methods for the treatment of cancer comprising administering an effective amount of compound or composition, as described herein, to a subject in need thereof.
  • a method for the treatment of cancer comprising administering an effective amount of a compound, or a pharmaceutical composition comprising a compound as described herein to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result.
  • the compounds of present application are administered orally.
  • the compounds and compositions, according to the method of the present application are administered orally to a subject using any amount and any route of administration effective for killing or inhibiting the growth of tumor cells.
  • the expression “amount effective to kill or inhibit the growth of tumor cells,” as used herein, refers to a sufficient amount of agent to kill or inhibit the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, and the like. [0316] In certain embodiments, the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or other mammal in need of it.
  • the compounds or compositions described herein are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer).
  • cancer including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ova
  • the compounds or compositions described herein are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer.
  • compounds or compositions described herein are active against solid tumors.
  • the present application provides pharmaceutically acceptable derivatives of the compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents.
  • Another aspect of the application relates to a method of treating or lessening the severity of a disease or condition associated with a proliferation disorder in a patient, said method comprising a step of administering to said patient, a compound of Formula I or a composition comprising said compound.
  • the compounds and compositions, according to the method of the present application may be administered using any amount and any route of administration effective for the treatment of cancer and/or disorders associated with cell hyperproliferation.
  • the present application provides methods for the treatment of a proliferative disorder in a subject in need thereof by administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof.
  • the proliferative disorder can be cancer or a precancerous condition.
  • the present application further provides the use of a compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, for the preparation of a medicament useful for the treatment of a proliferative disorder.
  • the present application also provides methods of protecting against a proliferative disorder in a subject in need thereof by administering a therapeutically effective amount of compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, to a subject in need of such treatment.
  • the proliferative disorder can be cancer or a precancerous condition.
  • the present application also provides the use of compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, for the preparation of a medicament useful for the prevention of a proliferative disorder.
  • proliferative disorder refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous.
  • exemplary proliferative disorders of the application encompass a variety of conditions wherein cell division is deregulated.
  • Exemplary proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, uterine fibroids, pre-cancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells.
  • a proliferative disorder includes a precancer or a precancerous condition.
  • a proliferative disorder includes cancer.
  • the methods provided herein are used to treat or alleviate a symptom of cancer.
  • cancer includes solid tumors, as well as, hematologic tumors and/or malignancies.
  • precancer cell or “precancerous cell” is a cell manifesting a proliferative disorder that is a precancer or a precancerous condition.
  • cancer cell or “cancerous cell” is a cell manifesting a proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers.
  • non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram- negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic
  • Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adeno
  • a “proliferative disorder of the hematologic system” is a proliferative disorder involving cells of the hematologic system.
  • a proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia.
  • a proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system.
  • the compositions of the present application may be used to treat a cancer selected from the group consisting of a hematologic cancer of the present application or a hematologic proliferative disorder of the present application.
  • a hematologic cancer of the present application can include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin), leukemia (including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms and mast cell neoplasms.
  • lymphoma including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin
  • leukemia including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic
  • a “proliferative disorder of the lung” is a proliferative disorder involving cells of the lung.
  • Proliferative disorders of the lung can include all forms of proliferative disorders affecting lung cells.
  • Proliferative disorders of the lung can include lung cancer, a precancer or precancerous condition of the lung, benign growths or lesions of the lung, and malignant growths or lesions of the lung, and metastatic lesions in tissue and organs in the body other than the lung.
  • the compositions of the present application may be used to treat lung cancer or proliferative disorders of the lung.
  • Lung cancer can include all forms of cancer of the lung.
  • Lung cancer can include malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors.
  • Lung cancer can include small cell lung cancer (“SCLC”), non-small cell lung cancer (“NSCLC”), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, and mesothelioma.
  • Lung cancer can include “scar carcinoma”, bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma.
  • Lung cancer can include lung neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types).
  • Proliferative disorders of the lung can include all forms of proliferative disorders affecting lung cells.
  • Proliferative disorders of the lung can include lung cancer, precancerous conditions of the lung.
  • Proliferative disorders of the lung can include hyperplasia, metaplasia, and dysplasia of the lung.
  • Proliferative disorders of the lung can include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia.
  • Proliferative disorders of the lung can include replacement of columnar epithelium with stratified squamous epithelium, and mucosal dysplasia.
  • Prior lung diseases that may predispose individuals to development of proliferative disorders of the lung can include chronic interstitial lung disease, necrotizing pulmonary disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, and Hodgkin's disease.
  • a “proliferative disorder of the colon” is a proliferative disorder involving cells of the colon.
  • the proliferative disorder of the colon is colon cancer.
  • compositions of the present application may be used to treat colon cancer or proliferative disorders of the colon.
  • Colon cancer can include all forms of cancer of the colon.
  • Colon cancer can include sporadic and hereditary colon cancers.
  • Colon cancer can include malignant colon neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors.
  • Colon cancer can include adenocarcinoma, squamous cell carcinoma, and adenosquamous cell carcinoma.
  • Colon cancer can be associated with a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis.
  • Colon cancer can be caused by a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Koz- Jeghers syndrome, Turcot's syndrome and juvenile polyposis.
  • Proliferative disorders of the colon can include all forms of proliferative disorders affecting colon cells.
  • Proliferative disorders of the colon can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon and metachronous lesions of the colon.
  • a proliferative disorder of the colon can include adenoma.
  • Proliferative disorders of the colon can be characterized by hyperplasia, metaplasia, and dysplasia of the colon.
  • Prior colon diseases that may predispose individuals to development of proliferative disorders of the colon can include prior colon cancer.
  • Current disease that may predispose individuals to development of proliferative disorders of the colon can include Crohn's disease and ulcerative colitis.
  • a proliferative disorder of the colon can be associated with a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC.
  • An individual can have an elevated risk of developing a proliferative disorder of the colon due to the presence of a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC.
  • a “proliferative disorder of the pancreas” is a proliferative disorder involving cells of the pancreas. Proliferative disorders of the pancreas can include all forms of proliferative disorders affecting pancreatic cells.
  • Proliferative disorders of the pancreas can include pancreas cancer, a precancer or precancerous condition of the pancreas, hyperplasia of the pancreas, and dysplasia of the pancreas, benign growths or lesions of the pancreas, and malignant growths or lesions of the pancreas, and metastatic lesions in tissue and organs in the body other than the pancreas.
  • Pancreatic cancer includes all forms of cancer of the pancreas.
  • Pancreatic cancer can include 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.
  • Pancreatic cancer can also include pancreatic neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types).
  • a “proliferative disorder of the prostate” is a proliferative disorder involving cells of the prostate.
  • Proliferative disorders of the prostate can include all forms of proliferative disorders affecting prostate cells.
  • Proliferative disorders of the prostate can include prostate cancer, a precancer or precancerous condition of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, and metastatic lesions in tissue and organs in the body other than the prostate.
  • Proliferative disorders of the prostate can include hyperplasia, metaplasia, and dysplasia of the prostate.
  • a “proliferative disorder of the skin” is a proliferative disorder involving cells of the skin.
  • Proliferative disorders of the skin can include all forms of proliferative disorders affecting skin cells.
  • Proliferative disorders of the skin can include a precancer or precancerous condition of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma and other malignant growths or lesions of the skin, and metastatic lesions in tissue and organs in the body other than the skin.
  • Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of the skin.
  • a “proliferative disorder of the ovary” is a proliferative disorder involving cells of the ovary.
  • Proliferative disorders of the ovary can include all forms of proliferative disorders affecting cells of the ovary.
  • Proliferative disorders of the ovary can include a precancer or precancerous condition of the ovary, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions in tissue and organs in the body other than the ovary.
  • Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of cells of the ovary.
  • a “proliferative disorder of the breast” is a proliferative disorder involving cells of the breast.
  • Proliferative disorders of the breast can include all forms of proliferative disorders affecting breast cells.
  • Proliferative disorders of the breast can include breast cancer, a precancer or precancerous condition of the breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast.
  • Proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.
  • a cancer that is to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) can be assigned a stage of MX, M0, or M1.
  • AJCC American Joint Committee on Cancer
  • a cancer that is to be treated can be staged according to an American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV.
  • AJCC American Joint Committee on Cancer
  • a cancer that is to be treated can be assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4.
  • a cancer that is to be treated can be staged according to an AJCC pathologic classification (pN) of pNX, pN0, PN0 (I-), PN0 (I+), PN0 (mol-), PN0 (mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.
  • pN AJCC pathologic classification
  • a cancer that is to be treated can include a tumor that has been determined to be less than or equal to about 2 centimeters in diameter.
  • a cancer that is to be treated can include a tumor that has been determined to be from about 2 to about 5 centimeters in diameter.
  • a cancer that is to be treated can include a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter.
  • a cancer that is to be treated can include a tumor that has been determined to be greater than 5 centimeters in diameter.
  • a cancer that is to be treated can be classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated.
  • a cancer that is to be treated can be classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells).
  • a cancer that is to be treated can be classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells).
  • a cancer that is to be treated can be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance.
  • a cancer that is to be treated can be classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy.
  • a cancer that is to be treated can be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome.
  • a cancer that is to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry.
  • a cancer that is to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., in S phase of cell division).
  • a cancer that is to be treated can be typed as having a low S-phase fraction or a high S-phase fraction.
  • a “normal cell” is a cell that cannot be classified as part of a “proliferative disorder”. A normal cell lacks unregulated or abnormal growth, or both, that can lead to the development of an unwanted condition or disease.
  • a normal cell possesses normally functioning cell cycle checkpoint control mechanisms.
  • One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, N.Y.
  • compounds of the application are useful in the treatment of proliferative disorders (e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases).
  • proliferative disorders e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases.
  • levels of cell proteins of interest e.g., pathogenic and oncogenic proteins are modulated, or their growth is inhibited by contacting said cells with a compound or composition, as described herein.
  • the compounds are useful in treating cancer.
  • the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it.
  • the compounds are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer).
  • cancer including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic
  • the anticancer agents are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer.
  • the anticancer agents are active against solid tumors.
  • the present application provides pharmaceutically acceptable derivatives of the compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents.
  • therapies or anticancer agents that may be used in combination with the compounds disclosed herein including surgery, radiotherapy, endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubi
  • compositions comprising the compounds disclosed herein further comprise one or more additional therapeutically active ingredients (e.g., chemotherapeutic and/or palliative).
  • additional therapeutically active ingredients e.g., chemotherapeutic and/or palliative.
  • the term “palliative” refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative.
  • palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs.
  • chemotherapy, radiotherapy and surgery can all be used palliatively (that is, to reduce symptoms without going for cure; e.g., for shrinking tumors and reducing pressure, bleeding, pain and other symptoms of cancer).
  • Pharmaceutical Compositions [0347] Administration of the disclosed compounds and pharmaceutical compositions can be accomplished via any mode of administration for therapeutic agents.
  • compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time- release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time- release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • intravenous both bolus and infusion
  • intraperitoneal subcutaneous or intramuscular form
  • Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and/or polyethylene glycol; for example,
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
  • the disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • the disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No.5,262,564, which is hereby incorporated by reference in its entirety.
  • Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled.
  • the disclosed compounds can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.
  • Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • compositions comprising a compound of Formula (I), and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may further include an excipient, diluent, or surfactant.
  • Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.
  • the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present disclosure.
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the disclosure may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the disclosure typically comprises directions for administration.
  • compositions of this disclosure may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray-drying, levigating, emulsifying, (nano-/micro-) encapsulating, entrapping, or lyophilization processes.
  • the compositions of this disclosure can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
  • the compositions are comprised of, in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient.
  • excipients are non- toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • liquid carriers particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this disclosure in an aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • compositions of this disclosure may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient.
  • a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising a compound of this disclosure that can be formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %.
  • Representative pharmaceutical formulations are described below.
  • Formulation Examples [0366] The following are representative pharmaceutical formulations containing a compound of this disclosure.
  • Formulation Example 1 -- Tablet formulation [0367] The following ingredients are mixed intimately and pressed into single scored tablets.
  • Formulation Example 2 Capsule formulation [0368] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule
  • Formulation Example 3 Suspension formulation [0369] The following ingredients are mixed to form a suspension for oral administration.
  • Formulation Example 4 Injectable formulation [0370] The following ingredients are mixed to form an injectable formulation.
  • a suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: Dosing [0372]
  • the dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Effective dosage amounts of the disclosed compounds range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition.
  • Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses.
  • the compositions are in the form of a tablet that can be scored.
  • Method A Experiments were performed using a Luna® 5 ⁇ m C18(2) 100 ⁇ , LC Column 250 x 21.2 mm, AXIATM Packed (00G-4252-P0-AX), at a flow rate of 20 mL/min, and a mass spectrometer using ESI as ionization source.
  • the solvent A was 4.0 mL of TFA in 4 L of water
  • solvent B was 4.0 mL of TFA in 4 L of acetonitrile.
  • the gradient consisted of 10-100% solvent B over 20 minutes, LC column temperature was 40°C. UV absorbance was collected at 220 nm and 254 nm.
  • Compound A’ (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid
  • Compound A’ is known in the art as “JQ1 (carboxylic acid)”, CAS # 202592-23-2 and is described in Filippakopoulos, et al. “Selective inhibition of BET bromodomains”, Nature 2010, 468, 1067-1073; Romero, et al., J. Med. Chem., 201659, 1271-1298.
  • Step 2 [0388] A 10-20 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (836 mg, 2.09 mmol), (3- ⁇ [(tert-butoxy)carbonyl]amino ⁇ phenyl)boronic acid (1.82 g, 3.7 eq., 7.68 mmol), cesium carbonate (2.04 g, 3 eq., 6.27 mmol), degassed ACN (15 mL) and Pd(Cy*Phine) 2 Cl 2 (269 mg, 0.1 eq., 209 ⁇ mol).
  • Step 3 [0389] Trifluoroacetic acid (2.00 mL) was slowly added to a solution of tert-butyl N- ⁇ 4'-[(9S)-9- (carbamoylmethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]-[1,1'-biphenyl]-3-yl ⁇ carbamate (7.27 mL, 1.85 mmol) in DCM (4 mL). The reaction was stirred at room temperature for 2 hours.
  • the mixture was stirred at 25 °C for 10hr.
  • the reaction mixture was quenched by addition of water (20 mL) at 0°C, and then diluted with ethyl acetate (10 mL) and extracted with ethyl acetate (10 mL ⁇ 2).
  • the combined organic layers were washed with brine (10 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure.
  • Step 2 [0392] To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 eq) and 5- methoxypyridine-2-carboxylic acid (2 eq) in DMF (5 mL) was added EDCI (21.5 eq), HOBt (1.5 eq), DMAP (0.1 eq), and DIEA (3 eq) in one portion at 25°C under N2. The mixture was stirred at 25 °C for 10hr. The reaction mixture was quenched by addition of water (20 mL) at 0°C, and then diluted with ethyl acetate (20 mL) and extracted with EA (20 mL ⁇ 2).
  • Step 3 [0393] To a mixture of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)-N-ethylacetamide (1 eq) and 5-methoxy-N-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)picolinamide (2 eq) in THF (3 mL) and H2O (1 mL) was added K3PO4 (2.5 eq) and X-Phos-Pd-G2 (0.1 eq) in one portion at 25°C under N2.
  • the mixture was stirred at 80 °C for 10 hr.
  • the reaction mixture was quenched by addition of water (20 mL) at 0°C, and then diluted with ethyl acetate (20 mL) and extracted with ethyl acetate (20 mL ⁇ 2).
  • the combined organic layers were washed with brine (10 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure.
  • Step 2 [0396] A 0.5-2 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (50.0 mg, 125 ⁇ mol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-benzofuran-2-carboxamide (135 mg, 3 eq., 372 ⁇ mol), cesium carbonate (122 mg, 3 eq., 375 ⁇ mol), degassed ACN (2.5 mL) and Pd(Cy*Phine) 2 Cl 2 (16.1 mg, 0.1 eq., 12.5 ⁇ mol).
  • the microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours.
  • the reaction mixture was filtered, evaporated in vacuo and crude material was dissolved in ethyl acetate (25 mL).
  • the organic layer was washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo.
  • Step 2 [0398] To solution of 5% piperazine and 2% DBU in DMA (2 mL) was added (9H-fluoren-9-yl)methyl N-[(1S)-1- ⁇ [3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl]carbamoyl ⁇ ethyl]carbamate (360 mg, 644 ⁇ mol). The reaction was stirred at room temperature for 30 minutes. Ethyl acetate (50 mL) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was filtered.
  • Step 3 [0399] To a stirred solution of (3S)-5-(4-chlorophenyl)-3,6,7-trimethyl-1H,2H,3H-thieno[2,3- e][1,4]diazepin-2-one (214 mg, 671 ⁇ mol) in dry THF (4 mL) at ⁇ 78 °C was added a 1M solution of potassium 2-methylpropan-2-olate (805 ⁇ L, 1.2 eq., 805 ⁇ mol). The reaction mixture was warmed to ⁇ 10°C and stirred for 30 minutes.
  • reaction mixture was cooled to ⁇ 78 °C and diphenyl phosphorochloridate (181 ⁇ L, 1.3 eq., 873 ⁇ mol) in THF (0.5 mL) was added. The resulting mixture was warmed to ⁇ 10°C and stirred for 45 minutes. Acetohydrazide (99.5 mg, 2 eq., 1.34 mmol) was added and the reaction was allowed to warm to temperature over 1 hour.1-butanol (3 mL) was added and the reaction mixture was heated to 90°C for 2 hours. The solvents were removed in vacuo.
  • Step 4 [0400] A 0.5-2 mL Biotage microwave reactor was charged with (9S)-7-(4-chlorophenyl)-4,5,9,13- tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene (33.0 mg, 92.5 ⁇ mol) N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-benzofuran-2-carboxamide (135 mg, 3 eq., 372 ⁇ mol), cesium carbonate (90.4 mg, 3 eq., 277 ⁇ mol), degassed ACN (2.5 mL) and Pd(Cy*Phine) 2 Cl 2 (25.8 mg, 0.1 eq., 20.0 ⁇ mol).
  • the microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours.
  • the reaction mixture was filtered, evaporated in vacuo and crude material was dissolved in ethyl acetate (25 mL).
  • the organic layer was washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo.
  • Step 2 [0402] A 0.5-2 mL Biotage microwave reactor was charged with (2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-1-(pyrrolidin-1- yl)ethan-1-one (108 mg, 238 ⁇ mol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1- benzofuran-2-carboxamide (302 mg, 3.5 eq., 833 ⁇ mol), cesium carbonate (233 mg, 3 eq., 714 ⁇ mol), degassed ACN (2 mL) and Pd(Cy*Phine)2Cl2 (30.7 mg, 0.1 eq., 23.8 ⁇ mol).
  • Step 2 [0405] A 0.5-2 mL Biotage microwave reactor was charged with methyl 2-[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (165 mg, 398 ⁇ mol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-benzofuran-2- carboxamide (506 mg, 3.5 eq., 1.39 mmol), cesium carbonate (389 mg, 3 eq., 1.19 mmol), degassed ACN (2 mL) and Pd(Cy*Phine)2Cl2 (51.3 mg, 0.1 eq., 39.8 ⁇ mol).
  • the microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours.
  • the reaction mixture was filtered, evaporated in vacuo and crude material was dissolved in ethyl acetate (25 mL).
  • the organic layer was washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo.
  • Step 3 [0406] To an ice bath cooled solution of methyl 2-[(9S)-7-[3'-(1-benzofuran-2-amido)-[1,1'-biphenyl]-4- yl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9- yl]acetate (151 mg, 245 ⁇ mol) in anhydrous THF (2 mL) was added lithium aluminum hydride (368 ⁇ L, 1.5 eq., 368 ⁇ mol, 1.0 M solution in THF). The reaction was stirred at 0°C for 1 hour.
  • the reaction was slowly quenched with MeOH (5 mL) and water (5 mL) and then diluted with water (10 mL).
  • the crude product was extracted into ethyl acetate (3 x 15 mL).
  • the combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo.
  • the crude reaction mixture was purified by preparative reverse phase HPLC and the acetonitrile mobile phase was evaporated. A solution of saturated sodium bicarbonate solution (1.5 mL) was added to neutralize the aqueous acidic solution.
  • the desired product was extracted with ethyl acetate (2 x 3 mL).
  • Step 2 [0418] A 10-20 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (836 mg, 2.09 mmol), (3- ⁇ [(tert-butoxy)carbonyl]amino ⁇ phenyl)boronic acid (1.82 g, 3.7 eq., 7.68 mmol), cesium carbonate (2.04 g, 3 eq., 6.27 mmol), degassed ACN (15 mL), and Pd(Cy*Phine) 2 Cl 2 (269 mg, 0.1 eq., 209 ⁇ mol).
  • Step 3 [0419] Trifluoroacetic acid (2.00 mL) was slowly added to a solution of tert-butyl N- ⁇ 4'-[(9S)-9- (carbamoylmethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]-[1,1'-biphenyl]-3-yl ⁇ carbamate (7.27 mL, 1.85 mmol) in DCM (4 mL). The reaction was stirred at room temperature for 2 hours.
  • Step 4 To a solution of 1-benzofuran-7-carboxylic acid (10.6 mg, 1.2 eq., 65.2 ⁇ mol) and ethylbis(propan-2-yl)amine (38.0 ⁇ L, 4 eq., 217 ⁇ mol) in DMF (1.5 mL) was added HATU (26.9 mg, 1.3 eq., 70.6 ⁇ mol). The mixture was stirred at room temperature for 10 minutes.
  • Step 2 [0424] To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid (50 mg, 125 ⁇ mol, 1.0 eq) in THF (0.8 mL) and H2O (0.2 mL) was added (3-(benzofuran-7-carboxamido)phenyl)boronic acid (42.2 mg, 150 ⁇ mol, 1.2 eq), XPhos-Pd-G2 (9.8 mg, 12.5 ⁇ mol, 0.1 eq), and K3PO4 (52.9 mg, 249.4 ⁇ mol, 2.0 eq) at 20°C, and the mixture was stirred at 80°C for 10 hrs.
  • Trifluoroacetic acid (30 eq.) is slowly added to a solution of 31A (1 eq.) in DCM. The reaction is stirred at room temperature for 2 hours. TFA and DCM are co-evaporated with toluene to give 32A.
  • Step 2 To a solution of (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (30.0 mg, 63.2 ⁇ mol, 1.0 eq) in dichloromethane (1.0 mL) was added pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (22.9 mg, 126.4 ⁇ mol, 2.0 eq) and triethylamine (19.2 mg, 189.6 ⁇ mol, 26.4 ⁇ L, 3.0 eq) at 25 °C.
  • the mixture was stirred at 0 °C for 1 hr.
  • the reaction mixture was quenched by addition of water (10.0 mL) at 0 °C.
  • the aqueous layer was extracted with ethyl acetate (10.0 mL ⁇ 3), the combined organic layers were washed with brine (10.0 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure.
  • Step 2 [0450] To a solution of tert-butyl (3-((3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-1,1,1- trifluoro-3-oxopropan-2-yl)carbamate (9.0 g, 18.3 mmol, 1.0 eq) in DCM (180.0 mL) was added TFA (62.7 g, 549.9 mmol, 40.7 mL, 30.0 eq) dropwise. The mixture was stirred at 25 °C for 10 hr.
  • reaction mixture was concentrated under reduced pressure to give 2-amino-N-(3-(4-chlorobenzoyl)-4,5- dimethylthiophen-2-yl)-3,3,3-trifluoropropanamide.trifluoroacetic acid salt, which was used into the next step directly without further purification.
  • Step 3 A solution of 2-amino-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3,3,3- trifluoropropanamide.trifluoroacetic acid salt (4.0 g, 8.2 mmol, 1.0 eq) in AcOH (8.0 mL) and THF (40.0 mL) was stirred at 50 °C for 2 hr. Water (30.0 mL) was added and the aqueous layer was extracted with ethyl acetate (10 mL ⁇ 2). The combined organic layers were washed with brine (10.0 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 4 [0452] 5-(4-Chlorophenyl)-6,7-dimethyl-3-(trifluoromethyl)-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin- 2-one (0.2 g, 536.5 ⁇ mol, 1.0 eq) was added to a suspension of NaH (42.9 mg, 1.07 mmol, 60% purity, 2.0 eq) in THF (3.0 mL) at 0°C. The reaction mixture was stirred for 10 min. BOPCl (273.1 mg, 1.1 mmol, 2.0 eq) was added and the resulting mixture was stirred for 2 h at 0 °C.
  • Acetohydrazide (59.6 mg, 804.7 ⁇ mol, 1.5 eq) was added to reaction mixture and the reaction was warmed to 25 °C and stirred for 2 h. The reaction mixture was heated to 50 °C and stirred for 10 hr. Acetic anhydride (0.2 mL) was added and the reaction heated at 80 °C for 1 hr. Water (10.0 mL) was added and the aqueous layer was extracted with ethyl acetate (5 mL ⁇ 2). The combined organic layers were washed with brine (10.0 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure.
  • Step 5 A mixture of 4-(4-chlorophenyl)-2,3,9-trimethyl-6-(trifluoromethyl)-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepine (200.0 mg, 486.8 ⁇ mol, 1.0 eq), (3-((tert- butoxycarbonyl)amino)phenyl)boronic acid (346.2 mg, 1.5 mmol, 3.0 eq), K 3 PO 4 (310.0 mg, 1.5 mmol, 3.0 eq) and XPhos-Pd-G 2 (38.3 mg, 48.7 ⁇ mol, 0.1 eq) in THF (2 mL) and H 2 O (0.4 mL) was degassed and purged with N 2 .
  • Step 6 [0454] To a mixture of tert-butyl (4'-(2,3,9-trimethyl-6-(trifluoromethyl)-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)carbamate (7.0 mg, 12.3 ⁇ mol, 1 eq) in DCM (0.2 mL) was added TFA (42.2 mg, 370.0 ⁇ mol, 27.4 ⁇ L, 30.0 eq) dropwise. The mixture was stirred at 25 °C for 2 hr.
  • Step 7 To a mixture of 4'-(2,3,9-trimethyl-6-(trifluoromethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-amine.trifluoroacetic acid salt (2.0 mg, 4.3 ⁇ mol, 1.0 eq) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2.1 mg, 12.8 ⁇ mol, 3.0 eq) in DMF (2.0 mL) was added EDCI (1.2 mg, 6.4 ⁇ mol, 1.5 eq), DIEA (1.7 mg, 12.8 ⁇ mol, 2.2 ⁇ L, 3.0 eq), HOBt (867.1 ⁇ g, 6.4 ⁇ mol, 1.5 eq) and DMAP (52.3 ⁇ g, 0.43 ⁇ mol, 0.1 eq) in one portion at 25 °C.
  • the mixture was stirred at 25 °C for 10 hr.
  • the reaction mixture was diluted with H2O (2.0 mL) and extracted into ethyl acetate (2.0 mL ⁇ 2).
  • the organic phase was washed with brine (1.0 mL), dried over anhydrous Na2SO4 and concentrated in vacuo.
  • Step 2 [0457] To solution of 5% piperazine and 2% DBU in DMA (2 mL) was added (9H-fluoren-9-yl)methyl N-[(1S)-1- ⁇ [3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl]carbamoyl ⁇ ethyl]carbamate (360 mg, 644 ⁇ mol). The reaction was stirred at room temperature for 30 minutes. Ethyl acetate (50 mL) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was filtered.
  • Step 3 [0458] To a stirred solution of (3S)-5-(4-chlorophenyl)-3,6,7-trimethyl-1H,2H,3H-thieno[2,3- e][1,4]diazepin-2-one (214 mg, 671 ⁇ mol) in dry THF (4 mL) at -78 °C was added a 1M solution of potassium 2-methylpropan-2-olate (805 ⁇ L, 1.2 eq., 805 ⁇ mol). The reaction mixture was warmed to -10°C and stirred for 30 minutes.
  • reaction mixture was cooled to -78 °C and diphenyl phosphorochloridate (181 ⁇ L, 1.3 eq., 873 ⁇ mol) in THF (0.5 mL) was added. The resulting mixture was warmed to -10°C and stirred for 45 minutes. Acetohydrazide (99.5 mg, 2 eq., 1.34 mmol) was added and the reaction was allowed to warm to temperature over 1 hour.1-butanol (3 mL) was added and the reaction mixture was heated to 90°C for 2 hours. The solvents were removed in vacuo.
  • Step 4 To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.0 g, 6.1 mmol, 1.0 eq) and 4- bromopyridin-2-amine (1.3 g, 7.3 mmol, 1.2 eq) in pyridine (10 mL) was added POCl3 (2.8 g, 18.4 mmol, 1.7 mL, 3.0 eq) dropwise at 0°C. The mixture was stirred at 25°C for 2 h. The reaction mixture was quenched by addition H2O (10 mL) at 25°C and extracted with ethyl acetate (20 mL ⁇ 2).
  • Step 5 [0460] To a solution of (S)-4-(4-chlorophenyl)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepine (400.0 mg, 1.1 mmol, 1.0 eq) and BPD (853.8 mg, 3.3 mmol, 3.0 eq) in dioxane (5 mL) was added KOAc (330.0 mg, 3.3 mmol, 3.0 eq) and [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (88.2 mg, 112.1 ⁇ mol, 0.1 eq) under N 2 atmosphere.
  • Step 6 [0461] To a solution of (S)-2,3,6,9-tetramethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (300.0 mg, 819.1 umol, 1.0 eq) and N-(4- bromopyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (286.6 mg, 901.0 ⁇ mol, 1.1 eq) in THF (3 mL) and H2O (0.6 mL) was added Xphos-Pd-G2 (64.4 mg, 81.9 ⁇ mol, 0.1 eq) and K3PO4 (521.6 mg, 2.4 mmol, 3.0 eq) under N2 atmosphere.
  • Step 3 [0464] To a solution of (S)-N-(4'-(6-(2-hydroxyethyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (400.0 mg, 679.5 ⁇ mol, 1.0 eq) in DCM (5 mL) was added Et3N (206.3 mg, 2.0 mmol, 283.7 ⁇ L, 3.0 eq) and MsCl (653.8 mg, 5.7 mmol, 441.8 ⁇ L, 8.4 eq) at 0 °C.
  • the mixture was stirred at 25 °C for 2 hrs.
  • the reaction mixture was concentrated under reduced pressure to remove DCM and the reaction mixture was quenched by addition saturated sodium bicarbonate aqueous solution 2 mL at 25°C, and then diluted with H2O (5 mL) and extracted with ethyl acetate (2 mL ⁇ 3).
  • Step 4 [0465] To a solution of (S)-2-(2,3,9-trimethyl-4-(3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'- biphenyl]-4-yl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)ethyl methanesulfonate (100 mg, 149.9 ⁇ mol, 1.0 eq) was added amine (10.1 mg, 149.9 ⁇ mol, 1.0 eq) at 25°C and the mixture was stirred at 50°C for 2 hrs.
  • Step 2 [0467] To a solution of methyl (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (5.8 g, 13.9 mmol, 1.0 eq) in THF (40 mL) and H 2 O (10 mL) was added (3-amino-4-fluorophenyl)boronic acid (2.9 g, 20.9 mmol, 1.5 eq), K 3 PO 4 (8.9 g, 41.9 mmol, 3.0 eq) and XPhos-Pd-G 2 (1.1 g, 1.4 mmol, 0.1 eq) at 25°C and the mixture was stirred at 80°C for 5 hrs.
  • Step 3 [0468] To a solution of methyl (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (2.5 g, 5.3 mmol, 1 eq) in DMF (20 mL) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.3 g, 7.9 mmol, 1.5 eq), EDCI (1.5 g, 7.9 mmol, 1.5 eq), DIEA (2.1 g, 15.9 mmol, 2.8 mL, 3.0 eq), DMAP (64.7 mg, 530.1 ⁇ mol, 0.1 eq) and HOBt (1.1 g, 7.9 mmol, 1.5 eq) and the mixture was stirred at
  • Step 4 [0469] To a solution of methyl (S)-2-(4-(4'-fluoro-3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'- biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (1.0 g, 1.6 mmol, 1.0 eq) in THF (2 mL), MeOH (2 mL), and H2O (2 mL) was added LiOH.H2O (330.6 mg, 7.9 mmol, 5.0 eq) and the mixture was stirred at 25°C for 5 hrs.
  • reaction mixture was concentrated under reduced pressure to remove MeOH.
  • Step 5 [0470] To (S)-2-(4-(4'-fluoro-3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'-biphenyl]-4-yl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 80.5 ⁇ mol, 1.0 eq) in DMF (1 mL) and was added methylamine.hydrochloride (10.9 mg, 161.1 ⁇ mol, 2.0 eq), HATU (45.9 mg, 120.8 ⁇ mol, 1.5 eq), and DIEA (52.0 mg, 402.8 ⁇ mol, 70.2 ⁇ L, 5.0 eq).
  • Step 2 [0472] To a solution of methyl (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (5.8 g, 13.9 mmol, 1.0 eq) in THF (40 mL) and H 2 O (10 mL) was added (3-amino-4-fluorophenyl)boronic acid (2.9 g, 20.9 mmol, 1.5 eq), K 3 PO 4 (8.9 g, 41.9 mmol, 3.0 eq) and XPhos-Pd-G 2 (1.1 g, 1.4 mmol, 0.1 eq) at 25°C and the mixture was stirred at 80°C for 5 hrs.
  • Step 3 [0473] To a solution of methyl (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (2.5 g, 5.3 mmol, 1 eq) in DMF (20 mL) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.3 g, 7.9 mmol, 1.5 eq), EDCI (1.5 g, 7.9 mmol, 1.5 eq), DIEA (2.1 g, 15.9 mmol, 2.8 mL, 3.0 eq), DMAP (64.7 mg, 530.1 ⁇ mol, 0.1 eq) and HOBt (1.1 g, 7.9 mmol, 1.5 eq) and the mixture was stirred at
  • Step 4 [0474] To a solution of methyl (S)-2-(4-(4'-fluoro-3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'- biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (1.0 g, 1.6 mmol, 1.0 eq) in THF (2 mL), MeOH (2 mL), and H 2 O (2 mL) was added LiOH.H 2 O (330.6 mg, 7.9 mmol, 5.0 eq) and the mixture was stirred at 25°C for 5 hrs.
  • reaction mixture was concentrated under reduced pressure to remove MeOH.
  • Step 5 [0475] To (S)-2-(4-(4'-fluoro-3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'-biphenyl]-4-yl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 80.5 ⁇ mol, 1.0 eq) in DMF (1 mL) and was added dimethylamine.hydrochloride (10.9 mg, 161.1 ⁇ mol, 2.0 eq), HATU (45.9 mg, 120.8 ⁇ mol, 1.5 eq) and DIEA (52.0 mg, 402.8 ⁇ mol, 70.2 ⁇ L, 5.0 eq).
  • Step 2 [0477] To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetamide (100.0 mg, 250.1 ⁇ mol, 1.0 eq) in THF (1.6 mL) and H2O (0.4 mL) was added (3-amino-4-fluorophenyl)boronic acid (46.5 mg, 300.1 ⁇ mol, 1.2 eq), K3PO4 (106.2 mg, 500.1 ⁇ mol, 2.0 eq), Xphos-Pd-G2 (19.7 mg, 25.0 ⁇ mol, 0.1 eq) at 25°C and the mixture was stirred at 90°C for 10 hrs.
  • Step 3 [0478] To a solution of give (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (30.0 mg, 63.2 ⁇ mol, 1.0 eq) in DCM (1 mL) was added pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (22.9 mg, 126.4 ⁇ mol, 2.0 eq), Et3N (19.2 mg, 189.6 ⁇ mol, 26.4 ⁇ L, 3.0 eq) at 25°C and the mixture was stirred at 25°C for 10 hrs.
  • Target engagement assay The ability of a compound to bind to BRD4 is assessed using HEK-293T cells and the NanoBRET Target Engagement Intracellular BET BRD Assay from Promega (Cat. No. N2131). Assays were run according to manufacturer’s specifications and luminescent readout was recorded using a CLARIOstar Plus instrument (BMG Labtech). Resulting BRET ratios were plotted and IC50s determined by non-linear regression analyses (GraphPad Prism). BRD4 degradation assay [0482] BRD4 degradation was monitored by immunofluorescence in HEK-293T cells.
  • 96-well plates black, clear-bottom
  • test compounds were added in a 10-point dilution series (typically 30 ⁇ M to 100 pM) using a TECAN D300e Digital Dispenser, and plates were subsequently incubated for 24 hours at 37°C.
  • Media was carefully removed, and cells were fixed in PBS + 2.5% formalin (50 ⁇ L) for 20 minutes at 37°C. Following formalin fixation, cells were washed once with PBS and methanol was added (30 ⁇ L). Plates were wrapped in parafilm and incubated at -20°C for 1 hour to overnight.
  • DAPI (1 ⁇ M final) plus secondary antibody (Southern Biotech 4030-30 anti-Rabbit IgG Alexa Fluor 488; diluted 1:2000 in PBS + 1X fish gelatin, 0.1% Triton X-100) were added at 40 ⁇ L/well, and plates were incubated at room temperature for 2 hours covered with foil. Cells were washed (3x) with PBS + 0.1% tween-20, followed by one wash with PBS, and the addition of 100 ⁇ L of PBS for imaging. Images were acquired using the ImageXpress Pico system (Molecular Devices). Cell Reporter Xpress software was utilized to segment cells and determine fluorescence intensities, which were used to construct dose- response curves and calculation of degradation DC50s (GraphPad Prism). Table 3 and Table 3A show results from the assays. TABLE 3

Abstract

Disclosed are compounds and salts thereof that are useful for modulating or degrading bromodomain (e.g., BRD4).

Description

COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THAT MODULATE BRD4 Field [0001] This disclosure provides for compounds and pharmaceutically acceptable salts thereof that are useful for modulating or degrading bromodomain (e.g., BRD4). The compounds disclosed herein bind to and, in some cases, degrade BET/BRD4. Also disclosed are pharmaceutical compositions comprising the compounds, or a salt (e.g., a pharmaceutically acceptable salt) thereof, and methods of using such compounds and their salts in the treatment of various bromodomain-mediated diseases or disorders. State of the Art [0002] Chromatin is a complex combination of DNA and protein that makes up chromosomes. It is found inside the nuclei of eukaryotic cells and is divided between heterochromatin (condensed) and euchromatin (extended) forms. The major components of chromatin are DNA and proteins. Histones are the chief protein components of chromatin, acting as spools around which DNA winds. The functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication. The chromatin structure is controlled by a series of post-translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the “histone tails” which extend beyond the core nucleosome structure. Histone tails tend to be free for protein-protein interaction and are also the portion of the histone most prone to post-translational modification. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation. These epigenetic marks are written and erased by specific enzymes that place the tags on specific residues within the histone tail, thereby forming an epigenetic code, which is then interpreted by the cell to allow gene specific regulation of chromatin structure and thereby transcription. [0003] Of all classes of proteins, histones are amongst the most susceptible to post- translational modification. Histone modifications are dynamic, as they can be added or removed in response to specific stimuli, and these modifications direct both structural changes to chromatin and alterations in gene transcription. Distinct classes of enzymes, namely histone acetyltransferases (HATs) and histone deacetylases (HDACs), acetylate or de-acetylate specific histone lysine residues (Struhl K., Genes Dev., 1989, 12, 5, 599-606). [0004] Bromodomains, which are approximately 110 amino acids long, are found in a large number of chromatin-associated proteins and have been identified in approximately 70 human proteins, often adjacent to other protein motifs (Jeanmougin F., et al, Trends Biochem. Sci., 1997, 22, 5,151-153; and Tamkun J. W., et al., Cell, 1992, 7, 3, 561-572). Interactions between bromodomains and modified histones may be an important mechanism underlying chromatin structural changes and gene regulation. Bromodomain-containing proteins have been implicated in disease processes including cancer, inflammation and viral replication. See, e.g., Prinjha et al, Trends Pharm. Sci., 33(3):146-153 (2012) and Muller et al, Expert Rev., 13(29):1-20 (2011). [0005] Cell-type specificity and proper tissue functionality requires the tight control of distinct transcriptional programs that are intimately influenced by their environment. Alterations to this transcriptional homeostasis are directly associated with numerous disease states, most notably cancer, immuno-inflammation, neurological disorders, and metabolic diseases. Bromodomains reside within key chromatin modifying complexes that serve to control distinctive disease-associated transcriptional pathways. This is highlighted by the observation that mutations in bromodomain-containing proteins are linked to cancer, as well as immune and neurologic dysfunction. Moreover, recent findings have demonstrated that small molecule inhibition of the bromodomains of BRD4 may have clinical utility in diverse human diseases, ranging from auto-immunity to cardiac hypertrophy. This is possible because the underlying mechanism resides in transcriptional regulation. Hence, the inhibition of bromodomains across the family creates varied opportunities as novel therapeutic agents in human dysfunction. [0006] Accordingly, the ability to modulate or degrade BRD4 would be a significant advancement in treating cancer and other bromodomain related diseases. [0007] Still further, an orally deliverable compound that provides for a superior Cmax and AUC in vivo is desired over compounds that are delivered by parenteral injection. Summary [0008] Disclosed are compounds as well as pharmaceutical compositions comprising said compounds and methods of using said compounds that modulate the activity of or which degrade BRD4. Such compounds are useful in treating diseases mediated, at least in part, by dysfunction of BRD4 including cancers and proliferative disorders. [0009] Also disclosed in some embodiments, are compounds as well as compositions comprising said compounds and methods of using said compounds that degrade BRD4, which in some embodiments these compounds are capable of providing for superior Cmax and AUC values when delivered orally. Such compounds are useful in treating diseases mediated, at least in part, by dysfunction of BRD4, including BRD4 mediated cancers. [0010] Provided herein is a compound of formula I-a that binds to or degrades BRD4:
Figure imgf000003_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R, R′, R2, R4, R5, T, T1, T2, T3, T4, T5, and ring A are as described in the detailed description. [0011] Also provided herein is a compound of formula I-b that binds to and modulates the activity of BRD4:
Figure imgf000004_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R20, R20′, R22, R24, R25, T20, T21, T22, T23, T24, T25, Q20, Q25, Q26, X20, Y20, ring A20, and ring B20 are as described in the detailed description. [0012] Also provided herein is a compound of formula I-c that binds to or degrades BRD4:
Figure imgf000004_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R40, R40′, R42, R44, R45, T40, T41, T42, T43, T44, T45, Q41, Q42, Q43, Q44, Q45, Q46, and ring A40 are as described in the detailed description. [0013] Also provided herein is a compound of formula IB-d that binds to or degrades BRD4:
Figure imgf000004_0003
IB-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R60, R60′, T60, T61, T62, Q61, Q64, R69 and q60 are as described in the detailed description. [0014] Also provided herein is a compound of formula IC-d that binds to or degrades BRD4:
Figure imgf000005_0001
IC-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R60, R60′, R62, R64, R65, T60, T61, T62, T63, T64, T65, Q60, Q65, Q66, Y60, ring A60, and ring B60 are as described in the detailed description. [0015] In one embodiment, provided is a compound represented by formula I-e:
Figure imgf000005_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. [0016] In one embodiment, provided is a compound of formula Ie:
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof. [0017] In one embodiment, provided is a compound represented by formula I-f:
Figure imgf000006_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. [0018] In one embodiment, provided is a compound of formula I-f:
Figure imgf000006_0003
I-f or a pharmaceutically acceptable salt thereof. [0019] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I-a, Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V-a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B- c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. Formula Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V-a, II-b, II-A- b, II-B-b, III-b, IV-b, V-b, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC- d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, and ID-d are as described in the detailed description. [0020] Provided herein is a method for degrading BRD4 which method comprises contacting BRD4 with an effective amount of a compound of formula I-a, Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V-a, I-b, Ia- b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, under conditions wherein BRD4 is degraded. [0021] Provided herein is a method to degrade BRD4 in a subject in need thereof, which method comprises administering to said subject an effective amount of a compound of formula I-a, Ia-a, II-a, II- A-a, II-B-a, III-a, IV-a, V-a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC- d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I-a, Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V- a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. [0022] Provided herein is a method for treating a proliferative disorder mediated, at least in part, by BRD4 in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula I-a, Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V-a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI- AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I-a, Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V-a, I-b, Ia-b, II-b, II-A-b, II-B-b, III- b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. [0023] In some embodiments, the proliferative disorder is liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, or Epstein- Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, or diffuse large B-cell lymphoma. [0024] In some embodiments, the proliferative disorder is prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, or Ewing’s sarcoma. [0025] In some embodiments, the proliferative disorder is non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, or gastrointestinal stromal tumor (GIST). [0026] In some embodiments, the proliferative disorder is non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, or gastrointestinal stromal tumor (GIST). [0027] In some embodiments, the proliferative disorder is non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), or microsatellite stable colorectal cancer (mssCRC). [0028] Provided herein is the use of a compound of formula I-a, Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V- a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, or a pharmaceutical composition comprising a compound of formula I-a, II-a, II-A-a, II-B-a, III- a, IV-a, V-a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I- f, for treating a proliferative disorder mediated, at least in part, by BRD4. [0029] Provided herein is the use of a compound of formula I-a, Ia-a, II-a, II-A-a, II-B-a, III-a, IV-a, V- a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, or a pharmaceutical composition comprising a compound of formula I-a, Ia-a, II-a, II-A-a, II-B- a, III-a, IV-a, V-a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II-B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, ID-d, I-e, or I-f, in the manufacture of a medicament, for treating a proliferative disorder mediated, at least in part, by BRD4. [0030] In one embodiment, disclosed are compounds represented by formula IA-a that bind to or degrade BRD4:
Figure imgf000009_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where
Figure imgf000009_0002
, where the wavy line indicates the point of attachment to the rest of the structure; R is selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR3, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R3)2 and -CH2C(O)NR1R1' where R1 and R1' are independently hydrogen, C1-C4 alkyl, or R1 and R1' together with the nitrogen atom form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S; R2 and R2' are independently hydrogen or fluoro, or when R2 and R2' are at the 2,2' or at the 6,6' position, R2 and R2' together with the carbon atoms to which they are joined form a C5-C8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl having 1 to 2 heteroatoms selected from O, N, NR3 and S, or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR3 and S, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl are unsubstituted or substituted with one or two R6 substituents; each R3 is independently hydrogen or C1-C4 alkyl; R4 and R5 are independently hydrogen, methyl or methoxy; each R6 is selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, N(R7)2, cyano, halo, and hydroxyl; each R7 is independently selected from the group consisting of hydrogen and C1-C3 alkyl or two R7 join with the nitrogen atom attached thereto to form a 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR3 and S or 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N, NR3 and S; R8 and R8' are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, -N(R7)2, cyano, halo, or hydroxyl; V is N or CR9; W and W' are independently hydrogen or fluoro; R9 is hydrogen or C1-C4 alkyl R10 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, ethoxy, and C3-C6 cycloalkyl; R11 is selected from the group consisting of C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, cyano, methoxy, ethoxy, and C3-C6 cycloalkyl; R13 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, and ethoxy; and h is 0, 1, 2, or 3. [0031] In one embodiment, disclosed are compounds represented by formula I-AA-a or I-BA-a that bind to or degrade BRD4:
Figure imgf000010_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where V, W, W', R, R2, R2', R4, R5, R8, R8', R9, R10, R11, and R13 are as defined above. [0032] In one embodiment, disclosed are compounds represented by formula II-AA-a or II-BA-a that bind to or degrade BRD4:
Figure imgf000011_0001
II-AA-a II-BA-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where V, W, W', R, R4, R5, R8, R8', R10 and R11 are as defined above, R12 and R12' together with the carbon atoms to which they are joined form a C5-C8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR3 and S, or a 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N, NR3 and S, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one to two R6 substituents. [0033] In one embodiment, disclosed are compounds represented by formula IIIA-a that bind to or degrade BRD4:
Figure imgf000011_0002
IIIA-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where W, W', R, R2, R2', R4, R5, R8, R8', R10 and R11 are as defined above. [0034] In one embodiment, disclosed are compounds represented by formula IVA-a that bind to or degrade BRD4:
Figure imgf000012_0001
IVA-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where W, W', R, R2, R2', R4, R5, R8, R8', R10 and R11 are as defined above. [0035] In one embodiment, disclosed are compounds represented by formula VA-a that bind to or degrade BRD4:
Figure imgf000012_0002
VA-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where W, W', R, R2, R2', R4, R5, R8, R8', R9, R10 and R11 are as defined above. [0036] In one embodiment for the compounds described above, W and W' are hydrogen. [0037] In one embodiment for the compounds described above, R is C1-C3 alkylene-N(R3)2 or -CH2C(O)NR1R1' where R1 and R1' are independently hydrogen or C1-C4 alkyl. In one embodiment, R is -CH2C(O)NH2 or –(CH2)2NHCH3. [0038] In one embodiment for the compounds described above, R2 and R2' are both hydrogen. In some embodiments, R2 and R2' join together to form a heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR3 and S or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR3 and S. In some embodiment the heterocycloalkyl or the heteroaryl has one O or S. [0039] In one embodiment for the compounds described above, R4 is hydrogen or methyl. In some embodiments R4 is methyl. [0040] In one embodiment for the compounds described above, R5 is hydrogen or methyl. In some embodiments R5 is methyl. [0041] In one embodiment for the compounds described above, R4 and R5 are both methyl. [0042] In one embodiment for the compounds described above, R8 and R8' are both hydrogen. [0043] In one embodiment for the compounds described above, R9 is hydrogen. [0044] In one embodiment for the compounds described above, R10 is hydrogen, methyl or ethyl. [0045] In one embodiment for the compounds described above, R11 is methyl or difluoromethyl. [0046] In one embodiment, disclosed are compounds represented by formula IA-b that bind to or degrade BRD4:
Figure imgf000013_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where R20 is selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR23, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R23)2 and -CH2C(O)NR21R21' where R21 and R21' are independently hydrogen, C1-C4 alkyl, or R21 and R21' together with the nitrogen atom form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S; R22 and R22' are independently hydrogen or fluoro, or when R22 and R22' are at the 2,2' or at the 6,6' position, R22 and R22' together with the carbon atoms to which they are joined form a C5-C8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl having 1 to 2 heteroatoms selected from O, N, NR23 and S, or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR23 and S, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl are unsubstituted or substituted with one or two R26 substituents; each R23 is independently hydrogen or C1-C4 alkyl; R24 and R25 are independently hydrogen, methyl or methoxy; each R26 is selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, N(R27)2, cyano, halo, and hydroxyl; each R27 is independently selected from the group consisting of hydrogen and C1-C3 alkyl or two R27 join with the nitrogen atom attached thereto to form a 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR23 and S or 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N, NR23 and S; R28 and R28' are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, -N(R27)2, cyano, halo, or hydroxyl; Q25 and Q26 are independently C or N provided that both cannot be N; W20 and W20' are independently hydrogen or fluoro; X20 is CR27', N, or NR23; Y20 is O, S, N or NR23 provided that when X20 is NR23, Y20 cannot be NR23; R27' is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, amino, N(R23)2, cyano, halo, hydroxyl, or nitro; Ring A20 is a 5- or 6-membered heteroaryl, phenyl, a 5- to 7-membered cycloalkyl, or a 4- to 7-membered heterocycloalkyl wherein said heteroaryl contains 1 to 2 heteroatoms selected from O, S, N, or NR23 and said heterocycloalkyl contains 1 to 3 heteroatoms selected from O, S, N, or NR23, and further wherein each of said heteroaryl, phenyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 2 R29; R29 is hydrogen, amino, (C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, cyano, hydroxy, halo, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 halo groups, C1-C4 alkoxy, C1-C4 alkoxy substituted with from 1 to 3 halo groups; C1-C4 alkyl substituted with C1-C2 alkoxy, amino, hydroxy, alkoxy, amino, (C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, cyano, halo, or hydroxyl; and further provided that the following compounds are excluded:
Figure imgf000014_0001
Figure imgf000015_0001
. [0047] In one embodiment, the disclosed compounds are as described above, further provided that: i) the total number of N in ring A20 including Q25 and Q26 is from one to three; and further provided that when either Q25 or Q26 is N, then neither X20 or Y20 can be O, S, or NR23; and ii) when ring A20 is a 6- or 7-membered heterocycloalkyl and Q25 is N, then Q25 is attached to CHR29 of the 6- or 7-membered heterocycloalkyl. [0048] In one embodiment, disclosed are compounds represented by formula II-AA-b or II-BA-b that bind to or degrade BRD4:
Figure imgf000015_0002
II-AA-b II-BA-b or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, where W20, W20', Ring A20, Q25, Q26, X20, Y20, R20, R22, R22', R24, R25, R28, R28' are as defined above. [0049] In one embodiment, the disclosed compounds are represented by formula IIIA-b:
Figure imgf000016_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, where W20, W20', X20, Y20, R20, R22, R22', R24, R25, R28, R28' are as defined above, t20 is zero, one, or two, and R32 is C1-C4 alkyl, C1-C4 alkoxy, amino, N(R23)2, cyano, halo or hydroxyl, provided that the following compounds are excluded:
Figure imgf000017_0001
. [0050] In one embodiment, disclosed are compounds of formula IVA-b:
Figure imgf000017_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, where W20, W20', Q25, Q26, X20, Y20, R20, R22, R22', R24, R25, R28, R28', R32 and t20 are as defined above; each of Q21, Q22, Q23 and Q24 are independently N or CR32; further provided that the number of Q21-Q26 that are N is from one to three; and further provided that when either Q25 or Q26 is N, then neither X20 or Y20 can be O, S or NR23; still further provided that the following compounds are excluded:
Figure imgf000018_0001
. [0051] In one embodiment, the disclosed compounds are represented by formula VA-b:
Figure imgf000018_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, where W20, W20', Q25, Q26, X20, Y20, R20, R22, R22', R24, R25, R28, R28' and R32 and t20 are as defined above, v20 is zero, one, or two, Q27 and Q28 are independently CHR32 or NR33 where R33 is selected from hydrogen and C1-C3 alkyl provided that if Q25 is N, then Q28 is CHR32; provided that the following compound is excluded:
Figure imgf000019_0001
. [0052] In one embodiment for the compounds described above, R20 is methyl. [0053] In one embodiment for the compounds described above, R20 is -CH2C(O)OR23 or a pharmaceutically acceptable salt thereof. In one embodiment, R20 is -CH2C(O)OH. [0054] In one embodiment for the compounds described above, R20 is -CH2C(O)NR21R21' where R21 and R21' are independently hydrogen or C1-C3 alkyl or R21 and R21' together with the nitrogen atom form a 4- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, NR23, and S where R23 is hydrogen or C1-C4 alkyl. In one embodiment, R20 is -CH2C(O)NH2. [0055] In one embodiment for the compounds described above, R22 and R22' are both hydrogen. In some embodiments, R22 and R22' join together to form a heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR23, and S or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR23, and S. In some embodiment the heterocycloalkyl or the heteroaryl has one O or S. [0056] In one embodiment for the compounds described above, R24 is hydrogen or methyl. In some embodiments, R24 is methyl. [0057] In one embodiment for the compounds described above, R25 is hydrogen or methyl. In some embodiments, R25 is methyl. [0058] In one embodiment for the compounds described above, R24 and R25 are both methyl. [0059] In one embodiment for the compounds described above, R28 and R28' are both hydrogen. [0060] In one embodiment for the compounds described above, R29 is hydrogen, methyl or ethyl. [0061] In one embodiment for the compounds described above, Y20 is O, S, N, or NH. In some embodiments, Y20 is O. [0062] In one embodiment for the compounds described above, X20 is N, NH or CR27. In some embodiments, X20 is CH or C-CH3. [0063] In some embodiments for the compounds described above, Y20 is O and X20 is CH. In some embodiments, Y20 is S and X20 is N. In some embodiments, Y20 is N and X20 is CH. In some embodiments, Y20 is N and X20 is O. In some embodiments, one of X20 and Y20 is N and the other is NH. [0064] In some embodiments for the compounds described above, both Q25 and Q26 are C. In some embodiments, one of Q25 and Q26 is N and the other is C. [0065] In one embodiment for the compounds described above, three of Q21, Q22, Q23, Q24, Q25, Q26 are N, provided that only one of Q25 and Q26 is N. In some embodiments, two of Q21, Q22, Q23, Q24, Q25, Q26 are N, provided that only one of Q25 and Q26 is N. In some embodiments, one of Q21, Q22, Q23, Q24, Q25, Q26 is N. In some embodiments, none of Q21, Q22, Q23, Q24, Q25, Q26 is N. [0066] In one embodiment for the compounds described above, W20 and W20' are hydrogen.
Figure imgf000020_0001
[0068] In one embodiment, disclosed are compounds represented by formula IA-c that bind to or degrade BRD4:
Figure imgf000020_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where R40 is selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR43, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R43)2 and -CH2C(O)NR41R41' where R41 and R41' are independently hydrogen, C1-C4 alkyl, or R41 and R41' together with the nitrogen atom form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S; R42 and R42' are independently hydrogen or fluoro, or when R42 and R42' are at the 2,2' or at the 6,6' position, R42 and R42' together with the carbon atoms to which they are joined form a C5-C8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl having 1 to 2 heteroatoms selected from O, N, NR43 and S, or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR43 and S, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl are unsubstituted or substituted with one or two R46 substituents; each R43 is independently hydrogen or C1-C4 alkyl; R44 and R45 are independently hydrogen, methyl or methoxy; each R46 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, -N(R47)2, cyano, halo, and hydroxyl; each R47 is independently selected from the group consisting of hydrogen and C1-C3 alkyl or two R47 join with the nitrogen atom attached thereto to form a 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR43 and S or 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N, NR43 and S; R48 and R48' are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, -N(R47)2, cyano, halo, or hydroxyl; W40 and W40' are independently hydrogen or fluoro; each of Q41, Q42, Q43 and Q44 are independently N or CR49 provided that no more than three of Q41, Q42, Q43, or Q44 are N and further provided that one of R49 is a bond to the NH-C(O)-; each R49 is independently selected from hydrogen and C1-C3 alkyl; Q45 and Q46 are independently C or N provided that both cannot be N; Ring A40 is a 5 or 6-membered heteroaryl, phenyl, a 5- to 7-membered cycloalkyl, or a 4- to 7-membered heterocycloalkyl wherein said heteroaryl contains 1 to 2 heteroatoms selected from O, S, N, or NR48 and said heterocycloalkyl contains 1 to 3 heteroatoms selected from O, S, N, or NR43, and further wherein each of said heteroaryl, phenyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 2 R50; and R50 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, and ethoxy. [0069] In one embodiment, disclosed are compounds represented by formula II-AA-c or II-BA-c that bind to or degrade BRD4:
Figure imgf000021_0001
II-AA-c II-BA-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where Ring A40, Q41, Q42, Q43, Q44, Q45, Q46, W40, W40', R40, R44, R45, R48, and R48' are as defined above, R51 and R51' together with the carbon atoms to which they are joined form a C5-C8 cycloalkyl, 5- to 7- membered heterocycloalkyl, phenyl, or a 5- to 6-membered heteroaryl wherein said heterocycloalkyl has up to 2 heteroatoms selected from O, S, N, and NR43 and said 5-membered heteroaryl has one heteroatom selected from NR43, O and S and said 6-membered heteroaryl has up to two heteroatoms selected from N wherein each of said cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are unsubstituted or substituted with one to two R46 substituents where R46 is as defined above. [0070] In one embodiment, disclosed are compounds represented by formula IIIA-c that bind to or degrade BRD4:
Figure imgf000022_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where Q41, Q42, Q43, Q44, Q45, Q46, W40, W40', R40, R44, R45, R48, R48', R50, R51 and R51' are as defined above and u40 is zero, one or two. [0071] In one embodiment, disclosed are compounds represented by formula IVA-c that bind to or degrade BRD4:
Figure imgf000022_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer thereof where Q41, Q42, Q43, Q44, Q45, Q46, W40, W40', R40, R44, R45, R47, R48, R48', R50, R51, and R51' are as defined above and u40 is zero, one or two. [0072] In one embodiment, disclosed are compounds represented by formula V-AA-c or V-BA-c that bind to or degrade BRD4:
Figure imgf000023_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer thereof where Q41, Q42, Q43, Q44, Q45, Q46, W40, W40', R40, R44, R45, R48, R48', R50, R51, and R51' are as defined above and u40 is zero, one or two; Y40 is N, NR43, O, S or CR50 provided that when Q45 is N, then Y40 is N; X40 is NR43, N, O, S or CR50 provided that when Q46 is N, then X40 is N; and further provided that when X40 or Y40 is NR43, O, or S, then Y40 or X40 is then N or CR50. [0073] In one embodiment, when Q45 is N, then Y40 is N or CR50. In one embodiment, when Q46 is N, then Y40 is N or CR50. In one embodiment, when X40 is NR43, O, or S, then Y40 is CR50 and when Y40 is NR43, O, or S, then X40 is CR50. [0074] In one embodiment for the compounds described above, W40 and W40' are hydrogen. [0075] In one embodiment for the compounds described above, R40 is C1-C3 alkylene-N(R43)2 or -CH2C(O)NR41R41' where R41 and R41' are independently hydrogen or C1-C4 alkyl. In one embodiment, R40 is -CH2C(O)NH2 or –(CH2)2NHCH3. [0076] In one embodiment for the compounds described above, R40 is -CH2C(O)O(R43). In one embodiment, R40 is -CH2C(O)OH. [0077] In one embodiment for the compounds described above, R42 and R42' are both hydrogen. In some embodiments, R42 and R42' join together to form a heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR43 and S or a 5- to 6-membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR43 and S. In some embodiments, the heterocycloalkyl or the heteroaryl has one O or S. [0078] In one embodiment for the compounds described above, R44 is hydrogen or methyl. In some embodiments R44 is methyl. [0079] In one embodiment for the compounds described above, R45 is hydrogen or methyl. In some embodiments R45 is methyl. [0080] In one embodiment for the compounds described above, R44 and R45 are both methyl. [0081] In one embodiment for the compounds described above, R48 and R48' are both hydrogen. [0082] In one embodiment R49 is hydrogen. [0083] In one embodiment for the compounds described above, R50 is hydrogen, methyl or ethyl. [0084] In one embodiment for the compounds described above, R51 and R51' are both hydrogen. [0085] In one embodiment for the compounds described above, four of Q41, Q42, Q43, Q44, Q45, Q46 are N. In some embodiments, three of Q41, Q42, Q43, Q44, Q45, Q46 are N. In some embodiments, two of Q41, Q42, Q43, Q44, Q45, Q46 are N. In some embodiments, one of Q41, Q42, Q43, Q44, Q45, Q46 is N. In some embodiments, none of Q41, Q42, Q43, Q44, Q45, Q46 is N.
Figure imgf000024_0001
[0087] In one embodiment, disclosed are compounds represented by formula IA-d that bind to or degrade BRD4:
Figure imgf000024_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where p60 is zero, one or two; R60 is selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R63)2 and -CH2C(O)NR61R61' where R61 and R61' are independently hydrogen, C1-C4 alkyl, or R61 and R61' together with the nitrogen atom form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; R62 and R62' are independently hydrogen or fluoro, or when R62 and R62' are at the 2,2' or at the 6,6' position, R62 and R62' together with the carbon atoms to which they are joined form a C5-C8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR63 and S, or a 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N, NR63 and S, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R66 substituents; each R63 is independently hydrogen or C1-C4 alkyl; R64 and R65 are independently hydrogen, methyl or methoxy; each R66 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, -N(R67)2, cyano, halo, and hydroxyl; each R67 is independently selected from the group consisting of hydrogen and C1-C3 alkyl or two R67 join with the nitrogen atom attached thereto to form a 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR63 and S or 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N, NR63 and S; R68 and R68' are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, -N(R67)2, cyano, halo, or hydroxyl; Q61 and Q62 are independently N or CR69; and each R69 is independently hydrogen or C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, and ethoxy. [0088] In one embodiment, the compounds are as described above, wherein Q61 and Q62 are independently N or CR69 provided only one of Q61 and Q62 is N. [0089] In one embodiment, disclosed are compounds represented by formula II-AA-d or II-BA-d that bind to or degrade BRD4:
Figure imgf000025_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where p60, Q61, Q62, R60, R64, R65, R68, R68', and R69 are as defined above, R72 and R72' together with the carbon atoms to which they are joined form a C5-C8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR63 and S, or a 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N, NR63 and S, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one to two R66 substituents. [0090] In one embodiment, disclosed are compounds represented by formula IIIA-d that bind to or degrade BRD4:
Figure imgf000026_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where p60, R60, R62, R62', R64, R65, R68, R68', and R69 are as defined above. [0091] In one embodiment, disclosed are compounds represented by formula IVA-d that bind to or degrade BRD4:
Figure imgf000026_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where p60, R60, R62, R62', R64, R65, R68, R68', and R69 are as defined above. [0092] In one embodiment, disclosed are compounds represented by formula VA-d that bind to or degrade BRD4:
Figure imgf000027_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where p60, R60, R62, R62', R64, R65, R68, R68', and R69 are as defined above. [0093] In one embodiment R60 is C1-3 alkylene-N(R63)2 or -CH2C(O)NR61R61' where R61 and R61' are independently hydrogen or C1-4 alkyl. In one embodiment, R60 is -CH2C(O)NH2 or –(CH2)2NHCH3. [0094] In one embodiment, R62 and R62’ are both hydrogen. In some embodiments, R62 and R62' join together to form a heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR63 and S or a 5- to 6- membered heteroaryl having 1 to 2 heteroatoms selected from O, N, NR63 and S. In some embodiments the heterocycloalkyl or the heteroaryl has one O or S. [0095] In one embodiment, R64 is hydrogen or methyl. In some embodiments R64 is methyl. [0096] In one embodiment, R65 is hydrogen or methyl. In some embodiments R65 is methyl. [0097] In one embodiment, R64 and R65 are both methyl. [0098] In one embodiment, R68 and R68' are both hydrogen. [0099] In one embodiment, R69 is hydrogen, methyl or ethyl. [0100] In one embodiment, one of Q61 and Q62 is nitrogen and the other is CR69. [0101] In one embodiment, Q61 and Q62 both are carbon or both are nitrogen. [0102] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-a. [0103] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula II-AA-a or II- BA-a. [0104] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IIIA-a. [0105] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IVA-a. [0106] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula V-a. [0107] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-b. [0108] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula II-AA-b or II-BA-b. [0109] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IIIA-b. [0110] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IVA-b. [0111] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula VA-b. [0112] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-c. [0113] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula II-AA-c or II-BA-c. [0114] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IIIA-c. [0115] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IVA-c. [0116] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula V-AA-c or V-BA-c. [0117] In one embodiment, there is provided a method to treat cancer in a subject which method comprises selecting a subject whose cancer is mediated at least in part by BRD4 and administering to said subject an effective amount of a compound of formula IA-c, II-AA-c, II-BA-c, IIIA-c, IVA-c, V- AA-c or V-BA-c or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-c, II-AA-c, II-BA-c, IIIA-c, IVA-c, V-AA-c or V-BA-c. [0118] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-d. [0119] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula II-AA-d or II- BB-d. [0120] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IIIA-d. [0121] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IVA-d. [0122] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula VA-d. [0123] In one embodiment, this disclosure provides for a method for degrading BRD4 which method comprises contacting BRD4 with an effective amount of a compound of Formula IA-a, I-AA-a, I-BA-a, II-AA-a, II-BA-a, IIIA-a, IVA-a, VA-a, IA-b, II-AA-b, II-BA-b, IIIA-b, IVA-b, VA-b, IA-c, II-AA-c, II- BA-c, IIIA-c, IVA-c or V-AA-c, V-BA-c, IA-d, II-AA-d, II-BA-d, IIIA-d, IVA-d, VA-d, I-e, or I-f under conditions wherein BRD4 is degraded. [0124] In one embodiment, there is provided a method to degrade BRD4 in a subject, which method comprises administering to said subject an effective amount of a compound of formula IA-a, I-AA-a, I- BA-a, II-AA-a, II-BA-a, IIIA-a, IVA-a, VA-a, IA-b, II-AA-b, II-BA-b, IIIA-b, IVA-b, VA-b, IA-c, II- AA-c, II-BA-c, IIIA-c, IVA-c or V-AA-c, V-BA-c, IA-d, II-AA-d, II-BA-d, IIIA-d, IVA-d, VA-d, I-e, or I-f, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-a, I-AA-a, I-BA-a, II-AA-a, II-BA-a, IIIA-a, IVA-a, VA-a, IA-b, II-AA-b, II-BA-b, IIIA-b, IVA-b, VA-b, IA-c, II-AA-c, II-BA-c, IIIA-c, IVA-c, V-AA-c, V-BA-c, IA-d, II-AA-d, II-BA-d, IIIA-d, IVA-d, VA-d, I-e, or I-f. [0125] In one embodiment, there is provided a method to treat cancer in a subject which method comprises selecting a subject whose cancer is mediated at least in part by BRD4 and administering to said subject an effective amount of a compound of formula IA-a, I-AA-a, I-BA-a, II-AA-a, II-BA-a, IIIA-a, IVA-a, VA-a, IA-b, II-AA-b, II-BA-b, IIIA-b, IVA-b, VA-b, IA-c, II-AA-c, II-BA-c, IIIA-c, IVA-c, V-AA-c, V-BA-c, IA-d, II-AA-d, II-BA-d, IIIA-d, IVA-d, VA-d, I-e, or I-f, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula IA-a, I-AA-a, I-BA-a, II-AA-a, II-BA-a, IIIA-a, IVA-a, VA- a, IA-b, II-AA-b, II-BA-b, IIIA-b, IVA-b, VA-b, IA-c, II-AA-c, II-BA-c, IIIA-c, IVA-c, V-AA-c, V-BA- c, IA-d, II-AA-d, II-BA-d, IIIA-d, IVA-d, VA-d, I-e, or I-f. Detailed Description [0126] This disclosure provides for compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions to treat diseases, disorders, or conditions mediated, at least in part, by BRD4 transcription factors. However, prior to providing a detailed description of the disclosure, the following terms will first be defined. If not defined, terms used herein have their generally accepted scientific meaning. [0127] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. [0128] “Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. [0129] A dash (“
Figure imgf000029_0001
-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named. [0130] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. [0131] The term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by ( + ) or ( - ) 10%, 5%, 1%, or any subrange or subvalue there between. In one embodiment, the term “about” when used with regard to a dose amount means that the dose may vary by +/- 10%. [0132] “Comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. [0133] “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure. [0134] “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure. [0135] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from C1-C6 carbon atoms. In some embodiments, the number of carbon atoms in an alkyl group can be quantified specifically by reciting, e.g., C1-C4 alkyl. This term includes, by way of example only, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), neopentyl ((CH3)3CCH2-) and n-hexyl (CH3CH2CH2CH2CH2CH2-). [0136] The term “alkylene” refers to a divalent alkyl group as described above. [0137] “Alkoxy” refers to -O-alkyl groups where alkyl is defined above. Such alkoxy groups have C1- C6 carbon atoms. In so embodiments, the number of carbon atoms in an alkoxy group can be quantified specifically by reciting, e.g., C1-C4 alkoxy. This term includes, by way of example only, linear and branched alkoxy groups such as methoxy (CH3O-), ethoxy (CH3CH2O-), n-propoxy (CH3CH2CH2O-), isopropoxy ((CH3)2CHO-), n-butoxy (CH3CH2CH2CH2O-), isobutoxy ((CH3)2CHCH2O-), sec-butoxy ((CH3)(CH3CH2)CHO-), t-butoxy ((CH3)3CO-), n-pentyl (CH3CH2CH2CH2CH2O-), neopentyl ((CH3)3CCH2O-) and n-hexyl (CH3CH2CH2CH2CH2CH2O-). [0138] The term “alkylene-oxy” refers to a divalent alkoxy having the formula: -O-alkylene- where the term alkylene is as described above. [0139] “Amino” refers to the group -NH2. “Alkylamino” refers to alkyl-NH- and “dialkylamino” refers to (alkyl)2N- where alkyl is as defined above. [0140] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of point of attachment. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkenyl regardless of point of attachment. [0141] “Halo” refers to fluoro, chloro, bromo, and iodo and in one embodiment, fluoro and chloro. [0142] “Haloalkyl” refers to an alkyl group as defined herein wherein at least 1 to up to 6 hydrogen atoms are replaced with halo. In some embodiments, the halo is fluoro. [0143] “Hydroxy” or “hydroxyl” refers to -OH. [0144] “Hydroxyalkyl” refers to an alkyl group as defined herein wherein at least 1 to up to 3 hydrogen atoms are replaced with hydroxy. [0145] “Heterocycloalkyl” or “heterocyclic” refers to a saturated or unsaturated but not heteroaromatic ring system having from 3 to 12 ring members and from 1 to 5 heteroatoms selected from N, O or S. The heteroatoms can also be oxidized, such as, but not limited to, S(O) and S(O)2. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4 or 3 to 5. The heterocycloalkyl group can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, C6-8, C3-9, C3-10, C3-11, and C3-12. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused- heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule. [0146] The heterocycloalkyl group can include groups such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, azocanyl, quinuclidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl (1,2-, 1,3- and 1,4-isomers), oxiranyl, oxetanyl, tetrahydrofuranyl, oxanyl (tetrahydropyranyl), oxepanyl, thiiranyl, thietanyl, thiolanyl (tetrahydrothiophenyl), thianyl (tetrahydrothiopyranyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, morpholinyl, thiomorpholinyl, dioxanyl, or dithianyl. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indolinyl, diazabicycloheptanyl, diazabicyclooctanyl, diazaspirooctanyl or diazaspirononanyl. [0147] The heterocycloalkyl groups can be linked via any position on the ring. For example, aziridinyl can be 1- or 2-aziridinyl, azetidinyl can be 1- or 2- azetidinyl, pyrrolidinyl can be 1-, 2- or 3-pyrrolidinyl, piperidinyl can be 1-, 2-, 3- or 4-piperidinyl, pyrazolidinyl can be 1-, 2-, 3-, or 4-pyrazolidinyl, imidazolidinyl can be 1-, 2-, 3- or 4-imidazolidinyl, piperazinyl can be 1-, 2-, 3- or 4-piperazinyl, tetrahydrofuranyl can be 1- or 2-tetrahydrofuranyl, oxazolidinyl can be 2-, 3-, 4- or 5-oxazolidinyl, isoxazolidinyl can be 2-, 3-, 4- or 5-isoxazolidinyl, thiazolidinyl can be 2-, 3-, 4- or 5-thiazolidinyl, isothiazolidinyl can be 2-, 3-, 4- or 5- isothiazolidinyl, and morpholinyl can be 2-, 3- or 4-morpholinyl. [0148] When heterocycloalkyl includes 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, oxanyl, tetrahydrothiophenyl, thianyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxzoalidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl and dithianyl. Heterocycloalkyl can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and morpholinyl. [0149] “3- to 7-membered heterocycloalkyl” refers to a heterocycloalkyl either saturated or partially unsaturated but not heteroaromatic and having at least 1 heteroatom and optionally up to three heteroatoms selected from oxygen, sulfur, N, and NR3 where R3 is as defined herein. Examples of 3- to 7-membered heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholino, thiomorpholino, N-methylpiperidinyl, and the like. [0150] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-14 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl. [0151] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above. [0152] The heteroaryl groups can be linked via any position on the ring available for such linkage. For example, pyrrole includes 1-, 2- and 3-pyrrolyl, pyridinyl includes 2-, 3- and 4-pyridinyl, imidazolyl includes 1-, 2-, 4- and 5-imidazolyl, pyrazolyl includes 1-, 3-, 4- and 5-pyrazolyl, triazolyl includes 1-, 4- and 5-triazolyl, tetrazolyl includes 1- and 5-tetrazolyl, pyrimidinyl includes 2-, 4-, 5- and 6- pyrimidinyl, pyridazinyl includes 3- and 4-pyridazinyl, 1,2,3-triazinyl includes 4- and 5-triazinyl, 1,2,4-triazinyl includes 3-, 5- and 6-triazinyl, 1,3,5-triazinyl includes 2-triazinyl, thiophenyl includes 2- and 3- thiophenyl, furanyl includes 2- and 3-furanyl, thiazolyl includes 2-, 4- and 5-thiazolyl, isothiazolyl includes 3-, 4- and 5-isothiazolyl, oxazolyl includes 2-, 4- and 5-oxazolyl, isoxazolyl includes 3-, 4- and 5-isoxazolyl, indolyl includes 1-, 2- and 3-indolyl, isoindolyl includes 1- and 2-isoindolyl, quinolinyl includes 2-, 3- and 4-quinolinyl, isoquinolinyl includes 1-, 3- and 4-isoquinolinyl, quinazolinyl includes 2- and 4-quinoazolinyl, cinnolinyl includes 3- and 4-cinnolinyl, benzothiophenyl includes 2- and 3- benzothiophenyl, and benzofuranyl includes 2- and 3-benzofuranyl. [0153] Some heteroaryl groups include those having from 5 to 9 ring members and from 1 to 3 ring atoms including N, O or S, such as pyrrolyl, pyridinyl, imidazolyl, pyrazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, benzothiophenyl, and benzofuranyl. Other heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrolyl, pyridinyl, imidazolyl, pyrazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5- isomers), thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl. Some other bicyclic and tricyclic heteroaryl groups include those having from 9 to 20 ring members and from 1 to 3 heteroatoms, such as indolyl, isoindolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, benzothiophenyl, benzofuranyl and bipyridinyl. Still other heteroaryl groups include those having from 5- to 6- ring members and from 1 to 2 ring atoms including N, O or S, such as pyrrolyl, pyridinyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl. [0154] As to the biphenyl rings, the following numbering is used with the claims provided herein:
Figure imgf000034_0001
[0155] Unless otherwise defined, the term “unsubstituted or substituted” means that a substituent may or may not be bound to the underlying group modified as unsubstituted or substituted. In the event that the optional substituent is not defined for the underlying group, then the optional substituents are selected from C1-C10 or C1-C6 alkyl, substituted C1-C10 or C1-C6 alkyl, C1-C10 or C1-C6 alkoxy, substituted C1-C10 or C1-C6 alkoxy, C6-C10 aryl, C3-C8 cycloalkyl, C2-C10 heterocyclyl, C1-C10 heteroaryl, substituted C6-C10 aryl, substituted C3-C8 cycloalkyl, substituted C2-C10 heterocyclyl, substituted C1-C10 heteroaryl, -NR80R81, wherein each R80 and R81 is independently hydrogen or C1-C10 or C1-C6 alkyl, halo, cyano, -CO2H or a C1-C6 alkyl ester thereof. [0156] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “alkoxycarbonylalkyl” refers to the group (alkoxy)-C(O)-(alkyl)-. [0157] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three. That is to say that each of the above definitions is constrained by a limitation that, for example, substituted aryl groups are limited to –substituted aryl-(substituted aryl)-substituted aryl. [0158] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan. [0159] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable or superimposable. The present disclosure contemplates various stereoisomers and mixtures thereof; however, it should be understood that the stereocenter depicted for the R, R20, R40, and R60 substituents in the various formulas described herein is fixed as shown. [0160] “Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. [0161] The compounds described herein may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds described herein may exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry. [0162] “Prodrug” means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein, for example, a hydroxy, amino or a carboxyl group, in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or a carboxyl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety. [0163] “Subject” refers to a mammal. The mammal can be a human or non-human animal mammalian organism. A “patient” refers to a human subject. [0164] “Treating” or “treatment” of a disease or disorder in a subject refers to 1) preventing the disease or disorder from occurring in a subject that is predisposed or does not yet display symptoms of the disease or disorder; 2) inhibiting the disease or disorder or arresting its development; or 3) ameliorating or causing regression of the disease or disorder. [0165] “Effective amount” refers to the amount of a compound described herein that is sufficient to treat the disease or disorder afflicting a subject or to prevent such a disease or disorder from arising in said subject or patient. [0166] “Administration” refers to any art recognized form of administration to a subject including oral (including oral gavage), pulmonary, transdermal, sublingual, injection (e.g., intravenous, intramuscular), transmucosal (e.g., vaginal, nasal, etc.), and the like. The route of administration is selected by the attending clinician and is based on factors such as the age, weight and general health of the patient as well as the severity of the condition. In one embodiment, the compounds and pharmaceutical compositions described herein are administered orally. [0167] As used herein, a BRD4 “modulator” may bind to BRD4, but not degrade BRD4. As used herein, a BRD4 “degrader” binds to BRD4 and also degrades BRD4. [0168] As used herein, the term “pharmaceutically acceptable salts” of compounds disclosed herein are within the scope of the present disclosure include acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, allergenic, or irritating, and is bioavailable). When the compound of the present disclosure has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalene sulfonic acid, and p-toluenesolfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound described herein have an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, trimethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine, and ornithine). Such salts can be prepared in situ during isolation and purification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed. Compounds [0169] In some embodiments, provided are compounds represented by formula I-a that bind to or degrade BRD4:
Figure imgf000037_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A is monocyclic 5-or 6-membered heteroaryl having 1-4 heteroatoms selected from O, N, NR3 and S, wherein ring A is unsubstituted or substituted with one to four R14; R and R' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR3, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R1)2, or -CH2C(O)N(R1)2, wherein each R1 is independently hydrogen, C1-C4 alkyl, or both R1 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S; or R and R' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein each of said cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two R6; each of T1 and T2 is independently CR8 or N; each of T, T3, T4, and T5 is independently CR2 or N; and further provided that no more than two of T, T1, T2, and T3 are N; each R2 is independently hydrogen or fluoro, or when two R2 are at the 2,2' or at the 6,6' position, the two R2 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R6; R3 is hydrogen or C1-C4 alkyl; R4 and R5 are independently hydrogen, methyl, or methoxy; each R6 is halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; each R7 is independently hydrogen or C1-C4 alkyl; or two R7 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR3, and S; each R8 is independently hydrogen, halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; and each R14 is independently halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R7)2, and C1-C2 alkoxy, C1-C4 alkoxy, C1-C4 alkoxy substituted with from 1 to 3 halo groups, C3-C6 cycloalkyl, or 5- to 6- membered heteroaryl. [0170] In some embodiments, provided are compounds represented by formula I-a:
Figure imgf000038_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A is a monocyclic, nitrogen containing heteroaryl attached to the carbonyl moiety via a ring carbon atom wherein ring A has 0, 1, or 2 additional nitrogen ring atoms and 0 or 1 additional oxygen or sulfur ring atom, wherein ring A is unsubstituted or substituted with one to four R14, provided that ring A is not pyrimidine or pyrazine; R is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR3, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R1)2, or -CH2C(O)N(R1)2, wherein each R1 is independently hydrogen, C1-C4 alkyl, or both R1 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S; R' is H; or R and R' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R6; each of T1 and T2 is independently CR8 or N; each of T, T3, T4, and T5 is independently CR2 or N; and further provided that no more than two of T, T1, T2, and T3 are N; each R2 is independently hydrogen or fluoro, or when two R2 are at the 2,2' or at the 6,6' position, the two R2 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R6; R3 is hydrogen or C1-C4 alkyl; R4 and R5 are independently hydrogen, methyl, or methoxy; each R6 is halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; each R7 is independently hydrogen or C1-C4 alkyl; or two R7 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl from zero to two additional heteroatoms selected from O, N, NR3, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR3, and S; each R8 is independently hydrogen, halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; and each R14 is independently halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R7)2, and C1-C2 alkoxy, C1-C4 alkoxy, C1-C4 alkoxy substituted with from 1 to 3 halo groups, C3-C6 cycloalkyl, or 5- to 6- membered heteroaryl; and provided that the compound at 1 µM concentration degrades BRD4 by 30% or more. [0171] In some embodiments provided are compounds represented by formula Ia-a:
Figure imgf000039_0001
Ia-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A is a monocyclic, nitrogen containing heteroaryl attached to the carbonyl moiety via a ring carbon atom wherein ring A has 0, 1, or 2 additional nitrogen ring atoms and 0 or 1 additional oxygen or sulfur ring atom, wherein ring A is unsubstituted or substituted with one to four R14, provided that ring A is not pyrimidine or pyrazine; R is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR3, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R1)2, or -CH2C(O)N(R1)2, wherein each R1 is independently hydrogen, C1- C4 alkyl, or both R1 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S; R' is H; or R and R' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R6; each of T1 and T2 is independently CR8 or N; T is CR2 or N; and further provided that no more than one of T, T1, and T2 is N; each R2 is independently hydrogen or fluoro, or when two R2 are at the 2,2' or at the 6,6' position, the two R2 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R6; R3 is hydrogen or C1-C4 alkyl; R4 and R5 are independently hydrogen, methyl, or methoxy; each R6 is halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; each R7 is independently hydrogen or C1-C4 alkyl; or two R7 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR3, and S; each R8 is independently hydrogen, halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; and each R14 is independently halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R7)2, and C1-C2 alkoxy, C1-C4 alkoxy, C1-C4 alkoxy substituted with from 1 to 3 halo groups, C3-C6 cycloalkyl, or 5- to 6- membered heteroaryl; and provided that the following compounds are excluded:
,
Figure imgf000041_0001
, ,
, ,
Figure imgf000042_0001
, ,
Figure imgf000043_0001
. [0172] In some embodiments of formula I-a or Ia-a, each of T, T1, and T2 is CH. [0173] In some embodiments of formula I-a or Ia-a, one of T, T1, and T2 is N. [0174] In some embodiments of formula I-a or Ia-a, both R and R' are H. In some embodiments of formula I-a or Ia-a, R and R' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl. In some embodiments of formula I-a or Ia-a, the R and R' together with the carbon atom to which they are attached form a spirocyclopropyl or spirooxetanyl group. [0175] In some embodiments of formula I-a or Ia-a, each R2 is independently hydrogen or fluoro. [0176] In some embodiments of formula I-a or Ia-a, ring A is
Figure imgf000043_0002
, , ,
Figure imgf000043_0003
V is N or CR14; R10 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, ethoxy, and C3-C6 cycloalkyl; R11 is selected from the group consisting of C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, cyano, methoxy, ethoxy, and C3-C6 cycloalkyl; R12 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, and ethoxy; and h is 0, 1, 2, or 3. [0177] In some embodiments of formula I-a or Ia-a, the compounds are represented by formula II-A-a or II-B-a:
Figure imgf000044_0001
II-A-a II-B-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. [0178] In some embodiments of formula I-a or Ia-a, the compounds are represented by formula III-a:
Figure imgf000044_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. [0179] In some embodiments of formula I-a or Ia-a, the compounds are represented by formula IV-a:
Figure imgf000044_0003
IV-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. [0180] In some embodiments of formula I-a or Ia-a, the compounds are represented by formula V-a:
Figure imgf000045_0001
V-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, mixture of stereoisomers, or tautomer of each thereof. [0181] In some embodiments of formula I-a or Ia-a, each R2 is hydrogen. [0182] In some embodiments of formula I-a or Ia-a, both R4 and R5 are methyl. [0183] In some embodiments of formula I-a or Ia-a, both R8 are hydrogen. [0184] In some embodiments of formula I-a or Ia-a, one or both R8 are fluoro. [0185] In some embodiments of formula I-a or Ia-a, each R14 independently is hydrogen, halo, or C1-C4 alkyl. [0186] In some embodiments of formula I-a or Ia-a, each R14 is hydrogen. [0187] In some embodiments of formula I-a or Ia-a, R is hydrogen, CH3, CF3, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2C(O)N(CH3)2, -CH2C(O)OH, -CH2C(O)OMe, -CH2C(O)NHEt, -CH2C(O)N(Et)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2(morpholin-1-yl), -CH2CH2(pyrrolidin-1-yl), -CH2C(O)(morpholin-1-yl), or -CH2C(O)(pyrrolidin-1-yl). In some embodiments of formula I-a or Ia-a, R is CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2. In some embodiments of formula I-a or Ia-a, R is -CH2C(O)OH, or -CH2C(O)OC1-5alkyl. [0188] In some embodiments, provided herein are compounds represented by formula I-b that bind to or degrade BRD4:
Figure imgf000046_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A20 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted with one to four R29; R20 and R20' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR23, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R21)2, or -CH2C(O)N(R21)2, wherein each R21 is independently hydrogen, C1-C4 alkyl, or both R21 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S; or R20 and R20' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein each of said cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two R26; each of T21 and T22 is independently CR28 or N; each of T20, T23, T24, and T25 is independently CR22 or N; and further provided that no more than two of T20, T21, T22, and T23 are N; each R22 is independently hydrogen or fluoro, or when two R22 are at the 2,2' or at the 6,6' position, the two R22 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with zero, one, or two R26; R23 is hydrogen or C1-C4 alkyl; R24 and R25 are independently hydrogen, methyl, or methoxy; each R26 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; each R27 is independently hydrogen or C1-C4 alkyl; or two R27 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR23, and S; each R28 is independently hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; Q20 is C, CH, or N; Q25 and Q26 are independently C or N provided that both cannot be N; each of X20 and Y20 is independently C, CR29, O, S, N, or NR34, provided that ring B20 formed thereby is a 5-membered heteroaryl; each R29 is independently halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R27)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R34 is hydrogen or C1-C4 alkyl, provided that: (i)
Figure imgf000047_0001
, each of Q21, Q22, Q23 and Q24 is independently N or CR32; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; the number of Q21-Q26 that are N is from one to three; and when either Q25 or Q26 is N, then neither X20 or Y20 can be O, S or NR34; and
Figure imgf000047_0002
each of t20 and v20 is independently zero, one, or two; Q27 and Q28 are independently CHR32 or NR33; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; R33 is hydrogen or C1-C3 alkyl; and when Q25 is N, then Q28 is CHR32. [0189] In some embodiments, provided herein are compounds represented by formula I-b:
Figure imgf000047_0003
I-b or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A20 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is substituted with zero to four R29; R20 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR23, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R21)2, or -CH2C(O)N(R21)2, wherein each R21 is independently hydrogen, C1-C4 alkyl, or both R21 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S; R20' is H; or R20 and R20' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R26; each of T21 and T22 is independently CR28 or N; each of T20, T23, T24, and T25 is independently CR22 or N; and further provided that no more than two of T20, T21, T22, and T23 are N; each R22 is independently hydrogen or fluoro, or when two R22 are at the 2,2' or at the 6,6' position, the two R22 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are substituted with zero, one, or two R26; R23 is hydrogen or C1-C4 alkyl; R24 and R25 are independently hydrogen, methyl, or methoxy; each R26 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; each R27 is independently hydrogen or C1-C4 alkyl; or two R27 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR23, and S; each R28 is independently hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; Q20 is C, CH, or N; Q25 and Q26 are independently C or N provided that both cannot be N; each of X20 and Y20 is independently C, CR29, O, S, N, or NR34, provided that ring B20 formed thereby is a 5-membered heteroaryl; each R29 is independently halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R27)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R34 is hydrogen or C1-C4 alkyl, provided that: (i)
Figure imgf000048_0001
, each of Q21, Q22, Q23 and Q24 is independently N or CR32; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; the number of Q21-Q26 that are N is from one to three; and when either Q25 or Q26 is N, then neither X20 or Y20 can be O, S or NR34; and (ii) when
Figure imgf000049_0001
, each of t20 and v20 is independently zero, one, or two; Q27 and Q28 are independently CHR32 or NR33; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; R33 is hydrogen or C1-C3 alkyl; and when Q25 is N, then Q28 is CHR32, and (iii) the compound at 1 µM concentration degrades BRD4 by 30% or more. [0190] In some embodiments, provided herein are compounds represented by formula Ia-b:
Figure imgf000049_0002
Ia-b or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A20 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R29; R20 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR23, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R21)2, or -CH2C(O)N(R21)2, wherein each R21 is independently hydrogen, C1-C4 alkyl, or both R21 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S; R20' is H; or R20 and R20' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R26; each of T21 and T22 is independently CR28 or N; T20 is CR22 or N; and further provided that no more than one of T20, T21, and T22 is N; each R22 is independently hydrogen or fluoro, or when two R22 are at the 2,2' or at the 6,6' position, the two R22 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R23 is hydrogen or C1-C4 alkyl; R24 and R25 are independently hydrogen, methyl, or methoxy; each R26 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; each R27 is independently hydrogen or C1-C4 alkyl; or two R27 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR23, and S; each R28 is independently hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; Q is C, CH, or N; Q25 and Q26 are independently C or N provided that both cannot be N; each of X20 and Y20 is independently C, CR29, O, S, N, or NR34, provided that ring B20 formed thereby is a 5-membered heteroaryl; each R29 is independently hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R27)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R34 is hydrogen or C1-C4 alkyl, provided that: (i)
Figure imgf000050_0001
, each of Q1, Q2, Q3 and Q4 is independently N or CR12; R12 is hydrogen, halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; the number of Q1-Q6 that are N is from one to three; and when either Q5 or Q6 is N, then neither X or Y can be O, S or NR14; and
Figure imgf000050_0002
each of t20 and v20 is independently zero, one, or two; Q27 and Q28 are independently CHR32 or NR33; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; R33 is hydrogen or C1-C3 alkyl; and when Q25 is N, then Q28 is CHR32; and (iii) the following compounds are excluded:
Figure imgf000051_0001
Figure imgf000052_0001
. [0191] In some embodiments of formula I-b or formula Ia-b, each of T20, T21, and T22 is CH. In some embodiments of formula I-b or formula Ia-b, one of T20, T21, and T22 is N. [0192] In some embodiments of formula I-b or formula Ia-b, both R20 and R20' are H. In some embodiments of formula I-b or formula Ia-b, R20 and R20' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl. In some embodiments of formula I-b or formula Ia-b, R20 and R20' together with the carbon atom to which they are attached form a spirocyclopropyl or spirooxetanyl group. [0193] In some embodiments of formula I-b or formula Ia-b, each R22 is independently hydrogen or fluoro. [0194] In some embodiments of formula I-b or formula Ia-b, the compounds are represented by formula
Figure imgf000052_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R20, R20′, R22, R24, R25, R28, X20, Y20, Q25, Q26, ring A20, and ring B20 are as defined herein. [0195] In some embodiments of formula I-b or formula Ia-b, the compounds are represented by formula II-A-b or II-B-b:
Figure imgf000053_0001
II-A-b II-B-b or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R20, R20′, R22, R24, R25, R28, X20, Y20, Q25, Q26, ring A20, and ring B20 are as defined herein. [0196] In some embodiments of formula I-b or formula Ia-b, the compounds are represented by formula III-b:
Figure imgf000053_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: t20 is zero, one, or two; and R32 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; and R20, R20′, R22, R24, R25, R28, X20, Y20, and ring B20 are as defined herein. [0197] In some embodiments of formula I-b or formula Ia-b, the compounds are represented by formula IV-b:
Figure imgf000054_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: each of Q21, Q22, Q23 and Q24 is independently N or CR32; and R32 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; and wherein R20, R20′, R22, R24, R25, R28, X20, Y20, Q21, Q22, Q23, Q24, Q25, Q26, and ring B20 are as defined herein. [0198] In some embodiments of formula I-b or formula Ia-b, the compounds are represented by formula V-b:
Figure imgf000054_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: v20 is zero, one, or two; Q27 and Q28 are independently CHR32 or NR33; R32 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; and R33 is hydrogen or C1-C4 alkyl; and R20, R20′, R22, R24, R25, R28, X20, Y20, Q25, Q26, and ring B20 are as defined herein. [0199] In some embodiments of formula I-b or formula Ia-b, each R22 is hydrogen. [0200] In some embodiments of formula I-b or formula Ia-b, both R24 and R25 are methyl. [0201] In some embodiments of formula I-b or formula Ia-b, both R28 are hydrogen. In some embodiments of formula I-b or formula Ia-b, one or both R28 are fluoro. [0202] In some embodiments of formula I-b or formula Ia-b, each R29 independently is hydrogen, halo, or C1-C4 alkyl. In some embodiments of formula I-b or formula Ia-b, each R29 is hydrogen. [0203] In some embodiments of formula I-b or formula Ia-b, R20 is hydrogen, -CH3, -CF3, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2C(O)N(CH3)2, -CH2C(O)OH, -CH2C(O)OMe, -CH2C(O)NHEt, -CH2C(O)N(Et)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2(morpholin-1-yl), -CH2CH2(pyrrolidin-1-yl), -CH2C(O)(morpholin-1-yl), or -CH2C(O)(pyrrolidin-1-yl). In some embodiments of formula I-b or formula Ia-b, R20 is -CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2. In some embodiments of formula I-b or formula Ia-b, R20 is -CH2C(O)OH or -CH2C(O)OC1-5alkyl. [0204] In some embodiments, provided are compounds represented by formula I-c that bind to or degrade BRD4:
Figure imgf000055_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A40 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6- membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R49; R40 and R40' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR43, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R41)2, or -CH2C(O)N(R41)2, wherein each R41 is independently hydrogen, C1-C4 alkyl, or both R41 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S; or R40 and R40' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein each of said cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two R46; each of T41 and T42 is independently CR48 or N; each of T40, T43, T44 and T45 is independently CR42 or N; and further provided that no more than two of T40, T41, T42 and T43 are N; each R42 is independently hydrogen or fluoro, or when two R42 are at the 2,2' or at the 6,6' position, the two R42 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R46; R43 is hydrogen or C1-C4 alkyl; R44 and R45 are independently hydrogen, methyl, or methoxy; each R46 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each R47 is independently hydrogen or C1-C4 alkyl; or two R47 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR43, and S; each R48 is independently hydrogen, halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each of Q41, Q42, Q43 and Q44 are independently N or CR50 provided that no more than three of Q41, Q42, Q43, or Q44 are N and provided that one of R50 is a bond to the NH-C(O)-; each R50 is independently selected from hydrogen and C1-C3 alkyl; Q45 and Q46 are independently C or N provided that both cannot be N; and each R49 is independently halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R47)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups. [0205] In some embodiments provided are compounds represented by formula I-c:
Figure imgf000056_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A40 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6- membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R49; R40 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR43, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R41)2, or -CH2C(O)N(R41)2, wherein each R41 is independently hydrogen, C1-C4 alkyl, or both R41 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S; R40' is H; or R40 and R40' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R46; each of T41 and T42 is independently CR48 or N; each of T40, T43, T44 and T45 is independently CR42 or N; and further provided that no more than two of T40, T41, T42 and T43 are N; each R42 is independently hydrogen or fluoro, or when two R42 are at the 2,2' or at the 6,6' position, the two R42 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R46; R43 is hydrogen or C1-C4 alkyl; R44 and R45 are independently hydrogen, methyl, or methoxy; each R46 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each R47 is independently hydrogen or C1-C4 alkyl; or two R47 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR43, and S; each R48 is independently hydrogen, halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each of Q41, Q42, Q43 and Q44 are independently N or CR50 provided that no more than three of Q41, Q42, Q43, or Q44 are N and provided that one of R50 is a bond to the NH-C(O)-; each R50 is independently selected from hydrogen and C1-C3 alkyl; Q45 and Q46 are independently C or N provided that both cannot be N; and each R49 is independently halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R47)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and provided that the compound at 1 µM concentration degrades BRD4 by 30% or more. [0206] In some embodiments provided are compounds represented by formula Ia-c:
Figure imgf000058_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A40 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6- membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R49; R40 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR43, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R41)2, or -CH2C(O)N(R41)2, wherein each R41 is independently hydrogen, C1-C4 alkyl, or both R41 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S; R40' is H; or R40 and R40' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R46; each of T41 and T42 is independently CR48 or N; T40 is CR42 or N; and further provided that no more than one of T40, T41, and T42 is N; each R42 is independently hydrogen or fluoro, or when two R42 are at the 2,2' or at the 6,6' position, the two R42 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R46; R43 is hydrogen or C1-C4 alkyl; R44 and R45 are independently hydrogen, methyl, or methoxy; each R46 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each R47 is independently hydrogen or C1-C4 alkyl; or two R47 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR43, and S; each R48 is independently hydrogen, halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each of Q41, Q42, Q43 and Q44 are independently N or CR50 provided that no more than three of Q41, Q42, Q43, or Q44 are N and provided that one of R50 is a bond to the NH-C(O)-; each R50 is independently selected from hydrogen and C1-C3 alkyl; Q45 and Q46 are independently C or N provided that both cannot be N; and each R49 is independently halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R47)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and provided that the following compounds are excluded:
Figure imgf000059_0001
. [0207] In some embodiments of formula I-c or formula Ia-c, each of T40, T41, and T42 is CH. [0208] In some embodiments of formula I-c or formula Ia-c, one of T40, T41, and T42 is N. [0209] In some embodiments of formula I-c or formula Ia-c, both R40 and R40' are H. In some embodiments of formula I-c or formula Ia-c, R40 and R40' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl. In some embodiments of formula I-c or formula Ia-c, the R40 and R40' together with the carbon atom to which they are attached form a spirocyclopropyl or spirooxetanyl group. [0210] In some embodiments of formula I-c or formula Ia-c, each R42 is independently hydrogen or fluoro. [0211] In some embodiments of formula I-c or formula Ia-c, the compounds are represented by formula II-c:
Figure imgf000059_0002
II-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. [0212] In some embodiments of formula I-c or formula Ia-c, the compounds are represented by formula II-A-c or II-B-c:
Figure imgf000060_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof; and wherein R2, R4, R5, R8, Q1, Q2, Q3, Q4, Q5, Q6, and ring A are as defined herein. [0213] In some embodiments of formula I-c or formula Ia-c, the compounds are represented by formula III-c:
Figure imgf000060_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: t40 is zero, one or two; and R52 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; and wherein R42, R44, R45, R48, Q41, Q42, Q43, Q44, Q45, Q46, and ring A40 are as defined herein. [0214] In some embodiments of formula I-c or formula Ia-c, the compounds are represented by formula IV-c:
Figure imgf000061_0001
IV-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: v40 is zero, one, or two; and R52 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; and wherein R42, R44, R45, R48, Q41, Q42, Q43, Q44, Q45, and Q46 are as defined herein. [0215] In some embodiments of formula I-c or formula Ia-c, the compounds are represented by formula V-c:
Figure imgf000061_0002
V-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: v40 is zero, one, or two; and R52 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; and wherein R42, R44, R45, R48, Q41, Q42, Q43, Q44, Q45, and Q46 are as defined herein. [0216] In some embodiments of formula I-c or formula Ia-c, each R42 is hydrogen. [0217] In some embodiments of formula I-c or formula Ia-c, both R44 and R45 are methyl. [0218] In some embodiments of formula I-c or formula Ia-c, both R48 are hydrogen. [0219] In some embodiments of formula I-c or formula Ia-c, one or both R48 are fluoro. [0220] In some embodiments of formula I-c or formula Ia-c, each R49 independently is hydrogen, halo, or C1-C4 alkyl. In some embodiments of formula I-c or formula Ia-c, each R49 is hydrogen. [0221] In some embodiments of formula I-c or formula Ia-c, R40 is hydrogen, -CH3, -CF3, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2C(O)N(CH3)2, -CH2C(O)OH, -CH2C(O)OMe, -CH2C(O)NHEt, -CH2C(O)N(Et)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2(morpholin-1-yl), -CH2CH2(pyrrolidin-1-yl), -CH2C(O)(morpholin-1-yl), or -CH2C(O)(pyrrolidin-1-yl). In some embodiments of formula I-c or formula Ia-c, R40 is -CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2. In some embodiments of formula I-c or formula Ia-c, R40 is -CH2C(O)OH or -CH2C(O)OC1-5alkyl. [0222] In some embodiments, provided is a compound represented by formula I-d:
Figure imgf000062_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring B60 is a monocyclic heteroaryl ring unsubstituted or substituted with one to four R74; monocyclic heteroaryl optionally fused to a 5- to 7-membered heterocycloalkyl ring and unsubstituted or substituted with one to four R74; or a bicyclic heteroaryl ring unsubstituted or substituted with one to four R74; R60 and R60' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R61)2, or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; or R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein each of said cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two R66; each of T61 and T62 is independently CR68 or N; each of T60, T63, T64, and T65 is independently CR62 or N; and further provided that no more than two of T60, T61, T62, and T63 are N; each R62 is independently hydrogen or fluoro, or when two R62 are at the 2,2' or at the 6,6' position, the two R62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R66; R63 is hydrogen or C1-C4 alkyl; R64 and R65 are independently hydrogen, methyl, or methoxy; each R66 is halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; each R67 is independently hydrogen or C1-C4 alkyl; or two R67 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR63 and S, or 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N, NR63 and S; each R68 is independently hydrogen, halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; and each R74 is independently halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R67)2, C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups, C3-C6 cycloalkyl, or 5- to 6- membered heteroaryl. [0223] In some embodiments, a compound of formula I-d, at 1 µM concentration, degrades BRD4 by 30% or more. [0224] In some embodiments, provided herein are compounds of formula IB-d which degrade BRD4:
Figure imgf000063_0001
IB-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein q60 is zero, one or two; R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene- N(R61)2 or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; R60' is hydrogen; or R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; T60 is CR62 or N; each of T61 and T62 is independently CR68 or N; further provided that no more than two of T60, T61, and T62 are N; Q61 and Q64 are independently N or CR69; R62 is H; each R63 is C1-C3 alkyl; R64 and R65 are independently hydrogen, methyl or methoxy; each R68 is independently selected from hydrogen, halo, cyano, hydroxy, N(R67)2, C1-C3 alkyl, or C1-C3 alkoxy; where each R67 is independently hydrogen or C1-C4 alkyl; and each R69 is independently hydrogen, hydroxy, cyano, halo, amino, (C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 halo groups, C1-C4 alkoxy, C1-C4 alkoxy substituted with from 1 to 3 halo groups; or C1-C4 alkyl substituted with C1-C2 alkoxy; with the proviso that the following compounds are excluded: ,
Figure imgf000064_0001
, ,
Figure imgf000065_0001
, an . [0225] In some embodiments of formula IB-d, Q61 is nitrogen and Q64 is CR69. [0226] In some embodiments of formula IB-d, R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, or -CH2C(O)N(R61)2. [0227] In some embodiments of formula IB-d, R60′ is hydrogen. [0228] In some embodiments of formula IB-d, R60 and R60′ together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl. [0229] In some embodiments of formula IB-d, R60 and R60′ together with the carbon atom to which they are attached form an oxetane ring. [0230] In some embodiments of formula IB-d, each R68 is independently selected from hydrogen and fluoro. [0231] In some embodiments of formula IB-d, said compound is represented by formula IIB-d:
Figure imgf000065_0002
IIB-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; R60' is hydrogen; T62 is N or CH; Q61 is N or CR69; and R69 is selected from fluoro, chloro, methyl, and methoxy; and q60, R64, and R65 are as defined herein. [0232] In some embodiments of formula IB-d, said compound is represented by formula IIIB-d:
Figure imgf000066_0001
IIIB-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; T62 is N or CH; Q61 is N or CR69; and R69 is selected from fluoro, chloro, methyl, and methoxy; and q60, R64, R65, and Q61 are as defined herein. [0233] In some embodiments of formula IB-d, R60 is -CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2. [0234] In some embodiments, provided herein is a compound of formula ID-d:
Figure imgf000066_0002
ID-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof where p60 is zero, one or two; R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R61)2 or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl optionally having an additional one to two heteroatoms selected from O, N, NR63, and S; R60' is hydrogen; or R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein each of said cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two R66; each R62 is independently hydrogen or fluoro, or when two R62 are at the 2,2' or at the 6,6' position, the two R62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R66; each R63 is independently hydrogen or C1-C4 alkyl; R64 and R65 are independently hydrogen, methyl or methoxy; each R66 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, -N(R67)2, cyano, halo, and hydroxyl; each R67 is independently hydrogen or C1-C3 alkyl; or two R67 together with the nitrogen atom to which they are attached form a form a 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms selected from O, N, NR63 and S; or 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from O, N, NR63 and S; each R68 is independently hydrogen, halo, cyano, hydroxy, N(R67)2, C1-C3 alkyl, or C1-C3 alkoxy; Q61 and Q64 are independently N or CR69; and each R69 is independently hydrogen, C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, or ethoxy. [0235] In some embodiments, a compound of formula ID-d is not a compound of formula IB-d. [0236] In some embodiments, a compound of formula ID-d is selected from , , , a
Figure imgf000068_0001
[0237] In some embodiments, provided are compounds represented by formula IC-d which are BRD4 modulators or BRD4 degraders:
Figure imgf000069_0001
IC-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A60 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R69; R60 and R60' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R61)2, or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; or R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl , wherein each of said cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two R66; each of T61 and T62 is independently CR68 or N; each of T60, T63, T64, and T65 is independently CR62 or N; and further provided that no more than two of T60, T61, T62, and T63 are N; each R62 is independently hydrogen or fluoro, or when two R62 are at the 2,2' or at the 6,6' position, the two R62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R66; R63 is hydrogen or C1-C4 alkyl; R64 and R65 are independently hydrogen, methyl, or methoxy; each R66 is halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; each R67 is independently hydrogen or C1-C4 alkyl; or two R67 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR63, and S; each R68 is independently hydrogen, halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; Q60 is C, CH, or N; Q65 and Q66 are independently C or N provided that both cannot be N; Y60 is C, CR69, O, S, N, or NR74, provided that ring B60 formed thereby is a 5-membered heteroaryl; each R69 is independently halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R67)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R74 is hydrogen or C1-C4 alkyl. [0238] In some embodiments, provided are compounds represented by formula IC-d:
Figure imgf000070_0001
IC-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A60 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R69; R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R61)2, or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; R60' is H; or R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R66; each of T61 and T62 is independently CR68 or N; each of T60, T63, T64, and T65 is independently CR62 or N; and further provided that no more than two of T60, T61, T62, and T63 are N; each R62 is independently hydrogen or fluoro, or when two R62 are at the 2,2' or at the 6,6' position, the two R62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R66; R63 is hydrogen or C1-C4 alkyl; R64 and R65 are independently hydrogen, methyl, or methoxy; each R66 is halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; each R67 is independently hydrogen or C1-C4 alkyl; or two R67 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR63, and S; each R68 is independently hydrogen, halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; Q60 is C, CH, or N; Q65 and Q66 are independently C or N provided that both cannot be N; Y60 is C, CR69, O, S, N, or NR74, provided that ring B60 formed thereby is a 5-membered heteroaryl; each R69 is independently halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R67)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R74 is hydrogen or C1-C4 alkyl; provided that the compound at 1 µM concentration degrades BRD4 by 30% or more. [0239] In some embodiments are provided compounds represented by formula ICa-d:
Figure imgf000071_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A60 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R69; R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R61)2, or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; R60' is H; or R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R66; each of T61 and T62 is independently CR68 or N; T60 is CR62 or N; and further provided that no more than one of T60, T61, and T62 is N; each R62 is independently hydrogen or fluoro, or when two R62 are at the 2,2' or at the 6,6' position, the two R62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R66; R63 is hydrogen or C1-C4 alkyl; R64 and R65 are independently hydrogen, methyl, or methoxy; each R66 is halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; each R67 is independently hydrogen or C1-C4 alkyl; or two R67 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two heteroatoms selected from O, N, NR63, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR63, and S; each R68 is independently hydrogen, halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; Q60 is C, CH, or N; Q65 and Q66 are independently C or N provided that both cannot be N; Y60 is C, CR69, O, S, N, or NR74, provided that ring B60 formed thereby is a 5-membered heteroaryl; each R69 is independently halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R67)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R74 is hydrogen or C1-C4 alkyl; provided that the following compounds are excluded:
,
Figure imgf000073_0001
,
, , ,
Figure imgf000074_0001
[0240] In some embodiments of formula IC-d or formula ICa-d, each of T60, T61, and T62 is CH. [0241] In some embodiments of formula IC-d or formula ICa-d, one of T60, T61, and T62 is N. [0242] In some embodiments of formula IC-d or formula ICa-d, both R60 and R60' are H. In some embodiments of formula IC-d or formula ICa-d, R60 and R60' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl. In some embodiments of formula IC-d or formula ICa-d, the R60 and R60' together with the carbon atom to which they are attached form a spirocyclopropyl or spirooxetanyl group. [0243] In some embodiments of formula IC-d or formula ICa-d, each R62 is independently hydrogen or fluoro. [0244] In some embodiments of formula IC-d or formula ICa-d, the compounds are represented by formula VIC-d:
Figure imgf000075_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R60, R60′, R62, R64, R65, R68, Q60, Q65, Q66, Y60, and ring A60 are as defined herein. [0245] In some embodiments of formula IC-d or formula ICa-d, the compounds are represented by formula VI-AC-d or VI-BC-d:
Figure imgf000075_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: q60 is zero, one or two; Q61 and Q64 are independently N or CR69; and two R62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, or a 5- to 6-membered heteroaryl,wherein each of said cycloalkyl, phenyl, heterocyclyl and heteroaryl are unsubstituted or substituted with one to two R66; and wherein R60, R60′, R62, R64, R65, R68, and R69 are as defined herein. [0246] In some embodiments of formula IC-d or formula ICa-d, the compounds represented by formula VIIC-d:
Figure imgf000076_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein r60 is zero, one, two, or three; and wherein R60, R60′, R62, R64, R65, R68, and R69 are as defined herein. [0247] In some embodiments of formula IC-d or formula ICa-d, the compounds are represented by formula VIIIC-d:
Figure imgf000076_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein r60 is zero, one, two, or three; and wherein R60, R60′, R62, R64, R65, R68, and R69 are as defined herein. [0248] In some embodiments of formula IC-d or formula ICa-d, the compounds are represented by formula IXC-d:
Figure imgf000077_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein s60 is zero, one, two, three, or four; and wherein R60, R60′, R62, R64, R65, R68, and R69 are as defined herein. [0249] In some embodiments of formula IC-d or formula ICa-d, each R62 is hydrogen. [0250] In some embodiments of formula IC-d or formula ICa-d, both R64 and R65 are methyl. [0251] In some embodiments of formula IC-d or formula ICa-d, both R68 are hydrogen. [0252] In some embodiments of formula IC-d or formula ICa-d, one or both R68 are fluoro. [0253] In some embodiments of formula IC-d or formula ICa-d, each R69 independently is hydrogen, halo, or C1-C4 alkyl. In some embodiments of formula IC-d or formula ICa-d, each R69 is hydrogen. [0254] In some embodiments of formula IC-d or formula ICa-d, R60 is hydrogen, -CH3, -CF3, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2C(O)N(CH3)2, -CH2C(O)OH, -CH2C(O)OMe, -CH2C(O)NHEt, -CH2C(O)N(Et)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2(morpholin-1-yl), -CH2CH2(pyrrolidin-1-yl), -CH2C(O)(morpholin-1-yl), or -CH2C(O)(pyrrolidin-1-yl). In some embodiments of formula IC-d or formula ICa-d, R60 is -CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2. In some embodiments of formula IC-d or formula ICa-d, R60 is -CH2C(O)OH or -CH2C(O)OC1-5alkyl. [0255] Representative and non-limiting examples of compounds within the scope of formula I-a, Ia-a, II- a, II-A-a, II-B-a, III-a, IV-a, V-a, I-b, Ia-b, II-b, II-A-b, II-B-b, III-b, IV-b, V-b, I-c, Ia-c, II-c, II-A-c, II- B-c, III-c, IV-c, V-c, I-d, IB-d, IIB-d, IIIB-d, IC-d, ICa-d, ID-d, VIC-d, VI-AC-d, VI-BC-d, VIIC-d, VIIIC-d, IXC-d, I-e, or I-f, or a pharmaceutically acceptable salts, solvates, stereoisomers, mixtures of stereoisomers, or tautomer of each thereof, are set forth in the following Table 1 below. The names of compounds have been generated using either ChemDraw v 20.1.1.125, ChemAxon MarvinJS v 21.18.0, or ISIS/Draw, a chemical structure drawing program developed by MDL Information Systems. Table 1
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
General Synthetic Methods [0256] The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0257] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein. [0258] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), Emka-Chemce (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 2016), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 2001), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 2019), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 8th Edition, 2019), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Synthesis of Representative Compounds [0259] The general synthesis of the compounds described herein is set forth in the reaction schemes below. Scheme 1 illustrates a general method for preparing compounds of formula IA-a, I-b, I-c, or IB-d. In Scheme 1, substituents W, W', R, R2, R2', R4, R5, R8, and R8' are as defined throughout the specification, and are used generally, such that:
Figure imgf000138_0002
[0260] LG is a leaving group (including, but not limited to, Br, Cl, I, triflate, and the like) and PG is a protecting group (including, but not limited to, Boc and the like). Ring X is a monocyclic 5- or 6- membered heteroaryl, as in compounds of Formula I-a, a 5,6-bicyclic, as in compounds of Formula I-b, a 6,5- or 6,6-bicyclic, as in compounds of Formula I-c, or a pyrazole-containing bicyclic, as in compounds of Formula IB-d.
Figure imgf000138_0001
Scheme 1 [0261] In some embodiments, Scheme 2 illustrates a general method for preparing compounds of formula I-a, I-b, I-c, or IB-d. In Scheme 2, substituents R, R′, R2, R4, R5, T, T1, T2, T3, T4, and T5 are as defined throughout the specification, and are used generally, such that: R is R, R20, R40, or R60; R’ is R’, R20’, R40’, or R60’; R2 is R2, R22, R42, or R62; R4 is R4, R24, R44, or R64; R5 is R5, R25, R45, or R65; T is T, T20, T40, or T60; T1 is T1, T21, T41, or T61; T2 is T2, T22, T42, or T62; T3 is T3, T23, T43, or T63; T4 is T4, T24, T44, or T64; and T5 is T5, T25, T45, or T65. [0262] LG is a leaving group (including, but not limited to, Br, Cl, I, triflate, and the like) and PG is a protecting group (including, but not limited to, Boc and the like). Ring X is a monocyclic 5- or 6- membered heteroaryl, as in compounds of Formula I-a, a 5,6-bicyclic, as in compounds of Formula I-b, a 6,5- or 6,6-bicyclic, as in compounds of Formula I-c, or a pyrazole-containing bicyclic, as in compounds of Formula IB-d.
Figure imgf000140_0001
Scheme 2 [0263] In some embodiments, Scheme 3 illustrates one method for preparing compounds of formula I-a, I-b, I-c, or IB-d. In Scheme 3, the specific compound structures are depicted solely for illustrative purposes.
Figure imgf000141_0001
Scheme 3 [0264] As to the reaction in Scheme 3, the first step is a conventional Suzuki coupling reaction wherein at least a stoichiometric equivalent of 3-(N-Boc-amino) phenyl boronic acid, compound 2, is combined with JQ1, compound 1, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g, palladium diacetate) and a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. Both compound 1 and compound 2 are commercially available from Sigma Aldrich, St. Louis, Missouri, USA. The reaction is typically maintained at from 10° to 65°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 3. [0265] In the next step, the t-butoxycarbonyl (t-BOC) protecting group is removed by conventional conditions to provide for compound 4. The t-BOC group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 4. [0266] In the final step, at least a stoichiometric amount of a suitably substituted carboxylic acid ring X compound, compound 5, is combined with compound 4 under conventional amidation reaction conditions well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC) as an activation agent for the carboxyl group. Other activation agents are well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N- dimethylformamide, and the like. The reaction is typically conducted at from about 0º to about 30º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 6. [0267] Other variants of compound 1 are commercially available or can be prepared by conventional reaction conditions well known in the art. For example, the following acid and esters, 7-9 corresponding to the amido starting materials are commercially available from Sigma Aldrich, St. Louis, Missouri, USA.
Figure imgf000142_0001
[0268] Each of the above compounds, 7, 8 and 9, can be derivatized as desired. For example, the carboxyl group can be amidated as described above. In one embodiment, amidation can utilize an amino acid or a diamino acid wherein N-hydroxy succinimide is included in the reaction medium to inhibit racemization. In another embodiment, amidation includes an alkylamine, a nitrogen-containing heterocycloalkyl, or cycloalkylamino (e.g.,-NH-cycloalkyl) which provides for compounds 40, 41 and 42:
Figure imgf000142_0002
where R16 is hydrogen or C1-C6 alkyl, g is one, two, three or four; and f is zero, one, two or three. [0269] In one embodiment, the carboxyl group is reduced under conventional conditions to provide for the corresponding -CH2CH2OH group. The hydroxyl group can be acylated by conventional methods to provide for -CH2CH2OC(O)R16 substituents where R16 is as defined above. [0270] In one embodiment, the carboxyl group is reduced under conventional conditions to provide for the corresponding aldehyde, e.g., -CH2C(O)H. The aldehyde can then be subjected to conventional reductive amination to provide for the following substituent -CH2CH2NHR3 where R3 is as defined above. [0271] In one embodiment, the carboxyl group can be subjected to decarboxylation to provide for the methyl substituent. [0272] These modifications allow for the preparation of compounds represented by the formula 10-12:
Figure imgf000143_0001
where R16 is as defined above. [0273] Schemes 4-8 illustrates some embodiments for preparing compounds of formula I-a, I-b, I-c, or IB-d having a tricyclic structure where R2 and R2' together with the carbon atoms to which they are joined form a C5-C8 cycloalkenyl, 5- to 7-membered heterocyclic, a C6 phenyl, or a 5- to 6- heteroaryl wherein said heterocyclic has up to 2 heteroatoms selected from O, S N, and NR3 and said heteroaryl has one heteroatom selected from O and S and up to two heteroatoms selected from N further wherein each of said cycloalkenyl, heterocyclic, phenyl, and heteroaryl are unsubstituted or substituted with one to two R6 substituents. In Schemes 4-8, the specific compound structures are depicted solely for illustrative purposes and other compounds with varying substituents could be used.
Figure imgf000143_0002
Scheme 4 [0274] As to the reactions in Scheme 4, the first step is formation of a fluorosulfonate wherein at least a stoichiometric equivalent of sulfuryl difluoride, is combined with 8-nitrophenanthren-2-ol (CAS 935655- 81-5; European Journal of Organic Chemistry, 2021, 810-813), compound 16, in an inert diluent such as dichloromethane, tetrachloromethane and the like in the presence of a suitable base such as triethylamine, diisopropylethylamine, pyridine and the like. The reaction is typically maintained at from 0° to 30°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like. [0275] In the next step, the fluorosulfonate is carbonylated (Tetrahedron Letters, 1992, 33, 1959-62), wherein at least a stoichiometric equivalent of a suitable base triethylamine, diisopropylethylamine or pyridine is combined with the fluorosulfonate in an inert diluent such as DMSO, DMF and the like typically in the presence of a palladium catalyst (e.g, palladium diacetate) under an atmosphere of carbon monoxide. The reaction is typically maintained at from 70° to 100°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 17. [0276] In the final step, compound 17, is reduced under conventional hydrogenation reaction conditions well known in the art including the use palladium on carbon as catalyst under a hydrogen atmosphere (Organic Syntheses.; Collective Volume, 5, p.30). Other nitro reducing reagents are well known in the art. The reaction is typically conducted in an inert solvent such as EtOH, ethyl acetate, toluene, and the like. The reaction is typically conducted from about 20º to about 60º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 18.
Figure imgf000144_0001
Scheme 5 [0277] As to the reactions in Scheme 5, compound 19 (CAS 854395-75-8), is reduced under conventional hydrogenation reaction conditions well known in the art including the use palladium on carbon as catalyst under a hydrogen atmosphere. Other nitro reducing reagents are well known in the art. The reaction is typically conducted in an inert solvent such as EtOH, ethyl acetate, toluene, and the like. The reaction is typically conducted at from about 20º to about 60º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 20.
Figure imgf000145_0001
Scheme 6 [0278] As to the reactions in Scheme 6, the first step is formation of an alkyl ester wherein compound 21 (Journal of the American Chemical Society 1940, 62, 527-32), is esterified under conventional conditions well known in the art in a suitable solvent such as methanol, ethanol and the like in the presence of a suitable catalyst, such as sulfuric acid. The reaction is typically maintained at from 60° to 90°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 22. [0279] In the final step, compound 22, is reduced under conventional hydrogenation reaction conditions well known in the art including the use palladium on carbon as catalyst under a hydrogen atmosphere. Other nitro reducing reagents are well known in the art. The reaction is typically conducted in an inert solvent such as EtOH, ethyl acetate, toluene, and the like. The reaction is typically conducted at from about 20º to about 60º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 23.
Figure imgf000145_0002
Scheme 7 [0280] As to the reactions in Scheme 7, the first step is the hydrogenolysis of the benzyl group of compound 24 (Org. Lett.2003, 5, 761–764) under conventional hydrogenation reaction conditions well known in the art including the use palladium on carbon as catalyst under a hydrogen atmosphere. The reaction is typically conducted in an inert solvent such as EtOH, ethyl acetate, toluene, and the like. The reaction is typically conducted at from about 20º to about 60º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 25. [0281] In the next step, the phenol is converted to a fluorosulfonate wherein at least a stoichiometric equivalent of sulfuryl difluoride, is combined with compound 25 (European Journal of Organic Chemistry, 2021, 810-813), in an inert diluent such as dichloromethane, tetrachloromethane and the like in the presence of a suitable base such as triethylamine, diisopropylethylamine or pyridine. The reaction is typically maintained at from 0° to 30°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for the intermediate fluorosulfonate. [0282] In the next step, the fluorosulfonate is carbonylated (Tetrahedron Letters, 1992, 33, 1959-62), wherein at least a stoichiometric equivalent of a suitable base triethylamine, diisopropylethylamine or pyridine is combined with the intermediate fluorosulfonate, in an inert diluent such as DMSO, DMF and the like typically in the presence of a palladium catalyst (e.g, palladium diacetate) under an atmosphere of carbon monoxide. The reaction is typically maintained at from 70° to 100°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 26. [0283] In the final step, compound 26, is deamidated under standard reaction conditions well known in the art including the use of acid catalysts such as sulfuric acid, hydrochloric acid and the like. Other deamidation conditions are well known in the art. The reaction is typically conducted in an inert solvent such as MeOH, EtOH, and the like. The reaction is typically conducted at from about 60º to about 90º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 27.
Figure imgf000147_0001
Scheme 8 [0284] As to the reaction in Scheme 8, in the first step is at least a stoichiometric amount of a suitably substituted carboxylic acid ring X compound, compound 5, is combined with the exemplary anilino ester products, compound 28 of schemes 3-6 under conventional amidation reaction conditions well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC) as an activation agent for the carboxyl group. Other activation agents are well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 0º to about 30º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 29. [0285] In the next step, the methyl ester is displaced with the anion formed between acetonitrile and a suitable base (Organic Letters, 2006, vol.8, 1161-1163), wherein at least a stoichiometric equivalent of acetonitrile, is combined with compound 29, in an inert diluent such as tetrahydrofuran, toluene, DMF, benzene and the like typically in the presence of a suitable base such as potassium tert-butylate, sodium methylate, sodium hydride, n-butyl lithium and the like. The reaction is typically maintained at from 20° to 120°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 30. [0286] In the next step, a conventional cyclization reaction (Bioorganic and Medicinal Chemistry Letters, 2000, 10, 1953-1957) wherein at least a stoichiometric equivalent of sulfur is combined with compound 30, in a protic diluent such as methanol, ethanol, n-butanol and the like, typically in the presence of a suitable base such as morpholine, triethylamine, pyridine, diisopropylethylamine, and the like. The reaction is typically maintained at from 40° to 70°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 31. [0287] In the next step, at least a stoichiometric amount of a suitably protected amino acid compound, compound 32, is combined with compound 31 under conventional amidation reaction conditions (Angewandte Chemie - International Edition, 2020, 59, 3028-3032) well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC), as an activation agent for the carboxyl group. Other activation agents are well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 0º to about 30º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 33. [0288] In the next step, the 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group is removed by conventional conditions and cyclization is affected by heating the intermediate in a protic solvent such as ethanol, methanol, 2-propanol and the like in the presence of a mild acid, such as silica to provide for compound 34. The Fmoc group is illustrative only and other conventional amino blocking groups such as benzyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like could be used. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 34. [0289] In the next step, the tert-butyl ester (t-Bu) protecting group is removed under conventional conditions. The t-Bu group is illustrative only and other conventional carboxylic acid blocking groups such as benzyl, methyl, ethyl and the like could be used. The intermediate carboxylic acid is combined with ammonium chloride or ammonium bicarbonate under conventional amidation reaction conditions (WO2020/86858) well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC), as an activation agent for the carboxyl group. Other activation agents are well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N- dimethylformamide, and the like. The reaction is typically conducted at from about 0º to about 30º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 35. [0290] In the final step, at least a stoichiometric amount acetic acid hydrazine, is combined with compound 35 under conventional cyclization reaction conditions (Angewandte Chemie - International Edition, 2020, 59, 3028-3032) in an inert diluent such as tetrahydrofuran, toluene, DMF, dichloromethane and the like typically in the presence of a suitable base such as potassium tert-butylate, triethylamine and the like. The reaction is typically maintained at from -78° to 0°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 36. [0291] In some embodiments, Schemes 9-11 illustrate additional general methods for preparing compounds of formula I-a, I-b, I-c, or IB-d. In Schemes 9-11, substituents R, R', R2, R4, R5, T, T1, T2, T3, T4, T5 and ring X are as defined above. It should be noted that compound 18a is described for illustrative purposes only and that other compounds can be similarly made to provide compounds of formula I-a, I-b, I-c, or IB-d. [0292] The general synthesis of suitably substituted α,α-disubstituted amino acids, compounds 7a and 11a, described herein is set forth in the reaction Scheme 9 and 10 below. Scheme 9 and 10 illustrate some embodiments for preparing compounds to be used as coupling partners in Scheme 11, the specific compound structures are depicted solely for illustrative purposes and other compounds could be used.
Figure imgf000150_0001
Scheme 9 [0293] As to the reaction in Scheme 8, the first step is a photoredox catalyzed carbofluorination reaction (ACS Catal.2019; 9(2): 1558–1563) wherein at least a stoichiometric equivalent of a di-Boc protected amino ester, compound 1a, is combined with an alkyltrifluoroborate salt, in an inert diluent such as DMF, acetonitrile and the like in the presence of Selectfluor and a suitable photocatalyst such as mesityl acridinium. The reaction is typically maintained at from 0° to 40°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 2a. [0294] In the next step, the Boc protecting groups are removed under conventional conditions. The intermediate amine is combined with Fmoc-OSu or Fmoc-Cl under conventional Fmoc protection reaction conditions well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 0º to about 30º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 3a. [0295] In the next step, the PMB protecting group is removed under conventional conditions reaction conditions well known in the art such as the use of DDQ (Tetrahedron Lett.1988, 29, 2459). The PMB group is illustrative only and other conventional alcohol blocking groups such as Methoxymethyl ether, TBDPS, THP and the like could be used. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 0º to about 30º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 4a. [0296] In the next step, the alcohol, compound 4a, is oxidized to a carboxylic acid wherein at least a stoichiometric equivalent of an oxidizing reagent potassium permanganate (Helvetica Chimica Acta, 1983, 66, 1241-1252), or Dess-Martin reagent/NaClO2 (Journal of the American Chemical Society, 1999, 121, 6355) is combined with the alcohol in an inert diluent such as acetone, acetic acid, propanol and the like. The reaction is typically maintained at from 0° to 40°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 5a. [0297] In the next step, at least a stoichiometric amount of compound 5a, is combined with carbonic acid amine under conventional amidation reaction conditions well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC) or (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU) as an activation agent for the carboxyl group. Other activation agents are well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 0º to about 30º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 6a. [0298] In the final step, hydrogenolysis of the benzyl group of compound 6a conventional hydrogenation reaction conditions well known in the art including the use palladium on carbon as catalyst under a under hydrogen atmosphere (Org. Lett.2003, 5, 761–764). The reaction is typically conducted in an inert solvent such as EtOH, ethyl acetate, toluene, and the like. The reaction is typically conducted at from about 20º to about 60º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 7a.
Figure imgf000152_0001
Scheme 10 [0299] As to the reaction in Scheme 9, the first step is a H/D exchange of the amino-acid-derived imine (Org. Biomol. Chem., 2011, 9, 7983), wherein at least a stoichiometric equivalent of an imine activated amino ester, compound 8 (Archives of Pharmacal Research, 2012, 35, 1015), is combined with a base, in an inert diluent such as THF, diethyl ether and the reaction is quenched with DBr. The reaction is typically maintained at from 0° to 40°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 9a. [0300] In the next step, the imine group is removed under conventional conditions such as 1N hydrochloric acid in THF. The intermediate amine is combined with Fmoc-OSu or Fmoc-Cl under conventional Fmoc protection reaction conditions well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 0º to about 30º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 10a. [0301] In the final step, deprotection of the tert-butyl ester group of compound 10a, under conventional reaction conditions well known in the art including the use trifluoroacetic acid (Int. J. Pept. Protein Res., 1978, 12, 258). The reaction is typically conducted in an inert solvent such as dichloromethane, chloroform, and the like. The reaction is typically conducted at from about 20º to about 60º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide compound 11a.
Figure imgf000153_0001
Scheme 11 [0302] As to the reaction in Scheme 11, in the first step at least a stoichiometric amount of a suitably protected amino acid compound, compound 7a or 11a, is combined with compound 12a (CAS# 50508- 66-2, where R4 and R5 = CH3; T4 and T5 = CH and R2 = H) under conventional amidation reaction conditions (Angewandte Chemie - International Edition, 2020, 59, 3028) well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC), as an activation agent for the carboxyl group. Other activation agents are well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 0º to about 30º C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 13a. [0303] In the next step, the 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group is removed by conventional conditions and cyclization is affected by heating the intermediate 14a in a protic solvent such as ethanol, methanol, 2-propanol and the like in the presence of a mild acid, such as silica or acetic acid to provide for compound 15a. The Fmoc group is illustrative only and other conventional amino blocking groups such as benzyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p- nitrobenzyloxycarbonyl and the like could be used. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 15a. [0304] In the next step, at least a stoichiometric amount acetic acid hydrazine, is combined with compound 15a under conventional cyclization reaction conditions (Angewandte Chemie - International Edition, 2020, 59, 3028) in an inert diluent such as tetrahydrofuran, toluene, DMF, dichloromethane and the like typically in the presence of a suitable base such as potassium tert-butylate, triethylamine and the like. The reaction is typically maintained at from -78° to 0°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 16a. [0305] In the final step, a conventional Suzuki coupling reaction wherein at least a stoichiometric equivalent of compound 17a, is combined with compound 16, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g, palladium diacetate, XPhos-Pd-G2) and a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically maintained at from 10° to 65°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 18a. [0306] Other starting materials used herein are either well known in the art, commercially available, or can be prepared by conventional synthetic methods. Methods [0307] In one embodiment, the compounds and compositions described herein are useful in methods for treating a BRD4 dependent disease or disorder or a disease or disorder that is mediated, at least in part by, BRD4. The methods comprise administering to a subject suffering from a BRD4 dependent disease or disorder an effective amount of a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein. [0308] In one embodiment, there is provided a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein for use in treating an BRD4 dependent disease or disorder. [0309] In one embodiment, the method relates a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein for use in manufacture of a medicament for reducing BRD4 protein levels where reduction of such protein levels treats or ameliorates the diseases or disorder. [0310] In one embodiment, the method relates a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof as described herein for use as described herein, wherein the BRD4 degradation at 1µM concentration of the compounds described herein is at least 50% or at least 70%. The BRD4 degradation is measured by the assay described in the biological example. [0311] The compounds and compositions described herein are useful in treating BRD4 dependent diseases or disorders such as liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma or diffuse large B-cell lymphoma. The cancer may be selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma. In one embodiment, the BRD4-dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST). In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the BRD4-dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC). [0312] The compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects. [0313] In general, methods of using the compounds of the present application comprise administering to a subject in need thereof an effective amount of a compound as described herein. [0314] In certain embodiments, compounds as described herein are useful in the treatment of proliferative disorders (e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, levels of cell proteins of interest, e.g., pathogenic and oncogenic proteins are modulated, or their expression is inhibited or the proteins are degraded by contacting said cells with a compound or composition, as described herein. In other embodiments, the compounds are useful in treating cancer. [0315] Thus, in another aspect of the application, methods for the treatment of cancer are provided comprising administering an effective amount of compound or composition, as described herein, to a subject in need thereof. In certain embodiments, a method for the treatment of cancer is provided comprising administering an effective amount of a compound, or a pharmaceutical composition comprising a compound as described herein to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result. In some embodiments, the compounds of present application are administered orally. The compounds and compositions, according to the method of the present application, are administered orally to a subject using any amount and any route of administration effective for killing or inhibiting the growth of tumor cells. Thus, the expression “amount effective to kill or inhibit the growth of tumor cells,” as used herein, refers to a sufficient amount of agent to kill or inhibit the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, and the like. [0316] In certain embodiments, the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or other mammal in need of it. In certain embodiments, the compounds or compositions described herein are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer). [0317] In certain embodiments, the compounds or compositions described herein are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, compounds or compositions described herein are active against solid tumors. [0318] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents. [0319] Another aspect of the application relates to a method of treating or lessening the severity of a disease or condition associated with a proliferation disorder in a patient, said method comprising a step of administering to said patient, a compound of Formula I or a composition comprising said compound. [0320] It will be appreciated that the compounds and compositions, according to the method of the present application, may be administered using any amount and any route of administration effective for the treatment of cancer and/or disorders associated with cell hyperproliferation. [0321] The present application provides methods for the treatment of a proliferative disorder in a subject in need thereof by administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. The proliferative disorder can be cancer or a precancerous condition. The present application further provides the use of a compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, for the preparation of a medicament useful for the treatment of a proliferative disorder. [0322] The present application also provides methods of protecting against a proliferative disorder in a subject in need thereof by administering a therapeutically effective amount of compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, to a subject in need of such treatment. The proliferative disorder can be cancer or a precancerous condition. The present application also provides the use of compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, for the preparation of a medicament useful for the prevention of a proliferative disorder. [0323] As used herein, the term “proliferative disorder” refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous. Exemplary proliferative disorders of the application encompass a variety of conditions wherein cell division is deregulated. Exemplary proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, uterine fibroids, pre-cancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term “rapidly dividing cell” as used herein is defined as any cell that divides at a rate that exceeds or is greater than what is expected or observed among neighboring or juxtaposed cells within the same tissue. A proliferative disorder includes a precancer or a precancerous condition. A proliferative disorder includes cancer. In some embodiments, the methods provided herein are used to treat or alleviate a symptom of cancer. The term “cancer” includes solid tumors, as well as, hematologic tumors and/or malignancies. A “precancer cell” or “precancerous cell” is a cell manifesting a proliferative disorder that is a precancer or a precancerous condition. A “cancer cell” or “cancerous cell” is a cell manifesting a proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers. [0324] Exemplary non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram- negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus. [0325] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Sezary Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenstram macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, merkel cell carcinoma, mesothelioma malignant, mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer of the tongue, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial uterine cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilms’ Tumor. [0326] A “proliferative disorder of the hematologic system” is a proliferative disorder involving cells of the hematologic system. A proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. A proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system. In some embodiments, the compositions of the present application may be used to treat a cancer selected from the group consisting of a hematologic cancer of the present application or a hematologic proliferative disorder of the present application. A hematologic cancer of the present application can include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin), leukemia (including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms and mast cell neoplasms. [0327] A “proliferative disorder of the lung” is a proliferative disorder involving cells of the lung. Proliferative disorders of the lung can include all forms of proliferative disorders affecting lung cells. Proliferative disorders of the lung can include lung cancer, a precancer or precancerous condition of the lung, benign growths or lesions of the lung, and malignant growths or lesions of the lung, and metastatic lesions in tissue and organs in the body other than the lung. In some embodiments, the compositions of the present application may be used to treat lung cancer or proliferative disorders of the lung. Lung cancer can include all forms of cancer of the lung. Lung cancer can include malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer can include small cell lung cancer (“SCLC”), non-small cell lung cancer (“NSCLC”), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, and mesothelioma. Lung cancer can include “scar carcinoma”, bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer can include lung neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types). [0328] Proliferative disorders of the lung can include all forms of proliferative disorders affecting lung cells. Proliferative disorders of the lung can include lung cancer, precancerous conditions of the lung. Proliferative disorders of the lung can include hyperplasia, metaplasia, and dysplasia of the lung. Proliferative disorders of the lung can include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia. Proliferative disorders of the lung can include replacement of columnar epithelium with stratified squamous epithelium, and mucosal dysplasia. Individuals exposed to inhaled injurious environmental agents such as cigarette smoke and asbestos may be at increased risk for developing proliferative disorders of the lung. Prior lung diseases that may predispose individuals to development of proliferative disorders of the lung can include chronic interstitial lung disease, necrotizing pulmonary disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, and Hodgkin's disease. [0329] A “proliferative disorder of the colon” is a proliferative disorder involving cells of the colon. In one embodiment, the proliferative disorder of the colon is colon cancer. In one embodiment, compositions of the present application may be used to treat colon cancer or proliferative disorders of the colon. Colon cancer can include all forms of cancer of the colon. Colon cancer can include sporadic and hereditary colon cancers. Colon cancer can include malignant colon neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Colon cancer can include adenocarcinoma, squamous cell carcinoma, and adenosquamous cell carcinoma. Colon cancer can be associated with a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis. Colon cancer can be caused by a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz- Jeghers syndrome, Turcot's syndrome and juvenile polyposis. [0330] Proliferative disorders of the colon can include all forms of proliferative disorders affecting colon cells. Proliferative disorders of the colon can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon and metachronous lesions of the colon. A proliferative disorder of the colon can include adenoma. Proliferative disorders of the colon can be characterized by hyperplasia, metaplasia, and dysplasia of the colon. Prior colon diseases that may predispose individuals to development of proliferative disorders of the colon can include prior colon cancer. Current disease that may predispose individuals to development of proliferative disorders of the colon can include Crohn's disease and ulcerative colitis. A proliferative disorder of the colon can be associated with a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC. An individual can have an elevated risk of developing a proliferative disorder of the colon due to the presence of a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC. [0331] A “proliferative disorder of the pancreas” is a proliferative disorder involving cells of the pancreas. Proliferative disorders of the pancreas can include all forms of proliferative disorders affecting pancreatic cells. Proliferative disorders of the pancreas can include pancreas cancer, a precancer or precancerous condition of the pancreas, hyperplasia of the pancreas, and dysplasia of the pancreas, benign growths or lesions of the pancreas, and malignant growths or lesions of the pancreas, and metastatic lesions in tissue and organs in the body other than the pancreas. Pancreatic cancer includes all forms of cancer of the pancreas. Pancreatic cancer can include 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. Pancreatic cancer can also include pancreatic neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types). [0332] A “proliferative disorder of the prostate” is a proliferative disorder involving cells of the prostate. Proliferative disorders of the prostate can include all forms of proliferative disorders affecting prostate cells. Proliferative disorders of the prostate can include prostate cancer, a precancer or precancerous condition of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, and metastatic lesions in tissue and organs in the body other than the prostate. Proliferative disorders of the prostate can include hyperplasia, metaplasia, and dysplasia of the prostate. [0333] A “proliferative disorder of the skin” is a proliferative disorder involving cells of the skin. Proliferative disorders of the skin can include all forms of proliferative disorders affecting skin cells. Proliferative disorders of the skin can include a precancer or precancerous condition of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma and other malignant growths or lesions of the skin, and metastatic lesions in tissue and organs in the body other than the skin. Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of the skin. [0334] A “proliferative disorder of the ovary” is a proliferative disorder involving cells of the ovary. Proliferative disorders of the ovary can include all forms of proliferative disorders affecting cells of the ovary. Proliferative disorders of the ovary can include a precancer or precancerous condition of the ovary, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions in tissue and organs in the body other than the ovary. Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of cells of the ovary. [0335] A “proliferative disorder of the breast” is a proliferative disorder involving cells of the breast. Proliferative disorders of the breast can include all forms of proliferative disorders affecting breast cells. Proliferative disorders of the breast can include breast cancer, a precancer or precancerous condition of the breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast. Proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast. [0336] A cancer that is to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) can be assigned a stage of MX, M0, or M1. A cancer that is to be treated can be staged according to an American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. A cancer that is to be treated can be assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4. A cancer that is to be treated can be staged according to an AJCC pathologic classification (pN) of pNX, pN0, PN0 (I-), PN0 (I+), PN0 (mol-), PN0 (mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c. [0337] A cancer that is to be treated can include a tumor that has been determined to be less than or equal to about 2 centimeters in diameter. A cancer that is to be treated can include a tumor that has been determined to be from about 2 to about 5 centimeters in diameter. A cancer that is to be treated can include a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter. A cancer that is to be treated can include a tumor that has been determined to be greater than 5 centimeters in diameter. A cancer that is to be treated can be classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated. A cancer that is to be treated can be classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells). A cancer that is to be treated can be classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells). A cancer that is to be treated can be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance. A cancer that is to be treated can be classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy. A cancer that is to be treated can be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome. [0338] A cancer that is to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry. A cancer that is to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., in S phase of cell division). A cancer that is to be treated can be typed as having a low S-phase fraction or a high S-phase fraction. [0339] As used herein, a “normal cell” is a cell that cannot be classified as part of a “proliferative disorder”. A normal cell lacks unregulated or abnormal growth, or both, that can lead to the development of an unwanted condition or disease. In one embodiment, a normal cell possesses normally functioning cell cycle checkpoint control mechanisms. [0340] One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Erma et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the application. [0341] In certain embodiments, compounds of the application are useful in the treatment of proliferative disorders (e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, levels of cell proteins of interest, e.g., pathogenic and oncogenic proteins are modulated, or their growth is inhibited by contacting said cells with a compound or composition, as described herein. In other embodiments, the compounds are useful in treating cancer. [0342] In certain embodiments, the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. In certain embodiments, the compounds are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer). [0343] In certain embodiments, the anticancer agents are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, the anticancer agents are active against solid tumors. [0344] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents. [0345] For example, other therapies or anticancer agents that may be used in combination with the compounds disclosed herein including surgery, radiotherapy, endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), to name a few. For a more comprehensive discussion of overview of cancer therapy see The Merck Manual, Twentieth Ed.2020, the entire contents of which are hereby incorporated by reference. See also the National Cancer Institute (NCI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA) website for a list of the FDA approved oncology drugs (www.fda.gov/cder/cancer/druglistframe). [0346] In certain embodiments, the pharmaceutical compositions comprising the compounds disclosed herein further comprise one or more additional therapeutically active ingredients (e.g., chemotherapeutic and/or palliative). For purposes of the application, the term “palliative” refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative. For example, palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs. In addition, chemotherapy, radiotherapy and surgery can all be used palliatively (that is, to reduce symptoms without going for cure; e.g., for shrinking tumors and reducing pressure, bleeding, pain and other symptoms of cancer). Administration, Pharmaceutical Compositions [0347] Administration of the disclosed compounds and pharmaceutical compositions can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. [0348] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time- release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts. [0349] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes, and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200. [0350] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds. [0351] The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier. [0352] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. [0353] In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No.5,262,564, which is hereby incorporated by reference in its entirety. [0354] Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate. [0355] Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. [0356] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, diluent, or surfactant. [0357] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume. [0358] In one embodiment, the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present disclosure. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. [0359] The kit of the disclosure may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the disclosure typically comprises directions for administration. [0360] Pharmaceutical dosage forms of a compound of this disclosure may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray-drying, levigating, emulsifying, (nano-/micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of this disclosure can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use. [0361] As noted above, the compositions are comprised of, in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non- toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. [0362] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. [0363] Compressed gases may be used to disperse a compound of this disclosure in an aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990). [0364] The compositions of this disclosure may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of this disclosure that can be formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [0365] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below. Formulation Examples [0366] The following are representative pharmaceutical formulations containing a compound of this disclosure. Formulation Example 1 -- Tablet formulation [0367] The following ingredients are mixed intimately and pressed into single scored tablets.
Figure imgf000167_0001
Formulation Example 2 -- Capsule formulation [0368] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule
Figure imgf000167_0002
Formulation Example 3 -- Suspension formulation [0369] The following ingredients are mixed to form a suspension for oral administration.
Figure imgf000167_0003
Figure imgf000168_0001
Formulation Example 4 -- Injectable formulation [0370] The following ingredients are mixed to form an injectable formulation.
Figure imgf000168_0002
Formulation Example 5 -- Suppository Formulation [0371] A suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
Figure imgf000168_0003
Dosing [0372] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. [0373] Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored. EXAMPLES [0374] This disclosure is further understood by reference to the following examples, which are intended to be purely exemplary of this disclosure. This disclosure is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of this disclosure only. Any methods that are functionally equivalent are within the scope of this disclosure. Various modifications of this disclosure, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description. Such modifications fall within the scope of the appended claims. [0375] In the specification and in the examples below, all temperatures are in degrees Celsius. In addition, the following abbreviations have the following meanings. If not defined, these abbreviations have their art recognized meaning.
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
LC-MS Methods (General Method) [0376] Method A: Experiments were performed using a Luna® 5 µm C18(2) 100 Å, LC Column 250 x 21.2 mm, AXIA™ Packed (00G-4252-P0-AX), at a flow rate of 20 mL/min, and a mass spectrometer using ESI as ionization source. The solvent A was 4.0 mL of TFA in 4 L of water, and solvent B was 4.0 mL of TFA in 4 L of acetonitrile. The gradient consisted of 10-100% solvent B over 20 minutes, LC column temperature was 40°C. UV absorbance was collected at 220 nm and 254 nm. Starting Materials [0377] Compound A’: (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid
Figure imgf000172_0001
[0378] Compound A’ is known in the art as “JQ1 (carboxylic acid)”, CAS # 202592-23-2 and is described in Filippakopoulos, et al. “Selective inhibition of BET bromodomains”, Nature 2010, 468, 1067-1073; Romero, et al., J. Med. Chem., 201659, 1271-1298. It is also commercially available from Sigma-Aldrich, St. Louis, Missouri, USA. [0379] Compounds B’: Each of the following compounds are commercially available from:
Figure imgf000172_0002
Figure imgf000172_0003
General Method A-a:
Figure imgf000173_0001
[0380] To a stirred solution of 1A (1 eq.) in DMF is added ethylbis(propan-2-yl)amine (3 eq.), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (1.3 eq.) and carbonic acid amine (3 eq.). The mixture is stirred at rt for 16 hours. The crude is diluted with water and extracted into EtOAc. The combined organic layers are washed with water, brine, dried over sodium sulfate and the solvents evaporated in vacuo. The resulting material is purified by silica chromatography to give 2A. General Method B-a:
Figure imgf000173_0002
[0381] A Biotage microwave reactor is charged with 2A (1 eq.), 3A (3.7 eq.), cesium carbonate (3 eq.), degassed ACN, and Pd(Cy*Phine)2Cl2 (0.1 eq.). The microwave tube is then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture is filtered, evaporated in vacuo and crude material purified by silica to 4A. R is as defined throughout the specification. General Method C-a:
Figure imgf000174_0001
[0382] Trifluoroacetic acid (2.00 mL) is slowly added to a solution of 4A (1 eq.) in DCM. The reaction is stirred at room temperature for 2 hours. TFA and DCM are co-evaporated with toluene to give 5A. R is as defined throughout the specification. General Method D-a:
Figure imgf000174_0002
[0383] To a solution of 6A (1.2 eq.) and ethylbis(propan-2-yl)amine (4 eq.) in DMA is added HATU (1.3 eq.). The mixture is stirred at room temperature for 10 minutes. 5A (1 eq.) is added and the reaction mixture is stirred at room temperature for 16 hours. The crude reaction mixture is purified by preparative reverse phase HPLC to give 7A. General Method E-a:
Figure imgf000174_0003
[0384] To a mixture of 8A (1 eq.) and 9A (2 eq) in DMF is added DIEA (5 eq) and HATU (1.5 eq) in one portion at 25°C under N2. The mixture is stirred at 25 °C for 10hr. The reaction mixture is quenched by addition of water (20 mL) at 0°C, and then diluted with ethyl acetate and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column to give 10A. General Method F-a:
Figure imgf000175_0001
[0385] To a mixture of 11A (1 eq) and 6A (2 eq) in DMF (5 mL) is added EDCI (1.5 eq), HOBt (1.5 eq), DMAP (0.1 eq), and DIEA (3 eq) in one portion at 25°C under N2. The mixture is stirred at 25 °C for 10hr. The reaction mixture is quenched by addition of water at 0°C, and then diluted with ethyl acetate and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column to give 12A. General Method G-a:
Figure imgf000175_0002
[0386] To a mixture of 10A (1 eq) and 12A(2 eq) in THF and H2O is added K3PO4 (2.5 eq) and X-Phos- Pd-G2 (0.1 eq) in one portion at 25°C under N2. The mixture is stirred at 80 °C for 10 hr. The reaction mixture is quenched by addition of water at 0°C, and then diluted with ethyl acetate and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC to 13A. Example 1 Preparation of (S)-2-(4-(3'-amino-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide TFA (Compound P-0):
Figure imgf000176_0001
[0387] To a stirred solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (103 mg, 257 µmol) in DMF (3.09 mL, 0.6 eq., 154 µmol) was added ethylbis(propan-2-yl)amine (134 µL, 3 eq., 771 µmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (127 mg, 1.3 eq., 334 µmol) and carbonic acid amine (60.9 mg, 3 eq., 771 µmol). The mixture was stirred at rt for 16 hours. The crude was diluted with water and extracted into EtOAc (3 x 20 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The resulting material was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide. Step 2:
Figure imgf000177_0001
[0388] A 10-20 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (836 mg, 2.09 mmol), (3-{[(tert-butoxy)carbonyl]amino}phenyl)boronic acid (1.82 g, 3.7 eq., 7.68 mmol), cesium carbonate (2.04 g, 3 eq., 6.27 mmol), degassed ACN (15 mL) and Pd(Cy*Phine)2Cl2 (269 mg, 0.1 eq., 209 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give tert-butyl (S)-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)carbamate. 1H NMR (500 MHz, d6-DMSO) δ 9.43 (s, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.69 – 7.60 (m, 3H), 7.56 – 7.48 (m, 2H), 7.45 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.27 (dt, J = 7.8, 1.3 Hz, 1H), 7.00 – 6.95 (m, 1H), 4.51 (t, J = 7.0 Hz, 1H), 3.24 (d, J = 7.1 Hz, 2H), 2.61 (s, 3H), 2.43 (s, 3H), 1.69 (m, 3H), 1.48 (s, 9H). Step 3:
Figure imgf000177_0002
[0389] Trifluoroacetic acid (2.00 mL) was slowly added to a solution of tert-butyl N-{4'-[(9S)-9- (carbamoylmethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12- pentaen-7-yl]-[1,1'-biphenyl]-3-yl}carbamate (7.27 mL, 1.85 mmol) in DCM (4 mL). The reaction was stirred at room temperature for 2 hours. TFA and DCM were co-evaporated with toluene (2 x 10 mL) to afford (S)-2-(4-(3'-amino-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetamide. m/z = 458.2 [M+H]+. Example 2-a (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-1H-pyrazole-3-carboxamide (Compound P-1-a)
Figure imgf000178_0001
[0390] To a solution of 1-methyl-1H-pyrazole-3-carboxylic acid (10.9 mg, 1.2 eq., 86.2 µmol) and ethylbis(propan-2-yl)amine (38.0 µL, 4 eq., 217 µmol) in DMA (1.5 mL) was added HATU (35.5 mg, 1.3 eq., 93.4 µmol). The mixture was stirred at room temperature for 10 minutes. 2-[(9S)-7-{3'-amino- [1,1'-biphenyl]-4-yl}-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12- pentaen-9-yl]acetamide trifluoroacetic acid (41.0 mg, 71.9 µmol) and the reaction mixture was stirred at room temperature for 16 hours. The crude reaction mixture was purified by preparative reverse phase HPLC to give (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-1H-pyrazole-3-carboxamide. Example 3-a N-{4'-[(9S)-9-[(ethylcarbamoyl)methyl]-4,5,13-trimethyl-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-7-yl]-[1,1'-biphenyl]-3-yl}-5- methoxypyridine-2-carboxamide (Compound P-12-a) Step 1:
Figure imgf000178_0002
[0391] To a mixture of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid (1 eq.) and ethylamine; hydrochloride (2 eq) in DMF was added DIEA (5 eq) and HATU (1.5 eq) in one portion at 25°C under N2. The mixture was stirred at 25 °C for 10hr. The reaction mixture was quenched by addition of water (20 mL) at 0°C, and then diluted with ethyl acetate (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column (SiO2, 0 to 100 % ethyl acetate in petroleum ether) to give (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N- ethylacetamide. Step 2:
Figure imgf000179_0001
[0392] To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 eq) and 5- methoxypyridine-2-carboxylic acid (2 eq) in DMF (5 mL) was added EDCI (21.5 eq), HOBt (1.5 eq), DMAP (0.1 eq), and DIEA (3 eq) in one portion at 25°C under N2. The mixture was stirred at 25 °C for 10hr. The reaction mixture was quenched by addition of water (20 mL) at 0°C, and then diluted with ethyl acetate (20 mL) and extracted with EA (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure to give a residue. The reaction mixture was purified by flash column (SiO2, 0 to 25 % ethyl acetate in petroleum ether) to give 5-methoxy-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)picolinamide. Step 3:
Figure imgf000179_0002
[0393] To a mixture of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)-N-ethylacetamide (1 eq) and 5-methoxy-N-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)picolinamide (2 eq) in THF (3 mL) and H2O (1 mL) was added K3PO4 (2.5 eq) and X-Phos-Pd-G2 (0.1 eq) in one portion at 25°C under N2. The mixture was stirred at 80 °C for 10 hr. The reaction mixture was quenched by addition of water (20 mL) at 0°C, and then diluted with ethyl acetate (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-N-(4'-(6-(2-(ethylamino)-2-oxoethyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)-5-methoxypicolinamide. 1H NMR (400 MHz, d4-MeOD) δ 8.36 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.14 (s, 1H), 7.78 - 7.74 (m, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 2.8 Hz, 1H), 7.49 - 7.43 (m, 2H), 4.68 (dd, J = 5.3, 9.0 Hz, 2H), 3.96 (s, 3H), 3.48 - 3.38 (m, 1H), 3.37 - 3.33 (m, 1H), 3.30 - 3.26 (m, 1H), 3.29 - 3.24 (m, 1H), 2.72 (s, 3H), 2.46 (s, 3H), 1.74 (s, 3H), 1.20 (t, J = 7.3 Hz, 3H). Example 2-b (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-1H-pyrazole-3-carboxamide (Compound P-4-b) (METHOD A-b):
Figure imgf000180_0001
[0394] To a solution of 3-methyl-1-benzofuran-2-carboxylic acid (12.0 mg, 1.3 eq., 68.3 µmol) and ethylbis(propan-2-yl)amine (27.5 µL, 3 eq., 158 µmol) in DMF (1.5 mL) was added HATU (28.0 mg, 1.4 eq., 73.6 µmol). The mixture was stirred at room temperature for 10 minutes. 2-[(9S)-7-{3'-amino-[1,1'- biphenyl]-4-yl}-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12- pentaen-9-yl]acetamide trifluoroacetic acid (30.0 mg, 52.6 µmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The crude reaction mixture was purified by preparative reverse phase HPLC and the acetonitrile mobile phase was evaporated. A solution of saturated sodium bicarbonate solution (1.5 mL) was added to neutralize the aqueous acidic solution. The desired product was extracted with ethyl acetate (2 x 3 mL). The combined organic layers were dried over sodium sulfate and the solvent evaporated to give (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-1H-pyrazole-3-carboxamide. Example 3-b (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)benzofuran-2-carboxamide (Compound P-1-b) (METHOD B-b): Step 1:
Figure imgf000180_0002
[0395] To a solution of 1-benzofuran-2-carboxylic acid (320 mg, 1.97 mmol) and ethylbis(propan-2- yl)amine (383 mg, 1.5 eq., 2.96 mmol) in DMF (10 mL), was added [(dimethylamino)({3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (900 mg, 1.2 eq., 2.37 mmol). The solution was stirred at room temperature for 10 minutes. 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (562 mg, 1.3 eq., 2.57 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with water (25 mL) and extracted into ethyl acetate (3 x 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over sodium sulfate and the solvents were evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give N-(3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzofuran-2-carboxamide which was used in the following step. m/z = 364.2 [M+H]. Step 2:
Figure imgf000181_0001
[0396] A 0.5-2 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (50.0 mg, 125 µmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-benzofuran-2-carboxamide (135 mg, 3 eq., 372 µmol), cesium carbonate (122 mg, 3 eq., 375 µmol), degassed ACN (2.5 mL) and Pd(Cy*Phine)2Cl2 (16.1 mg, 0.1 eq., 12.5 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material was dissolved in ethyl acetate (25 mL). The organic layer was washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-N-(4'-(6-(2-amino-2- oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3- yl)benzofuran-2-carboxamide. Example 4-b (S)-N-(4'-(2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'- biphenyl]-3-yl)benzofuran-2-carboxamide (Compound P-21-b): Step 1:
Figure imgf000182_0001
[0397] To a solution of 4-(tert-butoxy)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4-oxobutanoic acid (2.00 g, 4.86 mmol) in DMA (18 mL) was added [(dimethylamino)({3H-[1,2,3]triazolo[4,5- b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (2.03 g, 1.1 eq., 5.35 mmol) and ethylbis(propan-2-yl)amine (1.02 mL, 1.2 eq., 5.83 mmol) and the reaction was stirred for 10 minutes. 2 (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (1.35 g, 1.2 eq., 5.83 mmol) was added and the reaction was stirred at 60 °C for 12 hours. Water (50 mL) was added and the resulting solution was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over sodium sulfate and the solvents were removed in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% EtOAc in hexanes to give (9H-fluoren-9-yl)methyl (S)-(1-((3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-1- oxopropan-2-yl)carbamate, which was used directly in the next step without characterization. Step 2:
Figure imgf000182_0002
[0398] To solution of 5% piperazine and 2% DBU in DMA (2 mL) was added (9H-fluoren-9-yl)methyl N-[(1S)-1-{[3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl]carbamoyl}ethyl]carbamate (360 mg, 644 µmol). The reaction was stirred at room temperature for 30 minutes. Ethyl acetate (50 mL) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was filtered. The filtrate was diluted with additional ethyl acetate (50 mL) and washed with brine (50 mL), dried over sodium sulfate and the solvents were evaporated in vacuo to give (S)-2-amino-N-(3-(4-chlorobenzoyl)- 4,5-dimethylthiophen-2-yl)propanamide, which was used directly in the next step without characterization and purification. The crude material was dissolved in toluene (50 mL) and silica (1 g) was added. The reaction mixture was stirred at 90°C for 4 hours. The silica was filtered and washed with a solution of ethyl acetate and ethanol (3:1, v/v, 50 mL) and the solvents evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 50% 3:1 v/v EtOAc/EtOH in hexanes to give (S)-5-(4-chlorophenyl)-3,6,7-trimethyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one. 1H NMR (499 MHz, d6-DMSO) δ 11.07 (s, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.46 – 7.40 (m, 2H), 3.72 (q, J = 6.4 Hz, 1H), 2.26 (d, J = 0.9 Hz, 3H), 1.56 (s, 3H), 1.52 (d, J = 6.3 Hz, 3H). Step 3:
Figure imgf000183_0001
[0399] To a stirred solution of (3S)-5-(4-chlorophenyl)-3,6,7-trimethyl-1H,2H,3H-thieno[2,3- e][1,4]diazepin-2-one (214 mg, 671 µmol) in dry THF (4 mL) at −78 °C was added a 1M solution of potassium 2-methylpropan-2-olate (805 µL, 1.2 eq., 805 µmol). The reaction mixture was warmed to −10°C and stirred for 30 minutes. The reaction mixture was cooled to −78 °C and diphenyl phosphorochloridate (181 µL, 1.3 eq., 873 µmol) in THF (0.5 mL) was added. The resulting mixture was warmed to −10°C and stirred for 45 minutes. Acetohydrazide (99.5 mg, 2 eq., 1.34 mmol) was added and the reaction was allowed to warm to temperature over 1 hour.1-butanol (3 mL) was added and the reaction mixture was heated to 90°C for 2 hours. The solvents were removed in vacuo. The residue was dissolved in DCM (20 mL) and washed with saturated sodium bicarbonate (20 mL), brine (20 mL), dried over sodium sulfate and the solvents evaporated. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-4-(4-chlorophenyl)- 2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.1H NMR (499 MHz, d6-DMSO) δ 7.51 – 7.43 (m, 4H), 4.23 (q, J = 6.7 Hz, 1H), 2.59 (s, 3H), 2.40 (s, 3H), 1.88 (d, J = 6.7 Hz, 3H), 1.63 (s, 3H). Step 4:
Figure imgf000183_0002
[0400] A 0.5-2 mL Biotage microwave reactor was charged with (9S)-7-(4-chlorophenyl)-4,5,9,13- tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaene (33.0 mg, 92.5 µmol) N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-benzofuran-2-carboxamide (135 mg, 3 eq., 372 µmol), cesium carbonate (90.4 mg, 3 eq., 277 µmol), degassed ACN (2.5 mL) and Pd(Cy*Phine)2Cl2 (25.8 mg, 0.1 eq., 20.0 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material was dissolved in ethyl acetate (25 mL). The organic layer was washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-N-(4'-(2,3,6,9- tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)benzofuran-2- carboxamide. Example 5-b (S)-N-(4'-(2,3,9-trimethyl-6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)benzofuran-2-carboxamide (Compound P-2-b) (METHOD D-b):
Figure imgf000184_0001
[0401] To a stirred solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (106 mg, 264 µmol) in DMF (3 mL) was added ethylbis(propan-2-yl)amine (68.4 mg, 2 eq., 529 µmol), [(dimethylamino)({3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (131 mg, 1.3 eq., 344 µmol) and pyrrolidine (43.5 µL, 2 eq., 529 µmol). The mixture was stirred at room temperature for 16 hours. The crude was diluted with water and extracted into ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The resulting material was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-2-(4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-1-(pyrrolidin-1-yl)ethan-1-one. 1H NMR (500 MHz, d6-DMSO) δ 7.53 – 7.46 (m, 2H), 7.46 – 7.39 (m, 2H), 4.55 (t, J = 6.8 Hz, 1H), 3.72 – 3.59 (m, 2H), 3.50 (dd, J = 16.1, 7.2 Hz, 1H), 2.59 (s, 3H), 2.41 (t, 3H), 2.01 – 1.88 (m, 2H), 1.82 (pd, J = 6.7, 2.2 Hz, 2H), 1.63 (s, 3H). Step 2:
Figure imgf000185_0001
[0402] A 0.5-2 mL Biotage microwave reactor was charged with (2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]-1-(pyrrolidin-1- yl)ethan-1-one (108 mg, 238 µmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1- benzofuran-2-carboxamide (302 mg, 3.5 eq., 833 µmol), cesium carbonate (233 mg, 3 eq., 714 µmol), degassed ACN (2 mL) and Pd(Cy*Phine)2Cl2 (30.7 mg, 0.1 eq., 23.8 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-N-(4'-(2,3,9- trimethyl-6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)- [1,1'-biphenyl]-3-yl)benzofuran-2-carboxamide. Example 6-b (S)-2-(4-(3'-(benzofuran-2-carboxamido)-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (Compound P-9-b) (METHOD C-b):
Figure imgf000185_0002
[0403] A 0.5-2 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (40.0 mg, 99.8 µmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-benzofuran-2- carboxamide (109 mg, 3 eq., 299 µmol), cesium carbonate (97.5 mg, 3 eq., 299 µmol), degassed ACN (3 mL) and Pd(Cy*Phine)2Cl2 ((12.9 mg, 0.1 eq., 9.98 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-2-(4-(3'-(benzofuran-2-carboxamido)-[1,1'- biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid. Example 7-b (S)-N-(4'-(6-(2-hydroxyethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4- yl)-[1,1'-biphenyl]-3-yl)benzofuran-2-carboxamide (Compound P-20-b) (METHOD E-b): Step 1:
Figure imgf000186_0001
[0404] To a stirred cold suspension of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (294 mg, 733 µmol) in DMF (49 µL) and dichloromethane (3.92 mL, 2 eq., 1.47 mmol) was added thionyl chloride (268 µL, 5 eq., 3.67 mmol) dropwise. The mixture was stirred at room temperature for 3 hours. Methanol (9.80 mL, 733 µmol) was added, and the reaction was stirred at room temperature for 16 hours. The solvents were removed in vacuo and a saturated sodium bicarbonate solution (25 mL) was added to the residue. The aqueous solution was extracted with DCM (2 x 25 mL) and the combined organic layers were washed with brine (25 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give methyl (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- yl)acetate.1H NMR (499 MHz, d6-DMSO) δ 7.53 – 7.46 (m, 2H), 7.46 – 7.37 (m, 2H), 4.50 (dd, J = 7.8, 6.6 Hz, 1H), 3.67 (s, 3H), 3.54 – 3.38 (m, 2H), 2.60 (s, 3H), 2.41 (s, 3H), 1.63 (s, 3H). Step 2:
Figure imgf000186_0002
[0405] A 0.5-2 mL Biotage microwave reactor was charged with methyl 2-[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (165 mg, 398 µmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-benzofuran-2- carboxamide (506 mg, 3.5 eq., 1.39 mmol), cesium carbonate (389 mg, 3 eq., 1.19 mmol), degassed ACN (2 mL) and Pd(Cy*Phine)2Cl2 (51.3 mg, 0.1 eq., 39.8 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material was dissolved in ethyl acetate (25 mL). The organic layer was washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (methyl (S)-2-(4-(3'- (benzofuran-2-carboxamido)-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetate. 1H NMR (499 MHz, d6-DMSO) δ 10.64 (s, 1H), 8.16 (q, J = 2.0 Hz, 1H), 7.89 (dt, J = 7.4, 1.9 Hz, 1H), 7.84 (dt, J = 7.7, 1.1 Hz, 1H), 7.79 (d, J = 1.0 Hz, 1H), 7.76 – 7.70 (m, 3H), 7.57 – 7.44 (m, 5H), 7.38 (ddd, J = 8.1, 7.2, 0.9 Hz, 1H), 4.63 (dd, J = 7.9, 6.5 Hz, 0H), 4.53 (dd, J = 7.7, 6.7 Hz, 1H), 3.70 (s, 3H), 3.57 – 3.41 (m, 2H), 2.63 (s, 3H), 2.44 (s, 3H), 1.70 (s, 3H). Step 3:
Figure imgf000187_0001
[0406] To an ice bath cooled solution of methyl 2-[(9S)-7-[3'-(1-benzofuran-2-amido)-[1,1'-biphenyl]-4- yl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9- yl]acetate (151 mg, 245 µmol) in anhydrous THF (2 mL) was added lithium aluminum hydride (368 µL, 1.5 eq., 368 µmol, 1.0 M solution in THF). The reaction was stirred at 0°C for 1 hour. The reaction was slowly quenched with MeOH (5 mL) and water (5 mL) and then diluted with water (10 mL). The crude product was extracted into ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC and the acetonitrile mobile phase was evaporated. A solution of saturated sodium bicarbonate solution (1.5 mL) was added to neutralize the aqueous acidic solution. The desired product was extracted with ethyl acetate (2 x 3 mL). The combined organic layers were dried over sodium sulfate and the solvent evaporated to give (S)-N-(4'-(6-(2- hydroxyethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]- 3-yl)benzofuran-2-carboxamide. Example 8-b N-{4'-[(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12- pentaen-7-yl]-[1,1'-biphenyl]-3-yl}pyrazolo[1,5-a]pyrimidine-2-carboxamide (Compound P-38-b): Step 1:
Figure imgf000188_0001
[0407] To a mixture of (S)-4-(4-chlorophenyl)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepine (300 mg, 840.64 µmol, 1 eq) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.4 eq) in THF (2 mL) and H2O (0.4 mL) was added XPhos-Pd-G2 (0.1 eq) and K3PO4 (3 eq) in one portion at 25°C under N2. The mixture was stirred at 80 °C for 10 hr. The reaction mixture was quenched by addition water (5 mL) at 0°C, and extracted into ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column (SiO2, 0 to 100% ethyl acetate in petroleum ether) to give (S)-4'-(2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'- biphenyl]-3-amine. m/z (ESI+): 414.17 (M+H)+. Step 2:
Figure imgf000188_0002
[0408] To a mixture of (S)-4'-(2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4- yl)-[1,1'-biphenyl]-3-amine (50 mg, 120.91 µmol, 1 eq) and pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1.5 eq) in DMF (1 mL) was added EDCI (1.5 eq), DIEA (3 eq), DMAP (0.1 eq) and HOBt (1.5 eq) in one portion at 25°C under N2. The mixture was stirred at 25°C for 10hrs. The reaction mixture was quenched by addition water (5 mL) at 0°C, and extracted into ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give N-{4'-[(9S)-4,5,9,13- tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-7-yl]-[1,1'- biphenyl]-3-yl}pyrazolo[1,5-a]pyrimidine-2-carboxamide. 1H NMR (400 MHz, d4-MeOD) δ 9.06 (d, J = 7.1 Hz, 1H), 8.64 - 8.62 (m, 1H), 8.14 (s, 1H), 7.80 - 7.76 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 5.0 Hz, 2H), 7.24 (s, 1H), 7.16 (dd, J = 4.0, 7.1 Hz, 1H), 4.32 (d, J = 6.8 Hz, 1H), 2.72 (s, 3H), 2.46 (s, 3H), 2.02 (d, J = 6.8 Hz, 3H), 1.72 (s, 3H). General Method A-c:
Figure imgf000189_0001
[0409] To a stirred solution of 1A (1 eq.) in DMF is added ethylbis(propan-2-yl)amine (3 eq.), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (1.3 eq.) and carbonic acid amine (3 eq.). The mixture is stirred at rt for 16 hours. The crude is diluted with water and extracted into EtOAc. The combined organic layers are washed with water, brine, dried over sodium sulfate and the solvents evaporated in vacuo. The resulting material is purified by silica chromatography to give 2A. General Method B-c:
Figure imgf000189_0002
[0410] A Biotage microwave reactor is charged with 2AA (1 eq.), 3A (3.7 eq.), cesium carbonate (3 eq.), degassed ACN, and Pd(Cy*Phine)2Cl2 (0.1 eq.). The microwave tube is then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture is filtered, evaporated in vacuo and crude material purified by silica to 4A. R is as defined throughout the specification. General Method C-c:
Figure imgf000190_0001
[0411] Trifluoroacetic acid (2.00 mL) is slowly added to a solution of 4A (1 eq.) in DCM. The reaction is stirred at room temperature for 2 hours. TFA and DCM are co-evaporated with toluene to give 5A. R is as defined throughout the specification. General Method D-c:
Figure imgf000190_0002
[0412] To a solution of 6A (1.2 eq.) and ethylbis(propan-2-yl)amine (4 eq.) in DMA is added HATU (1.3 eq.). The mixture is stirred at room temperature for 10 minutes. 5A (1 eq.) is added and the reaction mixture is stirred at room temperature for 16 hours. The crude reaction mixture is purified by preparative reverse phase HPLC to give 7A. General Method E-c:
Figure imgf000190_0003
[0413] To a mixture of 8A (1 eq) and 6A (2 eq) in DMF (5 mL) is added EDCI (1.5 eq), HOBt (1.5 eq), DMAP (0.1 eq) and DIEA (3 eq) in one portion at 25°C under N2. The mixture is stirred at 25 °C for 10hr. The reaction mixture is quenched by addition of water at 0°C, and then diluted with ethyl acetate and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column to give 9A. General Method F-c:
Figure imgf000191_0001
[0414] To a mixture of 10A (1 eq) and 9A(2 eq) in THF and H2O is added K3PO4 (2.5 eq) and X-Phos- Pd-G2 (0.1 eq) in one portion at 25°C under N2. The mixture is stirred at 80 °C for 10 hr. The reaction mixture is quenched by addition of water at 0°C, and then diluted with ethyl acetate and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC to provide 11A. Example 2-c (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)quinoxaline-2-carboxamide (Compound P-1-c)
Figure imgf000191_0002
[0415] To a solution of quinoxaline-2-carboxylic acid (11.4 mg, 1.2 eq., 65.2 µmol) and ethylbis(propan-2-yl)amine (38.0 µL, 4 eq., 217 µmol) in DMF (1.5 mL) was added HATU (26.9 mg, 1.3 eq., 70.6 µmol). The mixture was stirred at room temperature for 10 minutes. 2-[(9S)-7-{3'-amino-[1,1'- biphenyl]-4-yl}-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12- pentaen-9-yl]acetamide; trifluoroacetic acid (31.0 mg, 54.3 µmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The crude reaction mixture was purified by preparative reverse phase HPLC and the acetonitrile mobile phase was evaporated. A solution of saturated sodium bicarbonate solution (1.5 mL) was added to neutralize the aqueous acidic solution. The desired product was extracted with ethyl acetate (2 x 3 mL). The combined organic layers were dried over sodium sulfate and the solvent evaporated to give (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)quinoxaline-2-carboxamide. Example 3-c (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)quinoline-2-carboxamide (Compound P-2-c)
Figure imgf000192_0001
[0416] To a solution of quinoline-2-carboxylic acid (9.41 mg, 54.3 µmol) and ethylbis(propan-2- yl)amine (38.0 µL, 4 eq., 217 µmol) in DMF (1.5 mL) was added HATU (26.9 mg, 1.3 eq., 70.6 µmol). The mixture was stirred at room temperature for 10 minutes. 2-[(9S)-7-{3'-amino-[1,1'-biphenyl]-4-yl}- 4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9- yl]acetamide; trifluoroacetic acid (31.0 mg, 54.3 µmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The crude reaction mixture was purified by preparative reverse phase HPLC and the acetonitrile mobile phase was evaporated. A solution of saturated sodium bicarbonate (1.5 mL) was added to neutralize the aqueous acidic solution. The desired product was extracted with ethyl acetate (2 x 3 mL). The combined organic layers were dried over sodium sulfate and the solvent evaporated to give (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)quinoline-2-carboxamide. Example 4-c (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)benzofuran-7-carboxamide (Compound P-5-c) Step 1:
Figure imgf000193_0001
[0417] To a stirred solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (103 mg, 257 µmol) in DMF (3.09 mL, 0.6 eq., 154 µmol) was added ethylbis(propan-2-yl)amine (134 µL, 3 eq., 771 µmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (127 mg, 1.3 eq., 334 µmol) and carbonic acid amine (60.9 mg, 3 eq., 771 µmol). The mixture was stirred at rt for 16 hours. The crude was diluted with water and extracted into EtOAc (3 x 20 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The resulting material was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide. Step 2:
Figure imgf000193_0002
[0418] A 10-20 mL Biotage microwave reactor was charged with 2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (836 mg, 2.09 mmol), (3-{[(tert-butoxy)carbonyl]amino}phenyl)boronic acid (1.82 g, 3.7 eq., 7.68 mmol), cesium carbonate (2.04 g, 3 eq., 6.27 mmol), degassed ACN (15 mL), and Pd(Cy*Phine)2Cl2 (269 mg, 0.1 eq., 209 µmol). The microwave tube was then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture was filtered, evaporated in vacuo and crude material purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give tert-butyl (S)-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)carbamate. 1H NMR (500 MHz, d6-DMSO) δ 9.43 (s, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.69 – 7.60 (m, 3H), 7.56 – 7.48 (m, 2H), 7.45 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.27 (dt, J = 7.8, 1.3 Hz, 1H), 7.00 – 6.95 (m, 1H), 4.51 (t, J = 7.0 Hz, 1H), 3.24 (d, J = 7.1 Hz, 2H), 2.61 (s, 3H), 2.43 (s, 3H), 1.69 (m, 3H), 1.48 (s, 9H). Step 3:
Figure imgf000194_0001
[0419] Trifluoroacetic acid (2.00 mL) was slowly added to a solution of tert-butyl N-{4'-[(9S)-9- (carbamoylmethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12- pentaen-7-yl]-[1,1'-biphenyl]-3-yl}carbamate (7.27 mL, 1.85 mmol) in DCM (4 mL). The reaction was stirred at room temperature for 2 hours. TFA and DCM were co-evaporated with toluene (2 x 10 mL) to give (S)-2-(4-(3'-amino-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetamide.trifluoroacetic acid salt. m/z (ESI+) = 458.2 [M+H]+. Step 4:
Figure imgf000194_0002
[0420] To a solution of 1-benzofuran-7-carboxylic acid (10.6 mg, 1.2 eq., 65.2 µmol) and ethylbis(propan-2-yl)amine (38.0 μ L, 4 eq., 217 μmol) in DMF (1.5 mL) was added HATU (26.9 mg, 1.3 eq., 70.6 μmol). The mixture was stirred at room temperature for 10 minutes. 2-[(9S)-7-{3'-amino- [1,1'-biphenyl]-4-yl}-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12- pentaen-9-yl]acetamide; trifluoroacetic acid (31.0 mg, 54.3 μ mol) was added and the reaction mixture was stirred at room temperature for 16 hours. The crude reaction mixture was purified by preparative reverse phase HPLC and the acetonitrile mobile phase was evaporated. A solution of saturated sodium bicarbonate solution (1.5 mL) was added to neutralize the aqueous acidic solution. The desired product was extracted with ethyl acetate (2 x 3 mL). The combined organic layers were dried over sodium sulfate and the solvent evaporated to give (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)benzofuran-7-carboxamide. Example 5-c (S)-2-(2,3,9-trimethyl-4-(3'-(quinoline-2-carboxamido)-[1,1'-biphenyl]-4-yl)-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (Compound P-3-c) Step 1:
Figure imgf000195_0001
[0421] To a solution of quinoline-2-carboxylic acid (100 mg, 0.58 mmol, 1.0 eq) in DMF (3 mL) was added (3-aminophenyl)boronic acid (95 mg, 0.70 mmol, 1.2 eq), EDCI (135 mg, 0.87 mmol, 1.5 eq) and HOBt (117 mg, 0.87 mmol, 1.5 eq), DIEA (224 mg, 303 µL, 1.74 mmol, 3.0 eq), and DMAP (7.1 µg, 0.058 mmol, 0.1 eq) at 25°C. The mixture was stirred at 25°C for 10 hrs. The residue was diluted with water (3 mL) and extracted with ethyl acetate (1 mL × 3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (3-(quinoline-2-carboxamido)phenyl)boronic acid. 1H NMR (400 MHz, d4-MeOD) δ 8.55 (d, J = 8.4 Hz, 1H), 8.31 (dd, J = 8.6, 10.8 Hz, 2H), 8.05 (d, J = 7.6 Hz, 2H), 7.95 (d, J = 7.2 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.78 - 7.69 (m, 1H), 7.50 - 7.37 (m, 2H) Step 2:
Figure imgf000195_0002
[0422] To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid (50 mg, 125 µmol, 1.0 eq) in THF (0.8 mL) and H2O (0.2 mL) was added (3-(quinoline-2-carboxamido)phenyl)boronic acid (43.8 mg, 150 µmol, 1.2 eq), XPhos-Pd-G2 (9.8 mg, 12.5 µmol, 0.1 eq), and K3PO4 (52.9 mg, 249.4 µmol, 2.0 eq) at 20°C, and the mixture was stirred at 80°C for 10 hrs. The reaction was diluted with water (3 mL) and extracted with ethyl acetate (1 mL × 3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-2-(2,3,9- trimethyl-4-(3'-(quinoline-2-carboxamido)-[1,1'-biphenyl]-4-yl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid. Example 6-c (S)-2-(4-(3'-(benzofuran-7-carboxamido)-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (Compound P-4-c) Step 1:
Figure imgf000196_0001
[0423] To a solution of benzofuran-7-carboxylic acid (94 mg, 0.58 mmol, 1.0 eq) in DMF (3 mL) was added (3-aminophenyl)boronic acid (95 mg, 0.70 mmol, 1.2 eq), EDCI (135 mg, 0.87 mmol, 1.5 eq) and HOBt (117 mg, 0.87 mmol, 1.5 eq), DIEA (224 mg, 303 µL, 1.74 mmol, 3.0 eq), and DMAP (7.1 µg, 0.058 mmol, 0.1 eq) at 25°C. The mixture was stirred at 25°C for 10 hrs. The residue was diluted with water (3 mL) and extracted with ethyl acetate (1 mL × 3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (3-(benzofuran-7-carboxamido)phenyl)boronic acid. 1H NMR (400 MHz, d6-DMSO) δ 8.19 - 8.12 (m, 1H), 8.10 - 8.02 (m, 1H), 7.87 (dd, J = 4.2, 7.2 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.76 - 7.66 (m, 1H), 7.64 - 7.53 (m, 1H), 7.46 - 7.29 (m, 2H), 7.16 - 7.03 (m, 1H). Step 2:
Figure imgf000196_0002
[0424] To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid (50 mg, 125 µmol, 1.0 eq) in THF (0.8 mL) and H2O (0.2 mL) was added (3-(benzofuran-7-carboxamido)phenyl)boronic acid (42.2 mg, 150 µmol, 1.2 eq), XPhos-Pd-G2 (9.8 mg, 12.5 µmol, 0.1 eq), and K3PO4 (52.9 mg, 249.4 µmol, 2.0 eq) at 20°C, and the mixture was stirred at 80°C for 10 hrs. The reaction was diluted with water (3 mL) and extracted with ethyl acetate (1 mL × 3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-2-(4-(3'- (benzofuran-7-carboxamido)-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid. General Method A-d:
Figure imgf000197_0001
[0425] To a solution of 1A (1.0 eq) and 2A (1.0 eq) at 0 °C in pyridine is added dichlorophosphorylbenzene (3.8 eq) dropwise, and the mixture is stirred at 0 °C for 1 hr. The reaction mixture is quenched by addition with water at 0 °C. The aqueous layer is extracted with ethyl acetate, the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by column chromatography to give 3A. General Method B-d:
Figure imgf000197_0002
[0426] To a solution of 3A (1.0 eq) in DCM is added TFA (30.0 eq) dropwise. The mixture is stirred at 25 °C for 10 hr. The reaction mixture is concentrated under reduced pressure to give 4A, which is used in the next step directly in method C further purification. General Method C-d:
Figure imgf000197_0003
[0427] A solution of 4A (1.0 eq) in AcOH and THF is stirred at 50 °C for 2 hr. Water is added and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by column chromatography to give 5A. General Method D-d:
Figure imgf000198_0001
[0428] 5A is added to a suspension of NaH (2.0 eq) in THF at 0°C. The reaction mixture is stirred 10 min. BOPCl (2.0 eq) is added and the resulting mixture is stirred for 2 h at 0 °C. Acetohydrazide (1.5 eq) is added to reaction mixture and the reaction is warmed to 25 °C and stirred for 2 h. The reaction mixture is heated to 50 °C and stirred for 10 hr. Acetic anhydride (1.0 eq.) is added and the reaction heated at 80 °C for 1 hr. Water is added and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over by Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography to give 6A. General Method E-d:
Figure imgf000198_0002
[0429] A mixture of 6A (1.0 eq), 7A (3.0 eq), K3PO4 (3.0 eq) and XPhos-Pd-G2 (0.1 eq) in THF and H2O is degassed and purged with N2. The mixture is stirred at 80 °C for 10 hrs under a N2 atmosphere. The reaction mixture is partitioned between ethyl acetate and H2O. The organic phase is separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC to give 8A. General Method F-d:
Figure imgf000199_0001
[0430] To a mixture of 8A (1 eq) in DCM is added TFA (30.0 eq) dropwise. The mixture is stirred at 25 °C for 2 hr. The reaction mixture is concentrated under reduced pressure to give 9A, which is used in Method G directly without purification. General Method G-d:
Figure imgf000199_0003
[0431] To a mixture of 9A (1.0 eq) and 10A (3.0 eq) in DMF is added EDCI (1.5 eq), DIEA (3.0 eq), HOBt (1.5 eq) and DMAP (0.1 eq) in one portion at 25 °C. The mixture is stirred at 25 °C for 10 hr. The reaction mixture is diluted with H2O and extracted into ethyl acetate. The organic phase is washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by prep-HPLC to give 11A. General Method H-d:
Figure imgf000199_0002
[0432] To a solution of 12A (1.0 eq) and 13A (1.2 eq) in pyridine is added POCl3 (3.0 eq) dropwise at 0°C. The mixture is stirred at 25°C for 2 h. The reaction mixture is quenched by addition of H2O at 25°C and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography to give 14A. General Method I-d:
Figure imgf000200_0001
[0433] To a solution of 6A (1.0 eq) and BPD (3.0 eq) in dioxane is added KOAc (3.0 eq) and [2-(2- aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (88.2 mg, 112.1 µmol, 0.1 eq) under N2 atmosphere. The mixture is stirred at 80°C for 5 h. The reaction mixture is diluted with H2O and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography to give 15A. General Method J-d:
Figure imgf000200_0002
[0434] To a solution of 15A (1.0 eq) and 14A (1.1 eq) in THF and H2O is added Xphos-Pd-G2 (0.1 eq) and K3PO4 (3.0 eq) under N2 atmosphere. The mixture is stirred at 80°C for 10 h. The reaction mixture is diluted with H2O and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by prep-HPLC to give 16A.
Figure imgf000201_0002
[0435] To a solution of 17A (1.0 eq) in THF is added LiAlH4 (5.0 eq) at 0°C and the mixture is stirred at 25°C for 2 hrs. The residue is diluted with H2O and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by column chromatography to give 18A. General Method L-d:
Figure imgf000201_0001
[0436] To a solution of 18A (1.0 eq) in DMF is added 14A (0.3 eq), HATU (0.2 eq) and 1- methylimidazole (0.5 eq) at 25°C and the mixture is stirred for 10 hrs. The residue is diluted with H2O and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC to give 19A. General Method M-d:
Figure imgf000202_0001
[0437] To a solution of 19A (1.0 eq) in DCM is added Et3N (3.0 eq) and MsCl (8.4 eq) at 0 °C. The mixture is stirred at 25 °C for 2 hrs. The reaction mixture is concentrated under reduced pressure to remove DCM and the reaction mixture is quenched by addition saturated sodium bicarbonate aqueous solution at 25°C, and then diluted with H2O and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 20A. General Method N-d:
Figure imgf000202_0002
[0438] To a solution of 20A (1.0 eq) was added 21A (1.0 eq) at 25°C and the mixture is stirred at 50°C for 2 hrs. The residue is diluted with H2O and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC to give the 22A. General Method O-d:
Figure imgf000203_0001
[0439] To a mixture of 6A (1 eq) and 23A (1.4 eq) in THF and H2O is added XPhos-Pd-G2 (0.1 eq) and K3PO4 (3 eq) in one portion at 25°C under N2. The mixture is stirred at 80 °C for 10 hr. The reaction mixture is quenched by addition water at 0°C, and extracted into ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by column chromatography to give 24A. General Method P-d:
Figure imgf000203_0002
[0440] To a mixture of 24A (1 eq) and 14A (1.5 eq) in DMF is added EDCI (1.5 eq), DIEA (3 eq), DMAP (0.1 eq) and HOBt (1.5 eq) in one portion at 25°C under N2. The mixture is stirred at 25°C for 10hrs. The reaction mixture is quenched by addition water at 0°C, and extracted into ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC to 25A. General Method Q-d:
Figure imgf000204_0001
[0441] To a solution of 26A (1 eq) in DMF is added morpholine (2 eq), DIEA (5 eq) and HATU (1.5 eq). The reaction mixture is stirred at 25°C for 10 hrs. The solvents are evaporated in vacuo. The residue is purified by prep-HPLC directly to 27A. General Method R-d:
Figure imgf000204_0002
[0442] To a stirred solution of 28A (1 eq) in DMF is added ethylbis(propan-2-yl)amine (3 eq.), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (1.3 eq.) and carbonic acid amine (3 eq.). The mixture is stirred at rt for 16 hours. The crude is diluted with water and extracted into EtOAc. The combined organic layers are washed with water, brine, dried over sodium sulfate and the solvents evaporated in vacuo. The residue is purified by silica chromatography to give 29A. General Method S-d:
Figure imgf000205_0001
[0443] A 10-20 mL Biotage microwave reactor was charged with 29A (1 eq.), 30A (3.7 eq.), cesium carbonate (3 eq.), degassed ACN and Pd(Cy*Phine)2Cl2 (0.1 eq.). The microwave tube is then sealed under an argon atmosphere and heated at 90 °C under microwave irradiation for 2 hours. The reaction mixture is filtered, evaporated in vacuo and crude material purified by silica chromatography to give 31A.
Figure imgf000205_0002
[0444] Trifluoroacetic acid (30 eq.) is slowly added to a solution of 31A (1 eq.) in DCM. The reaction is stirred at room temperature for 2 hours. TFA and DCM are co-evaporated with toluene to give 32A.
Example 2-d (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)-4-fluoropyrazolo[1,5-a]pyridine-3-carboxamide (Compound P-2-d)
Figure imgf000206_0001
[0445] To a solution of 4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid (9.47 mg, 1.2 eq., 52.6 µmol) and ethylbis(propan-2-yl)amine (38.0 µL, 4 eq., 217 µmol) in DMF (1.5 mL) was added [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (26.9 mg, 1.3 eq., 70.6 µmol). The mixture was stirred at room temperature for 10 minutes. 2-[(9S)-7-{3'-amino-[1,1'-biphenyl]-4-yl}-4,5,13-trimethyl-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide; trifluoroacetic acid (25.0 mg, 43.8 µmol) was added and the reaction mixture was stirred at 50 °C for 16 hours. The crude reaction mixture was purified by preparative reverse phase HPLC to give (S)-N-(4'-(6-(2-amino-2-oxoethyl)- 2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)-4- fluoropyrazolo[1,5-a]pyridine-3-carboxamide. Example 3-d (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound P- 4-d)
Figure imgf000206_0002
[0446] To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (10.6 mg, 1.2 eq., 65.2 µmol) and ethylbis(propan-2-yl)amine (38.0 µL, 4 eq., 217 µmol) in DMF (1.5 mL) was added [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (26.9 mg, 1.3 eq., 70.6 µmol). The mixture was stirred at room temperature for 10 minutes. 2-[(9S)-7-{3'-amino-[1,1'-biphenyl]-4-yl}-4,5,13-trimethyl-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide; trifluoroacetic acid (31.0 mg, 54.3 µmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The crude reaction mixture was purified by preparative reverse phase HPLC and the acetonitrile mobile phase was evaporated. A solution of saturated sodium bicarbonate solution (1.5 mL) was added to neutralize the aqueous acidic solution. The desired product was extracted with ethyl acetate (2 x 3 mL). The combined organic layers were dried over sodium sulfate and the solvent evaporated to give (S)-N-(4'-(6-(2-amino- 2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. Example 4-d (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-4-fluoro-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound P-3-d)
Figure imgf000207_0001
[0447] Step 1: To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (100.0 mg, 250.1 µmol, 1.0 eq) in THF (1.6 mL) and H2O (0.4 mL) was added 3-amino-4-fluorophenyl)boronic acid (46.5 mg, 300.1 µmol, 1.2 eq), K3PO4 (106.2 mg, 500.1 µmol, 2.0 eq), Xphos Pd G2 (CAS #: 1310584-14-5, 19.7 mg, 25.0 µmol, 0.1 eq) at 25 °C and the mixture was stirred at 90 °C for 10 hours. The residue was diluted with water (6 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic layers were washed with brine (6 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (S)-2-(4-(3'-amino-4'- fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- yl)acetamide, which was used in the next step without purification. [0448] Step 2: To a solution of (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (30.0 mg, 63.2 µmol, 1.0 eq) in dichloromethane (1.0 mL) was added pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (22.9 mg, 126.4 µmol, 2.0 eq) and triethylamine (19.2 mg, 189.6 µmol, 26.4 µL, 3.0 eq) at 25 °C. The mixture was stirred at 25 °C for 10 hrs. The residue was diluted with water (3 mL) and extracted with ethyl acetate (3 x 1 mL). The combined organic layers were washed with brine (3 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative reverse phase HPLC to give (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-4-fluoro-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide. Example 5-d N-{4'-[4,5,13-trimethyl-9-(trifluoromethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca- 2(6),4,7,10,12-pentaen-7-yl]-[1,1'-biphenyl]-3-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound P-9-d): Step 1:
Figure imgf000208_0001
[0449] To a solution of (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (5.0 g, 18.8 mmol, 1.0 eq) and 2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoropropanoic acid (4.6 g, 18.8 mmol, 1.0 eq) in pyridine (25.0 mL) at 0 °C was added dichlorophosphorylbenzene (13.9 g, 71.5 mmol, 10.0 mL, 3.8 eq) dropwise. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched by addition of water (10.0 mL) at 0 °C. The aqueous layer was extracted with ethyl acetate (10.0 mL × 3), the combined organic layers were washed with brine (10.0 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25% ethyl acetate in petroleum ether) to give tert-butyl (3-((3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2- yl)amino)-1,1,1-trifluoro-3-oxopropan-2-yl)carbamate. 1H NMR (400 MHz, CDCl3) δ 7.53 - 7.50 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.6 Hz, 2H), 5.14 - 5.04 (m, 1H), 2.26 (s, 3H), 1.68 (s, 3H), 1.44 (s, 9H). Step 2:
Figure imgf000208_0002
[0450] To a solution of tert-butyl (3-((3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-1,1,1- trifluoro-3-oxopropan-2-yl)carbamate (9.0 g, 18.3 mmol, 1.0 eq) in DCM (180.0 mL) was added TFA (62.7 g, 549.9 mmol, 40.7 mL, 30.0 eq) dropwise. The mixture was stirred at 25 °C for 10 hr. The reaction mixture was concentrated under reduced pressure to give 2-amino-N-(3-(4-chlorobenzoyl)-4,5- dimethylthiophen-2-yl)-3,3,3-trifluoropropanamide.trifluoroacetic acid salt, which was used into the next step directly without further purification. Step 3:
Figure imgf000209_0001
[0451] A solution of 2-amino-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3,3,3- trifluoropropanamide.trifluoroacetic acid salt (4.0 g, 8.2 mmol, 1.0 eq) in AcOH (8.0 mL) and THF (40.0 mL) was stirred at 50 °C for 2 hr. Water (30.0 mL) was added and the aqueous layer was extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25% ethyl acetate in petroleum ether) to give 5-(4-chlorophenyl)-6,7-dimethyl-3- (trifluoromethyl)-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one. 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 4.12 - 4.14 (m, 1H), 2.32 (s, 3H), 1.65 (s, 3H). Step 4:
Figure imgf000209_0002
[0452] 5-(4-Chlorophenyl)-6,7-dimethyl-3-(trifluoromethyl)-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin- 2-one (0.2 g, 536.5 µmol, 1.0 eq) was added to a suspension of NaH (42.9 mg, 1.07 mmol, 60% purity, 2.0 eq) in THF (3.0 mL) at 0°C. The reaction mixture was stirred for 10 min. BOPCl (273.1 mg, 1.1 mmol, 2.0 eq) was added and the resulting mixture was stirred for 2 h at 0 °C. Acetohydrazide (59.6 mg, 804.7 µmol, 1.5 eq) was added to reaction mixture and the reaction was warmed to 25 °C and stirred for 2 h. The reaction mixture was heated to 50 °C and stirred for 10 hr. Acetic anhydride (0.2 mL) was added and the reaction heated at 80 °C for 1 hr. Water (10.0 mL) was added and the aqueous layer was extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with brine (10.0 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25% ethyl acetate in petroleum ether) to give 4-(4-chlorophenyl)-2,3,9- trimethyl-6-(trifluoromethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine. 1H NMR (400 MHz, d4-MeOD) δ 7.56 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 5.18 - 5.12 (m, 1H), 2.73 (s, 3H), 2.47 (s, 3H), 1.75 (s, 3H). Step 5:
Figure imgf000210_0001
[0453] A mixture of 4-(4-chlorophenyl)-2,3,9-trimethyl-6-(trifluoromethyl)-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepine (200.0 mg, 486.8 µmol, 1.0 eq), (3-((tert- butoxycarbonyl)amino)phenyl)boronic acid (346.2 mg, 1.5 mmol, 3.0 eq), K3PO4 (310.0 mg, 1.5 mmol, 3.0 eq) and XPhos-Pd-G2 (38.3 mg, 48.7 µmol, 0.1 eq) in THF (2 mL) and H2O (0.4 mL) was degassed and purged with N2. The mixture was stirred at 80 °C for 10 hrs under a N2 atmosphere. The reaction mixture was partitioned between ethyl acetate (10.0 mL) and H2O (5.0 mL). The organic phase was separated, washed with brine (5.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give tert-butyl (4'-(2,3,9-trimethyl-6- (trifluoromethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3- yl)carbamate. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.62 (s, 4H), 7.40 - 7.35 (m, 1H), 7.31 - 7.27 (m, 2H), 6.58 - 6.55 (m, 1H), 4.71 (d, J = 6.8 Hz, 1H), 2.71 (s, 3H), 2.43 (s, 3H), 1.76 (s, 3H), 1.51 (m, 9H). Step 6:
Figure imgf000210_0002
[0454] To a mixture of tert-butyl (4'-(2,3,9-trimethyl-6-(trifluoromethyl)-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)carbamate (7.0 mg, 12.3 µmol, 1 eq) in DCM (0.2 mL) was added TFA (42.2 mg, 370.0 µmol, 27.4 µL, 30.0 eq) dropwise. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give 4'-(2,3,9- trimethyl-6-(trifluoromethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3- amine.trifluoroacetic acid salt, which was used into the next step directly without purification. Step 7:
Figure imgf000211_0002
[0455] To a mixture of 4'-(2,3,9-trimethyl-6-(trifluoromethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-amine.trifluoroacetic acid salt (2.0 mg, 4.3 µmol, 1.0 eq) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2.1 mg, 12.8 µmol, 3.0 eq) in DMF (2.0 mL) was added EDCI (1.2 mg, 6.4 µmol, 1.5 eq), DIEA (1.7 mg, 12.8 µmol, 2.2 µL, 3.0 eq), HOBt (867.1 µg, 6.4 µmol, 1.5 eq) and DMAP (52.3 µg, 0.43 µmol, 0.1 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 10 hr. The reaction mixture was diluted with H2O (2.0 mL) and extracted into ethyl acetate (2.0 mL × 2). The organic phase was washed with brine (1.0 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give N-{4'-[4,5,13-trimethyl-9- (trifluoromethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-7-yl]-[1,1'- biphenyl]-3-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide. 1H NMR (400 MHz, CDCl3) δ 9.85 (m, 1H), 8.80 - 8.65 (m, 2H), 8.08 - 8.03 (m, 1H), 7.66 - 7.54 (m, 4H), 7.39 (t, J = 7.8 Hz, 2H), 7.32 - 7.27 (m, 1H), 7.04 - 6.99 (m, 2H), 4.65 (br s, 1H), 2.67 (s, 3H), 2.39 (s, 3H), 1.72 (s, 3H). Example 6-d N-(4-{4-[(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl}pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound P-10-d): Step 1:
Figure imgf000211_0001
[0456] To a solution of 4-(tert-butoxy)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4-oxobutanoic acid (2.00 g, 4.86 mmol) in DMA (18 mL) was added [(dimethylamino)({3H-[1,2,3]triazolo[4,5- b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (2.03 g, 1.1 eq., 5.35 mmol) and ethylbis(propan-2-yl)amine (1.02 mL, 1.2 eq., 5.83 mmol) and the reaction was stirred for 10 minutes. 2 (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (1.35 g, 1.2 eq., 5.83 mmol) was added and the reaction was stirred at 60 °C for 12 hours. Water (50 mL) was added and the resulting solution was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over sodium sulfate and the solvents were removed in vacuo. The crude product was purified by silica chromatography eluting with 0 to 100% EtOAc in hexanes to give (9H-fluoren-9-yl)methyl (S)-(1-((3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-1- oxopropan-2-yl)carbamate, which was used directly in the next step without purification. Step 2:
Figure imgf000212_0001
[0457] To solution of 5% piperazine and 2% DBU in DMA (2 mL) was added (9H-fluoren-9-yl)methyl N-[(1S)-1-{[3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl]carbamoyl}ethyl]carbamate (360 mg, 644 µmol). The reaction was stirred at room temperature for 30 minutes. Ethyl acetate (50 mL) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was filtered. The filtrate was diluted with additional ethyl acetate (50 mL) and washed with brine (50 mL), dried over sodium sulfate and the solvents were evaporated in vacuo to give (S)-2-amino-N-(3-(4-chlorobenzoyl)- 4,5-dimethylthiophen-2-yl)propanamide, which was used directly in the next step without characterization and purification. The crude material was dissolved in toluene (50 mL) and silica (1 g) was added. The reaction mixture was stirred at 90°C for 4 hours. The silica was filtered and washed with a solution of ethyl acetate and ethanol (3:1, v/v, 50 mL) and the solvents evaporated in vacuo. The crude product was purified by silica chromatography eluting with 0 to 50% 3:1 v/v EtOAc/EtOH in hexanes to give (S)-5-(4-chlorophenyl)-3,6,7-trimethyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one. 1H NMR (499 MHz, d6-DMSO) δ 11.07 (s, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.46 – 7.40 (m, 2H), 3.72 (q, J = 6.4 Hz, 1H), 2.26 (d, J = 0.9 Hz, 3H), 1.56 (s, 3H), 1.52 (d, J = 6.3 Hz, 3H). Step 3:
Figure imgf000212_0002
[0458] To a stirred solution of (3S)-5-(4-chlorophenyl)-3,6,7-trimethyl-1H,2H,3H-thieno[2,3- e][1,4]diazepin-2-one (214 mg, 671 µmol) in dry THF (4 mL) at -78 °C was added a 1M solution of potassium 2-methylpropan-2-olate (805 µL, 1.2 eq., 805 µmol). The reaction mixture was warmed to -10°C and stirred for 30 minutes. The reaction mixture was cooled to -78 °C and diphenyl phosphorochloridate (181 µL, 1.3 eq., 873 µmol) in THF (0.5 mL) was added. The resulting mixture was warmed to -10°C and stirred for 45 minutes. Acetohydrazide (99.5 mg, 2 eq., 1.34 mmol) was added and the reaction was allowed to warm to temperature over 1 hour.1-butanol (3 mL) was added and the reaction mixture was heated to 90°C for 2 hours. The solvents were removed in vacuo. The residue was dissolved in DCM (20 mL) and washed with saturated sodium bicarbonate (20 mL), brine (20 mL), dried over sodium sulfate and the solvents evaporated. The crude product was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-4-(4-chlorophenyl)- 2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.1H NMR (499 MHz, d6-DMSO) δ 7.51 – 7.43 (m, 4H), 4.23 (q, J = 6.7 Hz, 1H), 2.59 (s, 3H), 2.40 (s, 3H), 1.88 (d, J = 6.7 Hz, 3H), 1.63 (s, 3H). Step 4:
Figure imgf000213_0001
[0459] To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.0 g, 6.1 mmol, 1.0 eq) and 4- bromopyridin-2-amine (1.3 g, 7.3 mmol, 1.2 eq) in pyridine (10 mL) was added POCl3 (2.8 g, 18.4 mmol, 1.7 mL, 3.0 eq) dropwise at 0°C. The mixture was stirred at 25°C for 2 h. The reaction mixture was quenched by addition H2O (10 mL) at 25°C and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0 to 100% ethyl acetate in petroleum ether) to give N-(4-bromopyridin-2-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide. 1H NMR (400 MHz, d6-DMSO) δ 10.58 (s, 1H), 9.44 (dd, J = 1.6, 7.2 Hz, 1H), 8.98 (dd, J = 2.0, 4.4 Hz, 1H), 8.80 - 8.78 (m, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.48 - 7.35 (m, 2H). Step 5:
Figure imgf000214_0001
[0460] To a solution of (S)-4-(4-chlorophenyl)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepine (400.0 mg, 1.1 mmol, 1.0 eq) and BPD (853.8 mg, 3.3 mmol, 3.0 eq) in dioxane (5 mL) was added KOAc (330.0 mg, 3.3 mmol, 3.0 eq) and [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (88.2 mg, 112.1 µmol, 0.1 eq) under N2 atmosphere. The mixture was stirred at 80°C for 5 h. LCMS showed the reaction was completed. The reaction mixture was diluted with H2O (8 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (8 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 5 to 7% methanol in ethyl acetate) to give (S)-2,3,6,9-tetramethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine. 1H NMR (400 MHz, d6- DMSO) δ 7.71 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.24 (q, J = 6.8 Hz, 1H), 2.61 (s, 3H), 2.40 (s, 3H), 1.89 (d, J = 6.8 Hz, 3H), 1.60 - 1.56 (m, 3H), 1.31 (s, 12H). Step 6:
Figure imgf000214_0002
[0461] To a solution of (S)-2,3,6,9-tetramethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (300.0 mg, 819.1 umol, 1.0 eq) and N-(4- bromopyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (286.6 mg, 901.0 µmol, 1.1 eq) in THF (3 mL) and H2O (0.6 mL) was added Xphos-Pd-G2 (64.4 mg, 81.9 µmol, 0.1 eq) and K3PO4 (521.6 mg, 2.4 mmol, 3.0 eq) under N2 atmosphere. The mixture was stirred at 80°C for 10 h. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give N-(4-{4-[(9S)-4,5,9,13-tetramethyl-3- thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl}pyridin-2- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. 1H NMR (400 MHz, d6-DMSO) δ 10.56 (s, 1H), 9.43 (dd, J = 1.6, 7.2 Hz, 1H), 8.99 (dd, J = 1.6, 4.4 Hz, 1H), 8.78 (s, 1H), 8.63 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.50 (dd, J = 1.6, 5.6 Hz, 1H), 7.40 (dd, J = 4.0, 6.8 Hz, 1H), 4.32 - 4.24 (m, 1H), 2.62 (s, 3H), 2.42 (s, 3H), 1.91 (d, J = 6.8 Hz, 3H), 1.69 (s, 3H). Example 7-d N-{4'-[(9S)-4,5,13-trimethyl-9-[2-(methylamino)ethyl]-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-7-yl]-[1,1'-biphenyl]-3-yl}pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound P-11-d):
Figure imgf000215_0001
[0462] To a solution of methyl (S)-2-(4-(3'-amino-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (500 mg, 1.1 mmol, 1.0 eq) in THF (3 mL) was added LiAlH4 (200.6 mg, 5.2 mmol, 5.0 eq) at 0°C and the mixture was stirred at 25°C for 2 hrs. The residue was diluted with H2O (9 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25 to 100% ethyl acetate in petroleum ether) to give (S)-2-(4-(3'-amino-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)ethan-1-ol. m/z (ESI+): 444.2 (M-H)+. Step 2:
Figure imgf000215_0002
[0463] To a solution of (S)-2-(4-(3'-amino-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)ethan-1-ol (900 mg, 2.0 mmol, 1.0 eq) in DMF (10 mL) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (93.4 mg, 572.5 µmol, 0.3 eq), HATU (107.1 mg, 381.6 µmol, 0.2 eq) and 1-methylimidazole (78.3 mg, 954.2 µmol, 76.1 µL, 0.5 eq) at 25°C and the mixture was stirred for 10 hrs. The residue was diluted with H2O (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-N-(4'-(6- (2-hydroxyethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'- biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. 1H NMR (400 MHz, d4-MeOD) δ 9.16 (dd, J = 1.6, 7.0 Hz, 1H), 8.90 (dd, J = 1.6, 4.2 Hz, 1H), 8.70 (s, 1H), 8.15 - 8.06 (m, 1H), 7.80 - 7.71 (m, 3H), 7.62 (d, J = 8.4 Hz, 2H), 7.54 - 7.44 (m, 2H), 7.29 (dd, J = 4.4, 7.0 Hz, 1H), 4.60 (s, 1H), 4.41 (dd, J = 5.4, 8.8 Hz, 1H), 4.08 - 3.94 (m, 2H), 2.75 (s, 3H), 2.74 - 2.64 (m, 2H), 2.49 (s, 3H), 1.78 (s, 3H). Step 3:
Figure imgf000216_0001
[0464] To a solution of (S)-N-(4'-(6-(2-hydroxyethyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (400.0 mg, 679.5 µmol, 1.0 eq) in DCM (5 mL) was added Et3N (206.3 mg, 2.0 mmol, 283.7 µL, 3.0 eq) and MsCl (653.8 mg, 5.7 mmol, 441.8 µL, 8.4 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove DCM and the reaction mixture was quenched by addition saturated sodium bicarbonate aqueous solution 2 mL at 25°C, and then diluted with H2O (5 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give (S)-2-(2,3,9- trimethyl-4-(3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'-biphenyl]-4-yl)-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)ethyl methanesulfonate. m/z (ESI+) 667.3 (M+H)+. Step 4:
Figure imgf000217_0001
[0465] To a solution of (S)-2-(2,3,9-trimethyl-4-(3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'- biphenyl]-4-yl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)ethyl methanesulfonate (100 mg, 149.9 µmol, 1.0 eq) was added amine (10.1 mg, 149.9 µmol, 1.0 eq) at 25°C and the mixture was stirred at 50°C for 2 hrs. The residue was diluted with H2O (3 mL) and extracted with ethyl acetate (1 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give the (S)-N-(4'-(2,3,9- trimethyl-6-(2-(methylamino)ethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'- biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. 1H NMR (400 MHz, d4-MeOD) δ 9.17 (dd, J = 1.5, 7.0 Hz, 1H), 8.90 (dd, J = 1.4, 4.0 Hz, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.70 - 7.67 (m, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.55 - 7.48 (m, 2H), 7.31 (dd, J = 4.2, 6.8 Hz, 1H), 4.42 (t, J = 6.4 Hz, 1H), 3.48 - 3.40 (m, 2H), 2.83 - 2.78 (m, 5H), 2.76 (s, 3H), 2.49 (s, 3H), 1.78. Example 8-d N-{4'-[(9S)-4,5,13-trimethyl-9-[2-(morpholin-4-yl)-2-oxoethyl]-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-7-yl]-[1,1'-biphenyl]-3-yl}pyrazolo[1,5- a]pyrimidine-3-carboxamide (compound P-12-d):
Figure imgf000217_0002
To a solution of (S)-2-(2,3,9-trimethyl-4-(3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'-biphenyl]- 4-yl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (1 eq) in DMF (1 mL) was added morpholine (2 eq), DIEA (5 eq) and HATU (1.5 eq). The reaction mixture was stirred at 25°C for 10hrs. The solvents were evaporated in vacuo. The residue was purified by prep-HPLC directly to give N-{4'-[(9S)-4,5,13-trimethyl-9-[2-(morpholin-4-yl)-2-oxoethyl]-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-7-yl]-[1,1'-biphenyl]-3-yl}pyrazolo[1,5- a]pyrimidine-3-carboxamide. 1H NMR (400 MHz, d4-MeOD) δ 9.15 (d, J = 6.8 Hz, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.69 (s, 1H), 8.10 (s, 1H), 7.76 - 7.71 (m, 3H), 7.57 (d, J = 8.0 Hz, 2H), 7.50 - 7.46 (m, 2H), 7.28 (dd, J = 4.0, 7.2 Hz, 1H), 4.77 - 4.72 (m, 1H), 3.83 - 3.78 (m, 4H), 3.74 - 3.61 (m, 6H), 2.74 (s, 3H), 2.49 - 2.47 (m, 3H), 1.78 - 1.75 (m, 3H). EXAMPLE 1-e Preparation of (S)-N-(4-fluoro-4'-(2,3,9-trimethyl-6-(2-(methylamino)-2-oxoethyl)-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
Figure imgf000218_0001
[0466] To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid (5.4 g, 13.5 mmol, 1.0 eq) in MeOH (50 mL) was added SOCl2 (5.6 g, 47.1 mmol, 3.4 mL, 3.5 eq) at 0°C. The mixture was stirred at 20°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH and quenched by addition of sat. NaHCO3 to pH=8, extracted with ethyl acetate (30 mL × 3), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate, which was used without purification. 1H NMR (400 MHz, d4-MeOH) δ 7.5 - 7.6 (m, 3 H), 7.3 - 7.4 (m, 1 H), 7.2 (d, J=8.2 Hz, 1 H), 3.8 (s, 3 H), 3.6 - 3.7 (m, 2 H), 3.0 (s, 3 H), 2.5 (s, 3 H), 1.8 (s, 3 H). Step 2:
Figure imgf000219_0001
[0467] To a solution of methyl (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (5.8 g, 13.9 mmol, 1.0 eq) in THF (40 mL) and H2O (10 mL) was added (3-amino-4-fluorophenyl)boronic acid (2.9 g, 20.9 mmol, 1.5 eq), K3PO4 (8.9 g, 41.9 mmol, 3.0 eq) and XPhos-Pd-G2 (1.1 g, 1.4 mmol, 0.1 eq) at 25°C and the mixture was stirred at 80°C for 5 hrs. The residue was diluted with H2O (150 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 20 to 100% petroleum ether in ethyl acetate) to give methyl (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)- 2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate. 1H NMR (400 MHz, d6- DMSO) δ 7.6 (d, J=8.4 Hz, 2 H), 7.5 (d, J=8.0 Hz, 2 H), 7.1 (t, J=7.8 Hz, 1 H), 6.9 (s, 1 H), 6.8 (d, J=8.0 Hz, 1 H), 6.6 (dd, J=8.0, 1.3 Hz, 1 H), 5.3 (br s, 2 H), 4.5 (t, J=7.2 Hz, 1 H), 3.7 (s, 3 H), 3.5 (dd, J=12.0, 7.3 Hz, 2 H), 2.6 (s, 3 H), 2.4 (s, 3 H), 1.7 (s, 3 H). Step 3:
Figure imgf000219_0002
[0468] To a solution of methyl (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (2.5 g, 5.3 mmol, 1 eq) in DMF (20 mL) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.3 g, 7.9 mmol, 1.5 eq), EDCI (1.5 g, 7.9 mmol, 1.5 eq), DIEA (2.1 g, 15.9 mmol, 2.8 mL, 3.0 eq), DMAP (64.7 mg, 530.1 µmol, 0.1 eq) and HOBt (1.1 g, 7.9 mmol, 1.5 eq) and the mixture was stirred at 25°C for 10 hrs. The residue was diluted with H2O (60 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give to methyl (S)-2-(4-(4'-fluoro- 3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate, which was used without purification. 1H NMR (400 MHz, d6-DMSO) δ 10.1 (s, 1 H), 9.4 (dd, J=7.0, 1.6 Hz, 1 H), 9.0 (dd, J=4.2, 1.8 Hz, 1 H), 8.8 (s, 1 H), 8.1 (s, 1 H), 8.0 (s, 1 H), 7.8 - 7.9 (m, 3 H), 7.6 - 7.6 (m, 2 H), 7.5 (d, J=8.0 Hz, 1 H), 7.5 - 7.5 (m, 1 H), 7.4 (dd, J=7.0, 4.3 Hz, 1 H), 3.7 - 3.8 (m, 3 H), 2.9 (s, 2 H), 2.8 (s, 2 H), 2.7 - 2.7 (m, 3 H), 2.5 (s, 3 H), 1.8 (s, 3 H). Step 4:
Figure imgf000220_0001
[0469] To a solution of methyl (S)-2-(4-(4'-fluoro-3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'- biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (1.0 g, 1.6 mmol, 1.0 eq) in THF (2 mL), MeOH (2 mL), and H2O (2 mL) was added LiOH.H2O (330.6 mg, 7.9 mmol, 5.0 eq) and the mixture was stirred at 25°C for 5 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH. The reaction mixture was quenched by addition HCl to pH=4 and extracted with ethyl acetate (6 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (basic condition) to give (S)-2-(4-(4'-fluoro-3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'- biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid. 1H NMR (400 MHz, d4-METHANOL) δ 9.2 (dd, J=7.2, 2.0 Hz, 1 H), 8.9 (dd, J=4.4, 1.6 Hz, 1 H), 8.8 (dd, J=7.6, 2.4 Hz, 1 H), 8.7 (s, 1 H), 7.7 (d, J=8.4 Hz, 2 H), 7.6 (d, J=8.2 Hz, 2 H), 7.5 (m, J=8.4, 4.8, 2.4 Hz, 1 H), 7.3 - 7.4 (m, 2 H), 4.6 - 4.7 (m, 1 H), 3.6 (d, J=7.2 Hz, 2 H), 2.7 - 2.8 (m, 3 H), 2.5 (s, 3 H), 1.8 (s, 3 H). Step 5:
Figure imgf000221_0001
[0470] To (S)-2-(4-(4'-fluoro-3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'-biphenyl]-4-yl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 80.5 µmol, 1.0 eq) in DMF (1 mL) and was added methylamine.hydrochloride (10.9 mg, 161.1 µmol, 2.0 eq), HATU (45.9 mg, 120.8 µmol, 1.5 eq), and DIEA (52.0 mg, 402.8 µmol, 70.2 µL, 5.0 eq). The mixture was stirred at 25°C for 10 hrs. The reaction mixture was extracted with ethyl acetate (1 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-N-(4-fluoro-4'-(2,3,9-trimethyl-6-(2- (methylamino)-2-oxoethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-[1,1'-biphenyl]-3- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. 1H NMR (400 MHz, d4-METHANOL) δ 9.1 - 9.2 (m, 1 H), 8.9 (dd, J=4.0, 1.4 Hz, 1 H), 8.8 (dd, J=7.4, 2.0 Hz, 1 H), 8.7 (s, 1 H), 7.7 (d, J=8.4 Hz, 2 H), 7.6 (d, J=8.0 Hz, 2 H), 7.5 (td, J=5.6, 2.4 Hz, 1 H), 7.4 (s, 1 H), 7.3 (d, J=1.8 Hz, 1 H), 7.3 - 7.3 (m, 1 H), 4.7 (d, J=3.2 Hz, 1 H), 3.4 - 3.5 (m, 1 H), 3.4 - 3.4 (m, 1 H), 2.9 (s, 3 H), 2.7 (s, 3 H), 2.5 (s, 3 H), 1.8 (s, 3 H).
EXAMPLE 1-f Preparation of (S)-N-(4'-(6-(2-(dimethylamino)-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-4-fluoro-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
Figure imgf000222_0001
Step 1:
Figure imgf000222_0002
[0471] To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetic acid (5.4 g, 13.5 mmol, 1.0 eq) in MeOH (50 mL) was added SOCl2 (5.6 g, 47.1 mmol, 3.4 mL, 3.5 eq) at 0°C. The mixture was stirred at 20°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH and quenched by addition of sat. NaHCO3 to pH=8, extracted with ethyl acetate (30 mL × 3), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate, which was used without purification. 1H NMR (400 MHz, d4-MeOH) δ 7.5 - 7.6 (m, 3 H), 7.3 - 7.4 (m, 1 H), 7.2 (d, J=8.2 Hz, 1 H), 3.8 (s, 3 H), 3.6 - 3.7 (m, 2 H), 3.0 (s, 3 H), 2.5 (s, 3 H), 1.8 (s, 3 H). Step 2:
Figure imgf000223_0001
[0472] To a solution of methyl (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (5.8 g, 13.9 mmol, 1.0 eq) in THF (40 mL) and H2O (10 mL) was added (3-amino-4-fluorophenyl)boronic acid (2.9 g, 20.9 mmol, 1.5 eq), K3PO4 (8.9 g, 41.9 mmol, 3.0 eq) and XPhos-Pd-G2 (1.1 g, 1.4 mmol, 0.1 eq) at 25°C and the mixture was stirred at 80°C for 5 hrs. The residue was diluted with H2O (150 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 20 to 100% petroleum ether in ethyl acetate) to give methyl (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)- 2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate. 1H NMR (400 MHz, d6- DMSO) δ 7.6 (d, J=8.4 Hz, 2 H), 7.5 (d, J=8.0 Hz, 2 H), 7.1 (t, J=7.8 Hz, 1 H), 6.9 (s, 1 H), 6.8 (d, J=8.0 Hz, 1 H), 6.6 (dd, J=8.0, 1.3 Hz, 1 H), 5.3 (br s, 2 H), 4.5 (t, J=7.2 Hz, 1 H), 3.7 (s, 3 H), 3.5 (dd, J=12.0, 7.3 Hz, 2 H), 2.6 (s, 3 H), 2.4 (s, 3 H), 1.7 (s, 3 H). Step 3:
Figure imgf000223_0002
[0473] To a solution of methyl (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (2.5 g, 5.3 mmol, 1 eq) in DMF (20 mL) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.3 g, 7.9 mmol, 1.5 eq), EDCI (1.5 g, 7.9 mmol, 1.5 eq), DIEA (2.1 g, 15.9 mmol, 2.8 mL, 3.0 eq), DMAP (64.7 mg, 530.1 µmol, 0.1 eq) and HOBt (1.1 g, 7.9 mmol, 1.5 eq) and the mixture was stirred at 25°C for 10 hrs. The residue was diluted with H2O (60 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give to methyl (S)-2-(4-(4'-fluoro- 3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate, which was used without purification. 1H NMR (400 MHz, d6-DMSO) δ 10.1 (s, 1 H), 9.4 (dd, J=7.0, 1.6 Hz, 1 H), 9.0 (dd, J=4.2, 1.8 Hz, 1 H), 8.8 (s, 1 H), 8.1 (s, 1 H), 8.0 (s, 1 H), 7.8 - 7.9 (m, 3 H), 7.6 - 7.6 (m, 2 H), 7.5 (d, J=8.0 Hz, 1 H), 7.5 - 7.5 (m, 1 H), 7.4 (dd, J=7.0, 4.3 Hz, 1 H), 3.7 - 3.8 (m, 3 H), 2.9 (s, 2 H), 2.8 (s, 2 H), 2.7 - 2.7 (m, 3 H), 2.5 (s, 3 H), 1.8 (s, 3 H). Step 4:
Figure imgf000224_0001
[0474] To a solution of methyl (S)-2-(4-(4'-fluoro-3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'- biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (1.0 g, 1.6 mmol, 1.0 eq) in THF (2 mL), MeOH (2 mL), and H2O (2 mL) was added LiOH.H2O (330.6 mg, 7.9 mmol, 5.0 eq) and the mixture was stirred at 25°C for 5 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH. The reaction mixture was quenched by addition HCl to pH=4 and extracted with ethyl acetate (6 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (basic condition) to give (S)-2-(4-(4'-fluoro-3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'- biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid. 1H NMR (400 MHz, d4-METHANOL) δ 9.2 (dd, J=7.2, 2.0 Hz, 1 H), 8.9 (dd, J=4.4, 1.6 Hz, 1 H), 8.8 (dd, J=7.6, 2.4 Hz, 1 H), 8.7 (s, 1 H), 7.7 (d, J=8.4 Hz, 2 H), 7.6 (d, J=8.2 Hz, 2 H), 7.5 (m, J=8.4, 4.8, 2.4 Hz, 1 H), 7.3 - 7.4 (m, 2 H), 4.6 - 4.7 (m, 1 H), 3.6 (d, J=7.2 Hz, 2 H), 2.7 - 2.8 (m, 3 H), 2.5 (s, 3 H), 1.8 (s, 3 H). Step 5:
Figure imgf000225_0001
[0475] To (S)-2-(4-(4'-fluoro-3'-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-[1,1'-biphenyl]-4-yl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 80.5 µmol, 1.0 eq) in DMF (1 mL) and was added dimethylamine.hydrochloride (10.9 mg, 161.1 µmol, 2.0 eq), HATU (45.9 mg, 120.8 µmol, 1.5 eq) and DIEA (52.0 mg, 402.8 µmol, 70.2 µL, 5.0 eq). The mixture was stirred at 25°C for 10 hrs. The reaction mixture was extracted with ethyl acetate (1 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-N-(4'-(6-(2-(dimethylamino)-2- oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-4-fluoro-[1,1'- biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. 1H NMR (400 MHz, d4-METHANOL) δ 9.1 (d, J=7.2 Hz, 1 H), 8.9 - 8.9 (m, 1 H), 8.8 (dd, J=7.6, 2.0 Hz, 1 H), 8.7 (s, 1 H), 7.7 (d, J=8.2 Hz, 2 H), 7.6 (d, J=8.4 Hz, 2 H), 7.4 - 7.5 (m, 1 H), 7.3 - 7.4 (m, 1 H), 7.3 (dd, J=6.8, 4.1 Hz, 1 H), 4.7 (d, J=6.8 Hz, 1 H), 3.5 - 3.7 (m, 2 H), 3.3 (br s, 3 H), 3.0 (s, 3 H), 2.8 (s, 3 H), 2.5 (s, 3 H), 1.8 (s, 3 H).
COMPARATIVE EXAMPLE A Comparative Example A -- Preparation of (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-4-fluoro-[1,1'-biphenyl]-3-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
Figure imgf000226_0001
[0476] To a stirred solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (103 mg, 257 µmol) in DMF (3.09 mL, 0.6 eq., 154 µmol) was added ethylbis(propan-2-yl)amine (134 µL, 3 eq., 771 µmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (127 mg, 1.3 eq., 334 µmol), and carbonic acid amine (60.9 mg, 3 eq., 771 µmol). The mixture was stirred at rt for 16 hours. The crude was diluted with water and extracted into EtOAc (3 x 20 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and the solvents evaporated in vacuo. The resulting solid was purified by silica chromatography eluting with 0 to 100% 3:1 v/v EtOAc/EtOH in heptane to give (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide. Step 2:
Figure imgf000227_0001
[0477] To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetamide (100.0 mg, 250.1 µmol, 1.0 eq) in THF (1.6 mL) and H2O (0.4 mL) was added (3-amino-4-fluorophenyl)boronic acid (46.5 mg, 300.1 µmol, 1.2 eq), K3PO4 (106.2 mg, 500.1 µmol, 2.0 eq), Xphos-Pd-G2 (19.7 mg, 25.0 µmol, 0.1 eq) at 25°C and the mixture was stirred at 90°C for 10 hrs. The residue was diluted with H2O (6 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide, which was used into the next step without further purification. m/z (ESI+) 475.3 (M-H)+. Step 3:
Figure imgf000227_0002
[0478] To a solution of give (S)-2-(4-(3'-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (30.0 mg, 63.2 µmol, 1.0 eq) in DCM (1 mL) was added pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (22.9 mg, 126.4 µmol, 2.0 eq), Et3N (19.2 mg, 189.6 µmol, 26.4 µL, 3.0 eq) at 25°C and the mixture was stirred at 25°C for 10 hrs. The residue was diluted with H2O (3 mL) and extracted with ethyl acetate (1 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-N-(4'-(6-(2-amino-2-oxoethyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-4-fluoro-[1,1'-biphenyl]-3-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide. 1H NMR (400 MHz, d6-DMSO) δ 10.24 (d, J=2.4 Hz, 1 H), 9.43 (dd, J=6.8, 1.2 Hz, 1 H), 8.96 (dd, J=4.2, 1.6 Hz, 1 H), 8.72 - 8.80 (m, 2 H), 7.64 - 7.77 (m, 3 H), 7.55 (d, J=8.2 Hz, 2 H), 7.47 (d, J=8.4 Hz, 2 H), 7.38 (dd, J=6.8, 4.2 Hz, 1 H), 7.00 (s, 1 H), 4.52 (t, J=6.8 Hz, 1 H), 3.26 (d, J=7.2 Hz, 2 H), 2.62 (s, 3 H), 2.44 (s, 3 H), 1.71 (s, 3 H). [0479] The compounds set forth in Table 2 were prepared following the procedures set forth above. Table 2
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
[0480] The compounds set forth in Table 2A were prepared following the procedures set forth above. Table 2A
Figure imgf000230_0002
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0002
Biological Examples Target engagement assay [0481] The ability of a compound to bind to BRD4 is assessed using HEK-293T cells and the NanoBRET Target Engagement Intracellular BET BRD Assay from Promega (Cat. No. N2131). Assays were run according to manufacturer’s specifications and luminescent readout was recorded using a CLARIOstar Plus instrument (BMG Labtech). Resulting BRET ratios were plotted and IC50s determined by non-linear regression analyses (GraphPad Prism). BRD4 degradation assay [0482] BRD4 degradation was monitored by immunofluorescence in HEK-293T cells. In brief, 96-well plates (black, clear-bottom) were seeded with HEK-293T cells at 10,000 cells/well and incubated overnight at 37°C to allow cell attachment. After overnight incubation, test compounds were added in a 10-point dilution series (typically 30 µM to 100 pM) using a TECAN D300e Digital Dispenser, and plates were subsequently incubated for 24 hours at 37°C. Media was carefully removed, and cells were fixed in PBS + 2.5% formalin (50 µL) for 20 minutes at 37°C. Following formalin fixation, cells were washed once with PBS and methanol was added (30 µL). Plates were wrapped in parafilm and incubated at -20°C for 1 hour to overnight. For immunostaining, plates were removed from -20°C and cells were washed with PBS (3x).50 µL of blocking solution (PBS + 1X fish gelatin, 0.3% Triton X-100) were added to each well and plates were incubated at room temperature for 30 minutes to 1 hour. Blocking buffer was removed, and 40 µL primary BRD4 antibody (Sigma-Aldrich HPA061646; diluted 1:1000 in PBS + 1X fish gelatin, 0.1% Triton X-100) was added. Plates were incubated at 4°C for 4 hours to overnight, after which cells were washed (3x) with PBS + 0.1% tween-20 at room temperature. DAPI (1µM final) plus secondary antibody (Southern Biotech 4030-30 anti-Rabbit IgG Alexa Fluor 488; diluted 1:2000 in PBS + 1X fish gelatin, 0.1% Triton X-100) were added at 40 µL/well, and plates were incubated at room temperature for 2 hours covered with foil. Cells were washed (3x) with PBS + 0.1% tween-20, followed by one wash with PBS, and the addition of 100 µL of PBS for imaging. Images were acquired using the ImageXpress Pico system (Molecular Devices). Cell Reporter Xpress software was utilized to segment cells and determine fluorescence intensities, which were used to construct dose- response curves and calculation of degradation DC50s (GraphPad Prism). Table 3 and Table 3A show results from the assays. TABLE 3
Figure imgf000244_0001
Figure imgf000245_0001
Table 3A
Figure imgf000245_0002
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Pharmacokinetic Study Comparing Compounds of Example 1-e (“Compound 1-e”), Compounds of Example 1-f (“Compound 1-f”), and Comparative Compound A [0483] An in-vivo study was performed to determine the relative pharmacokinetics of Compound 1-e, Compound 1-f, and Compound A in female BALB/C mice following oral gavage (10 mg/kg) in vehicle. The study was a single dose, bioavailability study. Three animals per dose were randomly allocated to each treatment arm. [0484] An appropriate amount of Compound 1-e, Compound 1-f, and Compound A were weighed to form a 10 mg/mL solution and mixed with vortexing with an appropriate volume of 20% solutol, 30% PEG 400, and 50% Captisol™ (Ligand, San Diego, CA) to form a clear solution. Animals were dosed within four hours of the formulation preparation. [0485] Formulation samples were removed from each of the formulation solutions, transferred into 1.5 mL polypropylene microcentrifuge tubes and dose validated by LC-MS/ MS prior to use. The dose formulation was administered to each mouse (10 mg/kg) via oral gavage at t=0. [0486] At each time point, about 0.02-0.03 mL of blood was withdrawn from the saphenous vein of each animal. All blood samples were transferred into pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifugation. [0487] Blood samples were processed for plasma by centrifugation at approximately 4°C, 3,200 g for 10 min. Plasma was collected respectively and transferred into pre-labeled polypropylene tubes, quick frozen over dry ice and kept at -60℃ or lower until LC-MS/MS analysis. [0488] Plasma concentrations of Compound 1-e, Compound 1-f, and Compound A were analyzed using non-compartmental analysis methods to obtain estimates of standard PK parameters as set out below. [0489] Log-transformed exposure parameters (AUCs and Cmax) were compared with standard methods to assess relative bioavailability and derived using Phoenix WinNonlin (Version 6.3). [0490] Arithmetic mean plasma concentrations versus time by treatment (linear scale) are described in table 4. TABLE 4
Figure imgf000248_0002
[0491] Overall exposure parameters, AUC(0-t), AUC(0-inf) and Cmax for Compound 1-e and Compound 1-f are significantly higher compared to Compound A. AUC(0-t) of Compound 1-e is 2.49-fold higher than Compound A and Cmax is 1.75-fold higher. AUC(0-t) of Compound 1-f is 4.97-fold higher than Compound A and Cmax is 3.45-fold higher. [0492] These results establish that Compound 1-e and Compound 1-f behave significantly better than Compound A notwithstanding their close structural similarities.

Claims

WHAT IS CLAIMED IS: 1. A compound represented by formula I-a:
Figure imgf000250_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A is monocyclic 5-or 6-membered heteroaryl having 1-4 heteroatoms selected from O, N, NR3 and S, wherein ring A is unsubstituted or substituted with one to four R14; R and R' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR3, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R1)2, or -CH2C(O)N(R1)2, wherein each R1 is independently hydrogen, C1-C4 alkyl, or both R1 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S; or R and R' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein each of said cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two R6; each of T1 and T2 is independently CR8 or N; each of T, T3, T4, and T5 is independently CR2 or N; and further provided that no more than two of T, T1, T2, and T3 are N; each R2 is independently hydrogen or fluoro, or when two R2 are at the 2,2' or at the 6,6' position, the two R2 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R6; R3 is hydrogen or C1-C4 alkyl; R4 and R5 are independently hydrogen, methyl, or methoxy; each R6 is halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; each R7 is independently hydrogen or C1-C4 alkyl; or two R7 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR3, and S; each R8 is independently hydrogen, halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; and each R14 is independently halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R7)2, and C1-C2 alkoxy, C1-C4 alkoxy, C1-C4 alkoxy substituted with from 1 to 3 halo groups, C3-C6 cycloalkyl, or 5- to 6- membered heteroaryl. 2. A compound represented by formula I-a:
Figure imgf000251_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A is a monocyclic, nitrogen containing heteroaryl attached to the carbonyl moiety via a ring carbon atom wherein ring A has 0, 1, or 2 additional nitrogen ring atoms and 0 or 1 additional oxygen or sulfur ring atom, wherein ring A is unsubstituted or substituted with one to four R14, provided that ring A is not pyrimidine or pyrazine; R is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR3, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R1)2, or -CH2C(O)N(R1)2, wherein each R1 is independently hydrogen, C1-C4 alkyl, or both R1 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S; R' is H; or R and R' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R6; each of T1 and T2 is independently CR8 or N; each of T, T3, T4, and T5 is independently CR2 or N; and further provided that no more than two of T, T1, T2, and T3 are N; each R2 is independently hydrogen or fluoro, or when two R2 are at the 2,2' or at the 6,6' position, the two R2 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R6; R3 is hydrogen or C1-C4 alkyl; R4 and R5 are independently hydrogen, methyl, or methoxy; each R6 is halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; each R7 is independently hydrogen or C1-C4 alkyl; or two R7 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl from zero to two additional heteroatoms selected from O, N, NR3, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR3, and S; each R8 is independently hydrogen, halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; and each R14 is independently halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R7)2, and C1-C2 alkoxy, C1-C4 alkoxy, C1-C4 alkoxy substituted with from 1 to 3 halo groups, C3-C6 cycloalkyl, or 5- to 6- membered heteroaryl; and provided that the compound at 1 µM concentration degrades BRD4 by 30% or more. 3. A compound represented by formula Ia-a:
Figure imgf000252_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A is a monocyclic, nitrogen containing heteroaryl attached to the carbonyl moiety via a ring carbon atom wherein ring A has 0, 1, or 2 additional nitrogen ring atoms and 0 or 1 additional oxygen or sulfur ring atom, wherein ring A is unsubstituted or substituted with one to four R14, provided that ring A is not pyrimidine or pyrazine; R is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR3, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R1)2, or -CH2C(O)N(R1)2, wherein each R1 is independently hydrogen, C1-C4 alkyl, or both R1 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S; R' is H; or R and R' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R6; each of T1 and T2 is independently CR8 or N; T is CR2 or N; and further provided that no more than one of T, T1, and T2 is N; each R2 is independently hydrogen or fluoro, or when two R2 are at the 2,2' or at the 6,6' position, the two R2 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R6; R3 is hydrogen or C1-C4 alkyl; R4 and R5 are independently hydrogen, methyl, or methoxy; each R6 is halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; each R7 is independently hydrogen or C1-C4 alkyl; or two R7 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR3, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR3, and S; each R8 is independently hydrogen, halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, or C1-C4 alkoxy; and each R14 is independently halo, cyano, hydroxy, N(R7)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R7)2, and C1-C2 alkoxy, C1-C4 alkoxy, C1-C4 alkoxy substituted with from 1 to 3 halo groups, C3-C6 cycloalkyl, or 5- to 6- membered heteroaryl; and provided that the following compounds are excluded:
,
Figure imgf000254_0001
, , , ,
Figure imgf000255_0001
, ,
Figure imgf000256_0001
. 4. The compound of claim 2 or 3, wherein each of T, T1, and T2 is CH. 5. The compound of claim 2 or 3, wherein one of T, T1, and T2 is N. 6. The compound of any one of claims claim 1-5, wherein both R and R' are H. 7. The compound of any one of claims claim 2-5, wherein R and R' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl. 8. The compound of claim 7, wherein the R and R' together with the carbon atom to which they are attached form a spirocyclopropyl or spirooxetanyl group. 9. The compound of any one of claims claim 2-8, wherein each R2 is independently hydrogen or fluoro. 10. The compound of claim 2 or 3 or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein
Figure imgf000256_0002
V is N or CR14; R10 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, ethoxy, and C3-C6 cycloalkyl; R11 is selected from the group consisting of C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, cyano, methoxy, ethoxy, and C3-C6 cycloalkyl; R12 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C2 alkyl substituted with 1 to 3 fluoro groups, -NH2, cyano, hydroxy, methoxy, and ethoxy; and h is 0, 1, 2, or 3. 11. The compound of claim 2 or 3 represented by formula II-A-a or II-B-a:
Figure imgf000257_0001
II-A-a II-B-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. 12. The compound of claim 2 or 3 represented by formula III-a:
Figure imgf000257_0002
III-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof.
13. The compound of claim 2 or 3 represented by formula IV-a:
Figure imgf000258_0001
IV-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. 14. The compound of claim 2 or 3 represented by formula V-a:
Figure imgf000258_0002
V-a or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, mixture of stereoisomers, or tautomer of each thereof. 15. The compound of any one of claims 2-14, wherein each R2 is hydrogen. 16. The compound of any one of claims 2-15, wherein both R4 and R5 are methyl. 17. The compound of any one of claims 2-16, wherein both R8 are hydrogen. 18. The compound of any one of claims 2-16, wherein one or both R8 are fluoro. 19. The compound of any one of claims 2-18, wherein each R14 independently is hydrogen, halo, or C1-C4 alkyl. 20. The compound of claim 19, wherein each R14 is hydrogen. 21. The compound of any one of claims 2-5 and 9-20, wherein R is hydrogen, CH3, CF3, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2C(O)N(CH3)2, -CH2C(O)OH, -CH2C(O)OMe, -CH2C(O)NHEt, -CH2C(O)N(Et)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2(morpholin-1-yl), -CH2CH2(pyrrolidin-1-yl), -CH2C(O)(morpholin-1-yl), or -CH2C(O)(pyrrolidin-1-yl). 22. The compound of claim 21, wherein R is CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2. 23. A compound represented by formula I-b:
Figure imgf000259_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A20 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted with one to four R29; R20 and R20' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR23, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R21)2, or -CH2C(O)N(R21)2, wherein each R21 is independently hydrogen, C1-C4 alkyl, or both R21 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S; or R20 and R20' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein each of said cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two R26; each of T21 and T22 is independently CR28 or N; each of T20, T23, T24, and T25 is independently CR22 or N; and further provided that no more than two of T20, T21, T22, and T23 are N; each R22 is independently hydrogen or fluoro, or when two R22 are at the 2,2' or at the 6,6' position, the two R22 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with zero, one, or two R26; R23 is hydrogen or C1-C4 alkyl; R24 and R25 are independently hydrogen, methyl, or methoxy; each R26 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; each R27 is independently hydrogen or C1-C4 alkyl; or two R27 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR23, and S; each R28 is independently hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; Q20 is C, CH, or N; Q25 and Q26 are independently C or N provided that both cannot be N; each of X20 and Y20 is independently C, CR29, O, S, N, or NR34, provided that ring B20 formed thereby is a 5-membered heteroaryl; each R29 is independently halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R27)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R34 is hydrogen or C1-C4 alkyl, provided that: (i)
Figure imgf000260_0001
, each of Q21, Q22, Q23 and Q24 is independently N or CR32; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; the number of Q21-Q26 that are N is from one to three; and when either Q25 or Q26 is N, then neither X20 or Y20 can be O, S or NR34; and
Figure imgf000260_0002
each of t20 and v20 is independently zero, one, or two; Q27 and Q28 are independently CHR32 or NR33; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; R33 is hydrogen or C1-C3 alkyl; and when Q25 is N, then Q28 is CHR32. 24. A compound represented by formula I-b:
Figure imgf000261_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A20 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is substituted with zero to four R29; R20 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR23, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R21)2, or -CH2C(O)N(R21)2, wherein each R21 is independently hydrogen, C1-C4 alkyl, or both R21 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S; R20' is H; or R20 and R20' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R26; each of T21 and T22 is independently CR28 or N; each of T20, T23, T24, and T25 is independently CR22 or N; and further provided that no more than two of T20, T21, T22, and T23 are N; each R22 is independently hydrogen or fluoro, or when two R22 are at the 2,2' or at the 6,6' position, the two R22 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are substituted with zero, one, or two R26; R23 is hydrogen or C1-C4 alkyl; R24 and R25 are independently hydrogen, methyl, or methoxy; each R26 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; each R27 is independently hydrogen or C1-C4 alkyl; or two R27 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR23, and S; each R28 is independently hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; Q20 is C, CH, or N; Q25 and Q26 are independently C or N provided that both cannot be N; each of X20 and Y20 is independently C, CR29, O, S, N, or NR34, provided that ring B20 formed thereby is a 5-membered heteroaryl; each R29 is independently halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R27)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R34 is hydrogen or C1-C4 alkyl, provided that: (i) when
Figure imgf000262_0001
, each of Q21, Q22, Q23 and Q24 is independently N or CR32; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; the number of Q21-Q26 that are N is from one to three; and when either Q25 or Q26 is N, then neither X20 or Y20 can be O, S or NR34; and (ii) when
Figure imgf000262_0002
, each of t20 and v20 is independently zero, one, or two; Q27 and Q28 are independently CHR32 or NR33; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; R33 is hydrogen or C1-C3 alkyl; and when Q25 is N, then Q28 is CHR32, and (iii) the compound at 1 µM concentration degrades BRD4 by 30% or more.
Figure imgf000263_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A20 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R29; R20 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR23, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R21)2, or -CH2C(O)N(R21)2, wherein each R21 is independently hydrogen, C1-C4 alkyl, or both R21 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S; R20' is H; or R20 and R20' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R26; each of T21 and T22 is independently CR28 or N; T20 is CR22 or N; and further provided that no more than one of T20, T21, and T22 is N; each R22 is independently hydrogen or fluoro, or when two R22 are at the 2,2' or at the 6,6' position, the two R22 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R26; R23 is hydrogen or C1-C4 alkyl; R24 and R25 are independently hydrogen, methyl, or methoxy; each R26 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; each R27 is independently hydrogen or C1-C4 alkyl; or two R27 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR23, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR23, and S; each R28 is independently hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; Q20 is C, CH, or N; Q25 and Q26 are independently C or N provided that both cannot be N; each of X20 and Y20 is independently C, CR29, O, S, N, or NR34, provided that ring B20 formed thereby is a 5-membered heteroaryl; each R29 is independently hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R27)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R34 is hydrogen or C1-C4 alkyl, provided that: (i)
Figure imgf000264_0001
, each of Q21, Q22, Q23 and Q24 is independently N or CR32; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; the number of Q21-Q26 that are N is from one to three; and when either Q25 or Q26 is N, then neither X20 or Y20 can be O, S or NR34; and
Figure imgf000264_0002
each of t20 and v20 is independently zero, one, or two; Q27 and Q28 are independently CHR32 or NR33; R32 is hydrogen, halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; R33 is hydrogen or C1-C3 alkyl; and when Q25 is N, then Q28 is CHR32; and (iii) the following compounds are excluded: , , , , , , , , ,
Figure imgf000266_0002
. 26. The compound of claim 24 or 25, wherein each of T20, T21, and T22 is CH. 27. The compound of claim 24 or 25, wherein one of T20, T21, and T22 is N. 28. The compound of any one of claims claim 24-27, wherein both R20 and R20' are H. 29. The compound of any one of claims claim 23-27, wherein R20 and R20' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl. 30. The compound of claim 29, wherein the R20 and R20' together with the carbon atom to which they are attached form a spirocyclopropyl or spirooxetanyl group. 31. The compound of any one of claims claim 24-30, wherein each R22 is independently hydrogen or fluoro. 32. The compound of claim 24 or 25 represented by formula II-b:
Figure imgf000266_0001
II-b or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. 33. The compound of claim 24 or 25 represented by formula II-A-b or II-B-b:
Figure imgf000267_0001
II-A-b II-B-b or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. 34. The compound of claim 24 or 25 represented by formula III-b:
Figure imgf000267_0002
III-b or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: t20 is zero, one, or two; and R32 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy.
35. The compound of claim 24 or 25 represented by formula IV-b:
Figure imgf000268_0001
IV-b or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: each of Q21, Q22, Q23 and Q24 is independently N or CR32; and R32 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy. 36. The compound of claim 24 or 25 represented by formula V-b:
Figure imgf000268_0002
V-b or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: v20 is zero, one, or two; Q27 and Q28 are independently CHR32 or NR33; R32 is halo, cyano, hydroxy, N(R27)2, C1-C4 alkyl, or C1-C4 alkoxy; and R33 is hydrogen or C1-C4 alkyl. 37. The compound of any one of claims 24-36, wherein each R22 is hydrogen. 38. The compound of any one of claims 24-37, wherein both R24 and R25 are methyl.
39. The compound of any one of claims 24-38, wherein both R28 are hydrogen. 40. The compound of any one of claims 24-38, wherein one or both R28 are fluoro. 41. The compound of any one of claims 24-40, wherein each R29 independently is hydrogen, halo, or C1-C4 alkyl. 42. The compound of claim 41, wherein each R29 is hydrogen. 43. The compound of any one of claims 24-27 and 31-42, wherein R20 is hydrogen, -CH3, -CF3, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2C(O)N(CH3)2, -CH2C(O)OH, -CH2C(O)OMe, -CH2C(O)NHEt, -CH2C(O)N(Et)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2(morpholin-1-yl), -CH2CH2(pyrrolidin-1-yl), -CH2C(O)(morpholin-1-yl), or -CH2C(O)(pyrrolidin-1-yl). 44. The compound of claim 43, wherein R20 is -CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2. 45. A compound represented by formula I-c:
Figure imgf000269_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A40 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R49; R40 and R40' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR43, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R41)2, or -CH2C(O)N(R41)2, wherein each R41 is independently hydrogen, C1-C4 alkyl, or both R41 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S; or R40 and R40' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein each of said cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two R46; each of T41 and T42 is independently CR48 or N; each of T40, T43, T44 and T45 is independently CR42 or N; and further provided that no more than two of T40, T41, T42 and T43 are N; each R42 is independently hydrogen or fluoro, or when two R42 are at the 2,2' or at the 6,6' position, the two R42 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R46; R43 is hydrogen or C1-C4 alkyl; R44 and R45 are independently hydrogen, methyl, or methoxy; each R46 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each R47 is independently hydrogen or C1-C4 alkyl; or two R47 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR43, and S; each R48 is independently hydrogen, halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each of Q41, Q42, Q43 and Q44 are independently N or CR50 provided that no more than three of Q41, Q42, Q43, or Q44 are N and provided that one of R50 is a bond to the NH-C(O)-; each R50 is independently selected from hydrogen and C1-C3 alkyl; Q45 and Q46 are independently C or N provided that both cannot be N; and each R49 is independently halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R47)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups. 46. A compound represented by formula I-c:
Figure imgf000270_0001
I-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A40 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R49; R40 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR43, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R41)2, or -CH2C(O)N(R41)2, wherein each R41 is independently hydrogen, C1-C4 alkyl, or both R41 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S; R40' is H; or R40 and R40' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R46; each of T41 and T42 is independently CR48 or N; each of T40, T43, T44 and T45 is independently CR42 or N; and further provided that no more than two of T40, T41, T42 and T43 are N; each R42 is independently hydrogen or fluoro, or when two R42 are at the 2,2' or at the 6,6' position, the two R42 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R46; R43 is hydrogen or C1-C4 alkyl; R44 and R45 are independently hydrogen, methyl, or methoxy; each R46 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each R47 is independently hydrogen or C1-C4 alkyl; or two R47 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR43, and S; each R48 is independently hydrogen, halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each of Q41, Q42, Q43 and Q44 are independently N or CR50 provided that no more than three of Q41, Q42, Q43, or Q44 are N and provided that one of R50 is a bond to the NH-C(O)-; each R50 is independently selected from hydrogen and C1-C3 alkyl; Q45 and Q46 are independently C or N provided that both cannot be N; and each R49 is independently halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R47)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and provided that the compound at 1 µM concentration degrades BRD4 by 30% or more. 47. A compound represented by formula Ia-c:
Figure imgf000272_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A40 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R49; R40 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR43, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R41)2, or -CH2C(O)N(R41)2, wherein each R41 is independently hydrogen, C1-C4 alkyl, or both R41 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S; R40' is H; or R40 and R40' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R46; each of T41 and T42 is independently CR48 or N; T40 is CR42 or N; and further provided that no more than one of T40, T41, and T42 is N; each R42 is independently hydrogen or fluoro, or when two R42 are at the 2,2' or at the 6,6' position, the two R42 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R43 is hydrogen or C1-C4 alkyl; R44 and R45 are independently hydrogen, methyl, or methoxy; each R46 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each R47 is independently hydrogen or C1-C4 alkyl; or two R47 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR43, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR43, and S; each R48 is independently hydrogen, halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy; each of Q41, Q42, Q43 and Q44 are independently N or CR50 provided that no more than three of Q41, Q42, Q43, or Q44 are N and provided that one of R50 is a bond to the NH-C(O)-; each R50 is independently selected from hydrogen and C1-C3 alkyl; Q45 and Q46 are independently C or N provided that both cannot be N; and each R49 is independently halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R47)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and provided that the following compounds are excluded:
Figure imgf000273_0001
. 48. The compound of claim 46 or 47, wherein each of T40, T41, and T42 is CH. 49. The compound of claim 46 or 47, wherein one of T4, T41, and T42 is N. 50. The compound of any one of claims 46-49, wherein both R40 and R40' are H.
51. The compound of any one of claims 45-49, wherein R40 and R40' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl. 52. The compound of claim 51, wherein the R40 and R40' together with the carbon atom to which they are attached form a spirocyclopropyl or spirooxetanyl group. 53. The compound of any one of claims claim 46-52, wherein each R42 is independently hydrogen or fluoro. 54. The compound of claim 46 or 47 represented by formula II-c:
Figure imgf000274_0001
II-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. 55. The compound of claim 46 or 47 represented by formula II-A-c or II-B-c:
Figure imgf000274_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof.
56. The compound of claim 46 or 47 represented by formula III-c:
Figure imgf000275_0001
III-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: t40 is zero, one or two; and R52 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy. 57. The compound of claim 46 or 47 represented by formula IV-c:
Figure imgf000275_0002
IV-c or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: v40 is zero, one, or two; and R52 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy.
58. The compound of claim 46 or 47 represented by formula V-c:
Figure imgf000276_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: v40 is zero, one, or two; and R52 is halo, cyano, hydroxy, N(R47)2, C1-C4 alkyl, or C1-C4 alkoxy. 59. The compound of any one of claims 46-58, wherein each R42 is hydrogen. 60. The compound of any one of claims 46-59, wherein both R44 and R45 are methyl. 61. The compound of any one of claims 46-60, wherein both R48 are hydrogen. 62. The compound of any one of claims 46-60, wherein one or both R48 are fluoro. 63. The compound of any one of claims 46-62, wherein each R49 independently is hydrogen, halo, or C1-C4 alkyl. 64. The compound of claim 63, wherein each R49 is hydrogen. 65. The compound of any one of claims 46-49 and 53-64, wherein R40 is hydrogen, -CH3, -CF3, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2C(O)N(CH3)2, -CH2C(O)OH, -CH2C(O)OMe, -CH2C(O)NHEt, -CH2C(O)N(Et)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2(morpholin-1-yl), -CH2CH2(pyrrolidin-1-yl), -CH2C(O)(morpholin-1-yl), or -CH2C(O)(pyrrolidin-1-yl). 66. The compound of claim 65, wherein R40 is -CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2.
67. A compound of formula IB-d:
Figure imgf000277_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein q60 is zero, one or two; R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene- N(R61)2 or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; R60' is hydrogen; or R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; T60 is CR62 or N; each of T61 and T62 is independently CR68 or N; further provided that no more than two of T60, T61, and T62 are N; Q61 and Q64 are independently N or CR69; R62 is H; each R63 is C1-C3 alkyl; R64 and R65 are independently hydrogen, methyl or methoxy; each R68 is independently selected from hydrogen, halo, cyano, hydroxy, N(R67)2, C1-C3 alkyl, or C1-C3 alkoxy; where each R67 is independently hydrogen or C1-C4 alkyl; and each R69 is independently hydrogen, hydroxy, cyano, halo, amino, (C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 halo groups, C1-C4 alkoxy, C1-C4 alkoxy substituted with from 1 to 3 halo groups; or C1-C4 alkyl substituted with C1-C2 alkoxy; with the proviso that the following compounds are excluded: , ,
Figure imgf000278_0001
, ,
Figure imgf000279_0001
68. The compound according to claim 67, wherein Q61 is nitrogen and Q64 is CR69. 69. The compound according to claim 67, wherein R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, or -CH2C(O)N(R61)2. 70. The compound according to claim 69, wherein R60’ is hydrogen. 71. The compound according to claim 70, wherein R60 and R60’ together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl. 72. The compound according to claim 71, wherein R60 and R60’ together with the carbon atom to which they are attached form an oxetane ring. 73. The compound according to claim 67, wherein each R68 is independently selected from hydrogen and fluoro. 74. The compound according to claim 67, wherein said compound is represented by formula IIB-d:
Figure imgf000279_0002
IIB-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; R60' is hydrogen; T62 is N or CH; Q61 is N or CR69; and R69 is selected from fluoro, chloro, methyl, and methoxy. 75. The compound according to claim 67, wherein said compound is represented by formula IIIB-d:
Figure imgf000280_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein wherein R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; T62 is N or CH; Q61 is N or CR69; and R69 is selected from fluoro, chloro, methyl, and methoxy. 76. The compound of claim 67, wherein R60 is -CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2. 77. A compound represented by formula IC-d:
Figure imgf000281_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A60 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R69; R60 and R60' are independently hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R61)2, or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; or R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, wherein each of said cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two R66; each of T61 and T62 is independently CR68 or N; each of T60, T63, T64, and T65 is independently CR62 or N; and further provided that no more than two of T60, T61, T62, and T63 are N; each R62 is independently hydrogen or fluoro, or when two R62 are at the 2,2' or at the 6,6' position, the two R62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R66; R63 is hydrogen or C1-C4 alkyl; R64 and R65 are independently hydrogen, methyl, or methoxy; each R66 is halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; each R67 is independently hydrogen or C1-C4 alkyl; or two R67 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR63, and S; each R68 is independently hydrogen, halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; Q60 is C, CH, or N; Q65 and Q66 are independently C or N provided that both cannot be N; Y60 is C, CR69, O, S, N, or NR74, provided that ring B60 formed thereby is a 5-membered heteroaryl; each R69 is independently halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R67)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R74 is hydrogen or C1-C4 alkyl. 78. A compound represented by formula IC-d:
Figure imgf000282_0001
IC-d or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A60 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R69; R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R61)2, or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; R60' is H; or R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R66; each of T61 and T62 is independently CR68 or N; each of T60, T63, T64, and T65 is independently CR62 or N; and further provided that no more than two of T60, T61, T62, and T63 are N; each R62 is independently hydrogen or fluoro, or when two R62 are at the 2,2' or at the 6,6' position, the two R62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R66; R63 is hydrogen or C1-C4 alkyl; R64 and R65 are independently hydrogen, methyl, or methoxy; each R66 is halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; each R67 is independently hydrogen or C1-C4 alkyl; or two R67 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR63, and S; each R68 is independently hydrogen, halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; Q60 is C, CH, or N; Q65 and Q66 are independently C or N provided that both cannot be N; Y60 is C, CR69, O, S, N, or NR74, provided that ring B60 formed thereby is a 5-membered heteroaryl; each R69 is independently halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R67)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R74 is hydrogen or C1-C4 alkyl; provided that the compound at 1 µM concentration degrades BRD4 by 30% or more.
79. A compound represented by formula ICa-d:
Figure imgf000284_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: ring A60 is phenyl, a 5- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein each of said phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, is unsubstituted or substituted with one to four R69; R60 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -CH2C(O)OR63, C1-C4 haloalkyl having 1 to 3 halo groups, C1-C3 alkylene-N(R61)2, or -CH2C(O)N(R61)2, wherein each R61 is independently hydrogen, C1-C4 alkyl, or both R61 together with the nitrogen atom to which they are attached form a 3- to 7- membered heterocycloalkyl having from zero to two additional heteroatoms selected from O, N, NR63, and S; R60' is H; or R60 and R60' together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with one or two R66; each of T61 and T62 is independently CR68 or N; T60 is CR62 or N; and further provided that no more than one of T60, T61, and T62 is N; each R62 is independently hydrogen or fluoro, or when two R62 are at the 2,2' or at the 6,6' position, the two R62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, further wherein each of said cycloalkyl, phenyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with one or two R66; R63 is hydrogen or C1-C4 alkyl; R64 and R65 are independently hydrogen, methyl, or methoxy; each R66 is halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; each R67 is independently hydrogen or C1-C4 alkyl; or two R67 together with the nitrogen atom to which they are attached form a form a 3- to 7-membered heterocycloalkyl having from zero to two heteroatoms selected from O, N, NR63, and S, or 5- to 6-membered heteroaryl having from zero to two additional heteroatoms selected from O, N, NR63, and S; each R68 is independently hydrogen, halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, or C1-C4 alkoxy; Q60 is C, CH, or N; Q65 and Q66 are independently C or N provided that both cannot be N; Y60 is C, CR69, O, S, N, or NR74, provided that ring B60 formed thereby is a 5-membered heteroaryl; each R69 is independently halo, cyano, hydroxy, N(R67)2, C1-C4 alkyl, C1-C4 alkyl substituted with from 1 to 3 substituents independently selected from halo, cyano, hydroxy, N(R67)2, and C1-C2 alkoxy, C1-C4 alkoxy, or C1-C4 alkoxy substituted with from 1 to 3 halo groups; and R74 is hydrogen or C1-C4 alkyl; provided that the following compounds are excluded: ,
Figure imgf000285_0001
, ,
, ,
Figure imgf000286_0001
,
,
Figure imgf000287_0001
80. The compound of claim 78 or 79, wherein each of T60, T61, and T62 is CH. 81. The compound of claim 78 or 79, wherein one of T60, T61, and T62 is N. 82. The compound of any one of claims claim 77-81, wherein both R60 and R60' are H. 83. The compound of any one of claims 77-81, wherein R60 and R60' together with the carbon atom to which they are attached form a substituted 3-7 membered cycloalkyl or a substituted 4-7 membered heterocyclyl. 84. The compound of claim 83, wherein the R60 and R60' together with the carbon atom to which they are attached form a spirocyclopropyl or spirooxetanyl group. 85. The compound of any one of claims claim 78-84, wherein each R62 is independently hydrogen or fluoro.
86. The compound of claim 78 or 79 represented by formula VIC-d:
Figure imgf000288_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. 87. The compound of claim 86 represented by formula VI-AC-d or VI-BC-d:
Figure imgf000288_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein: q60 is zero, one or two; Q61 and Q64 are independently N or CR69; and two R62 together with the carbon atoms to which they are attached form a C5-C8 cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, or a 5- to 6-membered heteroaryl,wherein each of said cycloalkyl, phenyl, heterocyclyl and heteroaryl are unsubstituted or substituted with one to two R66.
88. The compound of claim 86 represented by formula VIIC-d:
Figure imgf000289_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein r60 is zero, one, two, or three. 89. The compound of claim 86 represented by formula VIIIC-d:
Figure imgf000289_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein r60 is zero, one, two, or three.
90. The compound of claim 86 represented by formula IXC-d:
Figure imgf000290_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, wherein s60 is zero, one, two, three, or four. 91. The compound of any one of claims 78-90, wherein each R62 is hydrogen. 92. The compound of any one of claims 78-91, wherein both R64 and R65 are methyl. 93. The compound of any one of claims 78-92, wherein both R68 are hydrogen. 94. The compound of any one of claims 78-92, wherein one or both R68 are fluoro. 95. The compound of any one of claims 78-94, wherein each R69 independently is hydrogen, halo, or C1-C4 alkyl. 96. The compound of claim 95, wherein each R69 is hydrogen. 97. The compound of any one of claims 78-81 and 85-96, wherein R60 is hydrogen, -CH3, -CF3, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2C(O)N(CH3)2, -CH2C(O)OH, -CH2C(O)OMe, -CH2C(O)NHEt, -CH2C(O)N(Et)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2(morpholin-1-yl), -CH2CH2(pyrrolidin-1-yl), -CH2C(O)(morpholin-1-yl), or -CH2C(O)(pyrrolidin-1-yl). 98. The compound of claim 97, wherein R60 is -CH3, -CH2C(O)NHCH3, or -CH2C(O)N(CH3)2.
99. A compound represented by formula I-e:
Figure imgf000291_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. 100. A compound of formula I-e:
Figure imgf000291_0002
or a pharmaceutically acceptable salt thereof.
101. A compound represented by formula I-f:
Figure imgf000292_0001
I-f or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. 102. A compound of formula I-f:
Figure imgf000292_0002
I-f or a pharmaceutically acceptable salt thereof. 103. A compound or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, selected from Table 1. 104. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of any one of claims 1-103. 105. A method for modulating or degrading BRD4 which method comprises contacting BRD4 with an effective amount of a compound of any one of claims 1-103, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, under conditions wherein BRD4 is modulated or degraded.
106. A method to modulate or degrade BRD4 in a subject in need thereof, which method comprises administering to said subject an effective amount of a compound of any one of claims 1-103, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of any one of claims 1-103, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. 107. A method for treating a proliferative disorder mediated, at least in part, by BRD4 in a subject in need thereof, comprising administering to said subject an effective amount of a compound of any one of claims 1-103, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of any one of claims 1- 103, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof. 108. The method of claim 107, wherein the proliferative disorder is liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer, or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, or diffuse large B-cell lymphoma. 109. The method of claim 107, wherein the proliferative disorder is prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, or Ewing’s sarcoma. 110. The method of claim 107, wherein the proliferative disorder is non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, or gastrointestinal stromal tumor (GIST). 111. The method of claim 107, wherein the proliferative disorder is non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, or gastrointestinal stromal tumor (GIST). 112. The method of claim 107, wherein the proliferative disorder is non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), or microsatellite stable colorectal cancer (mssCRC).
113. Use of a compound of any one of claims 1-103, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, or a pharmaceutical composition of claim 104, for treating a proliferative disorder mediated, at least in part, by BRD4. 114. Use of a compound of any one of claims 1-103, or a pharmaceutically acceptable salt, solvate, stereoisomer, mixture of stereoisomers, or tautomer of each thereof, or a pharmaceutical composition of claim 104, in the manufacture of a medicament, for treating a proliferative disorder mediated, at least in part, by BRD4.
PCT/US2022/034515 2022-06-22 2022-06-22 Compounds and pharmaceutical compositions that modulate brd4 WO2022221786A2 (en)

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