WO2023220640A1 - Cdk protein degraders, pharmaceutical compositions, and therapeutic applications - Google Patents

Cdk protein degraders, pharmaceutical compositions, and therapeutic applications Download PDF

Info

Publication number
WO2023220640A1
WO2023220640A1 PCT/US2023/066834 US2023066834W WO2023220640A1 WO 2023220640 A1 WO2023220640 A1 WO 2023220640A1 US 2023066834 W US2023066834 W US 2023066834W WO 2023220640 A1 WO2023220640 A1 WO 2023220640A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
cyclopentyl
phenyl
piperazin
methyl
Prior art date
Application number
PCT/US2023/066834
Other languages
French (fr)
Inventor
Aparajita Hoskote Chourasia
Paul E. Erdman
Leah M. Fung
Shenlin Huang
Imelda LAM
Hannah MAJESKI
Akinori Okano
Patrick Papa
John Sapienza
Eduardo Torres
Brandon Whitefield
Original Assignee
Biotheryx, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biotheryx, Inc. filed Critical Biotheryx, Inc.
Publication of WO2023220640A1 publication Critical patent/WO2023220640A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • CDK protein degraders and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a CDK-medlated disorder, disease, or condition.
  • Cyclin-dependent kinases are protein kinases that are involved in critical cellular processes, such as a cell cycle. Malumbres etal., Nat. Cell Biol. 2009, 11, 1275-6; Ding et al., Int. J. Mol. Sci. 2020, 21, 1960. CDKs associate with different cyclins to control different cell cycle transitions in human cells Uzbekov and Prigent, Cells 2020, 11, 704. There are 20 CDKs and about 30 cyclins in the human. Malumbres et al., Nat. Cell Biol. 2009, 11, 1275-6.
  • CDK2 complexed with cyclin E drives cell-cycle progression from G1 to S phase.
  • Cell cycle dysregulation characterized by aberrant activation of CDKs is a hallmark of cancer. Malumbres and Barbacid, Nat. Rev. Cancer 2009, 9, 153-66; Otto and Sicinski, Nat. Rev. Cancer 2017, 17, 93-115; Ding et al., Int. J. Mol. Sci. 2020, 21, 1960.
  • the efficacy of CDK4/CDK6 inhibition is, however, limited by innate or acquired resistance. Alvarez-Fernandez and Malumbres, Cancer Cell 2020, 37, 514-29; Ogata et al., Breast Cancer 2021, 28, 206-15.
  • cancer remains a major worldwide public health problem. It was estimated that there will be 1,918,030 new cancer cases diagnosed and 609,360 cancer deaths in the US alone in 2022. Cancer Facts de Figures 2022. Therefore, there is a need for an effective therapy for cancer treatment.
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
  • A is a bond, heterocyclylene, or -S(O2)-;
  • E is C6-14 arylene, heteroarylene, or heterocyclylene
  • L is a linker
  • X is a bond or --C(O)--
  • R 1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) ⁇ C(O)R la , -C(O)OR la , -C(O)NR lb R lc , -C(O)SR la , -C(NR ia )NR lb R lc , -C(S)R la , -C(S)OR la , -C(S)NR lb R lc , -S(O)R la , -S(O) 2 R la , -S(O)NR lb R lc , or -S(O) 2 NR lb R lc ;
  • R 2 , R 3 , and R 4 are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R la , -C(O)OR la , -C(O)NR lb R lc , -C(O)SR la , -C(NR la )NR lb R lc , -C(S)R la , ⁇ C(S)OR la , -C(S)NR ib R lc , -OR la , -OC(O)R la , -OC(O)OR la , -OC(O)NR lb R lc , -
  • each A E is independently a bond, -O-, -N(R lb )---, --S-, C1-6 alkylene, Ci-6 heteroalkylene, C2-6 alkenylene, C2-6 heteroalkenyl ene, CM alkynylene, C 2 -6 heteroalkynylene, C3-10 cycloalkylene, Ce-i4 arylene, C7-15 aralkylene, heteroarylene, heterocyclylene, CM heteroalkylene-C6-i4 arylene, vC1-6 heteroalkylene-heterocyclylene, or C2-6 alkynylene-heterocyclylene; each X E is independently C(R E1 ) or N;
  • Y E is a bond, CM alkylene, -O-, -S-, -S(O)-, ⁇ S(O 2 )-, or -N(R E3 )-;
  • each R E1 is independently hydrogen, deuterium, halo, or C1-6 alkyl
  • each R E2 , R E3 , and R E3 is independently hydrogen or C1-6 alkyl
  • each R E4 is independently (i) deuterium, cyano, halo, or nitro;
  • a pharmaceutical composition comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
  • a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a CDK in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inhibiting the growth of a cell comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inducing degradation of a CDK comprising contacting the CDK with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • cow, pig, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the subject is a human.
  • treat is meant to include alleviating or abrogating a di sorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • the terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
  • the terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
  • contacting or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo.
  • a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule.
  • a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell.
  • the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.
  • terapéuticaally effective amount or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • therapeutically effective amount or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a biological molecule e.g., a protein, enzyme, RNA, or DNA
  • ICso or “ECso” refers to an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal response in an assay that measures such a response.
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit/risk ratio.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.
  • C1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl.”
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., w-propyl and isopropyl), butyl (including all isomeric forms, e.g., w-butyl, isobutyl, sec-butyl, and Ebutyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., w-hexyl, isohexyl, and sec-hexyl).
  • alkylene and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally be substituted with one or more substituents Q as described herein.
  • C1-6 alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C1-30), 1 to 20 (C1-2.0), 1 to 15 (Ci-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 carbon atoms.
  • linear C1-6 and branched C3-6 alkanediyl groups are also referred as “lower alkanediyl.”
  • alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane- 1,1 -diyl and ethane- 1,2-diyl), propanediyl (including all isomeric forms, e.g,, propane- 1,1 -diyl, propane-1, 2- diyl, and propane- 1,3 -diyl), butanediyl (including all isomeric forms, e.g., butane-l, l-diyl, butane- 1,2-diyl, butane- 1,3 -diyl, and butane-l,4-diyl), pentanediyl (including all isomeric forms, e.g.
  • substituted alkanediyl groups include, but are not limited to, -C(O)CH2-, -C(O)(CH 2 )2-, -C(O)(CH 2 )3-, -C(O)(CH 2 )4- -C(O)(CH 2 ) 5 -, -C(O)(CH 2 )6-, -C(O)(CH 2 )7-, -C(O)(CH 2 >- -C(O)(CH2)9-, -C(0)(CH 2 )IO-, -C(O)CH 2 C(O)- -C(O)(CH 2 ) 2 C(O)-, -C(O)(CH 2 )3C(O)-, -C(O)(CH 2 ) 4 C(O)-, or -C(O)(CH 2 ) 5 C(O)-.
  • heteroalkyl refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N.
  • the heteroalkyl is optionally substituted with one or more substituents Q as described herein.
  • C1-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (Ci-15), 1 to 10 (Ci-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C.3-10), or 3 to 6 (C3-6) carbon atoms.
  • linear C1-6 and branched C3-6 heteroalkyl groups are also referred as “lower heteroalkyl.”
  • heteroalkyl groups include, but are not limited to, --OCH3, -OCH2.CH3, -CH2.OCH3, -NHCHs, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and -NHCH2CH2CH3.
  • substituted heteroalkyl groups include, but are not limited to, -CH 2 NHC(O)CH 3 and -NHC(O)CH 2 CH 3 .
  • heteroalkylene and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from 0, S, and N.
  • the heteroalkylene is optionally substituted with one or more substituents Q as described herein.
  • C1-6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci -20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • linear C1-6 and branched C3-6 heteroalkylene groups are also referred as “lower heteroalkylene ”
  • heteroalkyl ene groups include, but are not limited to,
  • substituted heteroalkylene groups include, but are not limited to, C(O)CH 2 O C(O)(CH 2 )2O -, -C(O)CH 2 CH 2 CH 2 O- -C(O)CH2CH 2 CH 2 CH 2 O-, -C(O)(CH 2 ) 5 O- -C(O)(CH 2 ) 6 O- -C(O)(CH 2 ) 7 O-, -C(O)(CH 2 )SO-, -C(O)(CH 2 )9O- -C(0)(CH 2 )IOO-, -C(O)CH 2 OCH 2 CH 2 O- -C(O)CH 2 O(CH 2 CH 2 O) 2 --, --C(O)CH2O(CH2CH2O)3-, ⁇ C(O)
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s).
  • the alkenyl is optionally substituted with one or more substituents Q as described herein.
  • alkenyl embraces radicals having a “czx” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C2.-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-0) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeri c forms, e.g., propen- 1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms, e.g, buten- 1-yl, buten-2-yl, buten-3-yl, and 2-buten-l-yl).
  • alkenylene and “alkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s).
  • the alkenediyl is optionally substituted with one or more substituents Q as described herein.
  • alkenediyl embraces radicals having a “cis” or “ trans'” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C2-6 alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenediyl is a linear divalent hydrocarbon radical of 2 to 30 ( €2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 ( €2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • alkenediyl groups include, but are not limited to, ethenediyl (including all isomeric forms, e.g. , ethene- 1 ,1- diyl and ethene- 1,2-diyl), propenediyl (including all isomeric forms, e.g., 1 -propene- 1,1 -diyl, 1- propene- 1,2-diyl, and 1 -propene- 1,3 -diyl), butenediyl (including all isomeric forms, e.g, 1- butene- 1,1 -diyl, l-butene-l,2-diyl, and 1 -butene- 1,4-diyl), pentenediyl (including all isomeric forms, e.g., 1 -pentene- 1,1 -diyl, 1 -pentene- 1,2-diyl, and 1 -pentene- 1,5 -d
  • heteroalkenylene and “heteroalkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected from 0, S, and N in the hydrocarbon chain.
  • the heteroalkenylene is optionally substituted with one or more substituents Q as described herein.
  • heteroalkenylene embraces radicals having a “cz's” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C2-6 heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (Cs-2o), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (Cs-s) carbon atoms.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s).
  • An alkynyl group does not contain a carboncarbon double bond.
  • the alkynyl is optionally substituted with one or more substituents Q as described herein.
  • C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (CMO), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms.
  • ethynyl (-OCH)
  • alkynylene and alkynediyl are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s).
  • An alkynylene group does not contain a carbon-carbon double bond.
  • the alkynediyl is optionally substituted with one or more substituents Q as described herein.
  • C 2 -6 alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms.
  • the alkynediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical 6) carbon atoms.
  • alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g, l-propyne-l,3-diyl and l-propyne-3,3-diyl), butynediyl (including all isomeric forms, e.g., 1 -butyne- 1,3 -diyl, 1 -butyne- 1,4-diyl, and 2- butyne- 1,1 -diyl), pentynediyl (including all isomeric forms, e.g., l-pentyne-l,3-diyl, 1-pentyne- 1 ,4-diyl, and 2-pentyne- 1,1 -diyl), and hexynediyl (including all isomeric forms, e.g.,
  • heteroalkynylene and “heteroalkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s), and which contains one or more heteroatoms in its main chain, each independently selected from O, S, and N.
  • a heteroalkynylene group does not contain a carbon-carbon double bond.
  • the heteroalkynylene is optionally substituted with one or more substituents Q as described herein.
  • C2-6 heteroalkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms.
  • the heteroalkynylene is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2- e) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms.
  • cycloalkyl refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein.
  • the cycloalkyl is a saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic group.
  • the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms.
  • the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic.
  • the cycloalkyl is tricyclic. In still another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclofl .1. l]pentyl, bicyclo[2.1. l]hexyl, bicyclo[2.2. l]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.
  • cycloalkylene and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein.
  • cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclic groups.
  • the cycloalkanediyl has from 3 to 30 (C3-30), 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms.
  • cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane- 1,1 -diyl and cyclopropane- 1,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane- 1,1 -diyl, cyclobutane- 1,2-diyl, and cyclobutane- 1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane- 1,1 -diyl, cyclopentane- 1,2-diyl, and cyclopentane- 1,3 -diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane- 1, 1 -diy
  • aryl refers to a monovalent monocyclic aromatic hydrocarbon radical and/or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-15), or from 6 to 10 (C6-10) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • the aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
  • the aiyl is monocyclic.
  • the aryl is bicyclic.
  • the aryl is tricyclic.
  • the aryl is polycyclic.
  • the aryl is optionally substituted with one or more substituents Q as described herein.
  • arylene and “arenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic hydrocarbon radical or divalent polycyclic aromatic hydrocarbon radical that contains at least one aromatic hydrocarbon ring.
  • the arylene has from 6 to 20 (C6-20), from 6 to 15 (C6-15), or from 6 to 10 (Ce-io) ring atoms.
  • arylene groups include, but are not limited to, phenylene (including ail isomeric forms, e.g., phen-l,2-diyl, phen- 1,3 -diyl, and phen-l,4-diyl), naphthylene (including all isomeric forms, e.g., naphth-1 ,2-diyl, naphth-l,3-diyl, and naphth- 1,8-diyl), fluorenylene (including all isomeric forms, e.g, fluoren-l,2-diyl, fluoren-l,3-diyl, and fluoren- 1,8-diyl), azulenylene (including all isomeric forms, e.g, azulen-l,2-diyl, azulen- 1,3 -diyl, and azulen-1 ,8- diyl), anthrylene (including all iso
  • Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene (including all isomeric forms, e.g., dihydronaphth- 1 ,2-diyl and dihydronaphth- 1,8-diyl), indenylene (including all isomeric forms, e.g., inden- 1 ,2-diyl, inden- 1 ,5-diyl, and inden-l,7-diyl), indanylene (including all isomeric forms, e.g, indan- 1 ,2-diyl, indan-1 ,5-diyl, and indan- 1,7-diyl), or tetrahydronaphthylene (tetralinyl ene) (including all isomeric forms, e.g, tetrahydronap
  • aralkyl or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms.
  • aralkyl groups include, but are not limited to, benzyl, phenyl ethyl (including all isomeric forms, e.g., 1 -phenylethyl and 2- phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1 -phenyl propyl, 2- phenylpropyl, and 3 -phenyl propyl).
  • the aralkyl is optionally substituted with one or more substituents Q as described herein.
  • aralkylene or “arylalkylene” refers to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms.
  • aralkylene groups include, but are not limited to, benzylene (including all isomeric forms, e.g., phenylmethdiyl), phenyl ethylene (including all isomeric forms, e.g., 2-phenyl-ethan- 1,1 -diyl and 2-phenyl-ethan-l,2-diyl), and phenylpropylene (including all isomeric forms, e.g., 3-phenyl- propan- 1,1 -diyl, 3-phenyl-propan-l,2-diyl, and 3-phenyl-propan-l,3-diyl).
  • the aralkylene is optionally substituted with one or more substituents Q as described herein.
  • heteroaryl refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatom s, each independently selected from O, S, and N, in the ring.
  • heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • the heteroaryl is monocyclic.
  • heteroaryl groups examples include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • the heteroaryl is bicyclic.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadi azolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-£>]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-Z>]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-Z>]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[l,2-a]pyridinyl, imidazo[4,5- Z>]pyridinyl, and imidazo[4,5-c]pyridin
  • the heteroaryl is tricyclic.
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7- phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • the heteroaryl is optionally substituted with one or more substituents Q as described herein.
  • heteroarylene and “heteroarenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic group or divalent polycyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from 0, S, and N.
  • heteroarylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring the heteroarylene group is not bonded to the rest of a molecule via its nonaromatic heterocyclic ring.
  • Each ring of a heteroarylene group can contain one or two 0 atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, oxazoldiyl, pyrazindiyl, pyrazoldiyl, pyridazindiyl, pyridindiyl, pyrimidindiyl, pyrrol diyl, thiadiazol diyl, thiazoldiyl, thiendiyl, tetrazol diyl, triazinediyl, and triazol diyl.
  • bicyclic heteroarylene groups include, but are not limited to, benzofuran diyl, benzimidazoldiyl, benzoisoxazoldiyl, benzopyrandiyl, benzothiadiazoldiyl, benzothiazoldiyl, benzothiendiyl, benzotriazoldiyl, benzoxazoldiyl, furopyridindiyl (including all isomeric forms, e.g, furo[2,3-Z>]pyridindiyl, furo[2,3-c]pyridindiyl, furo[3,2-/>]pyridindiyl, furo[3,2-c]- pyridindiyl, furo[3,4-Z>]pyridindiyl, and furo[3,4-c]pyridindiyl), imidazopyridindiyl (including all isomeric forms, e.g, imidazo[l,2-a]pyridindiyl,
  • tricyclic heteroarylene groups include, but are not limited to, acridindiyl , benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (including all isomeric forms, e.g., 1,5-phenanthrolindiyl, 1,6- phenanthrolindiyl, 1,7-phenanthrolindiyl, 1,9-phenanthrolindiyl, and 2,10-phenanthrolindiyl), phenanthridindiyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenoxazindiyl, and xanthendiyl.
  • heteroaiylene is optionally substituted with one or more substituents Q as described herein.
  • heterocyclyl refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one nonaromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from 0, S, and N; and the remaining ring atoms are carbon atoms.
  • heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, di hydrobenzofuranyl, dihydrobenzisothiazolyl, dihydro- benzisoxazinyl (including all isomeric forms, e.g., l,4-dihydrobenzo[t/][l,3]oxazinyl, 3,4- dihydrobenzo[c][l,2]-oxazinyl, and 3,4-dihydrobenzo[ ⁇ 7][l,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydro
  • heterocyclylene refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from 0, S, and N; and the remaining ring atoms are carbon atoms.
  • the heterocyclylene group For a heterocyclylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclylene group has at least one bond to the rest of a molecule via its nonaromatic heterocyclic ring.
  • the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclylene groups include, but are not limited to, azepindiyl, benzodioxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e.g., l,4-dihydrobenzo[J][l,3]oxazindiyl, 3,4-dihydrobenzo[c][l,2]oxazindiyl, and 3,4-dihydrobenzo[tf][l,2]oxazindiyl), dihydrobenzothiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydrofur
  • halogen refers to fluoro, chloro, bromo, and/or iodo.
  • each Q a is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C 2 -6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Cs-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , ⁇ C(NR e )NR f R 8 , -C(S)R e , -C(S)OR e , ⁇ C(S)NR f R®, -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R
  • optically active and ’’enantiomerically active refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
  • the prefixes J? and 5 are used to denote the absolute configuration of the compound about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the compound, R and .S',
  • an isotopically enriched compound refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 3 H), deuterium ( 2 H), tritium ( 3 H), carbon- 11 ( n C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( i4 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( !5 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( !
  • an isotopically enriched compound is in a stable form, that is, non-radioactive.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 3 H), deuterium ( 2 H), carbon- 12 ( 12 C), carbon- 13 ( lj C), nitrogen- 14 ( 14 N), nitrogen- 15 ( 15 N), oxygen- 16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), phosphorus-31 ( 51 P), sulfur-32 ( 32 S), sulfur- 33 ( JJ S), sulfur-34 ( 34 S), sulfur-36 ( 3o S), chlorine-35 ( J3 C1), chlorine-37 ( 3 / Cl), bromine-79 ( /9 Br), bromine-81 ( 81 Br), and iodine-127 ( 127 I).
  • an isotopically enriched compound is in an unstable form, that is, radioactive.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-1 1 ( n C), carbon-14 ( 14 C), nitrogen-13 ( n N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), fluorine-18 ( 18 F), phosphorus-32 ( j2 P), phosphorus-33 ( 33 P), sulfur-35 ( 35 S), chlorine-36 ( 3b Cl), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-129 ( 129 I), and iodine- 131 ( 131 I).
  • any hydrogen can be 2 H, as example, or any carbon can be l3 C, as example, or any nitrogen can be l5 N, as example, or any oxygen can be 1S O, as example, where feasible according to the judgment of one of ordinary skill in the art.
  • isotopic enrichment refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope (e.g, 3 H for protium or hydrogen-1) of the element.
  • a less prevalent isotope e.g., D for deuterium or hydrogen-2
  • a more prevalent isotope e.g, 3 H for protium or hydrogen-1
  • isotopic enrichment factor refers the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.
  • hydrogen refers to the composition of naturally occurring hydrogen isotopes, which include protium ( 3 H), deuterium ( 2 H or D), and tritium ( 3 H), in their natural abundances.
  • Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%.
  • Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.
  • deuterium enrichment refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).
  • carbon refers to the composition of naturally occurring carbon isotopes, which include carbon-12 ( 12 C) and carbon-13 ( 13 C) in their natural abundances.
  • Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%.
  • Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.
  • carbon-13 enrichment or “ 13 C enrichment” refers to the percentage of incorporation of carbon- 13 at a given position in a molecule in the place of carbon.
  • carbon- 13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon-13 at the specified position. Because the naturally occurring distribution of carbon-13 is about 1.11% on average, carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average.
  • when a particular position in an isotopically enriched compound is designated as having carbon- 13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).
  • substantially pure and substantially homogeneous mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • substantially pure or “substantially homogeneous” refers to a collection of molecules, wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods.
  • a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound.
  • a deuterated compound that has an atom at a particular position designated as deuterium a compound that contains a protium at the same position is an impurity.
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount.
  • Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid.
  • the solvent is pharmaceutically acceptable.
  • the complex or aggregate is in a crystalline form.
  • the complex or aggregate is in a noncrystalline form.
  • the solvent is water
  • the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
  • an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautom ers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof’ has the same meaning as the phrase “(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a diastereo
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
  • A is a bond, heterocyclylene, or -S(O2)-;
  • E is C6-14 arylene, heteroarylene, or heterocyclylene
  • L is a linker
  • X is a bond or -C(O)-
  • R 1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Cs-u and, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii ) -C(O)R la , C(O)OR la , -C(O)NR lb R lc , -C(O)SR la , -C(NR ia )NR lb R lc , -C(S)R la , -C(S)OR la , -C(S)NR lb R lc , -S(O)R la , -S(O) 2 R la , -S(O)NR lb R lc , or -S(O) 2 NR lb R lc ;
  • R 2 , R', and R 4 are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R la , -C(O)OR la , -C(O)NR lb R lc , -C(O)SR la , -C(NR la )NR lb R lc , -C(S)R la , -C(S)OR la , -C(S)NR lb R lc , -OR la , -OC(O)R la , -OC(O)OR la , -OC(O)NR lb R lc , -OC
  • R E is: wherein: each A E is independently a bond, -O-, -N(R lb )-, -S-, C1-6 alkylene, Ci-6 heteroalkylene, C2-6 alkenylene, C2-6 heteroalkenyl ene, C2-6 alkynylene, C2-6 heteroalkynylene, C3-10 cycloalkylene, Ce-14 arylene, C7-15 aralkylene, heteroarylene, heterocyclylene, Ci-e heteroalkylene-C6-i4 arylene, Ci-e heteroalkylene-heterocyclylene, or C2-6 alkynylene-heterocyclylene; each X E is independently C(R E1 ) or N;
  • Y E is a bond, C1-6 alkylene, -0- -S-, -S(0)-, -S(0 2 )-, or -N(R E3 )-;
  • E is Cs-i4 arylene, optionally substituted with one or more substituents Q.
  • E is phenylene, optionally substituted with one, two, or three substituents Q.
  • E is phen-l,4-diy, optionally substituted with one, two, or three substituents Q.
  • E is bicyclic Cs-14 arylene, optionally substituted with one, two, or three substituents Q.
  • E is heteroarylene, optionally substituted with one or more substituents Q
  • E is monocyclic heteroarylene, optionally substituted with one, two, or three substituents Q.
  • E is 5-, 6-, or 7-membered heteroarylene, each optionally substituted with one, two, or three substituents Q.
  • E is 5-membered heteroarylene, optionally substituted with one, two, or three substituents Q.
  • E is 6-membered heteroarylene, optionally substituted with one, two, or three substituents Q.
  • E is pyridindiyl, optionally substituted with one, two, or three substituents Q.
  • E is pyridine-2, 5-diyl, optionally substituted with one, two, or three substituents Q.
  • E is 7-membered heteroarylene, optionally substituted with one, two, or three substituents Q.
  • E is bicyclic heteroarylene, optionally substituted with one, two, or three substituents Q.
  • E is 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one, two, or three substituents Q.
  • E is heterocyclylene; optionally substituted with one or more substituents Q.
  • E is monocyclic heterocyclylene, optionally substituted with one or more substituents Q.
  • E is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one, two, or three substituents Q.
  • E is 3-membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • E is 4-membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • E is 5-membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • E is 6-membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • E is piperi dindiyl, optionally substituted with one, two, or three substituents Q.
  • E is piperi din- 1,4-diyl, optionally substituted with one, two, or three substituents Q.
  • E is 7-membered heterocyclylene, optionally substituted with one, two, or three substituents Q
  • E is bicyclic heterocyclylene, optionally substituted with one or more substituents Q.
  • E is bridged, fused, or spiro heterocyclylene, each optionally substituted with one, two, or three substituents Q.
  • E is bridged heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • E is fused heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • E is spiro heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • a compound of Formula (II) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wlierein:
  • R 5 is hydrogen or R 5a ; each R 5a is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, Ci-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R la , -C(O)OR la , --C(O)NR lb R !c , -C(O)SR la , -C(NR la )NR lb R lc , -C(S)R la , -C(S)OR la , -C(S)NR lb R lc , -0R la , -OC(O)R la , -OC(O)OR la , -OC(O
  • a is an integer of 0, 1, 2, or 3;
  • R 1 , R 2 , R 3 , R 4 , R la , R lb , R lc , R ld , R E , A, L, and X are each as defined herein.
  • R E is not l,3-dioxo-2-(2,6- dioxopiperidin-3-yl)isoindolinyl, unsubstituted or substituted.
  • R E is not any one of l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolinyl, 1,3- dioxo-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindolinyl, and 2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolinyl.
  • R E is not any one of 1,3-dioxo-
  • each R 6 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) C(O)R la , -C(O)OR la , -C(O)NR lb
  • R 1 , R 2 , R 3 , R 4 , R la , R lb , R lc , R ld , R E , A, L, and X are each as defined herein.
  • R E is not 1,3- dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolinyl, unsubstituted or substituted.
  • R E is not any one of l,3-dioxo-2-(2,6- dioxopiperidin-3-yl)isoindolinyl, l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindolinyl, and 2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolinyl. In certain embodiments, in any one of the formulae provided herein, R E is not any one of l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolin-
  • a compound of Formula (I A) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 1 , R 4 , R 5a , R E , A, L, Y, and a are each as defined herein.
  • a compound of Formula (IB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R J , R 4 , R 5a , R E , A, L, Y, and a are each as defined herein.
  • a compound of Formula (IC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 6 , R E , A, L, and b are each as defined herein.
  • a compound of Formula (ID) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , R 6 , R E , A, L, and b are each as defined herein.
  • A is a bond.
  • A is heterocyclylene, optionally substituted with one or more substituents Q.
  • A is monocyclic heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one, two, or three substituents Q.
  • A is 3-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 4- membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formul ae provided herein, A is 5-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 6-membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is piperidindiyl or piperazindiyl, each optionally substituted with one, two, or three substituents Q
  • A is piperidin- 1 ,4-diyl or piperazin- 1,4-diyl, each optionally substituted with one, two, or three substituents Q.
  • A is 7-membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is bicyclic heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is bridged, fused, or spiro heterocyclylene, each optionally substituted with one, two, or three substituents Q.
  • A is bridged heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is fused heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is spiro heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is 3,8-diazabicyclo[3.2.1]octandiyl, octahydropyrrolo[3,4-c]pyrroldiyl, or 2,7-diazaspiro[3.5]nonandiyl, each optionally substituted with one, two, or three substituents Q.
  • A is 3,8-diazabicyclo[3.2.1]octan-3,8-diyl, octahydropyrrolo[3,4-c]pyrrol-2,5- diyl, or 2,7-diaza-spiro[3.5]nonan-2,7-diyl.
  • A is -SfOr)-.
  • a compound of Formula (IIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R J , R 4 , R 3a , R E , L, Y, and a are each as defined herein.
  • a compound of Formula (IIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E , L, Y, and a are each as defined herein.
  • a compound of Formula (IIC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , R 6 , R E , L, and b are each as defined herein.
  • a compound of Formula (IID) or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R J , R 4 , R b , R E , L, and b are each as defined herein.
  • each R 7 is independently (i) deuterium, cyano, halo, nitro, or oxo; (ii) C1-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R la , -C(O)OR la , -C(O)NR ib R lc ,
  • R 1 , R 2 , R 3 , R 4 , R la , R lb , R lc , R ld , R 5a , R E , L, Y, and a are each as defined herein.
  • a compound of Formula (IIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 1 , R 4 , R 7 , R 5a , R E , L, Y, a, and c are each as defined herein.
  • R E is a moiety having the structure of Formula (EC -I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E2 , R E4 , X E , Y E , m, and n are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-I-a): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E2 , R E4 , X E , m, and n are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-I-b): (EC-T-b) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4 , m, and n are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-I-c):
  • R E is a moiety having the structure of Formula (EC-I-d):
  • R E is a moiety having the structure of Formula (EC-I-e):
  • R E is a moiety having the structure of Formula (EC-I-f):
  • R E is a moiety having the structure of Formula (EC-I-g):
  • R E is a moiety having the structure of Formula (EC-I-h):
  • R E is a moiety having the structure of Formula (EC-I-i):
  • R E is a moiety having the structure of Formula (EC-I-j):
  • R E is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein each A E is as defined herein.
  • R E is a moiety having the structure of Formula EC-A1, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A2, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A3, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A4, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A5, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A6, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of
  • R E is a moiety having the structure of Formula EC-A7, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A8, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A9, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A10, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-All, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A12, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A13, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A14, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more di astereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A15, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A16, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A17, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A18, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-A19, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moi ety havi ng the structure of Formula EC-20, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula (EC -II): or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E2 , R E4 , R E5 , X E , m, and n are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-II-a): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4 , R E5 , m, and n are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-II-b): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4 , R E5 , m, and n are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-II-c):
  • R E is a moiety having the structure of Formula (EC-II-d): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E2 , R E4 , R E5 , m, and n are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-II-e): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E2 , R E4 , R E5 , m, and n are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-II-f): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E2 , R E4 , R E5 , m, and n are each as defined herein .
  • R E is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein each A E is as defined herein.
  • R E is a moiety having the structure of Formula EC-B1, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-B2, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R & is a moiety having the structure of Formula EC-B3, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a m oiety having the structure of Formula EC-B4, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-B5, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-B6, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof
  • R & is a moiety having the structure of Formula EC-B7, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-B8, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-B9, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-B10, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopi c vari ant thereof.
  • R E is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-B11, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC- 812, or an enantiomer, a mixture of enanti omers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-B13, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-B14, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-B15, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R h is a moiety having the structure of Formula EC-B16, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula (EC -III): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , Z, Z 1 , Z 2 , Z 3 , Z 4 , and m are each as defined herein.
  • R E4a is as defined herein.
  • Z 1 is a bond;
  • Z 2 is -S-;
  • R E is not l,3-dioxo-2-(2,6- dioxopiperidin-3-yl)isoindolinyl, unsubstituted or substituted. In certain embodiments, in Formula (EC-III), R E is not any one of 1 ,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolinyl, 1,3- dioxo-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindolinyl, and 2-(2, 6-dioxopiperi din-3 -yl)-l- oxoisoindolinyl.
  • R E is not any one of l,3-dioxo-2- (2,6-dioxopiperidin-3-yl)isoindolin-4-yl, l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolin-5-yl, l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindolin-4-yl, l,3-dioxo-2-(2,6-dioxopiperidin- 3-yl)-6-fluoroisoindolin-5-yl, 2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl, and 2-(2,6- di oxopiperi din-3 -yl)- 1 -ox oisoindol in-5 -yl .
  • R E is a moiety having the structure of Formula (EC-III-a): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4 , Z, m, and n are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-III-b): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4a , Z, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is CH2 .
  • R E is a moiety having the structure of Formula (EC-III-c): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4a , Z, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • R E is a moiety having the structure of Formula (EC-III-d): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4a , Z, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • R E is a moiety having the structure of Formula (EC-III-e): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and A E , R E1 , R E2 , R E4 , Z. and m are each as defined herein.
  • R E is a m oiety having the structure of Formula (EC-III-f): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4a , Z, and m are each as defined herein.
  • R is a moiety having the structure of Formula (EC-III-g): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4a , Z, and m are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-IIl-h): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and A E , R E1 , R E2 , R E4 , Z, and m are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-III-i):
  • R E is a moiety having the structure of Formula (EC-III-j): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4a , Z, and m are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-III-k): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and A E , R E1 , R E2 , R E4 , Z, and m are each as defined herein.
  • R E is a moiety having the structure of Formula (EC-III-1): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4a , Z, and m are each as defined herein.
  • R E is a m oiety having the structure of Formula (EC-III-m): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E , R E1 , R E2 , R E4a , Z, and m are each as defined herein.
  • R E is a moiety having the structure of or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein each A E is as defined herein.
  • R E is a moi ety havi ng the structure of Formula EC-C1, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-C2, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-C3, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-C4, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of
  • EC-C13 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moi ety havi ng the structure of Formula EC-C5, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-C6, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R & is a moiety having the structure of Formula EC-C7, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-C8, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-C9, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-C10, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-C11, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof
  • R E is a moiety having the structure of Formula EC-C12, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R E is a moiety having the structure of Formula EC-C13, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • a compound of Formula (IVA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , R 3a , R E2 , R E4 , A E , L, X E , Y, a, m, and n are each as defined herein.
  • a compound of Formula (VA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E1 , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (VIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R : 4 A E L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (VIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , R 5a , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (VIIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (IXA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E2 , R E4 , A E , L, X E , Y, a, m, and n are each as defined herein.
  • a compound of Formula (XA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R J , R 4 , R 5a , R E1 , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XIII A) or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 1 , R 4 , R 3a , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XIV A) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E2 , R E4 , R E5 , A E , L, X E , Y, a, m, and n are each as defined herein.
  • a compound of Formula (XVA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R E4 , R E3 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XVIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R E4 , R E " 3 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XVIIA) or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E2 , R E4 , R E5 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XIXA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 1 , R 4 , R 3a , R E2 , R E4 , R E5 , A E , L, X E , Y, a, m, and n are each as defined herein.
  • a compound of Formula (XXA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E1 , R E2 , R E4 , R E5 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XXIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R E4 , R ES , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XXIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E2 , R E4 , R E5 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XXIII A) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E2 , R E4 , R E5 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XXIVA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E1 , R E2 , R E4a , A E L, Y, Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -- CH2-.
  • a compound of Formula (XXVA) or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • a compound of Formula (XXVIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , R 3a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • XXVIIA or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • a compound of Formula (XXVIIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is CH2
  • a compound of F ormula i s a compound of F ormula (XXIXA) : or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , R 3a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • a compound of Formula (XXXA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • a compound of Formula (XXXIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • a compound of Formula (IVB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E2 , R E4 , A E , L, X E , Y, a, m, and n are each as defined herein.
  • a compound of Formula (VB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (VIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E1 , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (VIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (VIIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (IXB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E2 , R E4 , A E , L, X E , Y, a, m, and n are each as defined herein.
  • a compound of Formula (XB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R.’, R 4 , R 3a , R E1 , R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XIIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , RY R E2 , R E4 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XIVB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wfierein R 1 , R 2 , R 1 , R 4 , R 5a , R E2 , R E4 , R E5 , A E , L, X E , Y, a, m, and n are each as defined herein.
  • a compound of Formula (XVB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , herein.
  • a compound of Formula (XVIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , R 3a , R E1 , R E2 , R E4 , R E5 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XVIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E2 , R E4 , R E3 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XVIIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , y a , m, and n are each as defined herein.
  • a compound of Formula (XIXB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , RY R E2 , R E4 , R E5 , A E , L, X E , Y, a, m, and n are each as defined herein.
  • a compound of Formula (XXB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E1 , R E2 , R E4 , R E5 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XXIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R. 3 , R 4 , herein.
  • a compound of Formula (XXIIB) or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E2 , R E4 , R E5 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XX1IIB) or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R.’, R 4 , R 3a , R E2 , R E4 , R E5 , A E , L, Y, a, m, and n are each as defined herein.
  • a compound of Formula (XXIVB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , R 3a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • a compound of Formula (XXVB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -Chh
  • a compound of Formula (XXVIB) or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 1 , R 4 , R 5a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • R 1 , R 2 , R 1 , R 4 , R 5a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • XXVIIB or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • provi ded herein is a compound of Formula (XXVIIIB): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , y 2, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH?-.
  • a compound of Formula (XXIXB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 3a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • a compound of Formula (XXXB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R3a, £ Y, Z, a, and m are each as defined herein.
  • R 1 , R 2 , R 3 , R 4 , R3a, £ Y, Z, a, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • a compound of Formula (XXXIB) or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5a , R E1 , R E2 , R E4a , A E , L, Y, Z, a, and m are each as defined herein.
  • a compound of Formula (IIIC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R E2 , R E4 , A E , L, X E , m, and n are each as defined herein.
  • a compound of Formula (IVC) or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R J , R 4 , R E! , R E2 , R E4 , A E , L, m, and n are each as defined herein.
  • a compound of Formula (VC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R E1 , R E2 , R E4 , A E , L, m, and n are each as defined herein.
  • a compound of Formula (VIC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , R E2 , R E4 , A E , L, m, and n are each as defined herein.
  • a compound of Formula (VIIC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R E2 , R E4 , A E , L, m, and n are each as defined herein.
  • a compound of Formula (VIIIC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 1 , R 4 , R E2 , R E4 , R E3 , A E , L, X E , m, and n are each as defined herein.
  • a compound of Formula (IXC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R’, R 4 , R E! , R E2 , R E4 , R E5 , A E , L, m, and n are each as defined herein.
  • a compound of Formula (XC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 1 , R 4 , R E1 , R E2 , R E4 , R E5 , A E , L, m, and n are each as defined herein.
  • a compound of Formula (XIC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 1 , R 4 , R E2 , R E4 , R E3 , A E , L, m, and n are each as defined herein.
  • a compound of Formula (XIIC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R E2 , R E4 , R E5 , A E , L, m, and n are each as defined herein.
  • a compound of Formula (XIIIC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R E1 , R E2 , R E4a , A E , L, Z, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH?.-.
  • a compound of Formula (XIVC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 1 , R 4 , R E! , R E2 , R E4a , A E , L, Z, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CII2-.
  • a compound of Formula (XVC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R E1 , R E2 , R E4a , A E , L, Z, and m are each as defined herein.
  • R E4a is fluoro.
  • Z is -CH2-.
  • a compound of Formula (XVIC) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R E1 , R E2 , R E4a , A E , L, Z, and m are each as defined herein.
  • R l is Ci-6 alkyl, C3-10 cycloalkyl, or heterocyclyl, each optionally substituted with one or more substituents Q.
  • R 1 is Ci -6 alkyl, optionally substituted with one, two, or three substituents Q.
  • R 1 is methyl, ethyl, propyl, butyl, or pentyl, each optionally substituted with one, two, or three substituents Q.
  • R 1 is ethyl, isopropyl, or pent-3-yl.
  • R 1 is C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R 1 is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R 1 is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) halo or hydroxyl; or (ii) C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one, two, or three substituents Q.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one, two, or three substituents Q, each of which is independently (i) halo or hydroxyl; or (ii) C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
  • R 1 is cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one, two, or three substituents Q, each of which is independently fluoro, methyl, ethyl, or hydroxyl.
  • R 1 is cyclopropyl, optionally substituted with one, two, or three substituents Q.
  • R 1 is cyclobutyl, optionally substituted with one, two, or three substituents Q.
  • R 1 is cyclopentyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R 1 is cyclopentyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) halo or hydroxyl; or (ii) C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R 1 is cyclopentyl, optionally substituted with one, two, or three substituents Q, each of which is independently fluoro, methyl, ethyl, or hydroxyl.
  • R 1 is cyclopentyl. In certain embodiments, in any one of the formulae provided herein, R 1 is cyclohexyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R 1 is cycloheptyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R 1 is bicyclic C4-10 cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R 1 is bridged, fused, or spiro C4-10 cycloalkyl, each optionally substituted with one, two, or three substituents Q.
  • R l is heterocyclyl, optionally substituted with one, two, or three substituents Q.
  • R 1 is monocyclic heterocyclyl, optionally substituted with one, two, or three substituents Q.
  • R 1 is 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q.
  • R 1 is 5-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q.
  • R 1 is tetrahydrofuryl, optionally substituted with one, two, or three substituents Q.
  • R 1 is 6-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q.
  • R 1 is 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q.
  • R 1 is bicyclic heterocyclyl, optionally substituted with one, two, or three substituents Q.
  • R 1 is bridged, fused, or spiro heterocyclyl, each optionally substituted with one, two, or three substituents Q.
  • R 1 is ethyl, isopropyl, pent-3-yl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopentyl, 2-hydroxy- cyclopentyl, 3-hydroxycyclopentyl, 2-hydroxy-2-m ethyl cyclopentyl, 2-hydroxy-2-ethyl cyclopentyl, 3-hydroxy-2-methylcyclopentyl, 4-hydroxy-2-methylcyclopentyl, 3 -hydroxy cyclohexyl,
  • R 1 is cyclopentyl or 2- hydroxy-2-methylcyclopentyl. In certain embodiments, in any one of the formulae provided herein, R is cyclopentyl or ' — . In certain embodiments, in any one of the formulae provided herein, R 1 is
  • R 2 is (i) hydrogen, cyano, or halo; (ii) C1-6 alkyl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q, or (iii) -C(O)R la , -C(O)OR la , -C(O)NR lb R lc , -OR la , or -NR lb R lc , wherein each R la , R lb , and R lc is as defined herein.
  • R 2 is hydrogen.
  • R 2 is cyano. In certain embodiments, in any one of the formulae provided herein, R 2 is halo. In certain embodiments, in any one of the formulae provided herein, R 2 is fluoro, chloro, bromo, or iodo. In certain embodiments, in any one of the formulae provided herein, R 2 is C1-6 alkyl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R 2 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
  • R 2 is methyl, ethyl, isopropyl, cyanomethyl, difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, hydroxycarbonylmethyl, hydroxycarbonyldifluoromethyl, aminocarbonylmethyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, ethoxymethyl, or 2-methoxy ethyl.
  • R 2 is aralkyl, optionally substituted with one, two, or three substituents Q.
  • R 2 is benzyl.
  • R 2 is heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R 2 is oxazol-5-yl.
  • R 2 is -C(O)R la , -C(O)OR la , -C(O)NR lb R lc , -OR la , or -NR lb R lc , wherein each R la , R lb , and R lc is as defined herein.
  • R 2 is -C(O)R la , wherein R la is as defined herein.
  • R 2 is C(O)R la , wherein R la is C1-6 alkyl, optionally substituted with one or more substituents Q.
  • R 2 is acetyl. In certain embodiments, in any one of the formulae provided herein, R 2 is C(O)OR !a , wherein R la is as defined herein. In certain embodiments, in any one of the formulae provided herein, R 2 is C(O)OR la , wherein R la is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R 2 is hydroxycarbonyl or ethoxy carbonyl.
  • R 2 is -C(O)NR lb R lc , wherein R lb and R ic are each as defined herein. In certain embodiments, in any one of the formulae provided herein, R 2 is -C(O)NR lb R ic , wherein R lb and R lc are each independently hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R 2 is methylaminocarbonyl or dimethylaminocarbonyl.
  • R 2 is -OR la , wherein R la is as defined herein. In certain embodiments, in any one of the formulae provided herein, R 2 is -OR la , wherein R la is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R 2 is 2-ethoxy ethoxy. In certain embodiments, in any one of the formulae provided herein, R 2 is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 2 is -NR lb R lc , wherein R lb and R lc are each independently hydrogen or Ci-e alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R 2 is amino.
  • R 2 is hydrogen, cyano, fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, cyanomethyl, difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, hydroxycarbonylmethyl, hydroxycarbonyldifluoro- methyl, aminocarbonylmethyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, benzyl, oxazol-5-yl, acetyl, hydroxycarbonyl, ethoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, 2-ethoxyethoxy, or amino.
  • R 2 is difluoromethyl, acetyl, or dimethylaminocarbonyl. In certain embodiments, in any one of the formulae provided herein, R 2 is difluoromethyl. In certain embodiments, in any one of the formul ae provided herein, R 2 is acetyl . In certain embodiments, in any one of the formulae provided herein, R 2 is dimethylaminocarbonyl.
  • R 3 is hydrogen, deuterium, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R 3 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R 3 is deuterium. In certain embodiments, in any one of the formulae provided herein, R 3 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q In certain embodiments, in any one of the formulae provided herein, R 3 is methyl. In certain embodiments, in any one of the formulae provided herein, R 3 is hydrogen or methyl.
  • R 4 is hydrogen
  • R 5 is hydrogen, deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R 5 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R 5 is deuterium. In certain embodiments, in any one of the formulae provided herein, R 5 is halo. In certain embodiments, in any one of the formulae provided herein, R 5 is fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, R 5 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
  • R 5 is methyl or ethyl. In certain embodiments, in any one of the formulae provided herein, R 5 is hydrogen, fluoro, chloro, methyl, or ethyl. In certain embodiments, in any one of the formulae provided herein, R 5 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R 5 is methyl.
  • R 5a is deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R 5a is deuterium. In certain embodiments, in any one of the formulae provided herein, R 5a is halo. In certain embodiments, in any one of the formulae provided herein, R 5a is fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, R 3a is C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
  • R 5a is methyl or ethyl In certain embodiments, in any one of the formulae provided herein, R 5a is fluoro, chloro, methyl, or ethyl. In certain embodiments, in any one of the formulae provided herein, R 5a is methyl.
  • R E1 is hydrogen, deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R E1 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R E1 is deuterium. In certain embodiments, in any one of the formulae provided herein, R E1 is halo. In certain embodiments, in any one of the formulae provided herein, R E1 is fluoro. In certain embodiments, in any one of the formulae provided herein, R E1 is Ci-e alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R E1 is methyl. In certain embodiments, in any one of the formulae provided herein, R Ei is hydrogen, deuterium, fluoro, or methyl.
  • R E2 is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R E2 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R E2 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
  • R E3 is hydrogen or Ci-s alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R E3 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R E3 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
  • each R E4 is independently deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R E4 is deuterium. In certain embodiments, in any one of the formulae provided herein, R E4 is halo. In certain embodiments, in any one of the formulae provided herein, each R E4 is independently fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, R E4 is chloro.
  • each R E4 is independently Ci-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, each R E4 is independently methyl, ethyl, propyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, each R E4 is independently methyl, isopropyl, or trifluoromethyl. In certain embodiments, in any one of the formulae provided herein, each R E4 is independently fluoro, chloro, methyl, isopropyl, or trifluoromethyl. In certain embodiments, in any one of the formulae provided herein, each R E4 is independently methyl or trifluoromethyl.
  • R E4s is hydrogen, deuterium, or halo. In certain embodiments, in any one of the formulae provided herein, R E4s is hydrogen. In certain embodiments, in any one of the formulae provided herein, R E4S is deuterium. In certain embodiments, in any one of the formulae provided herein, R E4s is halo. In certain embodiments, in any one of the formulae provided herein, R E:4S is fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, R E4s is fluoro. In certain embodiments, in any one of the formul ae provided herein, R E4s is hydrogen, deuterium, fluoro, or chloro.
  • R Es is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q.
  • R E5 is hydrogen.
  • R E5 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
  • R E5 is methyl.
  • a E is (i) a bond; or (ii) C2-6 alkynylene, heterocyclylene, C1-6 heteroalkylene-Ce-u arylene, Ci-6 heteroalkyl ene-heterocycly I ene, or C2-6 alkynylene-heterocyclylene, each optionally substituted with one or more substituents Q.
  • a E is a bond.
  • a E is C2-6 alkynylene, optionally substituted with one, two, or three substituents Q.
  • a E is ethynediyl. In certain embodiments, in any one of the formulae provided herein, A E is heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A E is monocyclic heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A & is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one, two, or three substituents Q.
  • a E is 5- or 6-membered heterocyclylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A E is 6-membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • a E is piperidindiyl or piperazindiyl, each optionally substituted with one, two, or three substituents Q
  • a E is piperidin-l,3-diyl, piperidin- 1 ,4- diyl, or piperaz-l,4-diyl.
  • a E is C1-6 heteroalkylene-Ce-14 arylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A E is C1-6 heteroal kylene- phendiyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A E is (phendiyl)oxymethanediyl. In certain embodiments, in any one of the formulae provided herein, A E is C1-6 heteroalkylene- heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • a E is C1-6 heteroalkylene-(monocyclic heterocyclylene), optionally/ substituted with one, two, or three substituents Q.
  • a E is C1-6 heteroalkylene-(3-, 4-, 5-, 6-, or 7-membered heterocyclylene), each optionally substituted with one, two, or three substituents Q.
  • a E is Ci-6 heteroalkylene-(6-membered heterocyclylene), optionally substituted with one, two, or three substituents Q.
  • a E is Ci-6 heteroalkylene-piperazindiyl, optionally substituted with one, two, or three substituents Q.
  • a E is C1-6 heteroal kylene- piperazin- 1,4-diyl, optionally substituted with one, two, or three substituents Q.
  • any one of the formulae provided herein is Ci-6 heteroalkylene-piperazindiyl, optionally substituted with one, two, or three substituents Q.
  • a E is C2.6 alkynylene-heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • a E is C2-6 alkynylene- (monocyclic heterocyclylene), optionally substituted with one, two, or three substituents Q.
  • a E is C2-6 alkynylene-(3-, 4-, 5-, 6-, or 7-membered heterocyclylene), each optionally substituted with one, two, or three substituents Q.
  • a E is C2-6 alkynylene-(6-membered heterocyclylene), optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A E is (piperidindiyl)-ethynediyl.
  • a E is a bond, piperi din- 1,3 -diyl, piperidin-1 ,4-diyl, piperaz-l,4-diyl, (phen-1,4- diyl)oxymethanediyl, ( pi peridin- 1 ,4-diy l)ethynediy
  • L is a linker having the structure of Z L (R L -Z L )z-, wherein: each R L is independently C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, C3-10 cycloalkylene, Ce-i4 arylene, heteroarylene, or heterocyclylene, each of which is optionally- substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each Z L is independently a bond, -C(O)-, -C(O)O- -C(O)NR lb -, -C(O)S- -C(NR la )NR lb -, -C(S)-, -C(S)O-, -C(S)NR lb -, -O-, -OC(O)O-, -OC(O)NR lb -,
  • each R L is independently Ci-io alkylene, C2-10 alkynylene, C3-10 cycloalkylene, Ce-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each Z L is independently a bond, -C(O)-, -C(O)NR lb - -C(NR la )NR lb -, -O-, -OC(O)NR lb -, -NR lb - -NR la C(O)NR lb -, -NR la C(NR ld )NR ib ---, -NR la S(O)NR lb -, -NR la S(O) 2 NR lb -, -S-, -S(O)-, -S(O)2-, -S(O)NR Ib -,
  • each R L is independently Ci-io alkylene, C2-io alkynylene, C3-10 cycloalkylene, Ce-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each Z L is independently a bond, -C(O)-, -C(O)NR lb -, -O-, -OC(O)NR lb -, -NR lb -, -NR la C(O)NR lb - or -NR la C(NR ld )NR lb --; and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8; where each R la , R lb , and R ld is as defined herein.
  • each R L is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, ethynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, bicyclo[2.2.2]octanediyl, phendiyl, pyrazoldiyl, imidazoldiyl, tetrazoldiyl, pyrimidindiyl,
  • each Z L is independently a bond, -C(O)-, -C(O)O-, -C(O)NH-, -OC(O)NH-, -O-, -NH-, -N(CHs)-, or -NHC(O)NH-; and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
  • each R L is independently methanediyl, ethane- 1,2-diyl, propane-1, 3-diyl, butane- 1,4-diyl, pentane- 1,5-diyl, hexane- 1,6-diyl, heptane-l,7-diyl, octane- 1 ,8-diyl, nonane- 1,9-diyl, decane- 1 ,10-diyl, ethyne- 1,2-diyl, cyclobutane- 1, 3-diyl, cyclopentane- 1, 3-diyl, cyclohexane- 1, 3-diyl, cyclohexane-l,4-diyl, cycloheptane- 1,3 -diyl, cycloheptane- 1,4- diyl, bicyclo[2.2.2]oc
  • each Z L is independently a bond, --C(O)- -C(O)O-, -C(O)NH- -OC(O)NH-, -O-, -NH-, -N(CH 3 )-, or -NHC(O)NH-; and z is an integer of 1, 2,
  • each R L is independently methanediyl, ethane- 1,2-diyl, propane-1, 3-diyl, cyclohex- 1,3 -diyl, cyclohex- 1,4-diyl, phen- 1,3 -di yl, phen- 1,4-diyl, azetidin- 1 , 3-diyl, piperazin-1, 4-diyl, piperidin-1, 3-diyl, piperi din- 1,4-diyl, morpholin-2, 4-diyl, 4,7- diazaspiro[2.5]octan-4,7-diyl, 3-azabicyclo[3.2.1]octan-3,8-diyl, 8-azabicyclo[3.2.1]octan-3,8- diyl, 3,8-diazabicyclo[3.2.1]octan-3,8-diyl, or 2,7-diyl, ethane
  • each R L is independently methanediyl, ethane- 1,2-diyl, l,l-difluoroethane-l,2-diyl, propane-1, 3-diyl, cyclohex-1, 3-diyl, cyclohex- 1 ,4-diyl, phen-1,3- diyl, phen- 1,4-diyl, azetidin-1, 3-diyl, 3-fluoroazetidin-l, 3-diyl, piperazin- 1,4-diyl, 2- methylpiperazin- 1 , 4-diyl, piperidin-1 ,3 -diyl, piperi din- 1 , 4-diyl, 4-fluoropiperi din- 1 , 4-diyl, morpholin-2, 4-diyl, 4,7-diazaspiro[2.5]octan-4,7-diyl, 3-
  • each Z L is independently a bond or -O-; and z is an integer of 2, 3, 4, or 5.
  • L is: wherein each A L is independently a bond, -O-, -NH-, or -N(CH3)-.
  • L is: wherein each A L is independently a bond, -0-, -NH-,
  • L is: wherein each A L is independently a bond, -0---, or -N(CH3 )---.
  • L is: wherein each A L is independently a bond, -0-, -NH-, or -N(CH3)-; and wherein each amino
  • (NH) group is optionally substituted with methyl.
  • L is: wherein each A L is independently a bond, -O-, -NH-, wherein each amino
  • (NH) group is optionally substituted with methyl.
  • L is: wherein each A L is independently a bond, -O-, -NH-, or -N(CH3)-; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is: wherein each A L is independently a bond, -0- -NH-, or -N(CHs)-; and wherein each amino
  • (NH) group is optionally substituted with methyl.
  • L is: wherein each A L is independently a bond, -O-, -NH-, or -N(CH3)-.
  • L is: wherein each A L is independently a bend, -O-, -NH-, or ⁇ N(CH3)--; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is: wherein each A L is independently a bond, -O-, -NH-, wherein each amino group (NH) is optionally substituted with methyl.
  • L is: wherein each A L is independently a bond, -0-, -NH-, or -N(CH3)-.
  • L is:
  • each A L is independently a bend, -O-, -NH- or -N ⁇ CTH)-; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is: wherein each A L is independently a bond, -O-, -NH-, or -N(CH3) ⁇ -; and wherein each amino group is optionally substituted with methyl.
  • L is:
  • L is:
  • L is:
  • L is:
  • L is:
  • L is:
  • L is:
  • L is:
  • L is:
  • L is:
  • L is:
  • X is a bond
  • X is -C(O)-.
  • X E is C(R E1 ), wherein R &1 is as defined herein. In certain embodiments, in any one of the formulae provided herein, X E is C(H). In certain embodiments, in any one of the formulae provided herein, X E is N.
  • Y E is a bond. In certain embodiments, in any one of the formulae provi ded herein, Y E is -N(R E3 )-, wherein R EI is as defined herein.
  • Z is -CHi-. In certain embodiments, in any one of the formulae provided herein, Z is ⁇ C(O) ⁇ .
  • a is an integer of 0 or 1. In certain embodiments, in any one of the formulae provided herein, a is an integer of 0. In certain embodiments, in any one of the formulae provided herein, a is an integer of 1.
  • m is an integer of 0, 1, or 2. In certain embodiments, in any one of the formulae provided herein, m is an integer of 0. In certain embodim ents, in any one of the formulae provided herein, m is an integer of 1. In certain embodiments, in any one of the formulae provided herein, m is an integer of 2.
  • n is an integer of 0, 1, or 2. In certain embodiments, in any one of the formulae provided herein, n is an integer of 0. In certain embodiments, in any one of the formulae provided herein, n is an integer of 1. In certain embodiments, in any one of the formulae provided herein, n is an integer of 2.
  • ⁇ pyrimidine-6-carboxamide A406 or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a L (2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- (tri fluorom ethy 1 )ph en oxy )acetam ide B 104 ;
  • a L (3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- ⁇ /]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- methylphenoxy)acetamide B109; or

Abstract

Provided herein are CDK protein degraders, e.g., a compound of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a CDK-mediated disorder, disease, or condition.

Description

CDK PROTEIN DEGRADERS, PHARMACEUTICAL COMPOSITIONS, AND
THERAPEUTIC APPLICATIONS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the priority of U.S. Provisional Application Nos. 63/364,470, filed May 10, 2022; 63/378,671, filed October 6, 2022; and 63/496,380, filed April 14, 2023; the disclosure of each of which is incorporated herein by reference in its entirety.
FIELD
[0002] Provided herein are CDK protein degraders and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a CDK-medlated disorder, disease, or condition.
BACKGROUND
[0003] Cyclin-dependent kinases (CDKs) are protein kinases that are involved in critical cellular processes, such as a cell cycle. Malumbres etal., Nat. Cell Biol. 2009, 11, 1275-6; Ding et al., Int. J. Mol. Sci. 2020, 21, 1960. CDKs associate with different cyclins to control different cell cycle transitions in human cells Uzbekov and Prigent, Cells 2020, 11, 704. There are 20 CDKs and about 30 cyclins in the human. Malumbres et al., Nat. Cell Biol. 2009, 11, 1275-6. CDK2 complexed with cyclin E, or CDK4/CDK6 complexed with cyclin D drives cell-cycle progression from G1 to S phase. Topacio et al., Mol. Cell 2019, 74, 758-70, Uzbekov and Prigent, Cells 2020, 11, 704. Cell cycle dysregulation characterized by aberrant activation of CDKs is a hallmark of cancer. Malumbres and Barbacid, Nat. Rev. Cancer 2009, 9, 153-66; Otto and Sicinski, Nat. Rev. Cancer 2017, 17, 93-115; Ding et al., Int. J. Mol. Sci. 2020, 21, 1960.
Dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved by the FDA for treating advanced or metastatic hormone receptor positive breast cancer. Sanchez- Martinez et al., Bioorg. Med. Chem. Lett. 2019, 29, 126637; Zhang el al., Am. J. Cancer Res. 2021, 11, 1913-35. The efficacy of CDK4/CDK6 inhibition is, however, limited by innate or acquired resistance. Alvarez-Fernandez and Malumbres, Cancer Cell 2020, 37, 514-29; Ogata et al., Breast Cancer 2021, 28, 206-15. [0004] Despite the advances in cancer treatment, cancer remains a major worldwide public health problem. It was estimated that there will be 1,918,030 new cancer cases diagnosed and 609,360 cancer deaths in the US alone in 2022. Cancer Facts de Figures 2022. Therefore, there is a need for an effective therapy for cancer treatment.
SUMMARY OF THE DISCLOSURE
[0005] Provided herein is a compound of Formula (I):
Figure imgf000003_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
A is a bond, heterocyclylene, or -S(O2)-;
E is C6-14 arylene, heteroarylene, or heterocyclylene;
L is a linker;
X is a bond or --C(O)--;
R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) ~C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRia)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc;
R2, R3, and R4 are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, ~C(S)ORla, -C(S)NRibRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Ria, -OS(O)NRlbRk, -OS(O)2NRlbRk, -NRlbRk, -NRlaC(O)Rld, ~NRlaC(O)ORld, -NRlaC(O)NRlbRle, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NR!aS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRk -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRk, or -S(O)2NRlbRk;
Figure imgf000004_0001
wherein: each AE is independently a bond, -O-, -N(Rlb)---, --S-, C1-6 alkylene, Ci-6 heteroalkylene, C2-6 alkenylene, C2-6 heteroalkenyl ene, CM alkynylene, C2-6 heteroalkynylene, C3-10 cycloalkylene, Ce-i4 arylene, C7-15 aralkylene, heteroarylene, heterocyclylene, CM heteroalkylene-C6-i4 arylene, vC1-6 heteroalkylene-heterocyclylene, or C2-6 alkynylene-heterocyclylene; each XE is independently C(RE1) or N;
YE is a bond, CM alkylene, -O-, -S-, -S(O)-, ~S(O2)-, or -N(RE3)-;
Z is -CH2- or --C(O)-; one of Z1, Z2, Z3, and Z4 is -C= and the remaining three of Z1, Z2, Z3, and Z4 are each independently -C(RE4a)=; or Z! is a bond; one of Z2, Z3, and Z4 is C=, and the remaining two of Z2, Z3, and Z4 are each independently -C(RE4a)= or -S-; each RE1 is independently hydrogen, deuterium, halo, or C1-6 alkyl; each RE2, RE3, and RE3 is independently hydrogen or C1-6 alkyl; each RE4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla,
OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRic, -NRibRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, ■~NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc,
-NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each RE4a is independently hydrogen or RE4; each m is independently an integer of 0, 1, or 2; and each n is independently an integer of 0, 1, 2, or 3; and each Ria, Rlb, Rlc, and Rld is independently hydrogen, deuterium, C1-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroal kynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, OP(O)(ORb)ORc, OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and ~S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Co-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -0Re, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRs, -OC(O)SRe, -OC(NRe)NRfRs, -OC(S)Re, -OC(S)ORe, -OC(S)NRfR8, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfR8, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, ~NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRiRg, -NReS(O)Rh, ~NReS(O)2Rh, ~NReS(O)NRfRg -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0006] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
[0007] Additionally provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a CDK in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0008] Furthermore, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0009] Provided herein is a method of inhibiting the growth of a cell, comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0010] Provided herein is a method of inducing degradation of a CDK, comprising contacting the CDK with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
DETAILED DESCRIPTION
[0011] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
[0012] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
[0013] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
[0014] The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a di sorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
[0015] The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition. [0016] The terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
[0017] The term “contacting” or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule. In another embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In yet another embodiment, the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.
[0018] The term “therapeutically effective amount” or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
[0019] The term “ICso” or “ECso” refers to an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal response in an assay that measures such a response.
[0020] The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed.; Adejare Ed.; Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; Sheskey et al., Eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed., CRC Press, 2009.
[0021] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range
[0022] The term “alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., w-propyl and isopropyl), butyl (including all isomeric forms, e.g., w-butyl, isobutyl, sec-butyl, and Ebutyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., w-hexyl, isohexyl, and sec-hexyl).
[0023] The terms “alkylene” and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally be substituted with one or more substituents Q as described herein. For example, C1-6 alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C1-30), 1 to 20 (C1-2.0), 1 to 15 (Ci-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6
Figure imgf000010_0001
carbon atoms. As used herein, linear C1-6 and branched C3-6 alkanediyl groups are also referred as “lower alkanediyl.” Examples of alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane- 1,1 -diyl and ethane- 1,2-diyl), propanediyl (including all isomeric forms, e.g,, propane- 1,1 -diyl, propane-1, 2- diyl, and propane- 1,3 -diyl), butanediyl (including all isomeric forms, e.g., butane-l, l-diyl, butane- 1,2-diyl, butane- 1,3 -diyl, and butane-l,4-diyl), pentanediyl (including all isomeric forms, e.g., pentane-l,l-diyl, pentane-l,2-diyl, pentane- 1,3 -diyl, and pentane- 1,5 -diyl), and hexanediyl (including all isomeric forms, e.g., hexane-l,l-diyl, hexane- 1,2-diyl, hexane- 1,3 -diyl, and hexane- 1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)(CH2)4- -C(O)(CH2)5-, -C(O)(CH2)6-, -C(O)(CH2)7-, -C(O)(CH2>- -C(O)(CH2)9-, -C(0)(CH2)IO-, -C(O)CH2C(O)- -C(O)(CH2)2C(O)-, -C(O)(CH2)3C(O)-, -C(O)(CH2)4C(O)-, or -C(O)(CH2)5C(O)-.
[0024] The term “heteroalkyl” refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (Ci-15), 1 to 10 (Ci-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C.3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkyl groups are also referred as “lower heteroalkyl.” Examples of heteroalkyl groups include, but are not limited to, --OCH3, -OCH2.CH3, -CH2.OCH3, -NHCHs, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and -NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, -CH2NHC(O)CH3 and -NHC(O)CH2CH3.
[0025] The terms “heteroalkylene” and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from 0, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci -20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkylene groups are also referred as “lower heteroalkylene ” Examples of heteroalkyl ene groups include, but are not limited to,
Figure imgf000011_0001
-(CH2)7O-, ~(CH2)8O--, -(CH2)9O-, ~(CH2)IOO-, -CH2OCH2-, -CIECIEO-, -(CH2CH2O)2-
(CH2CH2O)3 --(CH2CH2O)4--, (CH2CH2O)5 -CH2NH -CH2NHCH2-, CH2CH2NH
- CH2CH2CH2NH- -(CH2)4NH- -CH2S- -CH2SCH2-, and -CH2CH2S- Examples of substituted heteroalkylene groups include, but are not limited to, C(O)CH2O C(O)(CH2)2O -, -C(O)CH2CH2CH2O- -C(O)CH2CH2CH2CH2O-, -C(O)(CH2)5O- -C(O)(CH2)6O- -C(O)(CH2)7O-, -C(O)(CH2)SO-, -C(O)(CH2)9O- -C(0)(CH2)IOO-, -C(O)CH2OCH2CH2O- -C(O)CH2O(CH2CH2O)2--, --C(O)CH2O(CH2CH2O)3-, ~C(O)CH2.O(CH2CH2O)4, -C(O)CH2O(CH2CH2O)5- -CH2NHC(O)CH2-, -CH2CH2C(O)NH-, -CH2N(CH3)-, -(CH2)2N(CH3)-, -(CH2)3N(CH3)-, or ~(CH2)4N(CH3)-.
[0026] The term “alkenyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s). The alkenyl is optionally substituted with one or more substituents Q as described herein. The term “alkenyl” embraces radicals having a “czx” or “trans" configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2.-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-0) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6
Figure imgf000012_0001
carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeri c forms, e.g., propen- 1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms, e.g, buten- 1-yl, buten-2-yl, buten-3-yl, and 2-buten-l-yl).
[0027] The terms “alkenylene” and “alkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s). The alkenediyl is optionally substituted with one or more substituents Q as described herein. The term “alkenediyl” embraces radicals having a “cis” or “ trans'" configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenediyl is a linear divalent hydrocarbon radical of 2 to 30 (€2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (€2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenediyl groups include, but are not limited to, ethenediyl (including all isomeric forms, e.g. , ethene- 1 ,1- diyl and ethene- 1,2-diyl), propenediyl (including all isomeric forms, e.g., 1 -propene- 1,1 -diyl, 1- propene- 1,2-diyl, and 1 -propene- 1,3 -diyl), butenediyl (including all isomeric forms, e.g, 1- butene- 1,1 -diyl, l-butene-l,2-diyl, and 1 -butene- 1,4-diyl), pentenediyl (including all isomeric forms, e.g., 1 -pentene- 1,1 -diyl, 1 -pentene- 1,2-diyl, and 1 -pentene- 1,5 -diyl), and hexenediyl (including all isomeric forms, e.g, 1 -hexene- 1,1 -diyl, l-hexene-l,2-diyl, l-hexene-l,3-diyl, 1- hexene- 1,4-diyl, l-hexene-l,5-diyl, and l-hexene-l,6-diyl).
[0028] The terms “heteroalkenylene” and “heteroalkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected from 0, S, and N in the hydrocarbon chain. The heteroalkenylene is optionally substituted with one or more substituents Q as described herein. The term “heteroalkenylene” embraces radicals having a “cz's” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or
Figure imgf000013_0001
configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (Cs-2o), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (Cs-s) carbon atoms. Examples of heteroalkenylene groups include, but are not limited to, CH=CHO ---, CH=CHOCH2~ -CH-CHCH2O-, -CH=CHS-, -CH=CHSCH2- -CH-CHCH2S-, or -CH=CHCH2NH-.
[0029] The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynyl group does not contain a carboncarbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (CMO), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-OCH), propynyl (including all isomeric forms, e.g, 1-propynyl (-OCCII3) and propargyl (-CH2C=CH)), butynyl (including all isomeric forms, e.g., 1-butyn-l-yl and 2-butyn- 1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-l-yl and l-methyl-2-butyn-l-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-l-yl and 2-hexyn-l-yl).
[0030] The terms “alkynylene” and “alkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynylene group does not contain a carbon-carbon double bond. The alkynediyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical
Figure imgf000014_0001
6) carbon atoms. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g, l-propyne-l,3-diyl and l-propyne-3,3-diyl), butynediyl (including all isomeric forms, e.g., 1 -butyne- 1,3 -diyl, 1 -butyne- 1,4-diyl, and 2- butyne- 1,1 -diyl), pentynediyl (including all isomeric forms, e.g., l-pentyne-l,3-diyl, 1-pentyne- 1 ,4-diyl, and 2-pentyne- 1,1 -diyl), and hexynediyl (including all isomeric forms, e.g., 1-hexyne- 1,3-diyl, 1 -hexyne- 1,4-diyl, and 2-hexyne- 1,1 -diyl).
[0031] The terms “heteroalkynylene” and “heteroalkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s), and which contains one or more heteroatoms in its main chain, each independently selected from O, S, and N. A heteroalkynylene group does not contain a carbon-carbon double bond. The heteroalkynylene is optionally substituted with one or more substituents Q as described herein. For example, C2-6 heteroalkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the heteroalkynylene is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2- e) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of heteroalkynylene groups include, but are not limited to, -OCCH2O-, -OCCH2S-, or -C=CCH2NH-
[0032] The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic group. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In still another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclofl .1. l]pentyl, bicyclo[2.1. l]hexyl, bicyclo[2.2. l]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.
[0033] The terms “cycloalkylene” and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclic groups. In certain embodiments, the cycloalkanediyl has from 3 to 30 (C3-30), 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane- 1,1 -diyl and cyclopropane- 1,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane- 1,1 -diyl, cyclobutane- 1,2-diyl, and cyclobutane- 1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane- 1,1 -diyl, cyclopentane- 1,2-diyl, and cyclopentane- 1,3 -diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane- 1, 1 -diyl, cyclohexane- 1,2-diyl, cyclohexane- 1,3 -diyl, and cyclohex-1, 4- diyl), cycloheptanediyl (including all isomeric forms, e.g., cycloheptane- 1,1 -diyl, cycloheptane- 1 ,2-diyl, cycloheptane- 1,3 -diyl, and cycloheptane-l,4-diyl), decalinediyl (including all isomeric forms, e.g., decaline-1,1 -diyl, decaline-1, 2 -diyl, and decaline- 1 ,8-diy I), and adamantdiyl (including all isomeric forms, e.g., adamant- 1,2-diyl, adamant- 1,3 -diyl, and adamant- 1,8-diyl).
[0034] The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbon radical and/or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-15), or from 6 to 10 (C6-10) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, the aiyl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In still another embodiment, the aryl is polycyclic. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.
[0035] The terms “arylene” and “arenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic hydrocarbon radical or divalent polycyclic aromatic hydrocarbon radical that contains at least one aromatic hydrocarbon ring. In certain embodiments, the arylene has from 6 to 20 (C6-20), from 6 to 15 (C6-15), or from 6 to 10 (Ce-io) ring atoms. Examples of arylene groups include, but are not limited to, phenylene (including ail isomeric forms, e.g., phen-l,2-diyl, phen- 1,3 -diyl, and phen-l,4-diyl), naphthylene (including all isomeric forms, e.g., naphth-1 ,2-diyl, naphth-l,3-diyl, and naphth- 1,8-diyl), fluorenylene (including all isomeric forms, e.g, fluoren-l,2-diyl, fluoren-l,3-diyl, and fluoren- 1,8-diyl), azulenylene (including all isomeric forms, e.g, azulen-l,2-diyl, azulen- 1,3 -diyl, and azulen-1 ,8- diyl), anthrylene (including all isomeric forms, e.g., anthr-l,2-diyl, anthr- 1,3 -diyl, and anthr-1,8- diyl), phenanthrylene (including all isomeric forms, e.g., phenanthr-l,2-diyl, phenanthr-l,3-diyl, and phenanthr- 1,8-diyl), pyrenylene (including all isomeric forms, e.g., pyren-l,2-diyl, pyren- 1,3-diyl, and pyren- 1,8-diyl), biphenylene (including all isomeric forms, e.g., biphen-2,3-diyl, biphen-3,4’-diyl, and biphen-4,4’-diyl), and terphenylene (including all isomeric forms, e.g., terphen-2,3-diyl, terphen-3,4’-diyl, and terphen-4,4’-diyl). Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene (including all isomeric forms, e.g., dihydronaphth- 1 ,2-diyl and dihydronaphth- 1,8-diyl), indenylene (including all isomeric forms, e.g., inden- 1 ,2-diyl, inden- 1 ,5-diyl, and inden-l,7-diyl), indanylene (including all isomeric forms, e.g, indan- 1 ,2-diyl, indan-1 ,5-diyl, and indan- 1,7-diyl), or tetrahydronaphthylene (tetralinyl ene) (including all isomeric forms, e.g, tetrahydronaphth- 1,2- diyl, tetrahydronaphth-l,5-diyl, and tetrahydronaphth- 1,8-diyl). In certain embodiments, arylene is optionally substituted with one or more substituents Q as described herein.
[0036] The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenyl ethyl (including all isomeric forms, e.g., 1 -phenylethyl and 2- phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1 -phenyl propyl, 2- phenylpropyl, and 3 -phenyl propyl). In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.
[0037] The term “aralkylene” or “arylalkylene” refers to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms. Examples of aralkylene groups include, but are not limited to, benzylene (including all isomeric forms, e.g., phenylmethdiyl), phenyl ethylene (including all isomeric forms, e.g., 2-phenyl-ethan- 1,1 -diyl and 2-phenyl-ethan-l,2-diyl), and phenylpropylene (including all isomeric forms, e.g., 3-phenyl- propan- 1,1 -diyl, 3-phenyl-propan-l,2-diyl, and 3-phenyl-propan-l,3-diyl). In certain embodiments, the aralkylene is optionally substituted with one or more substituents Q as described herein.
[0038] The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatom s, each independently selected from O, S, and N, in the ring. For a heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. In one embodiment, the heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadi azolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-£>]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-Z>]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-Z>]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[l,2-a]pyridinyl, imidazo[4,5- Z>]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, e.g., imidazo[2, 1-Z>]thiazolyl and imidazo[4,5-</|thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, e.g., 1,5 -naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, e.g., oxazolo[4,5- d]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-ft]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, e.g., pyrrolo[2,3- /?]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrol o[3,2-Z>]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [I,2,5]thiadiazolo[3,4-t7]pyrimidinyl and [ l,2,3]thiadiazolo[4,5-<i]pyrimidinyl), and thienopyridyl (including all isomeric forms, e.g, thieno[2,3-5]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-/>]pyridinyl, and thieno[3,2-c]pyridinyl). In yet another embodiment, the heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7- phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.
[0039] The terms “heteroarylene” and “heteroarenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic group or divalent polycyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from 0, S, and N. For a heteroarylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroarylene group is not bonded to the rest of a molecule via its nonaromatic heterocyclic ring. Each ring of a heteroarylene group can contain one or two 0 atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, oxazoldiyl, pyrazindiyl, pyrazoldiyl, pyridazindiyl, pyridindiyl, pyrimidindiyl, pyrrol diyl, thiadiazol diyl, thiazoldiyl, thiendiyl, tetrazol diyl, triazinediyl, and triazol diyl. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofuran diyl, benzimidazoldiyl, benzoisoxazoldiyl, benzopyrandiyl, benzothiadiazoldiyl, benzothiazoldiyl, benzothiendiyl, benzotriazoldiyl, benzoxazoldiyl, furopyridindiyl (including all isomeric forms, e.g, furo[2,3-Z>]pyridindiyl, furo[2,3-c]pyridindiyl, furo[3,2-/>]pyridindiyl, furo[3,2-c]- pyridindiyl, furo[3,4-Z>]pyridindiyl, and furo[3,4-c]pyridindiyl), imidazopyridindiyl (including all isomeric forms, e.g, imidazo[l,2-a]pyridindiyl, imidazo[4,5-&]pyridindiyl, and imidazo[4,5-c]- pyridindiyl), imidazothiazoldiyl (including all isomeric forms, e.g, imidazo[2,l-5]thiazoldiyl and imidazo[4,5-</]thiazoldiyl), indazoldiyl, indolizindiyl, indoldiyl, isobenzofurandiyl, isobenzothiendiyl (z.e., benzo[c]thiendiyl), i soindoldiyl, isoquinolindiyl, naphthyridindiyl (including all isomeric forms, e.g., 1,5-naphthyridindiyl, 1,6-naphthyridindiyl, 1,7- naphthyridindiyl, and 1,8-naphthyridindiyl), oxazolopyridindiyl (including all isomeric forms, e.g., oxazolo[4,5-Z>]pyridindiyl, oxazolo[4,5-c]pyridindiyl, oxazolo[5,4-/>]pyridindiyl, and oxazolo[5,4-c]pyridindiyl), phthalazindiyl, pteridindiyl, purindiyl, pyrrolopyridindiyl (including all isomeric forms, e.g., pyrrolo[2,3-i]pyridindiyl, pyrrolo[2,3-c]pyridindiyl, pyrrolo[3,2-5]- pyridindiyl, and pyrrolo[3,2-c]pyridindiyl), quinolindiyl, quinoxalindiyl, quinazolindiyl, thiadiazolopyrimidindiyl (including all isomeric forms, e.g., [l,2,5]thiadiazolo[3,4-c/]- pyrimidindiyl and [l,2,3]thiadiazolo[4,5-d]pyrimidindiyl), and thienopyridindiyl (including all isomeric forms, e.g., thieno[2,3-/>]pyridindiyl, thieno[2,3-c]pyridindiyl, thieno[3,2-d]pyridindiyl, and thieno[3,2-c]pyridindiyl). Examples of tricyclic heteroarylene groups include, but are not limited to, acridindiyl , benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (including all isomeric forms, e.g., 1,5-phenanthrolindiyl, 1,6- phenanthrolindiyl, 1,7-phenanthrolindiyl, 1,9-phenanthrolindiyl, and 2,10-phenanthrolindiyl), phenanthridindiyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenoxazindiyl, and xanthendiyl. In certain embodiments, heteroaiylene is optionally substituted with one or more substituents Q as described herein.
[0040] The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one nonaromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from 0, S, and N; and the remaining ring atoms are carbon atoms. For a heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, di hydrobenzofuranyl, dihydrobenzisothiazolyl, dihydro- benzisoxazinyl (including all isomeric forms, e.g., l,4-dihydrobenzo[t/][l,3]oxazinyl, 3,4- dihydrobenzo[c][l,2]-oxazinyl, and 3,4-dihydrobenzo[<7][l,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4- piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1 ,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.
[0041] The term “heterocyclylene” refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from 0, S, and N; and the remaining ring atoms are carbon atoms. For a heterocyclylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclylene group has at least one bond to the rest of a molecule via its nonaromatic heterocyclic ring. In certain embodiments, the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclylene groups include, but are not limited to, azepindiyl, benzodioxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e.g., l,4-dihydrobenzo[J][l,3]oxazindiyl, 3,4-dihydrobenzo[c][l,2]oxazindiyl, and 3,4-dihydrobenzo[tf][l,2]oxazindiyl), dihydrobenzothiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydroisoindoldiyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazindiyl, dihydropyridindiyl, dihydropyrimidindiyl, di hydropyrrol diyl, dioxolandiyl, 1 ,4-dithiandiyl, furanondiyl, imidazolidindiyl, imidazolindiyl, indolindiyl, isochromandiyl, isoindolindiyl, isothiazolidindiyl, isoxazolidindiyl, morpholindiyl, octahydroindoldiyl, octahydroisoindoldiyl, oxazolidinondiyl, oxazolidindiyl, oxirandiyl, piperazindiyl, piperidindiyl, 4-piperidondiyl, pyrazolidindiyl, pyrazolindiyl, pyrrolidindiyl, pyrrolindiyl, quinuclidindiyl, tetrahydrofurdiyl, tetrahydroisoquinolindiyl, tetrahydropyrandiyl, tetrahydrothiendiyl, thiamorpholindiyl, thiazolidindiyl, thiochromandiyl, tetrahydroquinolindiyl, and 1 ,3,5-trithiandiyl. In certain embodiments, the heterocyclylene is optionally substituted with one or more substituents Q as described herein.
[0042] The term “halogen,” “halide,” or “halo” refers to fluoro, chloro, bromo, and/or iodo.
[0043] The term “optionally substituted” is intended to mean that a group or substituent, such as an alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene group, may be substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, each of which is independently selected from, e.g., (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO?.), and oxo (=O); (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C&-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, ~OS(O)2.Ra, -OS(O)NRbRc, ~OS(O)2NRbRc, ~NRbRc, -NRaC(0)Rd, -NRaC(0)0Rd, ~NRaC(0)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, --NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, S(O)NRbRc, and ---S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all groups that can be substituted are “optionally substituted.”
[0044] In one embodiment, each Qa is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo, (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Cs-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, ~C(NRe)NRfR8, -C(S)Re, -C(S)ORe, ~C(S)NRfR®, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, ~OC(NRe)NRfRg, ~OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, ~OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRs, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRtRg; wherein each Re, Rf, R8, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1 and R8 together with the N atom to which they are attached form heterocyclyl.
[0045] In certain embodiments, “optically active” and ’’enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
In certain embodiments, an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
[0046] In describing an optically active compound, the prefixes J? and 5 are used to denote the absolute configuration of the compound about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the compound, R and .S',
[0047] The term “i sotopically enriched” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (3H), deuterium (2H), tritium (3H), carbon- 11 (nC), carbon-12 (12C), carbon-13 (13C), carbon-14 (i4C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (!5N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (! 7O), oxygen-18 (18O), fluorine-17 (b'F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (3oS), chlorine-35 (j5Cl), chlorine-36 (3oCl), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an isotopically enriched compound is in a stable form, that is, non-radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (3H), deuterium (2H), carbon- 12 (12C), carbon- 13 (ljC), nitrogen- 14 (14N), nitrogen- 15 (15N), oxygen- 16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), phosphorus-31 (51P), sulfur-32 (32S), sulfur- 33 (JJS), sulfur-34 (34S), sulfur-36 (3oS), chlorine-35 (J3C1), chlorine-37 (3 /Cl), bromine-79 (/9Br), bromine-81 (81Br), and iodine-127 (127I). In certain embodiments, an isotopically enriched compound is in an unstable form, that is, radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-1 1 (nC), carbon-14 (14C), nitrogen-13 (nN), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (j2P), phosphorus-33 (33P), sulfur-35 (35S), chlorine-36 (3bCl), iodine-123 (123I), iodine-125 (125I), iodine-129 (129I), and iodine- 131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be 2H, as example, or any carbon can be l3C, as example, or any nitrogen can be l5N, as example, or any oxygen can be 1SO, as example, where feasible according to the judgment of one of ordinary skill in the art.
[0048] The term “isotopic enrichment” refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope (e.g, 3H for protium or hydrogen-1) of the element. As used herein, when an atom at a particular position in a molecule is designated as a particular less prevalent isotope, it is understood that the abundance of that isotope at that position is substantially greater than its natural abundance.
[0049] The term “isotopic enrichment factor” refers the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.
[0050] The term “hydrogen” or the symbol “H” refers to the composition of naturally occurring hydrogen isotopes, which include protium (3H), deuterium (2H or D), and tritium (3H), in their natural abundances. Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%. Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.
[0051] The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%). [0052] The term “carbon” or the symbol “C” refers to the composition of naturally occurring carbon isotopes, which include carbon-12 (12C) and carbon-13 (13C) in their natural abundances. Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%. Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.
[0053] The term “carbon-13 enrichment” or “13C enrichment” refers to the percentage of incorporation of carbon- 13 at a given position in a molecule in the place of carbon. For example, carbon- 13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon-13 at the specified position. Because the naturally occurring distribution of carbon-13 is about 1.11% on average, carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon- 13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).
[0054] The terms “substantially pure” and “substantially homogeneous” mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a collection of molecules, wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular less prevalent isotope, a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound. Thus, for a deuterated compound that has an atom at a particular position designated as deuterium, a compound that contains a protium at the same position is an impurity.
[0055] The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
[0056] For a divalent group described herein, no orientation is implied by the direction in which the divalent group is presented. For example, unless a particular orientation is specified, the formula ~C(O)NH~ represents both -C(O)NH~ and -NHC(O)-.
[0057] The phrase “an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautom ers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof’ has the same meaning as the phrase “(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more di astereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein.”
Compounds
[0058] In one embodiment, provided herein is a compound of Formula (I):
Figure imgf000027_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
A is a bond, heterocyclylene, or -S(O2)-;
E is C6-14 arylene, heteroarylene, or heterocyclylene;
L is a linker;
X is a bond or -C(O)-;
R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Cs-u and, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii ) -C(O)Rla, C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRia)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc;
R2, R', and R4 are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, ~OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Ria, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(0)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc;
RE is:
Figure imgf000027_0002
Figure imgf000028_0001
wherein: each AE is independently a bond, -O-, -N(Rlb)-, -S-, C1-6 alkylene, Ci-6 heteroalkylene, C2-6 alkenylene, C2-6 heteroalkenyl ene, C2-6 alkynylene, C2-6 heteroalkynylene, C3-10 cycloalkylene, Ce-14 arylene, C7-15 aralkylene, heteroarylene, heterocyclylene, Ci-e heteroalkylene-C6-i4 arylene, Ci-e heteroalkylene-heterocyclylene, or C2-6 alkynylene-heterocyclylene; each XE is independently C(RE1) or N;
YE is a bond, C1-6 alkylene, -0- -S-, -S(0)-, -S(02)-, or -N(RE3)-;
Z is -CH2- or -C(0)-; one of Z1, Z2, Z3, and Z4 is ~C= and the remaining three of Zl, Z2, Z3, and Z4 are each independently -C(RE4a):::; or Z1 is a bond; one of Z2, Z3,
Figure imgf000028_0002
and the remaining two of Z2, Z3, and Z4 are each independently -C(RE4a)= or -S-; each RE1 is independently hydrogen, deuterium, halo, or C1-6 alkyl; each RE2, RE3, and RE3 is independently hydrogen or C1-6 alkyl; each RE4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(0)Rla, -C(0)0Rla, -C(0)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -0Rla, -0C(0)Rla, -0C(0)0Rla, -0C(0)NRlbRlc, -OC(O)SRla, ~0C(NRla)NRibRlc, -OC(S)Ria, -OC(S)ORla, -0C(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -0S(0)NRlbRlc, -0S(0)2NRlbRlc, -NRibRlc, ~NRlaC(0)Rld, -NRlaC(0)0Rld, -NRlaC(0)NRlbRlc, ~NRlaC(0)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)0Rld, -NRlaC(S)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld, - NRlaS(0)NRlbRlc, -NRlaS(0)zNRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; each RE4a is independently hydrogen or RE4; each m is independently an integer of 0, 1, or 2; and each n is independently an integer of 0, 1, 2, or 3; and each Rla, Rlb, Rlc, and Rld is independently hydrogen, deuterium, C1-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C--15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 and, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, ~C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, ~OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, ~NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and - S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C 1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRs, C(O)SR' , -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, OC(O)SRe, -OC(NRe)NRfR8, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rb, -NReS(O)NRfRs, -NReS(O)2NRfRs, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, R\ Rg, and Rh is independently (i) hydrogen or deuterium, (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and R8 together with the N atom to which they are attached form heterocyclyl.
[0059] In certain embodiments, in Formula (I), E is Cs-i4 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), E is phenylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is phen-l,4-diy, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is bicyclic Cs-14 arylene, optionally substituted with one, two, or three substituents Q.
[0060] In certain embodiments, in Formula (I), E is heteroarylene, optionally substituted with one or more substituents Q In certain embodiments, in Formula (I), E is monocyclic heteroarylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is 5-, 6-, or 7-membered heteroarylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is 5-membered heteroarylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is 6-membered heteroarylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is pyridindiyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is pyridine-2, 5-diyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is 7-membered heteroarylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is bicyclic heteroarylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one, two, or three substituents Q.
[0061] In certain embodiments, in Formula (I), E is heterocyclylene; optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), E is monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), E is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is 3-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is 4-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is 5-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is 6-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is piperi dindiyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is piperi din- 1,4-diyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is 7-membered heterocyclylene, optionally substituted with one, two, or three substituents Q In certain embodiments, in Formula (I), E is bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), E is bridged, fused, or spiro heterocyclylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is bridged heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is fused heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in Formula (I), E is spiro heterocyclylene, optionally substituted with one, two, or three substituents Q.
[0062] In another embodiment, provided herein is a compound of Formula (II):
Figure imgf000031_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wlierein:
Figure imgf000031_0002
R5 is hydrogen or R5a; each R5a is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, Ci-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, --C(O)NRlbR!c, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -0Rla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRibRlc, -OS(O)2NRibRlc, -NRlbRlc, ~NRlaC(O)Rld, ~NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NR!aS(O)2Rld, -NRlaS(O)NRibRlc, -NRlaS(O)2NRibRlc,
SR !a, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; a is an integer of 0, 1, 2, or 3; and
R1, R2, R3, R4, Rla, Rlb, Rlc, Rld, RE, A, L, and X are each as defined herein.
[0063] In certain embodiments, in Formula (I) or (II), RE is not l,3-dioxo-2-(2,6- dioxopiperidin-3-yl)isoindolinyl, unsubstituted or substituted. In certain embodiments, in Formula (I) or (II), RE is not any one of l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolinyl, 1,3- dioxo-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindolinyl, and 2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolinyl. In certain embodiments, in Formula (I) or (II), RE is not any one of 1,3-dioxo-
2-(2,6-dioxopiperidin-3-yl)isoindolin-4-yl, l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolin-5-yl, l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindolin-4-yl, l,3-dioxo-2-(2,6-dioxopiperidin-
3-yl)-6-fluoroisoindolin-5-yl, 2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl, and 2-(2,6- di oxopiperi di n-3 -yl)- 1 -oxoisoindol in-5 -y 1.
[0064] In yet another embodiment, provided herein is a compound of Formula (III):
Figure imgf000032_0001
or an enantiomer, a mixture of enanti omers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: each R6 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -0Rla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRiaC(O)SRld, ~NRlaC(NRld)NRlbRlc, ~NRlaC(S)Rld, ~NRlaC(S)ORid, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; b is an integer of 0, 1, 2, 3, or 4; and
R1, R2, R3, R4, Rla, Rlb, Rlc, Rld, RE, A, L, and X are each as defined herein.
[0065] In certain embodiments, in any one of the formulae provided herein, RE is not 1,3- dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolinyl, unsubstituted or substituted. In certain embodiments, in any one of the formulae provided herein, RE is not any one of l,3-dioxo-2-(2,6- dioxopiperidin-3-yl)isoindolinyl, l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindolinyl, and 2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolinyl. In certain embodiments, in any one of the formulae provided herein, RE is not any one of l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolin-
4-yl, l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolin-5-yl, l,3-dioxo-2-(2,6-dioxopiperidin-3- yI)-6-fluoroisoindolin-4-yl, l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindolin-5-yl, 2- (2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl, and 2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-
5-yl.
[0066] In yet another embodiment, provided herein is a compound of Formula (I A):
Figure imgf000033_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R1, R4, R5a, RE, A, L, Y, and a are each as defined herein.
[0067] In yet another embodiment, provided herein is a compound of Formula (IB):
Figure imgf000034_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, RJ, R4, R5a, RE, A, L, Y, and a are each as defined herein.
[0068] In yet another embodiment, provided herein is a compound of Formula (IC):
Figure imgf000034_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RE, A, L, and b are each as defined herein.
[0069] In yet another embodiment, provided herein is a compound of Formula (ID):
Figure imgf000034_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, R6, RE, A, L, and b are each as defined herein.
[0070] In certain embodiments, in any one of the formulae provided herein, A is a bond. In certain embodiments, in any one of the formulae provided herein, A is heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, A is monocyclic heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 3-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 4- membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formul ae provided herein, A is 5-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 6-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is piperidindiyl or piperazindiyl, each optionally substituted with one, two, or three substituents Q In certain embodiments, in any one of the formulae provided herein, A is piperidin- 1 ,4-diyl or piperazin- 1,4-diyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 7-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is bicyclic heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is bridged, fused, or spiro heterocyclylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is bridged heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is fused heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is spiro heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 3,8-diazabicyclo[3.2.1]octandiyl, octahydropyrrolo[3,4-c]pyrroldiyl, or 2,7-diazaspiro[3.5]nonandiyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A is 3,8-diazabicyclo[3.2.1]octan-3,8-diyl, octahydropyrrolo[3,4-c]pyrrol-2,5- diyl, or 2,7-diaza-spiro[3.5]nonan-2,7-diyl. In certain embodiments, in any one of the formulae provided herein, A is -SfOr)-.
[0071] In yet another embodiment, provided herein is a compound of Formula (IIA):
Figure imgf000036_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, RJ, R4, R3a, RE, L, Y, and a are each as defined herein.
[0072] In yet another embodiment, provided herein is a compound of Formula (IIB):
Figure imgf000036_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE, L, Y, and a are each as defined herein.
[0073] In yet another embodiment, provided herein is a compound of Formula (IIC):
Figure imgf000036_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, R6, RE, L, and b are each as defined herein.
[0074] In yet another embodiment, provided herein is a compound of Formula (IID):
Figure imgf000037_0001
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, RJ, R4, Rb, RE, L, and b are each as defined herein.
[0075] In yet another embodiment, provided herein is a compound of Formula (IIIA):
Figure imgf000037_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: each R7 is independently (i) deuterium, cyano, halo, nitro, or oxo; (ii) C1-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRibRlc, -C(O)SRia, -C(NRia)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRic, ~ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NR!aS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; c is an integer of 0, 1, 2, 3, or 4; and
R1, R2, R3, R4, Rla, Rlb, Rlc, Rld, R5a, RE, L, Y, and a are each as defined herein.
[0076] In still another embodiment, provided herein is a compound of Formula (IIIB):
Figure imgf000038_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R1, R4, R7, R5a, RE, L, Y, a, and c are each as defined herein.
[0077] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC -I):
Figure imgf000038_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE2, RE4, XE, YE, m, and n are each as defined herein.
[0078] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-I-a):
Figure imgf000038_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE2, RE4, XE, m, and n are each as defined herein.
[0079] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-I-b): (EC-T-b)
Figure imgf000039_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4, m, and n are each as defined herein.
[0080] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-I-c):
(EC-I-c)
Figure imgf000039_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4, m, and n are each as defined herein.
[0081 ] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-I-d):
(EC-I-d)
Figure imgf000039_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4, m, and n are each as defined herein.
[0082] In certain embodiments, in any one of the formulae provi ded herein, RE is a moiety having the structure of Formula (EC-I-e):
(EC-I-e)
Figure imgf000039_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE2, RE4, m, and n are each as defined herein.
[0083] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-I-f):
(EC-I-f)
Figure imgf000040_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE2, RE4, m, and n are each as defined herein.
[0084] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-I-g):
(EC-I-g)
Figure imgf000040_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE2, RE4, m, and n are each as defined herein
[0085] In certain embodiments, in any one of the formulae provi ded herein, RE is a moiety having the structure of Formula (EC-I-h):
(EC-I-h)
Figure imgf000040_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, REJ, RE4, m, and n are each as defined herein. [0086] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-I-i):
(EC-I-i)
Figure imgf000041_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE3, RE4, m, and n are each as defined herein.
[0087] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-I-j):
(EC-I-j)
Figure imgf000041_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, REJ, RE4, m, and n are each as defined herein.
[0088] In certain embodiments, in any one of the formulae provi ded herein, RE is a moiety having the structure of:
Figure imgf000041_0003
Figure imgf000042_0001
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein each AE is as defined herein.
[0089] In one embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A1, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A2, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A3, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A4, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A5, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A6, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[0090] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of
Figure imgf000043_0001
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[0091] In one embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A7, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A8, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A9, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A10, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-All, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A12, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A13, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A14, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more di astereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A15, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A16, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A17, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A18, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-A19, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in a compound of any one of the formulae provided herein, RE is a moi ety havi ng the structure of Formula EC-20, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[0092] In certain embodiments, in any one of the formulae provi ded herein, RE is a moiety having the structure of Formula (EC -II):
Figure imgf000045_0002
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE2, RE4, RE5, XE, m, and n are each as defined herein.
[0093] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-II-a):
Figure imgf000045_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4, RE5, m, and n are each as defined herein.
[0094] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-II-b):
Figure imgf000046_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4, RE5, m, and n are each as defined herein.
[0095] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-II-c):
(EC-II-c)
Figure imgf000046_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4, RE5, m, and n are each as defined herein.
[0096] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-II-d):
Figure imgf000046_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE2, RE4, RE5, m, and n are each as defined herein. [0097] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-II-e):
Figure imgf000047_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE2, RE4, RE5, m, and n are each as defined herein.
[0098] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-II-f):
Figure imgf000047_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE2, RE4, RE5, m, and n are each as defined herein .
[0099] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of:
Figure imgf000047_0002
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein each AE is as defined herein.
[00100] In one embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B1, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B2, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, R& is a moiety having the structure of Formula EC-B3, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a m oiety having the structure of Formula EC-B4, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00101] Ill certain embodiments, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of:
Figure imgf000048_0001
Figure imgf000049_0001
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00102] In one embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B5, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B6, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof In yet another embodiment, in a compound of any one of the formulae provided herein, R& is a moiety having the structure of Formula EC-B7, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B8, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B9, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B10, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopi c vari ant thereof.
[00103] In certain embodiments, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of:
Figure imgf000050_0001
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00104] In one embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B11, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC- 812, or an enantiomer, a mixture of enanti omers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B13, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B14, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-B15, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in a compound of any one of the formulae provided herein, Rh is a moiety having the structure of Formula EC-B16, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00105] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC -III):
Figure imgf000051_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, Z, Z1, Z2, Z3, Z4, and m are each as defined herein.
[00106] In certain embodiments, in any one of the formulae provided herein, one of Z1, Z2, Z3, and Z4 is -C= and the remaining three of Z1, Z2, Z3, and Z4 are each independently -C(RE4a)=, wherein RE4a is as defined herein. In certain embodiments, in any one of the formulae provided herein, Z1 is -C=; and Z2, Z3, and Z4 are each independently -C(RE4a)= w'herein RE4a is as defined herein. In certain embodiments, in any one of the formulae provided herein, Z1, Z3, and Z4 are each independently ~C(RE4a)=, wherein RE4a is as defined herein; and In certain embodiments, in any one of the formulae provided herein, Z1, Z2, and Z4 are each independently -C(RE4a)=, wherein RE4a is as defined herein; and Z3 is ~C=. In certain embodiments, in any one of the formulae provided herein, Z1, Z2, and Z3 are each independently -C(RE4a)=, wherein RE4a is as defined herein; and Z4 is -C=. [00107] In certain embodiments, in any one of the formulae provided herein, Z! is a bond; one of Z2, Z3, and Z4 is -C=, and the remaining two of Z2, Z3, and Z4 are each independently -C(RE4a)= or S . wherein RE4a is as defined herein. In certain embodiments, in any one of the formulae provided herein, Z1 is a bond; Z2 is -C=; Z3 is -C(RE4a)=, wherein RE4a is as defined herein; and Z4 is -S-. In certain embodiments, in any one of the formulae provided herein, Z1 is a bond; Z2 is -C=; Z3 is -S-; and Z4 is -C(RE4a)=, wherein RE4a is as defined herein. In certain embodiments, in any one of the formulae provided herein, Z1 is a bond; Z2 is -C(RE4a)=, wherein RE4a is as defined herein; Z3 is C=; and Z4 is -~S~. In certain embodiments, in any one of the formulae provided herein, Z1 is a bond; Z2 is -S-; Z2 is -C=; and Z4 is -C(RE4a)=, wherein RE4a is as defined herein. In certain embodiments, in any one of the formulae provided herein, Z1 is a bond; Z2 is -C(RE4a)=, wherein RE4a is as defined herein; Z3 is -S-; and Z4 is -C=. In certain embodiments, in any one of the formulae provided herein, Z1 is a bond; Z2 is -S-; Z3 is -C(RE4a)=, wherein RE4a is as defined herein; and Z4 is -C=.
[00108] In certain embodiments, in Formula (EC -III), RE is not l,3-dioxo-2-(2,6- dioxopiperidin-3-yl)isoindolinyl, unsubstituted or substituted. In certain embodiments, in Formula (EC-III), RE is not any one of 1 ,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolinyl, 1,3- dioxo-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindolinyl, and 2-(2, 6-dioxopiperi din-3 -yl)-l- oxoisoindolinyl. In certain embodiments, in Formula (EC-III), RE is not any one of l,3-dioxo-2- (2,6-dioxopiperidin-3-yl)isoindolin-4-yl, l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolin-5-yl, l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindolin-4-yl, l,3-dioxo-2-(2,6-dioxopiperidin- 3-yl)-6-fluoroisoindolin-5-yl, 2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl, and 2-(2,6- di oxopiperi din-3 -yl)- 1 -ox oisoindol in-5 -yl .
[00109] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-III-a):
Figure imgf000052_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4, Z, m, and n are each as defined herein.
[00110] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-III-b):
Figure imgf000053_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4a, Z, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is CH2 .
[00111] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-III-c):
Figure imgf000053_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4a, Z, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CH2-.
[001 12] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-III-d):
Figure imgf000053_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4a, Z, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CH2-.
[00113] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-III-e):
Figure imgf000054_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and AE, RE1, RE2, RE4, Z. and m are each as defined herein.
[00114] In certain embodiments, in any one of the formulae provided herein, RE is a m oiety having the structure of Formula (EC-III-f):
Figure imgf000054_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4a, Z, and m are each as defined herein.
[00115] In certain embodiments, in any one of the formulae provided herein, R is a moiety having the structure of Formula (EC-III-g):
Figure imgf000054_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4a, Z, and m are each as defined herein.
[00116] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-IIl-h):
Figure imgf000055_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and AE, RE1, RE2, RE4, Z, and m are each as defined herein.
[00117] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-III-i):
(EC-III-i)
Figure imgf000055_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4a, Z, and m are each as defined herein.
[00118] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-III-j):
Figure imgf000055_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4a, Z, and m are each as defined herein.
[00119] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-III-k):
Figure imgf000055_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and AE, RE1, RE2, RE4, Z, and m are each as defined herein.
[00120] In certain embodiments, in any one of the formulae provided herein, RE is a moiety having the structure of Formula (EC-III-1):
Figure imgf000056_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4a, Z, and m are each as defined herein.
[00121] In certain embodiments, in any one of the formulae provided herein, RE is a m oiety having the structure of Formula (EC-III-m):
Figure imgf000056_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein AE, RE1, RE2, RE4a, Z, and m are each as defined herein.
[00122] In certain embodiments, RE is a moiety having the structure of
Figure imgf000056_0001
Figure imgf000057_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein each AE is as defined herein.
[00123] In one embodiment, in a compound of any one of the formulae provided herein, RE is a moi ety havi ng the structure of Formula EC-C1, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-C2, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-C3, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-C4, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00124] In certain embodiments, RE is a moiety having the structure of
Figure imgf000057_0002
Figure imgf000058_0001
EC-C13 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00125] In one embodiment, in a compound of any one of the formulae provided herein, RE is a moi ety havi ng the structure of Formula EC-C5, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-C6, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, R& is a moiety having the structure of Formula EC-C7, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-C8, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-C9, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-C10, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-C11, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof In yet another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-C12, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in a compound of any one of the formulae provided herein, RE is a moiety having the structure of Formula EC-C13, or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00126] In one embodiment, provided herein is a compound of Formula (IVA):
Figure imgf000059_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, R3a, RE2, RE4, AE, L, XE, Y, a, m, and n are each as defined herein.
[00127] In another embodiment, provided herein is a compound of Formula (VA):
Figure imgf000059_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE1, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00128] In yet another embodiment, provided herein is a compound of Formula (VIA):
Figure imgf000060_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, R: 4 AE L, Y, a, m, and n are each as defined herein.
[00129] In yet another embodiment, provided herein is a compound of Formula (VIIA):
Figure imgf000060_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, R5a, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00130] In still another embodiment, provided herein is a compound of Formula (VIIIA):
Figure imgf000060_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00131] In one embodiment, provided herein is a compound of Formula (IXA):
Figure imgf000061_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE2, RE4, AE, L, XE, Y, a, m, and n are each as defined herein.
[00132] In another embodiment, provided herein is a compound of Formula (XA):
Figure imgf000061_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00133] In yet another embodiment, provided herein is a compound of Formula (XIA):
Figure imgf000062_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, RJ, R4, R5a, RE1, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00134] In yet another embodiment, provided herein is a compound of Formula (XIIA):
Figure imgf000062_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00135] In still another embodiment, provided herein is a compound of Formula (XIII A):
Figure imgf000062_0003
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R1, R4, R3a, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00136] In one embodiment, provided herein is a compound of Formula (XIV A):
Figure imgf000063_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE2, RE4, RE5, AE, L, XE, Y, a, m, and n are each as defined herein.
[00137] In another embodiment, provided herein is a compound of Formula (XVA):
Figure imgf000063_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, RE4, RE3, AE, L, Y, a, m, and n are each as defined herein.
[00138] In yet another embodiment, provided herein is a compound of Formula (XVIA):
Figure imgf000063_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, RE4, RE"3, AE, L, Y, a, m, and n are each as defined herein.
[00139] In yet another embodiment, provided herein is a compound of Formula (XVIIA):
Figure imgf000064_0001
or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE2, RE4, RE5, AE, L, Y, a, m, and n are each as defined herein.
[00140] In stil l another embodiment, provided herein is a compound of Formula
(XVIII A):
Figure imgf000064_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, R3a, RE2, RE4, RE5, AE, L, Y, a, m, and n are each as defined herein.
[00141] In one embodiment, provided herein is a compound of Formula (XIXA):
Figure imgf000064_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R1, R4, R3a, RE2, RE4, RE5, AE, L, XE, Y, a, m, and n are each as defined herein.
[00142] In another embodiment, provided herein is a compound of Formula (XXA):
Figure imgf000065_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE1, RE2, RE4, RE5, AE, L, Y, a, m, and n are each as defined herein.
[00143] In yet another embodiment, provided herein is a compound of Formula (XXIA):
Figure imgf000065_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, RE4, RES, AE, L, Y, a, m, and n are each as defined herein.
[00144] In yet another embodiment, provided herein is a compound of Formula (XXIIA):
Figure imgf000065_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE2, RE4, RE5, AE, L, Y, a, m, and n are each as defined herein.
[00145] In still another embodiment, provided herein is a compound of Formula (XXIII A):
Figure imgf000066_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE2, RE4, RE5, AE, L, Y, a, m, and n are each as defined herein.
[00146] In one embodiment, provided herein is a compound of Formula (XXIVA):
Figure imgf000066_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE1, RE2, RE4a, AE L, Y, Z, a, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -- CH2-.
[00147] In another embodiment, provided herein is a compound of Formula (XXVA):
Figure imgf000067_0001
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4,
Figure imgf000067_0002
Z, a, and m are each as defined herein. In certain embodiments,
RE4a is fluoro. In certain embodiments, Z is -CH2-.
[00148] In yet another embodiment, provided herein is a compound of Formula (XXVIA):
Figure imgf000067_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, R3a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CH2-.
[00149] In still another embodiment, provided herein is a compound of Formula
(XXVIIA):
Figure imgf000067_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein.
[00150] In one embodiment, provided herein is a compound of Formula (XXVIIIA):
Figure imgf000068_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is CH2
[00151] In another embodiment, provided herein i s a compound of F ormula (XXIXA) :
Figure imgf000068_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, R3a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CH2-.
[00152] In yet another embodiment, provided herein is a compound of Formula (XXXA):
Figure imgf000069_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CH2-.
[00153] In still another embodiment, provided herein is a compound of Formula (XXXIA):
Figure imgf000069_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein.
[00154] In one embodiment, provided herein is a compound of Formula (IVB):
Figure imgf000069_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE2, RE4, AE, L, XE, Y, a, m, and n are each as defined herein.
[00155] In another embodiment, provided herein is a compound of Formula (VB):
Figure imgf000070_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00156] In yet another embodiment, provided herein is a compound of Formula (VIB):
Figure imgf000070_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE1, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00157] In yet another embodiment, provided herein is a compound of Formula (VIIB):
Figure imgf000071_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00158] In still another embodiment, provided herein is a compound of Formula (VIIIB):
Figure imgf000071_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00159] In one embodiment, provided herein is a compound of Formula (IXB):
Figure imgf000071_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE2, RE4, AE, L, XE, Y, a, m, and n are each as defined herein. [00160] In another embodiment, provided herein is a compound of Formula (XB):
Figure imgf000072_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00161] In yet another embodiment, provided herein is a compound of Formula (XIB):
Figure imgf000072_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R.’, R4, R3a, RE1, RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00162] In yet another embodiment, provided herein is a compound of Formula (XIIB):
Figure imgf000072_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4,
Figure imgf000073_0001
L, Y, a, m, and n are each as defined herein.
[00163] In still another embodiment, provided herein is a compound of Formula (XIIIB):
Figure imgf000073_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, RY RE2, RE4, AE, L, Y, a, m, and n are each as defined herein.
[00164] In one embodiment, provided herein is a compound of Formula (XIVB):
Figure imgf000073_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wfierein R1, R2, R1, R4, R5a, RE2, RE4, RE5, AE, L, XE, Y, a, m, and n are each as defined herein.
[00165] In another embodiment, provided herein is a compound of Formula (XVB):
Figure imgf000073_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, herein.
Figure imgf000074_0001
[00166] In yet another embodiment, provided herein is a compound of Formula (XVIB):
Figure imgf000074_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, R3a, RE1, RE2, RE4, RE5, AE, L, Y, a, m, and n are each as defined herein.
[00167] In yet another embodiment, provided herein is a compound of Formula (XVIIB):
Figure imgf000074_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE2, RE4, RE3, AE, L, Y, a, m, and n are each as defined herein.
[00168] In still another embodiment, provided herein is a compound of Formula (XVIIIB):
Figure imgf000074_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4,
Figure imgf000075_0001
y a, m, and n are each as defined herein.
[00169] In one embodiment, provided herein is a compound of Formula (XIXB):
Figure imgf000075_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, RY RE2, RE4, RE5, AE, L, XE, Y, a, m, and n are each as defined herein.
[00170] In another embodiment, provided herein is a compound of Formula (XXB):
Figure imgf000075_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE1, RE2, RE4, RE5, AE, L, Y, a, m, and n are each as defined herein.
[00171] In yet another embodiment, provided herein is a compound of Formula (XXIB):
Figure imgf000075_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R.3, R4, herein.
Figure imgf000076_0001
[00172] In yet another embodiment, provided herein is a compound of Formula (XXIIB):
Figure imgf000076_0002
or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE2, RE4, RE5, AE, L, Y, a, m, and n are each as defined herein.
[00173] In still another embodiment, provided herein is a compound of Formula (XX1IIB):
Figure imgf000076_0003
or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R.’, R4, R3a, RE2, RE4, RE5, AE, L, Y, a, m, and n are each as defined herein.
[00174] In one embodiment, provided herein is a compound of Formula (XXIVB):
Figure imgf000077_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, R3a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CH2-.
[00175] In another embodiment, provided herein is a compound of Formula (XXVB):
Figure imgf000077_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -Chh
[00176] in yet another embodiment, provided herein is a compound of Formula (XXVIB):
Figure imgf000077_0003
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R1, R4, R5a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein. In certain embodiments,
RE4a is fluoro. In certain embodiments, Z is -CH2-.
[00177] In still another embodiment, provided herein is a compound of Formula
(XXVIIB):
Figure imgf000078_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein.
[00178] In one embodiment, provi ded herein is a compound of Formula (XXVIIIB):
Figure imgf000078_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4,
Figure imgf000078_0002
y 2, a, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CH?-.
[00179] In another embodiment, provided herein is a compound of Formula (XXIXB):
Figure imgf000079_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CH2-.
[00180] In yet another embodiment, provided herein is a compound of Formula (XXXB):
Figure imgf000079_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R3a,
Figure imgf000079_0001
£ Y, Z, a, and m are each as defined herein. In certain embodiments,
RE4a is fluoro. In certain embodiments, Z is -CH2-.
[00181] In still another embodiment, provided herein is a compound of Formula (XXXIB):
Figure imgf000080_0001
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, RE1, RE2, RE4a, AE, L, Y, Z, a, and m are each as defined herein.
[00182] In one embodiment, provided herein is a compound of Formula (IIIC):
Figure imgf000080_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, RE2, RE4, AE, L, XE, m, and n are each as defined herein.
[00183] In another embodiment, provided herein is a compound of Formula (IVC):
Figure imgf000080_0003
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, RJ, R4, RE!, RE2, RE4, AE, L, m, and n are each as defined herein.
[00184] In yet another embodiment, provided herein is a compound of Formula (VC):
Figure imgf000081_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, RE1, RE2, RE4, AE, L, m, and n are each as defined herein.
[00185] In yet another embodiment, provided herein is a compound of Formula (VIC):
Figure imgf000081_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, RE2, RE4, AE, L, m, and n are each as defined herein.
[00186] In still another embodiment, provided herein is a compound of Formula (VIIC):
Figure imgf000081_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, RE2, RE4, AE, L, m, and n are each as defined herein.
[00187] In one embodiment, provided herein is a compound of Formula (VIIIC):
Figure imgf000082_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R1, R4, RE2, RE4, RE3, AE, L, XE, m, and n are each as defined herein.
[00188] In another embodiment, provided herein is a compound of Formula (IXC):
Figure imgf000082_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R’, R4, RE!, RE2, RE4, RE5, AE, L, m, and n are each as defined herein.
[00189] In yet another embodiment, provided herein is a compound of Formula (XC):
Figure imgf000082_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R1, R4, RE1, RE2, RE4, RE5, AE, L, m, and n are each as defined herein.
[00190] In yet another embodiment, provided herein is a compound of Formula (XIC):
Figure imgf000083_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R1, R4, RE2, RE4, RE3, AE, L, m, and n are each as defined herein.
[00191] In still another embodiment, provided herein is a compound of Formula (XIIC):
Figure imgf000083_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, RE2, RE4, RE5, AE, L, m, and n are each as defined herein.
[00192] In one embodiment, provided herein is a compound of Formula (XIIIC):
Figure imgf000083_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, RE1, RE2, RE4a, AE, L, Z, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CH?.-.
[00193] In another embodiment, provided herein is a compound of Formula (XIVC):
Figure imgf000084_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R1, R4, RE!, RE2, RE4a, AE, L, Z, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CII2-.
[00194] In yet another embodiment, provided herein is a compound of Formula (XVC):
Figure imgf000084_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, RE1, RE2, RE4a, AE, L, Z, and m are each as defined herein. In certain embodiments, RE4a is fluoro. In certain embodiments, Z is -CH2-.
[00195] In still another embodiment, provided herein is a compound of Formula (XVIC):
Figure imgf000085_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, RE1, RE2, RE4a, AE, L, Z, and m are each as defined herein.
[00196] In certain embodiments, in any one of the formulae provided herein, Rl is Ci-6 alkyl, C3-10 cycloalkyl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is Ci -6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is methyl, ethyl, propyl, butyl, or pentyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is ethyl, isopropyl, or pent-3-yl.
[00197] In certain embodiments, in any one of the formulae provided herein, R1 is C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) halo or hydroxyl; or (ii) C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
[00198] In certain embodiments, in any one of the formulae provided herein, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one, two, or three substituents Q, each of which is independently (i) halo or hydroxyl; or (ii) C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one, two, or three substituents Q, each of which is independently fluoro, methyl, ethyl, or hydroxyl. In certain embodiments, in any one of the formulae provided herein, R1 is cyclopropyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is cyclobutyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is cyclopentyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is cyclopentyl, optionally substituted with one, two, or three substituents Q, each of which is independently (i) halo or hydroxyl; or (ii) C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is cyclopentyl, optionally substituted with one, two, or three substituents Q, each of which is independently fluoro, methyl, ethyl, or hydroxyl. In certain embodiments, in any one of the formulae provided herein, R1 is cyclopentyl. In certain embodiments, in any one of the formulae provided herein, R1 is cyclohexyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is cycloheptyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is bicyclic C4-10 cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is bridged, fused, or spiro C4-10 cycloalkyl, each optionally substituted with one, two, or three substituents Q.
[00199] In certain embodiments, in any one of the formulae provided herein, Rl is heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is monocyclic heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is 5-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is tetrahydrofuryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is 6-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is bicyclic heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R1 is bridged, fused, or spiro heterocyclyl, each optionally substituted with one, two, or three substituents Q.
[00200] In certain embodiments, in any one of the formulae provided herein, R1 is ethyl, isopropyl, pent-3-yl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopentyl, 2-hydroxy- cyclopentyl, 3-hydroxycyclopentyl, 2-hydroxy-2-m ethyl cyclopentyl, 2-hydroxy-2-ethyl cyclopentyl, 3-hydroxy-2-methylcyclopentyl, 4-hydroxy-2-methylcyclopentyl, 3 -hydroxy cyclohexyl,
4-hydroxycyclohexyl, 3-fluoro-5-hydroxycyclohexyl, 3-hydroxy-2-methylcyclohexyl, 5- hydroxy-2-methylcyclohexyl, 3 -hydroxy cycloheptyl, or 4-hydroxy-4-methyltetrahydrofuran-3- yl. In certain embodiments, in any one of the formulae provided herein, R1 is cyclopentyl or 2- hydroxy-2-methylcyclopentyl. In certain embodiments, in any one of the formulae provided herein, R is cyclopentyl or
Figure imgf000087_0001
' — . In certain embodiments, in any one of the formulae provided herein, R1 is
Figure imgf000087_0002
[00201] In certain embodiments, in any one of the formulae provided herein, R2 is (i) hydrogen, cyano, or halo; (ii) C1-6 alkyl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q, or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -ORla, or -NRlbRlc, wherein each Rla, Rlb, and Rlc is as defined herein. In certain embodiments, in any one of the formulae provided herein, R2 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R2 is cyano. In certain embodiments, in any one of the formulae provided herein, R2 is halo. In certain embodiments, in any one of the formulae provided herein, R2 is fluoro, chloro, bromo, or iodo. In certain embodiments, in any one of the formulae provided herein, R2 is C1-6 alkyl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R 2 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R2 is methyl, ethyl, isopropyl, cyanomethyl, difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, hydroxycarbonylmethyl, hydroxycarbonyldifluoromethyl, aminocarbonylmethyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, ethoxymethyl, or 2-methoxy ethyl. In certain embodiments, in any one of the formulae provided herein, R2 is
Figure imgf000088_0001
aralkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R2 is benzyl. In certain embodiments, in any one of the formulae provided herein, R2 is heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R2 is oxazol-5-yl.
[00202] In certain embodiments, in any one of the formulae provided herein, R2 is -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -ORla, or -NRlbRlc, wherein each Rla, Rlb, and Rlc is as defined herein. In certain embodiments, in any one of the formulae provided herein, R2 is -C(O)Rla, wherein Rla is as defined herein. In certain embodiments, in any one of the formulae provided herein, R2 is C(O)Rla, wherein Rla is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2 is acetyl. In certain embodiments, in any one of the formulae provided herein, R2 is C(O)OR!a, wherein Rla is as defined herein. In certain embodiments, in any one of the formulae provided herein, R2 is C(O)ORla, wherein Rla is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2 is hydroxycarbonyl or ethoxy carbonyl. In certain embodiments, in any one of the formulae provided herein, R2 is -C(O)NRlbRlc, wherein Rlb and Ric are each as defined herein. In certain embodiments, in any one of the formulae provided herein, R2 is -C(O)NRlbRic, wherein Rlb and Rlc are each independently hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2 is methylaminocarbonyl or dimethylaminocarbonyl. In certain embodiments, in any one of the formulae provided herein, R2 is -ORla, wherein Rla is as defined herein. In certain embodiments, in any one of the formulae provided herein, R2 is -ORla, wherein Rla is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2 is 2-ethoxy ethoxy. In certain embodiments, in any one of the formulae provided herein, R2 is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, in any one of the formulae provided herein, R2 is -NRlbRlc, wherein Rlb and Rlc are each independently hydrogen or Ci-e alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R2 is amino.
[00203] In certain embodiments, in any one of the formulae provided herein, R2 is hydrogen, cyano, fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, cyanomethyl, difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, hydroxycarbonylmethyl, hydroxycarbonyldifluoro- methyl, aminocarbonylmethyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, benzyl, oxazol-5-yl, acetyl, hydroxycarbonyl, ethoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, 2-ethoxyethoxy, or amino. In certain embodiments, in any one of the formulae provided herein, R2 is difluoromethyl, acetyl, or dimethylaminocarbonyl. In certain embodiments, in any one of the formulae provided herein, R2 is difluoromethyl. In certain embodiments, in any one of the formul ae provided herein, R2 is acetyl . In certain embodiments, in any one of the formulae provided herein, R2 is dimethylaminocarbonyl.
[00204] In certain embodiments, in any one of the formulae provided herein, R3 is hydrogen, deuterium, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R3 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R3 is deuterium. In certain embodiments, in any one of the formulae provided herein, R3 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q In certain embodiments, in any one of the formulae provided herein, R3 is methyl. In certain embodiments, in any one of the formulae provided herein, R3 is hydrogen or methyl.
[00205] In certain embodiments, in any one of the formulae provided herein, R4 is hydrogen.
[00206] In certain embodiments, in any one of the formulae provided herein, R5 is hydrogen, deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R5 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R5 is deuterium. In certain embodiments, in any one of the formulae provided herein, R5 is halo. In certain embodiments, in any one of the formulae provided herein, R5 is fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, R5 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R5 is methyl or ethyl. In certain embodiments, in any one of the formulae provided herein, R5 is hydrogen, fluoro, chloro, methyl, or ethyl. In certain embodiments, in any one of the formulae provided herein, R5 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R5 is methyl.
[00207] In certain embodiments, in any one of the formulae provided herein, R5a is deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, R5a is deuterium. In certain embodiments, in any one of the formulae provided herein, R5a is halo. In certain embodiments, in any one of the formulae provided herein, R5a is fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, R3a is C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R5a is methyl or ethyl In certain embodiments, in any one of the formulae provided herein, R5a is fluoro, chloro, methyl, or ethyl. In certain embodiments, in any one of the formulae provided herein, R5a is methyl.
[00208] In certain embodiments, in any one of the formulae provided herein, RE1 is hydrogen, deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, RE1 is hydrogen. In certain embodiments, in any one of the formulae provided herein, RE1 is deuterium. In certain embodiments, in any one of the formulae provided herein, RE1 is halo. In certain embodiments, in any one of the formulae provided herein, RE1 is fluoro. In certain embodiments, in any one of the formulae provided herein, RE1 is Ci-e alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, RE1 is methyl. In certain embodiments, in any one of the formulae provided herein, REi is hydrogen, deuterium, fluoro, or methyl.
[00209] In certain embodiments, in any one of the formulae provided herein, RE2 is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, RE2 is hydrogen. In certain embodiments, in any one of the formulae provided herein, RE2 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
[00210] In certain embodiments, in any one of the formulae provided herein, RE3 is hydrogen or Ci-s alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, RE3 is hydrogen. In certain embodiments, in any one of the formulae provided herein, RE3 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q.
[00211] In certain embodiments, in any one of the formulae provided herein, each RE4 is independently deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, RE4 is deuterium. In certain embodiments, in any one of the formulae provided herein, RE4 is halo. In certain embodiments, in any one of the formulae provided herein, each RE4 is independently fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, RE4 is chloro. In certain embodiments, in any one of the formulae provided herein, each RE4 is independently Ci-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, each RE4 is independently methyl, ethyl, propyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, each RE4 is independently methyl, isopropyl, or trifluoromethyl. In certain embodiments, in any one of the formulae provided herein, each RE4 is independently fluoro, chloro, methyl, isopropyl, or trifluoromethyl. In certain embodiments, in any one of the formulae provided herein, each RE4 is independently methyl or trifluoromethyl.
[00212] In certain embodiments, in any one of the formulae provided herein, RE4s is hydrogen, deuterium, or halo. In certain embodiments, in any one of the formulae provided herein, RE4s is hydrogen. In certain embodiments, in any one of the formulae provided herein, RE4S is deuterium. In certain embodiments, in any one of the formulae provided herein, RE4s is halo. In certain embodiments, in any one of the formulae provided herein, RE:4S is fluoro or chloro. In certain embodiments, in any one of the formulae provided herein, RE4s is fluoro. In certain embodiments, in any one of the formul ae provided herein, RE4s is hydrogen, deuterium, fluoro, or chloro.
[00213] In certain embodiments, in any one of the formulae provided herein, REs is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, RE5 is hydrogen. In certain embodiments, in any one of the formulae provided herein, RE5 is C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, RE5 is methyl.
[00214] In certain embodiments, in any one of the formulae provided herein, AE is (i) a bond; or (ii) C2-6 alkynylene, heterocyclylene, C1-6 heteroalkylene-Ce-u arylene, Ci-6 heteroalkyl ene-heterocycly I ene, or C2-6 alkynylene-heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is a bond. In certain embodiments, in any one of the formulae provided herein, AE is C2-6 alkynylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is ethynediyl. In certain embodiments, in any one of the formulae provided herein, AE is heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is monocyclic heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, A& is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is 5- or 6-membered heterocyclylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is 6-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is piperidindiyl or piperazindiyl, each optionally substituted with one, two, or three substituents Q In certain embodiments, in any one of the formulae provided herein, AE is piperidin-l,3-diyl, piperidin- 1 ,4- diyl, or piperaz-l,4-diyl.
[00215] In certain embodiments, in any one of the formulae provided herein, AE is C1-6 heteroalkylene-Ce-14 arylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is C1-6 heteroal kylene- phendiyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is (phendiyl)oxymethanediyl. In certain embodiments, in any one of the formulae provided herein, AE is C1-6 heteroalkylene- heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is C1-6 heteroalkylene-(monocyclic heterocyclylene), optionally/ substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is C1-6 heteroal kylene-(3-, 4-, 5-, 6-, or 7-membered heterocyclylene), each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is Ci-6 heteroalkylene-(6-membered heterocyclylene), optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is Ci-6 heteroalkylene-piperazindiyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is C1-6 heteroal kylene- piperazin- 1,4-diyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein,
Figure imgf000093_0001
Figure imgf000093_0002
[00216] In certain embodiments, in any one of the formulae provided herein, AE is C2.6 alkynylene-heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is C2-6 alkynylene- (monocyclic heterocyclylene), optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is C2-6 alkynylene-(3-, 4-, 5-, 6-, or 7-membered heterocyclylene), each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is C2-6 alkynylene-(6-membered heterocyclylene), optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, AE is (piperidindiyl)-ethynediyl. In certain embodiments, in any one of the formulae provided herein, AE is a bond, piperi din- 1,3 -diyl, piperidin-1 ,4-diyl, piperaz-l,4-diyl, (phen-1,4- diyl)oxymethanediyl, ( pi peridin- 1 ,4-diy l)ethynediy
Figure imgf000094_0001
Figure imgf000094_0002
[00217] In certain embodiments, in any one of the formulae provided herein, L is a linker having the structure of ZL (RL -ZL)z-, wherein: each RL is independently C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, C3-10 cycloalkylene, Ce-i4 arylene, heteroarylene, or heterocyclylene, each of which is optionally- substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each ZL is independently a bond, -C(O)-, -C(O)O- -C(O)NRlb-, -C(O)S- -C(NRla)NRlb-, -C(S)-, -C(S)O-, -C(S)NRlb-, -O-, -OC(O)O-, -OC(O)NRlb-, -OC(O)S-, -OC(NRla)NRlb- -OC(S)O- -OC(S)NRlb-, -OS(O)-, -OS(O)2-, -OS(O)NRlb- -OS(O)2NRlb-, -NRlb-, -NRlaC(O)NRlb-, -NRlaC(O)S-, -NRlaC(NRld)NRlb-, -NRlaC(S)NRlb-, -NRlaS(O)NRlb-, -NRlaS(O)2NR!b- -S-, -S(O)-, -S(O)2-, -S(O)NRlb-, or -S(O)2NRlb--; where each Rla, Rlb, and Rld is as defined herein; and z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[00218] In certain embodiments, each RL is independently Ci-io alkylene, C2-10 alkynylene, C3-10 cycloalkylene, Ce-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each ZL is independently a bond, -C(O)-, -C(O)NRlb- -C(NRla)NRlb-, -O-, -OC(O)NRlb-, -NRlb- -NRlaC(O)NRlb-, -NRlaC(NRld)NRib---, -NRlaS(O)NRlb-, -NRlaS(O)2NRlb-, -S-, -S(O)-, -S(O)2-, -S(O)NRIb-, or -■S(O)2NRlb-; and z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; where each Rla, Rlb, and Rld is as defined herein.
[00219] In certain embodiments, each RL is independently Ci-io alkylene, C2-io alkynylene, C3-10 cycloalkylene, Ce-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each ZL is independently a bond, -C(O)-, -C(O)NRlb-, -O-, -OC(O)NRlb-, -NRlb-, -NRlaC(O)NRlb- or -NRlaC(NRld)NRlb--; and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8; where each Rla, Rlb, and Rld is as defined herein.
[00220] In certain embodiments, each RL is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, ethynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, bicyclo[2.2.2]octanediyl, phendiyl, pyrazoldiyl, imidazoldiyl, tetrazoldiyl, pyrimidindiyl,
5.6.7.8.9.10-hexahydrocycloocta[</]-pyridazindiyl, 1,3-dioxandiyl, piperazindiyl, piperidindiyl, or 3,9-diazaspiro[5.5]undecanediyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each ZL is independently a bond, -C(O)-, -C(O)O-, -C(O)NH-, -OC(O)NH-, -O-, -NH-, -N(CHs)-, or -NHC(O)NH-; and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
[00221 ] In certain embodiments, each RL is independently methanediyl, ethane- 1,2-diyl, propane-1, 3-diyl, butane- 1,4-diyl, pentane- 1,5-diyl, hexane- 1,6-diyl, heptane-l,7-diyl, octane- 1 ,8-diyl, nonane- 1,9-diyl, decane- 1 ,10-diyl, ethyne- 1,2-diyl, cyclobutane- 1, 3-diyl, cyclopentane- 1, 3-diyl, cyclohexane- 1, 3-diyl, cyclohexane-l,4-diyl, cycloheptane- 1,3 -diyl, cycloheptane- 1,4- diyl, bicyclo[2.2.2]octane- 1,4-diyl, phen-1, 3-diyl, phen- 1,4-diyl, pyrazol- 1,3 -diyl, pyrazol-1,4- diyl, imidazol- 1,4-diyl, l,2,3-triazol-l,4-diyl, pyrimidin-2,4-diyl, pyrimidin-2,5-diyl,
5.6.7.8.9.10-hexahydrocycloocta[J]-pyridazin-l ,7-diyl, pyrazolidin- 1,3 -diyl, pyrazolidin- 1,4- diyl, l,3-dioxan-2,5-diyl, piperazin-1, 4-diyl, piperidin-1, 3-diyl, piperidin-l,4-diyl, or 3,9- diazaspiro[5.5]-undecane-3,9-diyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each ZL is independently a bond, --C(O)- -C(O)O-, -C(O)NH- -OC(O)NH-, -O-, -NH-, -N(CH3)-, or -NHC(O)NH-; and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. [00222] In certain embodiments, each RL is independently methanediyl, ethane- 1,2-diyl, propane-1, 3-diyl, cyclohex- 1,3 -diyl, cyclohex- 1,4-diyl, phen- 1,3 -di yl, phen- 1,4-diyl, azetidin- 1 , 3-diyl, piperazin-1, 4-diyl, piperidin-1, 3-diyl, piperi din- 1,4-diyl, morpholin-2, 4-diyl, 4,7- diazaspiro[2.5]octan-4,7-diyl, 3-azabicyclo[3.2.1]octan-3,8-diyl, 8-azabicyclo[3.2.1]octan-3,8- diyl, 3,8-diazabicyclo[3.2.1]octan-3,8-diyl, or 2,7-diazaspiro[3.5]nonan-2,7-diyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently fluoro or methyl; each ZL is independently a bond or -O-; and z is an integer of 2, 3, 4, or 5.
[00223] In certain embodiments, each RL is independently methanediyl, ethane- 1,2-diyl, l,l-difluoroethane-l,2-diyl, propane-1, 3-diyl, cyclohex-1, 3-diyl, cyclohex- 1 ,4-diyl, phen-1,3- diyl, phen- 1,4-diyl, azetidin-1, 3-diyl, 3-fluoroazetidin-l, 3-diyl, piperazin- 1,4-diyl, 2- methylpiperazin- 1 , 4-diyl, piperidin-1 ,3 -diyl, piperi din- 1 , 4-diyl, 4-fluoropiperi din- 1 , 4-diyl, morpholin-2, 4-diyl, 4,7-diazaspiro[2.5]octan-4,7-diyl, 3-azabicyclo[3.2. l]octan-3,8-diyl, 8- azabicyclo[3.2.1 ]octan-3,8-diyl, 3,8-diazabicyclo[3.2.1]octan-3,8-diyl, or 2,7- diazaspiro[3.5]nonan-2,7-diyl; each ZL is independently a bond or -O-; and z is an integer of 2, 3, 4, or 5.
[00224] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000096_0001
wherein each AL is independently a bond, -O-, -NH-, or -N(CH3)-.
[00225] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000096_0002
Figure imgf000097_0001
wherein each AL is independently a bond, -0-, -NH-,
Figure imgf000097_0002
[00226] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000097_0003
wherein each AL is independently a bond, -0---,
Figure imgf000097_0004
or -N(CH3 )---.
[00227] In certain embodiments, in any one of the formulae provi ded herein, L is:
Figure imgf000097_0005
wherein each AL is independently a bond, -0-, -NH-, or -N(CH3)-; and wherein each amino
(NH) group is optionally substituted with methyl.
[00228] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000097_0006
Figure imgf000098_0001
wherein each AL is independently a bond, -O-, -NH-,
Figure imgf000098_0002
wherein each amino
(NH) group is optionally substituted with methyl.
[00229] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000098_0003
wherein each AL is independently a bond, -O-, -NH-, or -N(CH3)-; and wherein each amino group (NH) is optionally substituted with methyl.
[00230] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000098_0004
Figure imgf000099_0001
Figure imgf000100_0001
wherein each AL is independently a bond, -0- -NH-, or -N(CHs)-; and wherein each amino
(NH) group is optionally substituted with methyl.
[00231 ] In certain embodiments, in any one of the formulae provi ded herein, L is:
Figure imgf000100_0002
Figure imgf000101_0001
wherein each AL is independently a bond, -O-, -NH-, or -N(CH3)-.
[00232] In certain embodiments, L is:
Figure imgf000101_0002
Figure imgf000102_0001
wherein each AL is independently a bend, -O-, -NH-, or ~N(CH3)--; and wherein each amino group (NH) is optionally substituted with methyl.
[00233] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000102_0002
wherein each AL is independently a bond, -O-, -NH-,
Figure imgf000102_0003
wherein each amino group (NH) is optionally substituted with methyl.
[00234] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000103_0001
wherein each AL is independently a bond, -0-, -NH-, or -N(CH3)-.
[00235] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000103_0002
Figure imgf000104_0001
wherein each AL is independently a bend, -O-, -NH- or -N^CTH)-; and wherein each amino group (NH) is optionally substituted with methyl.
[00236] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000104_0002
Figure imgf000105_0001
wherein each AL is independently a bond, -O-, -NH-, or -N(CH3)~-; and wherein each amino group is optionally substituted with methyl.
[00237] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000105_0002
Figure imgf000106_0001
[00238] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000106_0002
[00239] In certain embodiments, in any one of the formulae provi ded herein, L is:
Figure imgf000106_0003
Figure imgf000107_0001
[00240] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000107_0002
[00241] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000107_0003
Figure imgf000108_0001
[00242] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000108_0002
[00243] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000109_0001
[00244] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000109_0002
Figure imgf000110_0001
Figure imgf000111_0001
[00245] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000111_0002
Figure imgf000112_0001
[00246] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000112_0002
[00247] In certain embodiments, in any one of the formulae provided herein, L is:
Figure imgf000112_0003
- I l l -
Figure imgf000113_0001
[00248] In certain embodiments, in any one of the formulae provided herein, X is a bond.
In certain embodiments, in any one of the formulae provided herein, X is -C(O)-.
[00249] In certain embodiments, in any one of the formulae provi ded herein, XE is C(RE1), wherein R&1 is as defined herein. In certain embodiments, in any one of the formulae provided herein, XE is C(H). In certain embodiments, in any one of the formulae provided herein, XE is N.
[00250] In certain embodiments, in any one of the formulae provided herein, Y is
C(R5)=, wherein R3 is as defined herein. In certain embodiments, in any one of the formulae provided herein, Y is -C(H)=, In certain embodiments, in any one of the formulae provided herein, Y is -N=.
[00251] In certain embodiments, in any one of the formulae provided herein, YE is a bond. In certain embodiments, in any one of the formulae provi ded herein, YE is -N(RE3)-, wherein REI is as defined herein.
[00252] In certain embodiments, in any one of the formulae provided herein, Z is -CHi-. In certain embodiments, in any one of the formulae provided herein, Z is ~C(O)~.
[00253] In certain embodiments, in any one of the formulae provided herein, a is an integer of 0 or 1. In certain embodiments, in any one of the formulae provided herein, a is an integer of 0. In certain embodiments, in any one of the formulae provided herein, a is an integer of 1.
[00254] In certain embodiments, in any one of the formulae provided herein, m is an integer of 0, 1, or 2. In certain embodiments, in any one of the formulae provided herein, m is an integer of 0. In certain embodim ents, in any one of the formulae provided herein, m is an integer of 1. In certain embodiments, in any one of the formulae provided herein, m is an integer of 2.
[00255] In certain embodiments, in any one of the formulae provided herein, n is an integer of 0, 1, or 2. In certain embodiments, in any one of the formulae provided herein, n is an integer of 0. In certain embodiments, in any one of the formulae provided herein, n is an integer of 1. In certain embodiments, in any one of the formulae provided herein, n is an integer of 2.
[00256] All combinations of the embodiments provided herein for the groups in the formulae described herein are within the scope of this disclosure.
[00257] In one embodiment, provided herein is a compound of: 7-cyclopentyl-2-((4-((2-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-Az,A’-dimethyl-7//-pyrrolo[2,3-t7]pyiimidine-6- carboxamide A101;
7-cyclopentyl-2-((4-((4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-/V,iV-dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine-6- carboxamide Al 02;
7-cyclopentyl-2-((4-((6-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-Ar,Ar-dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A103;
7-cyclopentyl-2-((4-(4-(2-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin- 1 -yl)ethyl)piperazin- 1 -yl)phenyl)amino)-ApV-dimethyl-7//-pyrrolo[2,3 -t/]pyrimidine- 6-carboxamide A104;
7-cyclopentyl-2-((4-(4-(4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin- 1 -yl)butyl)piperazin- 1 -yl)phenyl)amino)-A^V-dimethyl-7//-pyrrolo[2,3 -t/]pyrimidine- 6-carboxamide A105;
7-cyclopentyi-2-((4-(4-(2-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperidin-4-yl)ethyl)piperazin-l-yl)phenyl)amino)-A7,A'r-dimethyl-7/7-pyrrolo[2,3<(|pyrimidine- 6-carboxamide A106;
7-cyclopentyl-2-((4-(4-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperidin-4-yl)butyl)piperazin-l-yl)phenyl)amino)-A,A-dimethyl-77/-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A107,
7-cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamido)- ethyl)piperazin-l-yl)phenyl)amino)-Ar,A’-dimethyl-7//-pyrrolo[2,3-^pyrimidine-6-carboxamide A108;
7-cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-4-methylphenoxy)- acetamido)ethyl)piperazin-l-yl)phenyl)amino)-A;,A'r-dimethyl-7//-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A109;
7-cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-4-(trifluoromethyl)- phenoxy)acetamido)ethyl)piperazin-l-yl)phenyl)amino)-AAV-dimethyl-7/f-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A110;
7-cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamido)- propyi)piperazin-l-yl)phenyl)amino)-7V,Az-dimethyl-7J/-pyrrolo[2,3-^pyrimidine-6-carboxamide Alli;
7-cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)-4-methylphenoxy)- acetamido)propyl)piperazin-l-yl)phenyl)amino)-A'r,A-dimethyl-7H-pyrrolo[2,3-(7]pyrimidine-6- carboxamide Al 12; 7-cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)-4-(trifluoromethyl)- phenoxy)acetamido)propyl)piperazin-l-yl)phenyl)amino)-A,A-dimethyl-7Ar-pyrrolo[2,3-dr]- pyrimidine-6-carboxamide A113;
7-cyclopentyl-2-((4-((2-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)ethyI)carbamoyl)phenyl)amino)-A'',Ar-dimethyl-7fir-pyrrolo[2,3-J]pyrimidine-6- carboxamide Al 14;
7-cyclopentyl-2-((4-((4-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-A7,A'r-dimethyl-777-pyrrolo[2,3-tf|pyrimidine-6- carboxamide Al 15; or
7-cyclopentyl-2-((4-((6-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-Ar,A-dimethyl-7/Apyrrolo[2,3-rf|pyrimidine-6- carboxamide Al 16; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00258] In another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- phenyl)amino)-A//-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A117, 7-cyclopentyl-2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- phenyl)amino)-A",A-dimethyl-7/f-pyrrolo[2,3-J]pyrimidine-6-carboxaniide A118;
7-cyclopentyl-2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- phenyl)amino)-7V,A'-dimethyl-7/f-pyrrolo[2,3-t/]pyriniidine-6-carboxamide A119;
7-cyclopentyl-2-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- phenyl)amino)-A",A’-dimethyl-7/7-pyrrolo[2,3-J]pyrimidine-6-carboxamide A120;
7-cyclopentyl-2-((4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)ethyl)piperazin-l- yl)phenyl)amino)-A,A7-dimethyl-7Z/-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A121;
7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)phenyl)amino)-A\A’-dimethyl-7/f-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A122;
7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)phenyl)amino)-Az,A;-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A123;
7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethoxy)phenyl)amino)-Az,A-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A124; 7-cy cl opentyl-2-((4-(2-(4-(3 -(2, 6-di oxopiperi din-3 -yl )phenyl)pi perazin- 1 -yl)- ethoxy)plienyl)amino)-A,r,A-dimethyl-7/f-pyrrolo[2,3-</]pyriniidiiie-6-carboxamide A125;
7-cyclopentyl-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A,Ar-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A126;
7-cyclopentyl-2-((4-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A",A'r-dimethyl-7/7-pyrrolo[2,3-^]pyrimidine-6-carboxaniide A127;
7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yI)- ethyl)phenyl)amino)-Ar,Ar-dimethyl-7J7-pyrrolo[2,3-«/]pyrimidine-6-carboxamide A128;
7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- ethyl)phenyl)amino)-A,Ar-dimethyl-7H-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A129;
7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- ethoxy)phenyl)amino)-Az,A-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A130;
7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- ethoxy)phenyl)amino)-Ay/V-dimethyl-7H-pyrrolo[2,3-^pyrimidine-6-carboxamide A131;
7-cyclopentyl-2-((4-((4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)methyl)phenyl)amino)-A^V-dimethyl-7Z7-pyrrolo[2,3-i/]pyrimidine-6- carboxamide A132;
7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l -yl)ethoxy)phenyl)amino)-AVV-dimethyl-7/f-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A133;
7-cyclopentyl-2-((4-(2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)phenyl)amino)-A,A7-dimethyl-7/7-pyrrolo[2,3-^pyrimidine-6-carboxamide A134;
7-cyclopentyl-2-((4-(2-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)piperazin-l-yl)ethyl)phenyl)amino)-A'’,Ar-dimethyl-7/7-pyrrolo[2,3-d]pyriniidine-6- carboxamide A135;
7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l -yl)ethyl)phenyl)amino)-A7,A'r-dimethyl-7H-pyrrolo[2,3-</|pyrirnidine-6-carboxamide A136;
7-cyclopentyl-2-((4-(2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethyl)phenyl)amino)-Ar,Ar-dimethyl-77/-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A137;
7-cyclopentyi-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperidin-4- yl)piperazin-l-yl)phenyl)amino)-A,A’-dimethyl-7//-pyrrolo[2,3-</jpyrimidine-6-carboxamide A138;
7-cyclopentyl-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin- 1 -yl)phenyl)amino)-A^V-dimethyl-77/-pyrrolo[2,3 -d]pyrimidine-6-carboxamide A139;
7-cyclopentyl-2-((4-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A,A'r-dimethyl-7J7-pyrrolo[2,3-</|pyrimidine-6-carboxamide Al 40;
7-cyclopentyl-2-((4-(4-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperazin-l-yl)phenyl)amino)-Az,7V-dimethyl-7//-pyrrolo[2,3-<T]pyrimidine-6- carboxamide A141;
7-cyclopentyl-2-((4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperazin-l-yl)phenyl)amino)-Ap\Mimethyl-7Z/-pyrrolo[2,3-<7]pyrimidine-6- carb oxami de Al 42;
7-cyclopentyl-2-((4-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)phenyl)amino)-Ar,Ar"dimetliyl-7/Apyrrolo[2,3-<7]pyrimidine-6-carboxamide A143;
7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)phenyl)amino)-Ar JA7-dimethyl-7/7-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A144;
7-cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- phenyl)piperazin-l-yl)pyridin-2-yl)amino)-AAV-dimethyl-7J7-pyrrolo[2,3-^pyrimidine-6- carboxamide Al 45;
7-cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7J/-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A146;
7-cyclopentyl-2-((5-(4-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A’-dimethyl-777-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A147;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- phenyl)piperazin-l-yl)pyridin-2-yl)amino)-ApV-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide Al 48;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-777-pyrrolo[2,3-i7]pyrimidine-6- carboxamide A149;
7-cyclopentyl-2-((5-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,AMimethyl-7JH-pyrrolo[2,3-J]pyrimidine-6- carboxamide A150;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l -yl)- benzyl)piperazin-l-yl)pyridin-2-yl)amino)-ApV-dimethyi-7//-pyrrolo[2,3-fl?]pyrimidine-6- carb oxami de A 151 ;
7-cyclopentyi-2-((5-(4-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A’,A'-dimethyl-7Ar-pyiTolo[2,3-<7]pyrimidine- 6-carboxamide A152;
7-cyclopentyl-2-((5-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- benzyl)piperazin-l-yl)pyridin-2-yl)amino)-Ap\Mimethyl-7//-pyrrolo[2,3-d]pyrimidine-6- carboxamide A153; or
7-cyclopentyl-2-((5-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7J/-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A154; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00259] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)cyclohexyl)- piperazin-l-yl)pyridin-2-yl)amino)-A/,A''-dimethyl-7Ar-pyrrolo[2,3-47]pyrimidine-6-carboxamide A155;
7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A\A-dimethyl-7/f-pyrrolo[2,3-tf|pyrimidine-6-carboxamide A156;
7-cyclopentyl-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)ethyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-AT,ALdimethyl-7//-pyrrolo[2,3-</]pyrimidine-6- carboxamide A157; 7"Cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A^V-dimethyl-7/7-pyrrolo[2,3-t/]- pyrimidine-6-carboxamide A158;
7-cyclopentyl-2-((5-(4-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-7//r-pyrrolo[2,3-tZ]-pyrimidine-6- carboxamide A159:
7-cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)ethyl)- piperidin-4-yl)piperazin-l -yl)pyridin-2-yl)amino)-A,A'r-dimethyl-7/7-pyrrolo[2,3-</|pyrimidine-6- carboxamide A160;
7-cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)propyl)piperazin-l-yl)pyridin-2-yl)amino)-A’,Ar-dimetliyl-7/7-pyrrolo[2,3-d]pyrimidine-6- carboxamide A161;
7-cyclopentyl-2-((5-(4-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-
3-yl)piperazin-l-yl)pyridin-2-yl)amino)-/V’,A7-dimethyl-7JH-pyiTolo[2,3-J]pyrimidine-6- carboxamide A162:
7-cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A-dimethyl-777-pyrrolo[2,3-fi(]- pyrimidine-6-carboxamide A163;
7-cyclopentyl-2-((5-(4-(l-(((25)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- morpholin-2-yl)methyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A7Ar-dimethyl-7/7- pyrrolo[2,3-i/]pyrimidine-6-carboxamide A164;
7-cyclopentyl-2-((5-(4-(l-(((2A)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- morpholin-2-yl)methyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7VjV-dimethyl-7//- pyrrolo[2,3-i(lpyrimidine-6-carboxamide A165;
7-cyclopentyi-2-((5-(4-(3-(l-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperidin-4-yl)- cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A7-dimethyl-7Z/-pyrrolo[2,3-(7]pyrimidine-6- carboxamide A166;
7-cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- methyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A7A7-dimethyl-7//-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A167;
7-cyclopentyl-2-((5-(4-(((2S)-4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin- 4-yl)morpholin-2-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A7^-dimethyl-7H-pyrrolo[2,3- tZ]pyrimidine-6-carboxamide A168;
7-cyclopentyl-2-((5-(4-(((2/?)-4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-
4-yl)morpholin-2-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,Ar-dimethyl-7/f-pyrrolo[2,3- <7jpyrimidine-6-carboxamide A169;
7-cyclopentyl-2-((5-(4-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- cyclohexyl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A';/V-dimethyl-7H-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A170;
7-cyclopentyl-2-((5-(4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)cyclohexyl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A',,A?-dimethyl-77f-pyrrolo[2,3-c7]- pyrimidine-6-carboxamide A171;
7-cyclopentyl-2-((5-(4-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A’,A-dimethyl-7/f-pyrrolo[2,3-^- pyrimidine-6-carboxamide A 172;
7-cyclopentyl-2-((5-(4-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)ethyl)cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7J7-pyrrolo[2,3-</|- pyrimidine-6-carboxamide A173;
7-cyclopentyl-2-((5-(4-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)ethyl)piperidin-4-yl)piperazin-l -yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7/7-pyrrolo[2,3-6Q- pyrimidine-6-carboxamide A174;
7-cyclopentyl-2-((5-(4-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'- bipiperidin]-l-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-7Af-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A175;
7-cyclopentyl-2-((5-(4-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'- bipiperidin]-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A//-dimethyl-7/7-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A176;
7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-N,N-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A177;
7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyi-7//-pyrrolo[2,3-c/]pyrimidine-6- carboxamide Al 78;
7-cyclopentyl-2-((5-(4-(l-(3-(4-(2,6-dioxopiperidin-3-yl)phenoxy)propyl)- piperidin-4-yl)piperazin-l -yl)pyridin-2-yl)amino)-A,ALdimethyl-7/7-pyrrolo[2,3-</jpyrimidine-6- carboxamide A179;
7-cyclopentyl-2-((5-(4-(3-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- propyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A-dimetliyl-77/-pyrrolo[2,3-67]pyrimidine-6- carboxamide A180;
7-cyclopentyl-2-((5-(4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4- yl)cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-yV,A-dimethyl-72/-pyrrolo[2,3-6Z]pyrimidine-6- carb oxami de A 181 ;
7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[l,4'-bipiperidin]- r-yl)pyridin-2-yl)amino)-Ar,Ar-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A182;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-4- yl)methyl)pyridin-2-yl)amino)-A7,A7-dimethyl-7Ar-pyiTolo[2,3-t7]pyrimidine-6-carboxamide A183;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]-l- yl)methyl)pyridin-2-yl)amino)-A/,A’-dimethyl-7/7-pyrrolo[2,3-^pyrimidine-6-carboxamide A184;
7-cyclopentyl-2-((5-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)methyl)pyridin-2-yl)amino)-A7,ALdimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A185;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-4- yl)oxy)pyridin-2-yl)amino)-A',A7-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6-carboxamide A186;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-4- yl)methoxy)pyridin-2-yl)amino)-Az,A-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A187;
7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4f-bipiperidin]- l-yl)ethyl)pyridin-2-yl)amino)-A7,A-dimethyl-7//-pyrrolo[2,3-</|pyrimidine-6-carboxamide A188;
7-cyclopentyl-2-((5-(2-(l'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 4-yl)ethyl)pyridin-2-yl)amino)-A7,Air"dimethyl-7/f-pyrrolo[2,3-c7|pyrimidine-6-carboxamide A189;
7-cyclopentyl-2-((5-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethyl)pyridin-2-yl)amino)-A;A-dimethyl-7/f-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A190;
7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)ethoxy )pyri din-2 -yl)amino)-A'’,jV-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A191;
7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 4-yl)ethoxy)pyri din-2 -yi)amino)-A,A-dimethyi-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A192;
7-cyclopentyl-2-((5-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)pyridin-2-yl)amino)-Az,A-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A193;
7-cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)azetidin-3-yl)piperazin-l-yi)pyridin-2-yl)amino)-A7,iV-dimethyl-7/f-pyrrolo[2,3-^- pyrimidine-6-carboxamide A194;
7-cyclopentyl-2-((5-(4-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-
4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7V,Az-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide Al 95;
7-cyclopentyi-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- [l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-A’,A;-dimethyl-7Ar-pyrrolo[2,3-Jjpyrimidine-6- carboxamide A196;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- cyclohexyl)piperazin-l-yi)pyridin-2-yl)amino)-AyA'-dimethyl-77f-pyrrolo[2,3-</|pyrimidine-6- carboxamide A197;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- cyclohexyl)piperidin-l-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7ZApyrrolo[2,3-^]pyrimidine-6- carboxamide Al 98;
7-cy clopentyl-2-((5 -(4-( 1 -(3 -(3 -(2, 6-dioxopiperi din-3 -yl)phenoxy)propyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- arboxamide A199; 7-cyclopentyl-2-((5-((4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-1 -yl)methyl)pyridin-2-yl)amino)-A/,A-dimethyl-7ZApyrrolo[2, 3 -t/Jpyrim idine-6- carboxamide A200;
7-cyclopentyl-2-((5-(2-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin- 1 -y l)ethyl)pyridin-2-yl)amino)-7V,jV-dimethyl -7/7-pyrrol o[2,3 -cfjpy rimi dine-6- carboxamide A201:
7-cyclopentyl-2-((5-(3-(l'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)propyl)pyridin-2-yl)amino)-A,A-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A202;
7-cyclopentyl-2-((5-(3-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)propyl)pyridin-2-yl)amino)-jV,A/-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A203;
7-cyclopentyl-2-((5-(3-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)propyl)pyridin-2-yl)amino)-Ay/V-dimethyl-7H-pyrrolo[2,3-^pyrimidine-6- carboxamide A204:
7-cyclopentyl-2-((5-(3-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-
4-yl)propyl)pyridin-2-yl)amino)-A,A-dimethyl-7/7-pyrrolo[2,3-t/|pyrimidine-6-carboxamide A205;
7-cy cl opentyl-2-(( 5 -(2-(4-(4-(3 -(2, 6-dioxopiperidin-3 -yl)pheny l)piperazin- 1 -y I)- piperidin-l-yl)ethyl)pyridin-2-yl)amino)-yV,2V-dimethyl-7J/-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A206;
7-cyclopentyl-2-((5-((25)-2-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)methyl)morpholino)pyridin-2-yl)amino)-Ar,A'-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A207:
7-cyclopentyl-2-((5-((2A)-2-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)methyl)morpholino)pyridin-2-yl)amino)-A7,A’-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A208;
7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- piperidin-l-yl)pyridin-2-yl)amino)-jV,Ar-dimethyl-77/-pyrrolo[2,3-J]pyrimidine-6-carboxamide A209;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-3 yl)oxy)pyridin-2-yl)amino)-Ar,7'Z-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A210;
7-cyclopentyl-2-((5-((3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)methyl)pyridin-2-yl)amino)-A/,7V-dimethyl-7/7-pyrrolo[2,3-</]pyrimidine-6- carboxamide A211;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[3,4'-bipiperidin]-l- yl)methyl)pyridin-2-yl)amino)-77,jV-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A212;
7-cyclopentyl-2-((5-(2-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)pyridin-2-yl)amino)-yV,7V-dimethyl-72/-pyrrolo[2,3-6Z]pyrimidine-6- carboxamide A213;
7-cyclopentyl-2-((5-(4-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)methyl)piperidin-l-yl)pyridin-2-yl)amino)-A,JV-dimethyl-77/-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A214;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- benzyl)piperazin-l-yl)pyridin-2-yl)amino)-A?,Ar-dimethyl-7/f-pyrrolo[2,3"^pyrimidine-6- carboxamide A215;
7-cyclopentyl-2-((5-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7J/-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A216;
7-cyclopentyi-2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A,,A;-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A217;
7-cyclopentyl-2-((5-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperidin-4-yl)pyridin-2-yl)amino)-A?,A'r-dimethyl-7/f-pyrrolo[2,3-i/]pyrimidine-6- carboxamide A218;
7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)--A’,AT"dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A219;
7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-Az rA'-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A220; 7-cy cl opentyl-2-((5 -(4-(( 1 -(3 -(2, 6-di oxopiperi din-3 -yl )phenyl)piperi din-4-y 1 )- methyl)piperazin-l-yl)pyridin-2-y!)amino)-A/,A-dimethyl-7Z7-pyrrolo[2,3-</]pyriniidiiie-6- carboxamide A221;
7-cyclopentyl-2-((5-(l-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperidin-4-yl)pyri din-2 -yl)amino)-A',A'r-dimethyl-777-pyrrolo[2,3-J_|pyrimidine-6- carboxamide A222:
7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)piperidin-l -yl)pyridin-2-yl)amino)-ATA-dimethyl-777-pyrrolo[2,3-</]pyrimidine-6- carboxamide A223;
7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-A7,Ar-dimethyl-7//-pyrrolo[2,3-^pyrimidine-6- carboxamide A224;
7-cyclopentyl-2-((5-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-r- yl)methy])pyridin-2-yl)amino)-A7,A7-dimethyl-7/7-pyiTolo[2,3-t/]pyrimidine-6-carboxarnide A225;
7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A?-dimethyl-7J/-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A226;
7-cy cl opentyl-2-(( 5 -( 1 -(2-(4-(4-(2, 6-di oxopiperi din-3 -yl)phenyl)piperi di n- 1 -yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-AT,7V-dimethyl-72/-pyrrolo[2,3-J]pyrimidine-6- carboxamide A227;
7-cyclopentyl-2-((5-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A7,A-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A228;
7-cyclopentyl-2-((5-(l-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperidin-4-yl)pyri din-2 -yl)amino)-AT, A-dimethy I -7/Z-pyrrol o[2,3 -t^pyrimi dine-6- carboxamide A229;
7-cyclopentyl-2-((5-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,ALdimethyl-7J7-pyrrolo[2,3-</|pyrimidine-6- carboxamide A230;
7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7/7-pyrrolo[2,3-(7]pyrimidine-6- carboxamide A231;
7-cyclopentyl-2-((5-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l -yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,Ar-dimethyl-7/7-pyrrolo[2,3-£/]pyrimidine-6- carboxamide A232;
7-cyclopentyl-2-((5-(l-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A';A-dimethyl-77/-pyrrolo[2,3-6/]pyrimidine-6- carboxamide A233;
7-cyclopentyl-2-((5-(l-(2-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A234;
7-cy clopenty 1 -2-((5 -( 1 -(2-(4-(3 -(2, 6-dioxopiperidin-3 -yl)pheny l)piperazi n- 1 -y 1)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A7,A-dimethyl-777-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A235;
7-cyclopentyl-2-((5-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- r-yl)ethyl)pyridin-2-yl)amino)-A7,Ar-dimetliyl-7/7-pyrrolo[2,3-</]pyriniidine-6-carboxamide A236;
7-cyclopentyl-2-((5-(r-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[4,4'-bipiperidin]- l-yl)pyridin-2-yl)amino)-Ar,A'r-dimethyl-7/f-pyrrolo[2,3-fi(|pyrimidine-6-carboxamide A237;
7-cyclopentyi-2-((5-(r-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[l,4'-bipiperidin]- 4-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A238;
7-cyclopentyl-2-((5-(2-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin- 1 -y l)ethyl)pyridin-2-yl)amino)-A,Ar-dimethyl -7/7-pyrrol o [2, 3 -<7]pyrimi dine-6- carboxamide A239:
7-cyclopentyi-2-((5-(2-(r-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-
4-yl)ethyl)pyridin-2-yl)amino)-A’,Ar-dimethyl-7H-pyrrolo[2,3-t(]pyrimidine-6-carboxamide A240;
7-cyclopentyl-2-((5-(2-(r-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)ethyl)pyridin-2-yl)amino)-A^V-dimethyl-77/-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A241;
7-cyclopentyl-2-((5-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin] r-yl)ethyl)pyridin-2-yl)amino)-A'r,A'r-dimethyl-7//-pyrroio[2,3-«i]pyrimidine-6-carboxamide A242;
7-cyclopentyl-2-((5-(2-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)ethoxy)pyridin-2-yl)amino)-AT2V-dimethyl-7/f-pyrrolo[2,3-<7|pyrimidine-6- carboxamide A243;
7-cy clopentyl-2-((5 -(2-(4-( 1 -(3 -(2, 6-dioxopiperi din-3 -yl)pheny l)pi p eri di n-4 -y 1 )- piperazin- 1 -yl)ethoxy)pyridin-2-yl)amino)-Ar,Ar-dimethyl -7/7-pyrrol o [2, 3 -<7]py rimi dine-6- carboxamide A244;
7-cyclopentyl-7V,ALdimethyl-2-((5-(4-(l-(4-(3-methyl-2,6-dioxopiperidin-3-yl)- phenethyl)piperidin-4-yl)piperazin-l-yl)pyri din-2 -yl)amino)-7/7-pyrrolo[2,3-</jpyrimidine-6- carboxamide A245;
7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperidin-l-yl)pyridin-2-yl)amino)-A7,A-dimethyl-7Af-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A246;
7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperidin-l-yl)pyridin-2-yl)amino)-ApV-dimethyl-7#-pyrrolo[2,3-<7]pyriniidine-6- carboxamide A247;
7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-72/-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A248;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- propoxy)pyridin-2-yl)amino)-Ar,A-dimethyl-7Af-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A249;
7-cyclopentyl-2-((5-(3-(l-(4-(2, 6-dioxopiperi din-3-yl)phenyl)piperidin-4-yl)- propoxy)pyridin-2-yl)amino)-AA,Ar-dimethyl-7JH-pyrrolo[2,3-«7]pyrimidine-6-carboxamide A250;
7-cyclopentyi-2-((5-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethoxy)pyridin-2-yl)amino)-A’',Ar-dimethyi-7J7-pyrrolo[2,3-c/]pyrimidine-6-carboxamide A251;
7-cycl opentyl-2-((5-(2-(l-(4-(2, 6-dioxopiperi din-3 -yl)phenyl)piperi din-4-yl)- ethoxy)pyridin-2-yl)amino)-Ar,A-dimethyl-7//-pyrrolo[2,3-i/]pyrimidine-6-carboxamide A252;
7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-A'//-dimethyl-7/7-pyrrolo[2,3-J]pyrimidine-6- carboxamide A253; 7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A^V-dimethyl-72/-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A254;
7-cyclopentyl-2-((5-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A/,A''-dimethyl-7J?/-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A255;
7-cyclopentyl-2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- methyl)piperazin-l-yi)pyridin-2-yl)amino)-7V,A7-dimethyl-7H-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A256;
7-cyclopentyl-2-((5-(4-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7Z7-pyrrolo[2,3-(7]pyrimidine-6- carboxamide A257;
7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- ethy l)piperazin- 1 -yl)pyridin-2-yl)amino)-;V,Az-dimethyl -777-pyrrol o[2,3 -djpyrimi dine-6- carboxamide A258:
7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A?-dimethyl-7J7-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A259;
7-cyclopentyl-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A/,Ar"dimethyl-7Z/-pyrrolo[2,3-t/j- pyrimidine-6-carboxamide A260;
7-cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-Af,A’-dimethyl-7//-pyrrolo[2,3-t(|- pyrimidine-6-carboxamide A261;
7-cyclopentyi-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-A'’,A7-dimethyl-7JH-pyrroio[2,3-<7]- pyrimidine-6-carboxamide A262;
7-cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar2V-dimethyl-7/f-pyrrolo[2,3-(7]- pyrimidine-6-carboxamide A263;
7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)benzyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A264;
7-cyclopentyl-2-((5-(4-(l-(3-(2,6-dioxopiperidin-3-yl)benzyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A'r,A-dimethyl-7/Z-pyrrolo[2,3-if|pyrimidine-6-carboxamide A265;
7-cyclopentyl-2-((5-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-A/,jV-dimethyl-777-pyrrolo[2,3-</]pyrimidine-6- carboxamide A266;
7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-A/,Ar-dimethyl-7//-pyrrolo[2,3-^pyrimidine-6- carboxamide A267;
7-cyclopentyl-2-((5-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-A,jV-dimethyl-7//-pyrrolo[2,3-«7]pyrimidine-6- carboxamide A268;
7-cyclopentyl-2-((5-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-3-fluoro- azetidin-l-yl)piperidin-l-yl)pyridin-2-yl)amino)-A',Ar"dimetliyl-7/7-pyrrolo[2,3-</]pyriniidine-6- carboxamide A269;
7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-3-fluoro- azetidin-l-yl)piperidin-l-yl)pyridin-2-yl)amino)-A,A'’-dimethyl-7/f-pyrrolo[2,3-^pyrimidine-6- carboxamide A270;
7-cyclopentyl-2-((5-(3-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro— ethyl)piperidin-4-yl)azetidin-l-yl)pyridin-2-yl)amino)-A7,Af-dimethyl-7//-pyrrolo[2,3-tZ]- pyrimidine-6-carboxamide A271 ;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A’,A-dimethyl-7/7-pyrrolo[2,3-</jpyrimidine-6-carboxamide A272;
7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-AT,A-dimethyl-7/f-pyrrolo[2,3-tf|pyrimidine-6-carboxamide A273;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A7,A’-dimethyl-77Z-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A274;
7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- azeti din-1 -yl)pyridin-2-yl)amino)-A',A?-dimethyl-7H-pyrrolo[2,3-c/]pyrimidine-6-carboxamide
A275;
7-cyclopentyl-2-((5-(4-(3-(4-(2,6-dioxopiperidin-3-yl)benzyl)-3-fluoroazetidin-l- yl)piperidin-l-yl)pyridin-2-yl)amino)-Ar,AMimethyl-7AApyrrolo[2,3-J]pyrimidine-6- carboxamide A276;
7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)benzyl)-3-fluoroazetidin-l- yl)piperidin-l-yl)pyridin-2-yl)amino)-A7,ALdimethyl-7Z/-pyrrolo[2,3-^pyrimidine-6- carboxamide A277;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A’,A-dimethyl-7JHr-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A278;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro- piperidin- 1 -yl)azetidin- 1 -yl)pyridin-2-yl)amino)-Ar,A-dimethyl-7Af-pyrrolo[2,3 - J]pyrimidine-6- carboxamide A279;
7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-l-yl)- azetidiii-l-yl)pyridin-2-yl)aniino)-Ar,A7-dimethyl-7J/-pyrrolo[2,3-cf|pyrimidine-6-carboxamide A280;
7-cyclopentyi-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro- piperidin-l-yl)azetidin-l-yl)pyridin-2-yl)amino)-A’,7V-dimethyl-7Z/-pyrrolo[2,3-J]pyrimidine-6- carboxamide A281;
7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoropiperidin- l-yl)azetidin-l-yl)pyridin-2-yl)amino)-A,A/-dimethyl-7/f-pyrrolo[2,3-</|pyrimidine-6- carboxamide A282;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoropiperidin- l-yl)azetidin-l-yl)pyridin-2-yl)amino)-A^V-dimethyl-77/-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A283;
7-cyclopentyl-2-((5-(4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-l-yl)- methyl)-4-fliioropiperidin-l-yl)pyridin-2-yl)amino)-A'',7V-dimethyl-7/7-pyrrolo[2,3-tf|pyrimidine- 6-carboxamide A284; 7-cyclopentyl-2-((5-(4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-l -yl)- methyl)-4-fluoropiperidin-l-yl)pyri din-2 -yl)amino)-A’,Ar-dimethyl-7Ar-pyrrolo[2,3-^]pyrimidine- 6-carboxamide A285,
7-cyclopentyl-2-((5-(l-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)-4-fluoropiperidin- 4-yl)methyl)piperidin-4-yl)pyridin-2-yl)amino)-JV^V-dimethyl-7//-pyrrolo[2,3-<^pyrimidine-6- carboxamide A286:
7-cyclopentyl-2-((5-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-fluoropiperidin- 4-yl)methyl)piperidin-4-yl)pyridin-2-yl)amino)-A'r,Ar-dimethyl-7Af-pyrrolo[2,3-^pyrimidine-6- carboxamide A287;
7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)-4-fluoropiperidin-l-yl)pyri din-2 -yl)amino)-A’,Ar-dimethyl-7//-pyrrolo[2,3-d]pyrimidine- 6-carboxamide A288;
7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)-4-fluoropiperi din-1 -yl)pyridin-2-yl)amino)-Ar fAr-dimethyl-71/-pyrrolo[2,3-</]pyrimidine- 6-carboxamide A289;
7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-7V,Ar-dimethyl-7H-pyrrolo[2,3-(fj- pyrimidine-6-carboxamide A290;
7-cy cl opentyl-2-(( 5 -(4-(2-( 1 -(4-(2, 6-dioxopiperidi n-3 -yl)-2-fluoropheny I )- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A/,Ar-dimethyl-7Z/-pyrrolo[2,3-t/j- pyrimidine-6-carboxamide A291;
2-((5-(4-(2-(l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-Ar,A-dimethyl-7JE/-pyrrolo[2,3-6Z]pyrimidine-6- carboxamide A292:
2-((5-(4-(2-(l-(2-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A,A-dimethyl-7H-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A293;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazm-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-AT,A-dimethyl-7JH-pyrrolo[2,3-<7|pyrimidine-6-carboxamide A294;
7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A295;
7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A7,Ar-dimethyl-7/7-pyrrolo[2,3-c/]pyrimidine-6-carboxamide A296;
7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)-5-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A',7V-dimethyl-7/7-pyrrolo[2,3-c7j- pyrimidine-6-carboxamide A297;
7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)-4-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A'-dimethyl-7/7-pyrrolo[2,3-i7]- pyrimidine-6-carboxamide A298;
7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)-4-fluoro-
[ 1 ,4' -bipiperi din] -■ 1 '-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-727-pyrrolo[2,3 - J]pyrimidine-6- carboxamide A299; or
7-cyclopentyl-2-((5-((r-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-4- yl)methoxy)pyridin-2-yl)amino)-A7,A-dimethyl-7/Apyrrolo[2,3-JJpyrimidine-6-carboxamide A300; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00260] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((5-(3-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- l,l-difluoroethyl)azetidin-l-yl)pyridin-2-yl)amino)-A7V-dimethyl-7JH-pyrrolo[2,3-d]pyrimidine- 6-carboxamide A351;
7-cy cl opentyl-2-((5 -(4-(2-( 1 -(5 -(2, 6-dioxopiperidi n-3 -yl)-2-fluoropheny I )- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,Ar-dimethyl-7/f-pyrrolo[2,3-d]- pyrimidine-6-carboxamide A352; or
7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenethyl)-4-fluoro- [l,4'-bipiperidin]-l '-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A353: or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00261 ] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((4-((2-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-Az,A7-dimethyl-7J7-pyrrolo[2,3-6/]- pyrimidine-6-carboxamide A401;
7-cyclopentyl-2-((4-((4-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- phenoxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-AAV-dimethyl-77/-pyrrolo[2,3-
</|pyrimidine-6-carboxamide A402;
7-cyclopentyl-2-((4-((6-(4-(2-(3-(2,4-dioxotetrahydropyrimidin4(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-Az//-dimethyl-7/7-pyrrolo[2,3- <7]pyrimidine-6-carboxamide A403;
7-cyclopentyl-2-((4-((2-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-Az,A7-dimethyl-7Ar-pyrrolo[2,3-£/]- pyrimidine-6-carboxamide A404;
7-cyclopentyl-2-((4-((4-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- phenoxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-A7,Az-dimethyl-7H-pyrrolo[2,3-
</|pyrimidine-6-carboxamide A405; or
7-cyclopentyl-2-((4-((6-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)- phenoxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-Az,Ar-dimethyl-7/Apyrrolo[2,3-
^pyrimidine-6-carboxamide A406; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00262] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((4-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2Z/)-yl)phenyl)- piperazin-l-yl)phenyl)amino)-A’,Ar-dimetliyl-7/Apyrrolo[2,3-</]pyrimidine-6-carboxamide A407;
7-cyclopentyl-2-((5-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)phenyl)- piperazin-l-yl)pyridin-2-yl)amino)-AjV-dimethyl-7//-pyrrolo[2,3-t(|pyrimidine-6-carboxaniide
A408;
7-cyclopentyl-2-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2/7)-yl)benzyl)- piperazin- 1 -yl)phenyl)amino)-A,Ar-dimethyl-777-pyrrolo[2,3 -tZ]pyrimidine-6-carboxamide A409; 7-cyclopentyl-2-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenethyl)- piperazin-l-yl)phenyl)amino)-A?',A/-dimethyl-7/f-pyrrolo[2,3-^pyrimidine-6-carboxaniide A410;
7-cyclopentyl-2-((5-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)phenoxy)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,Ar-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A411;
7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)ethyl)phenyl)amino)-AAV-dimethyl-7/7-pyrrolo[2,3-6f]pyrimidine-6-carboxamide A412;
7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)phenyl)- piperazin-l-yl)ethyl)phenyl)amino)-Ar,A’-dimethyl-7/7-pyrrolo[2,3-tf|pyrimidine-6-carboxamide A413;
7-cyclopentyl-2-((5-((4-(4-(2,4-dioxotetraliydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)methyl)pyridin-2-yl)amino)-Ar,Ar-dimethyl-727-pyrrolo[2,3-(/]pyrimidine-6- carboxamide A414;
7-cyclopentyl-2-((5-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)ethoxy)pyridin-2-yl)amino)-Ar,A7-diniethyl-7/Apyrrolo[2,3-t(|pyrimidine-6- carboxamide A415;
7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2J/)-yl)phenyl)- piperazin-l-yl)ethoxy)phenyl)amino)-7V,Ar-dimethyl-7/f-pyrrolo[2,3-^pyrimidine-6- carboxamide A416;
7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2#)-yl)phenyl)- piperazin-l-yl)ethoxy)phenyl)amino)-A,AMimethyl-7#-pyrrolo[2,3-^pyrimidine-6- carb oxami de A417;
7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)benzyl)- piperaziii-l-yl)ethoxy)phenyl)amino)"A^V-dimethyl-7//-pyrrolo[2,3"^pyrimidine-6- carboxamide A418;
7-cyclopentyl-2-((5-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin- 1 -yl)methyl)pyridin-2-yl)ammo)-Ar, AMimethy I -7/Apyrrol o[2,3 -d]pyrimi dine-6- carboxamide A419;
7-cyclopentyl-2-((4-(4-( 1 -(4-(2,4-dioxotetrahydropyrimidin- 1
Figure imgf000135_0001
1 )pheny 1)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-Ar,A7-dimethyl-7/f-pyrrolo[2,3-^pyrimidine-6- carboxamide A420;
7-cyclopentyl-2-((4-(4-( 1 -(3-(2,4-dioxotetrahydropyrimidin- 1 (2/7)-yl)phenyl)- piperidin-4-yl)piperazin-l -yl)phenyl)amino)-A',A?-dimethyl-7/f-pyrrolo[2,3-c/]pyrimidine-6- carboxamide A421;
7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(27/)-yl)benzyl)- piperazin-l-yl)ethyl)phenyl)amino)-Ar,A7-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A422;
7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)benzyl)- piperazin-l-yl)ethyl)phenyl)amino)-A!',A’-dimethyl-7//-pyrrolo[2,3--t7]pyrimidine-6-carboxamide A423;
7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrirnidin-l(277)-yl)benzyl)- piperazin-l-yl)ethoxy)phenyl)amino)-Ar,A-dimethyl-7Z/-pyrrolo[2,3-^]pyrimidine-6- carboxamide A424;
7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)phenyl)- piperaziii-l-yl)piperidin-l-yl)ethyl)phenyl)amino)-ArJV-dimetliyl-7H-pyrrolo[2J-J]pyrimidine- 6-carboxamide A425,
7-cyclopentyl-2-((4-(2-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)amino)-Ar,Az-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A426;
7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethoxy)phenyl)amino)-2V,A/-diraethyl-7//-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A427;
7-cyclopentyl-2-((4-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(21/)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-A,ALdimethyl-77f-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A428;
7-cyclopentyl-2-((4-(4-(l-(3-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-Ar,A7-dimethyl-7J/-pyrrolo[2,3<(|pyrimidine-6- carboxamide A429;
7-cyclopentyl-2-((5-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)benzyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-72/-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A430; 7-cyclopentyl-2-((4-(4-((l-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)-jV,A7-dimethyl-72/-pyrrolo[2,3-<Z]pyrimidine- 6-carboxamide A431,
7-cyclopentyl-2-((4-(4-((l-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)-A’,A?-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine- 6-carboxamide A432;
7-cyclopentyl-2-((4-(4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2Ar)-yl)phenyl)- piperidin-l-yl)ethyl)piperazin-l-yl)phenyl)amino)-Ar,A7-dimethyl-777-pyrrolo[2,3-tZ]pyrimidine- 6-carboxamide A433; or
7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)phenyl)- piperidin- 1 -yl)ethyl)piperazin- 1 -yl)phenyl)amino)-Ar,Ar-dimethyl-7Z/-pyrrolo[2,3 -<7]pyrimidine- 6-carboxamide A434; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00263] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((5-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(2/7)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A^A7-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A435;
2-((5-(4-(2-(l-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-l(2/f)-yl)phenyl)- piperidin-4-yl)ethyl)piperazin-l -yl)pyridin-2-yl)amino)-7-cyclopentyl-Af,Ar-dimethyl-7H- pyrrolo[2,3-iZ]pyrimidine-6-carboxamide A436;
7-cyclopentyl-2-((5-(4-(( 1 -(4-(2,4-dioxotetrahydropyrimidin- 1 (277r)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A",AMimethyl-77/-pyrrolo[2,3-i/|- pyrimidine-6-carboxamide A 437;
2-((5-(4-((l-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A?,Az-dimethyl-7/f- pyrrolo[2,3-J]pyrimidine-6-carboxamide A438;
7-cyclopentyl-2-((5-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(2J/)-yl)phenyl)- piperidin-4-yl)piperazin-l-yl)pyri din-2 -yl)amino)-A',7V-dimethyl-7H-pyrrolo[2,3-J_|pyrimidine-6- carboxamide A439; or
2-((5-(4-(l-(2-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)-2,2- difluoroethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A’,A7-dimethyl-77f- pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A440; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00264] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((4-((2-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-17/-indazol- 7-yl)oxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A",A'-dimethyl-7/7-pyrrolo[2,3-t7]- pyrimidine-6-carboxamide A501;
7-cyclopentyl-2-((4-((4-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-l//-indazol- 7-yl)oxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phemyl)amino)-A’,AMimethyl-7//-pyrrolo[2,3- <7]pyrimidine-6-carboxamide A502;
7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-lAf-indazol-
7-yl)oxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-A';A’-dimethyl-7.H-pyrrolo[2,3- <7]pyrimidine-6-carboxamide A503;
7-cyclopentyl-2-((4-((2-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-177-indazol- 6-yl)oxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A\AMimethyl-777-pyrrolo[2,3-tZ]- pyrimidine-6-carboxamide A504;
7-cyclopentyl-2-((4-((4-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-l/7-indazol-
6-yl)oxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-A’,Ar-dimethyl-7//-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A505; or
7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-17/-indazol-
6-yl)oxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-A^V-dimethyl-7/f-pyrrolo[2,3- <7]pyrimidine-6-carboxamide A506; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00265] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((4-((2-(4-(2-((3 -(2,4-dioxotetrahydropyrimidin- 1 (2//)-y 1)- 1 - methyl- 1/f-indazol -7-yl)oxy)acetyl)piperazin- 1 -yl)ethyl)carbamoyl)phenyl)amino)-7V, A^- dimethyl-7A7-pyrrolo[2,3-d]pyrimidine-6-carboxamide A551;
7-cyclopentyl-2-((4-((4-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2Ar)-yl)-l- methyl-177-indazol-7-yl)oxy)acetyl)piperazin-l -yl)butyl)carbamoyl)phenyl)amino)-A',,Ar- dimethyl-7/7-pyrrolo[2,3-</]pyriniidiiie-6-carboxamide A552;
7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2A/)-yl)-l- methyl- lAT-indazol-7-yl)oxy)acetyl)piperazin- 1 -yl)hexyl)carbamoyl)phenyl)amino)-A77- dimethyl-7H-pyrrolo[2,3-t7]pyrimidine-6-carboxamide A553;
7-cyclopentyl-2-((4-((2-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)-l- methyl-lJH-indazol-6-yl)oxy)acety4)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A7,Az- dimethyl-7Zf-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A554;
7-cyclopentyl-2-((4-((4-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)-l- methyl-177-indazol-6-yl)oxy)acetyl)piperazin-l -yl)butyl)carbamoyl)phenyl)amino)-A7,Ar- dimethyl-7/7-pyrrolo[2,3-</|pyrimidine-6-carboxamide A555; or
7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)-l- m ethyl- 17/-indazol-6-yl)oxy)acetyl)piperazin- 1 "yl)hexyl)carbamoyl)phenyl)amino)-A,A“ dimethyl-7H-pyrrolo[2,3-^pyrimidine-6-carboxamide A556; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00266] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((5-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)-l-methyl- l//-indazol-6-yl)ethyl)-4-fluoro-[l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-A’,A'-dimethyl-7H- pyrrol o[2, 3 -<7]pyrimidine-6-carboxamide A557;
7-cyclopentyl-2-((5-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)-l-methyl- l//r-indazol-7-yl)ethyl)-4-fluoro-[l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-Ar,AAdimethyl-7/7- pyrrolo[2,3-d]pyrimidine-6-carboxamide A558; or
7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)-l- methyl-177-indazol-6-yl)piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-jV,Ar-dimethyl- 7/7-pyrrolo[2,3-t(]pyrimidine-6-carboxamide A559; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00267] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((4-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)- amino)hexyl)carbamoyl)phenyl)amino)-A'r,Ar-dimethyl-777-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A601:
7-cyclopentyl-2-((4-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)- amino)hexyl)(methyl)carbamoyl)phenyl)amino)-A7,Ar-dimethyl-7/Z-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A602; or
7-cyclopentyl-2-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)- glycyl)piperazin-l-yl)pyridin-2-yl)amino)-jV,A/-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A603; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00268] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)- glycyl)piperazin-l-yl)pyridin-2-yl)amino)-jV,A''-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A611;
7-cyclopentyl-2-((4-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
4-yl)piperidin-l-yl)ethyl)carbamoyl)phenyl)amino)-MALdimethyl-7/7-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A612;
7-cyclopentyl-2-((4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l -oxoisoindolin- 4-y l)piperi din- 1 -yl)butyl)carbamoyl)phenyl)amino)-A',Ar-dimethyl-7/7-pyrrolo[2, 3 -cfjpyrimidine- 6-carboxamide A613;
7-cyclopentyl-2-((4-((6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin- 4-yl)piperidin-l-yl)hexyl)carbamoyl)phenyl)amino)-Ar,A/-diraethyl-7Z/-pyrrolo[2,3-<i]pyrimidine- 6-carboxamide A614;
7-cyclopentyl-2-((5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-4-yl)piperidin-l-yl)acetyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,Ar-dimethyl-7//- pyrrolo[2,3-t/]pyrimidine-6-carboxamide A615;
7-cyclopentyl-2-((5-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-4-yl)piperidin-l-yl)propanoyl)piperazin-l-yl)pyridin-2-yl)amino)-ArjV-dimethyl-7jE/- pyrrolo[2,3V|pyrimidine-6-carboxamide A616;
7-cy clopentyl-2-((5 -(4-(4-(4-(2-(2, 6-dioxopiperidin-3 -yl)-6-fluoro- 1 -oxo- isoindolin-4-yl)piperidin-l-yl)butanoyl)piperazin-l-yl)pyridin-2-yl)amino)-7VuV-dimethyl-7//- pyrrol o[2, 3 -<7]pyrimidine-6-carboxamide A617;
7-cyclopentyl-2-((4-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
5-yl)piperidin-l-yl)ethyl)carbamoyl)phenyl)amino)-A’,AMimethyl-7H-pyrrolo[2,3-</]pyrimidine-
6-carboxamide A618;
7-cyclopentyl-2-((4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
5-yl)piperidin-l-yl)butyl)carbamoyl)phenyl)amino)-JV,A/-dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine-
6-carboxamide A619;
7-cyclopentyl-2-((4-((6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l -oxoisoindolin-
5-yl)piperidin-l-yl)hexyl)carbamoyl)phenyl)amino)-A^V-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-
6-carboxamide A620;
7-cyclopentyl-2-((5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-5-yl)piperidin-l-yl)acetyl)piperazin-l-yl)pyridin-2-yl)amino)-7VjV-dimethyl-7//- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A621;
7-cyclopentyl-2-((5-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-5-yl)piperidin-l-yl)propanoyl)piperazin-l-yl)pyridin-2-yl)amino)-jV/7-dimethyl-7/7- pyrrolo[2,3-<7]pyrimidiiie-6-carboxamide A622; or
7-cyclopentyl-2-((5-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-5-yl)piperidin-l-yl)butanoyl)piperazin-l-yl)pyridin-2-yl)amino)-A’,A-dimethyl-7/7- pyrrol o[2, 3 -tZ]pyrimidine-6-carboxamide A623; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00269] In yet another embodiment, provided herein is a compound of:
7-cyclopentyl-2-((4-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4/f- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)carbamoyl)phenyl)amino)-Ar,A-dimethyl-7J/- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A651;
7-cyclopentyl-2-((4-((2-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-42/- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)amino)ethyl)carbamoyl)phenyl)amino)-/V,7V-dimethyl- 7//-pyrrolo[2,3-</|pyrimidine-6-carboxamide A652;
7-cyclopentyl-2-((4-((4-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4Ar- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)amino)butyl)carbamoyl)phenyl)amino)-Ar,A7-dimethyl- 7/7-pyirolo[2,3-cf|pyrimidine-6-carboxamide A653; or 7-cy cl opentyl-2-((4-((4-((5 -(2,6-di oxopi peri din-3 -y 1 )-4-oxo-5 , 6-dihy dro-477- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)carbamoyl)phenyl)amino)-A,r,A-dimethyl-7/A-pyrrolo- [2,3-<7]pyrimidine-6-carboxamide A654; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00270] In yet another embodiment, provided herein is a compound of:
3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethoxy)phenyl)piperidine-2, 6-dione B101;
3-(3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-3-oxopropoxy)phenyl)piperidine-2, 6-dione B102;
A'r-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-£/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- methylphenoxy)acetamide B103;
AL(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- (tri fluorom ethy 1 )ph en oxy )acetam ide B 104 ;
Az-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- methylphenoxy)acetamide Bl 05;
AA(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- (trifluoromethyl)phenoxy)acetamide B106;
Ar-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- methylphenoxy)acetamide Bl 07;
Az-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t7|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- (trifluoromethyl)phenoxy)acetamide B108;
AL(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- methylphenoxy)acetamide B109; or
A’-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- (trifl uoromethyl)phenoxy)acetami de B 110 ; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00271] In yet another embodiment, provided herein is a compound of:
3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)phenyl)piperidine-2, 6-dione Bill;
3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2, 6-dione Bl 12;
3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethoxy)phenyl)piperidine-2, 6-dione Bl 13;
3-(3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-af]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)phenyl)piperidine-2, 6-dione B114;
3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2, 6-dione Bl 15;
3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethoxy)phenyl)piperidine-2, 6-dione Bl 16;
3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tf|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propoxy)phenyl)piperidine-2, 6-dione B117;
3-(3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propoxy)phenyl)piperidine-2, 6-dione Bl 18;
3-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(7]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)piperi din- l-yl)phenyl)piperidine-2, 6-dione Bl 19;
3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)methyl)piperi din- 1 -yl)phenyl)piperi dine- 2, 6-dione B120;
3-(4-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)phenyl)piperidine- 2,6-dione B121;
3-(3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimi din-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperi din- l-yl)phenyl)piperidine-2, 6-dione B122;
3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-] -yl)methyl)piperidin-l-yl)phenyl)piperidine- 2,6-dione B123;
3-(3-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)phenyl)piperidine- 2,6-dione B124;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </|pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -yl)ethyl)piperazin- 1 -yl)phenyl)piperidine-2, 6- dione B125;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -yl)ethyl)piperazin- 1 -yl)phenyl)piperidine-2, 6- dione B126;
3-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)piperidine-2,6- di one B127; or
3-(3-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t(|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)piperidine-2,6- dione B128; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00272] In yet another embodiment, provided herein is a compound of:
3-(4-((l -(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)aniino)piperidin-l-yl)sulfonyl)ethyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione Bl 29;
3-(3-((l-(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-</]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione Bl 30;
3-(4-((l-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione B131;
3-(4-(4-(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tf]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperazin-l- yl)phenyl)piperidine-2, 6-dione B132;
3-(4-(4-(2-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione B133;
3-(4-(4-(3-((4-((6-(difluoromethyl)-8-((l/?,27?)-2-hydroxy-2-methylcyclopentyi)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B134;
3-(3-(4-(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperazin-l- yl)phenyl)piperidine-2, 6-dione B135;
3-(3-(4-(3-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-i7]pyrimidin-2-yl)aniino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B136;
3-(4-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-t7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propoxy)phenyl)- piperidine-2, 6-dione B137;
3-(3-(3-((4-((6-(difluoromethyl)-8-((177,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yi)sulfonyl)propoxy)phenyl)- piperidine-2, 6-dione B138;
3 -(4-(4-(4-((4-((6-(difluoromethyl)-8-(( 17?, 27?)-2-hydroxy-2-methy I cyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-i7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)benzyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B139;
3-(4-(4-(3-((4-((6-(diflUOromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)benzyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B140; 3-(3-(4-(3-((4-((6-(difluoromethyl)-8-((17?,2J?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)benzyl)piperazin-
1 -yl)phenyl)piperi di ne-2, 6-dione B141;
3-(3-(4-(4-((4-((6-(difluoromethyl)-8-((17?,2J?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tf]pyrimidin-2-yl)amino)piperidin-l -yl)sulfonyl)benzyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B142;
3-(4-((4-(4-((4-((6-(difluoromethyl)-8-((l/<2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-(7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperazin- l-yl)methyl)phenyl)piperidine-2, 6-dione B143;
3-(4-(4-((4-(4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B144;
3-(4-((4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- methyl)phenyl)piperidine-2, 6-dione B145;
3-(3-((4-((4-((6-(difluoromethyl)-8-((17?,21?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-tf|pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- methyl)phenyl)piperidine-2, 6-dione B146;
3-(4-(4-((4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)aniino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B147;
3-(4-(4-(3-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t(|pyrimidin-2-yl)amino)piperidin-l -yl)sulfonyl)propyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B148; or
3-(3-((l-(3-((4-((6-(difluoromethyl)-8-((l/^,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7, 8-dihy dropyrido[2, 3 -J]pyrimidin-2-yl)ami no)piperi din- 1 -y l)sulfonyl)propy I )pi peridin-4- yl)oxy)phenyl)piperidine-2, 6-dione B149; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00273] In yet another embodiment, provided herein is a compound of: 3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyriniidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- di one Bl 50;
3-(4-(2-(4-(4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyriniidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)- piperazin- l-yl)ethyl)phenyl)piperidine-2, 6-dione B151;
3-(4-(2-(4-(4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)- piperazin- l-yl)ethoxy)phenyl)piperidine-2, 6-dione B152;
3-(4-(2-(4-(3-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<f|pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)- piperazin- 1 -yl)ethyl)phenyl)piperidine-2, 6-dione B 153;
3-(3-(2-(4-((4-((6-(difluoromethyl)-8-((17?,2J?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-^pyrimidin-2-yl)amino)piperidin-l-yl)sulfbnyl)piperazin-l-yl)- ethoxy)phenyl)piperidine-2, 6-dione B154;
3-(4-(3-(4-((4-((6-(difluoromethyl)-8-((lZ7,2JR)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- propoxy )phenyl)piperidine-2, 6-dione B155;
3-(3-(3-(4-((4-((6-(difluoromethyl)-8-((l/?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyriniidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- propoxy )phenyl)piperidine-2, 6-dione Bl 56;
3-(4-(4-(4-((4-((6-(difluoromethyl)-8-((17?,2JR)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t(|pyrimidin-2-yl)amino)piperidin-l -yl)sulfonyl)phenethyl)- piperazin- l-yl)phenyl)piperidine-2, 6-dione B157;
3-(4-(4-(2-(4-((4-((6-(difluoromethyl)-8-((17<27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-fi?]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenoxy)- ethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B158;
3-(4-(4-(2-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-nietliylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenoxy)- ethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione Bl 59;
3 -(3 -(( 1 -(3 -((4-((6-(difluoromethyl)-8-(( 1R, 27?)-2-hydroxy-2-m ethyl cyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin- 4-yl)oxy)phenyl)piperidine-2, 6-dione B160;
3-(4-((l -(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin- 4-yl)oxy)phenyl)piperidine-2, 6-dione B161;
3-(4-((l-(4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-</]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin- 4-yl)oxy)phenyl)piperidine-2, 6-dione Bl 62;
3-(4-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyriniidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)piperazin-l-yl)phenyl)piperidine- 2,6-dione B163;
3-(4-(4-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-di one Bl 64;
3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-[l,4'-bipiperidin]-r-yl)phenyl)- piperidine-2, 6-dione B165;
3-(4-(4-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrinridin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B166;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tf|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-[l,4'-bipiperidin]-r-yl)phenyl)- piperidine-2, 6-dione B167;
3-(4-(4-(3-((4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-t7]pyrimidin-2-yi)- amino)piperi din- l-yl)sulfonyl)propyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B168;
3-(4-(4-(3-((4-((8-cyclopentyl-6-(difluoromethyl)-7-oxo-7,8-dihydropyrido[2,3- J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B169;
3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2,6- dione B170; 3-(4-(4-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [23 -^pyrimi din-2 -yl)amino)pyri din-3 -yl)piperazin-l-yl)piperidin-l-yl)methyl)piperi din- 1-yl)- phenyl)piperidine-2, 6-dione Bl 71;
3-(4-((5)-2-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-^]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)piperidin-l-yl)methyl)- morpholino)phenyl)piperidine-2, 6-dione B172;
3-(4-((/?)-2-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tZ]pyrimidin-2-yl)aniino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)- morpholino)phenyl)piperidine-2, 6-dione B173;
3-(4-((4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-cZ]pyrimidin-2-yl)aniino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperidin-l-yl)methyl)- phenyl)piperidine-2, 6-dione Bl 74;
3-(4-(2-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperidin-l-yl)ethy])- phenyl)piperidine-2, 6-dione Bl 75;
3-(4-(3-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<Z]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l -yl)methyl)azetidin-l-yl)- phenyl)piperidine-2, 6-dione B176;
3-(4-(4-((5)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-<7]pyriniidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)niethyl)morpholino)piperidin-l- yl)phenyl)piperidine-2, 6-dione B177;
3-(4-(4-((J?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)methyl)morpholino)piperidin-l- yl)phenyl)piperidine-2, 6-dione B178;
3-(4-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)cyclohexyl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B179;
3-(4-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)ethyl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione Bl 80;
3-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3" t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)ethyl)phenyl)piperidine-2,6- dione B181;
3-(4-(4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d/pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B182;
3-(4-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-] -yl)propyl)piperidin-l-yl)phenyl)piperidine-2,6- di one Bl 83;
3-(4-(3-(4-(4-(6-((6-acetyi-8-cyclopentyl-5-methyi-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)propoxy)phenyl)piperidine- 2,6-dione B184;
3-(4-(r-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-[4,4'-bipiperidin]-l-yl)phenyl)- piperidine-2, 6-dione B185;
3-(4-(4-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione Bl 86;
3-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2yl)amino)pyridin-3-yl)piperazin-l-yl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2,6- dione B187;
3-(4-(4-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tf|pyrimidin-2-yl)aniino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)piperazin-l-yl)phenyl)piperidine- 2,6-dione B188;
3-(4-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B189;
3-(4-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- ^pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B190;
3-(3-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)aniino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)ethoxy)phenyl)piperidine- 2,6-dione B191;
3-(3-(3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2 -yl)amino)pyridin-3-yl)piperazin-l-yl)piperi din-1 -yl)propoxy)phenyl)piperidine-
2, 6-dione B192;
3-(4-(4-(l-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-
2,6-dione B193;
3-(4-(4-(4-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3 -yl)methyl)piperazin-l-yl)piperi din- l-yl)phenyl)piperi dine-
2,6-dione B194;
3-(4-(r-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- yrimidin-2-yl)amino)pyridin-3-yl)methyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione B195;
3-(4-(4-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)methyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B196;
3-(4-(4-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B197;
3-(4-(4-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)-[l,4'-bipiperidin]-l '-yl)phenyl)piperidine-2, 6-dione B198;
3-(4-(4-(((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)methyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2,6- dione B199;
3-(4-(4-(4-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-2,6- dione B200;
3-(4-(4-(l-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2,6- di one B201; 3-(4-(r-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2,6- di one B202;
3-(4-(4-(l-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<y]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B203;
3-(4-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B204;
3-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2,6- di one B205;
3-(4-(r-(3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)propyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2,6-dione B206;
3-(4-(4-(l-(3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)propyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2,6- dione B207;
3-(4-(4-(4-(3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)propyl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-2,6- di one B208;
3-(4-(4-(3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)propyl)-[l,4’-bipiperidin]-r-yl)phenyl)piperidine-2,6-dione B209;
3-(3-(4-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)piperidine- 2,6-dione B210;
3-(4-(4-(((5)-4-(6-((6-aCetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3 -<7]pyrimidin-2-yl)amino)pyri din-3 -yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B211;
3-(4-(4-(((7?)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-tf]pyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B212;
3-(3-(4-(((5)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B213;
3-(4-(2-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2,6- dione B214;
3-(4-(2-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine-2,6-dione B215;
3-(4-((5)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3 -<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)phenyl)piperi dine- 2,6-dione B216;
3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3 -d]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)methyl)morpholino)phenyl)piperidine- 2,6-dione B217;
3-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J|- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B218;
3-(4-(4-(l-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7]pyrimidin-2-yl)amino)pyridin-3 -yl)methyl)piperi din-3 -yl)piperazin-l-yl)phenyl)piperi dine- 2,6-dione B219;
3-(3-(4-(l-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimi din-2-yl)amino)pyri din-3 -yl)methyl)piperi din-3 -yl)piperazin-l-yl)phenyl)piperidine- 2,6-dione B220;
3-(4-(4-(l-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-t/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-3-yl)piperazin-l-yl)phenyi)- piperidine-2, 6-dione B221;
3-(3-(4-(l-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3 -<f|pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperi din-3 -yi)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B222;
3-(3-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B223;
3-(4-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-t7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B224;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)ammo)pyridin-3 -yl)piperidin-4-yl)piperazin- 1 -yl)phenyl)piperidine-2, 6-dione B225;
3-(4-(4-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)methyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B226;
3-(4-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l-yl)phenyl)piperidine-2,6- di one B227;
3-(4-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- Jjpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)azetidin-l-yl)phenyl)piperidine-2,6- dione B228;
3-(4-(2-(2-(4-(6-((6-acetyl-8-cyclopentyi-5-methyl-7-oxo-7,8-dihydropyrido[2,3~ d]pyriinidin-2-yl)amino)pyridin-3-yl)piperazin-1 -yl)ethyl)-2,7-diazaspiro[3.5]nonan-7- yl)phenyl)piperidine-2, 6-dione B229;
3-(4-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2 -yl)amino)pyri din-3 -yl)oxy)propyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B230;
3-(4-(l-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- J]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B231;
3-(3-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7jpyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B232; 3-(3-(l-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyriniidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B233;
3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)propoxy)phenyl)piperidine-2, 6-dione B234;
3-(4-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B235;
3-(3-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- J]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B236;
3-(4-(3-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)propoxy)phenyl)piperidine-2, 6-dione B237;
3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tfl- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B238;
3-(4-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(7]~ pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione B239;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-^- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B240;
3-(4-(l'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/j- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2, 6-dione B241;
3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B242;
3-(3-(r-(6-((6-acetyl"8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione B243;
3-(3-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B244;
3-(3-(l'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/j- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2, 6-dione B245; 3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6- di one B246;
3-(4-(4-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)piperidine- 2,6-dione B247;
3-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B248;
3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6- di one B249;
3-(3-(l-((l-(6-((6-acetyl-8-cyclopentyI-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
Jjpyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B250;
3-(3-(4-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B251;
3-(4-(lX(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)methyl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2, 6-dione B252;
3-(4-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B253;
3-(4-(l-(2-(4-(6-((6-acetyl-8-cyclopentyi-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B254;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B255;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3 t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B256;
3-(3-(l -(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- di one B257;
3-(3-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)ainino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- di one B258;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperazin-l -yl)phenyl)piperidine-2,6- dione B259;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B260;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- ef|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- di one B261;
3-(4-(2-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yI)-[4,4'-bipiperidin]-l -yl)ethyl)phenyl)piperidine-2, 6-dione B262;
3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)ethyl)phenyl)piperidine-2, 6-dione B263;
3-(3-(4-(4-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </|pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-2,6- dione B264;
3-(3-(4-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)-[l ,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B265;
3-(3-(4-(((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7J- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)methyl)-[l,4'-bipiperidin]-l'-yl)phenyl)piperidine-2,6- dione B266;
3-(3-(r-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione B267;
3-(3-(4-(l-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2,6- di one B268;
3-(3-(4-(l-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-t7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B269;
3-(3-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)aniino)pyridin-3-yl)oxy)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B270;
3-(4-(l'-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2,6- dione B271,
3-(4-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- Jjpyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B272;
(1S)-3-(4-(4-(((5T)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-Jjpyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)- 3-methylpiperidine-2, 6-dione B273;
3-(4-(l-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B274;
3-(4-((r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine-2, 6-dione B275;
3-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3"t7]- pyrimidin-2-yl)amino)pyri din-3 -yl)oxy)ethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B276;
3-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-niethyl-7-oxo-7,8-dihydropyrido[2,3-<7|- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-l -yl)phenyl)piperidine-2, 6-dione B277;
3-(4-(2-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine- 2,6-dione B278;
3-(3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)azetidin-l-yl)phenyl)piperidine-2,6- di one B279;
3-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -y l)piperi din- 1 -yl)- 1 , 1 -difluoroethyl)phenyl)- piperidine-2, 6-dione B280;
3-(3-(2-(4-(4-(6-((6-acetyl-8-cyclopentyi-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin- 1 -yl)piperidin- 1 -yl)- 1 , 1 -difluoroethyl)phenyl)- piperidine-2, 6-dione B281;
3-(4-(2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin- 1 -yl)azetidin- 1 -y 1 ) - 1 , 1 -difluoroethyl)phenyl)- piperidine-2, 6-dione B282;
3-(3-(2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- Jjpyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -yl)azetidin- 1 -yl)- 1 , 1 -difluoroethyl)phenyl)- piperidine-2, 6-dione B283;
3-(4-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyriinidin-2-yl)amino)pyridin-3-yl)piperazin-1 -yl)azetidin-1 -yl)methyl)phenyl)piperidine-2,6- dione B284;
3-(3-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- cZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)methyl)phenyl)piperidine-2,6- dione B285;
3-(3-(2-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- J]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine- 2,6-dione B286;
3-(4-((r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3V|- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine- 2,6-dione B287; 3-(3-((r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-i/]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine- 2,6-dione B288;
3-(4-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- J]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fliioroazetidin-3-yl)ethyl)phenyl)- piperidine-2, 6-dione B289;
3-(3-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)- piperidine-2, 6-dione B290;
3-(4-((l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-y l)-3 -fluoroazetidin-3 -yl)methyl)phenyl)- piperidine-2, 6-dione B291;
3-(3-((l-(l-(6-((6-acetyl-8-cyclopentyI-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)methyl)phenyl)- piperidine-2, 6-dione B292;
3-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)azetidin-3-yl)phenyl)- piperidine-2, 6-dione B293;
3-(3-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)azetidin-3-yl)phenyl)- piperidine-2, 6-dione B294;
3-(4-(2-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyri din-3 -yl)azeti din-3 -yl)piperazin-l-yl)ethyl)phenyl)piperidine-2, 6- dione B295;
3-(3-(2-(4-(l-(6-((6-acetyl-8-cyclopentyi-5-methyl-7-<)xo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2,6- dione B296;
3-(4-((4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)methyl)phenyl)piperidine-2,6- di one B297;
3-(3-((4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3 <i]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l -yl)methyl)phenyl)piperidine-2,6- dione B298;
3-(3-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperidin-4-yl)ethyl)phenyl)piperidine-2,6- dione B299;
3-(3-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)ainino)pyridin-3-yl)azetidin-3-yl)-4-fluoropiperidin-4-yl)ethyl)phenyl)- piperidine-2, 6-dione B300;
3-(3-(8-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-3-azabicyclo[3.2.1]octan-3-yi)- phenyl)piperidine-2, 6-dione B301;
3-(3-(3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-8-azabicyclo[3.2.1]octan-8-yl)- phenyl)piperidine-2, 6-di one B302;
3-(3-(4-((3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B303;
3-(3-(4-((8-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B304;
3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B305;
3-(4-(4-((4-(6-((6-acetyl-8-cyClOpentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B306;
(S)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-tf]pyrinridin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)-3-m ethyl- piperidine-2, 6-dione B307;
(7?)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yi)phenyi)-3-methyi- piperidine-2, 6-dione B308;
(S)-3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-c/jpyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l -yl)phenyl)-3-m ethyl- piperidine-2, 6-dione B309;
(7?)-3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3 -d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)-3 -methyl- piperidine-2, 6-dione B310;
3-(4-(l -((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t(jpyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)phenyl)- piperidine-2, 6-dione B311;
3-(3-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)phenyl)- piperidine-2, 6-dione B312;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluorophenyl)piperidine-2,6- dione B313;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3-fluorophenyl)piperidine-2,6- dione B314;
3-(4-(4-(l-(6-((6-aCetyl-8-cyClOpentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-chlorophenyl)piperidine-2,6- dione B315;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tf|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3-chlorophenyl)piperidine-2,6- dione B316;
3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-i/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)phenyl)piperidine-2, 6-dione B317;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)ethyl)piperidin-l-yl)-5-f]uorophenyl)- piperidine-2, 6-dione B318; 3-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyriniidin-2-yl)amino)pyridin-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2 -fluorophenyl)- piperidine-2, 6-dione B319;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-3-fluorophenyl)- piperidine-2, 6-dione B320;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-fluorophenyl)- piperidine-2, 6-dione B321;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- 1-y l)-2-fluorophenyl)- piperidine-2, 6-dione B322;
3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B323; or
3-(4-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3 V|pyrimi din-2-yl)amino)pyri din-3 -yl)oxy)ethyl)piperazin- 1 -yl)piperi din- 1 -yi)phenyl)- piperidine-2, 6-dione B324; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00274] In yet another embodiment, provided herein is a compound of:
3-(4-(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperi din- 1 -yl)sulfonyl)ethoxy)phenyl)- piperidine-2, 6-dione B351;
3-(4-(4-(((4-((6-(difluoromethyl)-8-((17?,21?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2, 3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)methyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione B352;
3-(3-(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethoxy)phenyl)- piperidine-2, 6-dione B353; 3-(4-(4-(((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-t(]pyrimi din-2 -yl)amino)piperidin-l-yl)sulfonyl)methyl)-[l, 4'- bipiperi din]- r-yl)phenyl)piperidine-2, 6-dione B354;
3-(4-(4-(l-(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- ethyl)piperidin-4-yl)piperazin- 1 -yl)phenyl)piperidine-2, 6-dione B355;
3-(4-((4-(3-((4-((6-(difluoromethyl)-8-((l/<2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperazin- 1 -yl)methyl)phenyl)piperidine-2, 6-dione B356;
3-(4-(4-((4-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B357;
4-(3-(4-((4-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-fl?]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B358;
3-(4-(2-(4-((4-((6-(difluoromethyl)-8-((lZ^,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- ethyl)phenyl)piperidine-2, 6-dione B359;
3-(4-(4-(4-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)aniino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- piperidin-l-yl)phenyl)piperidine-2, 6-dione B360;
3-(3-((l-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-t7jpyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)-3-methylpiperidine-2, 6-dione B361; or
3-(4-((l-(3-((4-((6-(difluoromethyl)-8-((l/^,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7, 8-dihy dropyrido[2, 3 -J]pyrimidin-2-yl)ami no)piperi din- 1 -y l)sulfonyl)propy I )pi peridin-4- yl)oxy)phenyl)-3-methylpiperidine-2, 6-dione B362; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00275] In yet another embodiment, provided herein is a compound of: 3-(3-(4-((3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- eZ]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B363;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B364;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-4-fluorophenyl)- piperidine-2, 6-dione B365;
3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-l -yl)methyl)-4-fluoropiperidin- l-yl)phenyl)-3- methylpiperidine-2, 6-dione B366;
(S)-3-(3-(4-((4-(6-((6-acetyI-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)-4-fluoropiperidm-l-yl)phenyl)- 3 -methylpiperidine-2, 6-dione B367;
(5)-3-(4-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<Z]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)-3- methylpiperidine-2, 6-dione B368;
(7?)-3-(4-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)-3- methylpiperidine-2, 6-dione B369;
3-(4-(7-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-4,7-diazaspiro[2.5]octan-4-yl)phenyl)- piperidine-2, 6-dione B370;
(/^)-3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B371;
(5)-3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tf|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B372;
(A)-3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B373;
(LS)-3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B374; or
(7?)-3-(4-(4-(((5)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-</|pyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)- 3 -methylpiperidine-2, 6-dione B375; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00276] In yet another embodiment, provided herein is l-(4-((l-(3-((4-((6-(difhioro- methyl)-8-((l/?,27?)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-t7]pyrimidin- 2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperidin-4-yl)oxy)phenyl)dihydropyrimidine- 2,4(17/,3//)-dione B401; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00277] In yet another embodiment, provided herein is a compound of: l-(4-(4-(3-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-</]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)phenyl)dihydropyrimidine-2, 4(177, 37/)-dione B402; l-(2-chloro-4-(4-(3-((4-((6-(difluoromethyl)-8-((l/?,2/?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- propyi)piperazin-l-yl)phenyl)dihydropyrimidine-2,4(177,37/)-dione B403; l-(4-(4-(3-((4-((6-(difluoromethyl)-8-((l/?,2//)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)-2-fluorophenyl)dihydropyrimidine-2, 4(1/7, 37/)-dione B404; l-(4-(4-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)-2-methylphenyl)dihydropyrimidine-2, 4(1/7, 37/)-dione B405; l-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B406; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)dihydropyrimidine- 2,4(177,377)-dione B407; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluorophenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B408; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-chlorophenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B409; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-(trifluoromethyl)phenyl)- dihydropyrimidine-2, 4(177, 377)-dione B410; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-methylphenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B411; l-(4-(4-(l-(6-((6-acetyl-8-cyclOpentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2,3-dimethylphenyl)dihydro- pyrimidine-2, 4(177, 37/)-dione B412; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2,4-dimethylphenyl)- dihydropyrimidine-2, 4(177, 377)-dione B413; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-<)xo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2-chloro-3 -methyl- phenyl)dihydropyrimidine-2, 4(177, 377)-dione B414; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-5-chloro-2-methyl- phenyl)dihydropyrimidine-2,4(177,377)-dione B415; or l-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- 7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperazin-l -yl)phenyl)dihydro- pyrimidine-2, 4(1/7, 3//)-dione B416; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00278] In yet another embodiment, provided herein is a compound of: l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-chloro-5-methylphenyl)- dihydropyrimidine-2, 4(177, 37/)-dione JB451; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-7|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluoro-3-methylphenyl)- dihydropyrimidine-2,4(l/f,3//)-dione B452; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluoro-5-methylphenyl)- dihydropyrimidine-2,4(17/,3//)-dione B453; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-chloro-6-methylphenyl)- dihydropyrimidine-2, 4(177, 377)-dione B454; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-7|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3-fluoro-2-methylphenyl)- dihydropyrimidine-2,4(l/Z,3ZZ)-dione B455; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)dihydro- pyrimidine-2,4(17/,37Q-dione B456; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2-chlorophenyl)- dihydropyrimidine-2, 4(177, 377)-dione B457; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2-chlorophenyl)- dihydropyrimidine-2,4(l#,377)-dione B458; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l -yl)-2-fluorophenyl)- dihydropyrimidine-2, 4( 1 Z/,3//)-dione B459; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7]pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -yl)ethyl)piperidin- 1 -yl)-2-fluorophenyl)- dihydropyrimidine-2,4(l/7,3//)-dione B460; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)ethyl)piperidin-l-yl)-2-methylphenyl)- dihydropyrimidine-2, 4(1/7, 3/7)-dione B461; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
</]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l -yl)-2-methylphenyl)- dihydropyrimidine-2, 4(1/7, 3//)-dione B462; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-chloro-6-methyl- phenyl)dihydropyrimidine-2, 4(1/7, 3//)-dione B463; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-4-chloro-2-methyl- phenyl)dihydropyrimidine-2, 4(1/7, 3//)-dione B464; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
</]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-chloro-4-methyl- phenyl)dihydropyrimidine-2,4( l//,3//)-dione B465; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7]pyrimidin-2-yl)aniino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-4-chloro-2-methyl- phenyl)dihydropyrimidine-2, 4(1/7, 3//)-dione B466; l-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2-chlorophenyl)- dihydropyrimidine-2, 4(1/7, 3/7)-di one B467; l-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
</]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperazin-l-yl)-2-chlorophenyl)- dihydropyrimidine-2,4(l/7,3//)-dione B468; l-(4-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
</|pyrimidin-2-yl)aniino)pyridin-3 -yl)piperidin-4-yl)ethyl)piperazin- 1 -yl)phenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B469; l-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B470; l-(3-(4-((3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)piperidin-l-yl)- phenyl)dihydropyrimidine-2,4(l/7,377)-dione B471; or l-(4-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7jpyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazeti din-3 -yl)ethyl)-2-chloro- phenyl)dihydropyrimidine-2,4(177,377)-dione B472; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00279] In yet another embodiment, provided herein is 3-(6-(2-(4-(6-((6-acetyl-8- cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(7]-pyrimidin-2-yl)amino)pyridin-3- yl)piperazin-l-yl)-2-oxoethoxy)-l-methyl-177-indazol-3-yl)-piperidine-2, 6-dione B501; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00280] In yet another embodiment, provided herein is 3-(7-(2-(4-(3-((4-((6-(difluoro- methyl)-8-((17?,25)-2-hydroxy-2-methylcyclo-pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-
2-yl)amino)piperi din- 1 -yl)sulfonyl)propyl)-piperazin- 1 -yl)-2-oxoethoxy)-l -methyl- 177-indazol-
3 -yl)piperidine-2, 6-dione B502; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00281] In yet another embodiment, provided herein is 3-(6-(4-(l-(6-((6-acetyl-8-cyclo- pentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]-pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4- yl)piperazin-l-yl)-l-methyl-177-indazol-3-yl)-piperidine-2, 6-dione B503; or 3-(6-(2-(l-(l-(6-((6- acetyi-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)pyridin-3- yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l-methyl-177-indazol-3-yl)piperidine-2, 6-dione B504; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00282] In yet another embodiment, provided herein is:
3-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-17/-indazol-3-yl)-3- methylpiperidine-2, 6-dione B505;
3-(7-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l-methyl-lJcf- indazol-3-yl)piperidine-2, 6-dione B506;
3-(6-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)-l-methyl-l//-indazol-3-yl)- piperidine-2, 6-dione B507;
3-(6-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </]pyrimidin-2-yl)aniino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l-yl)-l -methyl- IH-indazol- 3 -yl)piperidine-2, 6-dione B508;
(S)-3-(6-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2, 3 -</]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)ethyl)piperazin-l-yl)-l -methyl- 1//- indazol-3-yl)-3-methylpiperidine-2, 6-dione B509;
(/?)-3-(6-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l-yl)-l-methyl-lH- indazol-3-yl)-3 -methylpiperidine-2, 6-dione B510; or
3-(6-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -y l)ethy l)piperi din- 1 -yl)-l -methyl- 1/7-indazol- 3 -y 1 )pip eri di ne-2 , 6 - di one B511 ; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00283] In yet another embodiment, provided herein is: l-(7-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-1 -yl)-l-methyl-l//-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B551; l-(6-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-l-methyl-l//-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B552, l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-cf|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-l/7-indazol-3-yl)- dihydropyrimidine-2,4( l//,3/7)-dione B553; l-(6-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)ammo)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-lZ/-indazol-3-yl)- dihydropyrimidine-2, 4(1/7, 3/7)-dione B554; l-(6-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-fluoro-l-methyl-l//-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3Z7)“dione B555, l-(6-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-7-fluoro-l-methyl-l/7-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B556, l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-fluoro-l-methyl-l//-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B557; l-(6-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-chloro-l-methyl-l/7-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B558; l-(6-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tf|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-7-chloro-l-methyl-l/7-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3//)-dione B559, l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-chloro-l-methyl-l/7-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B560;
(LS)-l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-y!)-2-methylpiperazin-l-yl)-l-methyl-l/7- indazol-3-yl)dihydropyrimidine-2,4(177,3/7)-dione B561; (/?)-! -(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2, 3 -cZ]pyrimi din-2 -yl)amino)pyri din-3 -yl)piperidin-4-yl)-2-methylpiperazin-l-yl)-l -methyl- 1/7- indazol-3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B562;
(7?)-l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<Z]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-methylpiperazin-l-yl)-l-methyl-l/7- indazol-3-yl)dihydropyrimidine-2,4(l//,3/7)-dione B563; l-(6-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l -methyl-l/7- indazol-3-yl)dihydropyrimidine-2,4( l//,3/7)-dione B564, l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)piperazin-l-yl)-6-chl oro-1 -methyl- 1/7-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B566; l-(7-(4-((4-(6-((6-acetyl-8-cyclopentyI-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
Jjpyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-l-yl)methyl)-4-fluoropiperi din- l-yl)-l -methyl- l//-indazol-3-yl)dihydropyrimidine-2,4(l/7,3/7)-dione B567;
(5)-l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-methylpiperazin-l-yl)-l -methyl-l//- indazol-3-yl)dihydropyrimidine-2,4( l//,3/7)-dione B568; l-(7-(2-(l-(l -(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l-methyl-l//- indazol-3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B569; l-(6-(2-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7jpyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)-l-methyl-l/7- indazol-3-yl)dihydropyrimidine-2,4(l//,3/7)-dione B570; l-(7-(2-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t(|pyrimidin-2-yl)aniino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)-l-methyl-l/7- indazol-3-yl)dihydropyrimidine-2,4( l//,3/7)-dione B571; l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(f|- pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)piperazin-l-yl)-4-chl oro-1 -methyl- l//-indazol- 3-yl)dihydropyrimidine-2,4(17/,3/7)-dione B572, l-(6-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin“l-yl)-l-methyl-l ZZ-indazol- 3-yl)dihydropyrimidine-2,4(17f,37/)-dione B573, l-(6-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- 7]pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -y l)ethy l)piperi din- 1 -y 1)- 1 -methyl- 1/7-indazol- 3-yl)dihydropyrimidine-2, 4(17/, 3.7/)-dione B574; or l-(6-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- 7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)methyl)piperidin-l-yl)-l-methyl-l//- indazol-3-yl)dihydropyrimidine-2, 4(17/, 3//)-dione B575; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00284] In yet another embodiment, provided herein is a compound of:
3-(5-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- 7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethyl)piperidin-4-yl)-6-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione B601;
3-(4-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- 7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l -yl)-2-oxoethyl)amino)- 1 -oxoisoindolin-2-yl)- piperidine-2, 6-dione B602; or
4-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione B603; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00285] In still another embodiment, provided herein is 3-(5-(l-(4-(2-(4-(6-((6-acetyl-8- cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-[2,3-7]pyrimidin-2-yl)amino)pyridin-3- yl)piperazin-l-yl)ethoxy)benzyl)piperidin-4-yl)-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione B604; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00286] In certain embodiments, a compound provided herein is deuterium-enriched. In certain embodiments, a compound provided herein is carbon-13 enriched. In certain embodiments, a compound provided herein is carbon-14 enriched. In certain embodiments, a compound provided herein contains one or more less prevalent isotopes for other elements, including, but not limited to, 15N for nitrogen; 17O or 18O for oxygen, and 34S, 35S, or 36S for sulfur.
[00287] In certain embodiments, a compound provided herein has an isotopic enrichment factor of no less than about 5, no less than about 10, no less than about 20, no less than about 50, no less than about 100, no less than about 200, no less than about 500, no less than about 1,000, no less than about 2,000, no less than about 5,000, or no less than about 10,000. In any events, however, an isotopic enrichment factor for a specified isotope is no greater than the maximum isotopic enrichment factor for the specified isotope, which is the isotopic enrichment factor when a compound at a given position is 100% enriched with the specified isotope. Thus, the maximum isotopic enrichment factor is different for different isotopes The maximum isotopic enrichment factor is 6,410 for deuterium and 90 for carbon-13.
[00288] In certain embodiments, a compound provided herein has a deuterium enrichment factor of no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment), no less than about 640 (about 10% deuterium enrichment), no less than about 1,300 (about 20% deuterium enrichment), no less than about 3,200 (about 50% deuterium enrichment), no less than about 4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80% deuterium enrichment), no less than about 5,450 (about 85% deuterium enrichment), no less than about 5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95% deuterium enrichment), no less than about 6,220 (about 97% deuterium enrichment), no less than about 6,280 (about 98% deuterium enrichment), no less than about 6,350 (about 99% deuterium enrichment), or no less than about 6,380 (about 99.5% deuterium enrichment). The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. In certain embodiments, at least one of the atoms of a compound provided herein, as specified as deuterium-enriched, has deuterium enrichment of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%. [00289] In certain embodiments, a compound provided herein is isolated or purified. In certain embodiments, a compound provided herein has a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.
[00290] The compounds provided herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified. Where a compound provided herein contains an alkenyl group, the compound may exist as one or mixture of geometric cisltrans (or Z/E) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so- called valence tautomerism in the compound that contains an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
[00291] A compound provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of ordinary skill in the art will recognize that administration of a compound in its (7?) form is equivalent, for the compound that undergoes epimerization in vivo, to administration of the compound in its (5) form. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
[00292] When a compound provided herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sei. 1977, 66, 1- 19; Handbook of Pharmaceutical Salts: Properties, Selection, and. Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a solvate. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a hydrate.
[00293] Suitable acids for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-l,5-disulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L- pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p- toluenesulfonic acid, undecylenic acid, and valeric acid.
[00294] Suitable bases for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, 7 including O,* but not limited to, 7 L-ar Oginine, 7 benethamine, 7 benzathine, 7 choline, 7 deanol, 7 diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethyl- amino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, tV-methyl- glucamine, hydrabamine, IH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, tri ethyl amine, A^-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)- 1,3 -propanediol, and tromethamine.
[00295] A compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
Pharmaceutical Compositions
[00296] In one embodiment, provided herein is a pharmaceutical composition, comprising a compound provided herein, e.g, a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
[00297] The pharmaceutical composition provided herein can be formulated in various dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration. The pharmaceutical composition can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g. , Remington: The Science and Practice of Pharmacy, supra, Modifled- Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.
[00298] In one embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for oral administration. In another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration. In still another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for topical administration.
[00299] The pharmaceutical composition provided herein can be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) (e.g, a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s). Examples of a unit-dosage form include, but are not limited to, an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form. Examples of a multiple-dosage form include, are not limited to, a vial, bottle of tablets or capsules, or bottle of pints or gallons.
[00300] The pharmaceutical composition provided herein can be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or m vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.
A. Oral Administration
[00301] The pharmaceutical composition provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emul sions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical composition can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
[00302] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g, STARCH 1500®); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, Ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), \TEGUM®, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); and microcrystalline celluloses, such as AVICEL® PH-101, AVICEL® PH-103, AVICEL® PH-105, and AVICEL® RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, and pre-gelatinized starch.
The amount of a binder or filler in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical composition provided herein.
[00303] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary' skill in the art.
[00304] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and VEEGUM® HV; citrus pulp; crosslinked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as com starch, potato starch, tapioca starch, and pregelatinized starch; clays; and algins. The amount of a disintegrant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical composition provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
[00305] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; and silica or silica gels, such as AEROSIL® 200 and CAB-O-SIL®. The amount of a lubricant in the pharmaceutical composition provided herein varies upon the type of formul ation, and is readily discernible to those of ordinary’ skill in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
[00306] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O- SIL®, and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes. A color lake is a combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate.
Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, VEEGUM®, acacia, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, and sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
[00307] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.
[00308] The pharmaceutical composition provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredient(s) from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or diy-coated tablets.
[00309] The tablet dosage forms can be prepared from an active ingredient(s) in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges. [00310] The pharmaceutical composition provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient(s). The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient(s).
[00311] The pharmaceutical composition provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, e.g, acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
[00312] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing an active ingredient(s), and a dialkylated mono- or poly-alkylene glycol, including, 1,2-diraethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350- dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These dosage forms can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and di thiocarbamates.
[00313] The pharmaceutical composition provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
[00314] The pharmaceutical composition provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents.
Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
[00315] Coloring and flavoring agents can be used in all of the dosage forms described herein.
[00316] The pharmaceutical composition provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
B. Parenteral Administration
[00317] The pharmaceutical composition provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration. [00318] The pharmaceutical composition provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosy stems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. See, e.g., Remington: The Science and Practice of Pharmacy, supra.
[00319] The pharmaceutical composition provided herein for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
[00320] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer’s injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer’s injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and mediumchain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3 -butanediol, liquid polyethylene glycol {e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, JV-methyl-2-pyrrolidone, Ar,JV-dimethylacetamide, and dimethyl sulfoxide.
[00321] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxy- benzoates, thimerosal, benzalkonium chloride {e.g., benzethonium chloride), methyl- and propylparabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants include those described herein, such as bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including a- cyclodextrin, P-cyclodextrin, hydroxypropyl-0-cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether 7-0-cyclodextrin (CAPTISOL®).
[00322] When the pharmaceutical composition provided herein is formulated for multiple dosage administration, multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
[00323] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including a lyophilized powder and hypodermic tablet, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.
[00324] The pharmaceutical composition provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
[00325] The pharmaceutical composition provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical composition provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient(s) in the pharmaceutical composition to diffuse through.
[00326] Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.
[00327] Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethyl ene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
C. Topical Administration
[00328] The pharmaceutical composition provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
[00329] The pharmaceutical composition provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including, but not limited to, emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulations of the pharmaceutical composition provided herein can also comprise liposomes, micelles, microspheres, and nanosystems.
[00330] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, nonaqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
[00331] The pharmaceutical composition can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ and BIOJECT ™.
[00332] The pharmaceutical composition provided herein can be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water- soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. See, e.g., Remington: The Science and Practice of Pharmacy, supra. These vehicles are emollient but generally require addition of antioxidants and preservatives.
[00333] Suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the “internal” phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
[00334] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
[00335] The pharmaceutical composition provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
[00336] Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with an active ingredient/ s); and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
[00337] The pharmaceutical composition provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.
[00338] The pharmaceutical composition provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical composition can be provided in the form of an aerosol or solution for delivery' using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1, 1,2-tetrafluoroethane or 1, 1,1, 2, 3,3,3 - heptafluoropropane. The pharmaceutical composition can also be provided as a dry’ powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.
[00339] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of an active ingredient(s); a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
[00340] The pharmaceutical composition provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
[00341] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical composition provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical composition provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium. [00342] The pharmaceutical composition provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
D. Modified Release
[00343] The pharmaceutical composition provided herein can be formulated as a modified release dosage form. As used herein, the term “modified release” refers to a dosage form in which the rate or place of release of an active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical composition in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphism of the active ingredient(s).
1. Matrix Controlled Release Devices
[00344] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated using a matrix-controlled release device known to those skilled in the art. See, e.g., Takada el al. in Encyclopedia of Controlled Drug Delivery, Mathiowitz Ed.; Wiley, 1999; Vol. 2.
[00345] In certain embodiments, the pharmaceutical composition provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
[00346] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum Ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate, gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®); poly(2 -hydroxyethylmethacrylate); polylactides; copolymers of L-glutamic acid and ethyl -L -glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3 -hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethyl acryl ate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.
[00347] In certain embodiments, the pharmaceutical composition provided herein is formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylenevinyl acetate copolymers, ethyl ene/propylene copolymers, ethyl ene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides. [00348] In a matrix-controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
[00349] The pharmaceutical composition provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
2. Osmotic Controlled Release Devices
[00350] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusi on through the delivery port(s).
[00351] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents is water- swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.” Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycol ate.
[00352] The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.
[00353] Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM™ EZ can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
[00354] The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
[00355] Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethyl aminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, EEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
[00356] Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798, 119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, poly ether sulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
[00357] The delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.
[00358] The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
[00359] The pharmaceutical composition in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
[00360] The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra, Santus and Baker, J Controlled Release, 1995, 35, 1-21; Verma et al.. Drug Dev. Ind. Pharm., 2000, 26, 695-708; Verma el al., J. Controlled Release, 2002, 79, 7-27.
[00361] In certain embodiments, the pharmaceutical composition provided herein is formulated as an AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, e.g., U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
[00362] In certain embodiments, the pharmaceutical composition provided herein is formulated as an ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
3. Multiparticulate Controlled Release Devices
[00363] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 pm to about 3 mm, about 50 pm to about 2.5 mm, or from about 100 pm to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and drygranulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, e.g, Multiparticulate Oral Drug Delivery, Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994; and Pharmaceutical Palletization Technology’,’ Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 37; CRC Press: 1989.
[00364] Other excipients or carriers as described herein can be blended with the pharmaceutical composition to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet. 4. Targeted Delivery
[00365] The pharmaceutical composition provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975;
6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.
Methods of Use
[00366] In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a CDK in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g, a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00367] In certain embodiments, the disorder, disease, or condition mediated by a CDK is a disorder, disease, or condition mediated by CDK2, CDK4, or CDK6. In certain embodiments, the disorder, disease, or condition mediated by a CDK is a disorder, disease, or condition mediated by CDK2. In certain embodiments, the disorder, disease, or condition mediated by a CDK is a disorder, disease, or condition mediated by CDK4. In certain embodiments, the disorder, disease, or condition mediated by a CDK is a disorder, disease, or condition mediated by CDK6.
[00368] In certain embodiments, the disorder, disease, or condition mediated by a CDK is a proliferative disease.
[00369] In another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00370] In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is hormone receptor positive breast cancer. In certain embodiments, the cancer is advanced or metastatic hormone receptor positive breast cancer.
[00371 ] In certain embodiments, the cancer is refractory and/or relapsed. In certain embodiments, the cancer is refractory. In certain embodiments, the cancer is relapsed. In certain embodiments, the cancer is metastatic. In certain embodiments, the cancer is unresectable. In certain embodiments, the cancer is metastatic.
[00372] In certain embodiments, the cancer is drug-resistant. In certain embodiment, the cancer is multi drug-resistant. In certain embodiments, the cancer is resistant to a chemotherapy. In certain embodiments, the cancer is resistant to an immunotherapy. In certain embodiments, the cancer is resistant to a standard therapy for the cancer.
[00373] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.
[00374] In certain embodiments, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 60 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 25 mg/kg/day, from about 0.1 to about 20 mg/kg/day, from about 0.1 to about 15 mg/kg/day, from about 0.1 to about 10 mg/kg/day, or from about 0.1 to about 5 mg/kg/day.
In one embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day. In another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 60 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 25 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 20 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 15 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 10 mg/kg/day. In still another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 5 mg/kg/day.
[00375] It is understood that the administered dose can also be expressed in units other than mg/kg/day. For example, doses for parenteral administration can be expressed as mg/m2/day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m2/day to given either the height or weight of a subject or both. For example, a dose of 1 mg/m2/day for a 65 kg human is approximately equal to 58 mg/kg/day.
[00376] Depending on the disorder, disease, or condition to be treated and the subject’s condition, a compound provided herein may be administered by oral, parenteral (e.g, intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. A compound provided herein may be formulated in suitable dosage unit with a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle, appropriate for each route of administration.
[00377] In one embodiment, a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered parenterally. In yet another embodiment, a compound provided herein is administered intravenously. In yet another embodiment, a compound provided herein is administered intramuscularly. In yet another embodiment, a compound provided herein is administered subcutaneously. In still another embodiment, a compound provided herein is administered topically.
[00378] A compound provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time. A compound provided herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.
[00379] A compound provided herein can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID), and three times daily (TID). In addition, the administration can be continuous, i.e., every day, or intermittently. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound provided herein is administration for one to six days per week, administration in cycles (e.g, daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
[00380] In certain embodiments, a compound provided herein is cyclically administered to a subject. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
[00381] A compound provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a condition, disorder, or disease described herein.
[00382] As used herein, the term “in combination” includes the use of more than one therapy (e.g, one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g, a prophylactic or therapeutic agent) to the subject. Triple therapy is also con tempi ated herein.
[00383] The route of administration of a compound provided herein is independent of the route of administration of a second therapy. In one embodiment, a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered intravenously. Thus, in accordance with these embodiments, a compound provided herein is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, via local delivery' by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, a compound provided herein and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, a compound provided herein is administered by one mode of administration, e.g, by IV, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., orally.
[00384] In one embodiment, provided herein is a method of inhibiting the growth of a cell, comprising contacting the cell with a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00385] In certain embodiments, the cell is a cancerous cell. In certain embodiments, the cell is a human cell. In certain embodiments, the cell is a human cancerous cell. In certain embodiments, the cell is a cell of breast cancer. In certain embodiments, the cell is a cell of hormone receptor positive breast cancer. In certain embodiments, the cell is a cell of advanced or metastatic hormone receptor positive breast cancer.
[00386] In another embodiment, provided herein is a method of inducing degradation of a CDK, comprising contacting the CDK with a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. [00387] In certain embodiments, the CDK is CDK2, CDK4, or CDK6. In certain embodiments, the CDK is CDK2. In certain embodiments, the CDK is CDK4. In certain embodiments, the CDK is CDK6.
[00388] A compound provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,525,907; 5,052,558; and 5,055,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
[00389] In certain embodiments, provided herein is a kit which, when used by a medical practitioner, can simplify the administration of an appropriate amount of a compound provided herein as an active ingredient to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein.
[00390] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needleless injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.
[00391] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be di ssolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, water for injection USP, sodium chloride injection, Ringer’s injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer’ s injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, coni oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. [00392] The disclosure will be further understood by the following non-limiting examples.
EXAMPLES
[00393] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); pL (microliters); mM (millimolar); pM (micromolar); mmol (millimoles); min (minute or minutes); h (hour or hours); ACN (acetonitrile); AczO (acetic anhydride); AIBN (2,2-azobis(2-methyl- propionitrile); 9-BBN (9-borabicycl(3.3.1)nonane); BINAP (2,2'-bis(diphenylphosphino)-l,l'- binaphthy 1 ); BociO (di-fe/T-butyl dicarbonate); t-BuOK (potassium fert-butoxide); i-BuONa (sodium tert-butoxide); CbzCl (benzyl chloroformate); DCE (1,2-dichloroethane); DCM (di chloromethane); DIEA or DIPEA (/VpV-diisopropylethylamine); DMAP (4-dimethylamino- pyridine); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); EDCI (1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide); EtOAc (ethyl acetate); EtOH (ethanol); HATU ( 1 -[bis- (diniethylamino)methylene]-lA-l,2,3-triazolo-[4,5-Z>]pyridinium 3-oxid hexafluoro-phosphate): HOAt (1 -hydroxy-7-azabenzotriazole); MeOH (methanol); NaBH(OAc)s (sodium triacetoxy- borohydride); NaOAc (sodium acetate); NBS (A-bromosuccinimide); NMM (A-methyl- morpholine); NMO (4-methylmorpholine A-oxide); NMP (A-methyl-2-pyrrolidone); Pdi(dba)3 (tris(dibenzylideneacetone)dipalladium(O)); Pd(dppf)Ch ([l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II)); Pd(OAc)2 (palladium acetate); Pd(tBusP)2 (bis(tri-fert- butylphosphine)palladium); PE (petroleum ether); PMBC1 (l-(chloromethyl)-4-methoxy- benzene); RuPhos (dicyclohexyl(2',6'-diisopropoxy-[l,r-biphenyl]-2-yl)phosphine); RuPhos Pd G3 ((2-dicyclohexylphosphino-2',6'-diisopropoxy-l,r-biphenyl)[2-(2'-amino-l,r-biphenyl)]- palladium(II) methanesulfonate); TBAF (tetrabutylammonium fluoride); TBSC1 (rm-butyl- (dimethyl)silyl chloride); TEA (triethylamine); TFA (trifluoroacetic acid); TfiO (trifluoromethanesulfonic anhydride); TfOH (triflic acid); THF (tetrahydrofuran); TPAP (tetrapropylammonium perruthenate); TsCl (tosyl chloride); p-TsOH (p-toluenesulfonic acid); Xantphos ((9,9-dimethyl-9A-xanthene-4,5-diyl)bis(diphenyl-phosphane)); LCMS (liquid chromatography- mass spectrometry); MS (mass spectrometry); NMR (nuclear magnetic resonance); and prep- HPLC (preparative high performance liquid chromatography).
[00394] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions are conducted at room temperature unless otherwise specified. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.
Example 1
Preparation of 7-cyclopentyl-2-((4-(4-(2-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)ethyl)piperazin-l-yl)phenyl)amino)-Ar,A-dimethyl-7/7-pyrrolo[2,3-dr]pyrimidine- 6-carboxamide A104
Figure imgf000204_0001
[00395] Compound A104 was prepared as described below.
[00396] Preparation of benzyl 2-(3-bromophenoxy)acetate 1.1. To a solution of 3-bromo- phenol (20 g, 116 mmol) in acetone (200 mL) were added K2.CO3 (32 g, 231 mmol) and benzyl 2 -bromoacetate (32 g, 139 mmol). After stirring at 60 °C for 3 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2§04, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 1.1 (37 g) in a quantitative yield. !H NMR (400 MHz, CDCh) <5 7.44-7.31 (m, 5H), 7.16-7.10 (m, 2H), 7.08-7.03 (m, 1H), 6.87-6.78 (m, 1H), 5.24 (s, 2H), 4.65 (s, 2H).
[00397] Preparation of benzyl 2-[3-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetate 1.2. A mixture of compound 1.1 (4 g, 12.5 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (5.72 g, 13.7 mmol), Pd(dppf)C12,CH2C12 (509 mg, 623 pmol), and K3PO4 (5.29 g, 24.9 mmol) in water (5 mL) in dioxane (50 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 1.2 (4.4 g) in 64% yield. MS (ESI) m/z: 532.4 [M+H]+.
[00398] Preparation of 2-[3-(2,6-dioxo-3-piperidyl)phenoxy]acetic acid 1.3, To a solution of compound 1.2 (4.4 g, 8.28 mmol) in EtOH (10 mL) was added 10% Pd/C (2 g) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 1.3 (2 g), which was used directly in the next step without further purification. MS (ESI) m/z: 264 [M+H]+.
[00399] Preparation of tert-butyl 4-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3- <7]pyrimidin-2-yl]amino]phenyl]piperazine-l -carboxylate 1.4. A mixture of 2-chloro-7-cyclo- pentyl-A,A-dimethylpyrrolo[2,3-d]pyrimidine-6-carboxamide (3 g, 10.3 mmol), tert-butyl 4-(4- aminophenyl)piperazine-l -carboxylate (3.41 g, 12.3 mmol), CS2CO3 (5.01 g, 15.37 mmol), Pd(OAc)2 (58 mg, 256 pmol), and BINAP (319 mg, 512 pmol) in dioxane (40 mL) was stirred at 100 °C for 6 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 1.4 (5.1 g) in 90% yield. !H NMR (400 MHz, CDCI3) 3 8.60 (s, 1H), 7.62-7.57 (m, 2H), 7.21 (s, 1H), 6.95-6.91 (m, 2H), 6.39 (s, 1H), 4.81-4.64 (m, 1H), 3.61-3.57 (m, 4H), 3.14 (s, 6H), 3.09-3.05 (m, 4H), 2.63- 2.50 (m, 2H), 2.05 (d, J= 3.2 Hz, HI), 2.03-1.96 (m, 3H), 1.72-1.62 (m, 2H), 1 48 (s, 9H); MS (ESI) m/z: 534.4 [M+H]+.
[00400] Preparation of 7-cyclopentyl-iV,A-dimethyl-2-(4-piperazin-l-ylanilino)pyrrolo- [2,3-<7]pyrimidine-6-carboxamide 1.5, To a solution of compound 1.4 (5 g, 9.37 mmol) in DCM (20 mL) was added 4M HC1 in dioxane (25 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 1.5 as an HC1 salt (5 g), which was used directly in the next step without further purification. ‘H NMR (400 MHz, DMSO-ufe) <5 10.76 (s, 1H), 9.76 (s, 2H), 9.01 (s, 1H), 7.54 (d, J= 9.0 Hz, 2H), 7.14 (d, J= 9.0 Hz, 2H), 6.82 (s, 1H), 4.62 (q, J= 8.8 Hz, HI), 3.55 (s, 3H), 3.51-3.42 (m, 4H), 3.04 (d, J = 2.0 Hz, 6H), 2.32-2.19 (m, 2H), 2.05-1.90 (m, 2H), 1.85-1.74 (m, 2H), 1.60-1.50 (m, 2H); MS (ESI) m/z: 434.2 [M+H]+.
[00401 ] Preparation of tert-butyl 4-[2-[4-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-<7]pyriniidin-2-yl]amino]phenyl]piperazin-l-yl]ethyl]piperazine-l-carboxylate 1.6. To a solution of compound 1.5 as an HCI salt (0.4 g, 851 pmol) in DMF (5 mL) were added DIEA (330 mg, 2.55 mmol), tert-butyl 4-(2-chloroethyl)piperazine-l -carboxylate (254 mg, 1.02 mmol), and KI (14, 1 mg, 85 pmol). After stirring at 80 °C for 16 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound 1.6 (270 mg) in 47%. MS (ESI) m/z:
646.6 [M+H]+.
[00402] Preparation of 7-cyclopentyl-A,A-dimethyl-2-[4-[4-(2-piperazin- 1 -ylethyl)- piperazin-l-yl]anilino]pyrrolo[2,3-t/]pyrimidine-6-carboxamide 1.7. To a solution of compound
1.6 (200 mg, 310 pmol) in DCM (2 mL) was added 4M HC1 in dioxane (4 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 1.7 as an HCI salt (230 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 546.5 [M+H]+.
[00403] Preparation of 7-cyclopentyl-2-((4-(4-(2-(4-(2-(3-(2,6-dioxopiperidin-3- yl)phenoxy)acetyl)-piperazin- 1 -yl)ethyl)piperazin- 1 -yl)phenyl)amino)-A7,A-dimethyl-7rt- pyrrolo[2,3-t/]pyrimidine-6-carboxamide A104 To a solution of compound 1.7 as an HCI salt (230 mg, 395 pmol) in DMSO (3 mL) were added compound 1.3 (95 mg, 359 pmol), HOAt (54 mg, 395 umol), EDCI (76 mg, 395 pmol), and NMM (80 mg, 790 pmol). After stirring for 6 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A104 as an HCI salt (72 mg) in 28% yield. ]H NMR (400 MHz, DMSO-c/e) 3 11.46-10.89 (m, 1H), 10.84 (s, 1H), 9.76 (s, 1H), 8.80 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.29-7.20 (m, 1H), 7.04 (d, J~-~- 7.8 Hz, 2H), 6.89-6.77 (m, 3H), 6.66 (s, 1H), 4.89 (s, 2H), 4.69 (q, J= 8.8 Hz, 1H), 4.58-4.30 (m, 2H), 3.89-3.52 (m, 13H), 3.44-3.13 (m, 6H), 3.05 (s, 6H), 2.75-2.59 (m, 2H), 2.44-2.35 (m, 2H), 2.27- 2.13 (m, 1H), 2.09-1.87 (m, 5H), 1.67-1.52 (m. 2H); MS (ESI) m/z: 791.3 [M+H]+.
Example 2
Preparation of 7-cyclopentyl-2-((4-(4-(4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)butyl)piperazin-l-yl)phenyl)amino)-/V,A-dimethyl-7rt-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A105
Figure imgf000207_0001
[00404] Compound A105 was prepared as shown as described below.
[00405] Preparation of tert-butyl 4-[4-[4-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-<7]pyrimidin-2-yl]amino]phenyl]piperazin-l-yl]butyl]piperazine-l-carboxylate 2.1. To a solution of 7-cy clopentyl-A, A-dimethyl -2-(4-piperazin-l-ylanilino)pyrrolo[2, 3-tfJ- pyramidine-6-carboxamide as an HC1 salt (156 mg, 332 pmol) in MeOH (3 mL) were added NaOAc (82 mg, 995 pmol) and tert-butyl 4-(4-oxobutyl)piperazine-1 -carboxylate (170 mg, 663 pmol) at 0 °C. After the mixture was stirred for 10 min, NaBHsCN (42 mg, 663 pmol) was added. The reaction mixture was stirred for 6 h, and then concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 2.1 (240 mg) in 86% yield. !H NMR (400 MHz, CD3OD-J4) <5 8.58 (s, 1H), 7.64-7.56 (m, 2H), 7.01-6.92 (m, 2H), 6.52 (s, 1H), 4.69- 4.60 (m, Hz, 1H), 3.48 (d, J - 6.0 Hz, 4H), 3.27 (td, J= 1.6, 3.2 Hz, 10H), 3.18 (q, J = 7.2 Hz, 2H), 3.11 (s, 6H), 2.65-2.61 (m, 4H), 2.55-2.46 (m, 2H), 2.04-1.98 (m, 3H), 1.83-1.72 (m, 2H), 1.70-1.59 (ra, 5H), 1.43 (s, 9H).
[00406] Preparation of 7-cyclopentyl-A,A-dimethyl-2-[4-[4-(4-piperazin-l-ylbutyl)- piperazin-l-yl]-anilino]pyrrolo[2,3-t7]pyrimidine-6-carboxamide 2.2. To a solution of compound 2.1 (240 mg, 356 pmol) in DCM (2 mL) was added 4M HC1 in dioxane (2 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 2.2 as an HC1 salt (300 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 574.5 [M+H]+.
[00407] Preparation of 7-cyclopentyl-2-((4-(4-(4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)- phenoxy)acetyl)-piperazin- 1 -yl)butyl)piperazin- 1 -yl)phenyl)amino)-A,Ar-dimethyl-7#-pyrrolo- [2,3-<7]pyrimidine-6-carboxamide A105. To a solution of 2-[3-(2,6-dioxo-3-piperidyl)phenoxy]- acetic acid (63 mg, 239 pmol) in DMSO (2.5 mL) were added compound 2.2 as an HC1 salt (160 mg, 262 pmol), EDCT (50 mg, 262 gmol), HOAt (36 mg, 262 pmol), and NMM (53 mg, 524 umol). After stirring for 2 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A105 (37 mg) in 18% yield. %INMR (400 MHz, DMSO-tA/DzO) d 8.67 (s, 1H), 7.64 (d, J= 9.2 Hz, 2H), 7.28-7.18 (m, 1H), 6.88 (d, J= 9.2 Hz, 2H), 6.83-6.77 (m, 3H), 6.54 (s, 1H), 4.77 (s, 2H), 4.68 (q, J = 8.8 Hz, 1H), 3.81 (dd, J= 5.2, 11.2 Hz, 1H), 3.45 (s, 4H), 3.04 (s, 10H), 2.70-2.61 (m, 1H), 2.55 (s, 2H), 2.49-2.40 (m, 5H), 2.37 (s, 2H), 2.31 (s, 6H), 2.22-2.12 (m, 1H), 2.06-2.00 (m, 1H), 1.94 (s, 4H), 1.68-1.56 (m, 2H), 1.45 (s, 4H); MS (ESI) m/z: 819.6 [M+H]+.
Example 3
Preparation of 7-cyclopentyl-2-((4-(4-(2-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperidin-4-yl)ethyl)piperazin-l-yl)phenyl)amino)-A7,A/-dimethyl-777-pyrrolo[2,3-i/|pyrimidine- 6-carboxamide A106
Figure imgf000208_0001
[00408] Compound A106 was prepared as described below.
[00409] Preparation of tert-butyl 4-[2-[4-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-<7]pyrimidin-2-yl]amino]phenyl]piperazin-l-yl]ethyl]piperidine-l-carboxylate 3.1. To a solution of 7-cyclopentyl-A(AMimethyl-2-(4-piperazin-l-ylanilino)pyrrolo[2,3-tf]- pyrimidine-6-carboxamide as an HC1 salt (400 mg, 851 gmol) in MeOH (4 mL) were added NaOAc (209 mg, 2.55 mmol) and tert-butyl 4-(2-oxoethyl)piperidine-l -carboxylate (232 mg, 1.02 mmol). After the mixture was stirred at 0 °C for 10 min, NaBHsCN (107 mg, 1.7 mmol was added. The reaction mixture was stirred for 4 h, and then concentrated and purified by column chromatography (SiO?., MeOH/DCM) to afford compound 3.1 (454 mg) in 81% yield. rH NMR (400 MHz, DMSO-tA) 9.29 (s, 1H), 8.69 (s, 1H), 7.69 (d, ./ 8.8 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.55 (s, 1H), 4.72 (t, J= 8.8 Hz, 1H), 3.91 (d, J= 9.6 Hz, 2H), 3.33 (s, 4H), 3.05 (s, 8H), 2,68 (d, ./ 6.8 Hz, 4H), 2.43 (d, ./ 9.2 Hz, 2H), 1,96 (s, 4H), 1,69-1,60 (m, 6H), 1 ,54-1.43 (m, 2H), 1.39 (s, 9H), 1.09-0.94 (m, 3H); MS (ESI) m/z: 645.5 [M+H]t [00410] Preparation of 7-cyclopentyl-MA7-dimethyl-2-[4-[4-[2-(4-piperidyl)ethyl]- piperazin-l-yl]anilino]pyrrolo[2,3-<7]pyriniidine-6-carboxamide 3.2. To a solution of compound 3.1 (150 mg, 233 pmol) in DCM (2.00 mL) was added 4M HC1 in dioxane (0.40 mL) at 0 °C. After stirring for 2 h, the reaction mixture was concentrated to yield compound 3.2 as an HC1 salt (124 mg), which was used directly in the next step without further purification. MS (ESI) mz: 545.5 [M+H]+.
[00411] Preparation of 7-cyclopentyl-2-((4-(4-(2-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phen- oxy)acetyl)-piperidin-4-yl)ethyl)piperazin-l-yl)phenyl)amino)-jV,A'r-dimethyl-7/7-pyrrolo[2,3-</|- pyrimidine-6-carboxamide A106 To a solution of compound 3.2 as an HC1 salt (100 mg, 172 pmol) and 2-[3-(2,6-dioxo-3-piperidyl)phenoxy]acetic acid (45.3 mg, 172 pmol) in DMF (1 mL) were added DIEA (66.7 mg, 516 pmol) and HATU (78.5 mg, 206 pmol) at 0 °C. After stirring for 1 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A106 (25.7 mg) in 18% yield.
Figure imgf000209_0001
NMR (400 MHz, DMSO-c/o) ri 10.83 (s, 1H), 9.22 (s, 1H), 8 68 (s, 1H), 7.65 (d, J= 9.2 Hz, 2H), 7.23 (t, J= 8.0 Hz, 1H), 6.88 (d, J= 9.2 Hz, 2H), 6.84-6.73 (m, 3H), 6.55 (s, 1H), 4.82-4.65 (m, 3H), 4.30 (d, .7 12.8 Hz, 1H), 3.82 (dd, J 4.8, 11.2 Hz, 2H), 3.30 (s, 2H), 3.05 (s, 10H), 2.71-2.64 (m, 1 H), 2.62-2.54 (m, 4H), 2.46 (s, 3H), 2.37-2.32 (m, 2H), 2.25-2.14 (m, 1H), 2.06-2.00 (m, 1H), 1.96 (s, 4H), 1.72 (s, 2H), 1.66-1.51 (m, 3H), 1.45- 1.36 (m, 2H), 1.21-1.08 (m, 1H), 1.04-0.90 (m, 1H); MS (ESI) m/z: 790.5 [M+H]+.
Example 4
Preparation of 7-cyclopentyl-2-((4-(4-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperidin-4-yl)butyl)piperazin-l-yl)phenyl)amino)-A',7V-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A107
Figure imgf000209_0002
[00412] Compound A107 was prepared as described below.
[00413] Preparation of tert-butyl 4-[4-[4-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-<7]pyrimidin-2-y]]amino]phenyl]piperazin-l-yl]butyl]piperidine-l-carboxylate 4.1 To a solution of 7-cyclopentyl-Ar,A-dimethyl-2-(4-piperazin- 1 -ylanilino)pyrrolo[2,3-i/]- pyrimidine-6-carboxamide as an HC1 salt (400 mg, 851 pmol) and tert-butyl 4-(4-bromobutyl)- piperidine-1 -carboxylate (327 mg, 1.02 mmol) in DMF (4 mL) was added DIEA (330 mg, 2.55 mmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCft, concentrated, and purified by column chromatography (SiCh, MeOHZDCM) to afford compound 4.1 (680 mg). !H NMR (400 MHz, CDCh) 3 8.53 (s, 1H), 7.50 (d, J= 8.8 Hz, 2H), 6.92-6.83 (m, 3H), 6.33 (s, 1H), 4.74-4.63 (m, 1H), 4.00 (s, 4H), 3.47 (t, J= 6.8 Hz, 2H), 3.09-3.07 (m, 6H), 2.63-2.51 (m, 8H), 2.40-2.27 (m, 2H), 1.95 (s, 4H), 1.72-1.66 (m, 2H), 1.61-1.55 (m, 6H), 1.30-1.29 (m, 1H), 1.24-1.16 (m, 9H), 1.04-0.96 (m, 4H); MS (ESI) m/z: 673.5 [M+H]+
[00414] Preparation of 7-cyclopentyl-A’,A-dimethyl-2-[4-[4-[4-(4-piperidyl)butyl]- piperazin-l-yl]aniHno]pyrrolo[2,3-tf]pyrimidine-6-carboxamide 4.2. To a solution of compound 4.1 (120 mg, 178 pmol) in DCM (2 mL) was added 4M HC1 in dioxane (1 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 4.2 as an HC1 salt (100 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 573.4 [M+H]+.
[00415] Preparation of 7-cyclopentyl-2-[4-[4-[4-[l-[2-[3-(2,6-dioxo-3-piperidyl)phen- oxy]acetyl]-4-piperidyl]butyl]piperazin-l-yl]anilino]-A,A-dimethylpyrrolo[2,3-</|pyrimidine-6- carboxamide A107. To a solution of compound 4.2 as an HC1 salt (100 mg, 164 pmol) and 2-[3- (2,6-dioxo-3-piperidyl)phenoxy]acetic acid (43 mg, 164 pmol) in DMF (1.00 mL) were added NMM (37 mg, 361 pmol), HO At (25 mg, 181 pmol), and EDCI (35 mg, 181 pmol). After stirring for 2 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A107 (39 mg) in 26% yield. rH NMR (400 MHz, DMSO-rfc) 3 10.83 (s, 1H), 9.22 (s, 1H), 8.68 (s, 1H), 8.17 (s, 1H), 7.65 (d, 9.2 Hz, 2H), 7.23 (t, J = 8.0 Hz, 1H), 6.88 (d, J- 9.2 Hz, 2H), 6.83-6.76 (m, 3H), 6.55 (s, 1H), 4.82-4.65 (m, 3H), 4.31 (d, J= 12.0 Hz, 1H), 3.88-3.77 (m, 2H), 3.33-3.32 (m, 2H), 3.09-3.01 (m, 10H), 2.69-2.63 (m, 1H), 2.57-2.53 (m, 4H), 2.46-2.41 (m, 3H), 2.34-2.30 (m, 2H), 2.22-2.12 (m, 1H), 2.06-2.00 (m, 1H), 1.99-1.90 (m, 4H), 1.73-1.60 (m, 4H), 1,52-1.40 (m, 3H), 1.36-1.27 (m, 2H), 1,25-1,20 (m, 2H), 1.14-1.02 (m, 1H), 1 ,00-0,85 (m, 1H); MS (ESI) m/z-. 818.5 [M+H] \
Example 5
Preparation of 7-cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamido)- ethyl)piperazin-l-yl)phenyl)amino)-/V,A7-dimethyl-7Ar-pyrrolo[2,3-^]pyrimidine-6-carboxamide
A108
Figure imgf000211_0001
[00416] Compound Al 08 was prepared as described below.
[00417] Preparation of tert-butyl A/-[2-[4-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-(7]pyrimidin-2-yl]amino]phenyl] piperazin-l-yl]ethyl]carbamate 5.1. To a solution of 7-cyclopentyl-A,A-dimethyl-2-(4-piperazin-l -ylanilino)pyrrolo[2,3-tZ]pyrimidine-6- carboxamide (400 mg, 923 pmol) in DMF (4 mL) were added DIEA (358 mg, 2.77 mmol) and tert-butyl A-(2-bromoethyl)carbamate (248 mg, 1.11 mmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford 5.1 (100 mg) in 18% yield. MS (ESI) m/z\ 577.2 [M+H] \
[00418] Preparation of 2-[4-[4-(2-aminoethyl)piperazin- 1 -yl]anilino]-7-cyclopentyl-A’,AL dimethylpyrrolo[2,3-</]pyrimidine-6-carboxamide 5.2. To a solution of compound 5.1 (100 mg, 173 pmol) in DCM (1.5 mL) was added 4M HC1 in dioxane (0.50 mL) at 0 °C. After stirring for 1 h, the reaction mixture was concentrated to afford compound 5.2 as an HC1 salt (1 10 mg), which was used directly in the next step without further purification. MS (ESI) m/z'. 477.2 [M+H]+.
[00419] Preparation of 7-cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)- acetamido)ethyl)piperazin-l-yl)phenyl)amino)-A,A’-dimethyl-777-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A108. To a solution of compound 5.2 as an HC1 salt (110 mg, 199 pmol) and 2-[3- (2,6-dioxo-3-piperidyl)phenoxy]acetic acid (52.5 mg, 199 pmol) in DMSO (1.00 mL) were added NMM (44.4 mg, 439 pmol), EDCI (42 mg, 219 pmol), and HOAt (29.9 mg, 219 pmol). After stirring for 1 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A108 as a TFA salt (63 mg) in 41% yield. rH NMR (400 MHz, DMSO-<$>) d 10.83 (s, 1H), 9.23 (s, 1H), 8.68 (s, 1H), 8.15 (s, 1H), 7.99 (t, ./= 5.6 Hz, 1H), 7.65 (d, J= 9.2 Hz, 2H), 7.31-7.19 (m, 1H), 6.92-6.81 (m, 5H), 6.55 (s, 1H), 4.71 (q, J= 8.8 Hz, 1H), 4.47 (s, 2H), 3.82 (dd, ./ 4.8, 11.2 Hz, 1H), 3.29 (s, 2H), 3.04 (d, J= 3.2 Hz, 10H), 2.70-2.58 (m, 2H), 2.54 (s, 4H), 2.46-2.42 (m, 3H), 2.22-2.11 (m, 1H), 2.06-2.00 (m, 1H), 1.99-1.89 (m, 4H), 1.69-1.55 (m, 2H); MS (ESI) m/z: 722.4 [M+H]T
Example 6
Preparation of 7-cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamido)- propyl)piperazin-l-yl)phenyl)amino)-A,Ar-dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine-6-carboxamide
Alli
Figure imgf000212_0001
[00420] Compound Alli was prepared as described below.
[00421] Preparation of tert-butyl A-[3-[4-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-<7]pyrimidin-2-yl]amino]phenyl]piperazin-l-yl]propyl]carbamate 6.1. A mixture of 7-cyclopentyl-A7,A7-dimethyl-2-(4-piperazin-l-ylanilino)pyrrolo[2,3-<7]pyrimidine-6-carboxamide as an HC1 salt (1.4 g, 2.98 mmol), tert-butyl A-(3-bromopropyl)carbamate (2.31 g, 9.7 mmol), and DIEA (1.25 g, 9.67 mmol) in DMF (30 mL) was stirred at 80 °C for 16 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU, concentrated, and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 6.1 (130 mg) in 35% yield. MS (ESI) m/z'. 591.5 [M+H]+.
[00422] Preparation of 2-[4-[4-(3-aminopropyl)piperazin- 1 -yl]anilino]-7-cyclopentyl-A, A7- dimethylpyrrolo[2,3-<7]pyrimidine-6-carboxamide 6.2. To a solution of compound 6.1 (130 mg, 220 pmol) in DCM (1 mL) was added 4M HC1 in dioxane (55 pL). After stirring for 0.5 h, the reaction mixture was concentrated to afford compound 6.2 as an HC1 salt (115 mg), which was used directly in the next step without further purification. MS (ESI) m/z' : 491.4 [M+H]+.
[00423] Preparation of 7-cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)- acetamido)-propyl)piperazin-l-yl)phenyl)amino)-7V,Az-dimethyl-7H-pyrrolo[2,3-^pyrimidine-6- carboxamide Alli. A mixture of compound 6.2 (103 mg, 209 pmol), 2-[3-(2,6-dioxo-3- piperidyl)phenoxy]acetic acid (50 mg, 190 pmol), NMM (42 mg, 415 pmol), HO At (28 mg, 206 pmol), and EDCI (40 mg, 209 pmol) in DMSO (1 mL) was stirred for 12 h. The reaction mixture was then purified by reverse phase prep-HPLC to afford compound Alli (87 mg) as a TFA salt in 58% yield. !H NMR (400 MHz, DMSO-&) <5 10.83 (s, 1H), 9.22 (s, 1H), 8.68 (s, 1H), 8.19-8.08 (m, 2H), 7.65 (d, J= 9.2 Hz, 2H), 7.27-7.18 (m, 1H), 6.92-6.78 (m, 5H), 6.55 (s, 1H), 4.78-4.63 (m, 1H), 4.45 (s, 2H), 3.86-3.73 (m, 1H), 3,23-3,18 (m, 3H), 3,06 (br s, 10H), 2.64-2.58 (m, 1H), 2.45 (br d, J= 4.4 Hz, 5H), 2.37-2.29 (m, 3H), 2.22-2.10 (m, 1H), 2.02-1.89 (m, 5H), 1.67-1.57 (m, 4H); MS (ESI) m/z: 736.4 [M+H]+.
Example 7
Preparation of 7-cyclopentyl-2-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- phenyl)amino)-A’,Ar-dimethyl-7Z7-pyrrolo[2,3-J|pyrimidine-6-carboxamide A117
Figure imgf000213_0001
[00424] Compound Al 17 was prepared as described below.
[00425] Preparation of tert-butyl A-[3-(2,6-dibenzyloxy-3-pyridyl)phenyl]carbamate 7.1.
To a solution of tert-butyl A’-(3-bromophenyl)carbamate (2.61 g, 9.59 mmol) in dioxane (30 mL) were added Pd(dppf)Ch (783 mg, 959 pmol), K3PO4 (2.03 g, 9.59 mmol), and 2,6-dibenzyloxy- 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (2 g, 4.79 mmol). After stirring at 80 °C for 10 h, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 7.1 (1.6 g) in 69% yield. ’H NMR (400 MHz, DMSO-tfc) d 9.37 (s, 1H), 7.79-7.71 (m, 1H), 7.67 (d, ./ = 8.0 Hz, 1H), 7.48- 7.23 (m, 12H), 7.16-7.09 (m, 1H), 6.55 (d, J= 8.0 Hz, 1H), 5.39 (d, J= 9.6 Hz, 4H), 1.49 (s, 9H).
[00426] Preparation of tert-butyl A-[3-(2,6-dioxo-3-piperidyl)phenyl]carbamate 7.2. To a solution of compound 7.1 (1.5 g, 3.11 mmol) in THF (15 niL) was added 10% Pd/C (500 mg). After stirring under Hz for 10 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 7.2 (850 mg) in 88% yield. !H NMR (400 MHz, DMSO-tfe) d 10.84 (s, 1H), 9.33 (s, 1H), 7.38 (s, 1H), 7.33-7.26 (m, 1H), 7.20 (t, .7= 7,6 Hz, 1H), 6.82 (d, J= 7.6 Hz, 1H), 3.80 (dd, .7= 5,2, 10.4 Hz, 1H), 2.75-2.60 (m, 1H), 2.48-2.43 (m, 1H), 2.19-2.02 (m, 2H), 1.47 (s, 9H).
[00427] Preparation of 3-(3-aminophenyl)piperidine-2,6-dione 7.3. A solution of compound 7.2 (600 mg, 1.97 mmol) in 4M HC1 in dioxane (6 mL) was stirred at 30 °C for 1 h. The reaction mixture was then concentrated to afford compound 7.3 as an HC1 salt (470 mg), which was used directly in the next step without further purification .
[00428] Preparation of 3-(3-iodophenyl)piperidine-2,6-dione 7.4. To a solution of compound 7.3 (470 mg, 1.95 mmol) in ACN (13 mL) was added p-TsOH (1.01 g, 5.86 mmol), followed by dropwise addition of a solution of KI (810 mg, 4.88 mmol) and NaNOz (269 mg, 3.91 mmol) in water (1.6 mL) at 0 °C. After stirring at 0 °C for 1 h and then at 25 °C for 10 h, the reaction mixture was treated with saturated aqueous NazSCh (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 7.4 (500 mg) in 81% yield.
[00429] Preparation of 7-cyclopentyl-2-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-phenyl)amino)-A,A-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A117. To a solution of compound 7.4 (500 mg, 1.59 mmol) in dioxane (10 mL) were added CszCOs (1.03 g, 3.17 mmol), RuPhos Pd G3 (265 mg, 317 pmol), RuPhos (148 mg, 317 pmol), and 7-cyclopentyl-AjV-dimethyl-2-(4-piperazin-l-ylanilino)pyrrolo[2,3-</jpyrimidine-6- carboxamide as an HC1 salt (597 mg, 1 .27 mmol). After stirring at 100 °C for 10 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound Al 17 (13 mg) in 1.3% yield. ’H NMR (400 MHz, DMSO-sfc) d 10.82 (s, 1H), 9.27 (s, 1H), 8.70 (s, 1H), 7.70 (d, J= 8.8 Hz, 2H), 7.20 (t, J= 8.0 Hz, 1H), 6.97 (d, J = 9.2 Hz, 2H), 6.91-6.88 (m, 2H), 6.66 (d, J= 7.2 Hz, 1H), 6.56 (s, 1H), 4.80-4.68 (m, 1H), 3.79 (dd, J= 5.2, 12.8 Hz, 1H), 3.33-3.28 (m, 8H), 3.22 (s, 6H), 2.66-2.63 (m, 2H), 2.50-2.47 (m, 2H), 2.15-2.06 (m, 1H), 1.98- 1.95 (m, 5H), 1.65-1.64 (m, 2H); MS (ESI) m/z: 621.4 [M+Hf.
Example 8
Preparation of 7-cyclopentyl-2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- phenyl)amino)-A7,A-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A119
Figure imgf000215_0001
[00430] Compound A119 was prepared as described below.
[00431] Preparation of 3-[4-(2-hydroxyethyl)phenyl]piperidine-2, 6-dione 8.1. To a solution of 2-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]ethanol (1 g, 2.43 mmol) in THF (5 mL) and EtOH (5 mL) was added 10% Pd/C (0.5 g) under N2. After stirring under H2 at 40 °C for 16 h, the reaction mixture was filtered and concentrated to afford compound 8.1 (609 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 234.1 [M+H]+.
[00432] Preparation of 2-[4-(2,6-dioxo-3-piperidyl)phenyl]acetaldehyde 8.2. To a solution of compound 8.1 (200 mg, 857 pmol) in DCM (5 mL) was added Dess-Martin (727 mg, 1.71 mmol). After stirring for 2 h, the reaction mixture was neutralized with NaHCCh to pH 7, diluted with H2O, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, and concentrated to afford compound 8.2 (176 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 232.2 [M+H]+
[00433] Preparation of 7-cyclopentyl-2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)- piperazin-l-yl)-phenyl)amino)-A/,7V-dimethyl-7H-pyrrolo[2,3-6f]pyrimidine-6-carboxamide Al 19. To a solution of 7-cyclopentyl-A,iV-dimethyl-2-(4-piperazin-l-ylanilino)pyrrolo[2,3- <7]pyrimidine-6-carboxamide as an HC1 salt (100 mg, 213 pmol) in MeOH (2 mL) was added NaOAc (52.4 mg, 638 pmol). After the mixture was stirred for 15 min, compound 8.2 (73.8 mg, 319 pmol) and NaBEECN (26.7 mg, 426 pmol) were added. The reaction mixture was stirred for 3 h, and then diluted with water and extracted with DCM The combined organic layers were dried over anhydrous NazSCk, concentrated, and purified by reverse phase prep-HPLC to afford compound A119 (28 mg) in 19% yield.
Figure imgf000216_0001
NMR (400 MHz, DMSO-dfc) d 10.81 (s, 1H), 9.22 (s, 1H), 8.68 (s, 1H), 8.25 (s, 1H), 7.65 (d, J= 8.8 Hz, 2H), 7.26-7.17 (m, 2H), 7.13 (d, J= 8.0 Hz, 2H), 6.89 (d, J= 9.2 Hz, 2H), 6.55 (s, 1H), 4.77-4.65 (m, 1H), 3.81 (dd, J = 4.8, 11.2 Hz, 1H), 3.07 (d, ./= 4.4 Hz, 1 OH), 2.80-2.72 (m, 2H), 2.71-2.63 (m, 1H), 2.63-2.54 (m, 6H), 2.48-2.38 (m, 3H), 2.24-2.11 (m, 1H), 2.07-1.89 (m, 5H), 1.63 (d, J= 5.2 Hz, 2H); MS (ESI) m/z: 649.3 [M+H]+.
Example 9
Preparation of 7-cyclopentyl-2-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- phenyl)amino)-A'r,A’-dimethyl-7Z/-pyrrolo[2,3-47]pyrimidine-6-carboxamide A120
Figure imgf000216_0002
[00434] Compound Al 20 was prepared as described below.
[00435] Preparation of 2-[3-(2,6-dioxo-3-piperidyl)phenyl]ethyl 4-methylbenzene- sulfonate 9.1. To a solution of 3-[3-(2-hydroxyethyl)phenyl]piperidine-2, 6-dione (500 mg, 2.14 mmol) in DCM (5 mL) were added TsCl (817 mg, 4.29 mmol), TEA (651 mg, 6.43 mmol), and DMAP (131 mg, 1 .07 mmol). After stirring for 12 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 9.1 (800 mg) in 96% yield. MS (ESI) m/z: 388.2 [M+H]“.
[00436] Preparation of 7-cyclopentyl-2-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)- piperazin-l-yl)-phenyl)amino)-Az,A’-dimethyl-71L/-pyrrolo[2,3-t/]pyrimidine-6-carboxamide
A120. To a solution of compound 9.1 (89 mg, 231 pmol) and 7-cyclopentyl-A7v-dimethyl-2-(4- piperazin-l-ylanilino)pyrrolo[2,3-c7]pyrimidine-6-carboxamide (100 mg, 231 pmol) in DMF (0.3 mL) was added DIEA (89 mg, 692 pmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by prep-TLC (SiO?., MeOHZDCM) and reverse phase prep-HPLC to afford compound A120 (58 mg) in 38% yield. ftl NMR (400 MHz, CDiOD) 3 8.61 (s, 1H), 8.46 (s, 1H), 7.62 (d, J= 9.2 Hz, 2H), 7.35-7.29 (m, 1H), 7.24-7.11 (m, 3H), 6.99 (d, J = 9.2 Hz, 2H), 6.55 (s, 1H), 4.75-4.67 (m, 1H), 3.93-3.80 (m, 1 H), 3.25 (d, J= 4.8 Hz, 4H), 3.15 (s, 6H), 2.99 (s, 4H), 2.94 (s, 4H), 2.77-2.62 (m, 2H), 2.59- 2.48 (m, 2H), 2.32-2.17 (m, 2H), 2.08-1.96 (m, 4H), 1.76-1.59 (m, 2H); MS (ESI) m/z: 649.5 [M+H]+.
Example 10
Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)phenyl)amino)-7V,A'-dimethyl -777-pyrrol o[2,3 -d]pyrimi dine-6-carboxamide A122
Figure imgf000217_0001
[00437] Compound Al 22 was prepared as described below.
[00438] Preparation of 4-[2-[terCbutyl(dimethyl)silyl]oxyethyl]aniline 10.1. To a solution of 2-(4-aminophenyl)ethanol (6 g, 43.7 mmol) in DCM (50 mL) were added TBSC1 (9.89 g, 65.6 mmol) and TEA (8.85 g, 87.5 mmol). After stirring for 12 h, the reaction mixture was concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 10.1 (11.6 g). MS (ESI) m/z: 252.2 [M+H]+.
[00439] Preparation of 2-[4-[2-[/eH-butyI(dimethyl)silyl]oxyethyl]anilino]-7-cyclopentyl- A(A-dimethylpyrrolo[2,3-d]pyrimidine-6-carboxamide 10.2. A mixture of 2-chloro-7-cyclo- pentyl-A(AMimethylpyrrolo[2,3-^pyrimidine-6-carboxamide (3 g, 10.3 mmol), compound 10.1 (2.58 g, 10.3 mmol), Pd(OAc)2 (115 mg, 512 pmol), BINAP (638 mg, 1.02 mmol), and CS2CO3
(6.68 g, 20.5 mmol) in dioxane (30 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 10.2 (3.3 g) in 61% yield. MS (ESI) m/z: 508.4 [M+H]+.
[00440] Preparation of 7-cyclopentyl-2-[4-(2-hydroxyethyl)anilino]-AyV-dimethyl- pyrrolo[2,3-J]pyriraidine-6-carboxamide 10.3, To a solution of compound 10.2 (3.3 g, 6.5 mmol) in DCM (10 mL) was added 4M HC1 in dioxane (10 mL). After stirring for 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 10.3 (2.9 g). MS (ESI) m/z: 433.4 [M+H]+,
[00441 ] Preparation of 2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-</j- pyrimidin-2-yl]amino]phenyl] ethyl 4-methylbenzenesulfonate 10.4. A mixture of compound 10.3 (2.9 g, 7.37 mmol), TsCl (2. 11 g, 11.1 mmol), and TEA (1.49 g, 14.7 mmol) in DCM (30 mL) was stirred for 2 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 10.4 (2.1 g) in 47% yield. MS (ESI) m/z: 548.3 [M+H]+.
[00442] Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-ethyl)phenyl)amino)-A,7'7-dimethyl-7H-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A122. To a solution of compound 10.4 (100 mg, 183 pmol) and 3-(4-piperazin-l-ylphenyl)- piperidine-2, 6-dione as an HC1 salt (56.6 mg, 183 pmol) in DMF (1 mL) were added KI (3.03 mg, 18.3 pmol) and DIEA (71 mg, 548 pmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with DMF (1 mL) and purified by reverse phase prep-HPLC to afford compound A122 (5.4 mg) in 5% yield. ‘HNMR (400 MHz, DMSO-^) 3 10.78 (s, 1H), 9.42 (s, 1H), 8.73 (s, 1H), 8. 15 (s, 1H), 7.74 (d, J= 8.4 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 7.06 (d, J= 8.8 Hz, 2H), 6.90 (d, J- 8.8 Hz, 2H), 6.58 (s, 1H), 4.79-4.65 (m, 1H), 3.73 (dd, ./- 4.8, 10.8 Hz, 1H), 3.13 (d, J= 4.8 Hz, 4H), 3.06 (s, 6H), 2.77-2.71 (m, 2H), 2.65-2.53 (m, 8H), 2. 46-2.42 (m, 2H), 2.21-2.02 (m, 2H), 2.01-1.94 (m, 4H), 1.70-1.60 (m, 2H); MS (ESI) m/z: 649.5 [M+H]+ Example 1 1
Preparation of 7-cyclopentyl-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A,A-dimethyl-777-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A126
Figure imgf000219_0001
[00443] Compound Al 26 was prepared as described below.
[00444] Preparation of 3-(4-bromophenyl)-l -[(4-methoxyphenyl) methyl]piperidine-2,6- dione 11.1. To a solution of 3-(4-bromophenyl)piperidine-2, 6-dione (0.8 g, 2.98 mmol) in DMF (10 mL) were added K2CO3 (412 mg, 2.98 mmol) and PMBC1 (514 mg, 3 28 mmol). After stirring at 30 °C for 16 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous Na2SOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 11.1 (1 g) in 86% yield. rH NMR (400 MHz, CDCh) J 7.47 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.00 (d, ./= 8.4 Hz, 2H), 6.83 (d, ./= 8.8 Hz, 2H), 5.02-4.88 (m, 2H), 3.82-3.72 (m, 4H), 2.86-2.64 (m, 2H), 2.28-2.08 (m, 2H).
[00445] Preparation of 7-cyclopentyl-2-[4-[4-[l-[4-[l-[(4-methoxyphenyl)methyl]-2,6- dioxo-3-piperidyl]phenyl]-4-piperidyl]piperazin-l-yl]anilino]-A,A-dimethyl-pyrrolo[2,3-<Z]- pyrimidine-6-carboxamide 11.2, To a mixture of compound 11.1 (488 mg, 1.26 mmol) and 7- cyclopentyl-A,A-dimethyl-2-[4-[4-(4-piperidyl)piperazin-l-yl]anilino]pyrrolo[2,3-</|pyrimidine- 6-carboxamide (501 mg, 969 pmol) in dioxane (10 mL) were added CS2CO3 (632 mg, 1.94 mmol) and RuPhos Pd G3 (162 mg, 194 jrmol) under N2. After stirring at 100 °C for 16 h, the reaction mixture was concentrated and purified by column chromatography (S1O2, MeOH/EtOAc) to afford compound 11.2 (300 mg) in 38% yield. !H NMR (400 MHz, DMSO- d6) 3 9.22 (s, 1H), 8.68 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7. 18 (d, ./ 8.8 Hz, 2H), 7.00 (d, ./ 8.8 Hz, 2H), 6.93-6.80 (m, 7H), 6.55 (s, 1H), 4.79 (s, 2H), 4.71 (td, J= 8.8, 17.2 Hz, 1H), 3.90 (dd, J = 4.6, 10,8 Hz, 1H), 3,76-3,68 (m, 5H), 3,05 (br s, 13H), 2,71-2,62 (m, 9H), 1,98-1 ,86 (m, 7H), 1.66-1.57 (m, 3H); MS (ESI) m/z: 824.7 [M+H]t [00446] Preparation of 7-cy cl opentyl-2-((4-(4-(l-(4-(2,6-dioxopiperi din-3 -yl)phenyl)- piperidin-4-yl)-piperazin-l-yl)phenyl)amino)-7V,Az-dimethyl-7/7-pyrrolo[2,3-J]pyrimidine-6- carboxamide A126. To a mixture of compound 11.2 (220 mg, 267 pmol) in DCM (1 mL) were added TFA (770 mg, 6.75 mmol) and TfOH (1.19 g, 7.93 mmol). After stirring at 30 °C for 16 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A126 as a TFA salt (46 mg) in 23% yield. *H NMR (400 MHz, DMSO-d6 ) 3 = 10.77 (s, 1H), 9.23 (s, 1H), 8.68 (s, 1H), 8.13 (s, 1H), 7.66 (br d. ./ 9.0 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.90 (dd, J= 5.8, 8.8 Hz, 4H), 6.55 (s, 1H), 4.71 (td, J= 8.8, 17.5 Hz, 1H), 3.79-3.67 (m, 2H), 3.05 (br s, 10H), 2.87-2.57 (m, 6H), 2.49-2.41 (m, 7H), 2.19-2.06 (m, 1H), 2.04-1.88 (m, 6H), 1.72-1.46 (m, 4H); MS (ESI) m/z: 704.3 [M+H]+
Example 12
Preparation of 7-cyclopentyl-2-((4-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)-piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A'7'v;-dimethyl-7Z/-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A127
Figure imgf000220_0001
[00447] Compound Al 27 was prepared as described below.
[00448] Preparation of 5 -(tert-butyl) 1-ethyl 2-(3-bromophenyl)pentanedioate 12.1. To a solution of ethyl 2-(3-bromophenyl)acetate (9 g, 37 mmol) and tert-butyl prop-2-enoate (4.75 g, 37 mmol) in THF (36 mL) was added t-BuONa (712 mg, 7.40 mmol) at -30 °C under N2. After stirring for 1 h at -30 °C under N2, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 12.1 (6 g) in 44% yield. 'H NMR (400 MHz, DMSO-^) <57.53-7.44 (m, 2H), 7.33-7.26 (m, 2H), 4.12-4.04 (m, 2H), 3.72-3.62 (m, 1H), 2.21-2.05 (m, 4H), 1.37 (s, 9H), 1.13 (t, ./ 7.1 Hz, 3H).
[00449] Preparation of 2-(3-bromophenyl)pentanedioic acid 12.2. To a mixture of compound 12.1 (5.3 g, 14.3 mmol) in MeOH (27 mL) and H2O (27 mL) was added NaOH (2.85 g, 71.4 mmol) at 0 °C. After stirring for 3 h at 60 °C, the reaction mixture was concentrated, diluted with water, acidified to pH 3 with cone. HC1, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, and concentrated to afford compound 12.2 (4 g), which was used directly in the next step without further purification.
Figure imgf000221_0001
NAIR (400 MHz, DMSO-tfe) (5 12.55-11.86 (m, 2H), 7.51-7.44 (m, 2H), 7.35-7.25 (m, 2H), 3.63- 3.54 (m, 1H), 2.22-2.05 (m, 3H), 1.89-1.82 (m, 1H).
[00450] Preparation of 3-(3-bromophenyl)tetrahydropyran-2, 6-dione 12.3. A solution of compound 12.2 (3.27 g, 11.4 mmol) in AcrO (22 mL) was stirred for 16 h at 80 °C under N2.
The reaction mixture was then concentrated to afford compound 12.3 (3.06 g), which was used directly in the next step without further purification. TH NMR (400 MHz, DMSO-d6 ) <5 7.56 (d, J = 0.9 Hz, 1H), 7.54-7.49 (m, 1H), 7.37-7.30 (m, 2H), 4.18 (dd, J= 5.3, 13.0 Hz, 1H), 3.03-2.82 (m, 2H), 2.41 (dq, J- 5.0, 12.9 Hz, 1H), 2.02 (ttd, ./ ■■■ 2.7, 5.5, 10.5 Hz, 1H).
[00451] Preparation of 5-amino-4-(3-bromophenyl)-5-oxo-pentanoic acid 12.4. To a solution of compound 12.3 (3 g, 11.2 mmol) in DCM (32 mL) under N2 was added 4M NH3 in MeOH (9.49 g, 557 mmol). After stirring for 15.5 h, the reaction mixture was concentrated to afford compound 12.4 (3.2 g), which was used directly in the next step without further purification. NMR (400 MHz, DMSO-^) d 7.58-7.41 (m, 3H), 7.36 (td, J = 2.2, 6.7 Hz, 1H), 7.31-7.23 (m, 3H), 3.26 (br s, 1H), 2.12-2.00 (m, 4H).
[00452] Preparation of 3 -(3 -brom ophenyl)piperidine-2, 6-dione 12.5. A solution of compound 12.4 (3.2 g, 11.18 mmol) in AczO (26 mL) was stirred for 16 h at 60 °C under N?..
The reaction mixture was concentrated to afford compound 12.5 (2.95 g), which was used directly in the next step without further purification. lH NMR (400 MHz, DMSO-d6 ) 3 10.86 (br s, 1H), 7.52-7.43 (m, 2H), 7.35-7.19 (m, 2H), 3.90 (dd, ./ 4.8, 12.1 Hz, 1H), 2.73-2.61 (m, 1 H), 2.53 (br d, J= 3.9 Hz, 1H), 2.25 (dq, J= 4.3, 12.5 Hz, 1H), 2.08-1.94 (m, 1H).
[00453] Preparation of 7-cyclopentyl-2-((4-(4-(l -(3-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-piperazin-l-yl)phenyl)amino)-A)A-dimethyl-77/-pyrrolo[2,3-rf|pyrimidine-6- carboxamide Al 27. To a mixture of 7-cyclopentyl-A,A-dimethyl-2-[4-[4-(4-piperidyl)piperazin- l-yl]anilino]pyrrolo[2,3-<7]pyrimidine-6-carboxamide (100 mg, 194 pmol) and compound 12.5 (62.3 mg, 232 pmol) in dioxane (2 mL) were added RuPhos Pd G3 (32.4 mg, 38.7 pmol), RuPhos (18.1 mg, 38.7 pmol), and CS2CO3 (126 mg, 387 pmol). After stirring at 100 °C for 16 h under N2, the reaction mixture was concentrated and purified by column chromatography (S1O2, MeOH/EtOAc) and reverse phase prep-HPLC to afford compound A127 as a TFA salt (5.4 mg) in 3.7% yield. ^I NAIR (400 MHz, DMSO-<&) 8 = 10.79 (s, HI), 9.21 (s, 1H), 8.68 (s, 1H), 8 18 (s, 1H), 7.65 (d, J= 9.0 Hz, 2H), 7.14 (t, J= 7.8 Hz, 1H), 6.93-6.77 (m, 4H), 6.59 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 4.80-4.63 (m, 1H), 3.80-3.68 (m, 3H), 3.05 (br d, ./ 2.1 Hz, 10H), 2.70-2.62 (m, 6H), 2.48-2.12 (m, 6H), 2.05-1.87 (m, 7H), 1.70-1.47 (m, 4H); MS (ESI) m/z: 704.2 [M+H]+.
Example 13
Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- ethyl)phenyl)amino)-A'r,A-dimethyl-77/-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A128
Figure imgf000222_0001
[00454] Compound A128 was prepared described below.
[00455] Preparation of [4-(2,6-dibenzyloxy-3-pyridyl)phenyl]methanol 13.1. A mixture of (4-bromophenyl)methanol (10 g, 53.5 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (24.5 g, 58.8 mmol), PdldppflCh CIbCb (2.18 g, 2.67 mmol), and K3PO4 (22.7 g, 107 mmol) in dioxane (100 mL) and H2O (20 mL) was stirred at 100 °C for 16 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 13.1 (18.3 g) in 86% yield. lH NMR (400 MHz, DMSO-tZe) d 7.72 (d, J- 8.0 Hz, 1H), 7.50 (d, 8.0 Hz, 2H), 7.47-7.42 (m, 2H), 7.41-7.30 (m, 9H), 6.55 (d, J= 8.0 Hz, 1H), 5.39 (d, J = 9.2 Hz, 4H), 5.18 (t, ./ 5.6 Hz, 1H), 4.51 (d, J= 5.6 Hz, 2H), 3.94 (s, 1 H); MS (ESI) m/z: 398.2 [M+H]+.
[00456] Preparation of terLbutyl-[[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]methoxy]- dimethylsilane 13.2. To a mixture of compound 13.1 (18.3 g, 46 mmol) and imidazole (6.27 g, 92.1 mmol) in DCM (210 mL) was added TBSC1 (8.33 g, 55.3 mmol) at 0 °C. After stirring for 2 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 13.2 (20.9 g) in 89% yield. [HNMR (400 MHz, DMSO-d>) d 7.72 (d, ./ 8.0 Hz, 1H), 7.52 (d, .7 8.4 Hz, 2H), 7.45-7.42 (m, 2H), 7.40-7.27 (m, 10H), 6.54 (d, .7= 8.0 Hz, 1H), 5.38 (d, .7= 11.6 Hz, 4H), 4.72 (s, 2H), 0.93-0.89 (m, 9H), 0.11-0.06 (m, 6H); MS (ESI) rn/z: 512.2 [M+H]t
[00457] Preparation of 3-[4-[[ter/-butyl(dimethyl)silyl]oxymethyl]phenyl]piperidine-2,6- dione 13.3. To a solution of compound 13.2 (2 g, 3.91 mmol) in THF (20 mL) was added 10% Pd/C (200 mg) under N2. After stirring under H2 for 2 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 13.3 (400 mg) in 27% yield. ]H NMR (400 MHz, DMSO-Je) d 10.82 (s, 1H), 7.29-7.24 (m, 2H), 7.21-7.16 (m, 2H), 4.69 (s, 2H), 3.87-3.80 (m, 1H), 2.72-2.59 (m, 1H), 2.50-2.44 (m, 1H), 2.25- 2.12 (m, 1H), 2.08-2.00 (m, 1H), 0.91 (s, 9H), 0.17-0.01 (m, 6H); MS (ESI) m/z: 334.2 [M+H]+.
[00458] Preparation of 3-[4-(hydroxymethyl)phenyl]piperidine-2, 6-dione 13.4. To a solution of compound 13.3 (300 mg, 900 pmol) in DCM (2 mL) was added 4M HC1 in dioxane (6 mL). After stirring for 1 h, the reaction mixture was filtered and purified by column chromatography (S1O2, EtOAc/PE) to afford compound 13.4 (180 mg) in 78% yield. rH NMR (400 MHz, DMSO-^6) d 10.73 (s, 1H), 7.19 (d, 8.0 Hz, 2H), 7.08 (d, J= 8.0 Hz, 2H), 5.06 (t,
5.6 Hz, 1H), 4.39 (d, J= 5.6 Hz, 2H), 3.80-3.69 (m, 1H), 3.08 (d, J = 5.2 Hz, 1H), 2.62-2.52 (m, 1H), 2.15-2.04 (m, 1H), 1.99-1.89 (m, 1H); MS (ESI) mA: 220 [M+H]+.
[00459] Preparation of 3-[4-(bromomethyl)phenyl]piperidine-2, 6-dione 13.5, To a solution of compound 13.4 (860 mg, 3.92 mmol) in ACN (10 mL) was added PBn (1.06 g, 3.92 mmol) dropwise at 0 °C. After stirring 80 °C for 1.5 h, the reaction mixture was treated with saturated aqueous NaHCOs and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S0r, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 13.5 (700 mg) in 63% yield. MS (ESI) m/z : 282 [M+H]+.
[00460] Preparation of 7-cyclopentyl-2-[4-(2-hydroxyethyl)anilino]-A,A-dimethyl- pyrrol o[2, 3 -<7]pyrimidine-6-carboxamide 13.6, To a solution of 2-chloro-7-cyclopentyl-/V/7- dimethylpyrrolo[2,3-<7]pyrimidine-6-carboxamide (2 g, 6.83 mmol) and 2-(4-aminophenyl)- ethanol (984 mg, 7.17 mmol) in dioxane (20 mL) were added CsrCCh (4.45 g, 13.66 mmol), Pd2(dba)s (626 mg, 683 gmol), and Xantphos (791 mg, 1.37 mmol). After stirring at 100 °C for 12 h under N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 13.6 (1.6 g) in 48% yield. MS (ESI) m/z: 394.3 [M+H]+.
[00461] Preparation of 2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-d]- pyrimidin-2-yl]amino]phenyl]ethyl 4-methylbenzenesulfonate 13.7. To a solution of compound
13.6 (500 mg, 1 .27 mmol) in DCM (5 mL) were added TEA (386 mg, 3,81 mmol) and TsCl (315 mg, 1.65 mmol) at 0 °C. After stirring for 3 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SOi, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound
13.7 (620 mg) in 74% yield. Tl NMR (400 MHz, DMSO-d6 ) d 9.47 (s, 1 H), 8.74 (s, 1H), 7.71 (d, ./= 8.4 Hz, 2H), 7.67 (d, J= 8.4 Hz, 2H), 7.40 (d, J= 8.0 Hz, 2H), 7.05 (d, J= 8.4 Hz, 2H), 6.58 (s, 1H), 4.77-4.69 (m, 1H), 4.20 (t, J= 6.4 Hz, 2H), 3.33 (s, 6H), 2.83 (t, J= 6.4 Hz, 2H), 2.37 (s, 3H), 2.20-2.14 (m, 1H), 1.98-1.88 (m, 5H), 1.69-1.61 (m, 2H); MS (ESI) m/z: 548.5 [M+H]+.
[00462] Preparation of terLbutyl 4-[2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2, 3-<7]pyrimidin-2-yl]amino]phenyl]ethyl]piperazine-l -carboxylate 13.8. To a solution of compound 13.7 (650 mg, 1.19 mmol) in DMF (8 mL) were added tert-butyl piperazine- 1- carboxylate (221 mg, 1.19 mmol), DIEA (460 mg, 3.56 mmol), and KI (19.7 mg, 119 gmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 13.8 (590 mg). MS (ESI) m/z: 562.5 [M+H]+.
[00463] Preparation of 7-cyclopentyl-A,A-dimethyl-2-[4-(2-piperazin-l-ylethyl)anilino]- pyrrolo[2,3-</]pyrimidine-6-carboxamide 13.9. To a solution of compound 13.8 (590 mg, 1.05 mmol) in DCM (4 mL) was added 4M HC1 in dioxane (4 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 13.9 as an HC1 salt (520 mg), which was used directly in the next step without further purification. AIS (ESI) m/z'. 462.3 [M+H]+.
[00464] Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)- piperazin-l-yl)-ethyl)phenyl)amino)-A,A-diniethyl-7/f-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A128, To a solution of compound 13.9 as an HC1 salt (88.3 mg, 177 umol) in DMF (2 mL) were added DIEA (68.7 mg, 532 pmol), compound 13.5 (50 mg, 177 pmol), and KI (2.9 mg, 17.7 umol). After stirring at 80 °C for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound Al 28 (47 mg). lH NAIR (400 MHz, DMSO-cfc) 3 10.82 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 7.71 (d, J= 8.4 Hz, 2H), 7.27-7.23 (m, 2H), 7.14 (dd, J = 8.0, 17,2 Hz, 4H), 6,57 (s, 1H), 4,80-4,64 (m, 1H), 3,83 (dd, J= 5.2, 11 ,2 Hz, 1H), 3,43 (s, 2H), 3.05 (s, 6H), 2.71-2.59 (m, 4H), 2.44-2.34 (m, 10H), 2.26-2.10 (m, 2H), 2.08-2.02 (m, 1H), 2.08-1.90 (m, 3H), 1.69-1.60 (m, 2H); MS (ESI) m, !z. 663.4 [MEH]*.
Example 14
Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- ethoxy)phenyl)amino)-A(A-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A130
Figure imgf000225_0001
[00465] Compound A130 was prepared described below.
[00466] Preparation of 2-(4-benzyloxyanilino)-7-cyclopentyl-AyV-dimethylpyrrolo[2,3-</]- pyrimidine-6-carboxamide 14.1. A mixture of 2-chloro-7-cyclopentyl-A7,A-dimethylpyrrolo- [2,3-J]pyrimidine-6-carboxamide (16 g, 54.7 mmol), 4-benzyloxyaniline (10.9 g, 54.7 mmol), Xantphos (3.16 g, 5.47 mmol), Pdr(dba)3 (2.5 g, 2.73 mmol), and CS2CO3 (35.6 g, 109 mmol) in dioxane (100 mL) was stirred at 100 °C for 16 h under N?.. The reaction mixture was filtered, concentrated, and purified by column chromatography (Si O2, EtOAc/PE) to afford compound 14.1 (15.5 g) in 60% yield. Pl NAIR (400 MHz, CDCI3) 3 8.61 (s, 1H), 7.58 (d, J= 9.2 Hz, 2H), 7.49-7 42 (m, 2H), 7.39 (t, J- 7.6 Hz, 2H), 7.35-7.30 (m, 1H), 7.15 (s, 1H), 6.97 (d, 8.8 Hz,
2H), 6.40 (s, 1H), 5.07 (s, 2H), 4.75 (q, J= 8.8 Hz, 1H), 3.15 (s, 6H), 2.13-1.82 (m, 6H), 1.73- 1.57 (m, 2H); MS (ESI) m/z: 456.4 [M+H]+.
[00467] Preparation of 7-cyclopentyl-2-(4-hydroxyanilino)-A,A;-dimethylpyrrolo[2,3-</] pyrimidine-6-carboxamide 14.2. To a solution of compound 14.1 (7.25 g, 15.9 mmol) in THF (35 mL) and EtOH (35 mL) was added 10% Pd/C (7 g) under N2. After stirring under H2 at 50 °C for 16 h, the reaction mixture was filtered and concentrated to afford compound 14.2 (11.2 g), which was used directly in the next step without further purification. rH NMR (400 MHz, CDCh) 8.61 (s, 1H), 7.52 (d, J= 8.8 Hz, 2H), 7.04-6.99 (m, 1H), 6.83 (d, J= 8.8 Hz, 2H), 6.40 (s, 1H), 4.75 (q, J= 8.8 Hz, 1H), 3.15 (s, 6H), 2.06-1.97 (m, 4H), 1.71-1.63 (m, 4H); MS (ESI) m/z: 366.2 [M+H]+.
[00468] Preparation of ZerZ-butyl 4-[2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-cZ]pyrimidin-2-yl]amino]phenoxy]ethyl]piperazine-l-carboxylate 14.3. To a solution of compound 14.2 (1 g, 2.74 mmol) and ZerZ-butyl 4-(2-chloroethyl)piperazine-l -carboxylate (1.36 g, 5.47 mmol) in DMF (10 mL) were added K2CO3 (756 mg, 5.47 mmol) and KI (45.4 mg, 274 pmol). After stirring at 80 °C for 16 h, the reaction mixture was diluted with DMF, concentrated, and purified by reverse phase prep-HPLC to afford compound 14.3 (379 mg) in 22% yield. LH NMR (400 MHz, CDCH3-4/) d 8.61 (s, 1H), 7.58 (d, J= 9.2 Hz, 2H), 7.26 (s, 1H), 6.93-6.86 (m, 2H), 6.40 (s, 1H), 4.81-4.67 (m, 1H), 4.15-4.10 (m, 2H), 3.52-3.41 (m, 4H), 3.15 (s, 6H), 2.82 (t, 5.6 Hz, 2H), 2.56-2.52 (m, 4H), 2.03-1.92 (m, 3H), 1.74-1.58 (m, 5H), 1.50-
1.41 (m, 9H).
[00469] Preparation of 7-cyclopentyl-Ar,Ar-dimethyl-2-[4-(2-piperazin-l-ylethoxy)anilino]- pyrrolo[2,3-<7]pyrimidine-6-carboxamide 14.4. To a solution of compound 14.3 (379 mg, 656 umol) in DCM (2 mL) was added 4M HC1 in dioxane (2 mL). After stirring at 20 °C for 2 h, the reaction mixture was concentrated to afford compound 14.4 as an HC1 salt (438 mg), which was used directly in the next step without further purification.
Figure imgf000226_0001
(400 MHz, DMSO-tZs) <5 9.99-9.89 (m, 1H), 9.66 (s, 2H), 8.84 (s, 1H), 7.65 (d, J- 9.2 Hz, 2H), 7.03 (d, J- 9.2 Hz, 2H), 6.70 (s, 1H), 4.73-4.61 (m, 1H), 4.41 (t, J= 4.8 Hz, 2H), 3.61 (d, J= 4.4 Hz, 8H), 3.39 (s, 2H), 3.05 (s, 6H), 2.38-2.30 (m, 2H), 2.02-1.83 (m, 4H), 1.67-1.51 (m, 2H); MS (ESI) m/z: 478.3 [M+H]+.
[00470] Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)- piperazin-l-yl)-ethoxy)phenyl)amino)-AjV-dimethyl-77f-pyrrolo[2,3-r7]pyrimidine-6- carboxamide A130. To a solution of compound 14.4 as an HC1 salt (91.1 mg, 177 pmol) and 3- [4-(bromomethyl)phenyl]piperidine-2, 6-dione (50 mg, 177 pmol) in DMF (1.5 mL) were added DIEA (68,7 mg, 532 pmol) and KI (2.9 mg, 17.7 pmol). After stirring at 80 °C for 16 h, the reaction solution was diluted with DMF (3 mL) and purified by reverse phase prep-HPLC to afford compound ABO (40 mg) in 31% yield. rH NMR (400 MHz, DMSO-J6) d 10.82 (s, 1H), 9.29 (s, 1H), 8.69 (s, 1H), 8.16 (s, 1 H), 7.68 (d, J= 9.2 Hz, 2H), 7.29-7.21 (m, 2H), 7.20-7.11 (m, 2H), 6.87 (d, J= 9.2 Hz, 2H), 6.55 (s, 1H), 4.71 (q, J = 8.8 Hz, 1H), 4.03 (t, J= 6.0 Hz, 2H), 3,83 (dd, J= 4.8, 11.6 Hz, 1H), 3,44 (s, 4H), 3,05 (s, 6H), 2,70-2,61 (m, 3H), 2,49-2,32 (m, 9H), 2.23-2.12 (m, 1H), 2.04 (dt, J= 4.8, 9.2 Hz, 1H), 1.95 (d, J= 2.4 Hz, 4H), 1.68-1.52 (m, 2H); MS (ESI) m/z: 649.4 [M 111 '
Example 15
Preparation of 7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)-piperazin-l-yl)- ethoxy)phenyl)amino)-A7,A-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A131
Figure imgf000227_0001
[00471] Compound A131 was prepared as described below.
[00472] Preparati on of 2-(4-benzy loxy anili no)- 7 -cy ci opentyl -N. A-dimethyl pyrrolo[2,3 -d] - pyrimidine-6-carboxamide 15.1, A mixture of 2-chloro-7-cyclopentyl-Ar,A-dimethylpyrrolo- [2,3-<7]pyrimidine-6-carboxamide ( 10 g, 34.2 mmol), 4-benzyloxyaniline (6.81 g, 34.2 mmol), Pd2(dba)3 (1.56 g, 1.71 mmol), Xantphos (1.98 g, 3.42 mmol), and CS2CO3 (22.3 g, 68.3 mmol) in dioxane (150 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 15.1 (9 g) in 57% yield. ]H NMR (400 MHz, DMSO-sfc) (5 9.31 (s, 1H), 8.70 (s, 1H), 7.71 (d, J = 9.2 Hz, 2H), 7.49-7.44 (m, 2H), 7.39 (t, J= 7.2 Hz, 2H), 7.36-7.30 (m, 1H), 6.96 (d, J= 9.2 Hz, 2H), 6.56 (s, 1H), 5.08 (s, 2H), 4.72 (s, 1H), 3.06 (s, 6H), 2.48-2.38 (m, 2H), 2.00-1.93 (m, 4H), 1.68-1.58 (m, 2H); MS (ESI) m/z: 456.2 [M+H] \
[00473] Preparation of 7-cyclopentyl-2-(4-hydroxyanilino)-2V,A-dimethylpyrrolo[2,3-<7]- pyrimidine-6-carboxamide 15.2, To a solution of compound 15.1 (4.5 g, 9.88 mmol) in EtOH (50 mL) was added 10% Pd/C (500 mg) under N?_. After stirring under H2 at 40 °C for 10 h, the reaction mixture was filtered and concentrated to afford compound 15.2 (3.2 g), which was used directly in the next step without further purification. 1H NMR (400 MHz, DMSO-de) <5 9.16 (s, 1H), 8.67 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.73-6.64 (m, 2H), 6.53 (s, 1H), 4.69 (t, J= 8.8 Hz, 1H), 3.05 (s, 6H), 2.47-2,38 (m, 2H), 1.93 (d, J= 6.0 Hz, 4H), 1,67-1,58 (m, 2H); MS (ESI) m/z: 366.4 [M+H]+.
[00474] Preparation of 7-cyclopentyl-2-[4-(2-hydroxyethoxy)anilino]-ApV-dimethyl- pyrrolo[2,3-</]pyrimidine-6-carboxamide 15.3. To a solution of compound 15.2 (1 g, 2.74 mmol) and 2 -bromoethanol (855 mg, 6.84 mmol) in DMF (10 mL) were added K2CO3 (756 mg, 5.47 mmol) and KI (45 mg, 274 pmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 15.3 (468 mg) in 41% yield. !H NMR (400 MHz, DMSO-</6) 3 9.29 (s, 1H), 8.70 (s, 1H), 7.74-7.66 (m, 2H), 6.92-6.84 (m, 2H), 6.56 (s, 1H), 4.84 - 5.6 Hz, 1H), 4.72 (t, J = 8.8 Hz, 1H), 3.96 (t, 5.2 Hz, 2H), 3.76-3.67 (m, 2H), 3.06 (s,
6H), 2.48-2.38 (m, 2H), 2.01-1.92 (m, 4H), 1.70-1.58 (m, 2H); MS (ESI) m/z: 410.2 [M+H]L
[00475] Preparation of 2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-<7]- pyrimidin-2-yl]amino]phenoxy]ethyl 4-methylbenzenesulfonate 15.4. To a solution of compound 15.3 (460 mg, 1.12 mmol) and TEA (341 mg, 3.37 mmol) in DCM (5 mL) was added TsCl (321 mg, 1.69 mmol) at 0 °C. After stirring for 12 h, the reaction mixture was concentrated and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 15.4 (690 mg) in 66% yield. [H NMR (400 MHz, DMSO-fifc) d 9.32 (s, 1H), 8.70 (s, 1H), 7.83-7.78 (m, 2H), 7.71-7.65 (m, 2H), 7.48 (d, ./ 8.0 Hz, 2H), 6.78 (d, J = 9.2 Hz, 2H), 6.56 (s, 1H), 4.71 (s, 1H), 4.36-4.29 (m, 2H), 4.17-4.08 (m, 2H), 4.06-3.99 (m, 1H), 3.05 (s, 6H), 2.41 (s, 3H), 1.99 (s, 1H), 1.97-1.92 (m, 3H), 1.63 (d, J= 5.6 Hz, 2H), 1.17 (t, J= 7.2 Hz, 1H); MS (ESI) m/z. 564.2 [M+H]+.
[00476] Preparation of tert-butyl 4-[2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-<f|pyrimidin-2-yl]amino]phenoxy]ethyl]piperazine-l-carboxylate 15.5. To a solution of compound 15.4 (490 mg, 869 pmol) in ACN (5 mL) were added tert-butyl piperazine- 1- carboxylate (162 mg, 869 pmol), CS2CO3 (566 mg, 1.74 mmol), and KI (14.4 mg, 86.9 pmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 15.5 (360 mg) in 71% yield. lH NMR (400 MHz, DMSO-di) d 9.35 (s, 1H), 8.76 (s, 1H), 7.75 (d, J= 9.2 Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H), 6,61 (s, 1H), 4,77 (s, 1H), 4.11 (t, 5.6 Hz, 2H), 3,38-3,33 (m, 4H), 3,11 (s, 6H),
2.76 (t, ,J= 5.6 Hz, 2H), 2.53-2.47 (m, 6H), 2.01 (d, J= 2.4 Hz, 4H), 1.72-1.63 (m, 2H), 1.45 (s, 9H); MS (ESI) m/z: 578.4 [M+H]t
[00477] Preparation of 7-cyclopentyl-A’,A-dimethyl-2-[4-(2-piperazin-l-ylethoxy)anilino]- pyrrolo[2,3-</]pyrimidine-6-carboxamide 15.6, To a solution of compound 15.5 (150 mg, 260 pmol) in DCM (1 mL) was added 4M HC1 in dioxane (0.5 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 15.6 (120 mg), which was used directly in the next step without further purification. rH NMR (400 MHz, DMSO-rfc) <5 10.45 (s, 1H), 10.03 (s, 2H), 8.94 (s, 1H), 7.60 (d, J= 9.2 Hz, 2H), 7.06 (d, ./= 9.2 Hz, 2H), 6.78 (s, 1H), 5.75 (s, 1H), 5.40-5.12 (m, 2H), 4.65 (t, J = 8.8 Hz, 1H), 4.45 (t, J= 4.8 Hz, 2H), 3.64-3.61 (m, 2H), 3.51 (s, 4H), 3.05 (s, 6H), 2.34-2.24 (m, 2H), 1.98 (t, J = 3.6 Hz, 2H), 1.89-1.80 (m, 2H), 1.62- 1.53 (m, 2H); MS (ESI) m/z: 478.2 [M+H]+.
[00478] Preparation of 7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)- pi perazin- 1 -yl)-ethoxy)phenyl)amino)-ArpV -dimethy 1 -7rt-pyrrol o[2, 3 -djpyrimi dine-6- carboxamide A131. To a solution of 3-[3-(bromomethyl)phenyl]piperidine-2, 6-dione (40 mg, 142 pmol) and compound 15.6 (67.7 mg, 142 pmol) in DMF (1 mL) were added DIEA (36.7 mg, 284 pmol) and KI (11.8 mg, 70.9 pmol). After stirring at 80 °C for 5 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A131 (42 mg) in 50% yield. *H NMR (400 MHz, DMSO-ufc) <5 10.82 (s, 1H), 9.28 (s, HI), 8.69 (s, 1H), 8.16 (s, 1H), 7.68 (d, ./ 8.4 Hz, 2H), 7.33-7.23 (m, 1H), 7.22-7.06 (m, 3H), 6.87 (d, J- 8.4 Hz, 2H), 6.55 (s, 1H), 4.76- 4.65 (m, 1H), 4.03 (s, 2H), 3.85 (dd, J= 4.0, 10.8 Hz, 1H), 3.45 (s, 2H), 3.05 (s, 6H), 2.73-2.58 (m, 4H), 2.56-2.53 (m, 1H), 2.49-2.34 (m, 9H), 2.21-2.13 (m, 1H), 2.08-2.01 (m, 1H), 2.00-1.89 (m, 4H), 1.62 (s, 2H); MS (ESI) m/z: 679.4 [M+H]+.
Example 16
Preparation of 7-cyclopentyl-2-((4-((4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)methyl)phenyl)amino)-Ar,A’-dimethyl-77f-pyrrolo[2,3-cf]pyrimidine-6- carboxamide A132
Figure imgf000230_0001
[00479] Compound A132 was prepared as described below.
[00480] Preparation of tert-butyl 4-[l-(4-bromophenyl)-4-piperidyl]piperazine-l- carboxylate 16.1. To a solution of tert-butyl 4-(4-piperidyl)piperazine-l-carboxylate (2 g, 7.42 mmol) and 1,4-dibromobenzene (2.1 g, 8.91 mmol) in DMSO (30 mL) were added Cui (283 mg, 1.48 mmol), K2CO3 (2.05 g, 14.9 mmol), and (2S)-pyrrolidine-2-carboxylic acid (342 mg, 2.97 mmol). After stirring at 95 °C for 12 h under N?„ the reaction mixture was filtered, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2.SO4, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford compound 16.1 (980 mg) in 31% yield. MS (ESI) m/z: 426.1 [M+H]+.
[00481] Preparation of tert-butyl 4-[l-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]- piperazine-1 -carboxylate 16.2. To a solution of compound 16.1 (980 mg, 2.31 mmol) and 2,6- dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.16 g, 2.77 mmol) in dioxane (15 mL) were added K3PO4 (1.47 g, 6.93 mmol), II2O (3 mL), and Pd(dppf)C12 CH2C12 (189 mg, 231 pmol). After stirring at 100 °C for 12 h under N?., the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford compound 16.2 (1 .2 g) in 71% yield. VH NMR (400 MHz, DMSO-Je) <57.67 (d, ./= 8.0 Hz, 1H), 7.44-7.29 (m, 12H), 6.94 (d, J= 8.8 Hz, 2H), 6.51 (d, J= 8.0 Hz, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 3.80-3.71 (m, 2H), 2.70-2.62 (m, 4H), 2.46-2.42 (m, 5H), 2.39-2.30 (m, 2H), 1.85-1.79 (m, 2H), 1.52-1.46 (m, 2H), 1.39 (s, 9H). MS (ESI) m/z: 635.5 [M+H]t
[00482] Preparation of tert-butyl 4-[l-[4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]- piperazine-1 -carboxylate 16.3, To a solution of compound 16.2 (1.2 g, 1.89 mmol) in THF (15 mL) and EtOH (5 mL) was added 10% Pd/C (200 mg). After stirring for 12 h under H2, the reaction mixture was filtered and concentrated to afford compound 16.3 (810 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 457.3 [M+H]+.
[00483] Preparation of 3-[4-(4-piperazin-l-yl-l-piperidyl)phenyl]piperidine-2, 6-dione
16.4, To a solution of compound 16.3 (100 mg, 219 nmol) in DCM (2 mL) was added 4M HC1 in dioxane (667 pL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 16.4 as an HC1 salt (75 mg), which was used directly in the next step without further purification. MS (ESI) m, 'z: 357.1 [M+H]+.
[00484] Preparation of 7-cyclopentyl-2-(4-formylanilino)-A(A’-dimethylpyrrolo[2,3-<7]- pyrimidine-6-carboxamide 16.5. To a solution of 2-chloro-7-cyclopentyl-/V,A-dimethyl-pyrrolo- [2,3-<7]pyrimidine-6-carboxamide (1 g, 3.42 mmol) and 4-aminobenzaldehyde (455 mg, 3.76 mmol) in dioxane (10 mL) were added CS2CO3 (2.23 g, 6.83 mmol), Xantphos (395 mg, 683 umol), and Pd2(dba)i (313 mg, 342 pmol). After stirring at 100 °C for 12 h under N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NarSCU, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 16.5 (1.12 g) in 86% yield. 41 NMR (400 MHz, DMSO- cfe) 6 10.15 (s, 1H), 9.83 (s, 1H), 8.84 (s, 1H), 8.06 (d, J= 8.8 Hz, 2H), 7.83 (d, J= 8.8 Hz, 2H), 6.64 (s, 1H), 4.84-4.77 (m, 1H), 3.06 (s, 6H), 2.49-2.41 (m, 2H), 2.08-1.99 (m, 4H), 1.74-1.64 (m, 2H); MS (ESI) OT/2: 378.1 [M+H]t
[00485] Preparation of 7-cyclopentyl-2-((4-((4-(l -(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-piperazin-l-yl)methyl)phenyl)amino)-Ar,A''-dimethyl-7/7-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A132. A solution of compound 16.4 (150 mg, 421 pmol) and compound 16.5 (206 mg, 547 pmol) in DMF (2 mL) and DCE (2 mL) was stirred for 3 h, followed by addition of NaBH(OAc)3 (134 mg, 631 pmol) in portions. After stirring for 1 h, the reaction mixture was diluted with water, treated with saturated aqueous NaHCCh (2 mL), and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4, concentrated, and purified by reverse phase prep-HPLC to afford compound A132 (35 mg) in 11% yield. LH NAIR (400 MHz, DMSO-ufe) 3 10.76 (s, 1H), 9.46 (s, 1H), 8.73 (s, 1H), 8.21 (s, 1H), 7.75 (d, J= 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.88 (d, .7= 8.8 Hz, 2H), 6.58 (s, 1H), 4.78-4.67 (m, 1H), 3.74-3.63 (m, 4H), 3.40-3.39 (m, 2H), 3.05 (s, 6H), 2.66-2.56 (m, 4H), 2.46- 2.24 (m, 10H), 2.18-2.06 (m, 2H), 2.03-1.91 (m, 6H), 1.86-1.79 (m, 2H), 1.68-1.60 (m, 2H), 1.53-1.42 (m, 2H); MS (ESI) m/z'. 718.3 [M+Hf.
Example 17
Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l - yl)piperidin-l-yl)ethoxy)phenyl)amino)-A,A’-dimethyl-777-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A133
Figure imgf000232_0001
[00486] Compound A133 was prepared as described below.
[00487] Preparation of ZerZ-butyl 4-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-l-yl]- piperidine-1 -carboxylate 17.1. To a solution of ZerZ-butyl 4-oxopiperidine-l -carboxylate (579 mg, 2.91 mmol) and 3 -(4-piperazin-l-ylphenyl)piperidine-2, 6-dione as an HC1 salt (300 mg, 968 umol) in DCE (10 mL) were added NaBH(OAc)3 (821 mg, 3.87 mmol) and NaOAc (238 mg, 2.91 mmol). After stirring at 60 °C for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound 17.1 (231 mg). MS (ESI) m/z'. 457.3 [M+H]+.
[00488] Preparation of 3-[4-[4-(4-piperidyl)piperazin-l-yl]phenyl]piperidine-2, 6-dione
17.2. To a solution of compound 17.1 (231 mg, 506 pmol) in DCM (2 mL) was added 4M HC1 in dioxane (2 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 17.2 as an HC1 salt (190 mg), which was used directly in the next step without further purifi cation. MS (ESI) m2: 357.2 [M+H]+.
[00489] Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethoxy)phenyl)amino)-A,Az-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A133 To a solution of 2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3- <7|pyrimidin-2-yl]amino]phenoxy]ethyl 4-methylbenzenesulfonate (100 mg, 177 pmol) and compound 17.2 as an HC1 salt (69.7 mg, 177 umol) in DMF (1 mL) were added DIEA (69 mg, 532 pmol) and KI (15 mg, 88.7 pmol). After stirring at 80 °C for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A133 (22 mg) in 17% yield. !H NMR (400 MHz, DMSO-tZs) <5 10.76 (s, 1H), 9.29 (s, 1H), 8.70 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.04 (d, J= 8.4 Hz, 2H), 6.88 (dd, J= 3.2, 8.8 Hz, 4H), 6.55 (s, 1H), 4.71 (q, J= 8.8 Hz, 1H), 4,03 (t, 7= 5.6 Hz, 2H), 3,72 (dd, J= 5.2, 10,8 Hz, 1H), 3.08 (s, 6H), 3,05 (s, 3H), 3.01-2.96 (m, 2H), 2.68-2.64 (m, 2H), 2.63-2.59 (m, 4H), 2.47-2.38 (m, 6H), 2.26-2.15 (m, 1H), 2.12 (dd, J - 3.6, 12.0 Hz, 1H), 2.04-1.92 (m, 6H), 1.77 (d, J- 12.4 Hz, 2H), 1.69-1.56 (ra, 2H), 1.52-1.37 (m, 2H); MS (ESI) m/z: 748.4 [M+H] \
Example 18
Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)phenyl)amino)-A7,A’-dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A134
Figure imgf000233_0001
[00490] Compound A134 was prepared as described below.
[00491] Preparation of te/7-butyl 4-[4-[3-(2,6-dioxo-3-piperidyl)phenyl]piperazin-l-yl]- piperi dine- 1 -carboxylate 18.1. To a solution of tert-butyl 4-oxopiperidine-l -carboxylate (386 mg, 1.94 mmol) and 3-(3-piperazin-l-ylphenyl)piperidine-2, 6-dione as an HC1 salt (300 mg, 968 umol) in DCE (12 mL) were added NaBH(OAc)s (821 mg, 3 87 mmol) and NaOAc (238 mg, 2.91 mmol). After stirring at 60 °C for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound 18.1 (113 mg). MS (ESI) m/z'. 457.5 [M+H] \
[00492] Preparation of 3-[3-[4-(4-piperidyl)piperazin-l-yl]phenyl]piperidine-2, 6-dione 18.2. To a solution of compound 18.1 (113 mg, 248 pmol) in DCM (1 mL) was added 4M HC1 in dioxane (1 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 18.2 as an HC1 salt (97 mg), which was used directly in the next step without further purification. MS (ESI) m/z\ 357,2 [M+H]+,
[00493] Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-piperidin-l-yl)ethoxy)phenyl)amino)-A(AMimethyl-7H-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A134. A mixture of compound 18.2 as an HC1 salt (63 mg, 161 umol), 2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-<7]pyrimidin-2-yl]amino]- phenoxy]ethyl 4-methylbenzenesulfonate (100 mg, 177 pmol), DIEA (69 mg, 532 pmol), and KI (14.7 mg, 88.7 pmol) in DMF (2 mL) was stirred at 80 °C for 12 h under N2. The reaction mixture was then purified by reverse phase prep-HPLC to afford compound A134 (35 mg).
Figure imgf000234_0001
NMR (400 MHz, DMSO-Je) d 10.78 (s, 1H), 9.29 (s, 1H), 8.70 (s, 1H), 7.69 (d, J - 8.8 Hz, 2H), 7.14 (t, J= 7.6 Hz, 1H), 6.88 (d, J= 9.2 Hz, 2H), 6.83-6.76 (m, 2H), 6.60 (d, J = 7.6 Hz, 1H), 6.55 (s, 1H), 4.71 (J= 8.8 Hz, 1H), 4.03 (t, J= 5.6 Hz, 2H), 3.75 (dd, J= 4.8, 11.2 Hz, 1H), 3.09 (s, 6H), 3.08-3.02 (m, 4H), 2.98 (d, J = 11.2 Hz, 2H), 2.69-2.59 (m, 7H), 2.48-2.38 (m, 3H), 2.25-2.11 (m, 2H), 2.08-1.92 (m, 7H), 1.76 (d, J= 11.2 Hz, 2H), 1.69-1.56 (m, 2H), 1.51-1.36 (m, 2H); MS (ESI) OT/2: 748.6 [M+H]t
Example 19
Preparation of 7-cyclopentyl-2-((4-(2-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)ethyl)phenyl)amino)-Az,jV-dimethyl-7H-pyrrolo[2,3-tf|pyrimidine-6-carboxamide
A135
Figure imgf000234_0002
[00494] Compound A135 was prepared as described below. [00495] Preparation of tert-butyl 4-[l-(4-bromophenyl)-4-piperidyl]piperazine-l- carboxylate 19.1. To a solution of tert-butyl 4-(4-piperidyl)piperazine-l -carboxylate (2 g, 7.42 mmol) and 1,4-dibromobenzene (2.1 g, 8.91 mmol) in DM SO (30 mL) were added Cui (283 mg, 1.48 mmol), K2CO3 (2.05 g, 14.9 mmol), and (25)-pyrrolidine-2-carboxylic acid (342 mg, 2.97 mmol). After stirring at 95 °C for 12 h under N2, the reaction mixture was filtered, diluted with water, and extracted with EtOAc. The combined organic layers were dried with anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 19.1 (980 mg) in 30% yield. MS (ESI) m/z: 426.1 [M+H]+.
[00496] Preparation of tert-butyl 4-[l -[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]- piperazine-1 -carboxylate 19.2, To a solution of compound 19.1 (980 mg, 2.31 mmol) and 2,6- dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.16 g, 2,77 mmol) in dioxane (15 mL) were added K3PO4 (1.47 g, 6.93 mmol), water (3 mL), and Pd(dppf)C12. CH2C12 (189 mg, 231 pmol). After stirring at 100 °C for 12 h under N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NarSOr, concentrated, and purified by column chromatography (SiCh, EtO AcZPE) to afford compound 19.2 (1 .2 g) in 71% yield. rH NMR (400 MHz, DMSO-Je) 37.67 (d, J= 8.0 Hz, 1H), 7.44-7.29 (m, 12H), 6.94 (d, J= 8.8 Hz, 2H), 6.51 (d, J= 8.0 Hz, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 3.80-3.71 (m, 2H), 2.70-2.62 (m, 4H), 2.46-2.42 (m, 5H), 2.39-2.30 (m, 2H), 1.85-1.79 (m, 2H), 1.52-1.46 (m, 2H), 1.39 (s, 9H); MS (ESI) m/z: 635.5 [M+H]\
[00497] Preparation of tert-butyl 4-[l-[4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]- piperazine-1 -carboxylate 19.3. To a solution of compound 19.2 (1.2 g, 1.89 mmol) in THF (15 mL) and EtOH (5 mL) was added 10% Pd/C (200 mg). After stirring for 12 h under H2, the reaction mixture was filtered and concentrated to afford compound 19.3 (810 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 457.3 [M+H]+.
[00498] Preparation of 3-[4-(4-piperazin-l-yl-l-piperidyl)phenyl]piperidine-2, 6-dione 19.4, To a solution of compound 19.3 (100 mg, 219 umol) in DCM (2 mL) was added 4M HC1 in dioxane (667 pL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 19.4 as an HC1 salt (75 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 357.1 [M+H]+. [00499] Preparation of 7-cyclopentyl-2-[4-(2-hydroxyethyl)anilino]-A(A'-dimethyl- pyrrolo[2,3-</]pyriniidiiie-6-carboxamide 19.5. To a solution of 2-chloro-7-cyclopentyl-Ar^V- dimethylpyrrolo[2,3-ffjpyrimidine-6-carboxamide (2 g, 6.83 mmol) and 2-(4-aminophenyl)- ethanol (984 mg, 7.17 mmol) in dioxane (20 mL) were added CS2CO3 (4.45 g, 13.7 mmol), Pd2(dba)j (626 mg, 683 pmol), and Xantphos (791 mg, 1.37 mmol). After stirring at 100 °C for 12 h under N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S(X concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 19.5 (1.6 g) in 48% yield. MS (ESI) m/z: 394.3 [M+H]4.
[00500] Preparation of 2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-</|- pyrimidin-2-yl]amino]phenyl]ethyl 4-methylbenzenesulfonate 19.6. To a solution of compound
19.5 (500 mg, 1.27 mmol) in DCM (5 mL) were added TEA (386 mg, 3.81 mmol) and TsCl (315 mg, 1 .65 mmol) at 0 °C. After stirring at 20 °C for 3 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiOz, EtOAcZPE) to afford compound 19.6 (620 mg) in 74% yield. !H NMR (400 MHz, DMSO-ifc) rl 9.47 (s, 1H), 8.74 (s, 1H), 7.71 (d, J= 8.4 Hz, 2H), 7.67 (d, J= 8.4 Hz, 2H), 7.40 (d, J= 8.0 Hz, 2H), 7.05 (d, J= 8.4 Hz, 2H), 6.58 (s, 1H), 4.77-4.69 (m, 1H), 4.20 (t, J= 6.4 Hz, 2H), 3.33 (s, 6H), 2.83 (t, J= 6.4 Hz, 2H), 2.37 (s, 3H), 2.20-2.14 (m, 1H), 1.98-1.88 (m, 5H), 1.69-1.61 (m, 2H); MS (ESI) m/z:
548.5 [M+H]+.
[00501] Preparation of 7-cyclopentyl-2-((4-(2-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-piperazin-l-yl)ethyl)phenyl)amino)-jV,A-dimethyl-777-pyrrolo[2,3-J]pyrimidine- 6-carboxamide A135. To a solution of compound 19.4 as an HCI salt (70 mg, 178 pmol) and compound 19.6 (107 mg, 196 pmol) in DMF (1 mL) were added DIEA (69 mg, 534 pmol) and KI (5.9 mg, 35.6 pmol). After stirring at 80 °C for 12 h under N2, the reaction mixture was diluted with water and extracted with DCM/MeOH. The combined organic layers were dried over anhydrous Na2SOr, concentrated, and purified by prep-TLC (SiCh, MeOH''DCM) and reverse phase prep-HPLC to afford compound Al 35 as a TFA salt (7 mg) in 5% yield. rH NMR (400 MHz, DMSO-tA) 3 10.80-10.71 (m, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 8.32 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.13 (d, ./ 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.57 (s, 1H), 4.77-4.67 (m, 1H), 3.74-3.66 (m, 3H), 3.46-3.41 (m, 2H), 3.09-3.01 (m, 6H), 2.69-2.59
(m, 6H), 2.48-2.42 (m, 8H), 2.34-2.23 (m, 2H), 2.17-2.06 (m, 1H), 2.05-1.91 (m, 6H), 1.88-1.79
(m, 2H), 1.70-1.60 (m, 2H), 1.54-1.42 (m, 2H); MS (ESI) m/z: 732.3 [M+H]+.
Example 20
Preparation of 7-cyclopentyl-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-AuV-dimethyl-7//-pyrrolo[2,3-i/]pyrimidine-6-carboxamide A138
Figure imgf000237_0001
[00502] Compound Al 38 was prepared as described below.
[00503] Preparation of tert-butyl 4-(4-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7/7- pyrrolo[2,3-<7]pyrimidin-2-yl)amino)phenyl)piperazin-l-yl)piperidine-l-carboxylate 20.1. A mixture of 7-cyclopentyl-A,A''-diraethyl-2-((4-(piperazin-l-yl)phenyl)amino)-7//-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide (1.25 g, 2.88 mmol) and tert-butyl 4-oxopiperidine-l -carboxylate (574 mg, 2.88 mmol) in MeOH (15 mL) was stirred at 60 °C for 1 h under N2, followed byaddition of NaBH(OAc)3 (917 mg, 4.32 mmol) and NaOAc (473 mg, 5.77 mmol). After stirring at 60 °C for 16 h under N2, the reaction mixture was diluted with saturated aqueous NaHCCh and extracted with DCM. The combined organic layers were dried over anhydrous NazSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 20.1 (390 mg) in 18% yield. MS (ESI) m/z: 617.3 [M+H]+.
[00504] Preparation of 7-cyclopentyl-yV,Az-dimethyl-2-((4-(4-(piperidin-4-yl)piperazin- 1 - yl)phenyl)amino)-727-pyrrolo[2,3-<7]pyrimidine-6-carboxamide 20.2, A mixture of compound 20.1 (100 mg, 162 pmol) and 4M HCI in dioxane (0.5 mL) in DCM (0.5 mL) was stirred for 1 h. The reaction mixture was then concentrated to afford compound 20.2 (50 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 517.4 [M+H]+.
[00505] Preparation of 7-cyclopentyl-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)benzyl)- piperidin-4-yl)-piperazin-l-yl)phenyl)amino)-A7,A'r-dimethyl-77f-pyrrolo[2,3-(/|pyrimidine-6- carboxamide A138. A mixture of 3-(4-(bromomethyl)phenyl)piperidine-2, 6-dione (25 mg, 88.6 umol), compound 20.2 (45. 8 mg, 88.6 pmol), KI (2.94 mg, 17.7 pmol), and DIEA (22.9 mg, 177 pmol) in DMF (0.5 mL) was stirred at 80 °C for 12 h. The reaction solution was then concentrated and purified by reverse phase prep-HPLC to afford compound A 138 (23 mg) in 34% yield. LH NMR (400 MHz, DMSO-tfe) 3 10.82 (s, 1H), 9.21 (s, 1H), 8.68 (s, 1H), 7.64 (d, J - 9.2 Hz, 2H), 7.30-7.22 (m, 2H), 7.19-7.14 (m, 2H), 6.87 (d, ./ 9.2 Hz, 2H), 6.54 (s, 1H), 4.77- 4.64 (m, 1H), 3.83 (dd, J= 4.8, 11.2 Hz, 1H), 3.42 (s, 2H), 3.04 (s, 10H), 2.85 (d, J= 10.8 Hz, 2H), 2.62 (s, 4H), 2.46 (s, 3H), 2.24-2.14 (m, 2H), 2.04 (dt, J= 5.2, 8.8 Hz, 2H), 1.97-1.88 (m, 6H), 1.75 (d, J= 12.8 Hz, 2H), 1.62 (dd, J= 1.6, 3.6 Hz, 2H), 1.49-1.39 (m, 2H); MS (ESI) m/z: 718.1 [M+H]+.
Example 21
Preparation of 7-cyclopentyl-2-((4-(4-(l -(4-(2,6-di ox opiperi din-3 -yl)phenethyl)-piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A,A-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A139
Figure imgf000238_0001
[00506] Compound A139 was prepared as described below.
[00507] Preparation of 7-cyclopentyl-Ar,Ar-dimethyl-2-[4-[4-(4-piperidyl)piperazin- 1 - yl]anilino]pyrrolo[2,3-tZ]pyrimidine-6-carboxamide 21.1. To a solution of fert-butyl 4-[4-[4-[[7- cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-t/]pyrimidin-2-yl]amino]phenyl]piperazin-l- yl]piperidine- 1 -carboxylate (120 mg, 195 pmol) in DCM (1 mL) was added 4M HC1 in dioxane (2 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 21.1 as an HC1 salt (100 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 517.2 [M+H] +.
[00508] Preparation of 7-cyclopentyl-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenethyl)- piperidin-4-yl)-piperazin-l-yl)phenyl)amino)-/V,A/-dimethyl-7J7-pyrrolo[2,3-J]pyrimidine-6- carboxamide A139. To a solution of compound 21.1 as an HC1 salt (100 mg, 181 pmol) in MeOH (2 mL) was added NaOAc (44.5 mg, 543 pmol). After the mixture was stirred for 15 min, 2-[4-(2,6-dioxo-3-piperidyl)phenyl]acetaldehyde (63 mg, 271 pmol) and NaBHsCN (23 mg, 362 pmol) were added. The reaction mixture was stirred for 5 h, and then diluted with water and extracted with DCM. The combined organic layers were concentrated and purified by reverse phase prep-HPLC to afford compound A139 as a TFA salt (16 mg) in 11% yield. *H NMR (400 MHz, DMSO-76) 0' 10.81 (s, 1H), 9.21 (s, 1H), 8.68 (s, 1H), 8.20 (s, 1H), 7.65 (d, 7 8.8 Hz, 2H), 7.22-7.15 (m, 2H), 7.15-7.09 (m, 2H), 6.87 (d, 7= 8.8 Hz, 2H), 6.54 (s, 1H), 4.71 (q, 7= 8.8 Hz, 1H), 3.80 (dd, 7= 5.2, 11.6 Hz, 1H), 3.11-2.97 (m, 12H), 2.75-2.68 (m, 2H), 2.68- 2.59 (m, 5H), 2.53 (s, 1H), 2.49-2.31 (m, 4H), 2.26-2.10 (m, 2H), 2.07-1.90 (m, 7H), 1.79 (d, 7= 11.2 Hz, 2H), 1.62 (d, 7- 4.8 Hz, 2H), 1.50-1.38 (m, 2H), MS (ESI) m/z: 732.6 [M+H]+.
Example 22
Preparation of 7-cyclopentyl-2-((4-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A,7/-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A140
Figure imgf000239_0001
[00509] Compound A140 was prepared as described below.
[00510] Preparation of 2-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)ethan-l-ol 22.1. A mixture of 2-(3-bromophenyl)ethan-l-ol (2 g, 9.95 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (4.98 g, 11.9 mmol), Pd(dppf)Cb. CH2CI2 (406 mg, 497 pmol), and K3PO4 (3.17 g, 14.9 mmol) in dioxane (15 mL) and II2O (3 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 22.1 (3.95 g) in 87% yield. rH NMR (400 MHz, DMSO-Ts) d 7.72 (d, 7- 8.0 Hz, 1H), 7.48-7.25 (m, 13H), 7.14 (d, 7= 7.6 Hz, 1H), 6.55 (d, J= 8.0 Hz, 1H), 5.39 (d, J= 1.2 Hz, 4H), 3.69-3.55 (m, 2H), 2.75 (t, J= 7.2 Hz, 2H); MS (ESI) m/z: 412.5 [M+H]f [00511 ] Preparation of 3-(3-(2-hydroxyethyl)phenyl)piperidine-2, 6-dione 22.2. To a solution of compound 22.1 (2 g, 4.86 mmol) in EtOH (20 mL) was added 10% Pd/C (200 mg) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 22.2 (1 g) in 81% yield. NAIR (400 MHz, DMSO-J6) <5 10.81 (s, 1H), 7.28-7.20 (m, 1 H ), 7.12 (d, J == 7.6 Hz, 1H), 7.08-6.99 (m, 2H), 3.81 (dd, ,/= 4.8, 11.2 Hz, 1H), 3.65-3.56 (m, 2H), 2.75-2.68 (m, 3H), 2.68-2.59 (m, 1H), 2.24-2.10 (m, 2H), 2.08-2.00 (m, 1H); MS (ESI) m/z\ 232.1 [M+H]+.
[00512] Preparation of 3-(2,6-dioxopiperidin-3-yl)phenethyl 4-m ethylbenzenesulfonate 22.3. To a solution of compound 22.2 (500 mg, 2.14 mmol) in DCM (5 mL) were added TEA (651 mg, 6.43 mmol) and TsCl (817 mg, 4.29 mmol) at 0 °C. After stirring at 20 °C for 2 h, the reaction mixture was filtered and concentrated to afford compound 22.3 (800 mg), which was used directly in the next step without further purification. MS (ESI) m'z'. 388.3 [M+H]+.
[00513] Preparation of tert-butyl 4-(4-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-t/]pyrimidin-2-yl)amino)phenyl)piperazin-l-yl)piperidine-l -carboxylate 22.4. A solution of 7-cyclopentyl-A,jV-dimethyl-2-((4-(piperazin-l-yl)phenyl)amino)-7/7-pyrrolo[2,3-6Z]- pyrimidine-6-carboxamide (780 mg, 1.80 mmol) and tert-butyl 4-oxopiperidine- l -carboxylate (359 mg, 1.8 mmol) in MeOH (10 mL) was stirred at 60 °C for 1 h, followed by addition of NaBH(OAc)s (572 mg, 2.7 mmol) and NaOAc (295 mg, 3.6 mmol). After stirring at 60 °C for 15 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 22.4 (960 mg) in 81% yield. }H NMR (400 MHz, DMSO-Jc) 39.21 (s, 1H), 8.68 (s, 1H), 7.65 (d, J= 9.2 Hz, 2H), 6.87 (d, J - 9.2 Hz, 2H), 6.54 (s, I H), 4.71 (q, ./ 8.8 Hz, 1H), 4.04-3.86 (m, 2H), 3.30-3.28 (m, 2H), 3.05 (s, 6H), 2.69 (s, 4H), 2.62 (s, 2H), 2.46-2.38 (m, 2H), 1.98-1.87 (m, 7H), 1.77 (d, J= 11.8 Hz, 2H), 1.62 (d, J= 4.8 Hz, 2H), 1.40 (s, 9H), 1.34-1.22 (m, 2H); MS (ESI) m/z: 617.2 [M+H]+.
[00514] Preparation of 7-cyclopentyl-A,A7-dimethyl-2-((4-(4-(piperidin-4-yl)piperazin-l- yl)phenyl)amino)-7rt-pyrrolo[2,3-tfjpyrimidine-6-carboxamide 22.5. A mixture of compound 22.4 (250 mg, 405 gmol) and 4M HC1 in dioxane (4 mL) was stirred for 1 h. The reaction mixture was then concentrated to afford compound 22.5 (250 mg), which was used directly in the step without further purification. MS (ESI) m/z: 517.1 [M+H]T
[00515] Preparation of 7-cyclopentyl-2-((4-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenethyl)- piperidin-4-yl)-piperazin-l-yl)phenyl)amino)-A,Az-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A140. To a solution of compound 22.3 (112 mg, 290 pmol) and compound 22.5 (150 mg, 290 pmol) in DMF (2 mL) were added KI (24.1 mg, 145 pmol) and DIEA (113 mg, 871 pmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered and purified by reverse phase prep-HPLC to afford compound A140 (76 mg) in 34% yield. 'H NMR (400 MHz, DMSO-fifc) b 10.82 (s, 1H), 9.21 (s, 1H), 8.68 (s, 1H), 7.65 (d, J = 9.2 Hz, 2H), 7.27-7.20 (m, 1H), 7.12 (d, J= 7.6 Hz, 1H), 7.07 (s, 1H), 7.03 (d, J= 7.6 Hz, 1H), 6.87 (d, J= 9.2 Hz, 2H), 6.54 (s, 1H), 4.78-4.64 (m, 1H), 3.81 (dd, J= 5.2, 11.1 Hz, 1H), 3.08-3.01 (m, 10H), 3.00-2.95 (m, 2H), 2.75-2,65 (m, 3H), 2.64-2.60 (m, 4H), 2,48-2.42 (m, 4H), 2.22-2.13 (m, 2H), 2,08-2,02 (m, 1H), 2.01-1.89 (m, 7H), 1.80-1.73 (m, 2H), 1.67-1.58 (m, 2H), 1.48-1.37 (m, 2H); MS (ESI) m/z: 732.2 [M+H]+
Example 23
Preparation of 7-cyclopentyl-2-((4-(4-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperazin-l-yl)phenyl)amino)-ApV-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6- carboxamide Al 41
Figure imgf000241_0001
[00516] Compound A141 was prepared as described below7.
[00517] Preparation of 2,6-dibenzyloxy-3-[3-[4-(dimethoxymethyl)-l-piperidyl]phenyl]- pyridine 23.1. A mixture of l-(3-bromophenyl)-4-(dimethoxymethyl)piperidine (400 mg, 1.27 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (584 mg, 1.4 mmol), Pd(dppf)Cb. (47 mg, 63.7 pmol), and K3PO4 (540 mg, 2.55 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by prep-TLC (SiCh, EtOAc/PE) to afford compound 23.1 (370 mg) in 55% yield. MS (ESI) m/z'. 525.7 [AI+H]+.
[00518] Preparation of 3-[3-[4-(dimethoxymethyl)-l-piperidyl]phenyl]piperidine-2,6- dione 23.2, To a solution of compound 23.1 (1 g, 1.91 mmol) in EtOH (10 mL) and THF (10 mL) was added 10% Pd/C (200 mg). After stirring at 40 °C for 12 h under H2, the reaction mixture was filtered and concentrated to afford compound 23.2 (600 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 347.1 [M+H]+.
[00519] Preparation of 1 -[3-(2,6-dioxo-3-piperidyl)phenyl]piperidine-4-carbaldehyde 23.3. To a solution of compound 23.2 (300 mg, 866 pmol) in DCM (3 mL) was added TFA (1 .32 g, 11.6 mmol). After stirring for 2 h, the reaction mixture was concentrated to afford compound 23.3 (240 mg), which was used directly in the next step without further purification.
[00520] Preparation of 7-cyclopentyl-2-((4-(4-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-methyl)piperazin-l-yl)phenyl)amino)-7V,A-dimethyl-7/7-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A141. To a solution of compound 23.3 (83 mg, 277 pmol) and 7- cyclopentyl-A,A-dimethyl-2-(4-piperazin-l-ylanilino)pyrrolo[2,3-tZ]pyrimidine-6-carboxamide (100 mg, 231 pmol) in MeOH (3 mL) were added NaOAc (56.8 mg, 692 pmol) and NaBHsCN (29 mg, 461 pmol). After stirring for 12 h, the rection mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCh, concentrated, and purified by reverse phase prep-HPLC to afford compound A141 (9 mg) in 5% yield. rH NMR (400 MHz, DMSO-tA) <5 10.79 (s, 1H), 9.23 (s, 1H), 8.68 (s, 1H), 7.65 (d, J= 9.2 Hz, 2H), 7.13 (d, J= 7.8 Hz, 1H), 6.88 (d, J= 9.2 Hz, 2H), 6.83-6.78 (m, 2H), 6.60-6.54 (m, 2H), 4.71 (t, ./ ■■■ 8.8 Hz, 1H), 3.75 (dd, ./ ■■■ 5.2, 11.2 Hz, 1H), 3.67 (d, J- 10.4 Hz, 3H), 3.61-3.51 (m, 1H), 3.06 (d, J= 2.4 Hz, 6H), 2.71-2.54 (m, 6H), 2.45 (d, J= 4.0 Hz, 2H), 2.25-2. 14 (m, 4H), 2.06-1.98 (m, 2H), 1 .96 (s, 4H), 1 .81 (d, J == 12.0 Hz, 3H), 1.73-1.57 (m, 4H), 1.25-1.17 (m, 2H).
Example 24
Preparation of 7-cyclopentyl-2-((4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperazin-l -yl)phenyl)amino)-Ar,Ar-dimethyl-7/f-pyrrolo[2,3-tf]pyrimidine-6- carboxamide Al 42
Figure imgf000243_0001
[00521] Compound A142 was prepared as described below.
[00522] Preparation of 4-(dimethoxymethyl)-l-(4-iodophenyl)piperidine 24.1. To a solution of 1,4-diiodobenzene (6.22 g, 18.8 mmol) and 4-(dimethoxymethyl)piperidine (1 .5 g, 9.42 mmol) in DMF (15 mL) were added Cui (718 mg, 3.77 mmol), K2CO.3 (3.91 g, 28.3 mmol) and Z-proline (434 mg, 3.77 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by prep-TLC (S1O2, EtOAc/PE) to afford compound 24.1 (2.3 g) in 68% yield. MS (ESI) m/z\ 362.1 [M+H]+.
[00523] Preparation of 2,6-dibenzyloxy-3-[4-[4-(dimethoxymethyl)-l-piperidyl]phenyl]- pyridine 24.2. To a solution of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- pyridine (3.19 g, 7.64 mmol) and compound 24.1 (2.3 g, 6.37 mmol) in dioxane (20 mL) and H2O (2 mL) were added Pd(dppf)Ch CH2C12 (520 mg, 637 pmol) and K3PO4 (2.70 g, 12.7 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 24.2 (930 mg) in 28% yield. lH NMR (400 MHz, CDCI3) 3 7.54-7.45 (m, 2H), 7.40 (d, J= 8.4 Hz, 2H), 7.37-7.32 (m, 3H), 7.32-7.22 (m, 7H), 7.22-7.17 (m, 2H), 6.89 (d, J = 8.0 Hz, 2H), 5.35 (s, 2H), 5.27 (s, 2H), 4.10-3.96 (m, 2H), 3.67 (d, ./= 12.4 Hz, 2H), 3.30 (s, 6H), 2.63 (t, J= 12.0 Hz, 2H), 1.28 (s, 2H); MS (ESI) m/z: 525.6 [M+H]+.
[00524] Preparation of 3-[4-[4-(dimethoxymethyl)-l-piperidyl]phenyl]piperidine-2,6- dione 24.3. To a solution of compound 24.2 (200 mg, 381 pmol) in MeOH (1 mL) and THE (1 mL) was added 10% Pd/C (0.2 g) under N2. After stirring under H2 at 40 °C for 6 h, the reaction mixture was filtered and concentrated to afford compound 24.3 (150 mg), which was used directly in the next step without further purification. NMR (400 MHz, DMSO-t/g) 3 10.74 (d, J= 1.6 Hz, 1H), 7.02 (d, J= 8.4 Hz, 2H), 6.91-6.85 (m, 2H), 4.08 (d, J = 6.4 Hz, 1H), 3.75-3.63 (m, 3H), 3.27 (s, 6H), 2.63-2.54 (m, 3H), 2.48-2.41 (m, 2H), 2.14-1.94 (m, 2H), 1.86-1.75 (m, 1H), 1.34-1.22 (m, 3H); MS (ESI) m/z: 347.4 [M+H]+.
[00525] Preparation of l-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-4-carbaldehyde 24.4, To a solution of compound 24.3 (150 mg, 433 umol) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol). After stirring for 2 h, the reaction mixture was neutralized to pH 8 with NaHCOs and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford compound 24.4 (130 mg), which was used directly in the next step without purification.
Figure imgf000244_0001
(400 MHz, DMSO-ak) d 10.76 (s, 1H), 9.63 (s, 1H), 7.08- 6.99 (m, 2H), 6.93-6.85 (m, 2H), 3.76-3.65 (m, 2H), 3.62-3.51 (m, 2H), 2,87-2,74 (m, 1H), 2,72- 2.54 (m, 2H), 2.21-1.88 (m, 4H), 1.74 (d, J = 10.8 Hz, 1H), 1.63-1.51 (m, 2H), 1.40-1.26 (m, 2H).
[00526] Preparation of 7-cyclopentyl-2-((4-(4-((l -(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-methyl)piperazin-l-yr)phenyl)amino)-jV,tV-dimethyl-7/f-pyrrolo[2,3-tf|- pyrimidine-6-carboxamide A142. To a solution of 7-cyclopentyl-AJV-dimethyl-2-(4-piperazin- l-ylanilino)pyrrolo[2,3-J]pyrimidine-6-carboxamide as an HCI salt (43 mg, 91.6 pmol) and compound 24.4 (110 mg) in DCM (1 mL) were added NaOAc (22.5 mg, 275 umol), NaBHsCN (1 1.5 mg, 183 pmol), and NaBH(OAc)s (77.6 mg, 366 umol). After stirring at 60 °C for 12 h, the reaction mixture was diluted with DMF (1 mL) and purified by reverse phase prep-HPLC to afford compound A142 (15.4 mg) in 23% yield. ^I NMR (400 MHz, CDaOD) J 8.62 (s, 1H), 8.46-8.39 (m, 1H), 7.63 (d, J= 9.2 Hz, 2H), 7.13 (d, J= 8.8 Hz, 2H), 7.03-6.95 (m, 4H), 6.56 (s, 1H), 4.76-4.67 (m, 1H), 3.82-3.75 (m, 1H), 3.70 (d, ./ 12.8 Hz, 2H), 3.27 (m, 4H), 3.15 (s, 6H), 2.96 (m, 4H), 2.77-2.61 (m, 6H), 2.60-2.52 (m, 2H), 2.23-2.15 (m, 2H), 2.07-1.99 (m, 4H), 1.92 (d, J= 11.2 Hz, 3H), 1.74-1.63 (m, 2H), 1.42 (d, J= 10.0 Hz, 2H); MS (ESI) m/z: 718.6 [M+H]+.
Example 25
Preparation of 7-cyclopentyl-2-((4-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)phenyl)amino)-7V,A-dimethyl-7/7-pyrrolo[2,3-d]pyrimidine-6-carboxamide A143
Figure imgf000245_0001
[00527] Compound A143 was prepared as described below.
[00528] Preparation of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]piperidine-l - carboxylate 25.1. A mixture of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (4.05 g, 9.7 mmol), tert-butyl 4-(4-bromophenyl)piperidine-l -carboxylate (3 g, 8.82 mmol), Pd(dppf)Ch CH2C12 (360 mg, 441 pmol), and K3PO4 (3.74 g, 17.6 mmol) in H?O (10 mL) and dioxane (40 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 25.1 (3.9 g) in 78% yield. !H NMR (400 MHz, CDCh) 3 7.63 (d, J= 8.0 Hz, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.49-7.30 (m, 10H), 7.27 (d, J = 7.6 Hz, 2H), 6.49 (d, J- 8.0 Hz, 1H), 5.46 (s, 2H), 5.38 (s, 2H), 4.28 (d, J- 11.8 Hz, 2H), 2.84 (t, J- 12.0 Hz, 2H), 2.75-2.61 (m, 1H), 1.88 (d, J = 12.8 Hz, 2H), 1.74-1.66 (m, 2H), 1.52 (s, 9H).
[00529] Preparation of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-l- carboxylate 25.2. To a solution of compound 25.1 (3.9 g, 7.08 mmol) in EtOH (40 mL) was added 10% Pd/C (2 g) under N?.. After stirring under H?. for 12 h, the reaction mixture was filtered and concentrated to afford compound 25.2 (2.3 g), which was used directly in the next step without further purification. lH NAIR (400 MHz, DMSO-fifc) 3 10.81 (s, 1H), 7.22-7.18 (m, 2H), 7.16-7.11 (m, 2H), 4.07 (d, J= 11.2 Hz, 2H), 3.81 (dd, J= 5.0, 11.2 Hz, 1H), 2.79 (s, 2H), 2.70-2.60 (m, 2H), 2.45 (t, J- 4.4 Hz, 1H), 2.23-2.10 (m, 1H), 2.07-1.95 (m, 1H), 1.74 (d, 12.0 Hz, 2H), 1.54-1.44 (m, 2H), 1.41 (s, 9H).
[00530] Preparation of 3-[4-(4-piperidyl)phenyl]piperidine-2, 6-dione 25.3. To a solution of compound 25.2 (300 mg, 806 pmol) in DCM (4 mL) was added 4M HO in dioxane (2 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 25.3 as an HC1 salt (260 mg), which was used directly in the next step without further purification.
[00531 ] Preparation of 7-cyclopentyl-2-[4-[4-[2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-l- piperidyl]ethyl]piperazin-l-yl]anilino]-jV,A/-dimethyl-pyrrolo[2,3-d]pyrimidine-6-carboxaniide A143. To a solution of compound 25.3 as an HC1 salt (131 mg, 426 pmol) in DMF (2 mL) were added DIEA (165 mg, 1.28 mmol) and l-bromo-2-chloroethane (122 mg, 851 pmol). After the mixture was stirred at 80 °C for 1 h, 7-cyclopentyl-A,A’-dimethyl-2-(4-piperazin-l- ylanilino)pyrrolo[2,3-J|pyrimidine-6-carboxamide as an HC1 salt (200 mg, 426 pmol) was added. The reaction mixture was stirred at 80 °C for 12 h, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by reverse phase prep-HPLC to afford compound A143 (6 mg) in 1% yield.
Figure imgf000246_0001
(400 MHz, DMSO-tA) <5 10.81 (s, 1H), 9.21 (s, 1H), 8.68 (s, 1H), 7.65 (d, J= 9.0 Hz, 2H), 7.25-7.17 (m, 2H), 7.16-7.09 (m, 2H), 6.93-6.83 (m, 2H), 6.55 (s, 1H), 4.81-4.59 (m, 1H), 3.82 (d, J = 5.0 Hz, 1H), 3.09-3.00 (m, 12H), 2.71-2.61 (m, 4H), 2.56 (d, J= 5.2 Hz, 8H), 2.47-2.43 (m, 2H), 2.20-2.12 (m, 1H), 2.05-2.00 (m, 2H), 1.99-1.91 (m, 4H), 1.76-1.70 (ra, 2H), 1.69-1.58 (m, 4H), MS (ESI) m/z: 732.6 [M+H]+.
Example 26
Preparation of 7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)phenyl)amino)-7V,A-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide
A144
Figure imgf000246_0002
[00532] Compound A144 was prepared as described below.
[00533] Preparation of 2,6-dibenzyloxy-3-(3-bromophenyl)pyridine 26.1. A mixture of 1- bromo-3-iodobenzene (2 g, 7.07 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxa- borolan-2-yl)pyridine (1.77 g, 4.24 mmol), Pd(dppf)C12-CH2C12 (144 mg, 177 pmol), and K3PO4 (1.5 g, 7.07 mmol) in dioxane (15 mL) and water (3 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 26.1 (1.34 g) in 40% yield. MS (ESI) m/z: 447.9 [M+H]+.
[00534] Preparation of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,6-dihydro- 2rt-pyri dine- 1 -carboxylate 26.2, A mixture of compound 26.1 (1 .34 g, 3 mmol), tert-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2/Lpyridine-l-carboxylate (1.11 g, 3.59 mmol), PdfdppflCb CFLCh (122 mg, 149 uniol), and K3PO4 (1.27 g, 5.99 mmol) in dioxane (10 mL) and H2O (3 mL) was stirred at 100 °C for 6 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiO?, EtOAc/PE) to afford compound 26.2 (1.5 g) in 89% yield. MS (ESI) m/z: 549.4 [M+H]+
[00535] Preparation of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)phenyl]piperidine-l- carboxylate 26.3. To a mixture of compound 26.2 (4 g, 7.29 mmol) in EtOH (20 mL) and THF (20 mL) was added 10% Pd/C (800 mg) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 26.3 (2.5 g), which was used directly in the next step without further purification.
[00536] Preparation of 3-[3-(4-piperidyl)phenyl]piperidine-2, 6-dione 26.4. To a solution of compound 26.3 (979 mg, 2,63 mmol) in DCM (6 mL) was added TFA (4.62 g, 40,5 mmol). After stirring for 2 h, the reaction mixture was concentrated and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 26.4 (713 mg) in 93% yield. MS (ESI) m/z: 273.1 [M+H]+.
[00537] Preparation of 3-[3"[l-(2,2-dimethoxyethyl)-4-piperidyl]phenyl]piperidine-2,6- dione 26.5. A mixture of compound 26.4 (713 mg, 2.62 mmol), 2 -bromo- 1,1 -dimethoxy ethane (664 mg, 3.93 mmol), DIEA (1 .02 g, 7.85 mmol), and KI (217 mg, 1.31 mmol) and in DMF (7 mL) was stirred at 80 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford compound 26.5 (150 mg) in 10% yield. MS (ESI) m/z: 361.1 [M-fH]+.
[00538] Preparation of 2-[4-[3-(2,6-dioxo-3-piperidyl)phenyl]-l-piperidyl]acetaldehyde 26.6. A mixture of compound 26.5 (40 mg, 111 pmol) in 2.5M HC1 (453 pL) was stirred at 50 °C for 2 h. The reaction mixture was then concentrated to afford compound 26.6 (35 mg), which was used directly in the next step without further purification.
[00539] Preparation of 7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-l-yl)-ethyl)piperazin-l-yl)phenyl)amino)-A(,A’-dimethyl-77/-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A144. To a solution of compound 26.6 (40 mg, 127 pmol), 7-cyclopentyl-Ar,AL dimethyl-2-(4-piperazin-l-ylanilino)pyrrolo[2,3-d]pyrimidine-6-carboxamide as an HC1 salt (89.7 mg, 191 pmol), and NaOAc (31.3 mg, 382 umol) in DCM (0.5 mL) was added NaBH(OAc)3 (40.5 mg, 191 pmol). After stirring for 12 h under N2, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A144 (5 mg) in 5% yield.
Figure imgf000248_0001
NMR (400 MHz, CDCh) 3 8.61 (s, 1H), 8.55 ( s, 1H), 8.50 ( s, 1H), 7.61 (d, - 8.8 Hz, 2H), 7.45 (s, 1H), 7.36-7.30 (m, 1H), 7.20 ( d, ./ ' 7.2 Hz, 1H), 7. 10-7.05 (m, 2H), 6.94 (d, .7 = 8.8 Hz, 2H), 6.41 (s, 1H), 4.76 (quin, .7 = 8.4 Hz, 1H), 3.79 (dd, .7= 5.2, 9.2 Hz, 1H), 3.40 ( d, J= 10.8 Hz, 2H), 3.20 ( s, 4H), 3.15 (s, 6H), 2.91-2.84 (m, 2H), 2.80 ( d, J= 6.0 Hz, 2H), 2.77 ( d, J = 4.8 Hz, 4H), 2.73-2.65 (m, 2H), 2.64-2.50 (m, 4H), 2.44 ( t, J= 11.2 Hz, 3H), 2.07-1.98 (m, 6H), 1.95-1.87 (m, 2H), 1.68 ( d, J= 5.2 Hz, 2H); MS (ESI) m/z: 732.5 [M+H]+.
Example 27
Preparation of 7-cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- phenyl)piperazin-l-yl)pyridin-2-yl)aniino)-Ar,A-diniethyl-777-pyrrolo[2,3-cf]pyrimidine-6- carboxamide Al 45
Figure imgf000248_0002
[00540] Compound Al 45 was prepared as described below. [00541] Preparation of tert-butyl 4-[3-[4-(6-nitro-3-pyridyl)piperazin-l-yl]phenyl]- piperazine-1 -carboxylate 27.1. To a solution of l-(6-nitro-3-pyridyl)piperazine (720 mg, 3.46 mmol) and tert-butyl 4-(3-bromophenyl)piperazine-l -carboxylate (1.42 g, 4.15 mmol) in dioxane (15 mL) were added RuPhos Pd G3 (289 mg, 346 pmol), RuPhos (323 mg, 692 pmol), and CS2CO3 (2.25 g, 6.92 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 27.1 (1.5 g) in 83% yield. }H NMR (400 MHz, DMSO-afe) d 8.31 (d, J= 3.2 Hz, 1H), 8.18 (d, J= 9.2 Hz, 1H), 7.57-7.50 (m, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.53 (d, J= 2.0 Hz, 1H), 6.49-6.42 (m, 2H), 3.67-3.62 (m, 4H), 3.47-3.41 (m, 4H), 3.31-3.27 (m, 4H), 3.11-3.05 (m, 4H), 1.42 (s, 9H); MS (ESI) m/z: 469.1 [M+H]+.
[00542] Preparation of tert-butyl 4-[3-[4-(6-amino-3-pyridyl)piperazin-l-yl]phenyl]- piperazine-1 -carboxylate 27.2. To a solution of compound 27.1 (1.5 g, 3.2 mmol) in THF (3 mL) and EtOH (12 mL) was added 19% Pd/C (150 mg) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 27.2 (1 g), which was used directly in the next step without further purification. rH NMR (400 MHz, CDCk) <5 7.79- 7.72 (m, 1H), 7.38-7.27 (m, 1H), 7.17-7.08 (m, 2H), 6.55-6.39 (m, 5H), 3.53-3.48 (m, 4H), 3.27- 3.21 (m, 4H), 3.13-3.03 (m, 8H), 1.41 (s, 9H); MS (ESI) m/z: 439.2 [M+Hf
[00543] Preparation of tert-butyl 4-[3-[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-J]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-l-yl]phenyl]piperazine-l-carboxylate 27.3. To a solution of compound 27.2 (800 mg, 1.82 mmol) and 2-chloro-7-cyclopentyl-A,A7- dimethylpyrrolo[2,3-d]pyrimidine-6-carboxamide (587 mg, 2.01 mmol) in dioxane (8 mL) were added CS2CO3 (1.19 g, 3.65 mmol), Pd2(dba)s (167 mg, 182 pmol), and Xantphos (211 mg, 365 pmol). After stirring at 100 °C for 5 h, the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 27.3 (810 mg) in 63% yield. XH NMR (400 MHz, DMSO-Js) 3 9.36 (s, 1H), 8.77 (s, 1H), 8.18 (d, J= 9.2 Hz, 1H), 8.07 (d, J= 2.8 Hz, 1H), 7.54-7.46 (m, 1H), 7.09 (t, J= 8.0 Hz, 1H), 6.60 (s, 1H), 6.55 (s, 1H), 6.49 (d, J= 8.0 Hz, 1H), 6.46-6.41 (m, 1H), 4.74 (t, J= 8.8 Hz, 1H), 3.44 (d, ./ 4.8 Hz, 4H), 3.27 (d, ./ 5.2 Hz, 8H), 3, 10-3,04 (m, 8H), 2,48-2,38 (ra, 2H), 1.99 (s, 6H), 1.65 (d, J- 5.2 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 695.5 [M+H] \
[00544] Preparation of 7-cyclopentyl-MAMimethyl-2-[[5-[4-(3-piperazin-l-ylphenyl)- piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide 27.4. To a solution of compound 27.3 (70 mg, 101 pmol) in DCM (1 mL) was added 4M HC1 in dioxane (333 pL).
After stirring for 2 h, the reaction mixture was concentrated to afford compound 27.4 (60 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 595.4 [M+H]+.
[00545] Preparation of 7-Cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)- piperazin- 1 -yl)-phenyl)piperazin- 1 -yl)pyridin-2-yl)amino)-ApV-dimethyl-7/7-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A145. To a solution of compound 27.4 (40 mg, 67.3 pmol) and 3-[4- (bromomethyl)phenyl]piperidine-2, 6-dione (19 mg, 67.3 pmol) in DMF (1 mL) were added DIEA (26.1 mg, 202 pmol) and KI (5.6 mg, 33.6 pmol). After stirring at 80 °C for 5 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A145 (14.4 mg) in 26% yield. ^NMR (400 MHz, DMSO-Je) <5 10.82 (s, 1H), 9.27 (s, 1H), 8.75 (s, 1H), 8.17 (d, J= 9.2 Hz, 1H), 8.05 (d, J= 3.2 Hz, 1H), 7.51-7.47 (m, 1H), 7.30 (d, J= 8.0 Hz, 2H), 7.19 (d, J= 8.0 Hz, 2H), 7.06 (t, J= 8.0 Hz, 1H), 6.60 (s, 1H), 6.52 (s, 1H), 6.48-6.40 (m, 2H), 4.78- 4.68 (m, 1H), 3.87-3.82 (m, 1H), 3.51 (s, 2H), 3.26 (s, 6H), 3.13 (s, 4H), 3.05 (s, 6H), 2.71-2.64 (m, 2H), 2.49-2.40 (m, 6H), 2.21-2.15 (m, 1H), 2.07-1.93 (m, 6H), 1.69-1.60 (m, 2H), 1.28-1.21 (m, 1H); MS (ESI) m/z\ 398.8 [M/2+H]+.
Example 28
Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- phenyl)piperazin-l -yl)pyridin-2-yl)amino)-ATA-dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A148
Figure imgf000250_0001
[00546] Compound A148 was prepared as described below. [00547] Preparation of tert-butyl 4-[4-[4-(6-nitro-3-pyridyl) piperazin-l-yl]phenyl]- piperazine-1 -carboxylate 28.1. A mixture of l-(6-nitro-3-pyridyl)piperazine (3 g, 14.4 mmol), tert-butyl 4-(4-bromophenyl)piperazine-l -carboxylate (5.9 g, 17.3 mmol), RuPhos Pd G3 (1.21 g, 1.44 mmol), RuPhos (672 mg, 1.44 mmol), and Cs?.COs (9.39 g, 28.8 mmol) in dioxane (30 mL) was stirred at 100 °C for 12 h under Nr. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCli, concentrated, and triturated with MeOH to afford compound 28.1 (3.2 g) in 47% yield. MS (ESI) m/z: 469.3 [M+H]+.
[00548] Preparation of tert-butyl 4-[4-[4-(6-amino-3-pyridyl)piperazin-l-yl]phenyl]- piperazine-1 -carboxylate 28.2, To a solution of compound 28.1 (4.3 g, 9.18 mmol) in EtOH (40 mL) and THF (10 mL) was added 10% Pd/C (5 g) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 28.2 (3 g), which was used directly in the next step without further purification. MS (ESI) m/z: 439 3 [M+H]+.
[00549] Preparation of tert-butyl 4-[4-[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-<7]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-l-yl]phenyl]piperazine-l-carboxylate 28.3, A mixture of compound 28.2 (3 g, 5.61 mmol), 2-chloro-7-cyclopentyl-A,A-dimethyl- pyrrolo[2,3-<7]pyrimidine-6-carboxamide (1.31 g, 4.49 mmol), Pd(OAc)r (31.5 mg, 140 pmol), BINAP (1.75 g, 2.8 mmol), and CS2CO3 (3.66 g, 11.2 mmol) in dioxane (40 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and triturated with EtOAc to afford compound 28.3 (2.4 g) in 61% yield. MS (ESI) m/z: 695.5 [M+H]+.
[00550] Preparation of 7-cyclopentyl-A(A-dimethyl-2-[[5-[4-(4-piperazin-l-ylphenyl)- piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-Jjpyrimidine-6-carboxamide 28.4. To a solution of compound 28.3 (2.4 g, 3.45 mmol) in DCM (20 mL) was added 4M HCI in dioxane (10 mL).
The reaction mixture was stirred for 1 h and concentrated to afford compound 28.4 as an HCI salt (2.2 g), which was used directly in the next step without further purification. MS (ESI) m/z: 595.5 [M+H]L
[00551] Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)- piperazin- l-yl)-phenyl)piperazin-l-yl)pyri din-2 -yl)amino)-A,A7-dimethyl-777-pyrrolo[2,3-(/J- pyrimidine-6-carboxamide A148. To a solution of compound 28.4 as an HC1 (69.6 mg, 110 umol) and 3-[4-(bromomethyl)phenyl]piperidine-2, 6-dione (30 mg, 106 pmol) in DMF (2 mL) were added DIEA (41.2 mg, 319 pmol) and KI (1.8 mg, 10.6 pmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A148 (18.5 mg) in 21% yield. ]H NMR (400 MHz, DMSO-tA) 3 10.83 (s, 1H), 9.30 (s, 1H), 8.75 (s, 1H), 8.33-8.21 (m, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.04 (d, J - 2.4 Hz, 1H), 7.49 (dd, J - 2.4, 9.2 Hz, 1H), 7.30-7.14 (m, 4H), 6.95-6.81 (m, 4H), 6.60 (s, 1H), 4.80-4.67 (m, 1H), 3.84 (dd, J = 5.2, 11.2 Hz, 1H), 3.50 (s, 2H), 3.27-3.22 (m, 8H), 3.17-3.14 (m, 4H), 3.09-3.00 (m, 10H), 2.67- 2.61 (m, 2H), 2.26-2.10 (m, 2H), 2.09-1.88 (m, 6H), 1.70-1.56 (m, 2H); MS (ESI) wz: 796.6 [M+H]+.
Example 29
Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- benzyl)piperazin-l-yl)pyridin-2-yl)amino)-ACV-dimethyl-7/f-pyrrolo[2,3-£f]pyrimidine-6- carboxamide A151
Figure imgf000252_0001
[00552] Compound Al 51 was prepared as described below.
[00553] Preparation of 4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-l-yl]benzaldehyde 29.1. A mixture of 3-(4-piperazin-l-ylphenyl)piperidine-2, 6-dione (100 mg, 366 pmol ), 4-fluoro- benzaldehyde (68 mg, 549 pmol), and DIEA (142 mg, 1.1 mmol) in NMP (2 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOt concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 29.1 (61 mg). MS (ESI) m/z: 378.3 [M+H]+. [00554] Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-benzyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-77/-pyrrolo[2,3-t/]- pyrimidine-6-carboxamide A151. A mixture of 7-cyclopentyl-Ar,ALdimethyl-2-[(5-piperazin-l- yl-2-pyridyl)amino]pyrrolo[2,3-tZ]pyrimidine-6-carboxamide (92.1 mg, 212 pmol), compound 29.1 (80 mg, 212 pmol), NaOAc (1 .9 mg, 21.2 pmol), and NaBEbCN (26.6 mg, 424 pmol) in MeOH (2 mL) was stirred for 12 h under N?„ The reaction mixture was then purified by reverse phase prep-HPLC to afford compound A151 (14 mg) in 8% yield. ^I NMR (400 MHz, DMSO- d6) 3 10.8 (s, 1H), 9.29-9.21 (m, 1H), 8.79-8.70 (m, 1H), 8.24-8.18 (m, 1H), 8.17-8.10 (m, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.42 (dd, J = 2.8, 9.2 Hz, 1H), 7.21 (d, J = 8.4Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.98 (dd, J = 2.8, 8.7 Hz, 4H), 6.60 (s, 1H), 4.80-4.66 (m, 1H), 3.75 (dd, J = 4.8, 10.9 Hz, 1H), 3.45 ( s, 2H), 3.27 (s, 10H), 3.12 ( s, 6H), 3.06 ( s, 6H), 2.68-2.60 (m, 2H), 2.46-2.40 (m, 2H), 2.21-2.10 (m, 1H), 2.08-1.90 (m, 6H), 1.64 ( d, J 5.2 Hz, 2H); MS (ESI) m/z\ 796.5 [M+H]+.
Example 30
Preparation of 7-cyclopentyl-2-((5-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A(A-dimethyl-7F-pyrrolo[2,3-J]pyrimidine- 6-carboxamide A154
Figure imgf000253_0001
[00555] Compound A154 was prepared as described below.
[00556] Preparation of 7-cyclopentyl-2-[[5-[4-(4-formylphenyl)piperazin-l-yl]-2-pyridyl]- amino]-A7,A'r-dimethylpyrrolo[2,3-t/]pyrimidine-6-carboxamide 30,1. A mixture of 7-cyclo- pentyl-7V,Az-dimethyl-2-[(5-piperazin-l-yl-2-pyridyi)amino]pyrrolo[2,3-t(|pyrimidine-6- carboxamide (1.5 g, 3.45 mmol), 4-fluorobenzaldehyde (428 mg, 3.45 mmol), DIEA (892 mg, 6.9 mmol), and H2O (124 mg, 6.9 mmol) in NMP (15 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 30.1 (438 mg) in 21% yield. MS (ESI) m/z: 539.3 [M+H] \
[00557] Preparation of 7-cyclopentyl-2-((5-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin- 1 -yl)-methyl)phenyl)piperazin- 1 -yl)pyridin-2-yl)amino)-A,A-dimethyl-77/-pyrrolo- [2,3-<7]pyrimidine-6-carboxamide A154. To a solution of 3-(4-piperazin-l-ylphenyl)piperidine- 2, 6-dione as an HC1 salt (37.4 mg, 121 umol) in DMF (1 mL) and THF (1 mL) was added NaOAc (22.8 mg, 278 pmol). After the mixture was stirred for 15 min, compound 30.1 (50 mg,
92.8 pmol) was added, followed by addition of NaBHsCN (11.7 mg, 186 pmol. The reaction mixture was stirred for 14 h, and then concentrated and purified by reverse phase prep-HPLC to afford compound Al 54 as a TFA salt (18 mg) in 21% yield. LH NMR (400 MHz, DMSO-ufe) 3 10.76 (s, 1H), 9.29 (s, 1H), 8.76 (s, 1H), 8.18 (d, J= 9.2 Hz, 1H), 8.15 (s, 1H), 8.06 (d, J= 2.8 Hz, 1H), 7.51 (dd, J - 3.2, 92 Hz, 1H), 7.20 (d, J - 8.4 Hz, 2H), 7.04 (d, J - 8.4 Hz, 2H), 6.98 (d, J= 8.4 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 6.60 (s, 1H), 4.86-4.60 (m, 1H), 3.72 (dd, J= 5.2,
10.8 Hz, 1H), 3.43 (s, 2H), 3.29 (br s, 6H), 3.16-3.02 (m, 12H), 2.66-2.56 (m, 3H), 2.44 (br d, J = 4.4 Hz, 4H), 2.15-2.06 (m, 1H), 2.05-1.90 (m, 6H), 1 .70-1 .60 (m, 2H); MS (ESI) m/z: 796.2 [M+H]+.
Example 31
Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)cyclohexyl)- piperazin-l-yl)pyridin-2-yl)amino)-A'’,A-dimethyl-7/f-pyrrolo[2,3-d]pyriniidine-6-carboxamide
A155
Figure imgf000254_0001
[00558] Compound A155 was prepared as described below.
[00559] Preparation of 3-[4-[2-(4-oxocyclohexyl)ethynyl]phenyl]piperidine-2, 6-dione
31.1. To a solution of 4-ethynylcyclohexanone (100 mg, 818 umol) in THF (1 mL) and ACN (1 mL) were added 3-(4-bromophenyl)piperidine-2, 6-dione (199 mg, 744 pmol), XPhos Pd G3 (62.9 mg, 74.4 pmol), and CS2CO3 (727 mg, 2.23 mmol). After stirring at 60 °C for 10 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 31.1 (130 mg) in 43% yield. MS (ESI) m/z: 310 [M+H]+.
[00560] Preparation of 3-[4-[2-(4-hydroxycyclohexyl)ethyl]phenyl]piperidine-2, 6-dione
31.2. A mixture of compound 31.1 (130 mg, 420 nmol) and PtCh (100 mg, 440 nmol) in THF (10 mL) was stirred for 2 h under Eb. The reaction mixture was then filtered and concentrated to afford compound 31.2 (100 mg), which was used directly in the next step without further purification. !H NMR (400 MHz, DMSO-Je) d 10.80 (s, 1H), 7.20-7.04 (m, 4H), 4,47-4,21 (m, 1H), 3.80 (dd, J= 4.8, 11.2 Hz, 1H), 2.73-2.60 (m, 1H), 2.58-2.52 (m, 2H), 2.45 (d, J= 4.0 Hz, 1EI), 2.27-2.10 (m, 2H), 2.06-1.96 (m, 1H), 1.88-1.67 (m, 3H), 1.53-1.39 (m, 4H), 1.22-1.04 (m, 3H), 0.97-0.88 (m, 1H).
[00561] Preparation of 3-[4-[2-(4-oxocyclohexyl)ethyl]phenyl]piperidine-2, 6-dione 31.3,
To a solution of compound 31.2 (80 mg, 254 pmol) in DCM (2 mL) was added Dess-Martin (129 mg, 304 pmol) at 0 °C under N2. After stirring for 10 h under N2, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound 31.3 (60 mg) in 57% yield. MS (ESI) m/z: 314.1 [M+H]+.
[00562] Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)- cyclohexyl)-piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7#-pyrrolo[2,3-d]pyrimidine-6- carboxamide A155. To a solution of compound 31.3 (50 mg, 160 praol) and 7-cyclopentyl-A,A- dimethyl-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)-7ff-pyrrolo[2,3-</|pyrimidine-6-carboxamide (69.3 mg, 160 pmol) in DCM (1 mL) was added NaBH(OAc)s (67.6 mg, 319 pmol) under N2. After stirring for 3 h under N2, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A155 (12 mg) in 10% yield. rH NMR (400 MHz, DMSO-</c) b 10.81 (s, 1H), 9.35-9.19 (m, 1H), 8.75 (d, J- 1.2 Hz, 1H), 8.23-7.97 (m, 2H), 7.41 (dd, J= 2.8, 8.8 Hz, 1H), 7.27-6.97 (m, 4H), 6.59 (s, 1H), 4.73 (q, J= 8.8 Hz, 1H), 3.80 (dd, J= 4.8, 11.2 Hz, HI), 3.16-3.01 (m, 10H), 2.72-2.52 (m, 8H), 2.46-2.37 (m, 2H), 2.26-2.11 (m, 2H), 2.06-1.92 (m, 5H), 1.84 (d, J- 10.6 Hz, 1H), 1.76-1.42 (m, 10H), 1.26-0.85 (m, 2H); MS (ESI) m/z: 732.6 [M+H]+.
Example 32
Preparation of 7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A,jV-dimethyl-777-pyrrolo[2,3-t/]pyrimidine-6-carboxamide
A156
Figure imgf000256_0001
[00563] Compound A156 was prepared as described below.
[00564] Preparation of fert-butyl 4-[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2, 3-d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-l-yl]piperidine-l -carboxylate 32.1. To a solution of 7-cyclopentyl-A(A-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-<7]- pyrimidine-6-carboxamide (2 g, 4.6 mmol) in DCE (25 mL) were added tert-butyl 4- oxopiperidine-1 -carboxylate (2.75 g, 13.8 mmol), NaBH(OAc)3 (2.93 g, 13.8 mmol), and AcOH (27.6 mg, 460 pmol). After stirring at 60 °C for 12 h, the reaction mixture was diluted with w7ater and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 32.1 (3.9 g). MS (ESI) m/z: 618.3 [M+H]+.
[00565] Preparation of 7-cyclopentyl-Ar,A'r-dimethyl-2-[[5-[4-(4-piperidyl)piperazin- 1 -y 1]- 2-pyridyl]amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide 32.2. A mixture of compound 32.1 (3.9 g, 6.31 mmol) in DCM (10 mL) and 4M HC1 in dioxane (10 mL) was stirred for 1 h. The reaction mixture was diluted with THF (5 mL), neutralized with K2CO3 (2 g), and concentrated to afford compound 32.2 as an HC1 salt (5 g), which was used directly in the next step without further purification. MS (ESI) m/z: 518.4 [M+H]+.
[00566] Preparation of 7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenethyl)- piperidin-4-yl)-piperazin-l-yl)pyridin-2-yl)amino)-77,A-dimethyl-777-pyrrolo[2,3-tZ]pyrimidine- 6-carboxamide A156. A mixture of compound 32.2 (210 mg, 405 nmol), 3-[4-(2-bromoethyl)~ phenyl]piperidine-2, 6-dione (100 mg, 338 nmol), DIEA (436 mg, 3.38 mmol), and KI (56 mg, 338 gmol) in DMF (2 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was filtered and purified by reversed phase prep-HPLC to afford compound Al 56 (35 mg) in 14% yield. rH NMR (400 MHz, CD3OD) (5 8.77 (s, 1H), 8.48 (s, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.00 (d, ./ 2.4 Hz, 1H), 7.51 (dd, J= 2.8, 9.2 Hz, 1H), 7.36-7.15 (m, 4H), 6.62 (s, 1H), 4.77 (quin, J = 8.8 Hz, 1H), 3.85 (dd, .7= 5,6, 10.4 Hz, 1H), 3.55 (d, .7= 1 1.6 Hz, 2H), 3.21 (s, 6H), 3.15 (s, 6H), 3.06-2.96 (m, 2H), 2.90 (t, J= 11.6 Hz, 2H), 2.84-2.74 (m, 4H), 2.69 (dd, J= 6.0, 10.4 Hz, 1H), 2.66-2.57 (m, 2H), 2.56-2.45 (m, 2H), 2.30-1.97 (m, 9H), 1.92-1.78 (m, 2H), 1.77-1.65 (m, 2H); MS (ESI) m/z: 733.8 [M+H]+.
Example 33
Preparation of 7-cyclopentyl-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)ethyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,7V-dimethyl-777-pyrrolo[2,3-i7]pyrimidine-6- carboxamide Al 57
Figure imgf000257_0001
[00567] Compound A157 was prepared as described below.
[00568] Preparation of 2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]ethanol 33.1. A mixture of 4-(2,6-dibenzyloxy-3-pyridyl)phenol (2 g, 5.22 mmol), 2-iodoethanol (1.79 g, 10.4 mmol), and K2CO3 (1.44 g, 10.4 mmol) in acetone (10 mL) was stirred at 60 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 33.1 (370 mg) in 17% yield.
MS (ESI) m/z: 427.9 [M+H]L
[00569] Preparation of 3-[4-(2 -hydroxy ethoxy )phenyl]piperidine-2, 6-dione 33.2. A mixture of compound 33.1 (370 mg, 866 pmol) and 10% Pd/C (300 mg) in EtOH (2 mL) and THF (2 mL) was stirred at 40 °C for 12 h under Eb. The reaction mixture was then filtered and concentrated to afford compound 33.2 (150 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 250.2 [M+H]+.
[00570] Preparation of 2-[4-(2,6-dioxo-3-piperidyl)phenoxy]ethyl 4-methylbenzene- sulfonate 33,3. A mixture of compound 33.2 (150 mg, 602 umol), TsCl (229 mg, 1.2 mmol), and TEA (183 mg, 1.81 mmol) in DCM (1.5 mL) was stirred for 2 h under N2. The reaction mixture was then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by prep-TLC (SiCh, EtOAc/PE) to afford compound 33.3 (60 mg) in 25% yield. MS (ESI) m/z: 404.2 [M+H]+,
[00571] Preparation of 7-cyclopentyl-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)- ethyl)-piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-AL<V-dimethyl-7/f-pyrrolo[2,3-d]- pyrimidine-6-carboxamide A157. A mixture of 7-cyclopentyl-A,A-dimethyl-2-[[5-[4-(4- piperidyl)piperazin- 1 -yl]-2-pyridyl]amino]pyrrolo[2,3- J]pyrimidine-6-carboxamide as an HC1 salt (61.8 mg, 112 pmol), compound 33.3 (50 mg, 124 pmol), DIEA (144 mg, 1.12 mmol), and KI (62 mg, 372 pmol) in DMF (0.5 mL) was stirred at 100 °C for 1 h under N2. The reaction mixture was then filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A157 (29 mg) in 31% yield. }H NMR (400 MHz, CDCh) d 8.75 ( s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.59 (d, J= 9.2 Hz, 1H), 7.21 (d, 8.8 Hz, 2H), 6.99 (d, 8.8 Hz,
211), 6 04 (s, 1H), 4.79-4.74 (m, 1 H), 4.32 (t, J = 4.7 Hz, 2H), 3.83 (dd, J = 5.6, 10.4 Hz, 1H), 3.58 (d, J= 12.0 Hz, 2H), 3.41-3.36 (m, 2H), 3.29-3.24 (m, 4H), 3.16 (s, 6H), 2.99-2.88 (m, 6H), 2.76-2.67 (m, 2H), 2.65-2.58 (m, 1H), 2.51 (dd, ./ 3.2, 8.4 Hz, 2H), 2.25-2.13 (m, 4H), 2.11- 2.01 (m, 4H), 1.88 (d, J= 11.6 Hz, 2H), 1.78-1.69 (m, 2H); MS (ESI) m/z: 749.4 [M+H] \
Example 34
Preparation of 7-cyclopentyl-2-((5-(4-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[ l,4'-bipiperidin]-
4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A'r-dimethyl-7Ef-pyrrolo[2,3-J|-pyrimidine-6- carboxamide Al 59
Figure imgf000259_0001
[00572] Compound Al 59 was prepared as described below.
[00573] Preparation of fert-butyl 4-((4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7/7- pyrrolo[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)piperidine-l -carboxylate 34.1. To a solution of 7-cyclopentyl-A(A’-dimethyl-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)- 7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide (350 mg, 805 pmol) in MeOH (4 mL) was added NaOAc (99.1 mg, 1.21 mmol), followed by addition of fert-butyl 4-formylpiperidine-l- carboxylate (344 mg, 1.61 mmol). After the mixture was stirred for 10 min, NaBELCN (152 mg, 2.42 mmol) was added. The reaction mixture was stirred for 16 h, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 34.1 (310 mg) in 59% yield. MS (ESI) m/z: 631.8 [M+H]+.
[00574] Preparation of 7-cyclopentyl-7V,Az-dimethyl-2-((5-(4-(piperidin-4-ylmethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7/f-pyrrolo[2,3-</|pyrimidine-6-carboxamide 34.2. To a solution of compound 34.1 (150 mg, 237 umol) in DCM (1 mL) was added 4M HC1 in dioxane (59 pL). After stirring for 0.5 h, the reaction mixture was concentrated to afford compound 34.2 as an HC1 salt (180 mg), which was used directly in the next step without further purification. MS (ESI) mA: 531.7 [M+H] \
[00575] Preparation of 7-cyclopentyl-2-((5-(4-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)- [l,4'-bipiperidin]-4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7/f-pyrroIo[2,3- tZ]-pyrimidine-6-carboxamide A159. To a solution of compound 34.2 (180 mg, 237 pmol) in THF (1 mL) and DMSO (1 mL) was added KOAc (69.8 mg, 711 pmol), followed by addition of 3-(4-(4-oxopiperidin-l-yl)phenyl)piperidine-2, 6-dione (102 mg, 355 pmol) and AcOH (1.4 mg, 23.7 nmol). After the mixture was stirred at 60 °C for 10 h, NaBEPCN (44.7 mg, 711 pmol) was added. The reaction mixture was stirred at 80 °C for 2 h, and then concentrated and purified by reverse phase prep-HPLC to afford compound Al 59 (43 mg) in 22% yield.
Figure imgf000260_0001
NMR (400 MHz, DMSO-^) 8 10.78 (s, 1H), 9.30 (s, 1H), 8.76 (s, 1H), 8.22-8.19 (m, 2H), 8.18-8.12 (m, 1H), 8.00 (d, J= 2.8 Hz, 1H), 7.43 (dd, 2.8, 9.1 Hz, 1H), 7.04 (d, ./ 8.8 Hz, 2H), 6.87 (br s, 2H), 6.60 (s, 1H), 4.78-4.69 (m, 1H), 3.72 (br dd, J= 4.8, 10.9 Hz, 6H), 3.57 (br d, J= 6.0 Hz, 1H), 3.16- 3.01 (m, 12H), 2.72-2.59 (m, 4H), 2.49-2.40 (m, 6H), 2.20-2.08 (m, 3H), 2.03 (br s, 4H), 1.94- 1.88 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.53 (m, 5H), 1.27-1.15 (m, 2H); MS (ESI) m/z: 802.5 [M+H]+.
Example 35
Preparation of 7-cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)ethyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7V,A7-dimethyl-7ff-pyrrolo[2,3-</|pyriniidine-6- carboxamide A160
Figure imgf000260_0002
[00576] Compound Al 60 was prepared as described below.
[00577] Preparation of 2,6-dibenzyloxy-3-[3-(2,2-dimethoxyethoxy)phenyl]pyridine 35.1.
A mixture of 3-(2,6-dibenzyloxy-3-pyridyl)phenol (4 g, 10.4 mmol), 2-bromo- 1,1 -dimethoxyethane (8.82 g, 52.2 mmol), and CS2CO3 (3.40 g, 10.4 mmol) in DMF (10 mL) was stirred at 80 °C for 16 h under N2. The reaction mixture was diluted with water and extracted with EtOAc.
The combined organic layers were washed with brine, dried over anhydrous NazSCH, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 35.1 (2 g) in 28% yield. 'H NMR (400 MHz, CDCh) J 7.52-7.49 (m, 1H), 7.35-7.32 (m, 2H), 7.31-7.24 (m, 6H), 7.23-7.15 (m, 7H), 5.33-5.31 (m, 2H), 5.27-5.25 (m, 2H), 4.61 (t, 5.2 Hz,
1H), 3.88 (d, J= 5.2 Hz, 2H), 3.34 (s, 6H).
[00578] Preparation of 3-[3-(2,2-dimethoxyethoxy)phenyl]piperidine-2, 6-dione 35.2. To a solution of compound 35.1 (1.4 g, 2,97 mmol) in THF (10 mL) was added 10% Pd/C (0.14 g) under N2. After stirring under H2 at 40 °C for 12 h, the reaction mixture was filtered and concentrated to afford compound 35.2 (380 mg), which was used directly in the next step without further purification. ’HNMR (400 MHz, CDCli) d 7.33-7.27 (m, 1H), 6.88 (dd, J= 2.4,
8.4 Hz, 1H), 6.84-6.79 (m, 2H), 4.72 (1, ./ 5.2 Hz, 1H), 4.01 (d, J- 5.2 Hz, 2H), 3.47 (s, 6H), 2.80-2.57 (m, 3H), 2.31-2.23 (m, 2H).
[00579] Preparation of 2-[3-(2,6-dioxo-3-piperidyl)phenoxy]acetaldehyde 35.3. To a solution of compound 35.2 (100 mg, 341 umol) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol). After stirring for 2 h, the reaction mixture was concentrated to afford compound 35.2 (30 mg), which was used directly in the next step without further purification. ’H NMR (400 MHz, CDCh) d 9,86 (s, 1H), 8,74-8,49 (m, 1H), 7,34 (t, J= 7.6 Hz, 1H), 6,91-6,67 (m, 3H), 5,09 (s, 2H), 3.88-3.71 (m, 1H), 2.86-2.64 (m, 2H), 2.42-2.17 (m, 2H).
[00580] Preparation of 7-cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)- ethyl)-piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A/,A7-dimethyl-777-pyrrolo[2,3-6f]- pyrimidine-6-carboxamide A160. A mixture of 7-cyclopentyl-A/,A-dimethyl-2-[[5-[4-(4- piperidyl)piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-<7]pyrimidine-6-carboxamide (50 mg, 96.6 pmol), compound 35.3 (28.7 mg, 1 16 pmol), and NaBHiCN (12.1 mg, 193 pmol) in MeOH (2 mL) was stirred for 12 h. The reaction mixture was then purified by reverse phase prep-HPLC to afford compound A160 (14 mg) in 19% yield. ’HNMR (400 MHz, CD3OD) d 8.73 (s, 1H), 8.46-8.34 (m, 1H), 8.24-8.15 (m, 1H), 7.97 (s, 1H), 7.54 (dd, J= 2.4, 9.02 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 6.98-6.86 (m, 3H), 6.63 (s, 1H), 4.79-4 74 (m, 1H), 4.29 (s, 2H), 3.86 (dd, J- 5.6,
10.4 Hz, 1H), 3.57-3.47 (m, 2H), 3.26 (s, 4H), 3.15 (s, 6H), 2.95-2.79 (m, 6H), 2.78-2.63 (m, 3H), 2.63-2.44 (m, 3H), 2.33-1.98 (m, 9H), 1.99-1.62 (m, 5H); MS (ESI) m/z: 749.4 [M+H]+.
Example 36
Preparation of 7-cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)propyl)piperazin- 1 -yl)pyridin-2-yl)amino)-Ar,AMiniethyl-777-pyrrolo[2, 3 -cZ]pyrimidine-6- carboxamide Al 61
Figure imgf000262_0001
[00581] Compound A161 was prepared as described below.
[00582] Preparation of 7-cyclopentyl-2-[[5-[4-(3-hydroxypropyl)piperazin- 1 -yl] -2- pyridyl]amino]-A,AMimethylpyrrolo[2,3-t/]pyrimidine-6-carboxamide 36.1, To a solution of 7- cyclopentyl-Ar,AT-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-d]pyrimidine-6- carboxamide (500 mg, 1.15 mmol) in DMF (5 mL) were added KI (19.1 mg, 115 pmol), DIEA (297 mg, 2.30 mmol), and 3 -iodopropan- l-ol (257 mg, 1.38 mmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh, and concentrated to afford compound 36.1 (434 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 493.4 [M+H] \
[00583] Preparation of 3-[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-t/]- pyrimidin-2-yl]amino]-3-pyridyl]piperazin-l-yl]propyl 4-methylbenzenesulfonate 36.2. To a solution of compound 2 (420 mg, 853 pmol) in DCM (5 mL) were added TsCl (195 mg, 1,02 mmol) and TEA (104 mg, 1.02 mmol). After stirring for 12 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSOr, concentrated, and purified by prep-TLC (SiOz, MeOH/DCM) to afford 36.2 (258 mg) in 47% yield. MS (ESI) m/z: 647.3 [M+H]+.
[00584] Preparation of 7-cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperazin-l-yl)propyl)piperazin-l-yl)pyridin-2-yl)amino)-A,/V-dimethyl-77f- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A161. To a solution of compound 36.2 (120 mg, 186 pmol) in DM! (2 mL) were added KI (31 mg, 186 pmol) and DIEA (72 mg, 557 pmol, and 3-(4- piperazin-l-ylphenyl)piperidine-2, 6-dione (69 mg, 223 pmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A161 as a TFA salt (13 mg) in 9% yield. !H NMR (400 MHz, DMSO-tfc) 3 0.78-0.85 (m, 4H), 1.10-1.17 (m, 5H), 1.25-1.33 (m, 1H), 1.51-1.54 (m, 3H), 1.62-1.64 (m, 4H), 1.70-1.85 (m, 8H), 2.20-2.23 (m, 6H), 2.26-2.31 (m, 8H), 2.87-2.91 (m, 1H), 3.89 (t, J -- 7.6 Hz, 1H), 5.76 (s, I H). 6.05 (d, J - 8.8 Hz, 2H), 6.21 (d, J - 8.6 Hz, 2H), 6.56-6.62 (m, 1H), 7.15 (d, J = 2.8 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.91 (s, 1H), 8.40 (s, 1H), 9.93 (s, 1H); MS (ESI) m/z\ 748.2 [M+H]+.
Example 37
Preparation of 7-cyclopentyl-2-((5-(4-(T-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 3 -yl)piperazin- 1 -yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7J7-pyrrolo[2,3 -t/]pyrimidine-6- carb oxami de A 162
Figure imgf000263_0001
[00585] Compound A162 was prepared as described below.
[00586] Preparation of tert-butyl 3-[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-d]pyrimidin-2-y1]amino]-3-pyridyl]piperazin-l-yl]piperidine-l -carboxylate 37.1, A mixture of 7-cyclopentyl-jV,A-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-t/|pyrimidine- 6-carboxamide (500 mg, 1.15 mmol), tert-butyl 3-oxopiperidine-l-carboxylate (382 mg, 1.92 mmol), 4 A molecular sieve (200 mg, 1.28 mmol), and AcOH (7.9 mg, 128 pmol) in THF (3.5 mL) and DMSO (3.5 mL) was stirred at 40 °C for 0.5 h, followed by addition of NaBHsCN (161 mg, 2.56 mmol). After stirring at 60 °C for 12.5 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 37.1 (240 mg) in 30% yield. MS (ESI) m/z\ 618.4 [M+H]+
[00587] Preparation of 7-cyclopentyl-Ar,A-dimethyl-2-[[5-[4-(3-piperidyl)piperazin-l-yl]- 2-pyridyl]amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide 37.2. A solution compound 37.1 (130 mg, 210 pmol) in 4M HC1 in dioxane (1.5 mL) and DCM (0.3 mL) was stirred for 4h. The reaction mixture was then concentrated to afford compound 37.2 as a HC1 salt (105 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 518.5 [M+H]+.
[00588] Preparation of 7-cyclopentyl-2-((5-(4-(r-(4-(2,6-dioxopiperidin-3-yI)phenyl)- [l,4'-bipiperidin]-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7/f-pyrrolo[2,3-i7]- pyrirnidine-6-carboxamide A162. To a solution of compound 37.2 as an HC1 salt (90 mg, 162 pmol) in THF (0.75 mL) and DMSO (0.75 mL) were added KOAc (47.8 mg, 487 pmol), 3-[4- (4-oxo-l -piped dyl)phenyl]piperidine-2, 6-dione (69.8 mg, 244 pmol), and AcOH (1 mg). After the mixture was stirred at 60 °C for 10 h, NaBHiCN (30.6 mg, 487 pmol) was added. The reaction mixture was stirred at 80 °C for 2 h, and then filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound Al 62 (37.5 mg) in 29% yield. rH NMR (400 MHz, DMSO-tZe) 6 10.77 (s, 1H), 9.27-9.23 (m, 1H), 8.74 (s, 1H), 8.21 (s, 1H), 8.12 (d, J= 9.2 Hz, 1H), 7.97 (d, J= 3.2 Hz, 1H), 7,41 (dd, J= 2.8, 9.3 Hz, 1H), 7,03 (d, J= 8.8 Hz, 2H), 6,88 (d, J= 8.8 Hz, 2H), 6.59 (s, 1H), 4.78-4.68 (m, 1H), 3.71 (br dd, J= 4.4, 10.8 Hz, 3H), 3.08 (br d, ./ - 4.8 Hz, 5H), 3.05 (br dd, J - 1.2, 2.0 Hz, 6H), 3.00 (br d, J- 0.8 Hz, 1 H), 2.81-2.76 (m, 1H), 2.69 (br dd, J= 4.4, 5.1 Hz, 4H), 2.62 (br s, 1H), 2.44-2.38 (m, 4H), 2.06 (br s, 9H), 1.86- 1.77 (m, 3H), 1.74-1.47 (m, 6H), 1.44-1.35 (m, I I I ),. 1.24-1.16 (m, 1H), 1.24-1.14 (m, 1H); MS (ESI) m/z: 788.8 [M+H]+.
Example 38
Preparation of 7-cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-A,A'-dimethyl-7/f-pyrrolo[2,3-^]- pyrimidine-6-carboxamide A163
Figure imgf000264_0001
[00589] Compound Al 63 was prepared as described below.
[00590] Preparation of tert-butyl 3-[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo-
[2,3-<7]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-l-yl]piperidine-l-carboxylate 38.1 To a solution of 7-cyclopentyl-7V,A-dimethyl-2-[(5-piperazin-l -yl-2-pyridyl)amino]pyrrolo[2,3-J]- pyrimidine-6-carboxamide (2 g, 4.6 mmol) and tert-butyl 3-oxopiperidine-l-carboxylate (1.83 g, 9.21 mmol) in DMF (10 mL) were added NaOAc (1.13 g, 13.8 mmol) and NaBEhCN (579 mg, 9.21 mmol). After stirring at 60 °C for 12 h, the reaction mixture was filtered and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 38.1 (1 g). MS (ESI) m/z: 618.4 [M+H]+.
[00591] Preparation of 7-cyclopentyl-A>A-dimethyl-2-[[5-[4-(3-piperidyl)piperazin-l-yl]- 2-pyridyl]amino]pyrrolo[2,3-tf|pyrimidine-6-carboxamide 38,2. To a solution of compound 38.1 ( 1 g, 1.62 mmol) in DCM (10 mL) was added 4M HC1 in dioxane (11.1 mL). After completion, the reaction mixture was concentrated to afford compound 38.2 as an HC1 salt (800 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 518.6 [M+H]+.
[00592] Preparation of 7-cyclopentyl-2-((5-(4-(l -((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)methyl)piperidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,jV-dimethyl-7J7- pyrrolo[2,3-<7]-pyrimidine-6-carboxamide A163 A mixture of compound 38.2 as an HC1 salt (300 mg, 408 pmol), l-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-4-carbaldehyde (147 mg, 490 pmol), NaBHjCN (51 mg, 817 pmol), and NaOAc (101 mg, 1.23 mmol) in DCM (1 mL) was stirred for 12 h under Nr. The reaction mixture was then concentrated and purified by reverse phase prep-HPLC to afford compound A163 as a TFA salt (19 mg) in 5% yield. rH NMR (400 MHz, CDsOD-A) A 8.74 (s, 1H), 8.46 (s, 1H), 8.19 (d, J -- 9.2 Hz, 1H), 7.98 (d, J - 2.4 Hz, 1H), 7.51 (dd, J = 2.8, 9.2 Hz, 1H), 7. 11 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.61 (s, 1 H), 4.80-4.72 (m, 1H), 3.77 (t, J -- 7.6 Hz, 1H), 3.69 (d, J = 12.4 Hz, 2H), 3.42 (d, J -- 10.8 Hz, 1H), 3.22 (s, 4H), 3.15 (s, 6H), 2.95-2.76 (m, 8H), 2.76-2.59 (m, 5H), 2.57-2.48 (m, 2H), 2.22-2.14 (m, 2H), 2.11-1.93 (m, 7H), 1.87 (d, J = 12.4 Hz, 2H), 1.81-1.66 (m, 3H), 1.59 (d, J - 10.4 Hz, 1H), 1.42 (q, J - 11.2 Hz, 2H); MS (ESI) m/z: 802.5 [M+H] \
Example 39
Preparation of 7-cyclopentyl-2-((5-(4-(((2S)-4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-
4-yl)morpholin-2-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A'’-dimethyl-7//-pyrrolo[2,3- t/]-pyrimidine-6-carboxamide Al 68
Figure imgf000266_0001
[00593] Compound A168 was prepared as described below.
[00594] Preparation of tert-butyl (25)-2-[[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-<7]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-l-yl] methyl]morpholine-4-carboxylate 39.1, To a solution of 7-cyclopentyl-A(AMimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]- pyrrolo[2,3-c/]pyrimidine-6-carboxamide (300 mg, 690 pmol) and tert-butyl (2A)-2-(p-tolyl- sulfonyloxymethyl)morpholine-4-carboxylate (256 mg, 690 pmol) in DMF (4 mL) were added DIEA (268 mg, 2.07 mmol) and KI (11.5 mg, 69 pmol). After stirring at 80 °C for 16 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 39.1 (450 mg) in 87% yield. MS (ESI) m/z'. 634.2 [M+H]+
[00595] Preparation of 7-cyclopentyl-A7,A’-dimethyl-2-[[5-[4-[[(27?)-morpholin-2-yl]- methyl]piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-t/]pyrimidine-6-carboxamide 39.2, To a solution of compound 39.1 (450 mg, 710 pmol) in DCM (2 mL) was added 4M HC1 in dioxane (4 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 39.2 as an HC1 salt (498 mg), which was used directly in the next step without further purification. MS (ESI) m/z-. 534.2 [M+H]+.
[00596] Preparation of 7-cyclopentyl-2-((5-(4-(((2A)-4-(l -(4-(2, 6-di ox opiperi din-3 -yl)- phenyl)piperidin-4-yl)morpholin-2-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A7-dimethyl- 7Z7-pyrrolo[2,3-t7]pyrimidine-6-carboxamide Al 68. To a solution of compound 39.2 as an HQ salt (99.6 mg, 175 pmol) in MeOH (1.5 mL) was added NaOAc (28.7 mg, 349 pmol). After the mixture was stirred for 15 min, 3-[4-(4-oxo-l-piperidyl)phenyl]piperidine-2, 6-dione (50 mg, 175 pmol) and NaBELCN (33 mg, 524 pmol) were added. The reaction mixture was stirred for 3 h, and then diluted with DMF (1 mL) and purified by reverse phase prep-HPLC to afford compound A168 as a TFA salt (21 mg) in 14% yield. TI NMR (400 MHz, DMSO-ufc) d 10.77 (s, 1H), 9.28 (s, 1H), 8.75 (s, 1H), 8.26 (s, 1H), 8.14 (d, J= 9.2 Hz, 1H), 7.98 (d, J= 2.8 Hz, 1H), 7.46-7.38 (m, 1H), 7.03 (d, J= 8.8 Hz, 2H), 6.88 (d, J= 8.8 Hz, 2H), 6.59 (s, 1H), 4.82-4.63 (m, 1H), 3.82-3.75 (m, 1 H), 3.73-3.66 (m, 3H), 3.61-3.57 (m, 1H), 3.50-3.46 (m, 1H), 3.10 (t, ./ 4.8 Hz, 4H), 3.05 (s, 6H), 2.90-2.83 (m, 1H), 2.75-2.69 (m, 1H), 2.68-2.57 (m, 6H), 2.55 (dd, J = 5.6, 10.8 Hz, 2H), 2.46-2.38 (m, 4H), 2.34-2.26 (m, 1H), 2.23-2.07 (m, 2H), 2.02-1.93 (m, 6H), 1.89-1.79 (m, 2H), 1.71-1.57 (m, 2H), 1.54-1.41 (m, 2H); MS (ESI) m/z: 804.5 [M+H] \
Example 40
Preparation of 7-cyclopentyl-2-((5-(4-(((27?)-4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-
4-yl)morpholin-2-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A(Ar-dimethyl-7H-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A169
Figure imgf000267_0001
[00597] Compound A169 was prepared as described below.
[00598] Preparation of tert-butyl (2A)-2-[[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-l-yl]methyl]morpholine-4-carboxylate 40.1. To a solution of tert-butyl (25)-2-(p-tolylsulfonyloxymethyl)morpholine-4-carboxylate (505 mg, 1.36 mmol) and 7-cyclopentyl-Ar^V-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]- pyrrolo[2,3-<7]pyrimidine-6-carboxamide as an HCI salt (400 mg, 849 pmol) in DMF (5 mL) were added KI (141 mg, 849 pmol) and DIEA (329 mg, 2.55 mmol). After stirring at 100 °C for 4 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by reverse phase prep-HPLC to afford compound 40.1 (410 mg) in 69% yield. MS (ESI) m/z: 634.4 [M+H]+.
[00599] Preparation of 7-cyclopentyl-A,A’-dimethyl-2-[[5-[4-[[(25)-morpholin-2-yl]- methyl]piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-t/]pyrimidine-6-carboxamide 40.2, To a solution of compound 40.1 (150 mg, 237 nmol) in DCM (1 mL) was added 4M HC1 in dioxane (59 pL). After stirring for 0.5 h, the combined organic layers were concentrated to afford compound 40.2 as an HC1 salt (140 mg), which was used directly in the next step without further purification. MS (ESI) m -z: 534.4 [M+H]+
[00600] Preparation of 7-cyclopentyl-2-((5-(4-(((27?)-4-(l -(4-(2, 6-di ox opiperi din-3 -yl)- phenyl)piperidin-4-yi)morpholin-2-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-jV,7V-dimethyl- 7/7-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A169. To a solution of compound 40.2 as an HC1 salt (130 mg, 228 pmol) in THF (1 mL) and DMSO (1 mL) were added KOAc (67 mg, 684 pmol), 3-[4-(4-oxo-l-piperidyl)phenyl]piperidine-2, 6-dione (72 mg, 251 umol), and AcOH (1.4 mg, 22.8 pmol). After the mixture was stirred at 60 °C for 10 h, NaBHsCN (43 mg, 684 pmol) was added. The reaction mixture was stirred at 80 °C for 2 h, and then concentrated and purified by reverse phase prep-HPLC to afford compound A169 (29 mg) in 14% yield. TH NMR (400 MHz, DMSO-flfc) J 10.77 (s, 1H), 9.27 (s, 1H), 8.75 (s, 1H), 8.15-8.12 (m, 3H), 7.98 (d, J= 2.8 Hz, 1H), 7.42 (dd, ./ 3.2, 9.2 Hz, 1H), 7.03 (d, 8.8 Hz, 2H), 6.88 (d, ./ 8.8 Hz, 2H), 6.59
(s, 1H), 4.76-4.68 (m, 1H), 3.79 (br d, J= 11.6 Hz, 2H), 3.72-3.68 (m, 3H), 3.60 (ddd, J= 0.8, 2.4, 4.8 Hz, 2H), 3.51-3.47 (m, 5H), 3.11 (br s, 2H), 3.05 (br s, 2H), 2.88 (br d, J = 11.6 Hz, 1H), 2.75-2.71 (m, 1H), 2.67-2.55 (m, 7H), 2.46-2.37 (m, 5H), 2.34-2.29 (m, 1H), 2.23-2.17 (m, 1H), 2.14-2.07 (m, 1H), 2.02-1.94 (m, 6H), 1.88-1.82 (m, 2H), 1.63 (br dd, J= 1.2, 5.2 Hz, 2H), 1.55- 1.45 (m, 2H); MS (ESI) m/z: 804.4 [M+H]L
Example 41
Preparation of 7-cyclopentyl-2-((5-(4-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- cyclohexyl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-/V,A-dimethyl-7//-pyiTolo[2,3-<7]- pyrimidine-6-carboxamide A170
Figure imgf000268_0001
[00601] Compound Al 70 was prepared as described below.
[00602] Preparation of 3-[4-[4-[4-(hydroxymethyl)cyclohexyl]piperazin-l-yl]phenyl]- piperidine-2, 6-dione 41.1. To a solution of 3-(4-piperazin-l-ylphenyl)piperidine-2, 6-dione (500 mg, 1 .83 mmol) and 4-(hydroxymethyl)cyclohexanone (469 mg, 3.66 mmol) in DMF (5 mL) were added NaBH(OAc)i (582 mg, 2.74 mmol) and AcOH (110 mg, 1.83 mmol). After stirring under N2 for 16 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiO?., MeOH/DCM) to afford compound 41.1 (400 mg) in 57% yield. rH NMR (400 MHz, DMSO-tfc) <5 10.77 (s, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.51-4.30 (m, 1H), 4.20-3.98 (m, 1H), 3.73 (dd, .7= 4,8, 11.2 Hz, 1H), 3.38-3.34 (m, 3H), 3.32 (d, J= 5.6 Hz, 3H), 3.20 (d, J= 6.4 Hz, 2H), 2.87-2.69 (m, 3H), 2.64-2.58 (m, 1H), 2.49-2.45 (m, 1H), 2.18-2,06 (m, 1H), 2.04-1.97 (m, 1H), 1,97-1.92 (m, 1H), 1.84-1.77 (m, 1H), 1.58 (s, 2H), 1.40 (dd, J= 4.4, 9.2 Hz, 1H), 1.33-1.21 (m, 2H), 0.98-0.83 (m, 1H); MS (ESI) m/z: 386.1 [M+H]+.
[00603] Preparation of 4-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin- 1 -yl]cyclohexane- carbaldehyde 41.2. To a solution of compound 41.1 (200 mg, 519 pmol) in DCM (4 mL) at 0 °C was added Dess-Martin (220 mg, 519 pmol) in portions. After stirring for 4 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (Si Ch, MeOH/DCM) to afford compound 41.2 (200 mg), which was used directly in the next step without further purification. MS (ESI) w/z: 384.2 [M+H]+.
[00604] Preparation of 7-cyclopentyl-2-((5-(4-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin- 1 -yl)-cyclohexyl)methyl)piperazin- 1 -yl)pyridin-2-yl)amino)-A/AMimethyl-7.H- pyrrolo[2,3-d]-pyrimidine-6-carboxamide A170. To a solution of 7-cyclopentyl-A'',A7-dimethyl- 2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-<f|pyrimidine-6-carboxamide (80 mg, 184 umol) and compound 41.2 (70.6 mg, 184 pmol) in DMF (0 5 mL) were added AcOH (1 mg) and NaBH(OAc)3 (117 mg, 552 pmol). After stirring for 2 h, the reaction mixture was filtered and purified by reverse phase prep-HPLC to afford compound A170 (28.5 mg) in 19% yield. *H NMR (400 MHz, DMSO-tA) d 10.77 (s, 1H), 9.28 (s, 1H), 8.75 (s, 1H), 8.14 (d, J= 9.2 Hz, 1H), 7.99 (d, J= 2.8 Hz, 1H), 7.42 (dd, J= 2.8, 9.2 Hz, 1H), 7.04 (d, J= 8.8 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 6.59 (s, 1H), 4.79-4.68 (m, 1 H), 3.72 (dd, .7 4.8, 11.1 Hz, 1 H), 3.16-3.00 (m, 14H), 2.69-2.57 (m, 5H), 2.49-2.34 (m, 7H), 2.31-2.20 (m, 1H), 2.17-2.09 (m, 3H), 2.03-1.94 (m, 5H), 1.85 (d, J= 10.8 Hz, 4H), 1.70-1.59 (m, 2H), 1.54-1.40 (m, 1H), 1.30-1.16 (m, 2H), 0.97-0.78 (m, 2H); MS (ESI) w/k 802.5 [M+H] \
Example 42
Preparation of 7-cyclopentyl-2-((5-(4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)cyclohexyl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7/7-pyrrolo[2,3-tZ]- pyrimidine-6-carboxamide A171
Figure imgf000270_0001
[00605] Compound A171 was prepared as described below.
[00606] Preparation of ethyl 2-(l,4-dioxaspiro[4.5]decan-8-ylidene)acetate 42.1, To a solution of 60% NaH (3.33 g, 83.2 mmol) in anhydrous THF (15 mL) was added dropwise 1,4- dioxaspiro[4.5]decan-8-one (10 g, 64 mmol) in anhydrous THF (100 mL) at 0 °C. After the mixture was stirred at 0 °C for 1 h, ethyl 2-diethoxyphosphoryl acetate (17.2 g, 76.8 mmol) was added dropwise at -20 °C. The reaction mixture was stirred at 20 °C for 2 h, and then diluted with water and extracted with EtO Ac. The combined organic layers were washed with brine, dried over anhydrous NazSOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 42.1 (5.5 g) in 55% yield ^1 NMR (400 MHz, CDCh) d 5.67 (s, 1H), 4.15-4.11 (m, 2H), 3.98 (s, 1H), 3.00 (t, .7 - 6.4 Hz, 2H), 2.41-2.36 (m, 1H), 2.31-2.27 (m, 1H), 1.86-1.69 (m, 4H), 1.30-1.26 (m, 3H).
[00607] Preparation of ethyl 2-(l,4-dioxaspiro[4.5]decan-8-yl)acetate 42.2. To a solution of compound 42.1 (5 g, 22.1 mmol) in THF (25 mL) was added 10% Pd/C (0.5 g) under N2.
After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 42.2 (4.5 g), which was used directly in the next step without further purification.
[00608] Preparation of ethyl 2-(l,4-dioxaspiro[4.5]decan-8-yl)acetate 42.3, To a solution of compound 42.2 (4.4 g, 19.3 mmol) in THF (30 mL) at 0 °C was added dropwise 2.5M LiAlHi (6.94 mL) over 15 min. After stirring at 0 °C for 1 h, the reaction mixture was treated with NH4CI at 0 °C, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, and concentrated to afford compound 42.3 (3.5 g), which was used directly in the next step without further purification. ’H NMR (400 MHz, CDCh) 0 3 94 (s, 1H), 3.70 (t, J = 6.4 Hz, 2H), 1.75 (d, J = 10.0 Hz, 4H), 1 .56-1 .44 (m, 5H), 1.33-1.26 (m, 2H).
[00609] Preparation of 4-(2-hydroxyethyl)cyclohexanone 42.4, A mixture of compound 42.3 (3 g, 16.1 mmol) and 4M HC1 in dioxane (20 mL) was stirred for 12 h. The reaction mixture was then treated with NaHCOs at 0 °C, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified bycolumn chromatography (SiCh, EtOAc/PE) to afford compound 42.4 (1.1 g) in 48% yield. TH NMR (400 MHz, CDCh) J 3.70-3.67 (m, 2H), 3.64 (s, 6H), 2.34-2.24 (m, 4H), 2.07-1.99 (m, 2H), 1.88 (ttd, J = 3.2, 7.2, 14.4 Hz, 1H), 1.53 (d, J = 6.8 Hz, 2H), 1.41-1.33 (m, 2H); MS (ESI) m/z: 143.1 [M+H]+.
[00610] Preparation of 3-[4-[4-[4-(2-hydroxyethyl)cyclohexyl]piperazin-l-yl]phenyl]- piperidine-2, 6-dione 42.5. To a solution of compound 42.4 (500 mg, 3.52 mmol) and 3-(4- piperazin-l-ylphenyl)piperidine-2, 6-dione (961 mg, 3.52 mmol) in DMF (10 mL) were added NaBH(OAc)s (2.24 g, 10.6 mmol) and NaOAc (865 mg, 10.6 mmol). After stirring at 60 °C for 12 h, the reaction mixture was concentrated and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 42.5 (550 mg) in 39% yield. lH NMR (400 MHz, CDCh) 4' 8.50 (s, 1H), 7.13 (d, J = 8.4 Hz, 3H), 6.93 (d, J = 8.4 Hz, 2H), 3.81-3.64 (m, 5H), 3.56-3.52 (m, 1H), 3.18 (td, J - 5.2, 16.4 Hz, 5H), 2.82-2.57 (m, 3H), 2.31-2.13 (m, 4H), 2.02-1.93 (m, 1H), 1.78 (d, J = 13.2 Hz, I H), 1.64-1.44 (m, 2H), 1.43-1.12 (m, 3H), 1.07-0.90 (m, 1H); MS (ESI) m/z: 400.3 [M+H]+.
[00611] Preparation of 2-[4-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-l-yl]cyclo- hexyl]acetaldehyde 42.6. To a solution of compound 42.5 (400 mg, 1 mmol) in DCM (2 mL) and ACN (2 mL) were added TPAP (70.4 mg, 200 pmol) and NMO (352 mg, 3 mmol). After stirring for 12 h, the reaction mixture was filtered and concentrated to afford compound 42.6 (400 mg, 50% purity), which was used directly in the next step without further purification. MS (ESI) m/z: 398.4 [M+H]+.
[00612] Preparation of 7-cyclopentyl-2-((5-(4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)- phenyl)piperazin- 1 -yl)cyclohexyl)ethyl)piperazin- 1 -yl)pyridin-2-yl)amino)-A,A-dimethyl-7/7- pyrrolo[2,3-t/]-pyrimidine-6-carboxamide A171. To a solution of compound 42.6 (200 mg, 252 pmol) and 7-cyclopentyl-A,A-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-(7]- pyrimidine-6-carboxamide (109 mg, 252 pmol) in DCM (2 mL) were added NaBH(OAc)j (160 mg, 755 pmol) and NaOAc (41.3 mg, 503 pmol). After stirring for 12 h, the reaction mixture was concentrated and purified by prep-TLC (SiCh, MeOH/DCM) and reverse phase prep-HPLC to afford compound A171 (9.7 mg) in 4% yield. !H NMR (400 MHz, CD3OD) 3 8.75 (s, 1H), 8.49 (s, 2H), 8.23 (d, J = 9.2 Hz, 1H), 8.02 (s, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.99 (d, J 7.2 Hz, 2H), 6.63 (s, 1H), 4.99 (s, 2H), 4.81-4.71 (m, 1H), 3,79 (dd, J - 6.0, 9.2 Hz, 1H), 3.47-3.33 (m, 10H), 3.15 (s, 8H), 3.08 (s, 2H), 2.88 (d, J - 6.4 Hz, 2H), 2.74-2.61 (m, 2H), 2.60-2.49 (m, 2H), 2.23-2. 14 (m, 3H), 2.06 (d, J 5 2 Hz, 4H), 2.03 (s, 1H), 1.98-1.88 (m, 2H), 1.76 (d, .7 = 14.4 Hz, 6H), 1.68-1.57 (m, 2H), 1.53 (d, ,7 - 10.8 Hz, 1H), 1.22-1.06 (m, 1H); MS (ESI) m/z: 816.8 [M+H]+.
Example 43
Preparation of 7-cyclopentyl-2-((5-(4-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)ethyl)cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-A(AMimethyl-777-pyrrolo[2,3</]- pyrimidine-6-carboxamide Al 73
Figure imgf000272_0001
[00613] Compound Al 73 was prepared as described below.
[00614] Preparation of /er/-butyl 4-[(L?)-2-(l,4-dioxaspiro[4.5]decan-8-yl)vinyl]- piperidine-1 -carboxylate 43.1. To a solution of (l-fert-butoxycarbonyl-4-piperidyl)methyl- triphenylphosphoniumiiodide (5 g, 8.53 mmol) in THF (12 mL) at -50 °C under N2 was added IM r-BuOK (9.87 mL). After the mixture was stirred for 1 h, l,4-dioxaspiro[4.5]decane-8- carbaldehyde (1.2 g, 7.05 mmol) was added in portions. The reaction mixture was stirred at 20 °C for 5 h, and the concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 43.1 (1.75 g) in 71% yield.
[00615] Preparation of tert-butyl 4-[2-(l,4-dioxaspiro[4.5]decan-8-yl)ethyl]piperidine-l- carboxylate 43.2. A mixture of compound 43.1 (1.85 g, 5.26 mmol) and 10% Pd/C (170 mg) in THF (20 mL) was stirred under H2 for 12 h. The reaction mixture was then filtered and concentrated to afford compound 43.2 (1.8 g), which was used directly in the next step without further purification.
[00616] Preparation of 4-[2-(l,4-dioxaspiro[4.5]decan-8-yl)ethyl]piperidine 43.3. To a solution of compound 43.2 (1.8 g, 5.09 mmol) in DCM (5 mL) was added 4M HC1 in dioxane (5 mL). After stirring for 12 h, the reaction mixture was filtered and concentrated to afford compound 43.3 as an HC1 salt (1.4 g), which was used directly in the next step without further purification. MS (ESI) m/z: 254,2 [M+H]+,
[00617] Preparation of 2,6-dibenzyloxy-3-[4-[4-[2-(l,4-dioxaspiro[4.5]decan-8-yl)ethyl]- 1 -piperidyl]phenyl]pyri dine 43.4. To a solution of compound 43.3 as an HC1 salt (500 mg, 1.73 mmol), 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (770 mg, 1 .73 mmol), CS2CO3 (1.12 g, 3.45 mmol), and RuPhos (80.5 mg, 173 pmol) in dioxane (15 mL) was added RuPhos Pd G3 (144 mg, 173 pmol). After stirring at 100 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) and prep-TLC (SiCh, EtOAc/PE) to afford compound 43.4 (1 g) in 94% yield. MS (ESI) m/z: 619,4 [M+H]+,
[00618] Preparation of 3-[4-[4-[2-(l,4-dioxaspiro[4.5]decan-8-yl)ethyl]-l-piperidyl]- phenyl]piperidine-2, 6-dione 43.5, To a solution of compound 43.4 (1 g, 1.62 mmol) in THF (10 mL) were added 20% Pd(OH)2 (0.1 g) and 10% Pd/C (0.1 g) under N2. After stirring under H2 at 50 °C for 48 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (S1O2, EtOAc/PE) to afford compound 43.5 (345 mg) in 48% yield). LH NMR (400 MHz, CDCh) 37.07 (d, J= 8.4 Hz, 1H), 6.91 (d, J= 8.4 Hz, 1H), 3.94 (s, 4H), 3.84-3.69 (m, 1H), 2.79-2.57 (m, 4H), 2,34-2, 17 (m, 2H), 1.94-1.63 (m, 10H), 1,35-1,18 (m, 10H); MS (ESI) m/z: 441.3 [M+H]T [00619] Preparation of 3-[4-[4-[2-(4-oxocyclohexyl)ethyl]-l-piperidyl]phenyl]piperidine- 2, 6-dione 43.6. To a solution of compound 43.5 (345 mg, 783 pmol) in THF (3 mL) was added 2M HCI (3 mL). After stirring for 2 h, the reaction mixture was neutralized to pH 7 with IM NaOH, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 43.6 (170 mg) in 47% yield. ^NMR (400 MHz, CDCh) 3 8.02 (s, 1H), 7.08 (d, ./ 8.4 Hz, 2H), 6.92 (d, ./ 8.4 Hz, 2H), 3.76-3.72 (m, 1H), 3.71-3.63 (m, 2H), 2.73-2.62 (m, 4H), 2.43-2.31 (m, 5H), 2.30-2.18 (m, 3H), 2.11 -1.98 (m, 4H), 1.80 (d, 9.6 Hz,
3H), 1.47-1.36 (m, 5H); MS (ESI) m/z: 397.1 [M+H]+.
[00620] Preparation of 7-cyclopentyl-2-((5-(4-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)- phenyl)piperidin-4-yl)ethyl)cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-77/- pyrrolo[2,3-(7]-pyrimidine-6-carboxamide A173. To a solution of compound 43.6 (80 mg, 202 umol) and 7-cyclopentyl-A/',A7-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-<i]- pyrimidine-6-carboxamide (87.7 mg, 202 pmol) in DCM (2 mL) was added NaBH(OAc)s (85.5 mg, 404 pmol). After stirring for 2 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by reverse phase prep-HPLC to afford compound A173 (58 mg) in 34% yield. rH NMR (400 MHz, DMSO-tfe) f5 10.76 (s, 1H), 9.25 (s, 1H), 8 75 (s, 1H), 8.17 (s, 1H), 8.13 (d, J= 9.2 Hz, 1H), 7.98 (d, J= 1.6 Hz, 1H), 7.48-7.34 (m, 1H), 7.02 (d, J= 8.4 Hz, 2H), 6.87 (d, J= 8.4 Hz, 2H), 6.59 (s, 1H), 4.72 (quin, 8.4 Hz, 1H), 3.73-3.61 (m, 4H), 3.11 (s, 4H), 3.05 (s, 6H), 2.69-2.54 (m, 8H), 2.43 (s, 2H), 2.22 (s, 1H), 2.03-1.92 (m, 5H), 1.73 (d, J= 11.2 Hz, 2H), 1.64 (s, 4H), 1.52-1.40 (m, 6H), 1.35-1.14 (m, 8H); MS (ESI) m/z: 815.6 [M+H]+.
Example 44
Preparation of 7-cyclopentyl-2-((5-(4-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)ethyl)piperidin-4-yl)piperaziii-l-yl)pyridin-2-yl)amino)-AT,Al-dimethyl-7J/-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A174
Figure imgf000275_0001
[00621] Compound A174 was prepared as described below.
[00622] Preparation of 2-[l-(4-iodophenyl)-4-piperidyl]ethanol 44.1, To a solution of 2- (4-piperidyl)ethanol (1.96 g, 15.2 mmol) and 1,4-diiodobenzene (10 g, 30.3 mmol) in DMF (100 mL) were added Cui (1.15 g, 6.06 mmol), K2CO3 (6.28 g, 45.5 mmol), and Z-proline (698 mg, 6.06 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCTi, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 44.1 (2.7 g) in 54% yield. MS (ESI) m/z: 332.1 [M+H]+.
[00623] Preparation of 2-[l -[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]ethanol
44.2, To a solution of compound 44.1 (2.7 g, 8.15 mmol) and (2,6-dibenzyloxy-3-pyridyl)- boronic acid (3.28 g, 9.78 mmol) in dioxane (20 mL) and H2O (2 mL) were added
Pd(dppf)Ch CH2C12 (666 mg, 815 pmol) and K3PO4 (3.46 g, 16.3 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NarSCh, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 44.2 (3 g) in 74% yield. *11 NAIR (400 MHz, DMSO-tZ) 7.67 (d, J= 8.0 Hz, 1H), 7.45-7.38 (m, 6H), 7.37-7.26 (m, 6H), 6.92 (d, J= 8.8 Hz, 2H), 6.50 (d, J= 8.0 Hz, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 4.37 (t, J= 5.2 Hz, 1H), 3.69 (d, J= 12.4 Hz, 2H), 3.53-3.42 (m, 2H), 2.69-2.56 (m, 2H), 1.72 (d, J= 11.6 Hz, 2H), 1.39 (q, J= 6.8 Hz, 2H); MS (ESI) m/z: 495.3 [M+H]+.
[00624] Preparation of 3-[4-[4-(2-hydroxyethyl)-l-piperidyl]phenyl]piperidine-2, 6-dione
44.3. To a solution of compound 44.2 (3 g, 6.07 mmol) in THF (15 mL) and MeOH (15 mL) was added 10% Pd/C (1 g) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 44.3 (1.7 g), which was used directly in the next step without further purification. ‘H NMR (400 MHz, DMSO-t/s) t) 10.76 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 4.36 (t, J= 5.2 Hz, 1H), 3.71 (dd, J= 5.2, 10.8 Hz, 1H), 3.63 (d, ./= 12.4 Hz, 2H), 3.51-3.43 (m, 2H), 2.68-2.55 (m, 3H), 2.49-2.40 (m, 1H), 2.17-1.95 (m, 2H), 1.73 (d, .7= 12.4 Hz, 2H), 1.52 (m, J= 4.0, 6.8, 10.4 Hz, 1H), 1.42-1.34 (m, 2H), 1.30- 1.15 (m, 2H); MS (ESI) m/z: 317.2 [M+H]t
[00625] Preparation of 2-[l-[4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]acetaldehyde 44.4. To a solution of compound 44.3 (500 mg, 1.58 mmol) in DCM (3 mL) and ACN (3 mL) were added TPAP (111 mg, 316 pmol) and NMO (555 mg, 4.74 mmol). After stirring for 12 h, the reaction mixture was filtered and concentrated to afford compound 44.4 (600 mg), which was used directly in the next step without further purification.
[00626] Preparation of 7-Cyclopentyl-2-((5-(4-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)- phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A(A’-dimethyl-7/7- pyrrolo[2,3-<7]-pyrimidine-6-carboxamide A174. To a solution of 7-cyclopentyl-A,A-dimethyl- 2-[[5-[4-(4-piperidyl)piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-tZ]pyrimidine-6-carboxamide (150 mg, 290 pmol) in MeOH (2 mL) were added NaOAc (71.3 mg, 869 pmol), compound 44.4 (182 mg, 580 pmol), and NaBHiCN (54.6 mg, 869 pmol). After stirring for 12 h, the reaction solution was diluted with DMF (2 mL) and purified by reverse phase prep-HPLC to afford compound A174 (26 mg) in 11% yield. rH NMR (400 MHz, DMSO-d6 ) 6 10.97-10.75 (m, 2H), 9.04 (s, 1 H), 8.17-8.12 (m, 2H), 8.03 (d, J= 2.0 Hz, 1H), 7.90 (d, J= 8.4 Hz, 2H), 7.66 (d, .7 = 9.6 Hz, 1H), 7.43 (d, 7 = 8.4 Hz, 2H), 6.85 (s, 1H), 4.78 (s, 1H), 3.97 (dd, 7 = 5.2, 12.0 Hz, 1H), 3.93-3.84 (m, 2H), 3.73-3.46 (m, 10H), 3.42-3.20 (m, 5H), 3.16-3.09 (m, 2H), 3.04 (s, 6H), 3.01- 2.94 (m, 1H), 2.77-2.64 (m, 1H), 2.53 (d, J= 4.4 Hz, 1H), 2.42 (d, J= 10.8 Hz, 2H), 2.25 (dt, J= 4.0, 12.4 Hz, 6H), 2.05-1.94 (m, 8H), 1.78 (s, 2H), 1.65-1.57 (m, 2H); MS (ESI) m/z: 816.8 [M+H]+.
Example 45
Preparation of 7-cyclopentyl-2-((5-(4-(2-(l'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'- bipiperidin]-l-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A’,A-dimethyl-7/7-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A175
Figure imgf000277_0001
[00627] Compound A175 was prepared as described below.
[00628] Preparation of 7-cyclopentyl-2-[[5-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2-pyridyl] - amino]-A7,A'r-dimethylpyrrolo[2,3-i/]pyrimidine-6-carboxamide 45.1. To a solution of 7-cyclo- pentyl-A’,Az-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-i(|pyrimidine-6- carboxamide (5 g, 11.5 mmol) in DMF (50 mL) were added 2 -bromoethanol (2 88 g, 23 mmol), K2CO3 (3.18 g, 23 mmol), and KI (191 mg, 1.15 mmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with II2O. The resulting precipitates were collected by filtration to afford compound 45.1 (4 g), which was used directly in the next step without further purification. MS (ESI) m/z\ 479.3 [M+H]+.
[00629] Preparation of 2-[[5-[4-(2-chloroethyl)piperazin-l-yl]-2-pyridyl]amino]-7- cyclopentyl-ACV-dimethyl-pyrrolo[2,3-t/]pyrimidine-6-carboxarnide 45.2. To a solution of compound 45.2 (3.9 g, 8.15 mmol) in DCM (40 mL) were added TsCl (3.11 g, 16.3 mmol), TEA (2.47 g, 24.5 mmol), and DMAP (100 mg, 815 pmol). After stirring for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound 45.2 (367 mg). MS (ESI) mA: 497.2 [M+H]+
[00630] Preparation of 7-cyclopentyl-2-((5-(4-(2-(l'-(4-(2,6-dioxopiperidin-3-yl)phenyl)- [4,4'-bipiperidin]-l-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A',,/V-dimethyl-7/f-pyrrolo[2,3- <7]-pyrimidine-6-carboxamide A175. To a solution of 3-[4-[4-(4-piperidyl)-l-piperidyl]phenyl]- piperidine-2, 6-dione as an HC1 salt (158 mg, 402 pmol) and compound 45.2 (300 mg, 604 pmol) in DMF (2 mL) were added DIEA (260 mg, 2.01 mmol), K2CO3 (55.6 mg, 402 pmol), and KI (66.8 mg, 402 pmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A175 (46 mg). lH NMR (400 MHz, DMSO-r/e) d - 10.77 (s, 1H), 9.25 (s, 1H), 8.74 (s, 1H), 8.16 (s, 4H), 8.12 (s, 1H), 7.98 (s, 1H), 7.41 (s, 1H), 7.09-6.97 (m, 2H), 6.93-6.82 (m, 2H), 6.59 (s, 1H), 4.79-4.66 (m, 1H), 3.75-3.65 (m, 6H), 3.14- 3.09 (m, 6H), 3.05 (dd, J= 0.8, 2.0 Hz, 8H), 2.67 (s, 2H), 2.61-2.56 (m, 7H), 2.38-2.30 (m, 2H), 2.15-2.07 (m, 2H), 2.00-1.94 (m, 4H), 1.78-1.60 (m, 6H), 1.29-1.18 (m, 6H); MS (ESI) m/z: 816.9 [M+H]+.
Example 46
Preparation of 7-cyclopentyl-2-((5-(4-(2-(T-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'- bipiperidin]-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A/,Af-dimethyl-7Lf-pyrrolo[2,3-tZ]- pyrimidine-6-carboxamide A176
Figure imgf000278_0001
[00631] Compound A176 was prepared as described below.
[00632] Preparation of terAbutyl 4-(2-(4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7/7- pyrrolo[2, 3 -<7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi dine- 1 -carboxylate 46.1. To a solution of 7-cyclopentyl-Ar,Ar-dimethyl-2-((5-(piperazin-l -yi)pyridin-2-yl)amino)- 7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide (500 mg, 1.15 mmol) in MeOH (6 mL) were added NaOAc (142 mg, 1.73 mmol) and /erLbutyl 4-(2-oxoethyl)piperi dine- 1 -carboxylate (523 mg, 2.3 mmol). After the mixture was stirred for 10 min, NaBHsCN (217 mg, 3.45 mmol) was added.
The reaction mixture was stirred for 16 h, and then diluted with water and extracted with EtO Ac.
The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiCb, EtOAc/PE) to afford compound 46.1 (420 mg) in 39% yield. MS (ESI) m/z: 646.4 [M+H]+.
[00633] Preparation of 7-cyclopentyl-A7,A-dimethyl-2-[[5-[4-[2-(4-piperidyl)ethyl]- piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-</|pyrimidine-6-carboxamide 46.2. To a solution of compound 46.1 (120 mg, 186 pmol) in DCM (1 mL) was added 4M HC1 in dioxane (1 mL).
After stirring for 0.5 h, the reaction mixture was concentrated to afford compound 46.2 as an HC1 salt (150 mg), which was used directly in the next step without further purification. MS (ESI) m/z-. 546.4 [M+H]+.
[00634] Preparation of 7-cyclopentyl-2-((5-(4-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)- [ 1 ,4'-bipiperidin]-4-yl)ethyl)piperazin- 1 -yl)py ridin-2-yl)amino)-Az,A-dimethyl-7/7-pyrrolo[2,3 - d]-pyrimidine-6-carboxamide A176. To a solution of compound 46.2 (150 mg, 275 pmol) in DMSO (1 mL) and THF (1 mL) were added KO Ac (80.9 mg, 825 pmol), AcOH (1.7 mg), and 3- [4-(4-oxo-l-piperidyl)phenyl]piperidine-2, 6-dione (94.4 mg, 330 pmol). After the mixture was stirred at 60 °C for 12 h, NaBHsCN (51.8 mg, 825 pmol) was added. The reaction mixture was stirred at 80 °C for 2 h and then purified by reverse phase prep-HPLC to afford compound A176 (50 mg) in 21% yield. *H NMR (400 MHz, DMSO-^) J 10.76 (br s, 1H), 9.24 (s, 1H), 8.75 (s, 1H), 8.19 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.98 (d, J= 2.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.03 (br d, .7= 8.4 Hz, 2H), 6.88 (br d, 8.4 Hz, 2H), 6,59 (s, 1H), 4,73 (quin, J= 8.4 Hz, 1H), 3.75- 3.68 (m, 5H), 3.14-3.02 (m, 11H), 2.93 (br d, J= 9.6 Hz, 2H), 2.67-2.58 (m, 6H), 2.44 (br d, J= 2.8 Hz, 2H), 2.37-2.32 (m, 2H), 2.21 (br t, ./ ■■■ 11.2 Hz, 2H), 2.14-2.09 (m, 1H), 2.03-1.93 (m, 5H), 1.83 (br d, J= 11.6 Hz, 2H), 1.73-1.62 (m, 4H), 1.59-1.49 (m, 2H), 1.39 (br d, J= 7.6 Hz, 2H), 1.34-1.27 (m, 1H), 1.23-1.10 (m, 2H); MS (ESI) m/z: 816.7 [M+H]+.
Example 47
Preparation of 7-cyclopentyl-2-((5-(4-(3-(l -(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- propyl)piperazin- 1 -y l)pyri din-2 -yl)amino)-A(AMimethyl-7ff-pyrrolo[2, 3 -t/]pyrimidine-6- carboxamide A180
Figure imgf000279_0001
[00635] Compound Al 80 was prepared as described below.
[00636] Preparation of 3-[l-(4-iodophenyl)-4-piperidyl]propan-l-ol 47.1. To a solution of 3-(4-piperidyl)propan-l-ol (9.75 g, 68.1 mmol) and 1,4-diiodobenzene (22.5 g, 68.1 mmol) in DMF (80 mL) were added Cui (2.59 g, 13.6 mmol), K2CO3 (18.8 g, 136 mmol), and (25)- pyrrolidine-2-carboxamide (3.11 g, 27.2 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 47.1 (9.12 g) in 38% yield.
Figure imgf000280_0001
(400 MHz, DMSO-cfc) 3 7.51-7.35 (m, 2H), 6.84-6.67 (m, 2H), 4.36 (t, J = 5.2 Hz, 1H), 3.65 (d, J = 12.4 Hz, 2H), 3.41-3.35 (m, 2H), 2.61 (dt, J = 2.4, 12.4 Hz, 2H), 1.70 (d, J = 11.6 Hz, 2H), 1.49-1.40 (m, 2H), 1.39-1.29 (m, 1H), 1.27-1.10 (m, 4H); MS (ESI) m/z 346.1 [M+H]+.
[00637] Preparation of 3-[l-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]propan-l- ol 47.2. To a solution of compound 47.1 (9.12 g, 26.4 mmol) and (2,6-dibenzyloxy-3-pyridyl)- boronic acid (9.74 g, 29.1 mmol) in dioxane (90 mL) and H2O (16 mL) were added
Pd(dppf)Ch CH2C12 (2.16 g, 2.64 mmol) and K3PO4 (16.83 g, 79.3 mmol). After stirring at 90 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 47.2 (9 g) in 66% yield. !H NMR (400 MHz, DMSO-^) 3 7.67 (d, J = 8.0 Hz, 1H), 7.45-7.34 (m, 10H), 7.34-7.32 (ra, 1H), 7.32-7.28 (m, 1H), 6.92 (d, J = 9.2 Hz, 2H), 6.51 (d, J = 8.0 Hz, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 4.36 (t, J = 5.2 Hz, 1H), 3.74-3.66 (m, 2H), 3.42-3.35 (m, 2H), 2.69-2.57 (m, 2H), 1.73 (d, J = 12.4 Hz, 2H), 1.51-1.40 (m, 2H), 1.40-1.31 (m, 1H), 1.29-1.20 (m, 4H); MS (ESI) m/z: 509.3 [M+H]+.
[00638] Preparation of 3-[4-[4-(3-hydroxypropyl)-l -piperidyl ]phenyl]piperidine-2, 6-dione 47.3, To a solution of compound 47.2 (9 g, 17.7 mmol) in THF (90 mL) were added 10% Pd/C (0.9 g) and 20% Pd(OH)2 (0.9 g) under N2. After stirring under 112 at 40 °C for 12 h, the reaction mixture was filtered and concentrated to afford compound 47.3 (6.56 g), which was used directly in the next step without further purification. rH NAIR (400 MHz, DMSO-de) <5 10.76 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.36 (t, J = 5.2 Hz, 1H), 3.71 (dd, J = 5.2, 10.8 Hz, 1H), 3.64 (d, J = 12.4 Hz, 2H), 3.43-3.35 (m, 2H), 2.68-2.55 (m, 3H), 2.49-2.41 (m, 1H), 2.18-2.05 (m, 1H), 2.00 (qd, J = 5.2, 13.2 Hz, 1H), 1.73 (d, J = 11.6 Hz, 2H), 1.50-1.40 (m, 2H), 1.39-1.29 (m, 1H), 1.28-1.19 (m, 4H); MS (ESI) m/z: 331.3 [M+H]+.
[00639] Preparation of 3-[l-[4-(2,6-dioxo-3-piperidyl)phenyl]-4- piperidyl]propanal 47.4, To a solution of compound 47.3 (800 mg, 2.42 mmol) in DCM (4 mL) and ACN (4 mL) were added TPAP (170 mg, 484 pmol) and NMO (851 mg, 7.26 mmol). After stirring for 12 h, the reaction mixture was filtered and concentrated to afford compound 47.4 (700 mg), which was used directly in the next step without further purification.
[00640] Preparation of 7-cyclopentyl-2-((5-(4-(3-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-propyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,jV-dimethyl-77f-pyrrolo[2,3-J|- pyrimidine-6-carboxamide A180. To a solution of compound 47.4 (350 mg, 671 prnol) and 7- cyclopentyl-A,A7-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo [2,3-d]pyrimidine-6- carboxamide (292 mg, 671 pmol) in DMF (3 mL) were added NaBH(OAc)i (427 mg, 2.01 mmol) and AcOH (80.6 mg, 1.34 mmol). After stirring for 12 h, the reaction mixture was concentrated and purified by prep-TLC (SiCh, MeOH/DCM) and reverse phase prep-HPLC to afford compound A180 (21.2 mg) in 4% yield.
Figure imgf000281_0001
NMR (400 MHz, CDiOD) d 8,77 (s, 1H), 8.19 (s, 4H), 8.15 (s, 1H), 8.01 (d, J - 2.8 Hz, 1H), 7.64 (dd, J - 2.8, 9.2 Hz, 1H), 7.13 (d, J - 8.4 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.66 (s, 1H), 4.81-4.75 (m, 1H), 3.82-3 75 (m, 1H), 3.69 (d, J - 12.0 Hz, 2H), 3.43 (s, 4H), 3.39 (d, J - 3.6 Hz, 4H), 3.16 (s, 6H), 3.11 (d, J = 8.4 Hz, 2H), 2.74-2.68 (m, 2H), 2.67-2.57 (m, 2H), 2.56-2.47 (m, 2H), 2.24-2.15 (m, 2H), 2.14-2.04 (m, 4H), 1.90-1.78 (m, 4H), 1.77-1.67 (m, 2H), 1.54-1.33 (m, 5H); MS (ESI) m/z: 747.8 [M+H]+.
Example 48
Preparation of 7-cyclopentyl-2-((5-(4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4- yl)cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-A,AT-dimethyl-7/7-pyrrolo[2,3-d]pyrimidine-6- carboxamide Al 81
Figure imgf000281_0002
[00641] Compound Al 81 was prepared as described below.
[00642] Preparation of ZerZ-butyl 4-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-3,6-dihydro-2Af- pyridine-1 -carboxylate 48.1. To a solution of 2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (15.7 g, 59.1 mmol) and Zert-butyl 4-bromo-3,6-dihydro-2/7- pyridine-l-carboxylate (12 g, 45.8 mmol) in dioxane (100 mL) and H2O (20 mL) were added Pd(dppf)Ch (1.67 g, 2.29 mmol) and K2CO3 (19 g, 137 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 48.1 (6 g) in 26% yield.
[00643] Preparation of tert-butyl 4-(l,4-dioxaspiro[4.5]decan-8-yl)piperidine-l - carboxylate 48.2, To a solution of compound 48.1 (6 g, 18.7 mmol) in EtOH (60 mL) was added 10% Pd/C (0.8 g) under N2. After stirring under Eb for 12 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 48.2 (6 g).
[00644] Preparation of 4-(4-piperidyl)cyclohexanone 48.3, To a solution of compound 48.2 (2 g, 6.15 mmol) in acetone (10 mL) was added TsOH (2.12 g, 12.3 mmol) at 0 °C. After stirring for 16 h, the reaction mixture was filtered and concentrated to afford compound 48.3 (1.4 g), which was used directly in the next step without further purification. MS (ESI) m/z: 182.1 [M+H]+.
[00645] Preparation of tert-butyl 4-(4-oxocyclohexyl)piperi dine- 1 -carboxyl ate 48.4, To a solution of compound 48.3 (1.4 g, 6.43 mmol) in DCM (10 mL) were added BOC2O (1.68 g, 7.72 mmol), TEA (1 .95 g, 19.3 mmol), and DMAP (78.6 mg, 643 umol). After stirring for 12 h, the reaction mixture was filtered and concentrated to afford compound 48.4 (800 mg), which was used directly in the next step without further purification.
[00646] Preparation of tert-butyl 4-[4-[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)- pyrrolo[2,3-</]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-l-yl]cyclohexyl]piperidine-l- carboxylate 48.5. To a solution of compound 48.4 (50 mg, 178 pmol) and 7-cyclopentyl-AjV- dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-tZ]pyrimidine-6-carboxamide (77.2 mg, 178 umol) in DMF (1 mL) were added NaBELCN (33.5 mg, 533 pmol) and AcOH (10.7 mg, 178 umol). After stirring for 12 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 48.5 (300 mg) in 29% yield. MS (ESI) m/z: 700.8 [M+H]+. [00647] Preparation of 7-cyclopentyl-M?/-dimethyl-2-[[5-[4-[4-(4-piperidyl)cyclohexyl]- piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-tZ]pyrimidine-6-carboxamide 48.6. To a solution of compound 48.5 (300 mg, 429 pmol) in DCM (5 mL) was added 4M HQ in dioxane (107 pL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 48.6 as an HC1 salt (270 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 600.4 [M+H]+.
[00648] Preparation of 7-cyclopentyl-2-((5-(4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phen- ethyl)piperidin-4-yl)cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-72f-pyrrolo- [2,3-</|pyrimidine-6-carboxamide A181. To a solution of 3-[4-(2-bromoethyl)phenyl]piperidine- 2, 6-dione (119 mg, 400 pmol) and compound 48.6 (200 mg, 333 umol) in DMF (2 mL) were added KI (5.5 mg, 33.3 pmol) and DIEA (431 mg). After stirring at 80 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A181 (30 mg) in 11% yield. 41 NMR (400 MHz, CD3OD) cl 8.74 (s, 1H), 8.51 (s, 2H), 8.25 (dd, J= 7.2, 8.8 Hz, 1H), 8.00 (t, J= 3.2 Hz, 1H), 7.53 (dd, J= 2.8, 9.2 Hz, 1H), 7.31- 7.27 (m, 2H), 7.26-7.22 (m, 2H), 6.62 (s, 1H), 4.76 (d, J = 8.8 Hz, 1H), 3.86 (dd, J = 5.6, 10 8 Hz, 1H), 3.59 (d, J= 9.2 Hz, 2H), 3.36-3.32 (m, 2H), 3.28-3.22 (m, 2H), 3.16 (s, 6H), 3.13 (s, 2H), 3.07-3.00 (m, 4H), 2.96-2.85 (m, 2H), 2.76-2.60 (m, 3H), 2.58-2.49 (m, 2H), 2.25-2.14 (m, 3H), 2.11-2.02 (m, 5H), 1.96 (s, 2H), 1.88-1.62 (m, 6H), 1.61-1.46 (m, 3H), 1.46-1.32 (m, 3H), 1.27-1.03 (m, 2H); MS (ESI) m/z-. 815.8 [M+H] \
Example 49
Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[l,4'-bipiperidin]- r-yl)pyridin-2-yl)amino)-A4A-dimethyl-7Ff-pyrrolo[2,3-r/]pyrimidine-6-carboxamide A182
Figure imgf000283_0001
[00649] Compound A182 was prepared as described below.
[00650] Preparation of tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidyl)phenyl]ethynyl]- piperi dine- 1 -carboxylate 49.1. A mixture of tert-butyl 4-ethynylpiperidine-l -carboxylate (4.29 g, 20.5 mmol), 3-(4-bromophenyl)piperidine-2, 6-dione (5 g, 18.7 mmol), XPhos Pd Gr (1.58 g, 1.86 mmol), and CS2CO3 (18.2 g, 56 mmol) in ACN (25 mL) and THF (25 mL) was stirred at 60 °C for 12 h under N2. The reaction mixture was then treated with NH4Q and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 49.1 (3.4 g) in 46% yield. MS (ESI) m/z: 419.4 [M+H]+.
[00651] Preparation of tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidyl)phenyl]ethyl]piperidine- 1 -carboxylate 49.2. A mixture of compound 49.1 (3.4 g, 8.58 mmol) and PtCh (600 mg, 2.64 mmol) in THF (30 mL) was stirred for 12 h under H2. The reaction mixture was then filtered, concentrated, and triturated with EtOAc/PE to afford compound 49.2 (3.2 g) in 93% yield. MS (ESI) m/z: 423.3 [M+H] \
[00652] Preparation of 3-[4-[2-(4-piperidyl)ethyl]phenyl]piperidine-2, 6-dione 49.3, A solution of compound 49.2 (200 mg, 499 umol) in 4M HC1 in dioxane (2 mL) in DCM (1 mL) was stirred for 1 h under N2. The reaction mixture was then concentrated to afford compound 49.3 as an HC1 salt (179 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 301.1 [M+H]+.
[00653] Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)- [ 1 ,4' -bipiperi din] - 1 '-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7/Apyrrolo[2,3 -</|pyrimidine-6- carboxamide A182. To a solution of compound 49.3 as an HC1 salt (168 mg, 499 pmol) in THF (1.5 mL) and DMSO (1.5 mL) were added KO Ac (122 mg, 1.25 mmol), 7-cyclopentyl-A,A7- dimethyl-2-[[5-(4-oxo-l -piperi dyl)-2-pyridyl]amino]pyrrolo[2,3-J]pyrimidine-6-carboxamide (186 mg, 416 jimol), and HO Ac (2.5 mg). After the mixture was stirred at 60 °C for 10 h, NaBILCN (78.4 mg, 1.25 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h, and then filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A182 (120 mg) in 37% yield. [H NMR (400 MHz, DMSO-de) 5 = 11.62 (br d, J= 1.2 Hz, 1H), 10.94 (br s, 1H), 10.82 (s, 1H), 9.02 (s, 1H), 8.17 (dd, J- 2.8, 9.6 Hz, 1H), 7.96 (br d, ./ = 2.8 Hz, 1H), 7.62 (d, J= 9.6 Hz, 1H), 7.21-7.09 (m, 4H), 6.84 (s, 1H), 4.82 (s, 1H), 3.86-3.80 (m, 3H), 3.52-3.42 (m, 2H), 3.40-3. 11 (m, 2H), 3.07 (s, 5H); MS (ESI) m/z: 732.5 [M+H]+. Example 50
Preparation of 7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-4- yl)methyl)pyridin-2-yl)amino)-A7,A’-dimethyl-77/-pyrrolo[2,3-<f]pyrimidine-6-carboxamide A183
Figure imgf000285_0001
[00654] Compound A183 was prepared as described below.
[00655] Preparation of ter/-butyl 4-[(6-amino-3-pyridyl)methyl]piperidine-l -carboxylate 50.1. To a solution of 9-BBN (1.23 g, 5.07 mmol) in THF (5 mL) was added dropwise tert-butyl 4-methylenepiperidine-l -carboxylate (1 g, 5.07 mmol) under N?.. After the mixture was stirred at 75 °C for Ih, 5-bromopyridin-2-amine (746 mg, 4.31 mmol), Pd(dppf)Ch (1.11 g, 1.52 mmol), and K2CO3 (771 mg, 5.58 mmol) in DMF (10 mL) and H2O (1 mL) was added dropwise under N2. The reaction mixture was stirred at 60 °C for 4 h, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 50.1 (0.85 g) in 53% yield. LH NMR (400 MHz, DMSO-ak) J 6.85 (d, J= 2.0 Hz, IH), 6.35 (dd, J= 2.4, 8.4 Hz, IH), 5.54 (d, J = 8.4 Hz, IH), 4.82 (s, 2H), 3.12-2.97 (m, 2H), 1.89-1.70 (m, 2H), 1.46
Figure imgf000285_0002
6.4 Hz, 2H), 0.73-0.64 (m, 3H), 0.55 (s, 9H), 0.19- 0.07 (m, 2H).
[00656] Preparation of tert-butyl 4-[[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3- cZ]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperidine-l-carboxylate 50.2. To a mixture of compound 50.1 (0.5 g, 1.72 mmol), 2-chloro-7-cyclopentyl-Ar y/V-dimethyl-7Z7-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide (503 mg, 1.72 mmol), and CS2CO3 (1.12 g, 3.43 mmol) in dioxane (10 mL) were added Pd(OAc)2 (39 mg, 172 umol) and BINAP (214 mg, 343 umol) under N2. After stirring at 100 °C for 4 h under N2, the reaction mixture was diluted with water. The resulting precipitates were collected by filtration and triturated with EtOAc/PE to afford compound 50.2 (0.45 g) in 44% yield NMR (400 MHz, DMSO-d6 ) d 9.45 (s, IH), 8.78 (s, IH), 8.22 (d, J= 8.4 Hz, IH), 8.08 (d, J= 2.0 Hz, IH), 7.57(s, IH), 6.61 (s, IH), 4.82-4.66 (m, 1H), 3.96-3.87 (m, 2H), 3.56 (s, 9H), 3.09-3.01 (m, 6H), 1.76-1.51 (m, 6H), 1.38 (s, 9H), 1 .08- 1.00 (m, 2H); MS (ESI) m/z: 548.4 [M+H]+.
[00657] Preparation of 7-cyclopentyl-A,A-dimethyl-2-[[5-(4-piperidylmethyl)-2-pyridyl]- amino]pyrrolo[2,3-7]pyrimidine-6-carboxamide 50.3, A mixture of compound 50.2 (0.45 g, 822 jimol) in DCM (3 mL) and 4M HC1 in dioxane (1 mL) was stirred for 2 h under N?.. The reaction mixture was then concentrated to afford compound 50.3 as an HC1 salt (0.45 g), which was used directly in the next step without further purification. MS (ESI) m/z: 448.4 [M+H]+.
[00658] Preparation of 7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'- bipiperidin]-4-yl)methyl)pyridin-2-yl)amino)-A,Az-dimethyl-7J7-pyrrolo[2,3-J]pyrimidine-6- carboxamide A183 To a solution of compound 50.3 as an HC1 salt (0.2 g, 413 pmol) in THF (1 mL) and DMSO (1 mL) was added KOAc (122 mg, 1.24 mmol) to pH 7-8, followed by addition of 3-(4-(4-oxopiperidin-l-yl)phenyl)piperidine-2, 6-dione (142 mg, 496 gmol) and AcOH (3 mg). After the mixture was stirred at 60 °C for 10 h, NaBHsCN (52 mg, 826 pmol) was added. The reaction mixture was stirred at 80 °C for 2 h and then purified by reverse phase prep-HPLC to afford compound A183 as a TFA salt (80 mg) in 25% yield. SH NMR (400 MHz, DMSO-d6 ) 8 10.77 (s, 1H), 9.54 (s, 1H), 8.80 (s, 1H), 8.24 (d, J= 8.4 Hz, 1H), 8.20 (s, 1H),8.1O (s, 1H), 7.63- 7.52 (m, 1H), 7.02 (br d, 7= 8.4 Hz, 2H), 6.88 (br d, 7= 8.4 Hz, 2H), 6.62 (s, 1H), 4.74 (br t, J =8.4 Hz, 1H), 3.71 (br dd, 7= 4.4, 11.0 Hz, 4H), 3.11-3.02 (m, 6H), 3.00 (br s, 1H), 2.70-2.53 (m, 4H), 2.49-2.39 (m, 5H), 2.35-2.24 (m, 2H), 2.18-2.06 (m, 1H), 2.04-1.91 (m, 5H), 1.89-1.76 (m, 2H), 1.72-1.43 (m, 7H), 1.34-1.15 (m, 2H); MS (ESI) m/z: 718.5 [M+H]+.
Example 51
Preparation of 7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]-l- yl)methyl)pyridin-2-yl)amino)-A(7V-dimethyl-7/f-pyrrolo[2,3-7]pyrimidine-6-carboxamide A184
Figure imgf000286_0001
[00659] Compound A184 was prepared as described below. [00660] Preparation of 7-cyclopentyl-2-[(5-formyl-2-pyridyl)amino]-A(A-dimethyl- pyrrolo[2,3-t/]pyrimidine-6-carboxamide 51.1. A mixture of 2-chloro-7-cyclopentyl-A^V- dimethylpyrrolo[2,3-</jpyrimidine-6-carboxamide (1 g, 3.42 mmol), 6-aminopyridine-3- carbaldehyde (459 mg, 3.76 mmol), Pd/(dba)3 (313 mg, 342 pmol), Xantphos (395 mg, 683 pmol), and CS2CO3 (1.11 g, 3.42 mmol) in dioxane (10 mL) was stirred at 100 °C for 12 h under N?„ The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated and purified by prep-TLC (SiCh, EtOAc/PE) to afford compound 51.1 (800 mg) in 51% yield. MS (ESI) m/z'. 379.1 [M+H]4.
[00661] Preparation of 7-cyclopentyl-2-((5-((T-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'- bipiperidin]-l -yl)methyl)pyridin-2-yl)amino)-A(AMimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A184. A mixture of 3-[4-[4-(4-piperidyl)-l-piperidyl]phenyl]piperidine-2, 6-dione (124 mg, 317 pmol), compound 51.1 (100 mg, 264 pmol), NaBH(OAc)s (112 mg, 529 pmol), and NaOAc (65 mg, 793 pmol) in DCM (2 mL) was stirred for 12 h under N2. The reaction mixture was then concentrated and purified by reverse phase prep-HPLC to afford compound A184 (19 mg) in 10% yield. !H NMR (400 MHz, DMSO<A) <5 10.76 (s, 1H), 9.61-9.50 (m, 1H), 8.80 (s, 1H), 8.31-8.22 (m, 1H), 8.16 (d, J= 1.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.93-6.81 (m, 2H), 6.62 (s, 1H), 4.82-4.63 (m, 1H), 3.74-3.63 (m, 3H), 3.40 (s, 2H), 3.06 (s, 6H), 2.88-2.81 (m, 2H), 2.67-2.54 (m, 3H), 2.47-2.41 (m, 3H), 2.03-1.94 (m, 5H), 1.92- 1.84 (m, 2H), 1.78-1.61 (m, 6H), 1.30-1.14 (m, 6H), 1.11-1.00 (m, 1H); MS (ESI) m/z: 718.3 [M+H]4.
Example 52
Preparation of 7-cyclopentyl-2-((5-((l '-(4-(2, 6-dioxopi peridin-3 -y l)pheny 1 )- [ 1 ,4'-bipi peridin] -4- yl)oxy)pyridin-2-yl)amino)-A(A7-dimethyl-7H-pyrrolo[2,3-J]pyriniidine-6-carboxamide A186.
Figure imgf000287_0001
[00662] Compound Al 86 was prepared as described below.
[00663] Preparation of tert-butyl 4-((6-nitropyridin-3-yl)oxy)piperidine-l-carboxylate
52.1. To a solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (1.7 g, 8.45 mmol) in DMA (10 mL) at 0 °C under N2 was added teBuOK (1 .03 g, 9.15 mmol). After the mixture was stirred for 1 h, 5-fluoro-2-nitropyridine (1 g, 7.04 mmol) in DMA (5 mL) was added dropwise. After stirring for 10 h under N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Nai-SCU, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 52.1 (960 mg) in 42% yield.
[00664] Preparation of tert-butyl 4-((6-aminopyridin-3-yl)oxy)piperidine-l-carboxylate
52.2, To a solution of compound 52.1 (960 mg, 2.97 mmol) in MeOH (10 mL) was added 10% Pd/C (250 mg). After stirring for 12 h under H2, the reaction mixture was filtered and concentrated to afford compound 52.2 (730 mg), which was used directly in the next step without further purification,
Figure imgf000288_0001
(400 MHz, DMSO-rfo) ri 7.66 (d, J = 2.4 Hz, 1H), 7.17- 7.11 (m, 1H), 6.43-6.37 (m, 1H), 5.50 (s, 2H), 4.23 (tt, J = 3.6, 7.6 Hz, 1H), 3.68-3.59 (m, 2H), 3.16-3.07 (m, 2H), 1.86-1.78 (m, 2H), 1.46 (tdd, J= 4.4, 8.6, 12.8 Hz, 2H), 1.40 (s, 9H); MS (ESI) m/z: 294.2 [M+H]+.
[00665] Preparation of tert-butyl 4-((6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7/7- pyrrolo[2,3-</|pyrimidin-2-yl)amino)pyridin-3-yl)oxy)piperidine-l -carboxylate 52.3. To a mixture of compound 52.2 (300 mg, 1.02 mmol) and 2-chloro-7-cyclopentyl-M,A-dimethyl-7/7- pyrrolo-[2,3-c/]pyrimidine-6-carboxamide (299 mg, 1.02 mmol) in dioxane (3 mL) were added Pd(OAc)2 (23 mg, 102 pmol), BINAP (127 mg, 204 praol), and CS2CO3 (666 mg, 2.05 mmol). After stirring at 90 °C for 12 h under N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 52.3 (400 mg) in 71% yield. rH NMR (400 MHz, DMSO-de) 3 9.40 (s, 1H), 8.77 (s, 1H), 8.19 (d, J= 9.2 Hz, 1H), 8.04 (d, J- 3.2 Hz, 1H), 7.49 (dd, J- 3.2, 9.2 Hz, 1H), 6.60 (s, 1H), 4.78-4.69 (m, 1H), 4.55 (td, J = 4.2, 8.0 Hz, 1H), 3.70-3.61 (m, 2H), 3.23-3.15 (m, 2H), 3.05 (br s, 6H), 2.42 (br d, J 7.6 Hz, 2H), 1.99 (s, 2H), 1.97 (br s, 2H), 1.93-1.85 (m, 2H), 1.68-1.60 (m, 2H), 1.54 (tdd, J = 4.4, 8.4, 12.4 Hz, 2H), 1.42-1.39 (m, 9H); MS (ESI) m/z: 550.5 [M+H]+.
[00666] Preparation of 7-cyclopentyl-A’,A'’-dimethyl-2-((5-(piperidin-4-yloxy)pyridin-2- yl)amino)-7J¥-pyrrolo[2,3-i(]pyrimidine-6-carboxamide 52.4. A solution of compound 52.3 (200 mg, 364 pmol) in 4M HC1 in dioxane (2 mL) and DCM (2 mL) was stirred for 1 h. The reaction mixture was then concentrated to afford compound 52.4 as an HC1 salt (170 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 450.2 [M+H]+.
[00667] Preparation of 7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'- bipiperidin]-4-yl)oxy)pyridin-2-yl)amino)-A(ALdimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A186 To a solution of compound 52.4 as an HC1 salt (170 mg, 350 pmol) in THF (2 mL) and DMSO (2 mL) was added KO Ac (103 mg, 1.05 mmol), followed by addition of HO Ac (63 mg, 1.05 mmol) and 3 -(4-(4-oxopiperi din- l-yl)phenyl)piperidine-2, 6-dione (100 mg, 350 pmol). After the mixture was stirred at 60 °C for 12 h, NaBHsCN (65.9 mg, 1.05 mmol) was added. The reaction mixture was stirred at 80 °C for 1 h, and then filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A186 as a TFA salt (44 mg) in 16% yield.
Figure imgf000289_0001
10.78 (s, 1H), 9.47 (s, 1H), 8.78 (s, 1H), 8. 19 (s, 1H), 8.17 (s, 1H), 8.03 (d, J = 3.2 Hz, 1H), 7.47 (dd, J= 2.8, 9.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.88 (d, J= 8.4 Hz, 2H), 6.60 (s, 1H), 4.74 (quin, J= 8.8 Hz, 1H), 4.40-4.33 (m, 1H), 3.71 (br dd, J = 4.4, 10.4 Hz, 4H), 3.05 (br s, 6H), 2.87-2.81 (m, 2H), 2.66-2.59 (m, 3H), 2.47-2.41 (m, 5H), 2.16-2.07 (m, 1H), 2.02-1.93 (m, 7H), 1.83 (br d, J = 11.2 Hz, 2H), 1.69-1.60 (m, 4H), 1.58-1.49 (m, 2FI); MS (ESI) m/z: 720.3 [M+H]t
Example 53
Preparation of 7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-4- yl)methoxy)pyridin-2-yl)amino)-A’yV-dimethyl-7//-pyrrolo[2,3-<Z]pyrimidine-6-carboxamide A187
Figure imgf000289_0002
[00668] Compound Al 87 was prepared as described below.
[00669] Preparation of tert-butyl 4-[(6-nitro-3-pyridyl)oxymethyl]piperidine-l- carboxylate 53.1. To a solution of tert-butyl 4-(hydroxymethyl)piperidine-l -carboxylate (9.09 g, 42.2 mmol) in DMA (50 mL) at 0 °C under N2 was added t-BuOK (5.13 g, 45.8 mmol). After the mixture was stirred at 0 °C for 1 h, 5-fluoro-2-nitropyridine (5 g, 35.2 mmol) in DMA (25 mL) was added dropwise. After stirring for 12 h, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 53.1 (4.9 g) in 41% yield. !H NMR (400 MHz, CDCh) 8 8.28 (d, ./= 9.2 Hz, 1H), 8.24 (d, J= 2.8 Hz, 1H), 7.38 (dd, J= 2.8, 9.2 Hz, 1H), 4.21 (br d, J= 12.4 Hz, 2H), 3.98 (d, ./= 6.4 Hz, 2H), 2.77 (br t, J= 12.2 Hz, 2H), 2.11 -2.00 (m, 1H), 1.85 (br d, J = 13.2 Hz, 2H), 1.48 (s, 9H), 1.32 (dq, J= 4.4, 12.4 Hz, 2H).
[00670] Preparation of tert-butyl 4-[(6-amino-3-pyridyl)oxymethyl]piperidine-l- carboxylate 53.2. A mixture of compound 53.1 (1.3 g, 3.85 mmol) and 10% Pd/C (300 mg) in MeOH (10 mL) was stirred for 10 h under Hi. The reaction mixture was then filtered and concentrated to afford compound 53.2 (1.1 g), which was used directly in the next step without further purification. rH NMR (400 MHz, DMSO-d6) 6 = 7.62 (d, J= 3.2 Hz, 1H), 7.09 (dd, J = 3.2, 8.8 Hz, 1H), 6.40 (d, J= 8.8 Hz, 1H), 5.43 (s, 2H), 3.95 (br d, J = 11.8 Hz, 2H), 3.72 (d, J = 6.4 Hz, 2H), 2.70 (br d, J= 5.2 Hz, 2H), 1.90-1.81 (m, 1H), 1.74-1.69 (m, 2H), 1 .39 (s, 8H), 1.18-1.06 (m, 2H).
[00671] Preparation of tert-butyl 4-[[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3- t/]pyrimidin-2-yl]amino]-3-pyridyl]oxymethyl]piperidine-l -carboxylate 53.3. To a solution of compound 53.1 (500 mg, 1.63 mmol) and 2-chloro-7-cyclopentyl-A(AMimethyl-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide (476 mg, 1.63 mmol) in dioxane (5 mL) were added BINAP (203 mg, 325 pmol), Pd(OAc)2 (36.5 mg, 163 pmol), and CS2CO3 (1.06 g, 3.25 mmol). After stirring at 100 °C for 12 h under N2, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NA2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 53.3 (670 mg) in 73% yield. MS (ESI) m/z: 564.3 [M+H]+. [00672] Preparation of 7-cyclopentyl-A,A-dimethyl-2-[[5-(4-piperidylmethoxy)-2- pyridyl]amino]pyrrolo[2,3-£/]pyrimidine-6-carboxamide 53.4. To a solution of compound 53.3 (400 mg, 710 pmol) in DCM (4 mL) was added 4M HC1 in dioxane (4 mL). After stirring for 0.5 h, the reaction mixture was concentrated to afford compound 53.4 as an HC1 salt (350 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 464 [M+H]+.
[00673] Preparation of 7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'- bipiperidin]-4-yl)methoxy)pyridin-2-yl)amino)-A'’,AT-dimethyl-7/f-pyrrolo[2,3-J]pyrimidine-6- carboxamide A187 To a solution of compound 53.4 as an HC1 salt (200 mg, 400 pmol) in THF (2 mL) and DMSO (2 mL) were added KOAc (118 mg, 1.2 mmol), AcOH (2.4 mg), and 3-[4-(4- oxo- l-piperidyl)phenyl]piperidine-2, 6-dione (137 mg, 480 pmol). After the mixture was stirred at 60 °C for 14 h, NaBEhCN (75.4 mg, 1.2 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h, and then filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A187 (35 mg) in 11% yield). !H NMR (400 MHz, DMSO-cZs) <5 10.77 (s, 1H), 9.38 (s, 1H), 8.76 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 8.01 (d, 3.2 Hz, 1H), 7.43 (dd, J = 3.2,
9.2 Hz, 1H), 7.03 (d, J= 8.8 Hz, 2H), 6.89 (d, J= 8.8 Hz, 2H), 6.60 (s, 1H), 4.73 (quin, J= 8.8 Hz, 1H), 3.88 (br d, J= 5.6 Hz, 2H), 3.72 (br dd, J= 4.8, 10.8 Hz, 4H), 3.05 (br s, 6H), 2.99 (br d, J= 12.8 Hz, 2H), 2.68-2.59 (m, 3H), 2.45-2.38 (m, 3H), 2.25 (br t, J= 11.2 Hz, 2H), 2.15-2.08 (m, 1H), 2.04-1.93 (m, 5H), 1.87-1.74 (m, 5H), 1.66-1.50 (m, 4H), 1.37-1.24 (m, 2H); MS (ESI) m/z: 734.5 [M+H]+.
Example 54
Preparation of 7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)ethyl)pyridin-2-yl)amino)-A,A-dimethyl-7.H-pyrrolo[2,3-</]pyrimidine-6-carboxamide Al 88
Figure imgf000291_0001
[00674] Compound Al 88 was prepared as described below. [00675] Preparation of tert-butyl A-[5-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-pyridyl]- carbamate 54.1. A mixture tert-butyl A-(5-bromo-2-pyridyl)carbamate (17 g, 62.2 mmol), 2- bromoethoxy-tert-butyldimethylsilane (19.4 g, 80.9 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (698 mg, 622 pmol), NiCb/dtbbpy (372 mg, 933 gmol), tris(trimethylsilyl)silane (15.5 g, 62.2 mmol), and Na2CO3 (13.2 g, 124 mmol) in DME (60 mL) was irradiated with a 10 W blue LED lamp at 25 °C for 14 h with stirring. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSOi, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound
54.1 (5.7 g) in 18% yield. MS (ESI) m/z'. 353.2 [M+H]4.
[00676] Preparation of tert-butyl A-[5-(2-hydroxyethyl)-2-pyridyl]carbamate 54.2. A mixture of compound 54.1 (500 mg, 1.42 mmol) and IM TBAF (2,84 mL) in THF (2 mL) was stirred for 3 h under N2. The reaction mixture was then concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, and concentrated to afford compound 54.2 (200 mg), which was used directly in the next step without further purification.
[00677] Preparation of 2-(6-amino-3-pyridyl)ethanol 54.3. To a solution of compound
54.2 (4 g, 16.8 mmol) was added 4M HC1 in dioxane (19.5 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 54.3 as an HC1 salt (4 g), which was used directly in the next step without further purification. MS (ESI) m/z\ 139.3 [M+H]4.
[00678] Preparation of 7-cyclopentyl-2-[[5-(2-hydroxyethyl)-2-pyridyl]amino]-Ar,N- dimethylpyrrolo[2,3-^Z] pyrimidine-6-carboxamide 54.4. To a solution of compound 54.3 as an HC1 salt (4.4 g, 22.7 mmol) and 2-chloro-7-cyclopentyl-A',A-dimethylpyrrolo[2,3-tf]pyrimidine- 6-carboxamide (6.64 g, 22.68 mmol) in dioxane (50 mL) were added Pd(OAc)2. (509 mg, 2.27 mmol), CS2CO3 (14.8 g, 45.4 mmol), and BINAP (2.82 g, 4.54 mmol). After stirring at 100 °C for 12 h, the reaction mixture was poured into water. The resulting precipitates were collected by filtration to afford compound 54.4 (7 g), which was used directly in the next step without further purification. MS (ESI) m/z'. 395.3 [M+H]4.
[00679] Preparation of 2-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-</]- pyrimidin-2-yl]amino]-3-pyridyl]ethyl 4-methylbenzenesulfonate 54.5, To a solution of compound 54.4 (7 g, 17.8 mmol) in DCM (70 mL) were added TsCl (6.77 g, 35.5 mmol) and TEA (5.39 g, 53.2 mmol). After stirring for 12 h, the mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous NazSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 54.5 (10.28 g) in 98% yield.
Figure imgf000293_0001
(400 MHz, CDCh) d 8.77 (s, HI), 8.43 (s, 1 H), 8.37 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.69 (d, J - 8.4 Hz, 2H), 7.46 (dd, J = 2.0, 8.8 Hz, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 6.47 (s, 1H), 4.81 (quin, J = 8.8 Hz, 1H), 4.23 (t, J = 6.8 Hz, 2H), 3.17 (s, 6H), 2.93 (t, J 6.8 Hz, 2H), 2.38 (s, 3H), 2.17-1.98 (m, 5H), 1.82-1 .64 (m, 3H); MS (ESI) m/z: 549.5 [M+H]+.
[00680] Preparation of 7-cyclopentyl-2-((5-(2-(l'-(4-(2,6-dioxopiperidin-3-yl)phenyl)- [4,4'-bipiperidin]-l-yl)ethyl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A188. To a solution of compound 54.5 (308 mg, 561 pmol) and 3-[4-[4-(4- piperidyl)-l-piperidyl]phenyl]piperidine-2, 6-dione (200 mg, 510 praol) in DMF (3 mL) were added KI (8.47 mg, 51 pmol), DIEA (198 mg, 1.53 mmol), and K2CO3 (70.5 mg, 510 pmol). After stirring at 100 °C for 12 h, the reaction mixture was concentrated and purified by prep-TLC (S1O2, MeOHZDCM) and reverse phase prep-HPLC to afford compound Al 88 (54 mg) in 14% yield. rH NMR (400 MHz, DMSO-J6) J 10.76 (s, 1H), 9.48 (s, 1H), 8.79 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.15 (s, 3H), 7.72-7.56 (m, 1H), 7.03 (d, J - 8.0 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.62 (s, 1H), 4.74 (t, J = 8.4 Hz, 1H), 3.78-3.61 (m, 4H), 3.09 (s, 2H), 3.06 (s, 6H), 2.74 (d, J = 6.8 Hz, 2H), 2.62 (d, J -- 6.4 Hz, 3H), 2.18-2.03 (m, 4H), 2.03-1 .94 (m, 5H), 1.80-1.62 (m, 7H), 1.35-1.08 (m, 8H); MS (ESI) m/z'. 732.4 [M+H]+.
Example 55
Preparation of 7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[1 ,4'-bipiperidin]- 4-yl)ethyl)pyridin-2-yl)amino)-A',iV-dimethyl-7/f-pyrrolo[2,3-J]pyrimidine-6-carboxamide A189
Figure imgf000293_0002
[00681 ] Compound Al 89 was prepared as described below. [00682] Preparation of tert-butyl 4-[2-(6-amino-3-pyridyl)ethynyl]piperidine-l- carboxylate 55.1. To a solution of 5-bromopyridin-2-amine (5 g, 28.9 mmol) and tert-butyl 4- ethynylpiperidine-1 -carboxylate (6.65 g, 31.8 mmol) in ACN (25 mL) and THF (25 mL) were added XPhos Pd Ch (2.45 g, 2.89 mmol) and CszCCh (28.3 g, 86.7 mmol). After stirring at 60 °C for 12 h, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCL, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 55.1 (3.6 g) in 41% yield. ft! NMR (400 MHz, DMSO-Jg) <5 7.94 (d, J= 1.6 Hz, 1H), 7.34 (dd, J= 2.4, 8.6 Hz, 1H), 6.37 (dd, J= 0.4, 8.6 Hz, 1H), 6.22 (s, 2H), 3.71-3.54 (m, 2H), 3.10 (br t, J = 9.2 Hz, 2H), 2.86-2.73 (m, 1H), 1.83-1.72 (m, 2H), 1.50-1.43 (m, 2H), 1.39 (s, 9H); MS (ESI) m/z: 302.3 [M+H]+.
[00683] Preparation of tert-butyl 4-[2-(6-amino-3-pyridyl)ethyl]piperidine-l -carboxylate 55.2. To a solution of compound 55.1 (3.6 g, 11.9 mmol) in THF (35 mL) was added PtCh. (721 mg, 3.18 mmol). After stirring for 12 h under 112, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound
55.2 (3.2 g) in 85% yield. rH NMR (400 MHz, DMSO-d6 ) 3 7.73 (d, J - 2.0 Hz, 1H), 7.22 (dd, J = 2.4, 8.4 Hz, 1H), 6.38 (d, J= 8.4 Hz, 1H), 5.63 (s, 2H), 3.91 (br d, 12.0 Hz, 2H), 2.65 (br s, 2H), 2.42-2.37 (m, 2H), 1.66 (br d, J= 12.0 Hz, 2H), 1.42 (br d, J= 2.4 Hz, 2H), 1.39 (s, 10H), 1.03-0.92 (m, 2H); MS (ESI) m/z: 306 [M+H]+.
[00684] Preparation of tert-butyl 4-[2-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-</jpyrimidin-2-yl]amino]-3-pyridyl]ethyl]piperidine-l-carboxylate 55.3. To a solution of compound 55.2 (500 mg, 1.64 mmol) and 2-chloro-7-cyclopentyl-A’,A'-dimethylpyrrolo[2,3-<^]- pyrimidine-6-carboxamide (479 mg, 1.64 mmol) in dioxane (5 mL) were added BINAP (204 mg, 327 pmol), Pd(OAc)2 (36.8 mg, 164 pmol), and CS2CO3 (1.07 g, 3.27 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCL, filtered, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound
55.3 (810 mg) in 77% yield. TH NMR (400 MHz, DMSO-tfe) 3 9.54 (s, 1H), 8.80 (s, 1H), 8.23 (d, J= 8.4 Hz, 1H), 8.14 (d, J= 1.6 Hz, 1H), 7.61 (dd, J= 2.4, 8.6 Hz, 1H), 6.62 (s, 1H), 4.74 (br t, J= 8.8 Hz, 1H), 3.98-3.87 (m, 2H), 3.05 (br s, 6H), 2.78-2.61 (m, 2H), 2.60-2.54 (m, 2H), 2,48-2,40 (m, 2H), 1.98 (br d, ./ 3.2 Hz, 4H), 1.75-1.61 (m, 4H), 1.56-1.47 (m, 2H), 1.38 (s, 10H), 1.09-0.93 (m, 2H); MS (ESI) zw/z: 562.4 [M + Hf
[00685] Preparation of 7-cyclopentyl-MA-dimethyl-2-[[5-[2-(4-piperidyl)ethyl]-2- pyridyl]amino]pyrrolo[2,3-d]pyriniidine-6-carboxamide 55.5. To a solution of compound 55.4 (150 mg, 267 pmol) in DCM (0.2 mL) was added 4M HC1 in dioxane (200 pL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 55.5 as an HC1 salt (200 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 462,3 [M+H]+.
[00686] Preparation of 7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)- [l,4'-bipiperidin]-4-yl)ethyl)pyridin-2-yl)amino)-A,A-dimethyl-7/f-pyrrolo[2,3-iZ]pyrimidine-6- carboxamide A189 To a solution of compound 55.5 as an HC1 salt (133 mg, 267 pmol) in THF (1 mL) and DMSO (1 mL) was added KO Ac (78.6 mg, 801 pmol), followed by addition of 3-[4- (4-oxo- l-piperidyl)phenyI]piperidine-2, 6-dione (91.8 mg, 320 pmol) and AcOH (1.6 mg, 26.7 iimol). After the mixture was stirred at 60 °C for 12 h, NaBHiCN (50.3 mg, 801 pmol) was added. The reaction mixture was stirred at 80 °C for 2 h, and then filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A189 (22 mg) in 11% yield. !H NMR (400 MHz, DMSO-^) 3 10.77 (s, 1H), 9.56-9.41 (m, 1H), 8.85-8.74 (m, 1H), 8.23-8.12 (m, 2H), 7.65-7.56 (m, 1H), 7.02 (br d, 8.4 Hz, 2H), 6.88 (br d, J= 8.4 Hz, 2H), 6.61 (s, 1H), 4.79- 4.68 (m, 1H), 3.77-3.65 (m, 4H), 3.05 (br s, 6H), 2.95-2.89 (m, 2H), 2.65-2.54 (m, 5H), 2.47 (br d, J= 4.4 Hz, 1H), 2.45-2.41 (m, 2H), 2.18-2.06 (m, 3H), 2.02-1 .94 (m, 5H), 1.81 (br dd, J= 1.2, 11.7 Hz, 2H), 1.74-1.69 (m, 2H), 1.68-1.61 (m, 2H), 1.57-1.47 (m, 4H), 1.24-1.11 (m, 3H); MS (ESI) m/z: 732.7 [M+H]+.
Example 56
Preparation of 7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-
4-yl)ethoxy)pyridin-2-yl)amino)-jV,A/-diraethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A192
Figure imgf000296_0001
[00687] Compound A192 was prepared as described below.
[00688] Preparation of tert-butyl 4-[2-[(6-nitro-3-pyridyl)oxy]ethyl]piperidine-l- carboxylate 56.1. To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-l -carboxylate (1.61 g, 7.04 mmol) in DMA (10 mL) at 0 °C under N2 was t-BuOK (1.03 g, 9.15 mmol), followed by addition of 5-fluoro-2-nitropyridine (1 g, 7.04 mmol) in portions. After stirring for 16 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 56.1 (2.3 g) in 91% yield. rH NMR (400 MHz, DMSO-tA) d 8.35-8.28 (m, 2H), 7.72 (dd, J= 3.0, 9.0 Hz, 1H), 4.25 (t, J= 6.3 Hz, 2H), 3.92 (br d, J= 11.0 Hz, 2H), 2.71 (br d, J= 16.0 Hz, 2H), 1.72-1.62 (m, 4H), 1.38 (s, 9H), 1.35- 1.29 (m, 1H), 1.1 1-0.97 (m, 2H); MS (ESI) m/z: 296.2 [M+H]’
[00689] Preparation of tert-butyl 4-[2-[(6-amino-3-pyridyl)oxy]ethyl]piperidine-l- carboxylate 56.2. To a solution of compound 56.1 (2.3 g, 6.55 mmol) in MeOH (40 mL) was added 10% Pd/C (288 mg). After stirring under H2 for 16 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford compound 56.2 (1.1 g) in 52% yield. rH NMR (400 MHz, DMSO-^) δ 7.68-7.52 (m, 1H), 7.09 (td, J= 3.0, 8.5 Hz, 1H), 6.40 (dd, J= 2.5, 9.0 Hz, 1H), 5.42 (br s, 2H), 3.91 (br d, ./= 3.5 Hz, 4H), 2.78-2.59 (m, 2H), 1.71-1.55 (m, 5H), 1.41-1.37 (m, 9H), 1.10-0.92 (m, 2H); MS (ESI) m/z: 322.1 [M+H]+.
[00690] Preparation of tert-butyl 4-[2-[[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-<7]pyrimidin-2-yl]amino]-3-pyridyl]oxy]ethyl]piperidine-l-carboxylate 56.3. To a mixture of compound 56.2 (350 mg, 1.06 mmol), 2-chloro-7-cyclopentyl-Ar,A7-dimethyl-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide (309 mg, 1.06 mmol), and CS2CO3 (688 mg, 2.11 mmol) in dioxane (10 mL) were added Pd(OAc)2 (23.7 mg, 106 pmol) and BINAP (132 mg, 211 pmol) under N2. After stirring at 100 °C for 14 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous \a::SO concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound
56.3 (500 mg) in 80% yield. MS (ESI) m/z: 578.6 [M+H]+.
[00691] Preparation of 7-cyclopentyl-A7,A7-dimethyl-2-[[5-[2-(4-piperidyl)ethoxy]-2- pyridyl]amino]pyrrolo[2,3-</|pyrimidine-6-carboxamide 56.4. A solution of compound 56.3 (220 mg, 381 pmol) and 4M HC1 in dioxane (1.5 mL) in DCM (3 mL) was stirred for 1 h. The reaction mixture was then concentrated to afford compound 56.4 as an HC1 slat (200 mg), which w7as used directly in the next step without further purification. MS (ESI) m/z: 478.2 [M+H]+.
[00692] Preparation of 7-Cyclopentyl-2-((5-(2-(T-(4-(2,6-dioxopiperidin-3-yl)phenyl)- [l,4'-bipiperidin]-4-yl)ethoxy)pyridin-2-yl)amino)-A’,A’-dimethyl-777-pyrrolo[2,3-tZ]pyrimidine- 6-carboxamide A192. To a solution of compound 56.4 as an HC1 salt (200 mg, 389 pmol) in THF (2 mL) and DMSO (2 mL) was added AcOH (2.3 mg, 38.9 pmol), followed by addition of 3-[4-(4-oxo-l-piperidyl)phenyl]piperidine-2, 6-dione (134 mg, 467 umol) and KOAc (115 mg, 1.17 mmol). After the mixture was stirred at 60 °C for 14 h, NaBHsCN (73.4 mg, 1.17 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h, and then diluted with water and extracted w7ith EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by reverse phase HPLC to afford compound A192 (88 mg) in 30% yield. !H NMR (400 MHz, DMSO-ufc) J 10.77 (s, 1H), 9.40 (s, 1H), 8.76 (s, 1H), 8.19 (s, 1H), 8. 17 (s, 1H), 8.01 (d, J- 3.0 Hz, 1H), 7.43 (dd, J = 3.0, 9.0 Hz, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.89 (d, 8.5 Hz, 2H), 6.60 (s, 1H), 4.73 (br t, J= 8.5 Hz, HI), 4.06 (br t, J=
6.3 Hz, 2H), 3.71 (br dd, J= 5.3, 10.8 Hz, 4H), 3.07-3.00 (m, 8H), 2.70-2.54 (m, 4H), 2.47 (br d, J - 4.5 Hz, 1H), 2.42 (br d, ./ 4.5 Hz, 2H), 2.36-2.29 (m, 2H), 2. 15-2.07 (m, 1H), 2.03-1.93 (m, 5H), 1.86 (br d, J= 11.0 Hz, 2H), 1.77 (br d, J= 15.5 Hz, 2H), 1.69-1.61 (m, 4H), 1.59-1.53 (m, 2H), 1.30-1.21 (m, 2H); AIS (ESI) m/z: 748.5 [M+H]+.
Example 57
Preparation of 7-cyclopentyl-2-((5-(4-(l-((l -(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,jV-dimethyl-7/f-pyrrolo[2,3-t/]- pyrimidine-6-carboxamide A194
Figure imgf000298_0001
[00693] Compound Al 94 was prepared as described below.
[00694] Preparation of /er/-butyl 3-[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-c/]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-l -yl]azetidine-l -carboxylate 57.1. A mixture of 7-cyclopentyl-A,A7-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-d]pyrimidine- 6-carboxamide (500 mg, 1.15 mmol), tert-butyl 3-oxoazetidine-l-carboxylate (394 mg, 2.3 mmol), NaBEhCN (217 mg, 3.45 mmol), and NaOAc (472 mg, 5.75 mmol) in MeOH (6 mL) was stirred at 25 °C for 12 h under N2. The reaction mixture was then concentrated and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous NazSCh, concentrated, and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 57.1 (750 mg) in 90% yield. ]H NMR (400 MHz, CDCh) d 8.69 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 7.98 (d, J= 2.4 Hz, 1H), 7.35 (dd, J= 2.4, 9.2 Hz, 1H), 6.45 (s, 1H), 4.79 (q, 8.8 Hz, 1H),
4.60-4.58 (m, 1H), 4.18-4.13 (m, 4H), 4.01-3.96 (m, 2H), 3.87 (dd, J= 5.6, 8.6 Hz, 2H), 3.83- 3.79 (m, 4H), 3.23-3.16 (m, 6H), 2.57 (d, J= 4.2 Hz, 6H), 2.07-2.04 (m, 2H), 1.45 (s, 6H).
[00695] Preparation of 2-[[5-[4-(azetidin-3-yl)piperazin-l-yl]-2-pyridyl]amino]-7-cyclo- pentyl-A,A-dimethylpyrrolo[2,3-d]pyrimidine-6-carboxamide 57.2. A mixture of compound
57.1 (200 mg, 339 pmol) and TFA (2.3 g, 20.2 mmol) in DCM (3 mL) was stirred for 2 h under N2. The reaction mixture was then concentrated to afford compound 57.2 (150 mg), which was used directly in the next step without further purification. MS (ESI) m/z'. 490.2 [M+H]+.
[00696] Preparation of 7-cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-methyl)azeti din-3 -yl)piperazin- 1 -yl)pyri din-2-yl)amino)-A, Ar-dimethyl-777- pyrrolo[2,3-</]-pyrimidine-6-carboxamide A194. A mixture of compound 57.2 (150 mg, 306 pmol), l-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-4-carbaldehyde (92 mg, 306 pmol), NaBH(OAc)3 (130 mg, 613 pmol), and NaOAc (75.4 mg, 919 pmol)in DCM (2 mL) was stirred for 12 h under N2. The reaction mixture was then concentrated and purified by reverse phase prep-HPLC to afford compound A194 (21 mg) in 9% yield.
Figure imgf000299_0001
(400 MHz, CD3OD) 8 8.81-8.67 (m, 1H), 8.19-8.05 (m, 1H), 8.04-7.89 (m, 1H), 7.62-7.49 (m, 1H), 7.11 (d, J= 8.4 Hz, 2H), 7.02-6.88 (m, 2H), 6.69-6.57 (m, 1H), 4.80-4.72 (m, 1H), 4.26 (s, 2H), 4.03 (s, 2H), 3.83- 3.74 (m, 1H), 3.73-3.63 (m, 2H), 3.37 (s, 1H), 3.22 (s, 4H), 3.18-3.08 (m, 8H), 2.78-2.65 (m, 3H), 2.64-2.44 (m, 7H), 2.25-2. 14 (m, 2H), 2.13-1.98 (m, 4H), 1 .88-1 .76 (m, 3H), 1.72 (d, ./ 5.6 Hz, 2H), 1.51-1.34 (m, 2H); MS (ESI) m/z: 774.4 [M+H]+.
Example 58
Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- [l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A196
Figure imgf000299_0002
[00697] Compound A196 was prepared as described below.
[00698] Preparation of 7-cyclopentyl-2-[[5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2- pyridyl]amino]-A'T,jV-dimethylpyrrolo[2,3-r(|pyrimidine-6-carboxamide 58.1. A mixture of 5- (l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-amine (1 g, 4.25 mmol), 2-chloro-7-cyclopentyl- A,A-dimethyl-pyrrolo[2,3-</]pyrimidine-6-carboxamide (1.24 g, 4.25 mmol), CS2CO3 (2.77 g, 8.5 mmol), Pd(OAc)2 (95.4 mg, 425 pmol), and BINAP (529 mg, 850 pmol) in dioxane (10 mL) was stirred at 100 °C for 16 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 58.1 (1.4 g) in 60% yield. MS (ESI) m/z: 492.2 [M+H]+.
[00699] Preparation of 7-cyclopentyl-A,A-dimethyl-2-[[5-(4-oxo-l-piperidyl)-2-pyridyl]- amino]pyrrolo[2,3-(7] pyrimidine-6-carboxamide 58.2. To a solution of compound 58.1 (1 g, 2.03 mmol) in dioxane (1.5 mL) and H2O (1 .5 mL) was added 4M HC1 (6 mL). After stirring for 16 h, the reaction mixture was neutralized to pH 7 with NaHCCh. The resulting precipitates were collected by filtration to afford compound 58.2 (769 mg), which was used directly in the next step without further purification. MS (ESI) m/z'. 448.3 [M+H]+.
[00700] Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-[l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-A',A’-dimethyl-7H-pyiTolo[2,3-7]- pyrimidine-6-carboxamide A196 To a solution of 3-[4-[4-(4-piperidyl)piperazin- 1 -yl]phenyl]- piperidine-2, 6-dione as an HC1 salt (203 mg, 518 pmol) in DMSO (1 mL) and THF (1 mL) was added KOAc (127 mg, 1.29 mmol), followed by addition of compound 58.2 (193 mg, 431 pmol) and AcOH (2.6 mg). After the mixture was stirred at 60 °C for 10 h, NaBHsCN (81.3 mg, 1.29 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h, and then diluted with DMF and purified by reverse phase prep-HPLC to afford compound A196 as a TFA salt (41 mg) in 11% yield. lH NMR (400 MHz, DMSO-76) <5 11.77-11.45 (m, 2H), 11.32 (d, 7 ■■■ 3.2 Hz, 1H),
10.78 (s, 1H), 9.04-8.97 (m, 1H), 8.17 (dd, 7= 2.8, 9.6 Hz, 1H), 8.14 (s, 1H), 7.98 (d, J= 2.4 Hz, 1H), 7.62 (d, 7 9.6 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 7.03-6.93 (m, 2H), 6.84 (s, 1H), 4.83-
4.78 (m, 1H), 3.84 (s, 2H), 3.76 (s, 1H), 3.67 (d, 7= 10.4 Hz, 2H), 3.53 (d, 7= 7.2 Hz, 2H), 3.45- 3.35 (m, 2H), 3.23 (d, 7= 6.8 Hz, 4H), 3.05 (s, 7H), 2.80 (t, 7= 11.6 Hz, 2H), 2.70-2.60 (m, 2H), 2.47-2.38 (m, 4H), 2.35-2.23 (m, 6H), 2.19-2.11 (m, 1H), 2.08-1.92 (m, 6H), 1.91-1.81 (m, 2H), 1.71-1.60 (m, 2H); MS (ESI) m/z'. 788.8 [M+Hp.
Example 59
Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-777-pyrrolo[2,3-7]pyrimidine-6- carboxamide A197
Figure imgf000300_0001
[00701] Compound A197 was prepared as described below. [00702] Preparation of 3-[4-[4-(l,4-dioxaspiro[4.5]decan-8-yl)piperazin-l-yl]phenyl]- piperidine-2, 6-dione 59.1. To a solution of 3-(4-piperazin-l-ylphenyl)piperidine-2, 6-dione (1 g, 3.66 mmol) and l,4-dioxaspiro[4.5]decan8-one (1 .14 g, 7.32 mmol) in DMF (10 mL) were added AcOH (220 mg, 3.66 mmol) and NaBH(OAc)3 (1.16 g, 5.49 mmol). After stirring under N2 for 16 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiO?., MeOH/DCM) and triturated with EtOAc/'PE to afford compound 59.1 (1 .24 g) in 82% yield. MS (ESI) m/z: 414.3 [M+H]+.
[00703] Preparation of 3-[4-[4-(4-oxocyclohexyl)piperazin-l-yl]phenyl]piperidine-2,6- dione 59.2. To a solution of compound 59.1 (1.24 g, 3 mmol) in THF (8 mL) and H2O ( 8 mL) was added /2-TSOH (1.03 g, 6 mmol). After stirring at 80 °C for 3 h, the reaction mixture was filtered, concentrated, and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 59.2 (820 mg) in 74% yield. MS (ESI) m/z: 446.1 [M+H]+
[00704] Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-77/-pyrrolo[2,3-d]- pyrimidine-6-carboxamide A197. To a solution of compound 59.2 (340 mg, 921 pmol) and 7- cyclopentyl-A(A-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-tZ]pyrimidine-6- carboxamide (200 mg, 460 pmol) in DMF (2 mL) were added AcOH (28 mg, 460 umol) and NaBH(OAc)s (293 mg, 1.38 mmol). After stirring at 60 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound Al 97 (56 mg) in 15% yield. !H NMR (400 MHz, CDCh) 3 8.77 (s, 1H), 8.70 (s, 1H), 8.50-8.35 (m, 2H), 8.00 (d, J = 2.8 Hz, 1H), 7.34 (dd, J = 2.8, 9.2 Hz, 1H), 7.10 (d, 8.8 Hz, 2H), 6.90 (d, 8.8 Hz, 2H), 6.43 (s, 1H), 4.78
(quin, J= 8.8 Hz, 1H), 3.72 (dd, J= 5.2, 9.2 Hz, 1H), 3.35-3.22 (m, 8H), 3.15 (s, 6H), 2.88 (s, 8H), 2.77-2.52 (m, 6H), 2.31-2. 14 (m, 2H), 2.12-1.95 (m, 8H), 1 .78-1 .68 (m, 2H), 1.61 (d, ./ 8.4 Hz, 4H); MS (ESI) m/z: 788.5 [M+H]+.
Example 60
Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- cyclohexyl)piperidin-l -yl)pyridin-2-yl)amino)-A,A'’-dimethyl-7/f-pyrrolo[2,3-J]pyrimidine-6- carboxamide Al 98
Figure imgf000302_0001
[00705] Compound A198 was prepared as described below.
[00706] Preparation of 4-(l,4-dioxaspiro[4.5]decan-8-yl)piperidine 60.1. To a solution of tert-butyl 4-(l,4-dioxaspiro[4.5]decan-8-yl)piperidine-l-carboxylate (3 g, 9.22 mmol) in DCM (15 mL) was added 4M HC1 in dioxane (15 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 60.1 as an HC1 salt (2.4 g), which was used directly in the next step without further purification. MS (ESI) m/z'. 226.1 [M i l] ,
[00707] Preparation of 5-[4-(l,4-dioxaspiro[4.5]decan-8-yl)-l-piperidyl]-2-nitropyridine
60.2. To a solution of compound 60.1 (1.5 g, 5.73 mmol) and 5-chloro-2-nitropyridine (908 mg, 5.73 mmol) in DMSO (15 mL) were added K2CO3 (2.38 g, 17.2 mmol) and KI (95.1 mg, 573 pmol). After stirring at 90 °C for 16 h, the reaction mixture was poured into water. The resulting precipitates were collected by filtration to afford compound 60.2 (1.92 g), which was used directly in the next step without further purification. Tl NMR (400 MHz, DMSO-^fe) d 8,22 (d, J 2 8 Hz, 1H), 8.12 (d, ,/ - 9.2 Hz, 1H), 7.44 (dd, J - 3.2, 9.2 Hz, 1H), 4.11 (d, J - 13.2 Hz, 2H), 3.83 (s, 4H), 2.93 (t, J = 11.6 Hz, 2H), 1.75 (d, J = 12.0 Hz, 2H), 1.65 (s, 4H), 1.45- 1.39 (m, 2H), 1.29-1.08 (m, 6H); MS (ESI) mA: 348.3 |.\1 H l .
[00708] Preparation of 5-[4-(l,4-dioxaspiro[4.5]decan-8-yl)-l-piperidyl]pyridin-2-amine 603. To a solution of compound 60.2 (2 g, 5.76 mmol) in THF (20 mL) was added 10% Pd/C (0.2 g) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 603 (1.59 g), which was used directly in the next step without further purification. rH NMR (400 MHz, DMSO-fife) 3 7.58 (d, J = 2.8 Hz, 1H), 7.13 (dd, J =
3.2, 8.8 Hz, 1H), 6.37 (d, J = 8.8 Hz, 1H), 5.34 (s, 2H), 3.83 (s, 4H), 3.32-3.21 (m, 2H), 2.46- 2.35 (m, 2H), 1.67 (d, J = 8.4 Hz, 6H), 1.46-1.36 (m, 2H), 1.33-1.11 (m, 6H); MS (ESI) mA: 318.3 [M+H]+. [00709] Preparation of 7-cyclopentyl-2-[[5-[4-(l,4-dioxaspiro[4.5]decan-8-yl)-l- piperidyl]-2-pyridyl]amino]-i¥,7V-dimethyl-pyrrolo[2,3-<f|pyrimidiiie-6-carboxamide 60.4. To a solution of compound 60.3 (1.3 g, 4.10 mmol) and 2-chloro-7-cyclopentyl-2V,¥-dimethylpyrrolo- [2,3-<7]pyrimidine-6-carboxamide (1.2 g, 4.1 mmol) in dioxane (15 mL) were added CszCCh (2.67 g, 8.2 mmol), BINAP (510 mg, 820 pmol), and Pd(OAc)2 (92 mg, 410 pmol). After stirring at 100 °C for 6 h, the reaction mixture was treated with NH4CI at 0 °C, diluted with H2O, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 60.4 (1.78 g) in 67% yield. XH NMR (400 MHz, DMSO-tZs) <5 9.28 (s, 1H),
8.75 (s, 1H), 8.12 (d, J -- 9.2 Hz, 1H), 7.99 (d, ./ = 2.8 Hz, 1H), 7.45-7.33 (m, 1H), 6.59 (s, 1H),
5.75 (s, 1H), 4.80-4.64 (m, 1H), 3.84 (s, 4H), 3.64 (d, J = 12.0 Hz, 2H), 3.05 (s, 6H), 2.61-2.52 (m, 2H), 2.47-2.36 (m, 2H), 2.01-1.92 (m, 4H), 1.73 (d, J = 12.8 Hz, 2H), 1.70-1.58 (m, 6H),
1.46-1.39 (m, 2H), 1.38-1.30 (m, 2H), 1.26-1.20 (m, 2H), 1.18-1.13 (m, 1H); MS (ESI) m/r.
574.6 [M+H]+.
[00710] Preparation of 7-cyclopentyl-Ar,A-dimethyl-2-[[5-[4-(4-oxocyclohexyl)-l- piperidyl]-2-pyridyl]amino]pyrrolo[2,3-<7]pyrimidine-6-carboxamide 60.5. To a solution of compound 60.4 (1.78 g, 3. 1 mmol) in THF (9 mL) was added 4M HC1 (6 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 60.5 (1.5 g), which was used directly in the next step without further purification. MS (ESI) m/z'. 530.3 [M+H]+.
[00711] Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-cyclohexyl)piperidin-l -yl)pyridin-2-yl)amino)-A'r,A’-dimethyl-77/-pyrrolo[2,3-t/]- pyrimidine-6-carboxamide A198. To a solution of compound 60.5 (200 mg, 378 pmol) and 3- (4-piperazin-l-ylphenyl)piperidine-2, 6-dione as an HC1 salt (117 mg, 378 umol) in MeOH (1 mL) and DCM (1 mL) were added AcOH (45.4 mg, 755 pmol) and NaBH(OAc)i (160 mg, 755 pmol). After stirring for 12 h, the reaction mixture was concentrated and purified by prep-TLC (SiOz, MeOH/DCM) and reverse phase prep-HPLC to afford compound Al 98 (6 mg) in 2% yield. TI NMR (400 MHz, DMSO-ufc) 3 10.77 (s, 1H), 9.21 (s, 1H), 8.74 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.40 (dd, J - 2.8, 9.2 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.88 (d, J - 8.8 Hz, 2H), 6.59 (s, 1H), 4.81-4.63 (m, 1H), 3.72 (dd, J - 5.2, 10.8 Hz, 1H), 3.65 (d, J = 12.0 Hz, 2H), 3.30 s, 2H), 3,10 (s, 4H), 3.05 s, 6H), 2,62 (d, J = 5.2 Hz, 1H), 2.60-2,55 (m, 6H), 2.23-2.16 (m, 1H), 2.16-2.06 (m, 1H), 2.05-1.88 (m, 6H), 1.82 (d, J ----- 11.2 Hz, 2H), 1.77-1.70 (m, 2H), 1.67-1.52 (m, 4H), 1.50-1.37 (m, 4H), 1.31-1.16 (m, 4H); MS (ESI) m/z: 787.6 [M+H]+.
Example 61
Preparation of 7-cyclopentyl-2-((5-((4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)methyl)pyridin-2-yl)amino)-Ar,AMimethyl-7rt-pyrrolo[2,3-r7]pyrimidine-6- carboxamide A200
Figure imgf000304_0001
[00712] Compound A200 was prepared as described below.
[00713] Preparation of tert-butyl 4-[l -[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]- piperazine-1 -carboxylate 61.1. To a solution of 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (8 g, 17.9 mmol) and tert-butyl 4-(4-piperidyl)piperazine-l -carboxylate (4.83 g, 17.9 mmol) in dioxane (60 mL) were added RuPhos (836 mg, 1.79 mmol), RuPhos Pd G3 (1.5 g, 1.79 mmol), and CS2CO3 (17.5 g, 53.8 mmol). After stirring at 100 °C for 16 h, the reaction mixture was concentrated and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 61.1 (10 g) in 81% yield. JH NMR (400 MHz, DMSO-^) S 7.67 (d, J - 8.0 Hz, 1H), 7.47-7.26 (m, 12H), 6.94 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 8.0 Hz, 1 H), 5.39 (s, 2H), 5 35 (s, 2H), 3.76 (d, J = 12.4 Hz, 2H), 3.60 (t, J = 6.8 Hz, 1H), 3.29 (d, J = 4.4 Hz, 4H), 2.66 (t, J = 11.6 Hz, 2H), 2.46-2.41 (m, 4H), 1.81 (d, J = 12.0 Hz, 2H), 1.49 (dd, J = 3.2, 11.6 Hz, 2H), 1.39 (s, 9H); MS (ESI) m/z'. 635.5 [M+H]+.
[00714] Preparation of tert-butyl 4-[l -[4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]- piperazine-1 -carboxylate 61.2, To a solution of compound 61.1 (10 g, 15.8 mmol) in THF (100 mL) were added 10% Pd/C (1 g) and 20% Pd(OH)2 (1 g) under N2. After stirring under H2 at 40 °C for 12 h, the reaction mixture was filtered and concentrated to afford compound 61.2 (5.7 g), which was used directly in the next step without further purification. ^ I NMR (400 MHz,
Figure imgf000305_0001
3 10.82 (s, 1H), 7.07 (d, J ----- 8.0 Hz, 2H), 6.93 (d, J ----- 8.8 Hz, 2H), 3.79-3.70 (m, 3H), 3.34 (s, 6H), 2.72-2.62 (m, 3H), 2.57-2.52 (m, 1H), 2.49-2.36 (m, 3H), 2.21-2.10 (m, 1H), 2.09- 1.99 (m, 1H), 1.86 (d, J = 11.6 Hz, 2H), 1.54 (dd, 7 = 2.8, 1 1.6 Hz, 2H), 1.44 (s, 9H); MS (ESI) m/z: 457.3 [M+H]+.
[00715] Preparation of 3-[4-(4-piperazin-l-yl-l-piperidyl)phenyl]piperidine-2, 6-dione
61.3, To a solution of compound 61.2 (1 g, 2.19 mmol) in DCM (10 mL) was added TFA (7.68 g, 67.3 mmol). After stirring for 1 h, the reaction mixture was concentrated to afford compound 61.3 (750 mg), which was used directly in the next step without further purification.
Figure imgf000305_0002
(400 MHz, DMSO-tZd) d 10.79 (s, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.01 (d, J -- 8.4 Hz, 2H), 3.85 (d, J = 12.4 Hz, 2H), 3.80-3.71 (m, 1H), 3.72-3.69 (m, 1H), 3.46 (d, J = 14.8 Hz, 9H), 2.90-2.74 (m, 2H), 2.64 (ddd, J 5.2, 11.6, 17.2 Hz, 1H), 2.21-2.07 (m, 3H), 2.01 (td, J = 4.4, 13,2 Hz, 1H), 1.83-1.66 (m, 2H); MS (ESI) m/z: 357.3 [M+H]+
[00716] Preparation of 7-Cyclopentyl-2-((5-((4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-piperazin-l-yl)methyl)pyridin-2-yl)amino)-A'',Ar-dimethyl-7H-pyrrolo[2,3-J_]- pyrimidine-6-carboxamide A200. To a solution of compound 61.3 (226 mg, 634 pmol) and 7- cyclopentyl-2-[(5-formyl-2-pyridyl)amino]-A,A-dimethylpyrrolo[2,3-7]pyrimidine-6- carboxamide (200 mg, 529 pmol) in DCM (3 mL) were added NaBH(OAc)s (336 mg, 1.59 mmol) and NaOAc (43.4 mg, 529 pmol). After stirring for 12 h, the reaction mixture was filtered, concentrated, and purified by reversed phase prep-HPLC to afford A200 (43 mg) in 11% yield. ’H NMR (400 MHz, CDrOD) 3 8.80-8.70 (m, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 2.0, 8.8 Hz, 1 H), 7.11 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H),
6.64 (s, 1H), 4.78 (s, 1H), 4.61-4.56 (m, 1H), 3.77-3.73 (m, 2H), 3.55 (s, 2H), 3.16 (s, 6H), 2.73-
2.64 (m, 6H), 2.63-2.51 (m, 7H), 2.45-2.34 (m, 2H), 2.20-2. 15 (m, 2H), 2.10 (d, J = 10.8 Hz, 4H), 2.00 (d, J = 5.2 Hz, 2H), 1.76 (d, J = 5.2 Hz, 2H), 1.63 (dt, J = 8.8, 11.6 Hz, 2H), 1.36-1.25 (m, 1H); MS (ESI) m/z: 719.8 [M+H]+.
Example 62
Preparation of 7-cyclopentyl-2-((5-(3-(^-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)propyl)pyridin-2-yl)amino)-A(A-dimethyl-7/f-pyrrolo[2,3-J]pyrimidine-6-carboxamide A202
Figure imgf000306_0001
[00717] Compound A202 was prepared as described below.
[00718] Preparation of 5-(3-((feA-butyldimethylsilyl)oxy)prop- 1 -yn- 1 -yl)pyridin-2-amine
62.1. To a solution of 5-bromopyridin-2-amine (10 g, 57.8 mmol) and tert-butyl dimethyl(prop- 2-yn-l-yloxy)silane (14.8 g, 86.7 mmol) in ACN (50 mL) and THF (50 mL) were added XPhos Pd G3 (2.45 g, 2.89 mmol) and CS2CO3 (56.5 g, 173 mmol). After stirring at 60 °C under N2 for 4 h, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 62.1 (5.5 g) in 36% yield. MS (ESI) m/z: 263 [M+H]+.
[00719] Preparation of 5-(3-((tert-butyldimethylsilyl)oxy)propyl)pyridin-2-amine 62.2, To a solution of compound 62.1 (5 g, 19.1 mmol) in EtOH (50 mL) was added PtCh (2 g, 8.81 mmol). After stirring for 12 h under H2, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiOr, EtOAc/PE) to afford compound 62.2 (2.1 g) in 41% yield. MS (ESI) m/z: 267 [M i l] ,
[00720] Preparation of 2-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)pyridin-2-yl)amino)- 7-cyclopentyl-A,A;-dimethyl-7//-pyrrolo[2,3-</]pyrimidine-6-carboxamide 62.3. To solution of compound 62.2 (500 mg, 1.88 mmol) and 2-chloro-7-cyclopentyl-A(AMimethyl-pyrrolo[2,3-J]- pyrimidine-6-carboxamide (549 mg, 1.88 mmol) in dioxane (5 mL) were added BINAP (234 mg, 375 pmol), Pd(OAc)2 (42.1 mg, 188 pmol), and CS2CO3 (1.22 g, 3.75 mmol). After stirring at 90 °C for 2 h under N2, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 62.3 (878 mg) in 90% yield. MS (ESI) m/z: 523.4 [M+H]+. [00721 ] Preparation of 7-cyclopentyl-2-((5-(3-hydroxypropyl)pyridin-2-yl)amino)-A,jV- dimethyl-7/7-pyrrolo[2,3-<7]pyriniidine-6-carboxamide 62.4. A solution of compound 62.3 (770 mg, 1 .47 mmol) in DMSO (8 mL) was added CsF (671 mg, 4.42 mmol). After stirring at 40 °C for 2 h, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCh, and concentrated to afford compound 62.4 (450 mg), which was used directly in the next step without further purification. MS (LSI ) /// .- 409.1 [MHI] \
[00722] Preparation of 3-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7J7-pyrrolo[2,3-t/|- pyrimidin-2-yl)amino)pyridin-3-yl)propyl 4-methylbenzenesulfonate 62.5. To a solution of compound 62.4 (450 mg, 1.1 mmol), TEA (334 mg, 3.3 mmol), and DMAP (13.5 mg, 110 pmol) in DCM (5 mL) was added TsCI (315 mg, 1,65 mmol) at 0 °C under N2. After stirring at 25 °C for 1 h, the reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSCL, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 62.5 (760 mg). MS (ESI) m/z: 563.3 [M+H]+.
[00723] Preparation of 7-cyclopentyl-2-((5-(3-(l'-(4-(2,6-dioxopiperidin-3-yl)phenyl)- [4,4'-bipiperidin]-l-yl)propyl)pyridin-2-yl)amino)-A(A-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A202. To a solution of compound 62.5 (200 mg, 355 pmol) and 3-(4-([4,4!- bipiperi din]- l-yl)phenyl)piperidine-2, 6-dione as an HC1 salt (279 mg, 711 pmol) in DMF (3 mL) were added DIE A (230 mg, 1.78 mmol) and KI (118 mg, 711 pmol). After stirring at 100 °C for 2 h, the reaction mixture was poured into an NH4Q solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSCh, concentrated, and purified by reverse phase prep-HPLC to afford compound A202 (27 mg) in 9% yield. ^I NMR (400 MHz, DMSO-d6 ) 6 10.77 (s, 1H), 9.53 (s, 1H), 8.80 (s, 1H), 8.28 (d, J= 8.4 Hz, 1H), 8.16 (br s, 1H), 8.14 (s, 1H), 7.65 (br d, J= 8.4 Hz, 1H), 7.03 (br d, J= 8.4 Hz, 2H), 6.87 (br d, J = 8.4 Hz, 2H), 6.62 (s, 1H), 4.80-4.67 (m, 1H), 3.74-3.66 (m, 4H), 3.05 (br s, 6H), 2.88 (br s, 2H), 2.69-2.56 (m, 7H), 2.44 (br d, J= 4.4 Hz, 2H), 2.14-2.07 (m, 1H), 1.99 (br d, J= 7.6 Hz, 5H), 1.93 (br d, J= 7.2 Hz, 2H), 1.83 (br d, .7 = 12.0 Hz, 2H), 1.74 (br d, J= 9.2 Hz, 2H), 1 .66 (br d, 7= 5.2 Hz, 2H), 1.41-1.26 (m, 4H), 1.23 (br s, 4H); MS (ESI) m/z: 746.3 [M+H] \ Example 63
Preparation of 7-cyclopentyl-2-((5-(3-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-
4-yl)propyl)pyridin-2-yl)amino)-A,Ar-dimethyl-7/T-pyrrolo[2,3-J|pyrimidine-6-carboxamide
A205
Figure imgf000308_0001
[00724] Compound A205 was prepared as described below.
[00725] Preparation of ZerZ-butyl 4-[3-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-7]pyrimidin-2-yl]amino]-3pyridyl]propyl]piperidine-l-carboxylate 63,1. To a solution of ZcrZ-butyl 4-[3-(6-amino-3-pyridyl)propyl]piperidine-l-carboxylate (450 mg, 1.41 mmol) and 2- chloro-7-cyclopentyl-A(AMimethyl-pyrrolo[2,3-d]pyrimidine-6-carboxamide (412 mg, 1.41 mmol) in dioxane (5 mL) were added BINAP (175 mg, 282 pmol), CS2CO3 (918 mg, 2.82 mmol), and Pd(OAc)2 (31.6 mg, 141 pmol). After stirring at 100 °C for 12 h under N2, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 63.1 (400 mg) in 49% yield. MS (ESI) m/z: 576.4 [M+H]+.
[00726] Preparation of 7-cyclopentyl-A(Ar-dimethyl-2-[[5-[3-(4-piperidyl)propyl]-2- pyridyl]amino]pyrrolo[2,3-t/]pyrimidine-6-carboxamide 63.2. To a solution of compound 63.1 (400 mg, 695 pmol) in DCM (3 mL) was added 4M HC1 in dioxane (3 mL). After stirring for 0.5 h, the reaction mixture was concentrated to afford compound 63.2 as an HC1 salt (380 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 476.4 [M+H]+.
[00727] Preparation of 7-cyclopentyl-2-((5-(3-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-
[l,4'-bipiperidin]-4-yl)propyl)pyridin-2-yl)amino)-ACV-dimethyl-7/7-pyrrolo[2,3-J]pyrimidine-6- carboxamide A205 To a solution of compound 63.2 (200 mg, 421 mmol) in THE (2 mL) and DMSO (2 mL) was added KOAc (124 mg, 1 .26 mmol), followed by addition of AcOH (76 mg) and 3 -[4-(4-oxo-l-piperidyl)phenyl]piperidine-2, 6-dione (144 mg, 505 pmol). After the mixture was stirred at 60 °C for 12 h, NaBHhCN (79.3 mg, 1.26 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h, and then concentrated and purified by reverse phase prep-HPLC to afford compound A205 (17 mg) in 5% yield. ^I NMR (400 MHz, DMSO-d6 ) d 10.76 (s, 1H), 9.44 (s, 1H), 8.79 (s, 1H), 8.22 (d, J= 8.8 Hz, 1H), 8.11 (d, J= 2.0 Hz, 1H), 7.60 (dd, J= 2.0, 8.8 Hz, 1H), 7.02 (d, 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.61 (s, 1H), 4.79-4.68 (m, 1H),
3.75-3.63 (m, 3H), 3.05 (br s, 6H), 2.85 (br d, J= 10.8 Hz, 2H), 2.65-2.53 (m, 4H), 2.43 (br d, J = 4.8 Hz, 4H), 2.14-2.05 (m, 3H), 2.03-1.95 (m, 5H), 1.78 (br d, J= 12.4 Hz, 2H), 1.71-1.41 (m, 9H), 1.23 (br d, ./= 6.8 Hz, 3H), 1.12-1.01 (m, 2H); MS (ESI) m/z'. 746.5 [M+H]+.
Example 64
Preparation of 7-cyclopentyl-2-((5-((25)-2-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)methyl)morpholino)pyridin-2-yl)amino)-7V,Az-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A207
Figure imgf000309_0001
[00728] Compound A207 was prepared as described below.
[00729] Preparation of [(2A)-4-(6-nitro-3-pyridyl)morpholin-2-yl]methanol 64.1. To a solution of 5-chloro-2-nitropyridine (3 g, 18.9 mmol) in DMSO (30 mL) were added K2CO3 (7.85 g, 56.8 mmol) and [(27?)-morpholin-2-yl]methanol HC1 (2.91 g, 18.9 mmol). After stirring at 90 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 64.1 (3 g) in 65% yield. MS (ESI) m/z\ 240. 1 [M+H]+.
[00730] Preparation of [(27?)-4-(6-amino-3-pyridyl)morpholin-2-yl]methanol 64.2. To a solution of compound 64.1 (3 g, 12.5 mmol) in THF (15 mL) and MeOH (15 mL) was added 10% Pd/C (1.5 g) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 64.2 (2.1 g), which was used directly in the next step without further purification. MS (ESI) m/z: 210.3 [M+H] \
[00731] Preparation of 7-cyclopentyl-2-[[5-[(2A’)-2-(hydroxymethyl)morpholin-4-yl]-2- pyridyl]amino]-7V,jV-dimethylpyrrolo[2,3-i:/]pyrimidine-6-carboxamide 64.3. To a solution of compound 64.2 (300 mg, 1.43 mmol) and 2-chloro-7-cyclopentyl-A'’,A'-dimethylpyrrolo[2,3-<7]- pyrimidine-6-carboxamide (420 mg, 1.43 mmol) in dioxane (5 mL) were added CsrCCh (701 mg, 2.15 mmol), BINAP (45 mg, 71.7 pmol), and Pd(OAc)2 (8 mg, 36 pmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCL, concentrated, and triturated with EtOAc to afford compound 64.3 (340 mg) in 38% yield. MS (ESI) m/z: 466.2 [M+H]+.
[00732] Preparation of [(27?)-4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-d]- pyrimidin-2-yl]amino]-3-pyridyl]morpholin-2-yl]methyl 4-methylbenzenesulfonate 64.4, To a solution of compound 64.3 (340 mg, 730 pmol) in DCM (5 mL) were added TsCl (279 mg, 1.46 mmol) and TEA (222 mg, 2.19 mmol). After stirring for 12 h, the reaction mixture was concentrated and triturated with EtOAc/PE to afford compound 64.4 (400 mg) in 86% yield. MS (ESI) m/z: 620.2 [M+H]+.
[00733] Preparation of 7-cyclopentyl-2-((5-((25)-2-((4-(4-(2,6-dioxopiperidin-3-yl)- phenyl)piperazin-l-yl)methyl)morpholino)pyridin-2-yl)amino)-AlA'’-dimethyl-7//-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A207. To a solution of compound 64.4 (200 mg, 323 pmol) and 3- (4-piperazin-l-ylphenyl)piperidine-2, 6-dione as a TFA salt (103 mg, 323 pmol) in DMF (4 mL) were added DIEA (125 mg, 968 pmol) and KI (5.4 mg, 32.3 pmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A207 (11 mg) in 5% yield. ’H NMR (400 MHz, DMSO-flfe) <510.77 (s, 1H), 9.29 (s, 1H), 8.75 (s, 1H), 8.16 (d, J= 9.2 Hz, 1H), 8.00 (d, J = 2.8 Hz, 1H), 7.44 (dd, J= 2.8, 9.2 Hz, 1H), 7.05 (d, J= 8.8 Hz, 2H), 6.89 (d, J- 8.8 Hz, 2H), 6.59 (s, 1H), 4.81-4.66 (m, 1H), 4.01-3.90 (m, 1H), 3.85-3.76 (m, 1H), 3.76-3.64 (m, 2H), 3.56 (d, J= 10.0 Hz, 1H), 3.49-3.45 (m, 1H), 3.12 (t, J= 4.8 Hz, 4H), 3.05 (s, 6H), 2.72-2.59 (m, 8H), 2.45-2.41 (m, 4H), 2.10-1.89 (m, 6H), 1.73-1.53 (m, 2H); MS (ESI) m/z: 721.4 [M+H] \
Example 65
Preparation of 7-cyclopentyl-2-((5-((2A!)-2-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)methyl)morpholino)pyridin-2-yl)amino)-7V,Az-dimethyl-7/f-pyrrolo[2,3-J]pyrimidine-6- carboxamide A208
Figure imgf000311_0001
[00734] Compound A208 was prepared as described below.
[00735] Preparation of [(25)-4-(6-amino-3-pyridyl)morpholin-2-yl]methanol 65.1, To a solution of [(25)-4-(6-nitro-3-pyridyl)morpholin-2-yl]methanol (1.4 g, 5.85 mmol) in THF (15 mL) and EtOH (15 mL) was added 10% Pd/C (500 mg) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 65.1 (1.01 g), which was used directly in the next step without further purification. MS (ESI) m/z: 300.1 [M+H]+.
[00736] Preparation of 7-cyclopentyl-2-[[5-[(2A)-2-(hydroxymethyl)morpholin-4-yl]-2- pyridyl]amino]-A(Ar-dimethylpyrrolo[2,3-</|pyrimidine-6-carboxamide 65.2. A solution of compound 65.1 (712 mg, 3.4 mmol), 2-chloro-7-cyclopentyl-A^A'-dimethylpyrrolo[2,3-d]- pyrimidine-6-carboxamide (996 mg, 3.4 mmol), Pd(OAc)z (76 mg, 340 pmol), BINAP (424 mg, 681 pmol), and CS2CO3 (2 22 g, 6.81 mmol) in dioxane (5 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 65.2 (876 mg) in 85% yield. MS (ESI) m/z: 466.3 [M+H]+.
[00737] Preparation of [(25)-4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-r/]- pyrimidin-2-yl]amino]-3-pyridyl]morpholin-2-yl]methyl 4-methylbenzenesulfonate 65.3. A solution of compound 65.2 (870 mg, 1.87 mmol), TsCl (713 mg, 3.74 mmol), and TEA (378 mg, 3.74 mmol) in DCM (10 mL) was stirred for 12 h under N2. The reaction mixture was then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaiSCh, concentrated, and purified by column chromatography (SiCh, MeQH/DCM) to afford compound 65.3 (1.03 g) in 66% yield. MS (ESI) m/z: 620.3 [M+H]+.
[00738] Preparation of 7-cyclopentyl-2-((5-((27?)-2-((4-(4-(2,6-dioxopiperidin-3-yl)- phenyl)piperazin-l-yl)methyl)morpholino)pyridin-2-yl)amino)-A’,7V-dimethyl-7/7r-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A208. To a solution of compound 65.3 (200 mg, 323 pmol) and 3- (4-piperazin-l-ylphenyl)piperidine-2, 6-dione as an HC1 salt (100 mg, 323 pmol) in DMF (2 mL) were added DIEA (125 mg, 968 pmol) and KI (54 mg, 323 pmol ). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A208 (77 mg) in 32% yield. rH NMR (400 MHz, DMSO-7,) 8 10.77 (s, 1H), 9.37 (s, 1H), 8,76 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 8.02 (d, J - 2.8 Hz, 1H), 7.45 (m, 1H), 7.05 (d, J = 8.6 Hz, 2H), 6.89 (d, 7 = 8.8 Hz, 2H), 6.59 (s, 1H), 4.73-4.76 (s, 1H), 3.95 (d, J - 11.6 Hz, 1 H), 3.78-3.83 (m, 1H), 3.74 (d, J - 4.8 Hz, 1H), 3.67-3.71 (m, 1H), 3.58 (s, 1H), 3.49-3.52 (s, 1H), 3.12 (t, J - 4.4 Hz, 4H), 3.05 (s, 6H), 2.54-2.73 (m, 7H), 2.40-2.48 (m, 5H), 2.06-2.18 (m, 1H), 1.94-2.03 (m, 5H), 1.63 (d, J - 5.2 Hz, 2H); MS (ESI) m/z: 721.5 [M+H]+.
Example 66
Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- piperidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7#-pyrrolo[2,3-7]pyrimidine-6-carboxamide
A209
Figure imgf000312_0001
[00739] Compound A209 was prepared as described below.
[00740] Preparation of tert-butyl 4-[l-(6-nitro-3-pyridyl)-4-piperidyl]piperazine-l- carboxylate 66.E To a solution of tert-butyl 4-(4-piperidyl) piperazine- 1 -carboxylate (1 g, 3.71 mmol) in DMSO (20 mL) were added K2CO3 (1.54 g, 11.1 mmol) and 5-chloro-2-nitropyridine (589 mg, 3.71 mmol). After stirring at 90 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiOz, MeOH/DCM) to afford compound 66.1 (2.05 g) in 83% yield.
[00741] Preparation of tert-butyl 4-[l-(6-amino-3-pyridyl)-4-piperidyl]piperazine-l- carboxylate 66.2. To a solution of compound 66.1 (2 g, 5.1 1 mmol) in THF (15 mL) and EtOH (15 mL) was added 10% Pd/C (500 mg) under N2. After stirring under Hz for 12 h, the reaction mixture was diluted with water, filtered, concentrated, and triturated with EtOAc/PE/DCM to afford compound 66.2 (660 mg) in 34% yield. MS (ESI) m/z'. 362.3 [M+H]+.
[00742] Preparation of tert-butyl 4-[l -[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-i/]pyrimidin-2-yl]amino]-3-pyridyl]-4-piperidyl]piperazine-l-carboxylate 66.3. To a solution of compound 66.2 (300 mg, 830 pmol) and 2-chloro-7-cyclopentyl-A;,A-dimethyl- pyrrolo[2,3-<7]pyrimidine-6-carboxamide (243 mg, 830 pmol) in dioxane (5 mL) were added Pd(OAc)2 (18.6 mg, 83 pmol), BINAP (103 mg, 166 pmol), and CS2CO3 (541 mg, 1.66 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCN, concentrated, and purified by column chromatography (SiCh, MeOH/PE) to afford compound 66.3 (267 mg) in 48% yield. MS (ESI) m/z'. 618.5 [M+H]+.
[00743] Preparation of 7-cyclopentyl-A(A’-dimethyl-2-[[5-(4-piperazin-l-yl-l-piperidyl)- 2-pyridyl]amino]pyrrolo[2,3-t7]pyrimidine-6-carboxamide 66.4, To a solution of compound 66.3 (267 mg, 432 pmol) in DCM (3 mL) was added 4M HC1 in dioxane (3 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 66.4 (200 mg), which was used directly in the next step without further purification. MS (ESI) m/z\ 518.6 [M+Na]“.
[00744] Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)- piperazin-l-yl)-piperidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7#-pyrrolo[2,3-tZ]pyrimidine- 6-carboxamide A209. To a solution of compound 66.4 (200 mg, 386 praol) and 3-[4-(2-bromo- ethyl)phenyl]piperidine-2, 6-dione (114 mg, 386 umol) in DMF (4 mL) were added DIEA (499 mg, 3.86 mmol) and KI (64 mg, 386 umol). After stirring at 100 °C for 2 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A209 (45 mg) in 15% yield. TH NMR (400 MHz, CD3OD) d 8.98 (s, 1H), 8.10 (m, 1H), 7.96 (d, J 2.4 Hz, 1H), 7.44 (d, J 9.6 Hz, 1H), 7.33-7.37 (m, 2H), 7.24-7.29 (m, 2H), 6.81 (s, 1H), 4.81-4.83 (m, 1H), 3.94 (d, J = 12.4 Hz, 5H), 3.88 (m, 2H), 3.73-3.85 (m, 3H), 3.62-3.72 (m, 2H), 3.52-3.58 (m, 2H), 3.20 (d, J - 5.6 Hz, 1H), 3.16 (d, J - 7.2 Hz, 7H), 2.95-3.02 (m, 2H), 2.68-2.76 (m, 1H), 2.59-2.67 (m, 1H), 2.43-2.51 (m, 2H), 2.40 (d, J = 13.2 Hz, 2H), 2.18-2.28 (tn, 2H), 2.03-2.14 (m, 6H), 1.69-1.79
Figure imgf000314_0001
733.5 [M+H] \
Example 67
Preparation of 7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-3- yl)oxy)pyridin-2-yl)amino)-A’,Ar-dimethyl-7//-pyrrolo[2,3-tf]pyrimidine-6-carboxamide A210
Figure imgf000314_0002
[00745] Compound A210 was prepared as described below.
[00746] Preparation of fert-buty I 3 -[(6-nitro-3-pyridyl)oxy]piperidine- 1 -carboxylate 67.1. To a solution of tert-butyl 3 -hydroxypiperidine- 1 -carboxylate (8.5 g, 42.2 mmol) in DMA (40 mL) was added dropwise ABuOK (5.13 g, 45.7 mmol) at 0 °C. After the mixture was stirred at 0 °C for 1 h, 5-fluoro-2-nitropyridine (5 g, 35.1 mmol) in DMA (10 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 12 h, and then poured into a NH4Q solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Xa :SO ;, filtered, concentrated, and purified by column chromatography ( SiO ■, EtOAc/PE) to afford compound 67.1 (4 g) in 35% yield. lH NMR (400 MHz, DMSO-d6 ) <5 8.40- 8.25 (m, 2H), 7.77 (dd, J= 2.8, 9.0 Hz, 1H), 3.85 (br s, 1H), 3.75-3.45 (m, 2H), 3.08 (br d, J= 6.4 Hz, 1H), 2.01-1.87 (m, 2H), 1.85-1.68 (m, 2H), 1.50 (dt, J= 4.4, 9.0 Hz, 1H), 1.39 (br s, 3H), 1.22-1.11 (m, 6H); MS (ESI) m/z: 346 [M+H] \
[00747] Preparation of tert-butyl 3-[(6-amino-3-pyridyl)oxy]piperidine-l-carboxylate 67.2. To a solution of compound 67.1 (4 g, 12.3 mmol) in EtOH (40 mL), H2O (10 mL), and THF (10 mL) were added Fe (5.53 g, 98.9 mmol) and NH4CI (3.31 g, 61.8 mmol). After stirring at 70 °C for 1 h, the reaction mixture was filtered, diluted with H2O, and extracted with EtOAc.
The combined organic layers were washed with brine, dried over anhydrous NazSCM, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 67.2 (3.5 g) in 96%. ]H NMR (400 MHz, DMSO-cA) d 7.64 (d, J= 2.8 Hz, 1H), 7.12 (dd, J = 2.8, 8.9 Hz, 1H), 6.40 (d, 8.8 Hz, 1H), 5.51 (br s, 2H), 4.14-4.00 (m, 1H), 3.70-3.54 (m, 1H),
3.40 (br d, J= 4.0 Hz, 2H), 3.19 (br s, 1H), 1.99 (s, 1H), 1.85 (br s, 1H), 1.76-1.63 (m, 2H), 1.31 (br s, 9H); MS (ESI) m/z\ 294.3 [M+H]\
[00748] Preparation of tert-butyl 3-[[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3- <7]pyrimidin-2-yl]amino]-3-pyridyl]oxy]piperidine-l -carboxylate 67.3. A mixture of compound 67.2 (500 mg, 1.7 mmol), 2-chloro-7-cyclopentyl-A,A-dimethyl-pyrrolo[2,3-J]pyrimidine-6- carboxamide (498 mg, 1.7 mmol), CS2CO3 (1.11 g, 3.41 mmol), BINAP (212 mg, 340 pmol), and Pd(OAc)2 (38.2 mg, 170 pmol) in dioxane (5 mL) was stirred at 100 °C for 12 h under N?.
The reaction mixture was then poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 67.3 (600 mg). MS (ESI) m/z: 550.7 [M+H]+.
[00749] Preparation of 7-cyclopentyl-MA-dimethyl-2-[[5-(3-piperidyloxy)-2-pyridyl]- amino]pyrrolo[2,3-t/]pyrimidine-6-carboxamide 67.4. To a solution of compound 67.3 (600 mg, 1.09 mmol) in DCM (6 mL) was added 4M HC1 in dioxane (272 pL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 67.4 as an HC1 salt (450 mg), which was used directly in the next step without further purification. MS (ESI) m/z\ 450.8 [M+H]+.
[00750] Preparation of 7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'- bipiperidin]-3-yl)oxy)pyridin-2-yl)amino)-A(A'r-dimethyl-7/f-pyrrolo[2,3-6?]pyrimidine-6- carboxamide A210 To a solution of compound 67.4 as an HC1 salt (200 mg, 411 pmol) in THF (1 mL) and DMSO (1 mL) were added NaOAc (101 mg, 1.23 mmol) and HO Ac (123 mg, 2.06 mmol), followed by addition of 3 -[4-(4-oxo-l-piperidyl)phenyl]piperidine-2, 6-dione (117 mg, 411 pmol). After the mixture was stirred at 60 °C for 12 h, NaBHsCN (52 mg, 823 umol) was added. The reaction mixture was stirred at 60 °C for 1 h and then purified by reverse phase perp- HPLC to afford compound A210 (51 mg) in 17% yield. rHNMR (400 MHz, DMSO-Jd) d 10.77 (s, 1H), 9.45 (br s, 1H), 8.77 (s, 1H), 8.19 (br d, 8.4 Hz, 1H), 8.13 (s, 1H), 8.09-8.00 (m, 1H), 7.54-7.44 (m, 1H), 7.06-7.02 (m, 2H), 6.89 (br d, J= 8.0 Hz, 2H), 6.60 (s, 1H), 4.78-4.70 (m, 1H), 4.53-4.24 (m, 1H), 3.79-3.69 (m, 3H), 3.05 (br d, J= 1.2 Hz, 6H), 2.90-2.78 (m, 1H), 2.68- 2.57 (m, 4H), 2.47 (br d, J= 4.0 Hz, 1H), 2.44-2.37 (m, 3H), 2.16-2.05 (m, 2H), 2.02-1.93 (m, 6H), 1.89-1.77 (m, 3H), 1.75 (s, 1H), 1.70-1.50 (m, 6H); MS (ESI) m/z: 720.3 [M+H]+.
Example 68
Preparation of 7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[3,4'-bipiperidin]-l- yl)methyl)pyridin-2-yl)amino)-A’,A'-dimethyl-777-pyrrolo[2,3-J]pyrimidine-6-carboxamide A212
Figure imgf000316_0001
[00751] Compound A212 was prepared as described below.
[00752] Preparation of ZerZ-butyl 5-(4-pyridyl)-3,6-dihydro-2//-pyridine-l-carboxylate 68.1. To a solution of ZerZ-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2//-pyri dine- 1 -carboxylate (5.09 g, 16.4 mmol) and 4-bromopyridine (1.3 g, 8.23 mmol) in DME (100 mL) were added Pd(dppf)Ch (301 mg, 411 pmol) and 2M Na2CO3 (37.5 mL). After stirring at 95 °C for 24 h under N?., the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 68.1 (2 g) in 93%. MS (ESI) m/r. 261.2 [VHI] .
[00753] Preparation of Zert-butyl 3 -(4-piperidyl)piperidine-l -carboxylate 68.2. To a solution of compound 68.1 (2 g, 7.68 mmol) in AcOH (20 mL) was added PtCh (0.5 g, 2.2 mmol). After stirring 40 °C for 10 h under H2, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 68.2 (1 g) in 49% yield. MS (ESI) m/z: 269.2 [M+H]+.
[00754] Preparation of ZurZ-butyl 3-[l-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]- piperidine-l-carboxylate 68.3. A mixture of compound 68.2 (1 g, 3.73 mmol), 2,6-bis(benzyl- oxy)-3-(4-bromophenyl)pyridine (1.39 g, 3.10 mmol), RuPhos Pd G3 (130 mg, 155 pmol), RuPhos (145 mg, 310 pmol), and CsiCCh (5.06 g, 15.5 mmol) in dioxane (10 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaiSOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 68.3 (220 mg) in 11% yield. MS (ESI) m/z: 634.4 [M+H]+.
[00755] Preparation of terrtbutyl 3-[l-[4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]- piperidine-1 -carboxylate 68.4. To a solution of compound 68.3 (200 mg, 316 pmol) in THF (1 mL) and EtOH (1 mL) was added 10% Pd/C (50 mg). After stirring at 40 °C for 12 h under H2, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 68.4 (100 mg) in 70% yield. MS (ESI) m/z: 456,3 [M+H]+.
[00756] Preparation of 3-[4-[4-(3-piperidyl)-l-piperidyl]phenyl]piperidine-2, 6-dione 68.5, A solution of compound 68.4 (100 mg, 220 pmol) in DCM (1 mL) and 4M HC1 in dioxane (2 mL) was stirred for 10 h. The reaction mixture was then filtered and concentrated to afford compound 68.5 (70 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 356.2 [M+H]+.
[00757] Preparation of 7-cyclopentyl-2-((5-((l'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[3,4'- bipiperidin]-l -yl)methyl)pyridin-2-yl)amino)-A,AMimethyl-77f-pyrrolo[2,3-d]pyrimidine-6- carboxamide A212. To a solution of compound 68.5 (90 mg, 253 pmol) in THF (1 mL) and DMSO (1 mL) were added NaOAc (62.3 mg, 760 pmol) and AcOH (76 mg, 1.27 mmol) to pH 6, followed by addition of 7-cyclopentyl-2-[(5-formyl-2-pyridyl)amino]-AJV-dimethyl-pyrrolo[2,3- J]pyrimidine-6-carboxamide (164 mg, 304 pmol). After the mixture was stirred at 60 °C for 13 h, NaBHsCN (31.8 mg, 506 pmol) was added. The reaction mixture was stirred at 80 °C for 1 h and then purified by reverse phase prep-HPLC to afford compound A212 (23 mg) in 25% yield. 1H NMR (400 MHz, DMSO-^) d 10.76 (s, 1H), 9.56 (s, 1H), 8.80 (s, 1H), 8.25 (d, J= 8.4 Hz, 1H), 8.18 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.66 (dd, J= 2.0, 8.8 Hz, 1H), 7.01 (d, J= 8.8 Hz, 2H), 6.85 (d, J- 8.8 Hz, 2H), 6.62 (s, 1H), 4.74 (quin, J- 8.8 Hz, 1H), 3.73-3.62 (m, 3H), 3.48- 3.40 (m, 4H), 3.05 (br s, 6H), 2.88-2.80 (m, 1H), 2.77-2.69 (m, 1H), 2.68-2.59 (m, 1H), 2.42 (br s, 2H), 2.16-2.07 (m, 1H), 2.02-1.87 (m, 6H), 1.77-1.60 (m, 7H), 1.51-1.08 (m, 6H), 1.03-0.89 (m, 1H); MS (ESI) m/z: 718.3 [M+H] \
Example 69
Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- benzyl)piperazin-l-yl)pyri din-2 -yl)amino)-A’,A-dimethyl-7/7-pyrrolo[2,3-tZ]pyrimidine-6- carb oxami de A215
Figure imgf000318_0001
[00758] Compound A215 was prepared as described below.
[00759] Preparation of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]piperidine-l - carboxylate 69.1. To a mixture of tert-butyl 4-(4-bromophenyl)piperidine-l -carboxylate (5 g, 14.7 mmol), (2,6-dibenzyloxy-3-pyridyl)boronic acid (5.42 g, 16.16 mmol), and K3PO4 (6.24 g, 29.39 mmol) in dioxane (24 mL) and H2O (6 mL) was added Pd(dppf)Ch CH2Ch (600 mg, 735 umol). After stirring at 100 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 69.1 (7.3 g) in 90% yield. MS (ESI) m/z: 551.4 [M+H]t
[00760] Preparation of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-l- carboxylate 69.2. To a mixture of 10% Pd/C (0.7 g) and 20% Pd(OH)2 (0.7 g) in THE (20 mL) was added compound 69.1 (7.25 g, 13.2 mmol) in THF (50 mL) under N2. After stirring under H2 at 40 °C for 16 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 69.2 (4.7 g) in 94% yield. MS (ESI) m/z: 317.7 [M+H]+
[00761] Preparation of 3-[4-(4-piperidyl)phenyl]piperidine-2, 6-dione 69.3, To a solution of compound 69.2 (4.72 g, 12.67 mmol) in DCM (50 mL) was added 4M HC1 in dioxane (10 mL). After stirring for 1 h, the reaction mixture was filtered and concentrated to afford compound 69.3 (3.9 g), which was used directly in the next step without further purification. MS (ESI) m/z: 273 [M+H]t
[00762] Preparation of 4-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-l-piperidyl]benzaldehyde 69.4. To a solution of compound 69.3 as an HC1 salt (1.8 g, 5.83 mmol) and 4-fluoro- benzaldehyde (724 mg, 5.83 mmol) in DMF (20 mL) was added K2CO3 (161 mg, 1.17 mmol). After stirring at 130 °C for 12 h, the reaction mixture was diluted with ice- water. The resulting precipitates were collected by filtration and further triturated with MeOH to afford compound 69.4 (620 mg) in 28% yield. MS (ESI) m/z: 377.3 [M+H]+.
[00763] Preparation of 7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-l-yl)-benzyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7/f-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A215. To a solution of 7-cyclopentyl-Af,Ar-dimethyl-2-[(5-piperazin- l-yl-2-pyridyl)amino]pyrrolo[2,3-d]pyrimidine-6- carboxamide (200 mg, 460 pmol), compound 69.4 (173 mg, 460 pmol), and NaOAc (113 mg, 1.38 mmol) in DMF (2 mL) was added NaBH(OAc)3 (293 mg, 1.38 mmol). After stirring at 60 °C for 2 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A215 (93 mg) as a TFA salt in 23% yield. rH NMR (400 MHz, DMSO-<7d) d' 12.18-11.77 (m, 1H), 10.83 (s, 1H), 9.03 (s, 1H), 8.14 (s, 1 H), 8.10 (dd, ./= 2.4, 9.6 Hz, 1H), 8.04 (d, ./= 8.4 Hz, 2H), 7.99 (d, J= 2.4 Hz, 1H), 7.93 (d, J= 8.4 Hz, 2H), 7.64 (d, J= 9.6 Hz, 1H), 7.30-7.24 (m, 2H), 7.24-7.19 (m, 2H), 6.85 (s, 1H), 4.81 (s, 1H), 3.91-3.78 (m, 4H), 3.75 (d, J= 12.0 Hz, 2H), 3.64 (d, J= 10.4 Hz, 2H), 3.48-3.16 (m, 7H), 3.05 (s, 6H), 3.02-2.97 (m, 1H), 2.73-2.62 (m, 1H), 2.56 (s, 2H), 2.47 (s, 1H), 2.35-2.23 (m, 2H), 2.22-2.12 (m, 1H), 2.09-1.92 (m, 7H), 1.63 (d, J = 5.6 Hz, 2H); MS (ESI) m/z: 795.5 [M+H]+.
Example 70
Preparation of 7-cyclopentyl-2-((5-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyI)piperidin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7/Z-pyrrolo[2,3-4/]pyrimidine- 6-carboxamide A216
Figure imgf000320_0001
[00764] Compound A216 was prepared as described below.
[00765] Preparation of 7-cyclopentyl-2-[[5-[4-(4-formylphenyl)piperazin-l-yl]-2-pyridyl]- amino]-A^V-dimethylpyrrolo[2,3- d]pyrimidine-6-carboxamide 70.1, A mixture of 7-cyclo- pentyl-A7,J'V-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-t/]pyrimidine-6- carboxamide (1 g, 2.3 mmol), 4-fluorobenzaldehyde (286 mg, 2.3 mmol), and K2CO3 (63.6 mg, 460 pmol) in DMF (10 mL) was stirred at 130 °C for 12 h. The reaction mixture was the diluted with ice-water. The resulting precipitates were collected by filtration and further triturated with MeOH to afford compound 70.1 (800 mg) in 65% yield. lH NMR (400 MHz, DMSO-de) d 9.72 (s, 1H), 9.03 (s, 1H), 8.20 (dd, ./ 2.4, 9.6 Hz, 1H), 8.05 (d, ./ 2.0 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.67 (d, J= 9.6 Hz, 1H), 7.13 (d, J= 8.8 Hz, 2H), 6.83 (s, 1H), 4.78 (s, 1H), 3.65-3.53 (m, 4H), 3.37 (s, 4H), 3.03 (s, 6H), 2.26 (d, J = 7.6 Hz, 2H), 2.09-1.85 (m, 5H), 1.61 (d, J=: 5.6 Hz, 2H); MS (ESI) m/z: 539.3 [M+H] \
[00766] Preparation of 7-cyclopentyl-2-((5-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin- 1 -yl)-methyl)phenyl)piperazin- 1 -yi)pyridin-2-yl)amino)-A(A-dimethyl-7A/-pyrrolo[2,3 - t/]pyrimidine-6-carboxamide A216. To a mixture of compound 70.1 (300 mg, 557 pmol), 3-[4- (4-piperidyl)phenyl]piperidine-2, 6-dione as an HC1 salt (172 mg, 557 pmol), and NaOAc (183 mg, 2.23 mmol) in DMF (2 mL) was added NaBH(OAc)s (354 mg, 1.67 mmol). After stirring at 60 °C for 12 h, the reaction mixture was filtered and purified by reverse phase prep-HPLC to afford compound A216 (143 mg) in 32% yield. rH NMR (400 MHz, DMSO-^) <5 10.82 (s, 1H), 9.40 (s, 1H), 8.78 (s, 1H), 8.21 (s, 1H), 8.20-8.18 (m, 1H), 8.08 (d, J= 2.8 Hz, 1H), 7.51 (dd, J= 2.8, 9.2 Hz, 1H), 7.23-7.16 (m, 4H), 7.15-7.09 (m, 2H), 6.98 (d, J= 8.4 Hz, 2H), 6.60 (s, 1H), 4.82-4.66 (m, 1H), 3.80 (dd, ./= 4.8, 1 1.6 Hz, 2H), 3.47 (s, 2H), 3.28 (d, .7= 2.8 Hz, 8H), 3.05 (s, 6H), 2.95 (d, 11.2 Hz, 2H), 2.71-2.59 (m, 1H), 2.45 (d, J- 4.0 Hz, 3H), 2.22-2.04 (m, 3H),
2.04-1.93 (m, 5H), 1.78-1.58 (m, 6H); MS (ESI) m/z: 795.8 [M+H]T
Example 71
Preparation of 7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-A',iV-dimethyl-7f/-pyrrolo[2,3-</]pyrimidine-6- carboxamide A223
Figure imgf000321_0001
[00767] Compound A223 was prepared as described below.
[00768] Preparation of 5-(4-(dimethoxymethyl)piperidin-l-yl)-2-nitropyridine 71.1. To a 5-chloro-2-nitropyridine (10 g, 63.1 mmol) and 4-(dimethoxymethyl)piperidine (10 g, 63.1 mmol) in DMSO (100 mL) were added K2CO3 (26.2 g, 189 mmol) and KI (1.05 g, 6.31 mmol). After stirring at 90 °C for 12 h under N2, the reaction mixture was diluted with water. The resulting precipitates were collected by filtration and triturated with EtOAc/PE to afford compound 71.1 (16.9 g) in 95% yield ^I NMR (400 MHz, DMSO-d6 ) 3 8.24-8.21 (m, 1H), 8.12 (d, ./= 9.2 Hz, 1H), 7.44 (dd, J= 3.2, 9.2 Hz, 1H), 4.12 (br s, 1H), 4.08 (br d, J= 6.8 Hz, 2H), 3.27-3.25 (m, 6H), 3.02-2.92 (m, 2H), 1.90 (ddt, 4.0, 7.2, 11.6 Hz, 1H), 1.72 (br d, 11.2 Hz, 2H), 1.28 (dq, J= 4.0, 12.4 Hz, 2H); MS (ESI) m/z: 282.2 [M+H] \
[00769] Preparation of 5-(4-(dimethoxymethyl)piperidin-l-yl)pyridin-2-amine 71.2. To a solution of compound 71.1 (16.9 g, 60.1 mmol) in H2O (34 mL) and EtOH (136 mL) were added NH4Q (12.9 g, 240 mmol) and Fe (26.8 g, 481 mmol). After stirring at 70 °C for 0.5 h under N2, the reaction mixture was filtered, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiO?., MeOH/DCM) and further triturated with EtOAc to afford compound 71.2 (8.6 g) in 57% yield. NMR (400 MHz, DMSO-de) δ 7 58 (d, J == 2.8 Hz, 1H), 7.14 (dd, ,J = 2.8, 8.8 Hz, 1H), 6.38 (d, J= 8.8 Hz, 1H), 5.35 (s, 2H), 4.08 (d, J= 6.8 Hz, 1H), 3.35-3.34 (m, 1H), 3.31 (br d, J- 3.2 Hz, 1H), 3.26 (s, 6H), 2.45 (dt, J- 2.0, 12.0 Hz, 2H), 1.68 (br d, J = 13.2 Hz, 2H), 1.64-1.57 (m, 1H), 1.33 (dq, J= 4.0, 12.0 Hz, 2H); MS (ESI) m/z: 252.3 [M+H]+.
[00770] Preparation of 7-cyclopentyl-2-((5-(4-(dimethoxymethyl)piperidin-l-yl)pyridin-2- yl)amino)-A\A7-dimethyl-7//-pyrrolo[2,3-<i]pyrimidine-6-carboxamide 71.3. To a mixture of 2- chloro-7-cyclopentyl-A’,A;-dimethyl-7Z7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide (5 g, 17. 1 mmol), CsiCOi (7.59 g, 23.3 mmol), and compound 71.2 (3.90 g, 15.5 mmol) in dioxane (50 mL) were added BINAP (483 mg, 776 pmol) and Pd(OAc)r (87 mg, 388 pmol). After stirring at 100 °C for 12 h under N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCh, filtered, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 71.3 (6.2 g) in 79% yield. *H NMR (400 MHz, DMSO-uk) 3 9.33 (s, 1H), 8.76 (s, 1H), 8.13 (d, J - 9.2 Hz, 1 H), 8.00 (d, J- 2.8 Hz, 1H), 7.41 (dd, .7 ■■■ 2.8, 9.2 Hz, 1H), 6.59 (s, 1H), 4.79-4.67 (m, 1H), 4.10 (d, J= 6.4 Hz, 1H), 3.64 (br d, J= 12.0 Hz, 2H), 3.27 (s, 6H), 3.05 (br s, 6H), 2.64-2.55 (m, 2H), 2.47-2.38 (m, 2H), 1.97 (br s, 3H), 1.77-1.60 (m, 6H), 1.42-1.31 (ra, 2H), MS (ESI) m/z: 508.4 [M+H]+.
[00771 ] Preparation of 7-cyclopentyl-2-((5-(4-formylpiperidin-l -yl)pyridin-2-yl)amino)- AA,A-dimethyl-7Z7-pyrrolo[2,3V|pyrimidine-6-carboxamide 71.4. To a solution of compound 71.3 (2 g, 3.94 mmol) in DCM (15 mL) was added TFA (7.68 g, 67.3 mmol). After stirring for 12 h under N2, the reaction mixture was concentrated to afford compound 71.4 as a TFA salt (4 g), which was used directly in the next step without purification. rH NMR (400 MHz, DMSO- ck) 3 11.49 (s, 1H), 9.65 (s, 1H), 8.99 (s, 1H), 8.13 (dd, J= 3.2, 9.6 Hz, 1H), 7.88 (d, J= 2.8 Hz, 1H), 7.51 (d, J= 9.6 Hz, 1H), 7.28-7.22 (m, 1H), 7.20-7. 12 (m, 2H), 6.82 (s, 1H), 3.64-3.55 (m, 2H), 3.06 (s, 6H), 2.34-2.27 (m, 4H), 2.04-1.96 (m, 5H), 1.68-1.58 (m, 4H); MS (ESI) m/z: 462.4 [M+H]+.
[00772] Preparation of 7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-methyl)piperidin-l-yl)pyridin-2-yl)amino)-?f,Ar-dimethyl-7/7-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A223. To a solution of 3-(3-(piperazin-l-yl)phenyl)piperidine-2,6- dione as an HC1 salt (150 mg, 484 umo!) in THF (1 mL) and DMSO (1 mL) was added NaOAc (119 mg, 1.45 mmol) to pH 7~8, followed by addition of compound 71.4 as a TFA salt (596 mg, 581 nmol) and HO Ac (87.2 mg) to pH 5~6. After the mixture was stirred at 60 °C for 12 h under N2, NaBHsCN (60.9 mg, 968 pmol) was added. The reaction mixture was stirred at 60 °C for 2 h, and then filtered and purified by reverse phase prep-HPLC to afford compound A223 (127 mg) in 35% yield. lH NMR (400 MHz, DMSO-de) 3 10.79 (s, 1H), 9.41 (s, 1H), 8.78 (s, 1H), 8.15 (br s, 1H), 8.14 (d, J = 4.0 Hz, 1H), 8.03 (d, .7= 2.8 Hz, 1H), 7.44 (dd, .7 = 2.8, 9.2 Hz, 1H), 7.07 (d, ./ 8.4 Hz, 2H), 6.92 (br d, 8.8 Hz, 2H), 6.60 (s, 1H), 4.74 (quin, ./ 8.8 Hz, 1H), 3.74 (dd, .7= 4.8, 11.2 Hz, 1H), 3.64 (br d, J= 12.0 Hz, 2H), 3.05 (br s, 6H), 2.85 (br s, 4H), 2.72-2.53 (m, 6H), 2.48-2.38 (m, 4H), 2.19-2.08 (m, 1H), 2.07-1.90 (m, 6H), 1.90-1.70 (m, 4H), 1.68-1.61 (m, 2H), 1.31 (q, .7= 10.8 Hz, 2H); MS (ESI) wk 719.5 [M+H]+.
Example 72
Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A'',A'r-dimethyl-7H-pyrrolo[2,3-tf]pyrimidine-6- carboxamide A231
Figure imgf000323_0001
[00773] Compound A231 was prepared as described below.
[00774] Preparation of 2-(l-(3-bromophenyl)piperidin-4-yl)ethan-l-ol 72.1. To a solution of 2-(4-piperidyl)ethanol (5 g, 38.7 mmol) and l-bromo-3-iodobenzene (13.1 g, 46.4 mmol) in DMF (50 mL) were added Z-proline (1.78 g, 15.5 mmol), Cui (2.95 g, 15.5 mmol), and K2CO3 (16.1 g, 116 mmol). After stirring at 100 °C for 12 h at N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiO?.,
EtOAc/PE) to afford compound 72.1.
Figure imgf000323_0002
(400 MHz, DMSO-^) 3 7.20-6.81 (m, 4H), 4.36 (t, J= 5.1 Hz, 1H), 3.75-3.59 (m, 2H), 3.52-3.42 (m, 2H), 2.68-2.58 (m, 2H), 1.71 (br d, J= 12.4 Hz, 2H), 1.53 (tdd, .7 3.6, 7.2, 14.4 Hz, 1H), 1,38 (q, ./ 6.4 Hz, 2H), 1.19-1.16 (m, 1H). [00775] Preparation of 2-(l-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)- ethan-l-ol 72.2. To a solution of compound 72.1 (7.4 g, 26.1 mmol) and (2,6-dibenzyloxy-3- pyridyl)boronic acid (8.73 g, 26.1 mmol) in water (30 mL) and dioxane (50 mL) were added Pd(dppf)Cl?. CH2C12 (1.06 g, 1.3 mmol) and K3PO4 (16.6 g, 78.2 mmol) under N2. After stirring at 100 °C for 2 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SC>4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 72.2 (10.1 g) in 78% yield. !H NMR (400 MHz, DMSO-r/e) d 7.73 (d, J = 8.0 Hz, 1H), 7.48-7.29 (m, 10H), 7.22-7.16 (m, 1H), 7.08 (s, 1H), 6.92-6.79 (m, 2H), 6.54 (d, J= 8.0 Hz, 1H), 5.38 (d, J= 10.8 Hz, 4H), 4.36 (t, J= 5.2 Hz, 1H), 3.56 (br d, ./= 12.4 Hz, 2H), 3.51-3.42 (m, 2H), 2.59-2.52 (m, 2H), 1.68 (br d, J= 12.0 Hz, 2H), 1.55-1.45 (m, 1H), 1.38 (q, J = 6.4 Hz, 2H), 1.23-1.12 (m, 2H).
[00776] Preparation of 3-(3-(4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2,6- dione 72.3. To a solution of compound 72.2 (10.1 g, 20.4 mmol) in THF (10 mL) and EtOH (10 mL) were added 10% Pd/C (2 g) and 20% Pd(OH)2/C (2 g) under N2. After stirring at 60 °C for 12 h under H2, the reaction mixture was filtered and concentrated to afford compound 72.3 (5 g), which was used directly in the next step without further purification.
[00777] Preparation of 2-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- acetaldehyde 72.4. To a solution of compound 72.3 (1.3 g, 4.11 mmol) in DCM (13 mL) was added Dess-Martin (2.09 g, 4.93 mmol) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (S1O2, EtOAc/PE) to afford compound 72.4 (400 mg) in 31% yield.
[00778] Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A7-dimethyl-7H-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A231. To a solution of 7-cyclopentyl-A,A-dimethyl-2-((5-(piperazin- l-yl)pyridin-2-yl)amino)-7/7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide (207 mg, 477 pmol) and compound 72.4 (150 mg, 477 pmol) in THF (2 mL) and DMSO (1 mL) were added KO Ac (140 mg, 1 .43 mmol) and HO Ac (28.6 mg, 477 nmol). After the mixture was stirred at 40 °C for 12 h, NaBHsCN (89.9 mg, 1.43 mmol) was added. The reaction mixture was stirred for 1 h, and then filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A231 (60 mg) in 16% yield. LH NMR (400 MHz, DMSO-cfc) 8 10.79 (s, 1 H), 9.27 (br d, J = 3.6 Hz, 1H),
8.75 (s, 1H), 8.18 (br s, 1H), 8.14 (d, J= 9.2 Hz, 1H), 7.98 (d, J= 2.0 Hz, 1H), 7.47-7.40 (m, 1H), 7.13 (t, J== 8.0 Hz, 1H), 6.87-6.75 (m, 2H), 6.63-6.55 (m, 2H), 4.73 (br 1, ./ 8.4 Hz, 1H),
3.75 (br dd, 7= 4.8, 10.8 Hz, 1H), 3.65 (br d, .7= 11.2 Hz, 2H), 3.15-3.03 (m, 11H), 2.73-2.58 (m, 6H), 2.45-2.36 (m, 5H), 2.22-2.14 (m, HI), 2.04-1.94 (m, 5H), 1.77 (br d, ./ 12.8 Hz, 2H), 1.63 (br d, J = 4.4 Hz, 2H), 1.45 (br s, 3H), 1.25 (br d, .7 = 10.4 Hz, 2H); MS (ESI) m/z: 733.6 [M+H]+.
Example 73
Preparation of 7-cyclopentyl-2-((5-(l-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-/V,jV-dimethyl-7/f-pyrrolo[2,3-d]pyrimidine-6- carboxamide A235
Figure imgf000325_0001
[00779] Compound A235 was prepared as described below.
[00780] Preparation of 2-[[5-[l-(2-bromoethyl)-4-piperidyl]-2-pyridyl]amino]-7-cyclo- pentyl-jV,A-dimethylpyrrolo [2,3-tZ]pyrimidine-6-carboxamide 73.1, To a solution of PBn (113 mg, 419 umol) in ACN (1 mL) was added 7-cyclopentyl-2-[[5-[l-(2-hydroxyethyl)-4-piperidyl]- 2-pyridyl]amino]-Ar//-dimethylpyrrolo[2,3-cZ]pyrimidine-6-carboxamide (200 mg, 419 pmol) in ACN (2 mL) dropwise. After stirring at 80 °C for 1 h, the reaction mixture was treated with saturated aqueous NH4CI at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to afford compound 73.1 (198 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 540.4 [M+H]+.
[00781] Preparation of 7-Cyclopentyl-2-((5-(l-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-ethyl)piperidin-4-yl)pyridin-2-yl)amino)-ACV-dimethyi-77f-pyrrolo[2,3-</]- pyrimidine-6-carboxamide A235. To a solution of compound 73.1 (197 mg, 364 umol) and 3- [3-(4-piperidyl)phenyl]piperidine-2, 6-dione (100 mg, 367 pmol) in DMF (2 mL) were added DIEA (475 mg, 3.67 mmol) and KI (61 mg, 367 pmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A235 (52 mg) in 18% yield. ’H NMR (400 MHz, CD3OD) 3 1.68-1.78 (m, 2H), 1.95-2.01 (m, 6H), 2.04-2.12 (m, 4H), 2.17-2.28 (m, 2H), 2.50-2.72 (m, 6H), 2.73-2.84 (m, 4H), 3.01-3.07 (m, 2H), 3.14-3.16 (m, 1H), 3.15 (s, 5H), 3.39 (d, 11.8 Hz, 2H), 3.50 (d, J= 1 1.8
Hz, 2H), 3.87 (dd, J= 10.2, 5.6 Hz, 1H), 4.78 (t, J= 8.8 Hz, 1H), 6.64 (s, 1H), 7.08-7.24 (m, 3H), 7.27-7.: 37 (m, 1H), 7.74 (dd, ./ = 8.8, 2.4 Hz, 1H), 8.20 (d, 2.13 Hz, 1H), 8.29 (d, 8.8
Hz, 1H), 8.45 (s, 1H), 8.79 (s, 1H); MS (ESI) m/z: 733.2 [M+H]+.
Example 74
Preparation of 7-cyclopentyl-2-((5-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- r-yl)ethyl)pyridin-2-yl)amino)-A,Ar-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A236
Figure imgf000326_0001
[00782] Compound A236 was prepared as described below.
[00783] Preparation of tert-butyl 4-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-l-piperidyl]- piperidine-l-carboxylate 74.1. To a solution of 3-[4-(4-piperidyl)phenyl]piperidine-2, 6-dione (500 mg, 1.84 mmol) and tert-butyl 4-oxopiperidine-l -carboxylate (366 mg, 1.84 mmol) in DMF (10 mL) and DMSO (3 mL) were added AcOH (331 mg, 5.51 mmol) and NaOAc (452 mg, 5.51 mmol). After the mixture was stirred for 0.5 h, NaBH(OAc)3 (1.56 g, 7.34 mmol) was added. The reaction mixture was stirred at 60 °C for 12 h under N2, and then diluted with aqueous saturated NH4CI and extracted with ACN. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and triturated with ACN to afford compound 74.1 (500 mg) in 57% yield. LH NMR (400 MHz, DMSO-dfe) 3 10.83 (s, 1H), 7.19 (s, 4H), 4.06 (d, J = 9.2 Hz, 2H), 3.83 (dd, J= 4.8, 11.6 Hz, 1H), 3.49 (d, 10.0 Hz, 2H), 3.05 (d, 10.8 Hz, 2H), 2.90-
2.60 (m, 5H), 2.46 (s, 1H), 2.27-2.07 (m, 5H), 2.02 (dd, J= 4.4, 12.8 Hz, 1H), 1.94 (d, J= 12.4 Hz, 2H), 1.62-1.50 (m, 2H), 1.40 (s, 9H); MS (ESI) m/z: 456.3 [M+H]+.
[00784] Preparation of 3-[4-[l-(4-piperidyl)-4-piperidyl]phenyl]piperidine-2, 6-dione 74.2. To a solution of compound 74.1 (500 mg, 1.1 mmol) in DCM (5 mL) was added 4M HC1 in dioxane (5 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 74.2 as an HC1 salt (410 mg), which was used directly in the next step without further purification.
[00785] Preparation of 7-cyclopentyl-2-((5-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- [1 , 4'-bipiperidin]-l'-yl)ethyl)pyri din-2 -yl)amino)-MA^dimethyl-7J7-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A236. To a solution of compound 74.2 (100 mg, 281 pmol) and 2-[6-[[7- cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-rf]pyrimidin-2-yl]amino]-3-pyridyl]ethyl 4- methylbenzenesulfonate (154 mg, 281 pmol) in DMF (1 mL) were added DLEA (182 mg, 1.41 mmol) and KI (93.4 mg, 563 pmol). After stirring at 80°C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A236 as a TFA salt (40 mg) in 18% yield. ^ NMR (400 MHz, DMSO-^) ri 10.83 (s, 1H), 9.53 (s, 1H), 8.80 (s, 1H), 8.26 (d, J= 8.4 Hz, 1H), 8.17 (d, 2.0 Hz, 1H), 8.16 (s, 1H), 7.66 (dd, J= 2.0, 8.4 Hz, 1H), 7.43-6.93 (m, 4H),
6.62 (s, 1H), 4.88-4.59 (m, 1H), 3.83 (dd, J= 4.8, 11.2 Hz, 1H), 3.32 (d, J= 10.4 Hz, 2H), 3.17 (d, J= 11.2 Hz, 2H), 3.06 (s, 6H), 2.89 (s, 1H), 2.80-2.61 (m, 7H), 2.46 (s, 4H), 2.37-2.28 (m, 1H), 2.27-2.11 (m, 3H), 2.07-1.88 (m, 8H), 1.84-1.74 (m, 2H), 1.73-1.55 (m, 4H); MS (ESI) m/z: 732.3 [M+H]+.
Example 75
Preparation of 7-cyclopentyl-2-((5-(r-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[4,4'-bipiperidin]- l-yl)pyridin-2-yl)amino)-A(AMimethyl-7.H-pyrrolo[2,3-J]pyrimidine-6-carboxamide A237
Figure imgf000327_0001
[00786] Compound A237 was prepared as described below.
[00787] Preparation of tert-butyl 4-[l-(6-nitro-3-pyridyl)-4-piperidyl] piperidine- 1 - carboxylate 75.1. To a solution of 5-chloro-2-nitropyridine (5.91 g, 37.3 mmol) and tert-butyl 4- (4-piperidyl)piperidine-l-carboxylate (10 g, 37.3 mmol) in DMSO (150 mL) was added K2CO3 (15.5 g, 112 mmol). After stirring at 90 °C for 12 h under N2, the reaction mixture was diluted with water. The resulting precipitates were collected by filtration and triturated with EtOAc/PE to afford compound 75.1 (14 g) in 84% yield. 'H NMR (400 MHz, CDCh) J 8.15 (d, J= 9.2 Hz, 1H), 8.12 (d, J= 3.2 Hz, 1H), 7.17 (dd, ./ = 3.2, 9.2 Hz, 1H), 4.15 (d, J= 6.0 Hz, 2H), 4.00 (d, J = 13.2 Hz, 2H), 2.97 (t, J= 12.0 Hz, 2H), 2.65 (d, J= 1.6 Hz, 2H), 2.62 (s, 4H), 1.88 (d, J=10.0 Hz, 2H), 1.71 (s, 2H), 1.46 (s, 9H), 1.43-1.37 (m, 2H); MS (ESI) mA: 391.2 [M+H]+.
[00788] Preparation of tert-butyl 4-[l-(6-amino-3-pyridyl)-4-piperidyl] piperidine-1- carboxylate 75.2. To a solution of compound 75.1 (10 g, 25.6 mmol) in THF (100 mL) and EtOH (100 mL) was added 10% Pd/C (1 g) under N2. After stirring for 12 h under H2, the reaction mixture was filtered and concentrated to afford compound 75.2 (13 g), which was used directly in the next step without further purification.
[00789] Preparation of tert-butyl 4-[l -[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-</jpyrimidin-2-yl]amino]-3-pyridyl]-4-piperidyl]piperidine-l-carboxylate 75.3. A mixture of 2-chloro-7-cyclopentyl-A,A-dimethylpyrrolo[2,3-eZ]pyrimidine-6-carboxamide (8.12 g, 27.7 mmol), fert-butyl 4-[l-(6-amino-3-pyridyl)-4-piperidyl]piperidine-l-carboxylate 75.2 (10 g, 27.7 mmol), CS2CO3 (13.6 g, 41.6 mmol), Pd(OAc)2 (156 mg, 694 pmol), and BINAP (864 mg, 1.39 mmol) in dioxane (150 mL) was stirred at 100 °C for 6 h under N2. The reaction mixture was then diluted with water. The resulting precipitates were collected by filtration and triturated with EtOAc/PE to afford compound 75.3 (15 g) in 84% yield. }H NMR (400 MHz, DMSO-tZe) 0 9.25-9.12 (m, HI), 8.74 (s, HI), 8.17-8.06 (m, 1H), 8.02-7.90 (m, 1H), 7.51-7.32 (m, 1H), 6.59 (s, 1H), 4.82-4.61 (m, 1H), 4.16-3.85 (m, 4H), 3.72-3.62 (m, 2H), 3.59-3.54 (m, 1H), 3.05 (s, 6H), 2.00-1.92 (m, 6H), 1.81-1.62 (m, 8H), 1.39 (s, 9H), 1.20-1.16 (m, 2H), 1.04 (td, J= 3.2, 6.0 Hz, 2H); MS (ESI) mA: 617.4 [M+H]+.
[00790] Preparation of 7-cyclopentyl-MA-dimethyl-2-[[5-[4-(4-piperidyl)-l-piperidyl]-2- pyridyl] amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide 75.4, To a solution of compound 75.3 (15 g, 24.3 mmol) in DCM (150 mL) was added 4M HC1 in dioxane (150 mL). After stirring for 1 h, the reaction mixture was concentrated to afford 75.4 as an HC1 salt (13.4 g), which was used directly in the next step without further purification.
Figure imgf000329_0001
NMR (400 MHz, DMSO-d6 ) d 11.65 (s, 1H), 9.12 (d, J= 8.0 Hz, 1H), 9.03 (s, 2H), 8.24 (d, J= 9.2 Hz, 2H), 7.66 (d, J= 9.2 Hz, 1H), 6.85 (s, 1H), 4.84-4.76 (m, 1H), 3.69 (d, J 11.6 Hz, 2H), 3.25 (d, ./ 12.0 Hz, 2H), 3.05 (s, 6H), 2.95 (s, 2H), 2.79 (d, J = 10.4 Hz, 2H), 2.30 (dd, J= 8.0, 11.6 Hz, 2H), 2.11-1.91 (m, 4H), 1.83 (d, ./ 11.2 Hz, 4H), 1.70-1.58 (m, 2H), 1.54-1.30 (m, 6H); MS (ESI) m/z: 517.6 [MH<.
[00791] Preparation of 7-cyclopentyl-2-((5-(l'-(4-(2,6-dioxopiperidin-3-yl)phenethyl)- [4,4'-bipiperidin]-l-yl)pyridin-2-yl)amino)-7V,Ar-dimethyl-7H-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A237. To a solution of compound 75.5 (174 mg, 338 pmol) and 3-[4-(2- bromoethyl)phenyl]piperidine-2, 6-dione (100 mg, 338 pmol) in DMF (3 mL) were added DIEA (218 mg, 1.69 mmol) and KI (112 mg, 675 pmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A237 as a TFA salt (53 mg) in 19% yield. ‘H NMR (400 MHz, DMSO-c/e) d 10.82 (s, 1H), 9.24 (s, 1H), 8.74 (s, 1H), 8.16 (s, 1H), 8.12 (d, ./ 9.2 Hz, 1H), 7.98 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.24-7. 17 (m, 2H), 7.16-7.09 (m, 2H), 6.59 (s, 1H), 4.73 (t, J= 8.8 Hz, 1H), 3.81 (dd, J= 4.4, 11.2 Hz, 1H), 3.66 (d, J= 10.4 Hz, 2H), 3.13 (d, J= 10.4 Hz, 2H), 3.05 (s, 6H), 2.77 (d, J= 6.8 Hz, 2H), 2.69 (d, J = 5.2 Hz, 2H), 2.57 (d, .7= 11.6 Hz, 2H), 2.43 (s, 2H), 2.16 (s, 3H), 2.06-1.92 (m, 5H), 1 .76 (t, J = 12.4 Hz, 4H), 1.64 (s, 2H), 1.38-1.23 (m, 4H), 1.23-1.15 (m, 4H); MS (ESI) m/z'. 732.3 [M+H]+.
Example 76
Preparation of 7-cyclopentyl-2-((5-(l'-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[ 1 ,4 -bipiperidin]-
4-yl)pyridin-2-yl)amino)-A/,A'-dimethyl-77/-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A238
Figure imgf000329_0002
[00792] Compound A238 was prepared as described below.
[00793] Preparation of tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7//-pyrrolo- [2, 3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidine-l -carboxylate 76.1. A mixture of 2-chloro- 7-cyclopentyl-A,7V-dimethyl-7/f-pyrrolo[2,3-</]pyrimidine-6-carboxamide (22 g, 75.2 mmol), tert-butyl 4-(6-aminopyridin-3-yl)piperidine-l -carboxylate (25 g, 90.2 mmol), CS2CO3 (36.7 g, 113 mmol), Pd(OAc)?. (422 mg, 1.88 mmol), and BINAP (2.34 g, 3.76 mmol) in dioxane (220 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water. The resulting precipitates were collected by filtration to afford compound 76.1 (45 g) in 95% yield. NMR (400 MHz, DMSO-O 3 9.51 (s, 1H), 8.80 (s, 1H), 8.25 (d, ./ 8.8 Hz, 1H), 8.18 (d, J= 2.0 Hz, 1H), 7.67 (dd, J= 2.0, 8.8 Hz, 1H), 6.62 (s, 1H), 4.74 (quin, J = 8.8 Hz, 1H), 4.09 (d, J= 11.6 Hz, 2H), 3.05 (s, 6H), 2.81 (d, J= 6.0 Hz, 2H), 2.72-2.61 (m, 1H), 2.48-2.35 (m, 2H), 1.99 (s, 4H), 1.77 (d, J= 12.4 Hz, 2H), 1.71-1.61 (m, 2H), 1.53 (dq, J= 3.6, 12.4 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 534.5 [M+H]+.
[00794] Preparation of 7-cyclopentyl-A,A-dimethyl-2-((5-(piperidin-4-yl)pyridin-2-yl)- amino)-7H-pyrrolo[2,3-J]pyriinidine-6-carboxamide 76.2, A mixture of compound 76.1 (45 g, 71.7 mmol) in DCM (250 mL) and 4M HC1 in dioxane (200 mL) was stirred for 12 h. The reaction mixture was then concentrated and treated with aqueous NaHCCh. The resulting precipitates were collected by filtration to afford compound 76.2 (29 g) in 93% yield. LH NMR (400 MHz, DMSO-fifc) 3 9.59 (s, 1H), 8.80 (s, 1H), 8.28 (d, J= 8.8 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1 H), 7.62 (dd, J= 2.4, 8.8 Hz, 1H), 6.63 (s, 1H), 4.75 (quin, J= 8.8 Hz, 1H), 3.36-3.35 (m, 2H), 3.05 (s, 6H), 2.95 (dt, J= 2.4, 12.4 Hz, 2H), 2.89-2.76 (m, 1H), 2.48-2.40 (m, 2H), 2.05-1.89 (m, 6H), 1.81 (dq, J= 3.6, 13.2 Hz, 2H), 1.72-1.58 (m, 2H); MS (ESI) m/z: 434.5 [M+H]L
[00795] Preparation of tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidine]-r-carboxylate 76.3. To a solution of compound 76.2 (6 g, 13.8 mmol) in DMSO (180 mL) were added tert-butyl 4- oxopiperidine-1 -carboxylate (8.27 g, 41.5 mmol) and NaBH(OAc)3 (11.7 g, 55.4 mmol). After stirring at 60 °C for 2 h, the reaction mixture was diluted with water. The resulting precipitates were collected by filtration to afford compound 76.3 (6.6 g) in 74% yield. !H NMR (400 MHz, DMSO-cfc) 3 8.74 (s, 1H), 8.34 (d, J= 8.8 Hz, 1H), 8.14 (d, J= 2.0 Hz, 1H), 7.69 (dd, J = 2.4, 8.8 Hz, 1H), 6.63 (s, 1H), 4.78-4.69 (m, 1H), 4.16 (d, ./= 13.6 Hz, 2H), 3.16 (s, 6H), 3.12 (d, J = 12.0 Hz, 2H), 2.86-2.68 (m, 2H), 2.63-2.48 (m, 4H), 2.40 (t, J= 11.2 Hz, 2H), 2.15-1.99 (m, 4H), 1.97-1.85 (m, 411), 1.85-1.69 (m, 4H), 1.46 (s, 9H), 1,45-1,35 (m, 2H); MS (ESI) m/z: 617.4 [M+H]+
[00796] Preparation of 2-((5-([l,4'-bipiperidin]-4-yl)pyridin-2-yl)amino)-7-cyclopentyl- A(A-dimetliyl-7Ar-pyrrolo[2,3-7]pyrimidine-6-carboxamide 76.4. A mixture of compound 76.3 (6.6 g, 10.7 mmol) in DCM (40 mL) and 4M HC1 in dioxane (30 mL) was stirred at 20 °C for 1 h. The reaction mixture was then concentrated to afford compound 76.4 as an HC1 salt (8.4 g), which was used directly in the next step without further purification. LH NMR (400 MHz, DMSO-dfc) J 11.93 (s, 1H), 11.74-11.54 (m, 1H), 9.39 (d, J= 8.8 Hz, 1H), 9.29-9.14 (m, 1H), 9.11-8.94 (m, 1H), 8.30 (d, 7 = 2.0 Hz, 1H), 8.14 (dd, J = 2.0, 9.2 Hz, 1H), 7.77-7.59 (m, 1H), 6.87 (s, 1H), 4.82 (quin, J= 8.4 Hz, 1H), 3.52 (d, 7= 10.8 Hz, 2H), 3.47-3.35 (m, 2H), 3.22-3.09 (m, 2H), 3.06 (s, 6H), 3.00-2.84 (m, 2H), 2.69-2.66 (m, 1H), 2.54 (s, 1H), 2.41-2.23 (m, 6H), 2, 17-1,91 (m, 8H), 1.72-1.59 (m, 2H); MS (ESI) mA: 517,4 [ M H ] .
[00797] Preparation of 7-cyclopentyl-2-((5-(l'-(4-(2,6-dioxopiperidin-3-yl)phenethyl)- [l,4'-bipiperidin]-4-yl)pyridin-2-yl)amino)-A/,Ar-dimethyl-7/7-pyrrolo[2,3-(7]pyrimidiiie-6- carboxamide A238 A mixture of 3-(4-(2-bromoethyl)phenyl)piperidine-2, 6-dione (181 mg, 610 pmol), K2.CO3 (28.1 mg, 203 pmol), KI (67.5 mg, 406 pmol), and DIEA (131 mg, 1 mmol) in DMF (3 mL) was stirred for 0.5 h, followed by addition of compound 76.4 as an HC1 salt (150 mg, 190 pmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with ACN (1 mL), acidified to pH 5~6 with TFA, concentrated, and purified by reverse phase prep-HPLC and prep-TLC (Si O2, EtOAc/PE) and triturated with ACN to afford compound A238 (45 mg) in 29% yield. ’H NMR (400 MHz, DMSO-t/6) <5 10.81 (s, 1H), 9.44 (s, 1H), 8.78 (s, 1H), 8.24 (d, 7= 8.4 Hz, 1H), 8.16 (d, 7= 2.0 Hz, 1H), 7 66 (dd, 7= 2.0, 8.8 Hz, 1H), 7.22-7.04 (m, 4H), 6.61 (s, HI), 4.85-4.58 (m, 1H), 3.80 (dd, 7= 4.8, 11.2 Hz, 1H), 3.28-3.26 (m, 2H), 3.05 (s, 6H), 3.01-2.93 (m, 4H), 2.74-2.63 (m, 4H), 2.45 (s, 2H), 2.27-2.13 (m, 4H), 2.09-1.84 (m, 8H), 1.75 (t, ./ 9.6 Hz, 4H), 1.70-1.59 (m, 4H), 1.51-1.39 (m, 2H); MS (ESI) mA: 732.5 [M+H]+.
Example 77
Preparation of 7-cyclopentyl-2-((5-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin] l '-yl)ethyl)pyridin-2-yl)amino)-A,A7-dimethyl-7Z/-pyrrolo[2,3-7]pyrimidine-6-carboxamide A242
Figure imgf000332_0001
[00798] Compound A242 was prepared as described below.
[00799] Preparation of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'- bipiperidine]- 1 '-carboxylate 77.1. To a mixture of 3-(3-(piperidin-4-yl)phenyl)piperidine-2,6- dione as an HC1 salt (3 g, 9.71 mmol), tert-butyl 4-oxopiperidine-l -carboxylate (3.87 g, 19.4 mmol), AcOH (1.75 g, 29.1 mmol), and NaOAc (2.39 g, 29. 1 mmol) in DMSO (30 mL) was added NaBH(OAc)j (8.24 g, 38.9 mmol). After stirring at 60 °C for 12 h, the reaction mixture was diluted with water. The resulting precipitates were collected by filtration to afford a crude product. NH4Q was added to the filtrate, which was extracted with ACN. The combined organic layers were concentrated to yield an additional crude product. The combined crude product was triturated with water to afford compound 77.1 (3.52 g) in 79% yield. rH NMR (400 MHz, DMSO-tfe) ri 10.84 (s, 1H), 7.20 (s, 4H), 4.20-3.97 (m, 2H), 3.91-3.73 (m, 1H), 3.53 (d, J = 10.8 Hz, 2H), 3.15-3.00 (m, 2H), 2.90-2.60 (m, 4H), 2.49-2.40 (m, 2H), 2.25-1.92 (m, 8H), 1.68-1.48 (ra, 2H), 1.41 (s, 9H); MS (ESI) m/z: 465.5 [M+H]L
[00800] Preparation of 3-(3-([l,4'-bipiperidin]-4-yl)phenyl)piperidine-2, 6-dione 77.2. A solution of compound 77.1 (3.5 g, 7.68 mmol) in DCM (20 mL) and 4M HC1 in dioxane (15 mL) was stirred at 20 °C for 1 h. The mixture was concentrated to afford compound 77.2 as an HC1 salt (3 g), which was used directly in the next step without further purification. rH NMR (400 MHz, DMSO-tZs) d 10.99 (d, J= 2.4 Hz, 1H), 9.13-8.81 (m, 2H), 7.20 (s, 4H), 3.89-3.79 (m, 1H), 3.54-3.40 (m, 5H), 3.17-3.02 (m, 2H), 3.01-2.79 (m, 3H), 2.73-2.62 (m, 1H), 2.47-2.43 (m, 1H), 2.31 (d, J= 12.4 Hz, 2H), 2.24-2.09 (m, 3H), 2.07-1.87 (m, 5H); MS (ESI) m/z: 365.3 [M+H] \
[00801] Preparation of 7-cyclopentyl-2-((5-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)- [l,4'-bipiperidin]-r-yl)ethyl)pyridin-2-yl)amino)-Ar,A/r-dimethyl-77f-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A242. A mixture of compound 77.2 as an HC1 salt (100 mg, 255 pmol), DIEA (165 mg, 1.28 mmol), K2CO3 (35 mg, 255 pmol), and KI (85 mg, 510 umol) in DMF (3 mL) was stirred for 0.5 h, followed by addition of 2-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7Jf- pyrrolo[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl 4-methylbenzenesulfonate (210 rag, 383 pmol). After stirring at 80 °C for 1.5 h, the reaction mixture was diluted with ACN, acidified to pH 5-6 with TFA at 0 °C, concentrated, and purified by reverse phase prep-I IPLC to afford compound A242 as a TFA salt (69 mg) in 33% yield. *H NMR (400 MHz, DMSO-r/e) 3 10.82 (s, 1H), 9.49 (s, III), 8.80 (s, HI), 8.24 (d, ./ 8.4 Hz, 1H), 8.20 (s, 2H), 8. 15 (d, ./ 2.0 Hz, 1H), 7.65 (dd, J= 2.0, 8.8 Hz, 1H), 7.24-7.17 (m, 2H), 7.17-7.09 (ra, 2H), 6.62 (s, 1H), 4.74 (td, J = 8.8, 17.6 Hz, 1H), 3.80 (s, 1H), 3.47-3.32 (m, 2H), 3.12-3.08 (m, 2H), 3.05 (s, 6H), 2.76-2.68 (m, 2H), 2.68-2.59 (m, 2H), 2.57 (d, J= 7.6 Hz, 2H), 2.54 (s, 2H), 2.46-2.36 (m, 4H), 2.23-2.11 (m, 1H), 2.10-1.90 (m, 7H), 1.80 (d, J- 6.4 Hz, 4H), 1.74-1.61 (m, 4H), 1.60-1.43 (m, 2H); MS (ESI) m/z'. 732.3 [M+H]+.
Example 78
Preparation of 7-cyclopentyl-ACV-dimethyl-2-((5-(4-(l-(4-(3-methyl-2,6-dioxopiperidin-3-yl)- phenethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A245
Figure imgf000333_0001
[00802] Compound A245 was prepared as described below.
[00803] Preparation of 3-(4-bromophenyl)-3-methylpiperidine-2, 6-dione 78.1. To a solution of methyl 2-(4-bromophenyl)propanoate (4.5 g, 18.5 mmol) and prop-2-enamide (1.97 g, 27.8 mmol) in THF (50 mL) was added t-BuOK (2.08 g, 18.5 mmol) at 0 °C. After stirring at 20 °C for 12 h, the reaction mixture was diluted with water, treated with an aqueous NH4CI solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 78.1 (3 g) in 53% yield. MS (ESI) m/z: 282, 1 [M+H]+. [00804] Preparation of 3-[4-[(£)-2-ethoxyvinyl]phenyl]-3-methyl-piperidine-2, 6-dione 78.2. A mixture of compound 78.1 (200 mg, 709 umol), 2-[(E)-2-ethoxyvinyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (168 mg, 851 pmol), CsF (215 mg, 1.42 mmol), and Pd(dppf)C12 CH?.C12 (58 mg, 70.9 pmol) in water (2 mL) and DMF (8 mL) was stirred at 80 °C for 2 h under N2. The reaction mixture was then treated with an aqueous NILCl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCL, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 78.2 (146 mg) in 72% yield. MS (ESI) m/z\ 274.3 [M+H] 4
[00805] Preparation of 2-[4-(3-methyl-2,6-dioxo-3-piperidyl)phenyl]acetaldehyde 78.3. A solution of compound 78.2 (146 mg, 534 pmol) in HCO2H (4 mL) was stirred for 14 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated to afford compound 78.3 (155 mg), which was used directly in the next step without further purification. MS (ESI) m/z\ 246.1 [M+H]’.
[00806] Preparation of 7-cyclopentyl-A’,A-dimethyl-2-((5-(4-(l-(4-(3-methyl-2,6-dioxo- piperi din-3 -yl)-phenethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7//-pyrrolo[2, 3-d]- pyrimidine-6-carboxamide A245. A mixture of compound 78.3 (155 mg, 632 umol), 7-cyclo- pentyl-/V,A-dimethyl-2-[[5-[4-(4-piperidyl)piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-d]- pyrimidine-6-carboxamide (327 mg, 632 pmol), NaBHsCN (119 mg, 1.90 mmol), NaOAc (156 mg, 1 .9 mmol), and AcOH (38 mg, 632 pmol) in THF (2 mL) and DMSO (2 mL) was stirred at 80 °C for 12 h under Nr. The reaction mixture was purified by reverse phase prep-HPLC to afford compound A245 (8.6 mg) in 1.6% yield.
Figure imgf000334_0001
(400 MHz, CD3OD) d 8.75 (s, 1H), 8.37 (s, 2H), 8.18 (d, J= 9.2 Hz, 1H), 7.98 (d, J= 2.4 Hz, 1H), 7.57-7.59 (m, 1H), 7.34 (s, 4H), 6.65 (s, 1H), 4.79 (s, 1H), 3.60 (d, J- 11.8 Hz, 2H), 3.23-3.29 (m, 6H), 3.18 (s, 6H), 3.06 (d, 7 8.4 Hz, 2H), 2.93-3.00 (m, 2H), 2.88 (s, 3H), 2.66-2.73 (m, 1H), 2.44-2.57 (m, 4H), 2.17-2.22 (m, 3H), 2.04-2.13 (m, 4H), 1.87 (d, J= 9.6 Hz, 2H), 1.70-1.78 (m, 2H), 1.54 (s, 3H); MS (ESI) m/z: 747.4 [M+H]+.
Example 79
Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperi din-1 -yl)pyridin-2-yl)amino)-Az,/V-dimethyl-7//-pyrrolo[2,3-djpyrimidine-6- carboxamide A246
Figure imgf000335_0001
[00807] Compound A246 was prepared as described below.
[00808] Preparation of l,2-di(piperidin-4-yl)ethane 79.1. To a solution of 1 ,2-di(pyridin- 4-yl)ethane (4 g, 21 mmol) in AcOH (40 mL) was added PtOz (1 g, 4.40 mmol) under Nr. After stirring at 40 °C for 12 h under H2, the reaction mixture was filtered and concentrated to afford compound 79.1 (7.75 g), which was used directly in the next step without further purification. MS (ESI) m/z: 197 [M+H]+
[00809] Preparation of tert-butyl 4-(2-(piperidin-4-yl)ethyl)piperidine-l -carboxylate 79.2. To a solution of compound 79.1 (4 g, 13.9 mmol) in EtOH (24 mL) was added 2M NaOH (24 mL), followed by addition of (Boc)rO (2.27 g, 10.4 mmol) in EtOH (12 mL) at 0 °C. After stirring at 25 °C for 4 h, the reaction mixture was concentrated and extracted with EtOAc. The combined organic layers were washed with brine water, dried over anhydrous NazSO4, concentrated, and purified by column chromatography (SiOz, MeOH/DCM) to afford compound 79.2 (984 mg) in 24% yield. MS (ESI) m/z: 297.4 [M+H]+.
[00810] Preparation of tert-butyl 4-(2-(l-(4-(l-(4-methoxybenzyl)-2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)ethyl)piperidine-l-carboxylate 79.3. To a solution of compound 79.2 (984 mg, 3.32 mmol) and 3 -(4-bromophenyl)-l-(4-methoxybenzyl)piperidine-2, 6-dione (1.29 g, 3.32 mmol) in dioxane (10 mL) were added CS2CO3 (3.24 g, 9.96 mmol), RuPhos (155 mg, 332 umol), and RuPhos Pd Gs (278 mg, 332 pmol). After stirring at 90 °C under N2 for 2 h, the reaction mixture was poured into aqueous NH4CI and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 79.3 (987 mg) in 49% yield. MS (ESI) m/z: 604.4 [M+H] \
[00811] Preparation of l-(4-methoxybenzyl)-3-(4-(4-(2-(piperidin-4-yl)ethyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione 79.4. A mixture of compound 79.3 (987 mg, 1.63 mmol) in DCM (5 mL) and 4M HC1 in dioxane (5 mL) was stirred for 1 h. The reaction mixture was then concentrated to afford compound 79.4 as an HC1 (780 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 504.3 [M+H]+.
[00812] Preparation of l-(4-methoxybenzyl)-3-(4-(4-(2-(l-(6-nitropyri din-3 -yl)piperidin-
4-yl)ethyl)piperidin- 1 -yl)phenyl)piperidine-2, 6-dione 79.5, To a solution of compound 79.4 as an HC1 salt (530 mg, 981 pmol) and 5-fluoro-2-nitropyridine (153 mg, 1.08 mmol) in DMSO (5 mL) was added K2CO3 (542 mg, 3.92 mmol). After stirring at 90 °C for 2 h, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (S1O2, EtOAc/PE) to afford compound 79.5 (443 mg) in 72% yield. MS (ESI) m/z: 626,3 [M+H]+.
[00813] Preparation of 3-(4-(4-(2-(l-(6-aminopyridin-3-yl)piperidin-4-yl)ethyl)piperidin- l-yl)phenyl)-l-(4-methoxybenzyl)piperidine-2, 6-dione 79.6. To a solution of compound 79.5 (400 mg, 639 pmol) in EtOH (10 mL) and H2O (2 mL) were added Fe (286 mg, 5.11 mmol) and NH4Q (137 mg, 2.56 mmol). After stirring at 70 °C for 0.5 h under N2, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiOr, MeOHZDCM) to afford compound 79.6 (257 mg) in 68% yield. MS (ESI) m/z: 596.3 [M+H]+.
[00814] Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(4-(l-(4-methoxybenzyl)-2,6-dioxo- piperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-l-yl)pyridin-2-yl)amino)-A7V-dimethyl-7Z/- pyrrolo[2,3-c(]pyrimidine-6-carboxamide 79.7, To a solution of compound 79.6 (200 mg, 336 pmol) and 2-chloro-7-cyclopentyl-A,AMimethyl-7H-pyrrolo[2,3-J]pyrimidine-6-carboxamide (108 mg, 369 pmol) in dioxane (4 mL) were added BINAP (41.8 mg, 67.1 pmol), Pd(OAc)2 (7.54 mg, 33.6 pmol), and CS2CO3 (219 mg, 671 pmol). After stirring at 90 °C for 2 h under N2, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSOr, concentrated, and purified by column chromatography (SiO2, MeOH/DCM) to afford compound 79.7 (350 mg) in 61% yield. MS (ESI) m/z: 852.3 [M+H] \
[00815] Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl) piperidin-4-yl)-ethyl)piperidin-l-yl)pyridin-2-yl)annno)-A(AMimethyl-7H-pyrrolo[2,3-d]- pyrimidine-6-carboxamide A246. A solution of compound 79.7 (300 mg, 176 pmol) in DCM (2 mL) were added TfOH (848 mg, 5.65 mmol) and TFA (1.54 g, 13.5 mmol). After stirring at 40 °C for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A246 (15 mg) in 10% yield. rH NMR (400 MHz, DMSO-A) <-) 10.76 (s, 1H), 9.98-9.50 (m, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 8.03-7.90 (m, 2H), 7.64-7.50 (m, 1H), 7.03 (br d, J - 8.0 Hz, 2H), 6.88 (br d, ./ 8.0 Hz, 2H), 6.64 (s, 1H), 4.82-4.67 (m, 1H), 3.71 (br dd, ./ 4.4, 11 .2 Hz, 1H), 3.64 (br t, ./= 10.4 Hz, 4H), 3.05 (br s, 6H), 2.68-2.59 (m, 5H), 2.44-2.34 (m, 2H), 2.18-2.07 (m, 1H), 2.03-1.93 (m, 5H), 1.77 (br t, J= 11.2 Hz, 4H), 1.65 (br s, 2H), 1.37-1.18 (m, 11H); MS (ESI) m/z: 732.4 [M+H]+.
Example 80
Preparation of 7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperidin-l-yl)pyridin-2-yl)amino)-A(/V-dimethyl-7.H-pyrrolo[2,3-J]pyrimidine-6- carboxamide A247
Figure imgf000337_0001
[00816] Compound A247 was prepared as described below.
[00817] Preparation of 7-cyclopentyl-2-[[5-[4-(2,2-dimethoxyethyl)-l-piperidyl]-2- pyridyl]amino]-ACV-dimethyl-pyiTolo[2,3-d]pyrimidine-6-carboxamide 80.1. To a solution of 5- [4-(2,2-dimethoxyethyl)-l-piperidyl]pyridin-2-amine (2.8 g, 10.6 mmol) and 2-chloro-7- cyclopentyl-A'yV-dimethylpyrrolo[2,3-tf|pyrimidine-6-carboxamide (3.09 g, 10.6 mmol) in dioxane (20 mL) were added Pd(OAc)2 (118 mg, 528 pmol), BINAP (657 mg, 1.06 mmol), and CS2CO3 (6.88 g, 21.1 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtO Ac. The combined organic layers were washed with brine, dried over anhydrous NazSCk, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 80.1 (2 g) in 36% yield. lH NMR (400 MHz, DMSO-c/e) d 9.12- 9.05 (m, 1H), 9.16-9.03 (m, 1H), 8.64 (s, 1H), 8.39 (d, J = 9.2 Hz, 1H), 7.77-7.65 (m, 1H), 6.94- 6.86 (m, IH), 5.74 (s, IH), 4.78 (s, 2H), 4.48 (t, J= 5.6 Hz, IH), 3.58 (d, J= 11.2 Hz, 2H), 3.31-
3.22 (m, 6H), 3.15 (s, IH), 3.05 (s, 6H), 2.29 (dd, J= 8.0, 11.6 Hz, 2H), 2.08-1.94 (m, 4H), 1.89 (d, .7= 9.6 Hz, 2H), 1.69 (d, J= 11.6 Hz, 2H), 1.66-1.60 (m, 2H), 1.57-1.49 (m, 2H); MS (ESI) m/z: 522.6 [M+H]+.
[00818] Preparation of 7-cyclopentyl-A,A-diniethyl-2-[[5-[4-(2 -oxoethyl)- 1 -piperi dy 1] -2- pyridyl]amino]pyrrolo [2,3-tZ]pyrimidine-6-carboxamide 80.2, To a solution of compound 80.1 (600 mg, 1.15 mmol) in DCM (6 mL) was added TFA (4.61 g, 40.4 mmol). After stirring for 1 h, the reaction mixture was concentrated to afford compound 80.2 as a TFA salt (1 g), which was used directly in the next step without further purification. MS (ESI) m/z: 476.4 [M+H]+.
[00819] Preparation of 7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-ethyl)piperidin-l-yl)pyridin-2-yl)amino)-AjV-dimethyl-777-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A247. To a solution of 3-(4-piperazin-l-ylphenyl)piperidine-2,6- dione as an HC1 salt (100 mg, 323 pmol) in MeOH (2 mL) was added NaOAc (79.4 mg, 968 umol), followed by addition compound 80.2 (190 mg, 323 pmol) and NaBI HCN (60.9 mg, 968 pmol). After stirring for 12 h, the reaction mixture was diluted with DMF (1 mL) and purified by reverse phase prep-HPLC to afford compound A247 (77 mg) in 31% yield. *H NMR (400 MHz, DMSO-d6 ) A 10.77 (s, 1H), 9.23 (s, IH), 8.75 (s, 1H), 8.15 (s, IH), 8.12 (d, J = 9.2 Hz, 1H), 7.99 (d, J= 2.8 Hz, IH), 7.42 (dd, J= 2.8, 9.2 Hz, IH), 7.06 (d, J= 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.59 (s, 1H), 4.73 (q, .7= 8.8 Hz, IH), 3.73 (dd, .7= 4.8, 11.2 Hz, IH), 3.61 (d, .7= 12.0 Hz, 2H), 3.15 (s, 4H), 3.05 (s, 6H), 2.71-2.56 (m, 7H), 2.47-2.32 (m, 5H), 2.19-2.07 (m, IH), 2.05-1.92 (m, 5H), 1.79 (d, J= 12.0 Hz, 2H), 1.64 (d, J= 4.8 Hz, 2H), 1.48 (s, 3H), 1.31 (d, J= 10.0 Hz, 2H); MS (ESI) m/z: 733.7 [M+H]+.
Example 81
Preparation of 7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- propoxy)pyridin-2-yl)amino)-A,A'’-dimethyl-777-pyrrolo[2,3-J]pyrimidine-6-carboxamide A249
Figure imgf000338_0001
[00820] Compound A249 was prepared as described below.
[00821 ] Preparation of 7-cyclopentyl-2-[[5-(3-hydroxypropoxy)-2-pyridyl]amino]-A,A’- dimethylpyrrolo[2,3-<7]pyrimidine-6-carboxamide 81.1. A mixture of 7-cyclopentyl-2-[(5- hydroxy-2-pyridyl)amino]-A',A7-dimethylpyiTolo[2,3-<7]pyrimidine-6-carboxamide (1 g, 2.73 mmol), 3 -bromopropan- l-ol (910 mg, 6.55 mmol), KI (45.3 mg, 273 pmol), and K2CO3 (754 mg, 5,46 mmol) in DMF (10 mL) was stirred at 80 °C for 12 h under N2. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and triturated with water to afford compound 81.1 (1 g) in 78% yield. MS (ESI) m/z'. 425.2 [M+H]T
[00822] Preparation of 3-[[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-cf]- pyrimidin-2-yl]amino]-3-pyridyl]oxy]propyl 4-methylbenzenesulfonate 81.2. A mixture of compound 81.1 (1 g, 2.36 mmol), TsCl (898 mg, 4.71 mmol), and TEA (715 mg, 7.07 mmol) in DCM (10 mL) was stirred for 12 h under N2. The reaction mixture was then concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 81.2 (600 mg) in 31% yield. MS (ESI) m/z: 579.3 [M+H]+.
[00823] Preparation of 7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperazin-l-yl)-propoxy)pyridin-2-yl)amino)-A(A-dimethyl-7J/-pyrrolo[2,3-</|pyriniidine-6- carboxamide A249. A mixture of compound 81.2 (600 mg, 1.04 mmol), 3-(4-piperazin-l-yl- phenyl)piperidine-2, 6-dione (283 mg, 1.04 mmol), DIEA (1.34 g, 10.4 mmol), and KI (172 mg, 1.04 mmol) in DMF (8 mL) was stirred at 80 °C for 12 h under N2. The mixture was then filtered and purified by reverse phase prep-HPLC to afford compound A249 (19 mg) in 2.6% yield. NMR (400 MHz, DMSO-tA) <5 10.80-10.71 (m, 1H), 9.36 (s, 1H), 8.76 (s, 1 H), 8.22 (s, 1H), 8.18 (d, J= 9.2 Hz, 1H), 8.01 (d, J= 2.8 Hz, 1H), 7.44 (dd, J= 3.2, 9.2 Hz, 1H), 7.04 (d, J == 8.8 Hz, 2H), 6.88 (d, ./ 8.8 Hz, 2H), 6.59 (s, 1H), 4.76-4.68 (m, 1H), 4.09 (t, ./ 6.4 Hz, 2H), 3.72 (dd, J= 5.2, 11.2 Hz, 1H), 3.53-3.45 (m, 1H), 3.14-3.09 (m, 5H), 3.05 (s, 6H), 2.68-2.62 (m, 3H), 2.45-2.36 (m, 3H), 2.36-2.29 (m, 1H), 2.15-2.07 (m, 1H), 2.02-1.89 (m, 8H), 1.67-1.59 (m, 2H); MS (ESI) m/z: 680.3 [M+H] \
Example 82
Preparation of 7-cyclopentyl-2-((5-(3-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- propoxy)pyridin-2-yl)amino)-A'A-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide A250
Figure imgf000340_0001
[00824] Compound A250 was prepared as described below.
[00825] Preparation of tert-butyl 4-(3-hydroxypropyl)piperidine-l -carboxylate 82.1, To a solution of 3-(4-piperidyl)propan-l-ol (3 g, 21 mmol) in DCM (20 mL) were added BoczO (5.49 g, 25,1 mmol), DMAP (256 mg, 2,09 mmol), and TEA (6,36 g, 62.8 mmol). After stirring for 1 h, the reaction mixture was concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 82.1 (2.1 g) in 40% yield.
[00826] Preparation of tert-butyl 4-[3-(/j-tolylsulfonyloxy)propyl]piperidine-l-carboxylate 82.2, To a solution of compound 82.1 (2.1 g, 8.63 mmol) in DCM (20 mL) were added DMAP (105 mg, 863 pmol), TEA (2.62 g, 25.9 mmol), and TsCl (3.29 g, 17.3 mmol). After completion, the reaction mixture was concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 82.2 (2.9 g) in 85% yield.
Figure imgf000340_0002
NMR (400 MHz, CDCh) <5 7.78 (d, ./= 8.4 Hz, 2H), 7.45 (d, 8.0 Hz, 2H), 4.07-3.94 (m, 4H), 2.67 (s, 2H), 2.46 (s, 3H),
1.68-1.56 (m, 4H), 1.44 (s, 9H), 1.30 (dt, J= 3.6, 7.2 Hz, 1H), 1.25-1.18 (m, 2H), 0.97 (q, J = 12.4 Hz, 2H).
[00827] Preparation of tert-butyl 4-[3-[[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-ii]pyrimidin-2-yl]amino]-3-pyridyl]oxy]propyl]piperidine-l-carboxylate 82.3. To a solution of 7-cyclopentyl-2-[(5-hydroxy-2-pyridyl)amino]-A,Ar-dimethylpyrrolo[2,3-djpyrimidine-6- carboxamide (922 mg, 2.52 mmol) and compound 82.2 (1 g, 2.52 mmol) in DMF (10 mL) were added K2CO3 (1.04 g, 7.55 mmol) and KI (41.8 mg, 252 pmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (Si O2, EtOAc/PE) to afford compound 82.3 (1.4 g) in 75% yield. MS (ESI) m/z: 592.5 [M+H]+.
[00828] Preparation of 7-cyclopentyl-A,A-dimethyl-2-[[5-[3-(4-piperidyl)propoxy]-2- pyridyl]amino]pyrrolo[2,3-zZ]pyrimidine-6-carboxamide 82.4. To a solution of compound 82.3 (1.4 g, 2.37 mmol) in DCM (5 mL) was added 4M HCI in dioxane (3.5 mL). After stirring for 0.25 h, the reaction mixture was concentrated to afford compound 82.4 as an HCI salt (1.2 g), which was used directly in the next step without further purification. MS (ESI) m/z: 492.3 [M+H]+.
[00829] Preparation of 7-cyclopentyl-2-[[5-[3-[l-[4-[l-[(4-methoxyphenyl)methyl]-2,6- dioxo-3-piperidyl]phenyl]-4-piperidyl]propoxy]-2-pyridyl]amino]-AyV-dimethylpyrrolo[2,3-<7j- pyrimidine-6-carboxamide 82.5, A mixture of compound 82.4 as an HCI salt (300 mg, 610 umol), 3-(4-bromophenyl)-l-[(4-methoxyphenyl)methyl]piperidine-2, 6-dione (284 mg, 732 umol), Pd-PEPPSI-IPent (26.3 mg, 30.5 nmol), and CS2CO3 (398 mg, 1.22 mmol) in dioxane (3 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then purified by prep- TLC (SiOz, MeOH/DCM) to afford compound 82.5 (200 mg) in 35% yield. MS (ESI) m/z: 799.5 [M+H]+.
[00830] Preparation of 7-cyclopentyl-2-((5-(3-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-propoxy)pyridin-2-yl)amino)-A',7V-dimethyl-7/7-pyrrolo[2,3-J]pyrimidine-6- carboxamide A250. To a solution of compound 82.5 (150 mg, 188 pmol) in DCM (1 mL) were added TfOH (3.39 g, 22.6 mmol) and TFA (1.54 g, 13.5 mmol). After stirring at 40 °C for 2 h, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A250 (29.6 mg). rH NMR (400 MHz, CDCh) 5 10.76 (s, 1H), 9.38 (s, 1H), 8.76 (s, 1H), 8.18 (d, .7= 9.2 Hz, 1H), 8.01 (s, 1H), 7.43 (d, .7= 9.2 Hz, 1H), 7.03 (d, .7= 8.8 Hz, 2H), 6.88 (d, J= 8.8 Hz, 2H), 6.60 (s, 1H), 4.73 (q, 7 = 8.8 Hz, 1H), 4.03 (t, 7 = 6.4 Hz, 2H), 3.78-3.60 (m, 3H), 3.05 (m, 6H), 2.68-2.58 (m, 3H), 2.45-2.39 (m, 2H), 2.18-2.06 (m, 1H), 2.05- 1.93 (m, 5H), 1.78 (d, .7= 9.6 Hz, 4H), 1.69-1.58 (m, 2H), 1.48-1.37 (m, 3H), 1.31-1.17 (m, 4H); MS (ESI) m/z: 679.5 [M+H] \
Example 83
Preparation of 7-cyclopentyl-2-((5-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethoxy)pyridin-2-yl)amino)-ApV-dimethyl-7//-pyrrolo[2,3-</]pyrimidine-6-carboxamide A252
Figure imgf000342_0001
[00831] Compound A252 was prepared as described below.
[00832] Preparation of 2-[l -[4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]ethyl 4-methyl- benzenesulfonate 83.1. To a solution of 3-[4-[4-(2-hydroxyethyl)-l-piperidyl]phenyl]piperidine- 2, 6-dione (500 mg, 1.58 mmol) in DCM (10 mL) were added TsCl (603 mg, 3.16 mmol), DMAP (19.3 mg, 158 pmol), and TEA (480 mg, 4.74 mmol). After stirring at 30 °C for 12 h, the reaction mixture was concentrated and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 83.1 (180 mg) in 24% yield. MS (ESI) m/z'. 471.3 [M+H]+.
[00833] Preparation of 7-cyclopentyl-2-((5-(2-(l -(4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)-ethoxy)pyridin-2-yl)amino)-A,A-dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A252. To a solution of compound 83.1 (180 mg, 383 pmol) in DMF (2 mL) were added KI (6.35 mg, 38.3 pmol), 7-cyclopentyl-2-[(5-hydroxy-2-pyridyl)amino]-A(A-dimethyl- pyrrolo[2,3-</]pyrimidine-6-carboxamide (140 mg, 383 pmol), and K2CO3 (106 mg, 765 pmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by reverse phase prep-HPLC to afford compound A252 (2.1 mg) in 0.8% yield. ^ NMR (400 MHz, DMSO-tZ?) ri 10.76 (s, 1H), 9.36 (s, 1H), 8.76 (s, 1H), 8.54- 8.41 (m, 1H), 8.18 (d, J= 8.8 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.52-7.37 (m, 1H), 7.10-6.96 (m, 2H), 6.89 (d, J= 8.4 Hz, 2H), 6.64-6.54 (m, 1H), 4.84-4.65 (m, 1H), 4.17-4.04 (m, 2H), 3.71- 3.64 (m, 2H), 3.09-3.00 (m, 6H), 2.72-2.58 (m, 4H), 2.40 (dd, 1 .6, 3.6 Hz, 2H), 2.07-1.91 (m, 6H), 1.89-1.77 (m, 2H), 1.75-1.64 (m, 4H), 1.38-1.31 (m, 2H), 1.28-1.19 (m, 2H); MS (ESI) w/z: 665.5 [M+H]+.
Example 84
Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro-[l,4’- bipiperidin]-r-yl)pyridin-2-yl)amino)-A,A-dimethyl-7//-pyrrolo[2,3-(7]pyrimidine-6- carboxamide A253
Figure imgf000343_0001
[00834] Compound A253 was prepared as described below.
[00835] Preparation of /er/-butyl 4-[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]ethynyl]-4- fluoro-piperidine-1 -carboxylate 84.1. To a solution of tert-butyl 4-ethynyl-4-fluoropiperidine-l- carboxylate (1.4 g, 6.16 mmol) and 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (2.5 g, 5.6 mmol) in THF (10 mL) and ACN (10 mL) were added XPhos Pd G3 (474 mg, 560 pmol) and Cs CO (5.47 g, 16.8 mmol). After stirring at 60 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na^SOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 84.1 (1.36 g) in 41% yield.
[00836] Preparation of tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidyl)phenyl]ethyl]-4-fluoro- piperidine-l-carboxylate 84.2. To a solution of compound 84.1 (1.36 g, 2.29 mmol) in THF (5 mL) were added 10% Pd/C (0.2 g) under N?.. After stirring under H2 at 40 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound 84.2 (360 mg) in 35% yield.
[00837] Preparation of 3-[4-[2-(4-fluoro-4-piperidyl)ethyl]phenyl]piperidine-2, 6-dione
84.3. To a solution of compound 84.2 (360 mg, 860 pmol) in DCM (4 mL) was added 4M HC1 in dioxane (2 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 84.3 (240 mg), which was used directly in the next step without further purification. MS (ESI) mA: 319.3 [M+H] \
[00838] Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-4- fluoro-[l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-A(A-dimethyl-7//-pyrrolo[2,3-d]pyrimidine-6- carboxamide A253. A mixture of compound 84.3 (100 mg, 314 pmol), 7-cyclopentyl-A(A- dimethyl-2-[[5-(4-oxo-l -piperidyl)-2-pyridyl]amino]pyrrolo[2,3-t/]pyrimidine-6-carboxamide (162 mg, 314 pmol), NaOAc (77.3 mg, 942 pmol), and NaBH(OAc)s (200 mg, 943 pmol) in THF (1.5 mL) and DM SO (1.5 mL) was stirred at 60 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by reverse phase prep-HPLC to afford compound A253 (26 mg) in 13% yield. lHNMR (400 MHz, CDCh) <5 8.70 (s, 1H), 8.50 (s, 1H), 8.36 (d, J 9.2 Hz, 1H), 8.28 (s, 1H), 8.02 (d, J - 2.8 Hz, 1 H), 7.96 (s, 1H), 7.34 (dd, J= 2.8, 9.2 Hz, 1H), 7.24-7.19 (m, 2H), 7.18-7.11 (m, 2H), 6.44 (s, 1H), 4.80 (q, J = 8.8 Hz, 1H), 3.77 (dd, J= 5.6, 9.2 Hz, 1H), 3.68 (d, J= 12.4 Hz, 2H), 3.17 (s, 6H), 3. 10-2.98 (m, 2H), 2.82-2.72 (m, 7H), 2.71-2.54 (m, 4H), 2.30-2.24 (m, 2H), 2.13-2.03 (m, 8H), 2.01-1 .97 (m, 2H), 1.96-1.81 (m, 4H), 1.76-1.66 (m, 2H); MS (ESI) m/z: 750.5 [M+H]+
Example 85
Preparation of 7-cyclopentyl-2-((5-(4-(2-( 1 -(4-(2,6-di ox opiperi din-3 -yl)phenyl)azeti din-3 -yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A(A'r-dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A258
Figure imgf000344_0001
[00839] Compound A258 was prepared as described below.
[00840] Preparation of 3 -(4-(3 -(2-((ter Abutyldimethyl silyl)oxy)ethyl)azetidin- 1 -yl)- phenyl)piperidine-2, 6-dione 85.1. To a solution of 2,6-bis(benzyloxy)-3-(4-(3-(2-((terAbutyl- dimethylsilyl)oxy)ethyl)azetidin-l-yl)phenyl)pyridine (2 g, 3.44 mmol) in THF (10 mL) and EtOH (10 mL) were added 10% Pd/C (300 mg) and 20% Pd(OH)2 (300 mg). After stirring at 40 °C for 12 h under Eb, the reaction mixture was filtered, concentrated, and purified by column chromatography (Si O2, EtOAc/PE) to afford compound 85.1 (800 mg) in 58% yield.
Figure imgf000344_0002
NMR (400 MHz, DMSO-tfc) 3 10.73 (s, 1H), 6.99 (d, J= 8.4 Hz, 2H), 6.35 (d, J= 8.4 Hz, 2H), 3.90 (t, .7 7.6 Hz, 2H), 3,68 (dd, .7 5.2, 10.8 Hz, 1H), 3.61 (t, J = 6.0 Hz, 2H), 3,43 (t, 6.4 Hz, 2H),
2.82-2.72 (m, 1H), 2.63-2.57 (m, 1H), 2.44-2.39 (m, 1H), 2.15-2.05 (m, 1H), 2.04-1.95 (m, 1H), 1.78 (q, J= 6.4 Hz, 2H), 0.87 (s, 9H), 0.04 (s, 6H); MS (ESI) m/z: 403.3 | \1 H i .
[00841 ] Preparation of 3 -(4-(3-(2-hydroxy ethyl )azeti din- l-yl)phenyl)piperidine-2, 6-dione
85.2. To a solution of compound 85.1 (800 mg, 1.99 mmol) in DMF (8 mL) was added CsF (905 mg, 5.96 mmol). After stirring at 80 °C for 3 h under N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOi, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 85.2 (410 mg) in 72% yield. 'H NMR (400 MHz, DMSO-Tc) <5 10.73 (s, 1H), 6.99 (d, 7 = 8.4 Hz, 2H), 6.35 (d, 7 = 8.4 Hz, 2H), 4.43 (t, 7= 5.2 Hz, 1H), 3.90 (t, 7= 7.6 Hz, 2H), 3.68 (dd, J= 5.2, 10.8 Hz, 1H), 3.44-3.39 (m, 4H), 2.79-2.70 (m, 1H), 2.67-2.57 (m, 1H), 2.46-2.42 (m, 1H), 2.15-2.05 (m, 1H), 2.03-1.95 (m, 1H), 1.74 (q, J= 6.8 Hz, 2H); MS (ESI) m/z: 288.9 [M+H]T
[00842] Preparation of 3 -(4-(3 -(2-bromoethy l)azetidin- 1 -yl)phenyl)piperi dine-2, 6-dione
85.3. To a solution of compound 85.2 (50 mg, 173 pmol) in ACN (1 mL) was added PBn (141 mg, 520 umol) at 0 °C. After stirring at 80 °C for 0.5 h under N2, the reaction mixture was concentrated to afford compound 85.3 (55 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 350.9 [M+H]‘f .
[00843] Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)- azetidin-3-yl)-ethyl)piperazin-l-yl)pyri din-2 -yl)amino)-A(AMimethyl-7/7-pyrrolo[2,3-7]- pyrimidine-6-carboxamide A258. To a solution of compound 85.3 (55 mg, 157 pmol) and 7- cyclopentyl-Ar,A-dimethyl-2-((5-(piperazin- 1 -y 1 )py ri din-2-yl)amino)-777-pyrrol o[2,3 -</]- pyrimidine-6-carboxamide (68 mg, 157 ijmol) in DMF (1 mL) were added DIEA (60.7 mg, 470 praol) and KI (5.2 mg, 31.3 pmol). After stirring at 80 °C for 12 h under N2, the reaction mixture was filtered and purified by reverse phase prep-HPLC to afford compound A258 (25 mg) in 23% yield. lH NMR (400 MHz, DMSO-Je) δ 10.74 (s, 1H), 9.29 (br s, 1H), 8.76 (s, 1H), 8.17-8.13 (m, 1H), 8.00 (d, 7= 2.8 Hz, 1H), 7.44 (dd, .7= 2.8, 9.2 Hz, 1H), 6.99 (d, 7= 8.4 Hz, 2H), 6.59 (s, 1H), 6.48 (br d, J= 8.4 Hz, 2H), 4.73 (quin, 7= 8.8 Hz, 1H), 3.68 (dd, J= 5.2, 10.4 Hz, 1H), 3.35 (br d, 7= 7.6 Hz, 2H), 3.29-3.26 (m, 1H), 3.22 (br t, .7= 8.0 Hz, 1H), 3.14 (br s, 4H), 3.05 (br s, 5H), 3.01-2.96 (m, 1H), 2.68-2.52 (m, 6H), 2.48-2.38 (m, 5H), 2.15-2.06 (m, 2H), 2.04-1.92 (m, 5H), 1.77-1.68 (m, 1H), 1.64 (br d, 7 = 5.2 Hz, 2H); MS (ESI) m/z: 705.7 [M+H]+.
Example 86
Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A'',A'r-dimethyl-7/T-pyrrolo[2,3-tf]pyrimidine-6- carboxamide A259
Figure imgf000346_0001
[00844] Compound A259 was prepared as described below.
[00845] Preparation of 2-(azetidin-3-yl)ethoxy-terrtbutyldimethylsilane 86.1, To a solution of 2-(azeti din-3 -yl)ethanol HC1 (2 g, 14.5 mmol) in DCM (16 mL) were added TEA (4.41 g, 43.6 mmol) and TBSC1 (2.41 g, 15.9 mmol). After stirring at 20 °C for 10 h under N2, the reaction mixture was poured into ice water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSCh, and concentrated to afford compound 86.1 (3 g), which was used directly in the next step without further purification. MS (ESI) m/z: 216.2 [M+H]+.
[00846] Preparation of ter/-butyl-[2-[l-[3-(2,6-dibenzyloxy-3-pyridyl)phenyl]azetidin-3- yl]ethoxy]dimethylsilane 86.2, To a solution of compound 86.1 (3 g, 6.72 mmol) in dioxane (30 mL) were added RuPhos (314 mg, 672 pmol), RuPhos Pd G3 (562 mg, 672 pmol), and CS2CO3 (4.38 g, 13.4 mmol). After stirring at 100 °C for 10 h under N2, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 86.2 (3.1 g) in 79% yield. MS (ESI) m/z: 581.3 [M+H]+.
[00847] Preparation of 3-[3-[3-[2-[ferrtbutyl(dimethyl)silyl]oxyethyl]azetidin-l-yl]- phenyl]piperidine-2, 6-dione 86.3. A mixture of compound 86.2 (3.1 g, 5.34 mmol), 10% Pd/C (800 mg), and 20% Pd(OH)2 (800 mg) in THF (15 mL) and EtOH (15 mL) was stirred at 40 °C for 5 h under H2. The reaction mixture was then concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 86.3 (1.2 g) in 56% yield. MS (ESI) m/z: 403.2 [M+H]+.
[00848] Preparation of 3-[3-[3-(2-hydroxyethyl)azetidin-l-yl]phenyl]piperidine-2, 6-dione
86.4, To a solution of compound 86.3 (1.2 g, 2.98 mmol) in DMF (12 mL) was added CsF (1.36 g, 8,94 mmol). After stirring at 40 °C for 10 h, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCU, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 86.4 (400 mg) in 47% yield.
Figure imgf000347_0001
(400 MHz, DMSO-de) d 10.78 (s, 1H), 7.09 (t, J= 7.6 Hz, 1H), 6.48 (d, J= 7.6 Hz, 1H), 6.29 (br d, J= 8.0 Hz, 1H), 6.23 (s, 1H), 4.44 (t, J= 5.4 Hz, 1H), 3.90 (dt, J= 2.4, 7.2 Hz, 2H), 3,73 (dd, .7= 5.4, 10,8 Hz, 1H), 3,45-3,38 (m, 4H), 2.80-2.74 (m, 1H), 2.67-2.57 (m, 1H), 2.46-2.41 (m, 1H), 2.21-2.10 (m, 1H), 2.06-2.00 (m, 1H), 1.74 (q, J- 6.8 Hz, 21 E)
[00849] Preparation of 3-[3-[3-(2-bromoethyl)azetidin-l-yl]phenyl]piperidine-2, 6-dione
86.5, To a solution of compound 86.4 (50 mg, 173 pmol) in ACN (1 mL) was added PBn (141 mg, 520 pmol) at 0 °C. After stirring at 80 °C for 0.5 h, the reaction mixture was filtered and concentrated to afford compound 86.5 (70 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 351.1 [M+H]\
[00850] Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)- azetidin-3-yl)-ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7//-pyrrolo[2,3-(/|- pyrimidine-6-carboxamide A259. To a solution of compound 86.5 (50 mg, 142 pmol), 7- cyclopentyl-A,A-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-<7]pyrimidine-6- carboxamide (61.9 mg, 142 pmol) in DMF (0.5 mL) were added DIEA (55.2 mg, 427 pmol), KI (2.4 mg, 14.2 pmol), and K2CO3 (19.7 mg, 142 pmol). After stirring at 80 °C for 10 h, the reaction mixture was filtered and purified by reverse phase prep-HPLC to afford compound A259 (16 mg) in 14% yield. rHNMR (400 MHz, DMSO-d6 ) <5 10.78 (s, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 7.99 (d, 2.8 Hz, 1H), 7.44 (dd, 2.8, 9.2 Hz, 1H), 7.10 (t, J= 8.0 Hz, 1H), 6.59 (s, 1H), 6.42 (br d, J= 6.8 Hz, 2H), 6.37 (s, 1H), 4.77-4.67 (m, 1H), 3.78-3.70 (m, 1H), 3.28-3.20 (m, 3H), 3.14 (br s, 4H), 3.05 (br s, 6H), 3.00-2.96 (m, 1H), 2.64- 2.54 (m, 6H), 2.43 (br dd, J- 4.8, 9.8 Hz, 5H), 2.04 (br s, 3H), 1.98 (br s, 4H), 1 .78-1.60 (m, 3H); MS (ESI) m/z: 705.6 [M+H]“
Example 87
Preparation of 7-cyclopentyl-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A(A'-dimethyl-7//-pyrrolo[2,3-t/]- pyrimi dine-6-carboxamide A260
Figure imgf000348_0001
[00851] Compound A260 was prepared as described below.
[00852] Preparation of 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoroethyl trifluoromethanesulfonate 87.1. To a solution of 3-(4-(l,l-difluoro-2-hydroxyethyl)phenyl)piperidine- 2, 6-dione (1 g, 3.71 mmol) and TEA (1.88 g, 18.6 mmol) in DCM (10 mL) was slowly added IT2O (1.26 g, 4.46 mmol) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaiSCU, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford compound 87.1 (260 mg) in 17% yield. MS (ESI) m/z: 402.1 [M+H]+.
[00853] Preparation of 7-cyclopentyl-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)- 2,2-difluoroethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A-dimethyl-7/f-pyrrolo- [2,3<(|pyrimidine-6-carboxamide A260. To a solution of 7-cyclopentyl-A(Ar-dimethyl-2-((5-(4- (piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7J7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide (200 mg, 386 pmol) and compound 87.1 (186 mg, 464 pmol) in DMF (2 mL) was added DIEA (499 mg, 3.86 mmol). After stirring at 100 °C for 2 h, the reaction mixture was filtered and purified by reverse phase prep-HPLC to afford compound A260 (42 mg) in 21% yield.
Figure imgf000348_0002
NMR (400 MHz, DMSO-Jd) 3 10.88 (s, 1H), 9.29 (s, 1H), 8.75 (s, HI), 8.18 (s, HI), 8.13 (d, ./ 9.2 Hz, 1H), 7.97 (d, J= 2.4 Hz, 1H), 7.50 (d, J= 8.0 Hz, 2H), 7.41 (br dd, J= 3.2, 9.2 Hz, 1H), 7.34 (br d, J= 8.0 Hz, 2H), 6.59 (s, 1H), 4.73 (quin, J = 8.8 Hz, 1H), 3.94 (dd, <7= 5.2, 11.6 Hz, 1H), 3.50-3.33 (m, 1H), 3.04 (br s, 6H), 2.92-2.83 (m, 3H), 2.72-2.61 (m, 5H), 2.52 (br d, J= 4.4 Hz, 1H), 2.41 (br d, J= 9.2 Hz, 3H), 2.27-2.17 (m, 4H), 2.05-1.95 (m, 5H), 1.70-1.61 (m, 4H), 1.41- 1.33 (m, 2H), 1.16 (d, J= 7.2 Hz, 3H); MS (ESI) m/z: 769.7 [M+H] \
Example 88
Preparation of 7-cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7Z/-pyrrolo[2,3-6/]- pyrimidine-6-carboxamide A261
Figure imgf000349_0001
[00854] Compound A261 was prepared as described below.
[00855] Preparation of 2-(3-bromophenyl)-2,2-difluoroethanol 88.1. To a solution of ethyl 2-(3-bromophenyl)-2,2-difluoroacetate (5 g, 17.92 mmol) in EtOH (50 mL) was added NaBHi (1.36 g, 35.8 mmol) slowly in portions at 0 °C. After stirring at 20 °C for 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SO4, and concentrated to afford compound 88.1 (4.3 g), which was used directly in the next step without further purification.
[00856] Preparation of 2-[3-(2,6-dibenzyloxy-3-pyridyl)phenyl]-2,2-difluoro-ethanol 88.2. To a solution of compound 88.1 (4.3 g, 18.1 mmol) and (2,6-dibenzyloxy-3-pyridyl)boronic acid (6.08 g, 18.1 mmol) in dioxane (50 mL) and HzO (5 mL) were added Pd(dppf)C12 CH2Ch (741 mg, 907 umol) and K3PO4 (7.7 g, 36.3 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOi, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 88.2 (6 g) in 70% yield. MS (ESI) m/z: 448.2 [M+H]+
[00857] Preparation of 3-[3-(l,l-difluoro-2-hydroxyethyl)phenyl]piperidine-2, 6-dione 88.3. To a solution of compound 88.2 (5 g, 11 .2 mmol) in EtOH (50 mL) and THF (50 mL) was added 10% Pd/C (2.5 g) under N2. After stirring under H2 at 40 °C for 12 h, the reaction mixture was filtered and concentrated to afford compound 88.3 (3.8 g), which was used directly in the next step without further purification. MS (ESI) m/z: 270.3 [M+H]T
[00858] Preparation of [2-[3-(2,6-dioxo-3-piperidyl)phenyl]-2,2-difluoroethyl] trifluoromethanesulfonate 88.4, To a solution of compound 88.3 (2.9 g, 10,8 mmol) in DCM (30 mL) were added TEA (5.45 g, 53.9 mmol) and TfiO (6.08 g, 21.5 mmol) at 0 °C. After stirring at 20 °C for 12 h, the reaction mixture was concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 88.4 (900 mg) in 21% yield. MS (ESI) m/z'. 402.1 [M+H]+.
[00859] Preparation of 7-cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenyl)- 2,2-difluoro-ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar TA-dimethyl-77/-pyrrolo- [2,3-<7]-pyrimidine-6-carboxamide A261. To a solution of 7-cyclopentyl-AW-dimethyl-2-[[5-[4- (4-piperidyl)piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide (130 mg, 251 pmol) and compound 88.4 (101 mg, 251 pmol) in DMF (2 mL) was added DIEA (325 mg, 2.51 mmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A261 (18 mg) in 8% yield. !H NMR (400 MHz, DM SO-d6 ) 8 10.87 (s, 1H), 9.24 (s, 1H), 8.75 (s, 1H), 8.13 (d, J= 8.8 Hz, 1H), 7.96 (s, 1H), 7.42 (d, J= 14.4 Hz, 5H), 6.59 (s, 1H), 4.82-4.65 (m, 1H), 3.97 (dd, 5.2, 12.0 Hz, 1H), 3.13-3.00 (m, 12H), 2.81 (d, J= 10.6 Hz, 2H), 2.74-2.65 (m, 1H), 2.62-2.56 (m, 4H), 2.47-2.36 (m, 4H), 2.28-2.14 (m, 4H), 1.95-1.90 (m, 4H), 1.68-1.58 (m, 4H), 1.43-1.28 (m, 2H); MS (ESI) m/z: 769.5 [M+H]+
Example 89
Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-/V,A-dimethyl-77/-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A267
Figure imgf000351_0001
[00860] Compound A267 was prepared as described below.
[00861] Preparation of tert-butyl 4-[[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]methyl]-4- hydroxypiperidine-1 -carboxylate 89.1. To a solution of 2,6-dibenzyloxy-3-(4-bromophenyl)- pyridine (2.09 g, 4.69 mmol) in THF (10 mL) at -78 °C was added 2.5M n-BuLi (2.06 mL) dropwise under Ar. After the mixture was stirred at -78 °C for 1.5 h, BFs Et?.O (732 mg, 5.16 mmol) was added slowly. After the mixture was stirred for 15 min, tert-butyl l-oxa-6- azaspiro[2.5]octane-6-carboxylate (1 g, 4.69 mmol) in THF (5 mL) was added. The reaction mixture was stirred at -78 °C for 2 h and then at 25 °C for 12 h. The reaction mixture was treated with saturated aqueous NH4CI, basified to pH 9 with 2N NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 89.1 (1.2 g) in 44% yield. MS (ESI) m/z: 582.3 [M+H]+.
[00862] Preparation of tert-butyl 4-[[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]methyl]-4- fluoropiperidine-1 -carboxylate 89.2. To a solution of DAST (555 mg, 3.44 mmol) in DCM (10 mL) at -78 °C was added compound 89.1 (1 g, 1.72 mmol) in DCM (5 mL) dropwise under N2. After stirring at 25 °C for 2 h, the reaction mixture was treated with saturated aqueous NaHCCh and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaaSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 89.2 (450 mg) in 45% yield. rH NMR (400 MHz, DMSO-tfo) 6 7.74 (d, J = 8.0 Hz, 1H), 7.51-7.22 (m, 14H), 6.55 (d, J= 8.0 Hz, 1H), 5.75 (s, 1H), 5.41 (s, 2H), 5.37 (s, 2H), 3.77 (br d, ./ 13.6 Hz, 2H), 3.29 (s, 1 H), 2.91 (s, 2H), 1.69-1.60 (m, 3H), 1.59-1.50 (m, 1H), 1.38 (s, 9H); MS (ESI) m/z: 583.4 [M+H]+.
[00863] Preparation of tert-butyl 4-[[4-(2,6-dioxo-3-piperidyl)phenyl]methyl]-4-fluoro- piperi dine- 1 -carboxylate 89.3. To a solution of compound 89.2 (430 mg, 737 pmol) in THF (4 mL) and EtOH (4 mL) were added 10% Pd/C (392 mg) and 20% Pd(OH)2 (103 mg). After stirring under H2 at 60 °C for 12 h, the reaction mixture was filtered and concentrated to afford compound 89.3 (280 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 349.1 [M+Hf.
[00864] Preparation of 3-[4-[(4-fluoro-4-piperidyl)methyl]phenyl]piperidine-2, 6-dione
89.4. To a solution of compound 89.3 (280 mg, 692 pmol) in DCM (3 mL) was added 4M HC1 in dioxane (173 pL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 89.4 as an HC1 salt (230 mg), which was used directly in the next step without further purification. !HNMR (400 MHz, DMSO-dfc) 6 10.82 (s, 1H), 7.23-7.15 (m, 4H), 3.84 (dd, J = 5.2, 11,3 Hz, 1H), 3,20 (br d, J= 12.4 Hz, 2H), 3.02-2.90 (m, 4H), 2.69-2.61 (m, 1H), 2.20-2.12 (m, 1H), 2.07-1.99 (m, 1H), 1.93-1.80 (m, 4H), 1.36 (s, 2H); MS (ESI) m/z: 305 [M+H]+.
[00865] Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)-4- fluoro[l ,4'-bipiperidin]-l'-yl)pyridin-2-yl)amino)-Az,A/-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A267. To a solution of compound 89.4 as an HC1 salt (114 mg, 335 pmol) in THF (1 mL) and DMSO (1 mL) were added KOAc (98.6 mg, 1.01 mmol) and HOAc (100 mg, 1.68 mmol) to pH 6, followed by addition of 7-cyclopentyl-A(AMimethyl-2-[[5-(4-oxo-l-piperidyl)-2- pyridyl]amino]pyrrolo[2,3-d]pyriniidine-6-carboxamide (150 mg, 335 pmol). After the mixture was stirred at 60 °C for 12 h, NaBHsCN (42.1 mg, 670 pmol) was added at 0 °C. The reaction mixture was stirred at 60 °C for 1 h, and filtered and purified by reverse phase perp-HPLC to afford compound A267 (59 mg) in 23% yield. rH NMR (400 MHz, DMSO-flfc) <-) 10.82 (s, 1H), 9.22 (s, 1H), 8.74 (s, 1H), 8.11 (br d, J= 9.2 Hz, 1H), 7.98 (br s, 1H), 7.45-7.36 (m, 1H), 7.19- 7.12 (m, 4H), 6.59 (s, 1H), 4.80-4.62 (m, 1H), 3.88-3.77 (m, 1H), 3.70-3.59 (m, 2H), 3.05 (br s, 6H), 2.93-2.83 (m, 2H), 2.72-2.59 (m, 6H), 2.38-2.32 (m, 4H), 2.21-2.14 (m, 1H), 2.08-2.03 (m, 1H), 1.97 (br s, 4H), 1.81 (br d, J= 11.2 Hz, 2H), 1.70-1.51 (m, 9H); MS (ESI) m/z: 736.4 [M+H]+
Example 90
Preparation of 7-cyclopentyl-2-((5-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-3-fluoro- azeti din-1 -yl)piperi din- l-yl)pyridin-2-yl)amino)-A’,A'-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A269
Figure imgf000353_0001
[00866] Compound A269 was prepared as described below.
[00867] Preparation of tert-butyl 3-hydroxy-3-(2-trimethylsilylethynyl)azetidine-l- carboxylate 90.1. To a solution of ethynyl(trimethyl)silane (8.61 g, 87.6 mmol) in THF (200 mL) was added dropwise 2.5M n-BuLi (33.9 mL) over 0.25 h at -78 °C under N2. After the mixture was stirred at -78 °C for 0.5 h, fert-butyl 3-oxoazetidine-l -carboxylate (10 g, 58.4 mmol) in THF (20 mL) was added dropwise at -78 °C The reaction mixture was stirred at
-78 °C for 0.5 h and at -20 °C for 1 h under N2, and then treated with brine and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SCU and concentrated to afford compound 90.1 (14 g), which was used directly in the next step without further purification. ^ NMR (400 MHz, DMSO-dk) 3 6.50 (s, 1H), 3.97 (br d, J= 8.8 Hz, 2H), 3.81 (br d, 8.8 Hz, 2H), 1.38 (s, 9H), 0.16 (s, 9H).
[00868] Preparation of tert-butyl 3-ethynyl-3-hydroxyazetidine-l-carboxylate 90.2, To a solution of compound 90.1 (1 g, 3.71 mmol) in MeOH (20 mL) was added K2CO3 (616 mg, 4.45 mmol). After stirring for 2 h, the reaction mixture was concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were concentrated to afford compound 90.2 (700 mg), which was used directly in the next step without further purification.
[00869] Preparation of tert-butyl 3 -ethynyl-3 -fluoroazetidine- 1 -carboxylate 90.3. To a solution of compound 90.2 (500 mg, 2.54 mmol) in DCM (20 mL) at -78°C was added A-ethyl- AL(trifluorosulfanyl)ethanamine (409 mg, 2.54 mmol) dropwise over 0.25 h. After stirring at -78 °C for 1.25 h and at -20 °C for 1 h, the reaction mixture was poured onto aqueous NaHCOs and extracted with DCM. The combined organic layers were concentrated to afford compound 90.3 (450 mg), which was used directly in the next step without further purification,
Figure imgf000353_0002
(400 MHz, DMSCM&) 34.29 (d, J= 5.2 Hz, 1H), 4.25-4.18 (m, 2H), 4.18-4.10 (m, 2H), 1.39 (s, 9H). [00870] Preparation of tert-butyl 3-[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]ethynyl]-3- fluoroazetidine-1 -carboxylate 90.4. To a solution of 2,6-dibenzyloxy-3-(4-bromophenyl)- pyridine (4 g, 8.96 mmol), tert-butyl 3-ethynyl-3-fluoroazetidine-l-carboxylate 90.3 (1.96 g, 9.86 mmol) in ACN (40 mL) and THF (40 niL) were added XPhos Pd Ch (759 mg, 896 pmol) and CS2CO3 (8.76 g, 26.9 mmol). After stirring at 60 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 90.4 (2.5 g) in 420% yield. rH NMR (400 MHz, DMSO- df,) d 7.83-7.77 (m, 1H), 7.67-7.61 (m, 2H), 7.59-7.53 (m, 2H), 7.47-7.42 (m, 2H), 7.41-7.27 (m, 8H), 6.58 (d, J= 8.0 Hz, 1H), 5.40 (d, J= 11.2 Hz, 4H), 4.41 -4.17 (m, 4H), 1.41 (s, 9H); MS (ESI) m/z: 565.3 [M+H]+.
[00871] Preparation of tert-butyl 3-[2-[4-(2,6-dioxo-3-piperidyl)phenyl]ethyl]-3-fluoro- azetidine-l-carboxylate 90.5. To a solution of compound 90.4 (500 mg, 886 pmol) in THF (20 mL) were added 10% Pd/C (188 mg), 20% Pd(OH)2 (124 mg), and CH3COOH (160 mg, 2.66 mmol) under N2. After stirring under H2 at 40 °C for 12 h, the reaction mixture was filtered and concentrated to afford compound 90.5 (340 mg), which was used directly in the next step without further purification.
[00872] Preparation of 3-[4-[2-(3-fluoroazetidin-3-yl)ethyl]phenyl]piperidine-2, 6-dione 90.6. To a solution of compound 90.5 (340 mg, 871 pmol) in DCM (4 mL) was added 4M HC1 in dioxane (218 pL) at 0 °C. After stirring at 0 °C for 3 h, the reaction mixture was concentrated to afford compound 90.6 (250 mg), which was used directly in the next step without further purification.
[00873] Preparation of 7-cyclopentyl-2-((5-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phenethyl)- 3-fluoro-azetidin-l-yl)piperidin-l -yl)pyridin-2-yl)amino)-A,r,A-dimethyl-7.H-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A269. To a mixture of 7-cyclopentyl-ArpV-dimethyl-2-[[5-(4-oxo- l-piperidyl)-2-pyridyl]amino]pyrrolo[2,3-iZ]pyrimidine-6-carboxaniide (60 mg, 134 pmol) in DCM (5 mL) was added compound 90.6 (78 mg, 268 pmol). After the mixture was stirred for 0.5 h, NaBH(OAc)3 (85 mg, 402 pmol) was added. The reaction mixture was stirred for 12 h under N2, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by reverse phase prep-HPLC to afford compound A269 as a TFA salt (62 mg) in 58% yield. }H NMR (400 MHz, DMSO-sfe) 3 10.81 (s, 1H), 9.24 (s, 1H), 8.74 (s, 1H), 8.21 (s, 1H), 8.12 (d, J= 9.2 Hz, 1H), 7.98 (d, J= 2.8 Hz, 1H), 7.42 (dd, J= 3.2, 9.2 Hz, 1H), 7.25-7.17 (m, 2H), 7.16-7.09 (m, 2H), 6.59 (s, 1H), 4.73 (br t, ./ 8.8 Hz, 1H), 3.81 (dd, ./ 4.8, 11.2 Hz, 1 H), 3.52-3.48 (m, 2H), 3.37 (br d, J = 6.4 Hz, 3H), 3.18 (br d, J= 8.4 Hz, 1H), 3.13 (br d, J = 8.8 Hz, 1H), 3.05 (br s, 6H), 2.79-2.57 (m, 5H), 2.47-2.40 (m, 2H), 2.29-1.90 (m, 9H), 1.75 (br d, ./ 10.4 Hz, 2H), 1.63 (br d, J = 5.2 Hz, 2H), 1.39-1.20 (m, 2H); MS (ESI) m/z: 722.3 [M+H]+.
Example 91
Preparation of 7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-3-fluoro- azetidin-l-yl)piperidin-l-yl)pyri din-2 -yl)amino)-jV,Mdimethyl-777-pyrrolo[2,3-d]pyrimidine-6- carboxamide A270
Figure imgf000355_0001
[00874] Compound A270 was prepared as described below.
[00875] Preparation of tert-butyl 3-[2-[3-(2,6-dibenzyloxy-3-pyridyl)phenyl]ethynyl]-3- fluoroazetidine-1 -carboxylate 91.1, To a solution of tert-butyl 3-ethynyl-3-fluoroazetidine-l- carboxylate (1.96 g, 9.86 mmol) in THF (40 mL) and ACN (40 mL) were added 2,6-dibenzyl- oxy-3-(3-bromophenyl)pyridine (4 g, 8.96 mmol), XPhos Pd G3 (759 mg, 896 pmol), and CS2CO3 (8.76 g, 26.9 mmol). After stirring at 60 °C for 12 h under N2, the reaction mixture was concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 91.1 (2.7 g) in 48% yield. rH NMR (400 MHz, DMSO-tZe) 3 7.82 (d, J- 8.0 Hz, 1H), 7.76 (s, 1H), 7.69-7.62 (m, 1H), 7.48-7.28 (m, 12H), 6.57 (d, J= 8.0 Hz, 1H), 5.41 (d, J= 8.8 Hz, 4H), 4.30 (br dd, ./ 6.0, 19,6 Hz, 4H), 1.41 (s, 9H); MS (ESI) rn/z: 565.3 [M+H] \
[00876] Preparation of tert-butyl 3-[2-[3-(2,6-dioxo-3-piperidyl)phenyl]ethyl]-3-fluoro- azetidine-1 -carboxylate 91.2. To a solution of compound 91.1 (1 g, 1.77 mmol) in THF (40 mL) were added 10% Pd/C (377 mg), 20% Pd(OH)2 (249 mg), and AcOH (319 mg, 5.31 mmol) under N2. After stirring under H2 at 40 °C for 12 h, the reaction mixture was filtered and concentrated to afford compound 91.2 (650 mg), which was used directly in the next step without further purification. !H NMR (400 MHz, DMSO-tTs) d 11.95-11.72 (m, 1H), 7.59-7.34 (m, 1H), 7.30- 7.20 (m, 1H), 7.18-7.02 (m, 2H), 3.94-3.78 (m, 3H), 3.17 (br s, 2H), 2.69-2.59 (m, 2H), 2.20- 2.05 (m, 2H), 1.91 (s, 4H), 1.45-1.11 (m, 9H).
[00877] Preparation of 3-[3-[2-(3-fluoroazetidin-3-yl)ethyl]phenyl]piperidine-2, 6-dione
91.3. To a solution of compound 91.2 (650 mg, 1.66 mmol) in DCM (7 mL) was added 4M HC1 in dioxane (7 mL) at 0 °C. After stirring at 25 °C for 4 h, the reaction mixture was concentrated to afford compound 91.3 as an HC1 salt (620 mg), which was used directly in the next step without further purification. MS (ESI) mZz: 291,3 [M+H]+.
[00878] Preparation of 7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)phenethyl)- 3-fluoro-azetidin-l-yl)piperidin-l-yl)pyridin-2-yl)amino)-A(A-dimethyl-777-pyrrolo[2,3- ^pyrimidine-6-carboxamide A270. To a mixture of 7-cyclopentyl-A(A’-dimethyl-2-[[5-(4-oxo- l-piperidyl)-2-pyridyl]amino]pyrrolo[2,3-tZ]pyrimidine-6-carboxamide (200 mg, 447 pmol) in DCM (10 mL) was added compound 91.3 (286 mg, 983 pmol). After the mixture was stirred at for 0.5 h, NaBH(OAc)3 (284 mg, 1.34 mmol ) was added. The reaction mixture was stirred for 12 h under N2, and then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by reverse phase prep-HPLC to afford compound A270 (66 mg) in 19% yield. ]H NMR (400 MHz, DMSO-tfc) J 10.82 (s, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.99 id, J - 2.4 Hz, 1H), 7.41 (dd, .7= 2.8, 9.2 Hz, 1H), 7.28-7.21 (m, 1H), 7.18-7.10 (m, 2H), 7.04 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 4.73 (br t, .7 8.4 Hz, 1H), 3.82 (dd, 7= 4.8, 11.6 Hz, 1H), 3.53-3.47 (m, 2H), 3.37 (br d, J= 8.8 Hz, 3H), 3.17 (br d, J= 8.4 Hz, 1H), 3.11 (br d, J= 8.4 Hz, 1H), 3.05 (br s, 6H), 2.78-2.60 (m, 5H), 2.46-2.39 (m, 2H), 2.28-2.16 (m, 2H), 2.10-1.91 (m, 6H), 1.74 (br d, J = 10.0 Hz, 2H), 1.63 (br d, .7= 4.8 Hz, 2H), 1.36-1.25 (m, 2H); MS (ESI) m/z'. 722.5 [M+H] d
Example 92
Preparation of 7-cyclopentyl-2-((5-(3-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)piperidin-4-yl)azetidin-l-yl)pyridin-2-yl)amino)-A(A-dimethyl-777-pyrrolo[2,3-d]- pyrimidine-6-carboxamide A271
Figure imgf000357_0001
[00879] Compound A271 was prepared as described below.
[00880] Preparation of tert-butyl 4-(l -(6-nitropyridin-3 -yl)azeti din-3 -yl)piperi dine- 1 - carboxylate 92.1. A mixture of tert-butyl 4-(azetidin-3-yl)piperidine-l -carboxylate (500 mg, 2.08 mmol), 5-fluoro-2-nitropyridine (296 mg, 2.08 mmol), and K2CO3 (863 mg, 6.24 mmol) in DMF (5.00 mL) was stirred at 90 °C for 12 h. The reaction mixture was then poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford compound 92.1 (500 mg) in 66% yield. MS (ESI) m/z: 308 [M+H]+.
[00881] Preparation of tert-butyl 4-(l-(6-aminopyridin-3-yl)azetidin-3-yl)piperidine-l- carboxylate 92.2. To a solution of compound 92.1 (500 mg, 1.38 mmol) in THF (5 mL) was added 10% Pd/C (1.47 g) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 92.2 (450 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 333.2 [M+H]+.
[00882] Preparation of tert-butyl 4-(l-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7/f- pyrrolo[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperidine-l-carboxylate 92.3.
To a solution of compound 92.2 (400 mg, 1.20 mmol) and 2-chloro-7-cyclopentyl-?/,A'r-dimethyl- 77/-pyrrolo[2,3-<f|pyrimidine-6-carboxamide (352 mg, 1.2 mmol) in dioxane (4.00 mL) were added BINAP (150 mg, 241 pmol), CS2CO3 (784 mg, 2.41 mmol), and Pd(OAc)2 (27 mg, 120 pmol). After stirring at 100 °C for 12 h under N2, the reaction mixture was poured into saturated aqueous NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiOr, EtOAc/PE) to afford compound 92.3 (410 mg) in 58% yield. MS (ESI) m/z: 589.3 [M+H]+. [00883] Preparation of 7-cyclopentyl-A,A-dimethyl-2-((5-(3-(piperidin-4-yl)azetidin-l- yl)pyridin-2-yI)amino)-77f-pyrrolo[2,3-t(]pyrimidine-6-carboxamide 92.4. A mixture of compound 92.3 (400 mg, 679 pmol) in DCM (0.70 mL) and TFA (537 mg, 4.71 mmol) was stirred for 2 h. The reaction mixture was then concentrated to afford compound 92.4 (330 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 489.4 [M+H]+.
[00884] Preparation of 7-Cyclopentyl-2-((5-(3-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)- 2,2-difluoro— ethyl)piperidin-4-yl)azetidin-l-yl)pyridin-2-yl)amino)-Ar/Vr-dimethyl-77/-pyrrolo- [2,3-<7]-pyrimidine-6-carboxamide A271. To a solution of compound 92.4 (100 mg, 205 pmol) and [2-[4-(2,6-dioxo-3-piperidyl)phenyl]-2,2-difluoro-ethyl] trifluoromethanesulfonate (58.8 mg, 147 pmol) in DMF (1 mL) was added DIEA (265 mg, 2,05 mmol). After stirring at 100 °C for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A271 (16 mg) in 10% yield. fll NMR (400 MHz, DMSO-tA) b' 10.99-10.75 (m, 1H), 9.17-9.04 (m, 1H), 8.72 (s, 1H), 8.06 (d, J= 8.8 Hz, 1H), 7.58-7.44 (m, 3H), 7.33 (br d, J= 7.6 Hz, 2H), 6.89 (br d, .7 8.8 Hz, 1H), 6.57 (s, 1H), 4.83-4.59 (m, 1H), 3.99-3.83 (m, 3H), 3.49 (br t, J= 6.4 Hz, 2H), 3.09-2.98 (m, 8H), 2.81 (br d, J= 10.8 Hz, 2H), 2.71-2.64 (m, 1H), 2.43 (br d, J= 7.6 Hz, 4H), 2.28-2.17 (m, 3H), 2.07-1.92 (m, 5H), 1.65-1.51 (m, 4H), 1.44-1.35 (m, 1H), 1.09-0.97 (m, 2H); MS (ESI) m/z: 740.5 [M+Hf.
Example 93
Preparation of 7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)benzyl)-3-fluoroazetidin-l- yl)piperidin-l-yl)pyridin-2-yl)amino)-A’,A-dimethyl-777-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A277
Figure imgf000358_0001
[00885] Compound A277 was prepared as described below.
[00886] Preparation of tert-butyl 3-[[3-(2,6-dioxo-3-piperidyl)phenyl]methyl]-3-fluoro- azetidine- 1 -carboxylate 93.1. A mixture of tert-butyl 3 -(bromomethyl )-3 -fluoroazetidine- 1 - carboxylate (5.2 g, 19.4 mmol), 3 -(3 -brom ophenyl)piperidine-2, 6-dione (4.6 g, 14.9 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (167 mg, 149 pmol), NiCh dtbbpy (89 mg, 224 pmol), tris(trimethylsilyl)silane (3.71 g, 14.9 mmol), and NazCCh (3.16 g, 29.8 mmol) in DME (40 mL) was irradiated with a 10 W blue LED lamp at 25 °C for 14 h with stirring. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NacSCk concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 93.1 (2.2 g) in 55% yield.
[00887] Preparation of 3-[3-[(3-fluoroazetidin-3-yl)methyl]phenyl]piperidine-2, 6-dione
93.2, To a solution of compound 93.1 (1.1 g, 2.92 mmol) in DCM (5 mL) was added TFA (5.63 g, 49.4 mmol). After stirring for 1 h, the reaction mixture was concentrated to afford compound 93.2 as a TFA salt (1.2 g), which was used directly in the next step without further purification. MS (ESI) m/z: 277.2 | VI • H f
[00888] Preparation of 7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)benzyl)-3- fluoroazetidin- 1 -y l)piperi din- 1 -yl)pyridin-2-yl)amino)-A(A-dimethyl-7LT-pyrrolo[2,3 -d]- pyrimidine-6-carboxamide A277. To a solution of compound 93.2 as an TFA salt (123 mg, 447 |imol) and 7-cyclopentyl-ALV-dimethyl-2-[[5-(4-oxo-l -piperidyl)-2-pyridyi]amino]pyrrolo[2,3- d]pyrimidine-6-carboxamide (200 mg, 447 pmol) in THF (2 mL) and DMSO (2 mL) was added NaOAc (73 mg, 894 pmol). After the mixture was stirred at 60 °C for 2 h, NaBH(OAc)3 (189 mg, 894 pmol) was added. The reaction mixture was stirred for 2 h, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by reverse phase prep-HPLC to afford compound A277 (50 mg) in 15% yield. ^NMR (400 MHz, CDsOD) 3 8.70 (s, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.96 (d, J - 2.8Hz, 1H), 7.48 (dd, J - 2.8, 9.2Hz, 1H), 7.35-7.27 (m, 1H), 7.22 (d, J - 7.6Hz, 1H), 7.19-7.11 (m, 2H), 6.61 (s, 1H), 4.74 (d, J = 8.8Hz, 1H), 3.87 (dd, J = 6.0, 10.0Hz, 1H), 3.60 (d, J 12.4Hz, 2H), 3.51 (dd, J --- 9.6, 15.2Hz, 2H), 3.26-3.21 (m, 2H), 3.15 (s, 7H), 2.81-2.60 (m, 4H), 2.57-2.46 (m, 2H), 2.35-2.27 (m, 1H), 2.26-2.15 (m, 2H), 2.13-1.96 (m, 5H), 1.88 (d, J = 11.2Hz, 2H), 1.77-1.67 (m, 2H), 1.51-1.38 (m, 2H); MS (ESI) m/z: 708.4 [M+H]+.
Example 94 Preparation of 7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,A7-dimethyl-7/f-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A278
Figure imgf000360_0001
[00889] Compound A278 was prepared as described below.
[00890] Preparation of l-(6-nitropyridin-3-yl)azetidin-3-ol 94.1. To a solution of 5- fluoro-2-nitropyridine (5 g, 35.2 mmol) and azetidin-3-ol HC1 (4.24 g, 38.7 mmol) in DMF (50 mL) was added K2CO3 (14.6 g, 106 mmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and triturated with DCM to afford compound 94.1 (5.8 g) in 84% yield. MS (ESI) m/z'. 196.1 [M+H]+.
[00891] Preparation of l-(6-aminopyridin-3-yl)azetidin-3-ol 94.2. To a solution of l-(6- nitropyridin-3-yl)azetidin-3-ol (1 g, 5.12 mmol) in THF (40 mL) was added 10% Pd/C (300 mg). After stirring for 12 h under H2, the reaction mixture was filtered and concentrated to afford compound 94.2 (800 mg), which was used directly in the next step without further purification. MS (ESI) m/z'. 166.2 [M+H]+.
[00892] Preparation of 7-cyclopentyl-2-((5-(3-hydroxyazetidin-l-yl)pyridin-2-yl)-amino)- A(A-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6-carboxamide 94.3, To a mixture of compound
94.2 (400 mg, 2,42 mmol), CS2CO3 (1.58 g, 4.84 mmol), and 2-chloro-7-cyclopentyl-A(A'r- dimethyl-7/7-pyrrolo[2,3-</]pyriniidine-6-carboxamide (708 mg, 2.42 mmol) in dioxane (4 mL) were added Pd(OAc)2 (27.2 mg, 121 nmol) and BINAP (15.1 mg, 24.2 pmol). After stirring at 100 °C for 12 h under N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound
94.3 (850 mg) in 67% yield. [00893] Preparation of 7-cyclopentyl-A,A-dimethyl-2-((5-(3-oxoazetidin-l-yl)pyridin-2- yl)amino)-777-pyrrolo[2,3-^Z]pyrinlidine-6-carboxamide 94.4, To a solution of compound 94.3 (560 mg, 1 .33 mmol) in DMSO (5.6 mL) was added TEA (1.12 g, 11.1 mmol), followed by addition of sulfur trioxide pyridine complex (1.48 g, 9.3 mmol). After stirring for 1 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 94.4 (180 mg) in 32% yield.
[00894] Preparation of 7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)- pi peri din- 1 -yl)-azetidin- 1 -yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7F-pyrrolo[2,3-i/]pyrimidine-6- carboxamide A278. To a solution of compound 94.4 (80 mg, 190 pmol) and 3-(4-(2-(piperidin- 4-yl)ethyl)phenyl)piperidine-2, 6-dione as an HC1 salt (192 mg, 572 pmol) in THF (1 mL) and DMSO (0.6 mL) was added KOAc (18.7 mg, 190 pmol), followed by addition of HOAc (11.4 mg, 190 umol). After the mixture was stirred at 60 °C for 12 h, NaBILCN (35.9 mg, 572 pmol) was added. The reaction mixture was stirred at 80 °C for 1 h, and then concentrated and purified by reverse phase prep-HPLC to afford compound A278 (6 mg) in 4% yield, ffl NMR (400 MHz, DMSO-tTs) <3 10.81 (s, 1H), 9.16 (s, 1H), 8.73 (s, 1H), 8.08 (d, .7= 8.8 Hz, 1H), 7.57 (d, .7 = 2.8 Hz, 1H), 7.17-7.08 (m, 4H), 6.93 (dd, J= 2.8, 8.8 Hz, 1H), 6.58 (s, 1H), 4.80-4.61 (m, 1H), 4.02-3.89 (m, 2H), 3.84-3.75 (m, 1H), 3.55 (br t,
Figure imgf000361_0001
6.4 Hz, 2H), 3.26-3.15 (m, 2H), 3.08-2.99 (m, 6H), 2.78 (br d, J= 10.8 Hz, 2H), 2.68-2.61 (m, 1H), 2.56 (br d, J = 7.6 Hz, 2H), 2.46-2.42 (m, 2H), 2.21-2.12 (m, 1H), 1.96 (br s, 3H), 1.82-1.76 (m, 2H), 1.71 (br d, 10.0 Hz, 2H), 1.63 (br d, .7= 4.4 Hz, 2H), 1.51-1.46 (m, 2H), 1.23 (br s, 3H), 1.16-1.13 (m, 1H), 0.88-0.79 (m, 1H); MS (ESI) m/z: 704.4 [M+H] '.
Example 95
Preparation of 7-cyclopentyl-2-((5-(4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-l-yl)- methyl)-4-fluoropiperidin-l-yl)pyridin-2-yl)amino)-A(A-dimethyl-777-pyrrolo[2,3-</]pyrimidine- 6-carboxamide A284
Figure imgf000362_0001
[00895] Compound A284 was prepared as described below.
[00896] Preparation of benzyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate 95.1. To a solution of (4-fluoro-4-piperidyl)methanol (5.5 g, 41.3 mmol) in ACN (200 mL) and H2O (50 mL) were added NaHCCh (10.4 g, 124 mmol) and CbzCl (10.6 g, 62 mmol) at 0 °C. After stirring for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 95.1 (61 g) in 83% yield. MS (ESI) m/z: 268.3 [M+H]+.
[00897] Preparation of benzyl 4-fluoro-4-formyl-piperidine-l -carboxylate 95.2. To a solution of oxalyl dichloride (4.56 g, 35.9 mmol) in DCM was added dropwise DMSO (2.81 g, 35.9 mmol) at -70 °C. The mixture was stirred at -70 °C for 0.5 h and then added dropwise to a solution of compound 95.1 (2.4 g, 8.98 mmol) in DCM. After the mixture was stirred at -70 °C for 1 h, TEA (7.27 g, 71.8 mmol) was added at -70 °C. The reaction mixture was stirred at -70 °C for 0.5 h, and then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 95.2 (2 g) in 84% yield. MS (ESI) m/z: 282 [M+H]+.
[00898] Preparation of benzyl 4-(dimethoxymethyl)-4-fluoropiperidine-l-carboxylate
95.3. To a solution of compound 95.2 (1.8 g, 6.79 mmol) in MeOH (30 mL) were added TsOH (584 mg, 3.39 mmol) and trimethoxymethane (3.6 g, 33.9 mmol). After stirring for 12 h, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 95.3 (2.2 g) in 67% yield. MS (ESI) m/z: 312.3 [M+H]+.
[00899] Preparation of 4-(dimethoxymethyl)-4-fluoropiperidine 95.4, A mixture of compound 95.3 (2.2 g, 7.07 mmol), 10% Pd/C (500 mg), and 20% Pd(OII)2 (500 mg) in THF (10 mL) and MeOH (10 mL) was stirred at 40 °C for 12 h under Eh. The reaction mixture was then filtered and concentrated to afford compound 95.4 (1.37 g), which was used directly in the next step without further purification.
[00900] Preparation of 5-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-2-nitropyridine
95.5. To a solution of compound 95.4 (700 mg, 3.95 mmol) in DMSO (20 mL) were added K2CO3 (1 .64 g, 11.9 mmol) and 5-fluoro-2-nitropyridine (561 mg, 3.95 mmol). After stirring at 90 °C for 6 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, anhydrous Na2SO4, and concentrated to afford compound 95.5 (1.2 g), which was used directly in the next step without further purification. MS (ESI) m/z: 300 [M+H]+.
[00901] Preparation of 5-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]pyridin-2-amine
95.6. A mixture of compound 95.5 (1.2 g, 4.01 mmol), 20% Pd(OH)2 (200 mg), and 10% Pd/C (200 mg) in MeOH (10 mL) and THF (10 mL) was stirred for 12 h under H2. The reaction mixture was filtered and concentrated to afford compound 95.6 (790 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 270.1 [M+H]+.
[00902] Preparation of 7-cyclopentyl-2-[[5-[4-(dimethoxymethyl)-4-fluoro- l-piperidyl]-2- pyridyl]amino]-A/,7V-dimethyl-pyiTolo[2,3-<7]pyrimidine-6-carboxamide 95.7. A mixture of compound 95.6 (790 mg, 2.93 mmol), 2-chloro-7-cyclopentyl-A(Ar-dimethylpyrrolo[2,3-</|- pyrimidine-6-carboxamide (945 mg, 3.23 mmol), Pd(OAc)2 (32.9 mg, 147 pmol), BINAP (18.3 mg, 29.3 pmol), and CS2CO3 (1.91 g, 5.87 mmol) in dioxane (20 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 95.7 (700 mg) in 45% yield. MS (ESI) m/z: 526.5 [M+H]+. [00903] Preparation of 7-cyclopentyl-2-[[5-(4-fluoro-4-formyl-l -piperidyl)-2-pyridyl]- amino]-A,AT-dimethyl-pyrrolo[2,3-df]pyrimidine-6-carboxamide 95.8. A solution of compound 95.7 (250 mg, 476 pmol) in HCO2H (6 mL) was stirred at 80 °C for 2 h. The reaction mixture was then concentrated to afford compound 95.8 (200 mg), which was used directly in the next step without further purification.
[00904] Preparation of 7-cyclopentyl-2-((5-(4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)- azetidin-l-yl)-methyl)-4-fluoropiperidin-l-yl)pyridin-2-yl)amino)-ACV-dimethyl-7/f-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A284. To a solution of compound 95.8 (196 mg, 409 pmol) in DMSO (5 mL) and THF (5 mL) were added NaOAc (101 mg, 1.23 mmol), 3-[4-(azetidin-3- yl)phenyl]piperidine-2, 6-dione (100 mg, 409 pmol), and NaBEECN (51.5 mg, 819 pmol). After stirring for 12 h, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh, concentrated, and purified by prep-TLC (SIO2, MeOH/DCM) to afford compound A284 (103 mg) in 34% yield. lH NMR (400 MHz, DMSO-6&) d 10.82 (s, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 8.14 (d, J= 9.2 Hz, 1H), 8.03 (d, 2 8 Hz, 1H), 7.46 (dd, 2.8, 9.2 Hz, 1H), 7.31 (d, ./ 8.0 Hz, 2H), 7.17 (d, J= 8.0 Hz,
2H), 6.59 (s, 1H), 4.84-4.60 (m, 1H), 3.82 (dd, .7= 4.8, 1 1.6 Hz, 1H), 3.76-3.54 (m, 3H), 3.49- 3.39 (m, 2H), 3.19 (d, J= 4.4 Hz, 2H), 3.05 (s, 6H), 2.99-2.91 (m, 2H), 2.76-2.60 (m, 3H), 2.47- 2.37 (m, 4H), 2.23-2.1 1 (m, 1H), 2.03-1.91 (m, 6H), 1.86-1.70 (m, 2H), 1.64 (d, J= 5.2 Hz, 2H); MS (ESI) m/z: 708.7 [M+H]+.
Example 96
Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7Z/-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A290
Figure imgf000364_0001
[00905] Compound A290 was prepared as described below. [00906] Preparation of 2,6-dibenzyloxy-3-(4-bromo-2-fluoro-phenyl)pyridine 96.1. To a solution of 4-bromo-2-fluoro-l -iodobenzene (3.75 g, 12.5 mmol) and (2,6-dibenzyloxy-3- pyridyl)boronic acid (5 g, 14.9 mmol) in dioxane (150 mL) and H2O (10 mL) were added K3PO4 (5.29 g, 24.9 mmol) and Pd(dppf)Cb (456 mg, 623 pmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SC>4, concentrated, and purified by column chromatography (S1O2, EtOAc/PE) to afford compound 96.1 (19 g) in 81% yield. MS (ESI) m/z1. 646.2 [M+H]+.
[00907] Preparation of 2,6-dibenzyloxy-3-[4-[4-(2,2-dimethoxyethyl)-l-piperidyl]-2- fluorophenyl]pyridine 96.2. A mixture of compound 96.1, 4-(2,2-dimethoxyethyl)piperidine (750 mg, 4,33 mmol), CS2CO3 (2.81 g, 8.61 mmol), and Pd-PEPPSI-IPent (75 mg, 87,2 praol) in dioxane (40 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU, and concentrated to afford compound 96.2 (5 g), which was used directly in the next step without further purification. MS (ESI) m/z'. 557.5 [M+H]+.
[00908] Preparation of 3-[4-[4-(2,2-dimethoxyethyl)-l-piperidyl]-2-fluorophenyl]- piperidine-2, 6-dione 96.3. A mixture of compound 96.2 (5 g, 7.33 mmol), 10% Pd/C (500 mg), and 20% Pd(OH)2 (500 mg) in THF (50 mL) and MeOH (50 mL) was stirred at 40 °C for 12 h under EL. The reaction mixture was then filtered and concentrated to afford compound 96.3 (2.85 g), which was used directly in the next step without further purification. MS (ESI) m/z'. 379.4 [M+H]+.
[00909] Preparation of 2-[l -[4-(2,6-dioxo-3-piperidyl)-3-fluoro-phenyl]-4-piperidyl]- acetaldehyde 96.4. To a solution of compound 96.3 (2.85 g, 7.53 mmol) in DCM (20 mL) was added TEA (15.4 g, 135 mmol). After stirring for 2 h, the reaction mixture was treated with aqueous NaHCCh and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to afford compound 96.4 (2.1 g), which was used directly in the next step without further purification. MS (ESI) m/z'. 333.4 [M+H]+.
[00910] Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro- phenyl)piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A'r,A'-dimethyl-7/7-pyrrolo[2,3-t/]- pyrimidine-6-carboxamide A290. To a solution of compound 96.4 (300 mg, 903 pmol) and 7- cyclopentyl-A,A-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-d]pyrimidine-6- carboxamide (300 mg, 690 pmol) in MeOH (15 mL) were added NaBELCN (170 mg, 2.71 mmol) and AcOH (108 mg, 1.81 mmol). After stirring for 12 h, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound A290 (187 mg) in 60% yield. 1H NMR (400 MHz, DMSO-d6 ) 3 10.79 (s, 1H), 9.24 (s, 1H), 8.75 (s, 1H), 8.19 (s, 1 El), 8.13 (d, ./ 9.2 Hz, 1H), 7.98 (d, 2.0 Hz, 1H), 7.42 (dd, J 1.6, 9.6 Elz, 1H),
7.08-7.02 (m, 1H), 6.72-6.68 (m, 2H), 6.59 (s, 1H), 4.76-4.69 (m, 1H), 3.87 (dd, J= 5.2, 12.0 Hz, 1H), 3.70 (d, J= 11.6 Hz, 2H), 3.12-3.03 (m, 10H), 2.71-2.62 (m, 4H), 2.39 (d, J= 7.2 Hz, 4H), 2.22-2.05 (m, 2H), 1.97 (s, 6H), 1.75 (d, J= 13.2 Hz, 2H), 1.64 (d, J= 4.4 Hz, 2H), 1.44 (d, J = 6.0 Hz, 4H), 1.30-1.15 (m, 3H); MS (ESI) m/z: 751.5 [M+H]+.
Example 97
Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l -yl)pyridin-2-yl)amino)-Af,A -dimethyl -7#-pyrrolo[2, 3 -<7]- pyrimidine-6-carboxamide A291
Figure imgf000366_0001
[00911] Compound A291 was prepared as described below.
[00912] Preparation of 2,6-dibenzyloxy-3-(4-bromo-3-fluorophenyl)pyridine 97.1, To a solution of l-bromo-2-fluoro-4-iodobenzene (5 g, 16.6 mmol) and (2,6-dibenzyloxy-3-pyridyl)- boronic acid (5.57 g, 16.6 mmol) in dioxane (100 mL) and H2O (10 mL) were added Pd(dppf)Ch CH2C12 (1.36 g, 1.66 mmol) and K3PO4 (7.05 g, 33.2 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 97.1 (7.1 g) in 74% yield. MS (ESI) m/z: 464.2 [M+H]+. [00913] Preparation of 2,6-dibenzyloxy-3-[4-[4-(2,2-dimethoxyethyl)-l -piperidyl]-3- fluorophenyl]pyridine 97.2. To a solution of compound 97.1 (2 g, 4.31 mmol) and 4-(2,2- dim ethoxy ethyl)piperi dine (746 mg, 4.31 mmol) in dioxane (25 mL) were added RuPhos (100 mg, 215 pmol), RuPhos Pd G3 (180 nig, 215 pmol), and CS2CO3 (4.21 g, 12.9 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaiSCU, concentrated, and purified by column chromatography (SiOi, EtOAc/PE) to afford compound 97.2 (1.4 g) in 57% yield. MS (ESI) m/z: 557.4 [M+H]+.
[00914] Preparation of 3-[4-[4-(2,2-dimethoxyethyl)-l-piperidyl]-3-fluorophenyl]- piperidine-2, 6-dione 97.3. A mixture of compound 97.2 (1.4 g, 2.51 mmol), 10% Pd/C (0.25 g) and 20% Pd(OH)2 (0.25 g) in THF (16 mL) was stirred under H2 for 12 h. The reaction mixture was then filtered and concentrated to afford 97.3 (750 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 379.3 [M+H]+.
[00915] Preparation of 2-[l-[4-(2,6-dioxo-3-piperidyl)-2-fluoro-phenyl]-4-piperidyl]- acetaldehyde 97.4, To a solution of compound 97.3 (280 mg, 740 pmol) in DCM (5 mL) was added TFA (3.07 g, 26.9 mmol). After stirring for 1 h, the reaction mixture was concentrated to afford compound 97.4 as a TFA salt (300 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 333.3 [M+H]+.
[00916] Preparation of 7-Cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)-2- fluorophenyl)-piperidin-4-yl)ethyl)piperazin- 1 -yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-7/A- pyrrolo[2,3-i/]-pyrimidine-6-carboxamide A291. To a solution of compound 97.4 as a TFA salt (300 mg, 672 pmol) and 7-cyclopentyl-A,AMimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]- pyrrolo[2,3-(7]pyrimidine-6-carboxamide (225 mg, 517 nmol) in MeOH (6 mL) were added AcOH (31 mg, 517 pmol) and NaBHsCN (48.7 mg, 775 pmol). After stirring for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A291 (183 mg) in 44% yield. XH NMR (400 MHz, DMSO-d6 ) d 10.81 (s, 1H), 9.32 (s, 1H), 8.76 (s, 1H), 8.16 (s, 1H), 8.15-8.13 (m, 1H), 8.00 (d, J= 2.8 Hz, 1H), 7.43 (dd, J= 2.8, 9.1 Hz, 1H), 7.03-6.91 (m, 3H), 6.59 (s, 1H), 4.79-4.67 (m, 1H), 3.79 (dd, J= 4.8, 11.6 Hz, 1H), 3.32 (d, J = 11.6 Hz, 2H), 3.09-3 ,2(m, 6H), 2.69-2.56 (m, 10H), 2.47-2.40 (m, 4H), 2.26 (s, 2H), 2.08-1.90 (m, 6H), 1.78 (d, .7- 11.6 Hz, 2H), 1.68-1.60 (m, 2H), 1.52-1.43 (m, 3H), 1.39-1.27 (m, 2H); MS (ESI) wz: 751.5 [M+H]+.
Example 98
Preparation of 2-((5-(4-(2-(l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A,A7-dimethyl-77/-pyrrolo[2,3-</|pyrimidine-6- carboxamide A292
Figure imgf000368_0001
[00917] Compound A292 was prepared as described below.
[00918] Preparation of methyl 2-[2-chloro-4-[4-(2,2-dimethoxyethyl)-l-piperidyl]phenyl]- acetate 98.1. To a solution of methyl 2-(4-bromo-2-chlorophenyl)acetate (500 mg, 1 .90 mmol) and 4-(2,2-dimethoxyethyl)piperidine (329 mg, 1.90 mmol) in dioxane (10 mL) were added RuPhos (88.5 mg, 190 pmol), CS2CO3 (1.24 g, 3.79 mmol), and RuPhos Pd G3 (79.4 mg, 94.9 nmol) under N2. After stirring under N2 at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NarSCU, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 98.1 (377 mg) in 56% yield. MS (ESI) m/z: 356.2 [M+H]+.
[00919] Preparation of 3-[2-chloro-4-[4-(2,2-dimethoxyethyl)-l-piperidyl]phenyl]- piperidine-2, 6-dione 98.2. To a solution of compound 98.1 (370 mg, 1.04 mmol) and prop-2- enamide (73.9 mg, 1.04 mmol) in THF (5 mL) was added LBuOK (128 mg, 1.14 mmol) at 0 °C under N2. After stirring at 50 °C for 12 h, the reaction mixture was treated with IM HC1 (2 mL) at 0 °C, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SOi, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 98.2 (260 mg) in 63% yield. MS (ESI) m/z'. 395.2 [M+H]L
[00920] Preparation of 2-[l-[3-chloro-4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]- acetaldehyde 98.3. A mixture of compound 98.2 (260 mg, 658 pmol) and TEA (1 .6 g, 14 mmol) in DCM (2 mL) was stirred for 2 h. The reaction mixture was then treated with IM NaHCOs (0.5 mL), diluted with water, and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford compound 98.3 (210 mg), which was used directly in the next step without further purification. ]H NMR (400 MHz, DMSO-t/c) 3 10.83 (s, 1H), 9.69 (s, 1H), 7.09 (d, J - 8.4 Hz, 1H), 6.92 (s, 1H), 6.88 (d, J== 8.8 Hz, 1H), 4.03 (dd, ./ 4.8, 12.0 Hz, 1H), 3.69 (d, ./= 12.4 Hz, 2H), 2.78-2.64 (m, 3H), 2.40 (d, J= 6.4 Hz, 3H), 2.22 (dq, 4.4, 12.8 Hz, 1H), 2 04-1.88 (m, 211), 1.71 (d, J = 12.4 Hz, 2H), 1.35-1.12 (m, 3H); MS (ESI) m/z: 349.2 [M+H]+.
[00921] Preparation of 2-((5-(4-(2-( l-(3-Chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)ethyl)-piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-ApV-dimethyl-7//- pyrrol o[2, 3 -d]pyrimidine-6-carboxamide A292. To a mixture of 7-cyclopentyl-A(Mdimethyl-2- [(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-J]pyrimidine-6-carboxamide (150 mg, 345 umol), AcOH (20.7 mg, 345 umol) in MeOH (4 mL) were added compound 98.3 (200 mg, 573 pmol) and NaBHsCN (32.5 mg, 518 pmol). After stirring for 1 h, the reaction mixture was filtered and purified by reverse phase prep-HPLC to afford compound A292 (108 mg) in 41% yield. rH NMR (400 MHz, DMSO-^) 3 10.83 (s, 1H), 9.29 (s, 1H), 8.75 (s, 1H), 8.17-8.11 (m, 1H), 7.99 (d, J= 2.8 Hz, 1H), 7.42 (dd, J= 2.8, 9.2 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.87 (dd, J= 2.4, 8.8 Hz, 1H), 6.59 (s, 1H), 4.73 (t, ./ = 8.8 Hz, 1H), 4.03 (dd, J = 5.2, 12.0 Hz, 1H), 3.70 (d, J= 12.4 Hz, 2H), 3.12 (s, 4H), 3.05 (s, 6H), 2.70-2.63 (m, 2H), 2.57- 2.52 (m, 4H), 2.48-2.36 (m, 6H), 2.22 (dd, 3.6, 12.4 Hz, 1H), 2.05-1.88 (m, 5H), 1.75 (d, 12.0 Hz, 2H), 1.69-1.57 (m, 2H), 1.44 (t, J= 6.4 Hz, 3H), 1.32-1.12 (m, 2H); MS (ESI) m/z: 767.5 [M+H]+
Example 99
Preparation of 2-((5-(4-(2-(l-(2-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A,A-dimethyl-7//-pyrrolo[2,3-</]pyrirnidine-6- carboxamide A293
Figure imgf000370_0001
[00922] Compound A293 was prepared as described below.
[00923] Preparation of methyl 2-(4-bromo-3-chlorophenyl)acetate 99.1. A mixture of 2- (4-bromo-3-chlorophenyl)acetic acid (5 g, 20 mmol) and H2SO4 (3.93 g, 40 mmol) in MeOH (50 mL) was stirred at 70 °C for 2 h. The reaction mixture was treated with saturated aqueous NaHCCh and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford compound 99.1 (26 g), which was used directly in the next step without further purification. lH NMR (400 MHz, DMSO-tZe) b 7.70 (d, J= 8.0 Hz, 1H), 7.55 (s, 1H), 7.18 (d, J- 8.4 Hz, 1H), 3.72 (s, 2H), 3.62 (s, 3H).
[00924] Preparation of methyl 2-[3-chloro-4-[4-(2,2-dimethoxyethyl)-l-piperidyl]phenyl]- acetate 99.2. To a mixture of compound 99.1 (5 g, 19 mmol), 4-(2,2-dimethoxyethyl)piperidine (3.29 g, 19 mmol), RuPhos (885 mg, 1.9 mmol), and CS2CO3 (18.6 g, 56.9 mmol) in dioxane (60 mL) was added RuPhos Pd G3 (794 mg, 949 pmol) under N2. After stirring under N2 at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SOi, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 99.2 (1.7 g) in 25% yield. T4 NMR (400 MHz, DMSO-de) 67.30 (d, ./ 2.0 Hz, 1H), 7. 16 (dd, ./ 2.0, 8.0 Hz, 1H), 7.09-7.02 (m, 1 H), 4.48 (t, J= 5.6 Hz, 1H), 3.64-3.59 (m, 5H), 3.25-3.18 (m, 8H), 2.62-2.54 (m, 2H), 1.76 (d, J= 11.6 Hz, 2H), 1.58-1.43 (m, 3H), 1.39-1.29 (m, 2H); MS (ESI) wk 356.1 [M+H]+.
[00925] Preparation of 3-[3-chloro-4-[4-(2,2-dimethoxyethyl)-l-piperidyl]phenyl]- piperidine-2, 6-dione 99.3. To a solution of prop-2-enamide (280 mg, 3.93 mmol) and methyl compound 99.2 (1.4 g, 3.93 mmol) in THF (15 mL) was added LBuOK (486 mg, 4.33 mmol) at 0 °C under N2. After stirring at 50 °C for 2 h, the reaction mixture was treated with IM HC1 (4 mL) at 0 °C, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 99.3 (400 mg). MS (ESI) m/z: 395.3 [M+H]+.
[00926] Preparation of 2-[l-[2-chloro-4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]- acetaldehyde 99.4. A mixture of compound 99.3 (380 mg, 962 pmol) and TEA (2.92 g, 25.6 mmol) in DCM (2 mL) was stirred for 1 h. The reaction mixture was then treated with IM NaHCCh (3 mL), diluted with water, extracted with DCM. The combined organic layers were dried over anhydrous Na2.SO4 and concentrated to afford compound 99.4 (280 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 349.1 [M+H]+.
[00927] Preparation of 2-((5-(4-(2-(l-(2-Chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)- piperidin-4-yl)ethyl)-piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A,.V-dimethyl-777- pyrrolo[2,3-c/]pyrimidine-6-carboxamide A293. To a mixture of 7-cyclopen1y4-A,Az-dimethyl-2- [(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-<Z]pyrimidine-6-carboxamide (108 mg, 248 pmol) and AcOH (15 mg, 248 pmol) in MeOH (5 mL) were added compound 99.4 (130 mg, 373 pmol) andNaBELCN (23.4 mg, 373 pmol). After stirring for 1 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A293 (35 mg) in 18% yield. !H NMR (400 MHz, DMSO-^) 6 10.82 (s, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 8.25 (s, 1H), 8.14 (d, J= 9.2 Hz, 1H), 7.99 (s, 1H), 7.52-7.37 (m, 1H), 7.27 (s, 1H), 7.21-6.95 (m, 2H), 6.59 (s, 1H), 4.84-4.61 (m, 1H), 3.81 (dd, J= 4.8, 11.6 Hz, 1H), 3.25 (d, J= 11.2 Hz, 3H), 3.17-2.97 (m, 10H), 2.83- 2.57 (m, 5H), 2.42-2.30 (m, 4H), 2.26-2.14 (m, 1H), 1.98 (s, 5H), 1.85-1.74 (m, 2H), 1.70-1.59 (m, 2H), 1.55-1.41 (m, 3H), 1.40-1.18 (m, 2H); MS (ESI) m/z: 767.6 [M+H]+.
Example 100
Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)-4-fluoro- [I,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-ACV-dimethyl-7ELpyrrolo[2,3-J]pyrimidine-6- carboxamide A299
Figure imgf000371_0001
[00928] Compound A299 was prepared as described below.
[00929] Preparation of tert-butyl 4-ethynyl-4-fluoro-piperidine-l -carboxylate 100.1. A mixture of tert-butyl 4-ethynyl-4-hydroxypiperidine-l -carboxylate (5 g, 22.2 mmol) and DAST (7.15 g, 44.4 mmol) in DCM (20 mL) was stirred for 8 h under N2. The reaction mixture was then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 100.1 (2 g) in 40% yield. [H NMR (400 MHz, CDCh) 3 3.62-3.42 (m, 4H), 2.71 (d, J= 5.0 Hz, 1H), 2.03-1.86 (m, 4H), 1.46 (s, 9H).
[00930] Preparation of tert-butyl 4-[2-[4-(2,6-dibenzyloxy-3-pyridyl)-3-fluorophenyl]- ethynyl]-4-fluoropiperidine-l-carboxylate 100.2. A mixture of 2,6-dibenzyloxy-3-(4-bromo-2- fluoro-phenyl)pyridine (1.7 g, 3.66 mmol), compound 100.1 (2 g, 8.8 mmol), XPhos Pd G3 (310 mg, 366 pmol), and CS2CO3 (3.58 g, 11 mmol) in ACN (10 mL) and THF (10 mL) was stirred at 60 °C for 12 h under N2. The reaction mixture was then concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSOi, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 100.2 (700 mg) in 28% yield. *H NMR (400 MHz, CDCh) 3 7.48 (d, J= 8.0 Hz, 1H), 7.40-7.34 (m, 2H), 7.34-7.29 (m, 3H), 7.26 ( d, J= 2.4 Hz, 2H), 7.24-7.21 (m, 1H), 7.20 (s, 3H), 7.18-7.11 (m, 2H), 6.41 (d, J= 8.0 Hz, 1H), 5.31 (d, J = 8.0 Hz, 4H), 3.62-3.41 (m, 4H), 2.08-1.86 (m, 4H), 1.41 (s, 9H).
[00931] Preparation of tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidyl)-3-fluorophenyl]ethyl]-4- fluoropiperidine-1 -carboxylate 100.3. A mixture of compound 100.2 (700 mg, 1.15 mmol), 20% Pd(OH)2 (0.1 g), and 10% Pd/C (0.1 g) in THF (5 mL) was stirred at 40 °C for 12 h under H2. The reaction mixture was filtered, concentrated, and purified by prep-TLC (SiOz, MeOH/DCM) to afford compound 100.3 (400 mg) in 58% yield. Tl NMR (400 MHz, CDCh) 3 8.16 (s, 1H), 7.14-7.05 (m, 1H), 7.00-6.90 (m, 2H), 4.02-3.84 (m, 3H), 3.10 (t, J= 12.0 Hz, 2H), 2.79-2.64 (m, 4H), 2.35-2.19 (m, 2H), 1.98-1.80 (m, 4H), 1.65-1.51 (m, 2H), 1.48-1.45 (m, 9H).
[00932] Preparation of 3-[2-fluoro-4-[2-(4-fluoro-4-piperidyl)ethyl]phenyl]piperidine-2,6- dione 100.4. A mixture of compound 100.3 (400 mg, 916 pmol) and 4M HC1 in dioxane (10 mL) was stirred for 2 h under N2. The reaction mixture was then concentrated to afford compound 100.4 as an HCI salt (350 mg), which was used directly in the next step without further purification.
[00933] Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro- phenethyl)-4-fluoro-[l,4'-bipiperidin]-l'-yl)pyridin-2-yl)amino)-A,A-dimethyl-72/-pyrrolo[2,3- </|pyrimidine-6-carboxamide A299. A mixture of compound 100.4 as an HCI salt (150 mg, 402 praol), 7-cyclopentyl-Ar,A-dimethyl-2-[[5-(4-oxo-l-piperidyl)-2-pyridyl]amino]pyrrolo[2,3-6/]- pyrimidine-6-carboxamide (198 mg, 443 pmol), NaOAc (99 mg, 1.21 mmol), and NaBHsCN (51 mg, 805 nmol) in THF (2 mL) and DMSO (2 mL) was stirred for 12 h under N2. The reaction mixture was filtered and purified by reverse phase prep-HPLC to afford compound A299 (40 mg) in 13% yield. LH NMR (400 MHz, DMSO-uk) 8 10.92-10.79 (m, 1H), 9.25 (s, 1H), 8.75 (s, 1H), 8.12 (d, 9.2 Hz, 1H), 7,99 (d, J= 2.8 Hz, 1H), 7,46-7,37 (m, 1H), 7,25-7,16 (m, 1H),
7.12-7.00 (m, 2H), 6.59 (s, 1H), 4.80-4.66 (m, 1H), 3.99 (dd, J= 4.8, 12.4 Hz, 1H), 3.68 (d, J = 11.6 Hz, 2H), 3.05 (s, 6H), 2.77-2.61 (m, 9H), 2.42 (d, J = 9.6 Hz, 3H), 2.23-2.13 (m, 1H), 2.03- 1.91 (m, 6H), 1.90-1.78 (m, 6H), 1.71-1.54 (m, 6H); MS (ESI) m/z: 768.4 [M+H] \
Example 101
Preparation of 7-cydopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenethyl)-4-fluoro- [l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-A,iV-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A353
Figure imgf000373_0001
[00934] Compound A353 was prepared as described below.
[00935] Preparation of tert-butyl 4-[2-[4-(2,6-dibenzyloxy-3-pyridyl)-2-fluorophenyl]- ethynyl]-4-fluoropiperidine-l-carboxylate 101.1. A mixture of 2,6-dibenzyl oxy-3 -(4-bromo-3- fluorophenyl)pyridine (5 g, 10.8 mmol), tert-butyl 4-ethynyl-4-fluoropiperi dine- 1 -carboxylate (3.67 g, 16.2 mmol), XPhos Pd G3 (911 mg, 1.08 mmol), and CS2CO3 (10.5 g, 32,3 mmol) in ACN (50 mL) and THF (50 mL) was stirred at 60 °C for 12 h under N2. The reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 101.1 (5.5 g) in 64% yield. MS (ESI) m/z: 611.3 [M+H]+.
[00936] Preparation of tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidyl)-2-fluorophenyl]ethyl]-4- fluoropiperidine-l-carboxylate 101.2, To a solution of compound 101.1 (5.5 g, 9.01 mmol) in THF (50 mL) were added 10% Pd/C (0.5 g) and 20% Pd(OH)2 (0.5 g) under N2. After stirring under H2 at 40 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound 101.2 (1.1 g) in 25% yield.
[00937] Preparation of 3-[3-fluoro-4-[2-(4-fluoro-4-piperidyl)ethyl]phenyl]piperidine-2,6- dione 101.3, To a solution of compound 101.2 (1.1 g, 2.52 mmol) in DCM (10 mL) was added 4M HC1 in dioxane (5 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 101.3 as an HC1 salt (0.9 g), which was used directly in the next step without further purification. MS (ESI) m/z: 337.1 [M+H]T
[00938] Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-2- fluorophenethyl)-4-fluoro-[l,4'-bipiperi din]- T-yl)pyri din-2 -yl)amino)-jV, A-dimethyl-7/T- pyrrolo[2,3-t./]pyrimidine-6-carboxaraide A353. To a solution of compound 101.3 (0.15 g, 446 umol) and 7-cyclopentyl-A,A-dimethyl-2-[[5-(4-oxo-l-piperidyl)-2-pyridyl]amino]pyrrolo[2,3- Jjpyrimidine-6-carboxamide (200 mg, 446 pmol) in THF (1 mL) and DMSO (1 mL) was added NaOAc (73 mg, 892 pmol). After the mixture was stirred at 60 °C for 4 h, NaBHsCN (56 mg, 892 umol) were added. The reaction mixture was stirred for 12 h and then purified by reverse phase prep-HPLC to afford compound A353 (11 mg) in 3% yield.
Figure imgf000374_0001
NMR (400 MHz, CDCh) 3 8.87 (s, 1H), 8.71 (s, 1H), 8.35 (d, J= 9.2 Hz, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 7.34 (d, J= 9.2 Hz, 1 H), 7.21 (t, J = 8.0 Hz, 1H), 6.99-6.85 (m, 2H), 6.44 (s, HI), 4.80 (q, J- 8.8 Hz, HI), 3.75 (dd, J= 5.2, 9.6 Hz, 1H), 3.66 (d, J= 11.6 Hz, 2H), 3.16 (s, 6H), 2.82-2.71 (m, 6H), 2.70-2.66 (m, 1H), 2.65-2.55 (m, 4H), 2.50 (s, 1H), 2.34-2.20 (m, 2H), 2.13-2.03 (m, 4H), 2.02-1.91 (m, 5H), 1.90-1.82 (m, 2H), 1.82-1.68 (m, 6H); MS (ESI) m/z: 768.4 [M+H]+.
Example 102
Preparation of 7-cyclopentyl-2-((4-((2-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2/7)-yl)- phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-AjV-dimethyl-777-pyrrolo[2,3-t7]- pyrimidine-6-carboxamide A401
Figure imgf000375_0001
[00939] Compound A401 was prepared as described below.
[00940] Preparation of benzyl 4-(2-((teH-butoxycarbonyl)amino)ethyl)piperazine-l- carboxylate 102.1. To a stirred solution of benzyl piperazine- 1 -carboxylate (500 mg, 2.27 mmol) in DCM (16 mL) and MeOH (4 mL) were added ferLbutyl (2-oxoethyl)carbamate (542 mg, 3.4 mmol) and NaBHiCN (128 mg). After stirring overnight, the reaction mixture was concentrated and purified by column chromatography (Si O2, MeOH/DCM) to afford compound 102.1 (760 mg) in 923% yield. MS (ESI) m/z: 364.2 [M i l] ,
[00941] Preparation of benzyl 4-(2-aminoethyl)piperazine-l -carboxylate 102.2. To a solution of compound 102.1 (760 mg, 2.09 mmol) in DCM (10 mL) was added HC1 in EtOAc
(10 mL). After stirring for 2 h, the rection mixture was concentrated to afford compound 102.2, which was used directly in the next step without further purification. MS (ESI) m/z: 264.2 [M+H]+.
[00942] Preparation of benzyl 4-(2-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-<7]pyrimidin-2-yl)amino)benzamido)ethyl)piperazine-l -carboxylate 102.3. To a solution of compound 102.2 (1.59 mmol) in DMF (20 mL) were added 4-((7-cyclopentyl-6- (dimethyicarbamoyl)-7//-pyrroio[2,3-tf|pyrimidin-2-yl)amino)benzoic acid (625 mg, 1.59 mmol), DIEA (615 mg, 4.77 mmol), and HATU (906 mg, 2.39 mmol). After stirring overnight, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCh, concentrated, and purified by column chromatography (SiOz, MeOH/DCM) to afford compound 102.3 (536 mg) in 53% yield. MS (ESI) m/z: 639.3 [M+H]+.
[00943] Preparation of 7-cyclopentyl-Ar,A7-dimethyl-2-((4-((2-(piperazin-l-yl)ethyl)- carbamoyl)phenyl)amino)-7J7-pyrrolo[2,3-7]pyrimidine-6-carboxamide 102.4. To a solution of compound 102.3 (536 mg, 0.84 mmol) in THF (20 mL) was added 10% Pd/C (536 mg). After stirring under H2 overnight, the reaction mixture was filtered and concentrated to afford compound 102.4 (422 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 505.3 [M+Hf.
[00944] Preparation of 7-cyclopentyl-2-((4-((2-(4-(2-(3-(2,4-dioxotetrahydropyrimidin- l(2//)-yl)-phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A^V-dimethyl-7#- pyrrolo[2,3-<7]-pyrimidine-6-carboxamide A401. To a solution of compound 102.4 (94 mg, 187 umol) in DMF (5 mL) were added DIEA (72 mg, 560 pmol), 2-(3-(2,4-dioxotetrahydro- pyrimidin-l(2//)- yl)phenoxy)acetic acid (97 mg , 370 pmol), HOBt (50 mg, 370 umol), and EDCI (53 mg, 280 umol). After stirring overnight, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by reverse phase prep-HPLC to afford compound A401 (41 mg) in 29% yield. ^NMR (400 MHz, DMSO-tfc) <5 10.35 (s, 1H), 9.81 (s, 1H), 8.79 (s, 1H), 8.24 (t, 7 5.6 Hz, 1H), 7.91 (d, 7 8.8 Hz, 2H), 7.79 (d, 7 8.8 Hz, 2H), 7.27 (t, ./ 8.0 Hz, 1H), 6.92-6.90 (m, 2H), 6.79 (d, J= 8.8 Hz, 1H), 6.61 (s, 1H), 4.81 (s, 2H), 4.75 (t, J = 9.2 Hz, 1H), 3.76 (t, J= 6.4 Hz, 2H), 3.49-3.43 (m, 4H), 3.42-3.37 (m, 2H), 3.10-2.98 (m, 6H), 2.69 (t, 7= 6.8 Hz, 2H), 2.45-2.38 (m, 4H), 2.04-1.94 (m, 5H), 1.73-1.63 (m, 2H), 1.32-1.24 (m, 3H); MS (ESI) m/z: 751.2 [M+H]+.
Example 103
Preparation of 7-cyclopentyl-2-((4-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin- 1 -yl)phenyl)amino)-Ar<V-dimethyl-77/-pyrrolo[2,3 -t/]pyrimidine-6-carboxamide A407
Figure imgf000376_0001
[00945] Compound A407 was prepared as described below.
[00946] Preparation of l-(3-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydro- pyrimidine-2, 4-dione 103.1. To a solution of 1,3 -dibromobenzene (500 mg, 2.12 mmol) and 3- [(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (497 mg, 2.12 mmol) in DMF (8 mL) were added
Figure imgf000377_0001
dimethylcyclohexane-l^-diamine (121 mg, 848 pmol), Cui (161 mg, 848 pmol), and
Figure imgf000377_0002
g, 4.24 mmol). After stirring at 100 °C for 2 h under N2, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous NazSOr, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 103.1 (160 mg) in 19% yield. iH NMR (400 MHz, CDCh) 3 7.45 (t, ./= 2.0 Hz, IH), 7.44-7.37 (m, 3H), 7.27 (s, 2H), 6.87-6.81 (m, 2H), 4.96 (s, 2H), 3.81-3.74 (m, 5H), 2.94-2.83 (m, 2H).
[00947] Preparation of 7-cyclopentyl-2-[4-[4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo- hexahydropyrimidin-l-yl]phenyl]piperazin-l-yl]anilino]-A(Ar-dimethyl-pyrrolo[2,3-tf]- pyrimidine-6-carboxamide 103.2, To a solution of compound 103.1 (160 mg, 411 pmol) and 7- cyclopentyl-A,A-dimethyl-2-(4-piperazin-l -ylanilino)pyrrolo[2,3-tZ]pyrimidine-6-carboxamide as an HC1 salt (193 mg, 411 pmol) in dioxane (10 mL) were added RuPhos Pd G3 (34.4 mg, 41.1 pmol) and CS2CO3 (402 mg, 1.23 mmol). After stirring at 100 °C for 16 h under N2, the reaction mixture was concentrated and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 103.2 (110 mg) in 36% yield. rHNMR (400 MHz, DMSO-^) J 9.24 (s, IH), 8.69 (s, IH), 7.69 (d, J= 9.2 Hz, 2H), 7.27-7.20 (m, 3H), 6.99-6.94 (m, 3H), 6.92-6.84 (m, 3H), 6.76 (dd, J= 1.2, 8.0 Hz, IH), 6.55 (s, IH), 4 81 (s, 2H), 4.72 (t, J= 8.8 Hz, IH), 3.78 (t, J= 6.8 Hz, 2H), 3.72 (s, 3H), 3.47-3.44 (m, 2H), 3.23-3.18 (m, 4H), 3.05 (s, 6H), 2.91 -2.84 (m, 2H), 2.47-2.40 (m, 2H), 1.98-1.91 (m, 4H), 1.69-1.55 (m, 4H).
[00948] Preparation of 7-cyclopentyl-2-((4-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2/Z)- yl)phenyl)-piperazin-l-yl)phenyl)amino)-A(/V-dimethyl-7.H-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A407. To a solution of compound 103.2 (100 mg, 135 pmol) in DCM (4 mL) were added TfOH (340 mg, 2.27 mmol) and TFA (308 mg, 2.7 mmol). After stirring for 6 h, the reaction mixture was diluted with DCM, basified with saturated aqueous NaHCCh to pH 8, and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, concentrated, and purified by reverse phase prep-HPLC to afford compound A407 (25 mg) in 29% yield. !H NMR (400 MHz, DMSO-^+D2O) 3 = 8.69 (s, IH), 7.69 (d, J= 8.8 Hz, 2H), 7.25 (t, ./ 8.0 Hz, IH), 7,00-6,93 (ra, 3H), 6.89 (d, ./ 8.0 Hz, IH), 6.76 (d, ./ 8.0 Hz, IH), 6.55 (s, 1H), 4.71 (t, J- 8.8 Hz, 1H), 3.77 (t, 6.8 Hz, 2H), 3.34-3.16 (m, 8H), 3.05 (s, 6H), 2.70 (t, J
= 6.8 Hz, 2H), 2.44 (d, J= 10.8 Hz, 2H), 1.97 (s, 4H), 1.64 (d, J= 5.2 Hz, 2H); MS (ESI) m/z:
622.4 [M+H]+.
Example 104
Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)pyridin-2-yl)amino)-A’,Ar-dimethyl-7Hr-pyrrolo[2,3-d]pyrimidine-6-carboxamide
A408
Figure imgf000378_0001
[00949] Compound A408 was prepared as described below.
[00950] Preparation of l-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydro- pyrimidine-2, 4-dione 104.1. To a solution of l-bromo-4-iodobenzene (2 g, 7.07 mmol) and 3- [(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (1.99 g, 8.48 mmol) in DMF (20 mL) were added Z-proline (326 mg, 2.83 mmol), CS2CO3 (4.61 g, 14.1 mmol), and Cui (539 mg, 2.83 mmol). After stirring at 90 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCE, concentrated, and purified by column chromatography (SiOr, EtOAc/PE) to afford compound 104.1 (1.7 g) in 62% yield. ’H NMR (400 MHz, DMSO-tZ) 8 7.78-7.72 (m, 1H), 7.62-7.56 (m, HI), 7.35-7.29 (m, 1H), 7.23 (dd, J = 1.6, 8.8 Hz, 2H), 7.20-7.14 (m, 1H), 6.86 (d, J= 8.8 Hz, 2H), 4.81 (s, 2H), 3.80 (dt, J= 3.2, 6.8 Hz, 2H), 3.34 (s, 3H), 2.92-2.87 (m, 2H).
[00951] Preparation of 7-cyclopentyl-A,A-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)- amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide 104.2. To a solution of tert-butyl 4-[6-[[7- cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-r/]pyrimidin-2-yl]amino]-3-pyridyl]piperazine-l- carboxylate (4 g, 7.48 mmol) in DCM (20 mL) was added 4M HC1 in dioxane (20 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 104.2 as an HC1 salt (4 g), which was used directly in the next step without further purification. MS (ESI) m/z: 435.3 [M+H]+.
[00952] Preparation of 7-cyclopentyl-2-[[5-[4-[4-[3-[(4-methoxyphenyl)methyl]-2,4- dioxo-hexahydropyrimidin-l-yl]phenyl]piperazin-l-yl]-2-pyridyl]amino]-A,A-dimethyl- pyrrolo[2,3-d]pyrimidine-6-carboxamide 104.3. To a solution of compound 104.1 (400 mg, 1.03 mmol) and compound 104.2 (447 mg, 1.03 mmol) in dioxane (4 mL) were added CS2CO3 (670 mg, 2.06 mmol) and Pd-PEPPSI-IPent (88.4 mg, 103 pmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 104.3 (450 mg) in 59% yield. MS (ESI) m/z: 646.6 [M+H]+.
[00953] Preparation of 7-cyclopentyl-2-((5-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)- yl)phenyl)-piperazin-l-yl)pyridin-2-yl)amino)-A(Ar-dimethyl-7//-pyrrolo[2,3-cZ]pyrimidine-6- carboxamide A408 To a solution of compound 104.3 (200 mg, 269 pmol) in DCM (2 mL) were added TfOH (1.7 g, 11.3 mmol) and TFA (1.54 g, 13.5 mmol). After stirring at 40 °C for 0.5 h, the reaction mixture was diluted with DMF (1 mL) and purified by reverse phase prep-HPLC to afford compound A408 (18 mg) in 11% yield.
Figure imgf000379_0001
(400 MHz, DMSO-Je) ci 11.53-11.04 (m, 1H), 10.29 (s, 1H), 8.98 (s, 1H), 8.15-8.04 (m, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.69-7.57 (m, 1 H), 7.21 (d, J= 9.2 Hz, 2H), 7.05 (d, 9.2 Hz, 2H), 6.81 (s, 1H), 4.87-4.76 (m, 1H), 3.72 (t, J
- 6.8 Hz, 2H), 3.51 (d, J = 13.2 Hz, 4H), 3.06 (s, 6H), 2.73-2.65 (m, 4H), 2.36-2.30 (m, 2H), 2.14-1.88 (m, 6H), 1.71-1.63 (m, 2H); MS (ESI) m/z: 623.2 [M+H]+.
Example 105
Preparation of 7-cyclopentyl-2-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2#)-yl)benzyl)- piperazin-l-yI)phenyl)amino)-A(A;-dimethyl-7Z/-pyrrolo[2,3-c/]pyrimidine-6-carboxamide A409
Figure imgf000379_0002
[00954] Compound A409 was prepared as described below.
[00955] Preparation of 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione 105.1. To a solution of hexahydropyrimidine-2, 4-dione (20 g, 175 mmol) in DMF (400 mL) was added CS2CO3 (57 g, 175 mmol) and 1 -(chi oromethyl)-4-m ethoxybenzene (27 g, 175 mmol). After stirring at 50 °C for 3 h, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCL, concentrated, and triturated with EtOAc/PE to afford compound 105.1 (15 g) in 37% yield. }H NMR (400 MHz, DMSO-tA) 3 7.80 (br s, 1H), 7.17 (d, 8.6 Hz, 2H), 6.84 (d, J =
8.6 Hz, 2H), 4.71 (s, 2H), 3.71 (s, 3H), 3.21 (dt, J= 2.6, 6.8 Hz, 2H), 2.62 (t, J= 6.8 Hz, 2H).
[00956] Preparation of l-[4-(dimethoxymethyl)phenyl]-3-[(4-methoxyphenyl)methyl]- hexahydropyrimidine-2, 4-dione 105.2. To a mixture of l-bromo-4-(dimethoxymethyl)benzene (2 g, 8.65 mmol) and compound 105.1 (2.03 g, 8.65 mmol) in dioxane (30 mL) were added Cs2.( ,'O; (5.64 g, 17.3 mmol), Pd?.(dba)3 (793 mg, 865 pmol), and Xantphos (1 g, 1.73 mmol) under N2. After stirring at 100 °C for 16 h, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous NarSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 105.2 (2.1 g) in 63% yield.
[00957] Preparation of 4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexahydropyrimidin-l- yl]benzaldehyde 105.3. To a solution of compound 105.2 (2.1 g, 5.46 mmol) in DCM (20 mL) was added TFA (3,08 g). After stirring for 1 h, the reaction mixture was concentrated to afford compound 105.3 (1.8 g), which was used directly in the next step without further purification, rid NMR (400 MHz, CDCh) 39.86-9 83 (m, 1H), 7.89-7.74 (m, 2H), 7.35 (d, J- 8.5 Hz, 2H), 7.25 (br s, 2H), 6.72 (d, J= 8.5 Hz, 2H), 4.86 (s, 2H), 3.77 (t, J= 6.7 Hz, 2H), 3.70-3.64 (m, 3H), 2.92-2.80 (m, 2H).
[00958] Preparation of 7-cyclopentyl-2-[4-[4-[[4-[3-[(4-methoxyphenyl)methyl]-2,4- dioxohexahydropyrimidin-l-yl]phenyl]methyl]piperazin-l-yl] anilino]-A,A-dimethyl-pyrrolo- [2,3-J]pyrimidine-6-carboxamide 105.4, To a mixture of 7-cyclopentyl-A,Ar-dimethyl-2-(4- piperazin-l-ylanilino)pyrrolo[2,3-c/]pyrimidine-6-carboxamide (130 mg, 300 pmol) in THF (3 mL) was added compound 105.3 (203 mg, 600 pmol), followed by addition of NaBH(OAc)s (127 mg, 600 pmol) and AcOH (1.8 mg, 30 pmol). After stirring at 30 °C for 16 h, the reaction mixture was poured into aqueous NH4CI and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 105.4 (130 mg) in 57%. *H NMR (400 MHz, DMSCWe) d 9.21 (s, 1H), 8.68 (s, 1H), 7.64 (d, ./ 8.9 Hz, 2H), 7.39-7.33 (m, 2H), 7.32- 7.27 (m, 2H), 7.23 (d, J = 8.6 Hz, 2H), 6.92-6.82 (m, 4H), 6.54 (s, 1H), 4.80 (s, 2H), 3.80 (t, J= 6.7 Hz, 2H), 3.72 (s, 3H), 3.53 (s, 2H), 3.17 (d, ./ 5.1 Hz, 1H), 3.05 (br s, 11H), 2.88 (t, ./ 6.6 Hz, 2H), 2.72-2.65 (m, 3H), 2.03-1.84 (m, 8H); MS (ESI) m/z: 756.4 [M+H]+.
[00959] Preparation of 7-cyclopentyl-2-((4-(4-(4-(2,4-dioxotetrahydropyrimidin- 1 (2H)- yl)benzyl)-piperazin-l-yl)phenyl)amino)-A,A-dimethyl-7J/-pyrrolo[2,3-cZ]pyrimidine-6- carboxamide A409. To a mixture of compound 105.4 (130 mg, 172 pmol) in DCM (3 mb) were added TFA (200 mg, 1.76 mmol) and TfOH (221 mg, 1.47 mmol). After stirring at 30 °C for 3 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A409 as a TFA salt (43 mg) in 36% yield. !H NMR (400 MHz, DMSO-tA) 5 10.36 (s, 1H), 9.22 (s, 1H), 8.68 (s, 1H), 8.13 (s, 1H), 7.65 (d, ./ 9.0 Hz, 2H), 7.40-7.34 (m, 2H), 7.34-7.28 (m, 2H), 6.88 (d, J= 9.0 Hz, 2H), 6.54 (s, 1H), 4.77-4.65 (m, 1H), 3.79 (t, J= 6.6 Hz, 2H), 3.66-3.53 (m, 2H), 3. 19-2.97 (m, 11H), 2.70 (t, J= 6.6 Hz, 2H), 2.60 (br s, 3H), 2.44 (br dd, , 7= 9.4, 11.1 Hz, 2H), 1 .95 (br d, .7= 2.1 Hz, 4H), 1.68-1.55 (m, 2H); MS (ESI) wz: 636.4 [M+H]+.
Example 106
Preparation of 7-cyclopentyl-2-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenethyl)- piperazin-l-yl)phenyl)amino)-A,Ar-dimethyl-7//-pyrrolo[2,3-7]pyrimidine-6-carboxamide A410
Figure imgf000381_0001
[00960] Compound A410 was prepared as described below.
[00961] Preparation of 3-[(4-methoxyphenyl)methyl]-l-[4-[(£)-2-methoxyvinyl]phenyl]- hexahydropyrimidine-2, 4-dione 106.1. To a solution of methoxymethyl(triphenyl)phosphonium chloride (405 mg, 1.18 mmol) in THF (5 mL) was added ABuOK (113 mg, 1 mmol) at 0 °C. After the mixture was stirred at 0 °C for 10 min, 4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo- hexahydropyrimidin-l-yl]benzaldehyde (200 mg, 591 pmol) in THF (1 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and at 25 °C for 30 min, and then poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous NarSCU, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 106.1 (120 mg) in 55% yield.
Figure imgf000382_0001
NMR (400 MHz, CDCh) ri 7.58 (d, J = 8.4 Hz, 1H), 7.43 (d, J= 8.4 Hz, 2H), 7.27-7.21 (m, 1H), 7.21-7.14 (m, 2H), 7.03 (d, J= 12.8 Hz, 1H), 6.83 (d, J= 8.8 Hz, 2H), 5.80 (d, J= 13.2 Hz, 1H), 4.96 (s, 2H), 3.85-3.66 (m, 8H), 2.91-2.83 (m, 2H).
[00962] Preparation of 2-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydro- pyrimidin-l-yl]phenyl]acetaldehyde 106.2. To a solution of compound 106.1 (110 mg, 300 pmol) in DCM (5 mL) was added TFA (1.54 g, 13.5 mmol). After stirring at 50 °C for 2 h, the reaction mixture was concentrated to afford compound 106.2 (120 mg), which was used directly in the next step without further purification.
[00963] Preparation of 7-cyclopentyl-2-[4-[4-[2-[4-[3-[(4-methoxyphenyl)methyl]-2,4- dioxohexahydrop-yrimidin-l-yl]phenyl]ethyl]piperazin-l-yl]anilino]-A,Az-dimethyl-pyrrolo[2,3- tZ]pyrimidine-6-carboxamide 106.3. To a solution of compound 106.2 (100 mg, 284 pmol) and 7-cyclopentyl-Ar,A-dimethyl-2-(4-piperazin-l-ylanilino)pyrrolo[2,3-t/]pyrimidine-6-carboxamide (123 mg, 284 pmol) in THF (5 mL) was added NaBH(OAc)3 (120 mg, 568 nmol). After stirring at 20 °C for 30 min, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO-i, concentrated, and triturated with EtOAc to afford compound 106.3 (120 mg) in 55% yield. !H NMR (400 MHz, DMSO-tsfc) d 8.72-8.65 (m, 1H), 7.76-7.61 (m, 2H), 7.35-7.15 (m, 6H), 6.99-6.90 (m, 2H), 6.88-6.82 (m, 2H), 6.58-6.53 (m, 1H), 6.51 (s, 3H), 4.89-4.77 (m, 2H), 4.76-4.67 (m, 1H), 3.85-3.68 (m, 6H), 3.25 (s, 3H), 3.15-2.98 (m, 9H), 2.93-2.78 (m, 4H), 2.45 (d, J= 2.4 Hz, 2H), 2.02-1.90 (m, 6H), 1.63 (d, J = 3.6 Hz, 2H).
[00964] Preparation of 7-cyclopentyl-2-((4-(4-(4-(2,4-dioxotetrahydropyrimidin- 1(2/7)- yl)phenethyl)-piperazin- 1 -yl)pheny l)amino)-A,A-dimethyl -7/7-pyrrol o[2,3 -<7]pyrimi dine-6- carboxamide A410. To a solution of compound 106.3 (110 mg, 143 pmol) in DCM (4 mL) were added TfOH (340 rag, 2.27 mmol) and TFA (308 mg, 2.7 mmol). After stirring for 1 h, the reaction mixture was diluted with DCM, basified by saturated aqueous NaHCCh to pH 8, and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by reverse phase prep-HPLC to afford compound A410 as a TFA salt (14 mg) in 13% yield. rH NMR (400 MHz, DMSO-tfrHW) 3 - 8.73-8.64 (m, I I I). 8.13 (s, 1H), 7.73-7.62 (m, 2H), 7.40-7.17 (m, 4H), 6.95 (d, 8.8 Hz, 2H), 6.55 (s, 1H), 4.76-4.60 (m,
1H), 3.76 (t, J= 6.8 Hz, 2H), 3.33-2.91 (m, 17H), 2.74-2.66 (m, 3H), 2.44-2.39 (m, 2H), 2.03- 1.87 (m, 4H), 1.69-1.56 (m, 2H); MS (ESI) mA: 622.3 [M H] .
Example 107
Preparation of 7-cyclopentyl-2-((5-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenoxy)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A'',A'r-dimethyl-7H-pyrrolo[2,3-tf]pyrimidine-6- carboxamide A411
Figure imgf000383_0001
[00965] Compound A411 was prepared as described below.
[00966] Preparation of l-(4-hydroxyphenyl)-3-[(4-methoxyphenyl)methyl]hexahydro- pyrimidine-2, 4-dione 107.1. A mixture of 4-bromophenol (1 g, 5.78 mmol), 3-[(4-methoxy- phenyl)methyl]hexahydropyrimidine-2, 4-dione (1.62 g, 6.94 mmol), CS2CO3 (3.77 g, 11.6 mmol), Cui (440 mg, 2.31 mmol), and (lA^^-A^^-dimethylcyclohexane-lA-diamine (329 mg, 2.31 mmol ) in DMF (10 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 107.1 (816 mg) in 41% yield. MS (ESI) m/z: 327 [M+H]+. [00967] Preparation of 1 -[4-(2-hydroxyethoxy)phenyl]-3-[(4-methoxyphenyl)methyl]- hexahydropyrimidine-2, 4-dione 107.2. To a solution of compound 107.1 (400 mg, 1.23 mmol) in DMF (3 mL) were added K2CO3 (339 mg, 2.45 mmol) and 2-iodoethanol (422 mg, 2.45 mmol). After stirring at 80 °C for 3 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCE, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 107.2 (552 mg) in 56% yield. MS (ESI) m/z\ 371.2 [M+H]+.
[00968] Preparation of 2-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydro- pyrimidin-l-yl]phenoxy]ethyl 4-methylbenzenesulfonate 107.3. To a solution of compound 107.2 (552 mg, 1.49 mmol) in DCM (5 mL) were added TsCl (852 mg, 4.47 mmol) and TEA (181 mg, 1.79 mmol). After stirring for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NTuSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford 107.3 (750 mg) in 86% yield. MS (ESI) m/z: 525.2 [M+H]+.
[00969] Preparation of 7-cyclopentyl-2-[[5-[4-[2-[4-[3-[(4-methoxyphenyl)methyl]-2,4- dioxohexahydropyrimidin-l-yl]phenoxy]ethyl]piperazin-l-yl]-2-pyridyl]amino]-A^V-dimethyl- pyrrolo[2,3-<7]pyrimidine-6-carboxamide 107.4. To a solution of 7-cyclopentyl-A7,A’-dimethyl-2- [(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide (199 mg, 458 umol) and compound 107.3 (200 mg, 381 pmol) in DMF (2 mL) were added KI (31.6 mg, 191 pmol) and DIEA (148 mg, 1.14 mmol). After stirring for 6 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SO4, concentrated, and purified by prep-TLC (SiO?., MeOH/DCM) to afford compound 107.4 (176 mg) in 56% yield. MS (ESI) m/z: 787.3 [M+H]+.
[00970] Preparation of 7-cyclopentyl-2-((5-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l (2//)- yl)phenoxy)-ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-77/-pyrrolo[2,3-t7]- pyrimidine-6-carboxamide A411. A mixture of compound 107.4 (86 mg, 109 umol), TfOH (170 mg, 1.13 mmol), and TFA (770 mg, 6.75 mmol) was stirred at 40 °C for 6 h. The reaction mixture was then concentrated and purified by reverse phase prep-HPLC to afford compound A411 (40 mg) in 27% yield. ‘HNMR (400 MHz, CDCh) J 8.71 (s, 1H), 8.31 (d, J = 9.2 Hz, 1H), 7.99 (d, 2.4 Hz, 1H), 7.90 (s, 1H), 7.37 (dd, 2.0, 8.8 Hz, 1H), 7.23 (d, ./= 8.8 Hz,
2H), 6.97 (d, J= 8.8 Hz, 2H), 6.45 (s, 1H), 4.80 (t, J= 8.8 Hz, 1H), 4.20 (t, J= 5.2 Hz, 2H), 3.83 (t, ./= 6.8 Hz, 2H), 3.26-3.21 (m, 4H), 3.16 (s, 6H), 2.97 (t, ./= 5.2 Hz, 2H), 2.89-2.82 (m, 6H), 2.62-2.52 (m, 2H), 2.15-1.98 (m, 6H); MS (ESI) m/z: 667.2 [M+H]+.
Example 108
Preparation of 7-cyclopentyl-2-((5-((4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)methyl)pyridin-2-yl)amino)-Ar,A7-dimethyl-77f-pyrrolo[2,3-<7|pyrimidine-6- carboxamide A414
Figure imgf000385_0001
[00971] Compound A414 was prepared as described below.
[00972] Preparation of 7-cyclopentyl-2-[(5-formyl-2-pyridyl)amino]-A(A-dimethyl- pyrrolo[2,3-<7]pyrimidine-6-carboxamide 108.1. A mixture of 2-chloro-7-cyclopentyl-A(A- dimethylpyrrolo[2,3-i/]pyrimidine-6-carboxamide (2 g, 6.83 mmol), 6-aminopyridine-3- carbaldehyde (1 g, 8.2 mmol), Pd(OAc)2 (38 rag, 171 pmol), BINAP (213 rag, 342 pmol), and CS2CO3 (4.45 g, 13.7 mmol) in dioxane (20 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SC>4, concentrated, and triturated with EtOAc/PE to afford compound 108.1 (2.6 g). MS (ESI) m/z: 379.3 [M+H]+.
[00973] Preparation of 7-cyclopentyl-2-((5-((4-(4-(2,4-dioxotetrahydropyrimidin-l(2/7)- yl)phenyl)-piperazin-l-yl)methyl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7Z/-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A414. To a solution of 1 -(3 -piperazin- 1-ylpheny l)hexahydro- pyrimidine-2, 4-dione as a TFA salt (100 mg, 258 pmol) in MeOH (2 mL) were added NaOAc (63.4 mg, 773 pmol) and compound 108.1 (107 mg, 283 pmol). After the mixture was stirred for 15 min, NaBELCN (32.4 mg, 515 pmol) was added. The reaction mixture was stirred for 12 h and then purified by reverse phase prep-HPLC to afford compound A414 as a TFA salt (41.8 mg) in 24% yield. lH NMR (400 MHz, DMSO-fifc) d 10.29 (s, 1H), 9.59 (s, 1H), 8.81 (s, 1H), 8.29 (d, J= 8.8 Hz, 1H), 8.26 (s, 1H), 8.21 (d, J= 2.0 Hz, 1H), 7.71 (dd, J= 2.4, 8.8 Hz, 1H), 7.20 (t, 8.0 Hz, 1H), 6.88 (s, 1H), 6.80 (dd, J= 2.0, 8.4 Hz, 1H), 6.74-6.69 (m, 1H), 6.62 (s,
1H), 4.75 (quin, J= 8.8 Hz, 1H), 3.74 (t, J= 6.8 Hz, 2H), 3.51 (s, 2H), 3.17-3.12 (m, 4H), 3.05 (s, 6H), 2.68 (t, ./ 6.8 Hz, 2H), 2.55-2.51 (m, 4H), 2.47-2.40 (m, 2H), 2.03-1.94 (m, 4H), 1.70- 1.60 (m, 2H); MS (ESI) m/z: 637.5 [M+H]+.
Example 109
Preparation of 7-cyclopentyl-2-((5-(2-(4-(4-(2,4-dioxotetrahydropyrimidin- 1 (277)-yl)phenyl)- piperazin-l-yl)ethoxy)pyridin-2-yl)amino)-A(AMimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carb oxami de A415
Figure imgf000386_0001
[00974] Compound A415 was prepared as described below.
[00975] Preparation of 2-[(5-benzyloxy-2-pyridyl)amino]-7-cyclopentyl-A(A-dimethyl- pyrrolo[2,3-J]pyrimidine-6-carboxamide 109.1. A mixture of 5-benzyloxypyridin-2-amine (3.42 g, 17.1 mmol), 2-chloro-7-cyclopentyl-jVrALdimethylpyrrolo[2,3-<Z]pyrimidine-6-carboxamide (5 g, 17.1 mmol), CS2CO3 (11.1 g, 34.2 mmol), Pd(OAc)2 (191.7 mg, 854 pmol), and BINAP (1.06 g, 1.71 mmol) in dioxane (50 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 109.1 (7.5 g) in 96% yield. MS (ESI) m/z: 457.3 [M+H]+.
[00976] Preparation of 7-cyclopentyl-2-[(5-hydroxy-2-pyridyl)amino]-AlAz-dimethyl- pyrrolo[2,3-<7]pyrimidine-6-carboxamide 109.2. To a solution of compound 109.1 (7.5 g, 16.4 mmol) in THF (40 mL) and EtOH (40 mL) was added 10% Pd/C (7 g) under N2. After stirring under H2 at 50 °C for 16 h, the reaction mixture was filtered and concentrated to afford compound 109.2 (3.86 g), which was used directly in the next step without further purification.
MS (ESI) m/z: 367 [M+H]t
[00977] Preparation of 7-cyclopentyl-2-[[5-(2-hydroxyethoxy)-2-pyridyl]amino]-A’,A- dimethyl-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide 109.3. To a solution of compound 109.2 (1.5 g, 4.09 mmol) and 2-bromoethanol (1.28 g, 10.2 mmol) in DMF (15 mL) were added K2CO3 (1.41 g, 10.2 mmol) and KI (67,9 mg, 409 pmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 109.3 (1.15 g) in 62% yield. MS (ESI) m/z: 411.3 [M+H]+.
[00978] Preparation of 2-[[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-J]- pyrimidin-2-yl]amino]-3-pyridyl]oxy]ethyl 4-methylbenzenesulfonate 109.4, To a solution of compound 109.3 (1.15 g, 2.8 mmol) in DCM (10 mL) were added TEA (851 mg, 8,41 mmol) and TsCl (1.07 g, 5.6 mmol). After stirring for 16 h, the reaction mixture was concentrated and purified by column chromatography (SiCh, EtOAc/PE and MeOH/DCM) to afford compound 109.4 (1 11 g) in 63% yield. MS (ESI) m/z: 565.3 [M+H]+
[00979] Preparation of 7-cyclopentyl-2-((5-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2J7)- yl)phenyl)-piperazin-l-yl)ethoxy)pyridin-2-yl)amino)-A,7V-dimethyl-7/7-pyrrolo[2,3-<i]- pyrimidine-6-carboxamide A415. To a solution of l-(4-piperazin-l-ylphenyl)hexahydro- pyrimidine-2, 4-dione as a TFA salt (82.5 mg, 213 pmol) and compound 109.4 (120 mg, 213 pmol) in DMF (1.5 mL) were added DIEA (82 mg, 638 pmol) and KI (3.5 mg, 21.3 pmol) .
After stirring at 80 °C for 16 h, the reaction mixture was diluted with DMF (1 mL) and purified by reverse phase prep-HPLC to afford compound A415 as a TFA salt (28 mg) in 18% yield. lH NMR (400 MHz, DMSO-Je) <5 10.27 (s, 1H), 9.43 (s, HI), 8.77 (s, 1H), 8.20 (d, ./ 9.0 Hz, 1H), 8.13 (s, 2H), 8.09-8.02 (m, 1H), 7.56-7.39 (m, 1H), 7.19-7.10 (m, 2H), 7.00-6.91 (m, 2H), 6.60 (s, 1H), 4.73 (q, J= 8.8 Hz, 1H), 4.21 (t, J= 5.2 Hz, 2H), 3.69 (t, J= 6.8 Hz, 2H), 3.18-3.15 (m, 4H), 3.09-3.02 (m, 6H), 2.88-2.85 (m, 2H), 2.77-2.69 (m, 4H), 2.68 (t, J- 6.7 Hz, 2H), 2.43 (dd, J= 9.2, 10.8 Hz, 2H), 2.05-1.98 (m, 4H), 1.64 (d, J= 4.8 Hz, 2H); MS (ESI) m/z: 667.5 [M+H]+. Example 110
Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin- 1 (22/)-yl)phenyl)- piperazin-l-yl)ethoxy)phenyl)amino)-A(/V-dimethyl-7Jf-pyrrolo[2,3-if]pyrimidine-6- carboxamide A416
Figure imgf000388_0001
[00980] Compound A416 was prepared as described below.
[00981] Preparation of tert-butyl 4-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexa- hydropyrimidin-l-yl]phenyl]piperazine-l-carboxylate 110.1. A mixture of tert-butyl 4-(4- bromophenyl)piperazine-l -carboxylate (2.62 g, 7.68 mmol), 3-[(4-methoxyphenyl)methyl]- hexahydropyrimidine-2, 4-dione (1.8 g, 7.68 mmol), CS2CO3 (5 g, 15.4 mmol), Cui (292 mg, 1.54 mmol), and (lA,27?)-cyclohexane-l,2-diamine;diiodoplatinum (843 mg, 1.54 mmol) in dioxane (50 mL) was stirred at 100 °C for 16 h under N2. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 110.1 (1 g) in 23% yield. MS (ESI) m/z: 495.3 [M+H]+
[00982] Preparation of l-(4-piperazin-l-ylphenyl)hexahydropyrimidine-2, 4-dione 110.2, To a solution of compound 110.1 (1 g, 2.02 mmol) in DCM (10 mL) were added TFA (7.7 g,
67.5 mmol) and TfOH (4.25 g, 28.3 mmol). After stirring at 40 °C for 2 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated and purified by reverse phase prep-HPLC to afford compound 110.2 (400 mg) in 51% yield. MS (ESI) m/z: 275.4 [M+H]+.
[00983] Preparation of 7-Cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin- l(2rt)-yl)phenyl)-piperazin-l-yl)ethoxy)phenyl)amino)-A,A’-dimethyl-7Ff-pyrrolo[2,3- tf|pyrimidine-6-carboxamide A416. To a solution of compound 110.2 (68.9 mg, 177 pmol, TFA) and 2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl) pyrrolo[2,3-<7]pyrimidin-2-yl]amino]- phenoxy]-ethyl 4-methylbenzenesulfonate ( 100 mg, 177 pmol) in DMF (1.5 mL) were added KI (2.95 mg, 17.7 pmol) and DIEA (69 mg, 532 pmol). After stirring at 80 °C for 16 h, the reaction mixture was diluted with DMF and purified by reverse phase prep-HPLC to afford compound A416 as a TFA salt (41 mg) in 33% yield. ]H NMR (400 MHz, DMSO-di,) 3 10.26 (s, 1H), 9.35-9.23 (m, 1H), 8.70 (s, 1H), 8.13 (s, 1H), 7.70 (d, ./ 8.8 Hz, 2H), 7.15 (d, ./ 8.8 Hz, 2H), 6.92 (dd, J = 9.2, 13.2 Hz, 4H), 6.55 (s, 1H), 4.71 (q, J = 8.8 Hz, 1H), 4.11 (t, ./= 5.2 Hz, 2H), 3.69 (t, ./ 6.8 Hz, 2H), 3.16 (s, 4H), 3.05 (s, 6H), 2.85-2.74 (m, 2H), 2.68 (t, ./ 6.8 Hz, 6H), 2.45 (d, ./= 10.4 Hz, 2H), 1 .97-1 .96 (m, 4H), 1.63 (d, ./= 4.8 Hz, 2H); MS (ESI) m/z: 666.5 [M+H]+.
Example 111
Preparation of 7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2//)-yl)phenyl)- piperazin-l-yl)ethoxy)phenyl)amino)-A,A-dimethyl-7/f-pyrrolo[2,3-t(]pyrimidine-6- carboxamide A417
Figure imgf000389_0001
[00984] Compound A417 was prepared as described below.
[00985] Preparation of ZerZ-butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexa- hydropyrimidin-l-yl]phenyl]piperazine-l -carboxylate 111.1. To a solution of 3-[(4-methoxy- phenyl)methyl]hexahydropyrimidine-2, 4-dione (686 mg, 2.93 mmol) and ZerZ-butyl 4-(3-bromo- phenyl)piperazine-l -carboxylate (1 g, 2,93 mmol) in dioxane (10 mL) were added CS2CO3 (1 .91 g, 5.86 mmol), Pdz(dba)3 (268 mg, 293 pmol), and Xantphos (339 mg, 586 pmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCL, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 111.1 (900 mg) in 62% yield. MS (ESI) m/z: 495.4 [M+H]+.
[00986] Preparation of 1 -(3 -piperazin- l-ylphenyl)hexahydropyrimidine-2, 4-dione 111.2. To a solution of compound 111.1 (900 mg, 1.82 mmol) in DCM (10 mL) were added TFA (4.62 g, 40.5 mmol) and TfOH (1.7 g, 11.3 mmol). After stirring at 45 °C for 1 h, the reaction mixture was concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were concentrated and purified by reverse phase prep-HPLC to afford compound 111.2 as a TFA salt (410 mg) in 58% yield. MS (ESI) m/z: 275.2 (M+H] \
[00987] Preparation of 7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2//)- yl)phenyl)-piperazin-l-yl)ethoxy)phenyl)amino)-Ar,A-dimethyl-7/7-pyrrolo[2,3-c/]pyrimidine-6- carboxamide A417. To a solution of compound 111.2 as a TFA salt (68.9 mg, 177 pmol) and 2- [4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-£Z]pyrimidin-2-yl]amino]phenoxy]ethyl 4- methylbenzenesulfonate (100 mg, 177.41 pmol) in DMF (2 mL) were added DIEA (68.8 mg, 532 pmol) and KI (3 mg, 17,7 pmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A417 as a TFA salt (46 mg) in 36% yield. 1H NMR (400 MHz, DMSO-tfe) 6 10.31 (s, 1H), 9.32 (s, 1H), 8.70 (s, 1H), 8.13 (s, 1H), 7.71 (d, J= 8.8 Hz, 2H), 7.22 (t, J= 8.0 Hz, 1H), 6.97-6.88 (m, 3H), 6.83 (d, J= 8.0 Hz, 1H), 6.74 (d, ./ 7.6 Hz, 1H), 6.56 (s, 1H), 4.71 (quin, J = 8.8 Hz, 1H), 4.15 (s, 2H), 3 80-3.70 (m, 2H), 3.26-3.15 (m, 4H), 3.05 (s, 6H), 2.96-2.73 (m, 4H), 2.68 (t, J= 6.4 Hz, 2H), 2.49-2.31 (m, 4H), 2.01-1.90 (m, 4H), 1.63 (d, J = 4.0 Hz, 2H); MS (ESI) m/z: 666.5 [M+H]+.
Example 112
Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)benzyl)- piperazin-l-yl)ethoxy)phenyl)amino)-Az,A-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A418
Figure imgf000390_0001
[00988] Compound A418 was prepared as described below.
[00989] Preparation of 7-cyclopentyl-2-[4-[2-[4-[[4-[3-[(4-methoxyphenyl)methyl]-2,4- dioxo-hexahydropyrimidin-l-yl]phenyl]methyl] piperazin-l-yl]ethoxy]anilino]-A,AMimethyl- pyrrol o[2,3 -<7]pyrimi dine-6-carboxamide 112.1. To a solution of 7-cyclopentyl-A(A’-dimethyl-2- [4-(2-piperazin-l-ylethoxy)anilino]pyrrolo[2,3-tZ]pyrimidine-6-carboxaniide as an HC1 salt (90 mg, 175 umol) in MeOH (2 mL) were added NaOAc (43 mg, 525 pmol) and 4-[3-[(4-methoxy- phenyl)methyl]-2,4-dioxohexahydropyrimidin-l-yl]benzaldehyde (89 mg, 263 pmol). After the mixture was stirred for 15 min, NaBFLCN (22 mg, 350 pmol) was added. The reaction mixture was stirred for 12 h, and then concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 112.1 (120 mg) in 74% yield. MS (ESI) m'z: 800.5 [M+H]t
[00990] Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l (27/)- yl)benzyl)-piperazin-l-yl)ethoxy)phenyl)amino)-A,ALdimethyl-77/-pyrrolo[2,3-</]pyrimidine-6- carboxamide A418. A mixture of compound 112.1 (210 mg, 263 pmol), TFA (3.08 g, 27 mmol), and TfOH (1.7 g, 11.3 mmol) in DCM (5 mL) was stirred at 45 °C for 1 h. The reaction mixture was then concentrated and purified by reverse phase prep-HPLC to afford compound A418 (73 mg) in 38% yield. LH NMR (400 MHz, DMSO-ofe) 6 10.50-10.31 (m, 1H), 9.50-9.33 (m, 1H), 8.70 (s, 1H), 8.13 (s, 1H), 7.78-7.68 (m, 2H), 7.56-7.38 (m, 2H), 7.32 (s, 2H), 7.03-6.83 (m, 2H), 6.56 (s, 1H), 4.76-4.67 (m, 1H), 4.42-4.20 (m, 2H), 3.84-3.75 (m, 2H), 3.63-3.48 (m, 4H), 3.05 (s, 10H), 2.95-2.77 (m, 2H), 2.71 (t, 6.4 Hz, 2H), 2.45 (d, J= 12.0 Hz, 4H), 1.99-1.91 (m,
4H), 1.67-1.59 (m, 2H); MS (ESI) m/z'. 680.5 [M+H]+.
Example 113
Preparation of 7-Cyclopentyl-2-((4-(4-(l-(3-(2,4-dioxotetrahydropyrimidin-l(2/7)-yl)phenyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-ACV-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A421
Figure imgf000391_0001
[00991] Compound A421 was prepared as described below. [00992] Preparation of 1 -(3-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydro- pyrimidine-2, 4-dione 113.1. To a mixture of l-bromo-3 -iodobenzene (1 g, 3.53 mmol) and 3- [(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (828 mg, 3.53 mmol) in DMF (13 mL) were added CS2CO3 (2.3 g, 7.07 mmol), Cui (269 mg, 1.41 mmol), and (17?,2A)-Arl,A2- dimethylcyclohexane-l,2-diamine (201 mg, 1.41 mmol) under N2. After stirring at 100 °C for 2 h, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSOi, concentrated, and purified by column chromatography (SiOi, EtOAc/PE) to afford compound 113.1 (1.2 g) in 87% yield. rH NMR (400 MHz, DMSO-^) 3 7.74 (d, J= 1.6 Hz, 1H), 7.64-7.58 (m, 1H), 7.48-7.42 (m, 1H), 7.36 (dd, J= 1.7, 4.9 Hz, 1H), 7.27-7.18 (m, 2H), 6.86 (d, 8.6 Hz, 2H), 4.80 (s, 2H), 3.85-
3.77 (m, 2H), 3.72 (s, 3H), 2.88 (dt, J = 3.3, 6.6 Hz, 2H); MS (ESI) m/z: 390.8 [M+H]+.
[00993] Preparation of 7-cyclopentyl-2-[4-[4-[l-[3-[3-[(4-methoxyphenyl)methyl]-2,4- dioxohexahydropyrimidin-l-yl]phenyl]-4-piperidyl]piperazin-l-yl]anilino]-AjV-dirnethyl- pyrrolo[2,3-iZ]pyrimidine-6-carboxamide 113.2. To a mixture of 7-cyclopentyl-A,A-dimethyl-2- [4-[4-(4-piperidyl)piperazin-l-yl]anilino]pyiTolo[2,3-J]pyrimidine-6-carboxamide (300 mg, 581 pmol) and compound 113.1 (339 mg, 871 pmol) in dioxane (7 mL) were added CS2CO3 (378 mg, 1.16 mmol) and RuPhos Pd G3 (97 mg, 116 pmol) under N2. After stirring at 100 °C for 16 h, the reaction mixture was concentrated and purified by column chromatography (SiCh, MeOH/EtOAc) to afford compound 113.2 (160 mg) in 33% yield. rH NMR (400 MHz, DMSO- d6) 3 9.22 (s, 1H), 8.68 (s, 1H), 7.65 (d, J= 9.0 Hz, 2H), 7.27-7.14 (m, 4H), 6.92-6.82 (m, 7H), 6.55 (s, 1H), 4.80 (s, 2H), 3.80-3.67 (m, 8H), 3.12-2.98 (m, 12H), 2.90-2.83 (m, 3H), 2.72-2.63 (m, 8H), 2.02-1.85 (m, 7H); MS (ESI) m/z: 825 7 [M+H] \
[00994] Preparation of 7-cyclopentyl-2-((4-(4-(l -(3-(2,4-dioxotetrahydropyrimidin-l (2H)- yl)phenyl)-piperidin-4-yl)piperazin-l-yl)phenyl)amino)-jVr/V-dimethyl-7//-pyrrolo[2,3- Jjpyrimidine-6-carboxamide A421. To a solution of compound 113.2 (155 mg, 188 pmol) in DCM (1.6 mL) were added TfOH (272 mg, 1.81 mmol) and TFA (246 mg, 2.16 mmol). After stirring for 2 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A421 as a TFA salt (60 mg) in 42% yield. ^NMR (400 MHz, DMSO-dV) 3 10.29 (s, 1H), 9.22 (s, 1H), 8.68 (s, 1H), 8.14 (s, 1H), 7.65 (d, J= 9.0 Hz, 2H), 7.19 (t, J= 8.1 Hz, 111), 6.92-6.86 (m, 3H), 6,82 (dd, J = 1.9, 8.3 Hz, 1H), 6,69 (dd, J = 1.2, 7.8 Hz, 1H), 6,55 (s, 1H), 4.77-4.65 (m, 1H), 3.75 (br t, .7- 6.6 Hz, 4H), 3.06 (br s, 10H), 2.75-2.63 (m, 8H), 2.43 (br d, J = 11.3 Hz, 3H), 2.02-1.86 (m, 6H), 1.69-1.47 (m, 4H); MS (ESI) wA: 705.3 [M+H]+.
Example 114
Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin- 1 (277)-yl)benzyl)- piperazin-l-yl)ethyl)phenyl)amino)-A(AMiniethyl-777-pyrrolo[2,3-rf]pyrimidine-6-carboxamide
A422
Figure imgf000393_0001
[00995] Compound A422 was prepared as described below.
[00996] Preparation of 7-cyclopentyl-2-[4-[2-[4-[[4-[3-[(4-methoxyphenyl) methyl]-2,4- dioxohexahydropyrimidin-lyl]phenyl]methyl]piperazin-l-yl]ethyl]anilino]-A,Ar-dimethyl- pyrrolo[2,3-<7]pyrimidine-6-carboxamide 114.1. To a solution of 7-cyclopentyl-A(A-dimethyl-2- [4-(2-piperazin-l-ylethyl)anilino]pyrrolo[2,3-«7]pyrimidine-6-carboxamide as an HC1 salt (147 mg, 296 pmol) in MeOH (3 mL) were added NaOAc (72.7 mg, 887 pmol), 4-[3-[(4- methoxyphenyl)methyl]-2,4-dioxohexahydropyrimidin-l-yl]benzaldehyde (150 mg, 443 pmol), and NaBHsCN (37 mg, 591 pmol). After stirring for 12 h, the reaction mixture was purified by column chromatography (SiCh, MeOH/DCM) to afford compound 114.1 (222 mg). MS (ESI) m/z: 784.3 [M+H]+.
[00997] Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2/7)- yl)benzyl)-piperazin-l-yl)ethyl)phenyl)amino)-Ar^-dimethyl-77/-pyrrolo[2,3-«/|pyrimidine-6- carboxamide A422. To a solution of compound 114.1 (170 mg, 217 pmol) in DCM (2 mL) were added TFA (3.08 g, 27 mmol) and TfOH (1.7 g, 11.3 mmol). After stirring at 40 °C for 1 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A422 (9.5 mg) in 10% yield. 'HNMR (400 MHz, DMSO-de) J 10.35 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 7.71 (d, ./ 8.8 Hz, 2H), 7.33-7.24 (m, 4H), 7.12 (d, ./ 8.4 Hz, 2H), 6.57 (s, 1H), 4.72 (t, J = 8.8 Hz, 1H), 3.78 (t, J= 6.8 Hz, 2H), 3.44 (s, 2H), 3.05 (s, 6H), 2.73-2.69 (m, 2H), 2.69-2.63 (m, 4H), 2.49-2.48 (m, 6H), 2.48-2.47 (m, 3H), 2.05-1.88 (m, 5H), 1.69-1.60 (m, 2H); MS (ESI) m/z:
664.5 [M+H]+.
Example 115
Preparation of 7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2/7)-yl)benzyl)- piperazin-l-yl)ethyl)phenyl)amino)-A,A-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6-carboxamide
A423
Figure imgf000394_0001
[00998] Compound A423 was prepared as described below
[00999] Preparation of l-(3-(l,3-dioxolan-2-yl)phenyl)-3-(4-methoxybenzyl)dihydro- pyrimidine-2, 4(1/7, 377)-dione 115.1, A mixture of 2-(3-bromophenyl)-l,3-dioxolane (1.6 g, 6.98 mmol), 3-(4-methoxybenzyl)dihydropyrimidine-2, 4(1/7, 3/7)-dione (1.64 g, 6.98 mmol), Pd2(dba)s (640 mg, 698 pmol), Xantphos (808 mg, 1.40 mmol), and CS2CO3 (4.55 g, 14 mmol) in dioxane (16 mL) was stirred at 100 °C for 16 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 115.1 (1.9 g) in 60% yield. ffl NMR (400 MHz, CDCh) 3 7.43-7.37 (m, 4H), 7.31 (td, J= 2.0, 7.6 Hz, 1H), 6.87-6.80 (m, 2H), 5.83 (s, 1H), 4.97 (s, 2H), 4.15-4.00 (m, 4H), 3.83-3.78 (m, 5H), 2.88 (t, J= 6.8 Hz, 2H); MS (ESI) m/z: 383.1 [M+H]+.
[001000] Preparation of 3 -(3 -(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin- 1 (27/)-y 1)- benzaidehyde 115.2. To a solution of compound 115.1 (1.2 g, 3.14 mmol) in DCM (10 mL) was added TFA (2.75 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 115.2 (1 .05 g), which was used directly in the next step without further purification. }H NMR (400 MHz, CDCh) 3 10.01 (s, 1H), 8.09 (s, 1H), 7.79-7.76 (m, 1H), 7.64-7.54 (m, 2H), 7.40 (d, ./ 8.8 Hz, 2H), 6.87-6.81 (m, 2H), 4.42 (s, 2H), 3.86 (t, ./ 6.8 Hz, 2H), 3.79 (s, 3H), 2.93 (t, J= 6.8 Hz, 2H); MS (ESI) m/z: 339.2 [M+H]+. [001001] Preparation of 7-cyclopentyl-2-((4-(2-(4-(3-(3-(4-methoxybenzyl)-2,4-dioxo- tetrahydropyrimidin- 1 (2//)-yl)benzyl)piperazin- 1 -yl)ethyl)phenyl)amino)-A,Ar-dimethyl-7Ar- pyrrolo[2,3-<7]pyrimidine-6-carboxamide 115.3. A mixture of compound 115.2 (66 mg, 195 pmol), 7-cyclopentyl-A,A-dimethyl-2-((4-(2-(piperazin- 1 -yl)ethyl)phenyl)amino)-7/f- pyrrolo[2,3-t(|pyrimidine-6-carboxamide (75 mg, 162 pmol), and NaBFECN (20.4 mg, 325 pmol) in MeOH (2 mL) was stirred for 3 h. The reaction mixture was then filtered, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 115.3 (116 mg) in 87% yield. MS (ESI) m/z: 784.6 [M+Hf.
[001002] Preparation of 7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2J7)- yl)benzyl)-piperazin-l-yl)ethyl)phenyl)amino)-A^V-dimethyl-77/-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A423. A mixture of compound 115.3 (116 mg, 148 pmol), TfOH (0.2 mL), TFA (0.8 mL) was stirred at 40 °C for 1 h. The reaction mixture was then concentrated and purified by reverse phase prep-HPLC to afford compound A423 (16 mg) in 16% yield. XH NMR (400 MHz, DMSO-dk) 6 10.34 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 7.72 (d, ./ 8.8 Hz, 2H), 7.37-7.30 (m, 1H), 7.26 (s, 1H), 7.23-7.19 (m, 1H), 7.18-7.14 (m, 1H), 7.12 (d, .7= 8.4 Hz, 2H), 6.57 (s, 1H), 4.76-4.69 (m, 1H), 3.79 (t, J= 6.8 Hz, 2H), 3.50-3.44 (m, 3H), 3.13-2.98 (m, 6H), 2.73-2.68 (m, 3H), 2.45-2.39 (m, 4H), 2.04-1.91 (m, 4H), 1.71-1.59 (m, 2H); MS (ESI) m/z: 664.3 [M+H]+.
Example 1 16
Preparation of 7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzyl)- piperazin-l-yl)ethoxy)phenyl)amino)-A,A-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A424
Figure imgf000395_0001
[001003] Compound A424 was prepared as described below.
[001004] Preparation of l-[3-(l,3-dioxolan-2-yl)phenyl]-3-[(4-methoxyphenyl)methyl]- hexahydropyrimidine-2, 4-dione 116.1. A mixture of 2-(3 -bromophenyl)- 1,3 -di oxolane (500 mg, 2.18 mmol), 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (511 mg, 2.18 mmol), Pd2(dba)3 (200 mg, 218 gmol), Xantphos (253 mg, 437 pmol), and CS2CO3 (1.42 g, 4.37 mmol) in dioxane (5 mL) was stirred at 100 °C for 16 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 116.1 (449 mg) in 49% yield. 41 NMR (400 MHz, CDCh) d 7.44.7.38 (m, 3H), 7.38-7.34 (m, 2H), 7.30 (td, J= 2.0, 7.6 Hz, 1H), 6 85-6.79 (m, 2H), 5.82 (s, 1H), 4.96 (s, 2H), 4.13-4.08 (m, 2H), 4.08-4.02 (m, 2H), 3.81-3.79 (m, 2H), 3.78 (s, 3H), 2.92- 2.81 (m, 2H); MS (ESI) m/z: 383.2 [M+H] \
[001005] Preparation of 3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexahydropyrimidin-l- yl]benzaldehyde 116.2. To a solution of compound 116.1 (449 mg, 1.17 mmol) in DCM (4 mL) was added IM TFA (2 mL). After stirring for 16 h, the reaction mixture was neutralized with NaHCCh, diluted with water, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated to afford compound 116.2 (436 mg), which was used directly in the next step without further purification. !H NMR (400 MHz, CDCh) d 10.01 (s, 1H), 7.80-7.72 (m, 2H), 7.63-7.53 (m, 2H), 7.41 (d, J= 8.4 Hz, 2H), 6.83 (d, J= 8.8 Hz, 2H), 4.97 (s, 2H), 3.85 (t, J= 6.8 Hz, 2H), 3.78 (s, 3H), 2.92 (t, J= 6.8 Hz, 2H); MS (ESI) m/z: 339.2 [M+H]+.
[001006] Preparation of 7-cyclopentyl-2-[4-[2-[4-[[3-[3-[(4-methoxyphenyl)methyl]-2,4- dioxohexahydropyrimidin-l-yl]phenyl] methyl]piperazin-l-yl]ethoxy]anilino]-/V,A'-dimethyl- pyrrolo[2,3-7]pyrimidine-6-carboxamide 116.3. To a solution of 7-cyclopentyl-A(A7-dimethyl-2- [4-(2-piperazin-l-ylethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carboxamide as an HC1 salt (120 mg, 233 pmol) in MeOH (2 mL) was added NaOAc (38.3 mg, 467 pmol). After the mixture was stirred for 15 min, compound 116.2 (79 mg, 233 umol) and NaBHjCN (44 mg, 700 pmol) were added. The reaction mixture was stirred for 5 h and then purified by column chromatography (SiOr, MeOH/DCE) to afford compound 116.3 (190 mg) in 76% yield. MS (ESI) m/z: 800.6 [M+H]+.
[001007] Preparation of 7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l (27/)- yl)benzyl)-piperazin-l-yl)ethoxy)phenyl)amino)-A,A-dimethyl-77/-pyrrolo[2,3-7]pyrimidine-6- carboxamide A424. To a solution of compound 116.3 (130 mg, 163 pmol) in DCM (1 mL) were added TFA (1.54 g, 13.5 mmol) and TfOH (850 mg, 5.66 mmol). After stirring at 40 °C for 2 h, the reaction mixture was diluted with ACN and purified by reverse phase prep-HPLC to afford compound A424 as a TFA salt (19 mg) in 16% yield. 41 NMR (400 MHz, DMSO-de) 6 10.36 (s, 1H), 9.30 (s, 1H), 8.70 (s, 1H), 8.13 (s, 1H), 7.70 (d, 7= 8.8 Hz, 2H), 7.40-7.32 (m, 1H), 7.28 (s, 1H), 7.24 (d, 7 8.0 Hz, 1H), 7.18 (d, 7 7.6 Hz, 1H), 6.89 (d, 7 = 8.8 Hz, s2H), 6.55 (s, 1H), 4.71 (q, 7= 8.8 Hz, 1H), 4.09 (s, 2H), 3.79 (t, 7= 6.8 Hz, 2H), 3.58 (s, 2H), 3.05 (s, 6H), 2.94- 2.82 (m, 2H), 2.75-2.66 (m, 4H), 2.55 (s, 4H), 2.49-2.37 (m, 4H), 1.95 (s, 4H), 1.69-1.57 (m, 2H); MS (ESI) m/z: 680.3 [M H] ,
Example 117
Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrimidin- 1 (2#)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethoxy)phenyl)amino)-A,A-dimethyl-7//-pyrrolo[2,3-7]pyrimidine- 6-carboxamide A427
Figure imgf000397_0001
[001008] Compound A427 was prepared as described below.
[001009] Preparation of fert-butyl 4-[4-[4-(2,4-dioxohexahydropyrimidin-l-yl)phenyl]- piperazin-l-yl] piperi dine- 1 -carboxylate 117.1 To a solution of l-(4-piperazin-l-ylphenyl)- hexahydropyrimidine-2, 4-dione as a TFA salt (500 mg, 1.29 mmol) in DCE (10 mL) were added NaOAc (317 mg, 3.86 mmol) and ZerLbutyl 4-oxopiperidine-l -carboxylate (770 mg, 3.86 mmol). After the mixture was stirred for 15 min, NaBH(OAc)3 (1.09 g, 5.15 mmol) was added. The reaction mixture was stirred at 60 °C for 12 h, and then diluted with water and extracted with DCE. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 117.1 (400 mg) in 65% yield. MS (ESI) m/z: 458.2 [M+H]+. [001010] Preparation of 1 -[4-[4-(4-piperidyl)piperazin- 1 -yl]phenyl]hexahydropyrimidine- 2, 4-dione 117.2. To a solution of compound 117.1 (400 mg, 874 pmol) in DCM (2 mL) was added 4M HC1 in dioxane (3.8 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 117.2 as an HC1 salt (440 mg), which was used directly in the next step without further purification. MS (ESI) m/z\ 358.1 [M+H]+.
[001011] Preparation of 7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-
1 (2/7)-yl)phenyl)-piperazin- 1 -y l)piperi din- 1 -yl)ethoxy)phenyl)amino)-ACV-dimethyl-7#- pyrrolo[2,3-J]pyrimidine-6-carboxamide A427. To a solution of compound 117.2 as an HC1 salt (50 mg, 127 pmol) and 2-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-d]pyrimidin-2- yl]-amino]phenoxy]ethyl 4-methylbenzenesulfonate (72 mg, 127 pmol) in DMF (2 mL) were added DIEA (49 mg, 381 pmol) and KI (2 mg, 12.7 pmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with ACN and then dropped into ultrapure water. The resulting precipitates were collected by filtration to afford compound A427 (19 mg) in 19% yield. ^I NMR (400 MHz, DMSO-d6 ) 3 10.24 (s, 1H), 9.28 (s, 1H), 8.70 (s, 1H), 7.74-7.59 (m, 2H), 7.14 (d, J= 9 2 Hz, 2H), 6.94-6.85 (m, 4H), 6.55 (s, 1H), 4.71 (t, ./ 8.8 Hz, 1H), 4.03 (t, ./ 5.6 Hz, 2H), 3.69 (t, J = 6.8 Hz, 2H), 3.12-3.08 (m, 4H), 3.08-3.02 (m, 6H), 3.01-2.96 (m, 2H), 2.70-2.65 (m, 4H), 2.63-2.59 (m, 4H), 2.47-2.38 (m, 2H), 2.26-2.14 (m, 1H), 2.06-1.99 (m, 2H), 1.98-1.90 (m, 4H), 1.81-1.71 (m, 2H), 1.68-1.56 (m, 2H), 1.50-1.37 (m, 2H); MS (ESI) m/z: 749.5 [M+H]+.
Example 1 18
Preparation of 7-cyclopentyl-2-((4-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(2/7)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-A,A-dimethyl-7/f-pyrrolo[2,3-<f]pyrimidine-6- carboxamide A428
Figure imgf000398_0001
[001012] Compound A428 was prepared as described below.
[001013] Preparation of 3-[(4-methoxyphenyl)methyl]-l-[4-[(E)-2-methoxyvinyl]phenyl]- hexahydropyrimidine-2, 4-dione 118.1. To a solution of methoxymethyl(triphenyl)phosphonium chloride (2.43 g, 7.09 mmol) in THF (10 mL) was added /-BuOK (796 mg, 7.09 mmol) at 0 °C. After the mixture was stirred for 30 min, 4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexahydro- pyrimidin-l-yl]benzaldehyde (0.8 g, 2.36 mmol) was added. The reaction mixture was stirred for 16 h, and then poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 118.1 (800 mg) in 92% yield. iH NMR (400 MHz, CDCh) 3 7.58 (d, J= 8.5 Hz, IH), 7.43 (d, J= 8.5 Hz, 2H), 7.24 (br d, J= 8.5 Hz, 2H), 7.21- 7.14 (m, 2H), 7.03 (d, J= 13.0 Hz, IH), 6.83 (d, J= 8.6 Hz, 2H), 4.96 (s, 2H), 3.81-3.75 (m, 6H), 3.70 (s, 2H), 2.91 -2.83 (m, 2H).
[001014] Preparation of 2-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydro- pyrimidin-l-yl]phenyl]acetaldehyde 118.2. To a mixture of compound 118.1 (370 mg, 1.01 mmol) in CHCh (9.6 mL) was added oxalyl dichloride (385 mg, 3.03 mmol) in CHCh (1 .5 mL). After stirring for 1 h, the reaction mixture was poured into aqueous NaHCCh and extracted with DCM The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to afford compound 118.2 (300 mg), which was used directly in the next step without further purification.
[001015] Preparation of 7-cyclopentyl-2-[4-[4-[l-[2-[4-[3-[(4-methoxyphenyl)methyl]-2,4- dioxo-hexahydropyrimidin-l-yl]phenyl]ethyl]-4-piperidyl]piperazin-l-yl]anilino]-/V,iV-dimethyl- pyrrolo[2,3-d]pyrimidine-6-carboxamide 118.3. To a mixture of 7-cyclopentyl-Az,A-dimethyl-2- [4-[4-(4-piperidyl)piperazin-l-yl]anilino]pyrrolo[2,3-c/]pyrimidine-6-carboxamide (200 mg, 387 pmol) in THF (5 mL) was added compound 118.2 (273 mg, 774 pmol), followed by addition of NaBH(OAc)3 (164. mg, 774 pmol) and AcOH (2.3 mg, 38.7 pmol). After stirring for 16 h, the reaction mixture was poured into aqueous NHiCl and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, MeOH/EtOAc) to afford compound 118.3 (250 mg) in 76% yield. }H NMR (400 MHz, DMSO-sfc) 3 9.22 (s, IH), 8.68 (s, IH), 7.65 (d, J= 9.0 Hz, 2H), 7.29-7.18 (m, 7H), 6.87 (t, ./= 8.2 Hz, 5H), 6.54 (s, IH), 4.80 (s, 2H), 4.14-4.05 (m, IH), 3.77 (t, J= 6.6 Hz, 2H), 3.72 (s, 4H), 3.05 (br s, 15H), 2.87 (br t, J= 6.7 Hz, 3H), 2.75 (br s, 3H), 2.64 (br s, 6H), 1.95 (br s, 7H). [001016] Preparation of 7-cyclopentyl-2-((4-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(2rt)- yl)phenethyl)-piperidin-4-yl)piperazin-l-yl)phenyl)amino)-A(A-dimethyl-7rtr-pyrrolo[2,3-</]- pyrimidine-6-carboxamide A428. To a solution of compound 118.3 (240 mg, 281 pmol) in DCM (2.4 mL) were added TfOH (408 mg, 2.72 mmol) and TFA (370 mg, 3.24 mmol). After stirring for 2 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A428 as a TFA salt (88 mg) in 40% yield. lH NMR (400 MHz, DMSO-t/e) 3 10.34 (s, 1H), 9.22 (s, 1H), 8.68 (s, 1H), 8.15 (s, 1H), 7.65 (d, ./ 9.0 Hz, 2H), 7.24 (s, 4H), 6.88 (d, ./= 9.0 Hz, 2H), 6.55 (s, 1H), 4.71 (quin, 8.9 Hz, 1H), 3.76 (t, J= 6.7 Hz, 2H), 3.05 (br s, 11H), 2.80-2.74 (m, 2H), 2.73-2.62 (m, 8H), 2.45-2.25 (m, 4H), 2.16 (br t, J= 10.7 Hz, 2H), 2.02-1.79 (m, 6H), 1.70-1.41 (m, 4H); MS (ESI) m/z: 733.4 [M+H]+.
Example 119
Preparation of 7-cyclopentyl-2-((5-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(2#)-yl)benzyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A’pV-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A430
Figure imgf000400_0001
[001017] Compound A430 was prepared as described below.
[001018] Preparation of tert-butyl 4-[4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo- [2,3-t/]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-l -yl]piperidine-l-carboxylate 119.1, To a solution of 7-cyclopentyl-A(Ar-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-J]- pyrimidine-6-carboxamide as an HC1 salt (1.17 g, 2.47 mmol) in DCM (15 mL) was added NaOAc (609 mg, 7,42 mmol), followed by addition of tert-butyl 4-oxopiperidine-l -carboxylate (1.48 g, 7.42 mmol) and NaBH(OAc)} (2.1 g, 9.89 mmol). The reaction mixture was stirred at 60 °C for 12 h, and then concentrated and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 119.1 (1.18 g). MS (ESI) m/z: 618.4 [M+H]+.
[001019] Preparation of 7-cyclopentyl-A’,A’-dimethyl-2-[[5-[4-(4-piperidy l)piperazin- 1 -yl]- 2-pyridyl]amino]pyrrolo[2,3-t/]pyrimidine-6-carboxamide 119.2. To a solution of compound 119.1 (1.1 g, 1.78 mmol) in DCM (5 mL) was added 4M HC1 in dioxane (5 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 119.2 as an HC1 salt (900 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 518.3 [M+H]+.
[001020] Preparation of 7-cyclopentyl-2-[[5-[4-[l-[[4-[3-[(4-methoxyphenyl)methyl]-2,4- dioxohexahydropyrimidin-l-yl]phenyl]methyl]-4-piperidyl]piperazin-l-yl]-2-pyridyl]amino]- A(A-dimethyl-pyrrolo[2,3-J|pyrimidine-6-carboxamide 119.3, To a solution of compound 119.2 as an HC1 salt (164 mg, 296 pmol) in MeOH (3 mL) was added NaOAc (72.7 mg, 887 umol), followed by addition of 4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexahydropyrimidin-l-yl]- benzaldehyde (150 mg, 443 gmol) and NaBHsCN (37 mg, 591 pmol). After stirring for 12 h, the reaction mixture was purified by column chromatography (SiCh, MeOH/DCM) to afford compound 119.3 (237 mg). MS (ESI) m/z: 840.3 [M+H]+
[001021] Preparation of 7-cyclopentyl-2-((5-(4-(l -(4-(2,4-di ox otetrahy dropyrimidin- 1 (2H)- yl)benzyl)-piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A7-dimethyl-77f-pyrrolo[2,3- Jjpyrimidine-6-carboxamide A430. To a solution of compound 119.3 (180 mg, 214 pmol) in DCM (2 mL) were added IT A (3.08 g, 27 mmol) and TfOH (1 .7 g, 11.3 mmol). After stirring at 40 °C for 1 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A430 (32 mg) in 21% yield. ^ NMR (400 MHz, DMSO-Je) 3 10.35 (s, 1H), 9.23 (s, 1H), 8.74 (s, 1H), 8.13 (d, J= 9.2 Hz, 1H), 7.97 (d, 3.2 Hz, 1H), 7.41 (dd, J= 2.8, 9.2 Hz, 1H), 7.34-
7.20 (m, 4H), 6.59 (s, 1H), 4.79-4.66 (m, 1H), 3.78 (t, J= 6.4 Hz, 2H), 3.43 (s, 2H), 3.12-3.08 (m, 4H), 3.05 (s, 6H), 2.86 (d, J= 11.2 Hz, 3H), 2.70 (t, J= 6.8 Hz, 2H), 2.64 (s, 4H), 2.30-2.17 (m, 2H), 2.01-1.90 (m, 6H), 1.76 (d. ./ 9.6 Hz, 2H), 1.68-1.59 (m, 2H), 1.50-1.40 (m, 2H); MS (ESI) m/z: 720.3 [M+H]+.
Example 120
Preparation of 7-cyclopentyl-2-((4-(4-(( 1 -(4-(2,4-dioxotetrahy dropyrimidin- 1 (2Z/)-y l)pheny 1)- piperidin-4-yl)methyl)piperazin-l -yl)phenyl)amino)-Ar,A7-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A431
Figure imgf000402_0001
[001022] Compound A431 was prepared as described below
[001023] Preparation of l-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydro- pyrimidine-2, 4-dione 120.1. A mixture of l-bromo-4-iodobenzene (0.5 g, 1 .77 mmol), 3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (497 mg, 2.12 mmol), CS2CO3 (1.15 g, 3.53 mmol), Cui (135 mg, 707 pmol), and (17?,2J?)-Arl,A2-dimethylcyclohexane-l,2-diamine (101 mg, 707 pmol) in DMF (5 mL) was stirred at 100 °C for 10 h under N2. The reaction mixture was then poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography ( Si () \ EtOAc/PE) to afford compound 120.1 (370 mg) in 48% yield. MS (ESI) m/z-. 390.9 [M+H]+.
[001024] Preparation of l-[4-[4-(dimethoxymethyl)-l-piperidyl]phenyl]-3-[(4-methoxy- phenyl)methyl]hexahydropyrimidine-2, 4-dione 120.2. To a solution of compound 120.1 (250 mg, 642 umol) in dioxane (3 mL) were added CS2CO3 (419 mg, 1.28 mmol), RuPhos Pd G3 (54 mg, 64.2 pmol), and 4-(dimethoxymethyl)piperidine (153 mg, 963 pmol) under N2. After stirring at 90°C for 10 h, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSO-;, concentrated, and purified by column chromatography (S1O2, EtOAc/PE) to afford compound 120.2 (225 mg) in 75% yield. lH NMR (400 MHz, DMSO-d6 ) ri 7.29-7.09 (m, 4H), 6.99-6.80 (m, 4H), 4.79 (s, 2H), 3.79-3.66 (m, 7H), 3.28 (s, 5H), 2.86 (t, J - 6.8 Hz, 2H), 2.73-2.57 (m, 4H), 1.81 -1.64 (m, 3H), 1.41-1.25 (m, 2H).
[001025] Preparation of 1 -[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexahydro- pyrimidin- l-yl]phenyl]piperidine-4-carbaldehyde 120.3, To a solution of compound 120.2 (115 mg, 246 umol) in DCM (1 mL) was added TFA (266 mg, 2.33 mmol). After stirring for 1 h, the reaction mixture was concentrated to afford compound 120.3 (100 mg), which was used directly in the next step without further purification.
[001026] Preparation of 7-cyclopentyl-2-[4-[4-[[l-[4-[3-[(4-methoxyphenyl)methyl]-2,4- dioxohexahydropyrimidin-l-yl]phenyl]-4-piperidyl]methyl]piperazin-l-yl]anilino]-A,A;- dimethylpyrrolo[2,3-t/]pyrimidine-6-carboxamide 120.4. To a solution of compound 120.3 (100 mg, 237 pmol) and 7-cyclopentyl-A)A-dimethyl-2-(4-piperazin-l-ylanilino)pyrrolo[2,3-£f]- pyrimidine-6-carboxamide (51 mg, 119 pmol) in THF (2 mL) was added NaBH(OAc)3 (50 mg, 237 nmol). After stirring at 60 °C for 10 h, the reaction mixture was concentrated and purified by column chromatography (SiO2, MeOHZDCM) to afford compound 120.4 (100 mg) in 96% yield.
[001027] Preparation of 7-cyclopentyl-2-((4-(4-((l-(4-(2,4-dioxotetrahydropyrimidin- l(2Z/)-yl)phenyl)-piperidin-4-yl)methyl)piperazin-l -yl)phenyl)amino)-A,A/-dimethyl-7//- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A431. To a solution of compound 120.4 (65 mg, 77.5 umol) in DCM (1 mL) were added TfOH (170 mg, 1.13 mmol) and TFA (154 mg, 1.35 mmol). After stirring for 10 min, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A431 (7.5 mg) in 13% yield. rH NMR (400 MHz, DMSO-t/c;) d 10.26 (s, 1H), 9.43-9.09 (m, 1H), 8.70 (s, 1H), 7.82-7.53 (m, 2H), 7.14 (d, J= 8.4 Hz, 2H), 6.94 (d, J= 7.6 Hz, 4H), 6.64-6.47 (m, 1H), 4.83-4.64 (m, 1H), 3.70 (t, J= 6.8 Hz, 5H), 3.06 (s, 11H), 2.69 (t, 6.4 Hz, 6H), 2.30-2.17 (m, 2H), 2.04-1.93 (m, 5H), 1.88-1.80 (m, 2H), 1.71-1.59 (m,
3H), 1.41-1.10 (m, 3H); AIS (ESI) m/z: 719.4 [M+H]+.
Example 121
Preparation of 7-cyclopentyl-2-((4-(4-((l-(3-(2,4-dioxotetrahydropyrimidin-l(277)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)-Ar,ALdimethyl-7J7-pyrrolo[2,3-t/]pyrimidine-
6-carboxamide A432
Figure imgf000403_0001
[001028] Compound A432 was prepared as described below.
[001029] Preparation of 1 -(3-bromophenyl)-4-(dimethoxymethyl)piperidine 121.1 To a solution of l-bromo-3 -iodobenzene (3.55 g, 12.6 mmol) and 4-(dimethoxymethyl)piperidine (1 g, 6.28 mmol) in DMF (50 mL) were added Cui (478 mg, 2.51 mmol), K2CO3 (2.6 g, 18.8 mmol), and L-proline (289 mg, 2.51 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 121.1 (1.1 g) in 56% yield. MS (ESI) m/z: 314.2 [M+H]+.
[001030] Preparation of l-[3-[4-(dimethoxymethyl)-l-piperidyl]phenyl]-3-[(4-methoxy- phenyl)methyl]hexahydropyrimidine-2, 4-dione 121.2. To a solution of compound 121.1 (800 mg, 2.55 mmol) and 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (596 mg, 2.55 mmol) in dioxane (10 mL) were added CS2CO3 (1.66 g, 5.09 mmol) and RuPhos Pd G3 (213 mg, 255 umol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4CI and brine, dried over anhydrous NajSOr, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 121.2 (900 mg) in 70% yield. MS (ESI) m/z: 468.3 [M+H]+.
[001031] Preparation of l-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydro- pyrimidin-l-yl]phenyl]piperidine-4-carbaldehyde 121,3. To a solution of compound 121.2 (300 mg, 642 pmol) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol). After stirring for 1 h, the reaction mixture was concentrated, diluted with water, neutralized with saturated aqueous NaHCOi, and extracted with EtOAc. The combined organic layers were concentrated to afford compound 121.3 (270 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 422.3 [M+H] \
[001032] Preparation of 7-cyclopentyl-2-[4-[4-[[l -[3-[3-[(4-methoxyphenyl)methyl]-2,4- dioxohexahydropyrimidin- 1 -yl]phenyl]-4-piperidyl]methyl]piperazin- 1 -yl]anilino]-ApV- dimethylpyrrolo[2,3-6?]pyrimidine-6-carboxamide 121.4. To a solution of 7-cyclopentyl-Ar,A7- dimethyl-2-(4-piperaziii-l-ylanilino)pyrrolo[2,3-d]pyrimidine-6-carboxamide as an HC1 salt (200 mg, 426 pmol) in MeOH (2 mL) were added NaOAc ( 105 mg, 1.28 mmol) and compound 121.3 (269 mg, 638 pmol). After the mixture was stirred for 15 min, NaBHsCN (53.5 mg, 851 pmol) was added. The reaction mixture was stirred for 12 h, and then concentrated and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 121.4 (300 mg) in 84% yield. MS (ESI) m/z: 841.6 [M+H]+.
[001033 ] Preparation of 7-cy clopentyl-2-((4-(4-(( 1 -(3 -(2,4-dioxotetrahydropy rimidin-
1 (2/7)-yi)phenyl)-piperidin-4-yi)methyl)piperazin- 1 -yl)phenyl)amino)-A,A-dimethyl-7/7- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A432. To a solution of compound 121.4 (300 mg, 358 umol) in DCM (5 mL) were added TFA (3.08 g, 27 mmol) and TfOH ( 1.7 g, 11.3 mmol). After stirring at 50 °C for 1 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A432 as a TFA salt (49 mg) in 17% yield. rH NMR (400 MHz, DMSO-tfc) J 10.31 (s, 1H), 9.26 (s, 1H), 8.69 (s, 1H), 8.14 (s, 1H), 7.67 (d, J= 9.2 Hz, 2H), 7.19 (t, J - 8.0 Hz, III), 6.90 (d, J- 9.2 Hz, 2H), 6.88 (s, 1H), 6.84-6.78 (m, 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 4.71 (s, 1H), 3.74 (t, J= 6.8 Hz, 2H), 3.69 (d, J= 12.0 Hz, 2H), 3.12 (s, 4H), 3.05 (s, 6H), 2.74-2.63 (ra, 8H), 2.48-2.35 (m, 4H), 1.96 (s, 4H), 1.86-1.72 (m, 3H), 1.63 (d, ./ 5.2 Hz, 2H), 1 .23 (d, J= 9.2 Hz, 2H); MS (ESI) m/z: 719.5 [M+H]+.
Example 122
Preparation of 7-cyclopentyl-2-((4-(4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin- 1 (2/7)-yl)phenyl)- piperidin-l -yl)ethyl)piperazin-l-yl)phenyl)amino)-.¥yV-dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A433
Figure imgf000405_0001
[001034] Compound A433 was prepared as described below.
[001035] Preparation of /er/-butyl 4-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexa- hydropyrimidin-l-yl]phenyl]piperidine-l -carboxylate 122.1. To a solution of 3-[(4-methoxy- phenyl)methyl]hexahydropyrimidine-2, 4-dione (2 g, 8.54 mmol) in dioxane (30 mL) were added Pd2(dba)s (782 mg, 854 pmol), Xantphos (988 mg, 1.71 mmol), terAbutyl 4-(4-bromophenyl)- piperidine-1 -carboxylate (3.49 g, 10.3 mmol), and CS2CO3 (5.56 g, 17.1 mmol). After stirring at 100 °C for 10 h, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 122.1 (2 g) in 44% yield. MS (ESI) m/z: 438.2 [M+H]+.
[001036] Preparation of 3 -[(4-methoxyphenyl)methyl]- 1 -[4-(4-piperidyl)phenyl]hexahydro- pyrimidine-2, 4-dione 122.2. To a solution of compound 122.1 (2 g, 4.05 mmol) in DCM (10 mL) was added 4M: HCI in dioxane (833 pL). .After stirring for 30 min, the reaction mixture was concentrated to afford compound 122.2 as an HCI salt (1.52 g), which was used directly in the next step without further purification. MS (ESI) m/z: 394,2 [M+H]+.
[001037] Preparation of 7-cyclopentyl-2-[4-[4-[2-[4-[4-[3-[(4-methoxyphenyl)methyl]-2,4- dioxohexahydropyrimidin-l-yl]phenyI]-l-piperidyl]ethyl]piperazin-l-yl]anilino]-jV,A-dimethyl- pyrrolo[2,3-J]pyrimidine-6-carboxamide 122.3. To a solution of 7-cyclopentyl-A,AMimethyl-2- (4-piperazin-l-ylanilino)pyrrolo[2,3-d]pyrimidine-6-carboxamide (1 g, 2.31 mmol) in DMF (10 mL) were added K2CO3 (588 mg, 4.26 mmol), compound 122.2 as an HCI salt (1.51 g, 3.51 mmol), and l-bromo-2-chloroethane (457 mg, 3.19 mmol). After stirring at 80 °C for 4 h, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 122.3 (700 mg) in 36% yield.
[001038] Preparation of 7-cyclopentyl-2-((4-(4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin- l(2B)-yl)phenyl)-piperidin-l -yl)ethyl)piperazin-l-yl)phenyl)amino)-A/,A’-dimethyl-7//-pyrrolo- [2,3-cf]pyrimidine-6-carboxamide A433. To a solution of compound 122.3 (650 mg, 762 pmol) in DCM (10 mL) was added TfOH (8.5 g, 56.6 mmol). After stirring for 10 min, the reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by reverse phase prep-HPLC to afford compound A433 (69 mg) in 12% yield.
Figure imgf000406_0001
(400 MHz, DMSO-A) 10.34 (s, 1H), 9.24 (s, 1H), 8.69 (s, 1H), 8.16 (s, 1H), 7.66 (d, J= 9.0 Hz, 2H), 7.33-7.20 (m, 4H), 6.90 (d, J= 8.8 Hz, 2H), 6.56 (s, 1H), 4.85-4.64 (m, 1H), 3.77 (t, 7 6.4 Hz, 2H), 3.18-3.00 (m, 12H), 2.73-2.66 (m, 4H), 2.65-2.55 (m, 7H), 2.48-2.40 (m, 2H), 2.35-2.26 (m, 2H), 1.97 (s,
4H), 1.84-1.59 (m, 6H); MS (ESI) m/z: 733.6 [M+H]7
Example 123
Preparation of 7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperidin-l-yl)ethyl)piperazin-l-yl)phenyl)amino)-jV,A'-dimethyl-7//-pyrrolo[2,3-(7]pyrimidine- 6-carboxamide A434
Figure imgf000407_0001
[001039] Compound A434 was prepared as described below.
[001040] Preparation of 1 -(3-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydro- pyrimidine-2, 4-dione 123.1. To a solution of l-bromo-3 -iodo-benzene (2 g, 7.07 mmol) and 3- [(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (994 mg, 4.24 mmol) in DMF (20 mL) were added (l.R,27?)-A!,A^-dimethylcyclohexane-l,2-diamine (201 mg, 1.41 mmol), Cui (269 mg, 1.41 mmol), and CS2CO3 (2.3 g, 7.07 mmol). After stirring at 100 °C for 12 h under N2, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 123.1 (1.1 g). MS (ESI) m/z: 390.7 [M+H]+.
[001041] Preparation of tert-butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexa- hydropyrimidin-l-yl]phenyl]-3,6-dihydro-2//-pyridine-l-carboxylate 123.2. A mixture of compound 123.1 (1.1 g, 2.83 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3, 6-dihydro-2rt-pyridine-l -carboxylate (1.05 g, 3.39 mmol), Pd(dppf)C12-CH2C12 (115 mg, 141 nmol), and K3PO4 (1.2 g, 5.65 mmol) in dioxane (10 mL) and H2O (3 mL) was stirred at 100 °C for 6 h under N2. The reaction mixture was then filtered, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford 123.2 (1 g), which was used directly in the next step without further purification. NMR (400 MHz, CDCh) 3 7.39 (s, 2H), 7.39-7.28 (m, 2H), 7.27-7.13 (m, 2H), 6.83 (d, J- 8.8 Hz, 2H), 6.04 (s, 1H), 4.97 (s, 2H), 4.08 (s, 2H), 3.78 (s, 5H), 3.63 (t, J= 5.6 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H), 2.51 (s, 2H), 1.50 (s, 9H).
[001042] Preparation of tert-butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexa- hydropyrimidin-l-yl]phenyl]piperidine-l -carboxylate 123.3, To a mixture of compound 123.2 (1.4 g, 2,85 mmol) in MeOH (30 mL) was added 10% Pd/C (600 mg) under N2. After stirring under H?. at 40 °C for 12 h, the reaction mixture was filtered and concentrated to afford compound 123.3 (1.2 g), which was used directly in the next step without further purification.
[001043] Preparation of l-[3-(4-piperidyl)phenyl]hexahydropyrimidine-2, 4-dione 123.4, To a solution of compound 123.3 (1.2 g, 2.43 mmol) in DCM (6 mL) were added IT A (4.62 g, 40.5 mmol) and TfOH (1.02 g, 6.8 mmol). After stirring at 50 °C for 1 h, the reaction mixture was concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were concentrated and purified by reverse phase prep-HPLC to afford compound 123.4 (320 mg) in 64% yield. MS (ESI) m/z\ 274.1 [M+H]+.
[001044] Preparation of 7-cyclopentyl-2-[4-[4-(2-hydroxyethyl)piperazin-l-yl]anilino]- A(A-dimethylpyrrolo[2,3-</]pyrimidine-6-carboxamide 123.5. To a solution of 7-cyclopentyl- A(/V-dimethyl-2-(4-piperazin- 1 -ylanilino)pyrrolo[2,3 -tfjpyrimidine-6-carboxamide (200 mg, 461 pmol) and 2-iodoethanol (159 mg, 923 pmol) in DMF (2 mL) was added CS2CO3 (301 mg, 923 umol). After stirring at 80 °C for 12 h, the reaction mixture was concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSOy concentrated, and purified by prep-TLC (SiO?., EtOAc/) to afford compound 123.5 (140 mg) in 63% yield. MS (ESI) m/z\ 478.2 [M+H]+
[001045] Preparation of 2-[4-[4-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-c(|- pyrimidin-2-yl]amino]phenyl]piperazin-l-yl]ethyl 4-methylbenzenesulfonate 123.6. To a solution of compound 123.5 (140 mg, 293 pmol) in DCM (4 mL) were added TsCl (84 mg, 440 umol) and TEA (89 mg, 879 pmol). After stirring for 12 h, the reaction mixture was concentrated and purified by prep-TLC (SiOi, MeOH/DCM) to afford compound 123.6 (35 mg) in 19% yield.
Figure imgf000408_0001
496.2 [M+H]+. [001046] Preparation of 7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-
1 (27/)-yl)phenyl)-piperidin- 1 -yl)ethyl)piperazin- 1 -yl)phenyl)amino)-A,A-dimethyl-7//-pyrrolo- [2,3-<7]pyrimidine-6-carboxamide A434. To a solution of compound 123.4 (15 mg, 55.4 pmol) in DMF (1 mL) were added DIEA (21 mg, 166 pmol), compound 123.6 (35 mg, 55.4 pmol), and KI (9.2 mg, 55.4 pinol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A434 (12 mg) in 29% yield. }H NMR (400 MHz, DMSO-&) 3 10.33 (s, 1H), 9.21 (s, 1H), 8.68 (s, 1H), 7.65 (d, ./ 9.2 Hz, 2H), 7.33-7.27 (m, 1H), 7.21 (s, 1H), 7.17-7.10 (m, 2H), 6.91-6.85 (m, 2H), 6.54 (s, 1H), 4.78-4.64 (m, 1H), 3.83- 3.74 (m, 2H), 3.11-2.98 (m, 14H), 2.71-2.67 (m, 2H), 2.60-2.53 (m, 6H), 2.46-2.29 (m, 3H), 2.09-2.02 (m, 2H), 1.98-1.91 (m, 4H), 1.78-1.71 (m, 2H), 1.68-1.59 (m, 4H); MS (ESI) m/z: 733.3 [M+H]+.
Example 124
Preparation of 7-cyclopentyl-2-((5-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A,iV-dimethyl-7//-pyrrolo[2,3-£f]pyrimidine-6- carboxamide A435
Figure imgf000409_0001
[001047] Compound A435 was prepared as described below.
[001048] Preparation of 3-[(4-methoxyphenyl)methyl]-l-[4-(2-tetrahydropyran-2-yloxy- ethyl)phenyl]hexahydropyrimidine-2, 4-dione 124.1. A mixture of 2-[2-(4-bromophenyl)- ethoxy]tetrahydropyran (3 g, 10.5 mmol), 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine- 2, 4-dione (2.22 g, 9.47 mmol), Pd?.(dba)3 (963 mg, 1.05 mmol), CS2CO3 (6.86 g, 21 mmol), and Xantphos (1.22 g, 2.1 mmol) in dioxane (30 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then treated with aqueous NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 124.1 (3.5 g) in 53% yield. MS (ESI) m/z: 439.3 [M+H]+. [001049] Preparation of 1 -[4-(2-hydroxyethyl)phenyl]-3-[(4-methoxyphenyl)methyl]- hexahydropyrimidine-2, 4-dione 124.2. A mixture of compound 124.1 (1 g, 1.60 mmol) and IM HC1 in THF (2 mL) in THF (10 mL) was stirred for 12 h under N2. The reaction mixture was then treated with aqueous NaHCOi and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO<i, concentrated, and purified by reverse phase prep-HPLC to afford compound 124.2 (300 mg) in 53% yield. MS (ESI) m/z: 355 [M+H]+.
[001050] Preparation of 2-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexahydro- pyrimidin-l-yl]phenyl]ethyl 4-methylbenzenesulfonate 124.3, A mixture of compound 124.2 (100 mg, 282 pmol), TsCl (108 mg, 564 pmol), and TEA (86 mg, 847 pmol) in DCM (1 mL) was stirred for 3 h under N2. The reaction mixture was then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by prep-TLC (SiCh, EtOAc/PE) to afford compound 124.3 (95 mg) in 66% yield. MS (ESI) m/z: 509.3 [M+H]+.
[001051] Preparation of 7-cyclopentyl-2-[[5-[4-[l-[2-[4-[3-[(4-methoxyphenyl)methyl]- 2,4-dioxohexahydropyrimidin- 1 -yl]phenyl]ethyl]-4-piperidyl]piperazin- 1 -yl]-2-pyridyl]amino]- A(A-dimethylpyrrolo[2,3-d]pyrimidine-6-carboxamide 124.4. A mixture of 7-cyclopentyl-Ar,Ar- dimethyl-2-[[5-[4-(4-piperidyl)piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-t/]pyrimidine-6- carboxamide (82.4 mg, 159 pmol), compound 124.3 (85 mg, 167 pmol), DIEA (185 mg, 1.43 mmol), and KI (79 mg, 478 nmol) in DMF (0.9 mL) was stirred at 80 °C for 12 h under N2. The reaction mixture was then treated with aqueous NTLCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SO4, concentrated, and purified by reverse phase prep-HPLC to afford compound 124.4 (70 mg) in 41% yield. MS (ESI) m/z: 854.3 [M+H]+.
[001052] Preparation of 7-Cyclopentyl-2-((5-(4-(l-(4-(2,4-dioxotetrahydropyrimidin- l(2/7)-yl)phenethyl)-piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7J7- pyrrol o[2, 3 -<7]pyrimidine-6-carboxamide A435. A solution of compound 124.4 (60 mg, 70.3 umol), TFA (462 mg, 4.05 mmol), and TfOH (255 mg, 1.7 mmol) in DCM (0.6 mL) was stirred at 40 °C for 1 h under N2. The reaction mixture was then diluted with water and extracted with DCM. The combined organic layers were concentrated and purified by reverse phase prep- HPLC to afford compound A435 (18 mg) in 34% yield. 'H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.43-8.09 (m, 2H), 8.02 (d, J= 9.2 Hz, 1H), 7.94 (d, ./= 1.2 Hz, 1H), 7.66 (dd, J= 2.4, 9.2 Hz, 1H), 7.41-7.31 (m, 4H), 6.66 (s, 1H), 4.76 (d, J= 8.8 Hz, 1H), 3.86 (t, J= 6.8 Hz, 2H), 3.67- 3.59 (m, 2H), 3.30 (s, 2H), 3.27 (s, 4H), 3.16 (s, 6H), 3.00 (s, 4H), 2.88 (s, 4H), 2.84-2.80 (m, 2H), 2.76-2.67 (m, 1H), 2.57-2.47 (m, 2H), 2.24-2.16 (m, 2H), 2.13-2.03 (m, 4H), 1.94-1.83 (m, 2H), 1.73 (d, J= 6.0 Hz, 2H); MS (ESI) m/z: 734.4 [M+H]+.
Example 125
Preparation of 2-((5-(4-(2-(l-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-l(2Z7)-yl)phenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A,A-dimethyl-7/7- pyrrolo[2,3-d]pyrimidine-6-carboxamide A436
Figure imgf000411_0001
[001053] Compound A436 was prepared as described below.
[001054] Preparation of 1 -[4-[4-(2, 2-dimethoxy ethyl)- 1-piperi dyl]phenyl]-3-[(4-methoxy- phenyl) methyl]hexahydropyrimidine-2, 4-dione 125.1. A mixture of 4-(2,2-dimethoxyethyl)- piperidine (2.23 g, 12.9 mmol), l-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydro- pyrimidine-2, 4-dione (5 g, 12.9 mmol), RuPhos (300 mg, 642 pmol), RuPhos Pd G3 (537 mg, 642 pmol), and CS2CO3 (12.6 g, 38.5 mmol) in dioxane (50 mL) was stirred at 80 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 125.1 (6 g) in 87% yield. LH NMR (400 MHz, CDCh) 3 7.43 (d, J = 8.8 Hz, 2H), 7. 12 (d, J = 8.8 Hz, 2H), 6.92 (d, J= 8.0 Hz, 2H), 6.85-6.79 (m, 2H), 4.95 (s, 2H), 4.51 (t, 5.6 Hz, 1H), 3.79 (s, 3H),
3.72 (t, J= 6.8 Hz, 2H), 3.64 (d, J= 12.4 Hz, 2H), 3.34 (s, 6H), 2.85 (t, J= 6.8 Hz, 2H), 2.72 (t, ./ 11.6 Hz, 2H), 1.82 (d, J 12.4 Hz, 2H), 1.61-1.58 (m, 3H), 1.40 (d, ./ - 10.0 Hz, 2H); MS (ESI) m/z: 482.3 [M+H]+.
[001055] Preparation of 2-[l-[4-[3-[(4-methoxyphenyl)methyl] -2,4-dioxo-hexahydro- pyrimidin-l-yl]phenyl]-4-piperidyl]acetaldehyde 125.2. To a solution of compound 125.1 (1 g, 2.08 mmol) in DCM (10 mL) was added TFA (7.68 g, 67.3 mmol). After stirring for 1 h, the reaction mixture was concentrated to afford compound 125.2 (800 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 436.2 [MHI]+.
[001056] Preparation of 7-cyclopentyl-2-[[5-[4-[2-[l-[4-[3-[(4-methoxyphenyl)methyl]- 2,4-dioxohexahydropyrimidin-l-yl]phenyl]-4-piperidyl]ethyl]piperazin-l-yl]-2-pyridyl]amino]- A,A-dimethyl-pyrrolo[2,3-J]pyrimidine-6-carboxamide 125.3, To a solution of compound 125.2 (400 mg, 918 pmol) and 7-cyclopentyl-Ar,A?-dimethyl-2-[(5-piperazin-l -yl-2-pyridyl)amino]- pyrrolo[2,3-cZ]pyrimidine-6-carboxamide (399 mg, 918 pmol) in THF (2 mL) and DMSO (2 mL) was added NaOAc (75 mg, 918 pmol). After the mixture was stirred at 60 °C for 4 h, NaBHfOAc)?, (389 mg, 1.84 mmol) was added. The reaction mixture was stirred for 12 h, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 125.3 (210 mg) in 25% yield. MS (ESI) m/z: 854.4 [M+H]+.
[001057] Preparation of 2-((5-(4-(2-(l-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-l(277)- yl)phenyl)-piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-ApV-dimethyl- 777-pyrrolo[2,3-fi?]pyrimidine-6-carboxamide A436. To a solution of compound 125.3 (210 mg, 246 pmol) in DCM (3 mL) were added TFA (280 mg, 2.46 mmol) and TfOH (185 mg, 1.23 mmol). After stirring at 40 °C for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound A436 (25 mg) in 14% yield. }H NMR (400 MHz, DMSO-Jo) d 10.24 (s, 1H), 9.27 (s, 1H), 8.75 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 8.00 (d, ./ 2.8 Hz, 1H), 7.44 (dd, J= 2.8, 9.2 Hz, 1H), 7.13 (d, ./ = 8.8 Hz, 2H), 6.92 (d, J= 9.2 Hz, 2H), 6.59 (s, 1H), 4.73 (quin, J= 8.8 Hz, 1H), 3.68 (q, J= 7.2 Hz, 4H), 3.18 s, 4H), 3.05 (s, 6H), 2.73-2.60 (m, 8H), 2.55 (s, 2H), 2.43 (dd, J- 9.6, 11.2 Hz, 2H), 1.98 (d, J = 2.0 Hz, 4H), 1.77 (d, J- 12.0 Hz, 2H), 1.69-1.59 (m, 2H), 1.48 (s, 3H), 1.35-1.18 (m, 2H); MS (ESI) m/z: 734.6 [M+H]L Example 126
Preparation of 7-cyclopentyl-2-((4-((4-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-l/7-indazol-
7-yl)oxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-A(A-dimethyl-7H-pyrrolo[2,3-
J|pyrimidine-6-carboxamide A502
Figure imgf000413_0001
[001058] Compound A502 was prepared as described below.
[001059] Preparation of /er/-butyl (4-(4-(2-((3 -(2, 6-dioxopiperidin-3-yl)-l -methyl- 1//- indazol-7-yl)oxy)acetyl)piperazin-l-yl)butyl)carbamate 126.1. To a solution of 3-(l-methyl-7- (2-oxo-2-(piperazin-l-yl)ethoxy)-l//-indazol-3-yl)piperidine-2, 6-dione (200 mg, 0.52 mmol) in DCM (4 mL) and MeOH (1 mL) were added tert-butyl (4-oxobutyl)carbamate (97 mg, 0.52 mmol) and NaBEhCN (66 mg, 1.04 mmol). After stirring overnight, the reaction mixture was concentrated and purified by column chromatography (SiCh, MeOHZDCM) to afford compound 126.1 (176 mg) in 61% yield. MS (ESI) m/z: 557.2 [M+H]+.
[001060] Preparation of 3-(7-(2-(4-(4-aminobutyl)piperazin-l-yl)-2-oxoethoxy)-l-methyl- l//-indazol-3-yl)piperidine-2, 6-dione 126.2. To a solution of compound 126.1 (84 mg, 0.15 mmol) in DCM (4 mL) was added HC1 in EtOAc (1 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 126.2 (0.15 mmol), which was used directly in the next step without further purification. MS (ESI) m/z: 457.2 [M+H]+.
[001061] Preparation of 7-cyclopentyl-2-((4-((4-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l- methyl-l//-indazol-7-yl)oxy)acetyl)piperazin-1-yl)butyl)carbamoyl)phenyl)amino)-A,A- dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A502. To a solution of compound 126.2 (0.15 mmol) in DMF (2 mL) were added DIEA (58 mg, 0.45 mmol), 4-((7-cyclopentyl-6- (dimethylcarbamoyl)-7//-pyrrolo[2,3-<7]pyrimidin-2-yl)amino)beiizoic acid (59 mg, 0.15 mmol), HOBt (41 mg, 0.3 mmol), and EDCI (57 mg, 0.3 mmol). After stirring overnight, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (S1O2, MeOH/DCM) to afford compound A502 (22 mg) in 17% yield. LH NMR (400 MHz, DMSO-fiC) 3 10.89 (s, 1H), 9.82 (s, 1H), 8.80 (s, 1H), 8.28 (t, J= 5.6 Hz, 1H), 7.91 (d, ./= 8.4 Hz, 2H), 7.80 (d, J= 8.4 Hz, 2H), 7.23 (d, J= 8.0 Hz, 1H), 6.96 (t, J= 7.6 Hz, 1H), 6.83 (d, J= 1.6 Hz 1H), 6.62 (s, 1H), 5.00 (s, 2H), 4.79-4.71 (m, 1H), 4.31 (dd, 5.2, 9.4 Hz, 1H), 4.23 (s, 3H), 3.51- 3.44 (m, 4H), 3.29-3.24 (m, 2H), 3.09-3.02 (m, 7H), 2.69-2.60 (m, 2H), 2.43-2.37 (m, 2H), 2.36- 2.28 (m, 5H), 2.20-2.12 (m, 1H), 2.06-1.96 (m, 5H), 1.74-1 65 (m, 2H), 1.56-1.45 (m, 5H); MS (ESI) m/z: 832.6 [M+H]+.
Example 127
Preparation of 7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,4-dioxotetrahydropyrimidin-l(2Z/)-yl)-l- methyl-l//-indazol-6-yl)piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A,ALdimethyl- 777-pyrrolo[2,3-</]pyrimidine-6-carboxamide A559
Figure imgf000414_0001
[001062] Compound A559 was prepared as described below.
[001063 ] Preparation of 1 -[6-[4-(2,2-dimethoxy ethyl)- 1 -piperidyl]- 1 -methyl-indazol-3 -yl]-
3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione 127.1. A mixture of l-(6-bromo- l-methylindazol-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (800 mg, 1.8 mmol), 4-(2,2-dimethoxyethyl)piperidine (469 mg, 2.71 mmol), RuPhos Pd G3 (151 mg, 180 iimol), RuPhos (84 mg, 180 pmol), and Cs< ()< (1.76 g, 5.41 mmol) in dioxane (15 mL) was stirred at 110 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous, NazSCh concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 127.1 (960 mg) in 76% yield. 'H NMR (400 MHz, DMSCWe) <5 7.37 (d, J - 9.2 Hz, 1H), 7.24 (br d, J = 8.4 Hz, 2H), 6.92-6.84 (m, 3H), 6.80 (s, 1H), 4.84 (s, 2H), 4.49 (br t, J= 5.2 Hz, 1H), 3.92-3.89 (m, 1H), 3.87 (s, 3H), 3.80-3.69 (m, 5H), 3.57 (s, 6H), 2.92 (br t, ./= 6.4 Hz, 2H), 2.70 (br t, J = 12.0 Hz, 2H), 1.77 (br d, ./= 12.4 Hz, 2H), 1 .51 (br d, ./= 4.8 Hz, 2H), 1.31 (br d, J-
11.2 Hz, 2H), 1.10 (br d, J= 5.8 Hz, 1H), 0.97 (br d, J = 5.8 Hz, 1H); MS (ESI) m/z: 536.4 [M+H]+.
[001064] Preparation of 2-[l-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydro- pyrimidin-l-yl]-l-methyl-indazol-6-yl]-4-piperidyl]acetaldehyde 127.2. To a solution of compound 127.1 (500 mg, 934 pmol) in DCM (12 mL) was added TFA (6.14 g, 53,9 mmol). After stirring for 1 h, the reaction mixture was treated with aqueous NaHCOs and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford 127.2 (419 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 490.4 [M+H]’f .
[001065] Preparation of 7-cyclopentyl-2-[[5-[4-[2-[l-[3-[3-[(4-methoxyphenyl)methyl]- 2,4-dioxohexahydropyrimidin-l-yl]-l-methyl-indazol-6-yl]-4-piperidyl]ethyl]piperazin-l-yl]-2- pyridyl]amino]-A(A-dimethylpyrrolo[2,3-<7]pyrimidine-6-carboxamide 127.3, To a solution of compound 127.2 (293 mg, 598 pmol) in MeOH (4 mL) was added NaOAc (227 mg, 2.76 mmol), followed by addition of 7-cyclopentyl-A’,A-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]- pyrrolo[2,3-<7]pyrimidine-6-carboxamide (200 mg, 460 pmol). After the mixture was stirred for 0.5 h, NaBHsCN (58 mg, 921 pmol) was added. The reaction mixture was stirred at 35°C for 12 h under N2, and then diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 127.3 (130 mg) in 31% yield. ’H NMR (400 MHz, DMSO-dis) J 9.27 (s, 1H), 8.75 (s, 1H), 8.14 (d, J= 9.2 Hz, 1H), 7.99 (d, 2.8 Hz, HI), 7.43
(dd, J= 2.8, 9.2 Hz, 1H), 7.37 (d, J= 9.2 Hz, 1H), 7.24 (d, J= 8.8 Hz, 2H), 6.93-6.85 (m, 3H), 6.81 (s, 1H), 6.59 (s, 1H), 4.84 (s, 2H), 4.73 (br t, J = 8.8 Hz, 1H), 3.92-3.86 (m, 5H), 3.79 (br d, J= 12.4 Hz, 2H), 3.73 (s, 3H), 3.15-3.01 (m, 10H), 2.92 (t, J= 6.8 Hz, 2H), 2.72 (br t, J= 11.2 Hz, 2H), 2.54 (br s, 2H), 2.47-2.37 (m, 4H), 1.98 (br d, J= 4.0 Hz, 5H), 1.80 (br d, J= 12.0 Hz, 2H), 1.70-1.60 (m, 2H), 1.57-1.18 (m, 6H); MS (ESI) m/z: 908.5 [M+H] \
[001066] Preparation of 7-cyclopentyl-2-((5-(4-(2-( l-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-y 1)- 1 -methyl- l/f-indazol-6-yl)piperidin-4-yl)ethyl)piperazin- 1 -yl)pyridin-2-yl)amino)- A,A;-dimethyl-7//-pyrrolo[2,3-</]pyrimidine-6-carboxamide A559. To a solution of compound 127.3 (130 mg, 143 pmol) in IT A (3 mL) was added TfOH (509 mg, 3.39 mmol). After stirring at 70 °C for 2 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SOr, concentrated, and purified by reverse phase prep-HPLC to afford compound A559 (20 mg) in 18% yield. lH NMR (400 MHz, DMSO-de) J 10.50 (br s, 1H), 9.27 (s, 1H), 8.75 (s, 1 H), 8.14 (d, ./ 9.2 Hz, I I I), 7.99 (d, ./ 2.4 Hz, 1H), 7.43 (br d, J = 8.8 Hz, 2H), 6.90 (br d, ./ = 8.8 Hz, 1H), 6.81 (s, 1H), 6.59 (s, 1H), 4.73 (brt, J= 8.4 Hz, 1H), 3.92-3.85 (m, 5H), 3 79 (br d, ./ 12.0 Hz, 2H), 3.12 (br s, 4H), 3.05 (br s, 6H), 2.77-2.68 (m, 4H), 2.53 (br s, 2H), 2.41 (br d, J = 6.8 Hz, 4H), 1.98 (br s, 4H), 1.80 (br d, J = 12.0 Hz, 2H), 1.64 (br d, J= 4.4 Hz, 2H), 1.58-1.09 (m, 7H); MS (ESI) m/z: 788.7 [M+H]+.
Example 128
Preparation of 7-cyclopentyl-2-((4-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)hexyl)carbamoyl)phenyl)amino)-Af,A-dimethyl-7J/-pyrrolo[2,3-</]pyrimidine-6- carboxamide A601
Figure imgf000416_0001
[001067] Compound A601 was prepared as described below.
[001068] Preparation of ZerZ-butyl (6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)hexyl)carbamate 128.1. To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-4-fluoro- isoindoline-l,3-dione (117 mg, 423 pmol) in NMP (10 mL) were added ZerZ-butyl (6-amino- hexyljcarbamate (91 mg, 423 pmol) and DIEA (163 mg, 1.27 mmol). After heated at 150 °C for 1 h in a microwave reactor, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford 128.1 (70 mg) in 35% yield. MS (ESI) m/z: 473.2 [M+H]+.
[001069] Preparation of 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1, 3-dione 128.2. To a solution of compound 128.1 (70 mg, 148 pmol) in DCM (6 mL) was added HC1 in EtOAc (2 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 128.2 (80 mg), which was used directly in the next step without further purification. MS (ESI) OT/Z: 373.2 [M+H]+.
[001070] Preparation of 7-Cyclopentyl-2-((4-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo- isoindolin-4-yl)amino)hexyl)carbamoyl)phenyl)amino)-jV,A-dimethyl-7//-pyrrolo[2,3-r/]- pyrimidine-6-carboxamide A601. To a solution of compound 128.2 (80 mg) in DMF (10 mL) were added DIEA (57 mg, 0.44 mmol), 4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7/7- pyrrolo[2,3-J]pyrimidin-2-yl)amino)benzoic acid (58 mg, 0.148 mmol), and HATU (84 mg, 0.22 mmol). After stirring overnight, the reaction mixture was concentrated and purified by column chromatography (SiCh, MeOH/DCM) and further purified by reverse phase prep-HPLC to afford compound A601 (21 mg) in 18% yield. 1HNMR (400 MHz, DMSO-afe) <5 11.09 (s, 1H), 9.81 (s, 1H), 8.79 (s, 1H), 8.27 (t, J= 5.6 Hz, 1H), 7.90 (d, J= 8.4 Hz, 2H), 7.80 (d, J= 8.8 Hz, 2H), 7.57 (t, .7 ■■■ 7.2 Hz, 1H), 7.09 (d, ./ ■■■ 8.4 Hz, 1H), 7.01 (d, ./ ■■■ 6.8 Hz, 1H), 6.62 (s, 1H), 6.54- 6.52 (m, 1H), 5.04 (dd, J= 5.2, 12.8 Hz, 1H), 4.80-4.71 (m, 1H), 3.30-3.23 (m, 4H), 3.06 (s, 6H), 2.93-2.83 (m, 1 H ), 2.59-2.54 (m, 1H), 2.49-2.40 (m, HI), 2.02-1.97 (m, 5H), 1.69-1.66 (m, 2H), 1.61 -1.52 (m, 4H), 1.38-1.33 (m, 4H), 1.29-1.23 (m, 2H); MS (ESI) m/z = 761.8 [M+H]+.
Example 129
Preparation of 7-cyclopentyl-2-((4-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4/f- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)carbamoyl)phenyl)amino)-A,A-dimethyl-7H- pyrrolo[2,3-J)pyrimidine-6-carboxamide A651
Figure imgf000417_0001
[001071] Compound A651 was prepared as described below.
[001072] Preparation of methyl 4-((7-cyclopentyl-6-(dimethylcarbamoyl)-77/-pyrrolo[2,3- t/]pyrimidin-2-yl)amino)benzoate 129.1, To a solution of 2-chloro-7-cyclopentyl-A,Ar-dimethyl- 7//-pyrrolo[2,3-J]pyrimidine-6-carboxamide (5 g, 17.1 mmol) in dioxane (1 L) were added methyl 4-aminobenzoate (3.1 g, 20.5 mmol), BINAP (2.27 g, 3.42 mmol), CsrCCh (11.1 g, 34.2 mmol), and Pd(0Ac)2 (385 mg, 1.71 mmol). After stirring at 100 °C under N2 overnight, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford 129.1 (5.72 g) in 82% yield. MS (ESI) m/z'. 408.2 [M+H]“.
[001073] Preparation of 4-((7-cyclopentyl-6-(dimethylcarbamoyl)-777-pyrrolo[2,3-t/]- pyrimidin-2-yl)amino)benzoic acid 129,2. To a solution of compound 129,1 (4,44 g, 10,9 mmol) in THF (12 mL), MeOH (24 mL), and water (6 mL) was added LiOH H2O (916 mg, 21.8 mmol). After stirring at 40 °C overnight, the reaction mixture was acidified to pH 3 and extracted with EtOAc. The combined organic layers were dried over anhydrous NaiSO4 and concentrated to afford compound 129.2 (4.61 g), which was used directly in the next step without further purification. MS (ESI) Wz: 394.2 [M+H]+,
[001074] Preparation of 7-cyclopentyl-2-((4-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6- dihydro-4f7-thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)carbamoyl)phenyl)amino)-A,A7-dimethyl- 7Z7-pyrrolo[2,3-</jpyrimidine-6-carboxamide A651 To a solution of compound 129.1 (100 mg, 0.254 mmol) in DMF were added DIEA (99 mg, 0.763 mmol), 3-(l-((4-(aminomethyl)phenoxy)- methyl)-4-oxo-4/f-thieno[3,4-c]pyrrol-5(6/7)-yl)piperidine-2, 6-dione (98 mg, 0.254 mmol), and HATU (145 mg, 0.381 mmol). After stirring overnight, the reaction mixture was concentrated and purified by column chromatography (SiOz, MeOH/DCM) and reverse phase prep-HPLC to afford compound A651 (42 mg) in 22% yield. !HNMR (400 MHz, DMSO-tA) 5 10.96 (s, 1 H), 9.82 (s, 1H), 8.79 (t, J = 6.8 Hz, 2H), 8.00 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.26 (d, 8.4 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.61 (s, 1H), 5.28 (s, 2H), 5.01 (dd, J =
4.8, 13.2 Hz, 1H), 4.77-4.70 (m, 1H), 4.41 (d, J= 6.0 Hz, 2H), 4.36-4.20 (m, 2H), 3.06 (s, 6H), 2.92-2.83 (m, 1H), 2.59-2.54 (m, 1H), 2.46-2.44 (m, 1H), 2.35-2.31 (m, I H), 2.01-1.96 (m, 5H), 1.70-1.68 (m, 2H); MS (ESI) m/z: 761.4 [M+Hf .
Example 130
Preparation of 3-(3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-^- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-3-oxopropoxy)phenyl)piperidine-2, 6-dione B102
Figure imgf000419_0001
[001075] Compound B102 was prepared as described below.
[001076] Preparation of tert-butyl 3-(3-bromophenoxy)propanoate 130.1, To a solution of 3-bromophenol (1 g, 5.78 mmol) in tert-butyl prop-2-enoate (8.83 g, 68.9 mmol) was added DMAP (71 mg, 578 pmol). After stirring at 100 °C for 36 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 130.1 (690 mg) in 40% yield. !H NMR (400 MHz, CDCh) 7.15-7.10 (m, 1H), 7.10-7.04 (m, 2H), 6.86-6.80 (m, 1H), 4.19 (t, J = 6.4 Hz, 2H), 2.69 (t, J= 6.4 Hz, 2H), 1.46 (s, 9H).
[001077] Preparation of tert-butyl 3-[3-(2,6-dibenzyloxy-3-pyridyl)phenoxy]propanoate 130.2. A mixture of compound 130.1 (500 mg, 1.66 mmol), 2,6-dibenzyloxy-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (693 mg, 1.66 mmol), K3PO4 (705 mg, 3.32 mmol), and Pd(dppf)C12-CH2Cb (68 mg, 83 pmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 100 °C overnight under N2. The reaction mixture was then filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 130.2 (690 mg) in 81% yield. MS (ESI) m/z: 512.6 [M+H]+.
[001078] Preparation of tert-butyl 3-[3-(2,6-dioxo-3-piperidyl)phenoxy]propanoate 130.3, To a solution of compound 130.2 (690 mg, 1 .35 mmol) in EtOH (5 mL) and THF (4 mL) was added 10% Pd/C (350 mg) under N2. After stirring under H2 at 40 °C overnight, the reaction mixture was filtrated and concentrated to afford compound 130.3 (380 rag), which was used directly in the next step without further purification. MS (ESI) m/z: 334.1 [M+H]+.
[001079] Preparation of 3-[3-(2,6-dioxo-3-piperidyl)phenoxy]propanoic acid 130.4, To a solution of compound 130.3 (120 mg, 360 pmol) in DCM (5 mL) was added TFA (1 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 130.4 (100 mg) as a TFA salt, which was used directly in the next step without further purification.
[001080] Preparation of 3-[3-[3-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-pyrido[2,3- <7]pyrimidin-2-yl)amino]-3-pyridyl]piperazin-l-yl]-3-oxo-propoxy]phenyl]piperidine-2, 6-dione B102. To a solution of compound 130.4 (100 mg, 361 pmol) in DMSO (3 mL) were added NAIM (80 mg, 793 pmol), HOAt (54 mg, 397 pmol), EDCI (76 mg, 397 pmol), and 6-acetyl-8- cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrido[2,3-tZ]-pyrimidin-7-one (161 mg, 361 umol). After stirring at 30 °C overnight, the reaction mixture was purified by reverse phase prep-HPLC to afford compound B102 (85 mg) in 33% yield. LH NMR (400 MHz, DM SO-fife) d 10.81 (s, 1H), 10, 13 (s, 1H), 8.96 (s, 1H), 8.09 (d, .7= 2.8 Hz, 1H), 7.89 (d, .7= 8,8 Hz, 1H), 7.52-7.49 (m, 1H), 7.24 (t, J= 7.6 Hz, 1H), 6.88-6.82 (m, 1H), 6.81-6.76 (m, 2H), 5.89- 5.75 (m, 1H), 4.21 ( t, J= 6.4 Hz, 2H), 3.82-3.81(m, 1H), 3.72-3.59 (m, 4H), 3.23-3.09 (m, 4H), 2.90-2.61 (m, 2H), 2.64 (s, 1H), 2.46-2.40 (m, 5H), 2.31 (s, 3H), 2.27-2.15 (m, 3H), 2.07-1.97 (m, 1H), 1.93-1.84 (m, 2H), 1.83-1.69 (m, 2H), 1.64-1.50 (m, 2H); MS (ESI) m/z: 707.2 [M+H]+.
Example 131
Preparation of A-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- methylphenoxy)acetami de Bl 03
Figure imgf000420_0001
[001081] Compound B103 was prepared as described below.
[001082] Preparation of benzyl 2-(3-bromo-2-methylphenoxy)acetate 131.1. To a solution of 3-bromo-2-methylphenol (2 g, 10.7 mmol) in acetone (20 mL) were added K2CO3 (2.96 g, 21.4 mmol) and benzyl 2-bromoacetate (2.94 g, 12.8 mmol). After stirring at 60 °C for 6 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 131.1 (2.9 g) in 78% yield. rH NMR (400 MHz, CDCh) d 7.41- 7.29 (m, 5H), 7.20 (d, J= 8.0 Hz, 1H), 6.96 (s, 1H), 6.64 (d, J= 8.2 Hz, 1H), 5.23 (s, 2H), 4.68 (s, 2H), 2.37 (s, 3H).
[001083] Preparation of benzyl 2-[3-(2,6-dibenzyloxy-3-pyridyl)-2-methylphenoxy]acetate 131.2, To a solution of compound 131.1 (500 mg, 1,49 mmol) in dioxane (15 mL) were added K3PO4 (633 mg, 2.98 mmol), H2O (1.5 mL), Pd(dppf)C12 CH2.Cb. (122 mg, 149 pmol), and 2,6- dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (747 mg, 1.79 mmol).
After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 131.2 (600 mg) in 70% yield. MS (ESI) m/z: 546.5 [M+H]T
[001084] Preparation of 2-[3-(2,6-dioxo-3-piperidyl)-2-methylphenoxy]acetic acid 131.3, To a solution of compound 131.2 (600 mg, 1.1 mmol) in EtOH (6 mL) was added 10% Pd/C (300 mg) under N?.. After stirring under H2 for 6 h, the reaction mixture was filtered and concentrated to afford compound 131.3 (280 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 278 [M+H]+.
[001085] Preparation of tert-butyl A-[2-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo- pyrido[2,3-zZ]pyrimidin-2-yl)amino]-3-pyridyl]piperazin-l-yl]ethyl]carbamate 131.4. To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrido[2,3-d]- pyrimidin-7-one (500 mg, 1.12 mmol) in DMF (5 mL) were added DIEA (866 mg, 6.7 mmol) and Zer/-butyl A-(2-bromoethyl)carbamate (300 mg, 1 .34 mmol). After the mixture was stirred at 80 °C for 12 h, tert-butyl A-(2-bromoethyl)carbamate (200 mg, 894 gmol) and KI (18.6 mg, 112 umol) were added. The reaction mixture was stirred at 80 °C for 12 h, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr, concentrated, and purified by prep-TLC (SiOz, MeOH/DCM) to afford compound 131.4 (280 mg) in 42% yield. MS (ESI) m/z: 591.5 [M+H]+.
[001086] Preparation of 6-acetyl-2-[[5-[4-(2-aminoethyl)piperazin-l -yl]-2-pyridyl]amino]- 8-cyclopentyl-5-methylpyrido[2,3-tZ]pyrimidin-7-one 131.5. To a solution of compound 131.4 (280 mg, 474 pmol) in DCM (4 mL) was added 4M HC1 in dioxane (2 mL). After stirring for 1 h, the reaction mixture was concentrated and purified by reverse prep-HPLC to afford compound 131.5 as an HC1 salt (90 mg) in 34% yield. MS (ESI) m/z'. 491 .2 [M+H]+.
[001087] Preparation ofA-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin- 3-yl)-2-methylphenoxy)acetamide B103. To a solution of compound 131.3 (47.4 mg, 171 pmol) in DMSO (1 mL) were added NMM (51.8 mg, 512 pmol), HOAt (25.6 mg, 187 pmol, EDCI (36 mg, 188 pmol), and compound 131.5 as an HC1 salt (90 mg, 171). After stirring for 1 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound B103 (26 mg) in 20% yield. LH NMR (400 MHz, DMSCWe) d 10.80 (s, 1H), 10.09 (s, 1H), 8.95 (s, 1H), 8.05 (d, J= 2.8 Hz, 1H), 7,83 (s, 1H), 7,80 (t, ./= 5.6 Hz, 1H), 7.47 (dd, J = 3.2, 9.2 Hz, 1H), 7.10 (s, 1H), 6.84-6.70 (m, 2H), 5.82 (quin, J= 8.8 Hz, 1H), 4.49 (s, 2H), 4.07 (dd, J= 5.2, 11.6 Hz, 1H), 3.36-3.32 (m, 2H), 3.31-2.28 (m, 2H), 3.18-3.11 (m, 4H), 2 75-2.67 (m, 1 H), 2.56 (d, J- 4.4 Hz, 5H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27-2.20 (m, 2H), 2.17 (s, 3H), 2.16-2.08 (m, 1H), 1.95-1.83 (m, 3H), 1.96-1.83 (m, 1 I I ), 1.81-1.72 (m, 2H), 1.62-1.53 (m, 2H); MS (ESI) m/z: 750.5 [M+H]+.
Example 132
Preparation of A-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2-
(trifluorornethyl)phenoxy)acetamide Bl 04
Figure imgf000422_0001
[001088] Compound B104 was prepared as described below.
[001089] Preparation of benzyl 2-[3-bromo-2-(trifluoromethyl)phenoxy]acetate 132.1. To a solution of benzyl 2-hydroxyacetate (2.74 g, 16.5 mmol,) in DMF (40 mL) was added NaH (724 mg, 18.1 mmol) at 0 °C. After the mixture was stirred for 60 min, 1 -bromo-3-fluoro-2- (trifluoromethyl)benzene (2 g, 8.23 mmol) was added. The reaction mixture was stirred for 12 h under N2, and then treated with saturated aqueous NH4CI and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4CI and brine, dried over anhydrous Nai’SCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 132.1 (770 mg) in 24% yield.
[001090] Preparation of benzyl 2-[3-(2,6-dibenzy1oxy-3-pyridyl)-2-(trifluoromethyl)- phenoxy] acetate 132.2, A mixture of compound 132.1 (680 mg, 257 pmol), 2,6-dibenzyloxy-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (129 mg, 308 pmol), K3PO4 (109 mg, 514 umol), Pd(dppf)C12-CH2C12 (21 mg, 25.7 pmol), and H2O (0.2 mL) in dioxane (2 mL) was stirred at 100 °C for 16 h under N2. The reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 132.2 (800 mg) in 78% yield. MS (ESI) m/z'. 600.4 [M+H] \
[001091] Preparation of 2-[3-(2,6-dioxo-3-piperidyl)-2-(trifluoromethyl)phenoxy]acetic acid 132.3. To a solution of compound 132.2 (800 mg, 1.33 mmol) in EtOH (8 mL) was added 10% Pd/C (400 mg) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 132.3 (400 mg), which was used directly in next step without further purification.
[001092] Preparation ofAr-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-</|-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yi)ethyl)-2-(3-(2,6-dioxopiperidin- 3-yl)-2-(trifluoromethyl)phenoxy)acetamide B104. A mixture of compound 132.3 (33.8 mg, 102 pmol), 6-acetyl-2-[[5-[4-(2-aminoethyl)piperazin-l-yl]-2-pyridyl]amino]-8-cyclopentyl-5- methylpyrido[2,3-d]pyrimidin-7-one (50 mg, 102 pmol), HOAt (15.3 mg, 112 pmol), NMM (31 mg, 306 pmol), and EDCI (21.5 mg, 112 pmol) in DMSO (2 mL) was stirred for 2 h. The reaction mixture was filtered and purified by reverse phase prep-HPLC to afford compound B104 (16 mg) in 20% yield. !H NMR (400 MHz, DMSO-cfc) d 10.85 (br s, 1H), 10.10 (s, 1H), 8.96 (s, 1H), 8.06 (d, J= 2.8 Hz, 1H), 7.85 (d, J= 9.2 Hz, 1H), 7.63-7.58 (m, 1H), 7.57-7.52 (m, 1H), 7.51 -7.44 (m, 1H), 7.15 (br d, J- 8.0 Hz, 1H), 7.08-6.99 (m, 1H), 5.83 (br t,
Figure imgf000423_0001
8.8 Hz, 1H), 4.65 (s, 2H), 4.33-4.15 (m, 1H), 3.16 (br s, 4H), 2.79-2.70 (m, 1H), 2.70-2.60 (m, 2H), 2.57 (br s, 4H), 2.48-2.46 (m, 2H), 2.43 (s, 3H), 2 32 (s, 4H), 2.29-2.19 (m, 3H), 2.01-1.94 (m, 1H), 1.92-1.83 (m, 2H), 1.81-1.73 (m, 2H), 1.63-1.53 (m, 2H); MS (ESI) m/z: 804.4 [M+H]L
Example 133
Preparation of rV-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimi din-2 -yl )amino)pyri din-3 -yl )pi perazin- 1 -yl)propyl)-2-(3 -(2, 6-di ox opiperi din-3 -yl)-4- methylphenoxy)acetamide B109
Figure imgf000424_0001
[001093] Compound B109 was prepared as described below.
[001094] Preparation of /er/-butyl A-[3-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo- pyrido[2,3-tfjpyrimidin-2-yl)amino]-3-pyridyl]piperazin-l-yl]propyl]carbamate 133.1. To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrido[2,3-d]- pyrirnidin-7-one (400 mg, 894 pmol) in DMF (4 mL) were added DIEA (347 mg, 2.68 mmol) and ferLbutyl 2V-(3-bromopropyl)carbamate (255 mg, 1.07 mmol). After stirring at 80 °C for 16 h, the reaction mixture was diluted with water. The resulting precipitates were collected by filtration to afford compound 133.1 (530 mg), which was used directly in the next step without further purification. rH NMR (400 MHz, CDC13) J 8.84 (s, 1H), 8.47-8.27 (m, 1H), 8.25-8.12 (m, 1H), 8.07 (s, 1H), 5.95-5.81 (m, 1H), 5,31 (s, 1H), 3,83-3,53 (m, 1H), 3,36-3,11 (m, 6H), 3.01-2.86 (m, 1H), 2.67 (s, 3H), 2.56 (s, 4H), 2.38 (s, 4H), 2.07 (s, 2H), 1.95-1.84 (m, 2H), 1.71 (d, J = 4.8 Hz, 41 1), 1.45 (s, 9H).
[001095] Preparation of 6-acetyl-2-[[5-[4-(3-aminopropyl)piperazin-l-yl]-2-pyridyl]- amino]-8-cyclopentyl-5-methylpyrido[2,3-J]pyrimidin-7-one 133.2. To a solution of compound
133.1 (530 mg, 876 pmol) in DCM (2 mL) was added 4M HC1 in dioxane (1 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 133.2 as an HC1 salt (480 mg), which was used directly in the next step without further purification. rH NMR (400 MHz, DMSO-<&) J 11 .65 (s, 1H), 9.04 (s, 1H), 8.35 (s, 2H), 8.25-8.06 (m, 2H), 7.90 (d, J= 6.0 Hz, 1H), 5.84 (d, 6.0 Hz, 1H), 3.92 (d, .7 = 7.6 Hz, 2H), 3.61 (d, .7 = 7.2 Hz, 2H), 3.46-3.18 (m,
6H), 2.96 (s, 2H), 2.59-2.52 (m, 2H), 2.42 (s, 3H), 2.35 (s, 2H), 2.21 (s, 3H), 1.98 (s, 2H), 1.81
(s, 2H), 1.60 (s, 2H); MS (ESI) m/z: 505.4 [M+H]+.
[001096] Preparation ofA-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tZ]-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxo- piperidin-3-yl)-4-methylphenoxy)acetamide B109. To a solution of compound 133.2 (72.8 mg, 144 pmol) and 2-[3-(2,6-dioxo-3-piperidyl)-4-methylphenoxy]acetic acid (40 mg, 144 pmol) in DMF (1 mL) were added HOAt (21.6 mg, 159 pmol), NMM (32 mg, 317 pmol), and EDCI (30.4 mg, 159 pmol). After stirring for 2 h, the reaction solution was diluted with DMF and purified by reverse phase prep-HPLC to afford compound B109 (42 mg) in 37% yield. ^NMR (400 MHz, DMSO-<A) J 10,83 (s, 1H), 10,09 (s, 1H), 8.95 (s, 1H), 8,10 (t, J= 5.6 Hz, 1H), 8,03 (d, J= 3.2 Hz, 1H), 7.84 (d, J= 9.2 Hz, 1H), 7.44 (dd, J= 2.8, 9.2 Hz, 1H), 7.07 (d, J= 9.2 Hz, 1H), 6.79-6.71 (m, 2H), 5.82 (t, J- 8.8 Hz, 1H), 4.40 (s, 2H), 3.97 (dd, ./ •■■• 4.8, 12.0 Hz, 1H), 3.20 (d, J= 6.4 Hz, 2H), 3.14 (s, 4H), 2.78-2.65 (m, 1H), 2.52 (s, 4H), 2.48-2.47 (m, 1H), 2.42 (s, 3H), 2.36-2.32 (m, 2H), 2.31 (s, 3H), 2.24 (dt, J = 2.8, 8.4 Hz, 2H), 2.17 (s, 3H), 2.15-2.08 (m, 1H), 1.99-1.91 (m, 1H), 1.90-1.72 (m, 4H), 1.68-1.53 (m, 4H); MS (ESI) m/z: 764.5 [M+H]+.
Example 134
Preparation of 3-(3-((l-(2-((4-((6-(difluoromethyl)-8-((lA,2A)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-c/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione B130
Figure imgf000425_0001
[001097] Compound B130 was prepared as described below.
[001098] Preparation of 6-(difluoromethyl)-8-[(17?,27?)-2-hydroxy-2-methylcyclopentyl]-2-
[(l-vinyl-sulfonyl-4-piperidyl)amino]pyrido[2,3-</]pyrimidin-7-one 134.1, To a mixture of 6-
(difluoromethyl)-8-[(17?,27?)-2-hydroxy-2-methylcyclopentyl]-2-(4-piperidylamino)pyrido[2,3- t/]pyrimidin-7-one (100 mg, 254 pmol) and TEA (39 mg, 381 pmol) in DCM (2 mL) was added 2-chloroethanesulfonyl chloride (21 mg, 127 pmol) at 0 °C. After stirring for 2 h, the reaction mixture was poured into water at 0 °C and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by prep-TLC (SiO?., MeOH/DCM) to afford compound 134.1 (30 mg) in 15% yield MS (ESI) m/z'. 484.0 [M+H]+.
[001099] Preparation of 3-(3-((l-(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2- methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-tf]pyrimidin-2-yl)amino)piperidin-l-yl)- sulfonyl)ethyl)piperidin-4-yl)oxy)phenyl)piperidine-2, 6-dione B130. To a mixture of compound 134.1 (30 mg, 62 pmol) and 3-[3-(4-piperidyloxy)phenyl]piperidine-2, 6-dione (21.5 mg, 74.5 pmol) in ACN (1 mL) was added DIEA (12 mg, 93 pmol). After stirring at 80 °C for 36 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound B130 (8 mg) in 17% yield. !H NMR (400 MHz, CDCh) 3 8.57 (s, 1H), 7.85-7.82 (m, 1H), 7.37- 7.28 (m, 1H), 6.96-6.79 (m, 3H), 6.75-6.63 (s, 1H), 6.45-6.29 (s, 1H), 5.89-5.73 (m, 1H), 4.51 - 4.37 (m, 1H), 4.11-3.73 (m, 4H), 3.26-3.20 (m, 2H), 3.17-3.06 (m, 2H), 2.99-2.91 (m, 2H), 2.84- 2.62 (m, 6H), 2.57-2.50 (m, 2H), 2.35-2.10 (m, 8H), 1.97-1.85 (m, 8H), 1.17 (s, 3H); MS (ESI) m/z: 772.2 [M+H]+.
Example 135
Preparation of 3-(3-((l-(2-((4-((6-(difluoromethyl)-8-((17?,21?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-c/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione B131
Figure imgf000426_0001
[001100] Compound B131 was prepared as described below.
[001101] Preparation of 2-[[l-(3-chloropropylsulfonyl)-4-piperidyl]amino]-6-(difluoro- methyl)-8-[(17?,2/?)-2-hydroxy-2-methyl-cyclopentyl]pyrido[2,3-</]pyrimidin-7-one 135.1, To a solution of 3 -chloropropane- 1 -sulfonyl chloride (63 mg, 356 pmol) and 6-(difluoromethyl)-8- [(17?,2/?)-2-hydroxy-2-methyl-cyclopentyl]-2-(4-piperidylamino)pyrido[2,3-t7]pyrimidin-7-one (140 mg, 356 pmol) in DCM (5 mL) was added TEA (72 mg, 712 pmol). After stirring at 0 °C for 6 h, the reaction mixture was concentrated and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 135.1 (50 mg) in 26% yield. MS (ESI) m/z\ 534.1 [M+H] \
[001102] Preparation of 3-(4-((l-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2- methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)- sulfonyl)propyl)piperidin-4-yl)oxy)phenyl)piperidine-2, 6-dione B131 To a solution of compound 135.1 (37 mg, 69 pmol) and 3-[4-(4-piperidyloxy)phenyl]piperidine-2, 6-dione (20 mg, 69 pmol) in DMF (0.5 mL) were added DIEA (27 mg, 208 pmol) and KI (5.8 mg, 35 pmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound B131 (25 mg) in 44% yield. rH NMR (400 MHz, CD3OD) 6 8.72-8.68 (m, 1H), 8.07 (s, 1H), 7.19 (d, J= 8.8 Hz, 2H), 6.98 (d, J= 8.8 Hz, 2H), 6.93-6.65 (m, 1H), 5.93-5.87 (m, 1H), 4.61-4.59 (m, 2H), 4.23-3.97 (m, 1 H), 3.82 (t, J- 6 8 Hz, 3H), 3.20-3.01 (m, 10H), 2.70-2.64 (m, 3H), 2.21-1.69 (m, 16H), 1.36-1.32 (m, 3H); MS (ESI) m/z: 786.3 [M+H]+.
Example 136
Preparation of 3-(4-(4-(3-((4-((6-(difluoromethyl)-8-((lA,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)benzyl)piperazin- 1 -yl)phenyl)piperidine-2, 6-dione B140
Figure imgf000427_0001
[001103] Compound B140 was prepared as described below.
[001104] Preparation of 3-(bromomethyl)benzenesulfonyl chloride 136.1. To a solution of 3-methylbenzenesulfonyl chloride (1 g, 5.25 mmol) in ACN (10 mL) were added NBS (1.03 g, 5.77 mmol) and AIBN (86.1 mg, 524 pmol). After stirring at 80 °C for 14 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCH, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 136.1 (700 mg) in 50% yield.
[001105] Preparation of 2-[[l-[3-(bromomethyl)phenyl]sulfonyl-4-piperidyl]amino]-6- (difluoromethyl)-8-[(17?,27?)-2-hydroxy-2-methylcyclopentyl]pyrido[2,3-<7]pyrimidin-7-one 136.2, To a solution of compound 136.1 (32.9 mg, 122 pmol) in DCM (1 mL) were added TEA (31 mg, 305 pmol) and 6-(difluoromethyl)-8-[(2/?)-2-hydroxy-2-methylcyclopentyl]-2-(4- piperidylamino)pyrido[2,3-t/]pyrimidin-7-one (40 mg, 102 pmol) at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography ( S:O EtOAc/PE) to afford compound 136.2 (25 mg) in 39% yield, MS (ESI) m/z: 626.2 [M+H]+.
[001106] Preparation of 3-(4-(4-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2- methylcy cl opentyl)-7-oxo-7,8-dihydropyrido[2,3V|pyrimi din-2 -yl)amino)piperidin-l-yl)- sulfonyl)benzyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B140. To a solution of compound 136.2 (10 mg, 16 nmol) in DMF (1 mL) were added 3-(4-piperazin-l-ylphenyl)piperidine-2,6- dione (5.2 mg, 19.2 umol) and TEA (3.2 mg, 31 .9 pmol). After stirring for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound A140 as a TFA salt (4 mg) in 28% yield. ‘H NMR (400 MHz, DMSO-ufc) d 10.76 (s, 1H), 8.72 (s, 1H), 8.44 (s, 1H), 8.16 (d, J = 6.8 Hz, 1H), 8.07 (s, 1H), s7.78-7.60 (m, 4H), 7.02 (d, J = 8.4 Hz, 2H), 6.88-6.81 (m, 2H), 5.77 (s, 1H), 4.35 (s, 1H), 3.77 (s, 1H), 3.74-3.60 (m, 5H), 3.27-3.18 (m, 2H), 3.11-3.12 (m, 4H), 2.64-2.58 (m, 2H), 2.54-2.56 (m, 4H), 2.48-2.41 (m, 2H), 2.16-2.07 (m, 2H), 2.03-1.97 (m, 1H), 1.97-1.84 (m, 3H), 1.84-1.70 (m, 2H), 1.67-1.57 (m, 2H), 1.53-1.40 (m, 1H), 1.01-0.87 (m, 3H); MS (ESI) m/z: 410.3 [M/2+H]t
Example 137
Preparation of 3-(4-((5)-2-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-Jjpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)- morpholino)phenyl)piperidi ne-2, 6- di one B 172
Figure imgf000429_0001
[001107] Compound B172 was prepared as described below.
[001108] Preparation of [(2A)-4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl] morpholin-2-yl]- methanol 137.1. To a solution of 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (2 g, 4.48 mmol), [(27?)-morpholin-2-yl]methanol as an HC1 salt (688 mg, 4.48 mmol), RuPhos (209 mg, 448 pmol), RuPhos Pd G3 (375 mg, 448 pmol), and CS2CO3 (2.92 g, 8.96 mmol) in dioxane (40 mL) was stirred at 100 °C for 14 h under N2. The reaction mixture was then filtered, concentrated, and purified by column chromatography (Si(h, EtOAcZPE) to afford compound 137.1 (1.1 g) in 51% yield. [H NMR (400 MHz, CDCh) J 2.70 (t, J= 11.2 Hz, 1H), 2.89 (td, J= 11.8, 3.4 Hz, 1H), 3.49 (t, J = 10.8 Hz, 2H), 3.69-3.80 (m, 2H), 3.81-3.89 (m, 1H), 4.05-4.10 (m, 1H), 4.10- 4.16 (m, 1H), 5.36 (s, 2H), 5.43 (s, 2H), 6.37-6.45 (m, 1H), 6.46 (d, J = 8.2 Hz, 1H), 6.94 (d. ./ 8.6 Hz, 2H), 7.28 (d, J= 6.8 Hz, 1H), 7.30-7.36 (m, 3H), 7.36-7.41 (m, 3H), 7.41-7.47 (m, 2H), 7.50 (d, ./ 8.8 Hz, 2H), 7.58 (d, ./ 8.0 Hz, 1H); MS (ESI) m/z: 483.1 [M+l]+.
[001109] Preparation of 3-[4-[(27?)-2-(hydroxymethyl)morpholin-4-yl]phenyl]piperidine-
2, 6-dione 137.2, To a solution of compound 137.1 (1.1 g, 2.28 mmol) in THF (10 mL) and MeOH (10 mL) was added 10% Pd/C (500 mg) under N2. After stirring under H2 at 45 °C for 24 h, the reaction mixture was filtered and concentrated to afford compound 137.2 (690 mg), which was used in the next step without further purification. MS (ESI) m z: 305.3 [M+H]L
[001110] Preparation of [(2A)-4-[4-(2,6-dioxo-3-piperidyl)phenyl]morpholin-2-yl]methyl 4-methylbenzenesulfonate 137.3. To a solution of compound 137.2 (390 mg, 1.28 mmol) in DCM (8 mL) were added TEA (389 mg, 3.84 mmol) and TsCl (489 mg, 2.56 mmol). After stirring for 16 h, the reaction mixture was filtered, concentrated, and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 137.3 (450 mg) in 77% yield.
Figure imgf000429_0002
(400 MHz, CDCh) d 2.18-2.31 (m, 3H), 2.45 (s, 4H), 2.56-2.77 (m, 4H), 2.83 (m, J = 11.6, 3.2 Hz, 1H), 3.36 (d, J- 11.8 Hz, 1H), 3.46 (d, J= 11.8 Hz, 1H), 3.69-3.73 (m, 1H), 3.86-4.00 (m, 2H), 4.04-4.16 (m, 3H), 6.89 (d, J= 8.4 Hz, 2H), 7.11 (d, 8.4 Hz, 2H), 7.26 (s, 1H), 7.36 (d, 8.2 Hz, 2H),
7.81 (d, J= 8.2 Hz, 2H), 8.01 (s, 1H); MS (ESI) m/z'. 459.2 [M+H]+.
[001111] Preparation of 3-(4-((5)-2-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydro-pyrido[2,3-Jjpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)- morpholino)phenyl)piperidine-2, 6-dione B172 A mixture of 6-acetyl-8-cyclopentyl-5-methyl-2- [[5-[4-(4-piperidyl)piperazin-l-yl]-2-pyridyl]amino]pyrido[2,3-J]pyrimidin-7-one (200 mg, 377 umol), compound 137.3 (173 mg, 377 pmol), DIEA (487 mg, 3.77 mmol), and KI (63 mg, 377 pmol) in NMP (2 mL) was stirred at 100 °C for 12 h. The reaction mixture was then filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound Bl 72 (90 mg) in 28% yield. [H NMR (400 MHz, DMSO-fifc) 3 1.51-1.65 (m, 2H), 1.73-1.89 (m, 2H), 1.89-2.05 (m, 3H), 2.06-2.30 (m, 5H), 2.34 (s, 4H), 2.41-2.48 (m, 4H), 2.59-2.73 (m, 1H), 2.96-3.34 (m, 7H), 3.34-3.48 (m, 3H), 3.49-3.81 (m, 6H), 3.86 (dd, J= 11.6, 4.8 Hz, 1H), 3.90-4.13 (m, 4H), 4.48 (d, ./ 7.6 Hz, 1H), 5.82 (m, J - 17.6, 8.8 Hz, 1H), 7.22-7.29 (m, 2H), 7.38 (d, J= 11.4 Hz, 2H), 7.53 (s, 1H), 7.84 (d, .7 = 9.4 Hz, 1H), 8.13 (s, 1H), 8.32 (d, ,/ = 8.2 Hz, 1H), 9.09 (s, 1H), 10.80 (s, 1H); MS (ESI) m/z 817.5 [M+H]+.
Example 138
Preparation of 3-(4-(
Figure imgf000430_0001
-2-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)- m orpholino)phenyl)piperidi ne-2, 6-dione B 173
Figure imgf000430_0002
[001112] Compound B173 was prepared as described below.
[001113] Preparation of [(25)-4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]morpholin-2-yl]- methanol 138.1 , A mixture of 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (2 g, 4.48 mmol), [(25)-morpholin-2-yl]methanol (525 mg, 4.48 mmol), RuPhos Pd G3 (375 mg, 448 pmol), RuPhos (209 mg, 448 umol), and CS2CO3 (2.92 g, 8.96 mmol) in dioxane (20 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then concentrated and purified by prep-TLC (Si O2, EtOAc/PE) to afford compound 138.1 (700 mg) in 28% yield. Tl NMR (400 MHz, CDCh) 3 7.59 (d, J = 8.0 Hz, 1H), 7.52 (d, ./= 8.6 Hz, 2H), 7.45-7.30 (m, 9H), 6.47 (d, J= 8.0 Hz, 1H), 5.44 (s, 2H), 5.37 (s, 2H), 4.18-4.06 (m, 2H), 3.91-3.68 (m, 4H), 3.50 (1. ./ 10.4 Hz, 2H), 2.90 (dt, J= 3.2, 11.6 Hz, 1H), 2.71 (t, ./= 11.2 Hz, 1H), 1.31-1.20 (m, 2H).
[001114] Preparation of 3-[4-[(25)-2-(hydroxymethyl)morpholin-4-yl]phenyl]piperidine- 2, 6-dione 138.2. To a solution of compound 138.1 (700 mg, 1.28 mmol) in THF (10 mL) was added 10% Pd/C (200 mg) under Ar. After stirring under H2 for 12 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 138.2 (260 mg) in 71% yield. rH NMR (400 MHz, CDCh) 3 7.96-7.87 (ra, 1H), 7.14 (d, J= 8.4 Hz, 2H), 7.04-6.92 (m, 2H), 4.08 (d, J= 11.6 Hz, 1H), 3.96-3.80 (m, 2H), 3.77-3.65 (m, 3H), 3.52-3.38 (m, 2H), 2.96-2.84 (m, 1H), 2.80-2.59 (m, 3H), 2.35-2.16 (m, 2H), 1.97-1.88 (m, 1H), 1.56 (s, 5H).
[001115] Preparation of [(25)-4-[4-(2,6-dioxo-3-piperidyl)phenyl]morpholin-2-yl]methyl 4- m ethylbenzenesulfonate 138.3. A mixture of compound 138.2 (160 mg, 526 pmol), 4- methylbenzenesulfonyl chloride (200 mg, 1 .05 mmol), and TEA (232 mg, 2.3 mmol ) in DCM (3 mL) was stirred for 12 h under N2. The reaction mixture was then concentrated to afford compound 138.3 (110 mg), which was used directly in the next step without further purification. MS (ESI) wz: 459.1 [ M H ] .
[001116] Preparation of 3-(4-((7?)-2-((4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo- 7,8-dihydro-pyrido[2,3-J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l- yl)methyl)-morpholino)phenyl)piperidine-2, 6-dione Bl 73. A mixture of 6-acetyl-8-cyclopentyl- 5-methyl-2-[[5-[4-(4-piperidyl)piperazin-l-yl]-2-pyridyl]amino]pyrido[2,3-J]pyrimidin-7-one (200 mg, 377 pmol), compound 138.3 (173 mg, 377 pmol), DIEA ( 146 mg, 1.13 mmol), and KI (31.3 mg, 188 pmol) in NMP (2 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then filtered and purified by reverse phase prep-HPLC to afford compound B173 (46 mg) in 14% yield.
Figure imgf000432_0001
10.00 (m, 1H), 8.95 (s, 1H), 8.08-7.99 (m, 1H), 7.89-7.79 (m, 1H), 7.49-7.41 (m, 1H), 7.12-7.02 (m, 2H), 6.94-6.86 (m, 2H), 5.89-5.76 (m, 1H), 3.92 (d, J= 11.4 Hz, 1H), 3.77-3.67 (m, 2H), 3.66-3.58 (m, 1H), 3.55 (d, J= 12.0 Hz, 1H), 3.47 (d, J= 11.4 Hz, 1H), 3.14 (s, 4H), 3.01-2.90 (m, 2H), 2.69-2.58 (m, 7H), 2.44-2.38 (m, 6H), 2.30 (s, 3H), 2.27-2.19 (m, 3H), 2.16-2.10 (m, 111), 2.10-1.91 (m, 4H), 1.87 (s, 2H), 1.79-1.72 (m, 4H), 1.60 (s, 2H), 1.49-1.38 (m, 2H); MS (ESI) m/z: 817.3 [M+H]+.
Example 139
Preparation of 3-(4-(4-((3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-tf|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B186
Figure imgf000432_0002
[001117] Compound B186 was prepared as described below.
[001118] Preparation of tert-butyl 3 -[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido- [2,3-<yjpyrimidin-2-yl)amino]-3-pyridyl]piperazin-l-yl]azetidine-l-carboxylate 139.1. To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrido[2,3-<7]- pyrimidin-7-one (500 mg, 1.12 mmol) and tert-butyl 3 -oxoazetidine- 1 -carboxylate (383 mg, 2.23 mmol) in DCE (5 mL) were added NaBH(OAc)3 (710 mg, 3.35 mmol) and NaOAc (92 mg, 1.12 mmol). After stirring at 60 °C for 12 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, and concentrated to afford compound 139.1 (600 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 603.4 [M+H]+.
[001 119] Preparation of 6-acetyl-2-[[5-[4-(azetidin-3-yl)piperazin-l-yl]-2-pyridyl]amino]- 8-cyclopentyl-5-methylpyrido[2,3-<f]pyrimidin-7-one 139.2. To a solution of compound 139.1 (200 mg, 332 pmol) in DCM (4 mL) was added TFA (3.07 g, 26.9 mmol). After stirring for 1 h, the reaction mixture was concentrated to afford compound 139.2 (200 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 503.2 [M+H]+.
[001120] Preparation of 3-(4-(4-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido-[2,3-J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l - yl)methyl)piperidin-l-yl)-phenyl)piperidine-2, 6-dione B186 To a solution of compound 139.2 (200 mg, 398 pmol) and l-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-4-carbaldehyde (179 mg, 597 pmol) in DCE (2 mL) were added NaBH(OAc)i (253 mg, 1.19 mmol) and NaOAc (33 mg, 398 umol). After stirring at 60 °C for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound B186 (18 mg) in 6% yield. !H NMR (400 MHz, DMSO-d6 ) 3 10.82 (s, 1H), 9.09 (s, 1H), 8.32 (d, J= 8.8 Hz, 1H), 8.11 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7,80 (d, J= 9.6 Hz, 1H), 7.40 (d, J= 8.4 Hz, 2H), 5.84-5.73 (m, 5H), 4,77-4,61 (m, 2H), 4.60 (s, 3H), 4.00-3.93 (m, 1H), 3.67-3.45 (m, 8H), 3.45-3.23 (m, 4H), 2.76-2.54 (m, 2H), 2.49-2.36 (m, 5H), 2.32 (s, 3H), 2.25-2.10 (m, 4H), 2.10-2.02 (m, 2H), 2.02-1.86 (m, 5H), 1.82- 1.69 (m, 2H), 1.61-1.47 (m, 2H); MS (ESI) m/z: 787.5 [M+H]+
Example 140
Preparation of 3-(4-(4-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)-[l ,4'-bipiperidin]-4-yl)piperazin-l -yl)phenyl)piperidine- 2,6-dione B188
Figure imgf000433_0001
[001121] Compound B188 was prepared as described below.
[001122] Preparation of 8-(6-nitro-3-pyridyl)-l,4-dioxa-8-azaspiro[4.5]decane 140.1 To a solution of 5-chloro-2-nitropyridine (5 g, 31.5 mmol) in DMSO (50 mL) were added 1,4-dioxa- 8-azaspiro[4.5]decane (4.52 g, 31.5 mmol) and K2CO3 (13.1 g, 94.6 mmol). After stirring at 90 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S0i, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 140.1 (6.3 g) in 67% yield. MS (ESI) m/z: 266.2 [M+H]+
[001123] Preparation of 5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-amine 140,2. To a solution of compound 140.1 (6.3 g, 23.8 mmol) in THF (40 mL) and EtOH (40 mL) was added 10% Pd/C (2 g) under N2. After stirring under II2 for 3 h, the reaction mixture was filtered and concentrated to afford compound 140.2 (5.7 g), which was used directly in the next step without further purification. MS (ESI) m/z: 236.2 [M+H]+.
[001124] Preparation of 6-bromo-8-cyclopentyl-2-[[5-(l,4-dioxa-8-azaspiro[4.5]decan-8- yl)-2-pyridyl]amino]-5-methylpyrido[2,3-d]pyrimidin-7-one 140.3. To a solution of compound 140.2 (3.5 g, 14.9 mmol) in THF (40 mL) at 0 °C under N2 was added IM LiHMDS (16.9 mL) dropwise. After the mixture was stirred for 1 h, 6-bromo-2-chloro-8-cyclopentyl-5-methyl- pyrido[2,3-d]pyrimidin-7-one (2.32 g, 6.76 mmol) was added in portions. The reaction mixture was stirred for 2 h, and then diluted with H2O (70 mL), filtered, concentrated, and triturated with EtOAc/PE to afford compound 140.3 (4 g). MS (ESI) m/z: 542 [M+H]+.
[001125] Preparation of 8-cyclopentyl-2-[[5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2- pyridyl]amino]-6-(l-ethoxyvinyl)-5-methylpyrido[2,3-iZjpyrimidin-7-one 140.4. A mixture of compound 140.3 (4 g, 7.39 mmol), tributyl(l-ethoxyvinyl)stannane (3.2 g, 8.87 mmol), and Pd(L BuiP)2 (378 mg, 739 pmol) in NMP (50 mL) was stirred at 80 °C for 12 h under N2. The reaction mixture was then treated with water and an aqueous KF solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 140.4 (500 mg) in 13% yield. MS (ESI) m/z: 533.4 [M+H] \
[001126] Preparation of 6-acetyl-8-cyclopentyl-2-[[5-(l,4-dioxa-8-azaspiro[4.5]decan-8- yl)-2-pyridyl]amino]-5-methylpyrido[2,3-tZ]pyrimidin-7-one 140.5. To a solution of compound 140.4 (500 mg, 939 pmol) in THF (6 mL) was added 2M HC1 (6 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 140.5 (500 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 505.5 [M+H]+ [001127] Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-oxo-l-piperidyl)-2- pyridyl]amino]pyrido[2,3-^pyrimidin-7-one 140.6. To a solution of compound 140.5 (500 mg, 991 nmol) in dioxane (1 mL) and H2O (1 mL) was added 4M HC1 (4 mL). After stirring for 2 h, the reaction mixture was neutralized with NaHCCh, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCE, and concentrated to afford compound 140.6 (370 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 461.2 [M+H]+.
[001128] Preparation of 3-(4-(4-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4’-bipiperidin]-4-yl)piperazin-l - yl)phenyl)piperidine-2, 6-dione B188. To a solution of 3 -[4-[4-(4-piperidyl)piperazin- 1 -yl]- phenyl]piperidine-2, 6-dione as an HC1 salt (154 mg, 391 pmol) in THF (2 mL) and DMSO (2 mL) were added NaOAc (32 mg, 391 pmol), compound 140.6 (180 mg, 391 pmol), and AcOH (24 mg, 391 pmol). After the mixture was stirred at 60 °C for 12 h, NaBH(OAc)3 (166 mg, 782 pmol) was added. The reaction mixture was stirred for 4 h and then purified by reverse phase prep-HPLC to afford compound B188 (29 mg) in 9% yield.
Figure imgf000435_0001
NMR (400 MHz, DMSO-fife) <5 11.00-11.44 (m, 1H), 10.75 (s, 1H), 9.09 (s, 1H), 8.30 (m, 1H), 8.09 (s, 1H), 7.81 (d, J 9.2 Hz, 1H), 7.12-7.20 (m, 2H), 7.02-7. 11 (m, 2H), 6.09 (s, 1H), 3.91 (d, J = 10.8 Hz, 2H), 3.80 (d, J = 6.4 Hz, 1H), 3.60-3.74 (m, 4H), 3.31-3.58 (m, 6H), 3.13 (s, 2H), 2.88 (t, J 11 .2 Hz, 2H), 2.53- 2.69 (m, 3H), 2.47 (d, J = 4.4 Hz, 3H), 2.40-2.46 (s, 4H), 2.34 (s, 3H), 2.09-2.28 (m, 6H), 1.91- 2.01 (m, 3H), 1.73-1.89 (m, 4H), 1.49-1.62 (m, 2H); MS (ESI) m/z: 801.6 [M+H]+.
Example 141
Preparation of 3-(4-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- (/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B190
Figure imgf000435_0002
[001129] Compound B190 was prepared as described below.
[001130] Preparation of 2,6-dibenzyloxy-3-[4-[4-(l,4-dioxaspiro[4.5]decan-8-yl)-l- piperidyl]phenyl]pyridine 141.1. To a solution of 4-(l,4-dioxaspiro[4.5]decan-8-yl)piperidine (800 mg, 3.55 mmol) and 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (1.58 g, 3.55 mmol) in dioxane (10 mL) were added RuPhos (166 mg, 355 pmol), RuPhos Pd G3 (297 mg, 355 pmol), and CS2CO3 (3.47 g, 10.7 mmol). After stirring at 100 °C for 12 h, the reaction mixture was concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 141.1 (600 mg) in 29% yield. rH NMR (400 MHz, CDCh) 3 7.59 (d, J = 8.0 Hz, 1H), 7.49 (d, J --- 8.8 Hz, 2H), 7.46-7.38 (m, 5H), 7.38 (s, 5H), 6.97 (d, J --- 8.0 Hz, 2H), 6.46 (d, J --- 8.0 Hz, 1H), 5.43 (s, 2H), 5.36 (s, 2H), 3.96 (s, 4H), 3.83-3.69 (m, 2H), 2.68 (t, J = 11.6 Hz, 2H), 1.79 (d, J -- 4.4 Hz, 6H), 1,55-1,43 (m, 3H), 1 .41-1 .15 (m, 5H); MS (ESI) m/z: 591,6 [M+H]+.
[001131] Preparation of 3-[4-[4-(l,4-dioxaspiro[4.5]decan-8-yl)-l-piperidyl]phenyl]- piperidine-2, 6-dione 141,2. To a solution of compound 141.1 (1.3 g, 2.2 mmol) in THF (15 mL) were added 10% Pd/C (2.34 g) and 20% Pd(OH)2 (200 mg) under Ar. After stirring under Fh at 50 °C for 24 h, the reaction mixture was filtered and concentrated to afford compound 141.2 (800 mg), which was used directly in the next step without further purification. MS (ESI) m/z\ 413.3 [M+H]+.
[001132] Preparation of 3-[4-[4-(4-oxocyclohexyl)-l-piperidyl]phenyl]piperidine-2, 6-dione
141.3. To a solution of compound 141.2 (400 mg, 970 pmol) in THF (3 mL) was added 4M HC1 (3 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 141.3 (350 mg), which was used directly in the next step without further purification. !H NMR (400 MHz, CDCh) 37 98 (s, 1H), 7.09 (d, J - 8.8 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 3.75 (s, 1H), 3.72 (t, J - 4.4 Hz, 2H), 2.77-2.57 (m, 4H), 2.47-2.39 (m, 2H), 2.39-2.30 (m, 2H), 2.29-2.18 (m, 2H), 2.15-2.06 (m, 2H), 1.86-1.80 (m, 2H), 1.51 (d, 4.0 Hz, 1H), 1.48 (d, J = 3.2 Hz, 1H),
1.46 (s, 1H), 1.40-1.31 (m, 2H), 0.95-0.88 (m, 1H); MS (ESI) m/z: 369.3 [M -Hl
[001133] Preparation of 3-(4-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperidin-l- yl)phenyl)-piperidine-2, 6-dione B190 To a solution of compound 141.3 (200 mg, 543 pmol) and 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyridyl) amino]pyrido[2,3-d]- pyrimidin-7-one (243 mg, 543 pmol) in DMF (2 mL) were added NaBTECN (102 mg, 1.63 mmol) and AcOH (65 mg, 1.09 mmol). After stirring at 60 °C for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound B190 (4.5 mg).
Figure imgf000437_0001
NMR (400 MHz, DMSO-sfc) 3 10.76 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.05 (d, J - 2.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 2.8, 9.2 Hz, 1H), 7 02 (d, J = 8.8 Hz, 2H), 6.87 (d, J - 8.8 Hz, 2H), 5.91-5.72 (m, 1H), 3.74-3.68 (m, 2H), 3.67 (s, 1H), 3.15 (s, 4H), 2.67 (s, 1H), 2.62-2.54 (m, 8H), 2.42 (s, 3H), 2.30 (s, 3H), 2.26-2.18 (m, 3H), 2.04-1.96 (m, 1H), 1.92-1.83 (m, 2H), 1.83-1.71 (m, 6H), 1.61 -1.51 (m, 4H), 1.49-1.37 (m, 4H), 1.26-1.13 (m, 4H); MS (ESI) m/z: 800.9 [M+H]4.
Example 142
Preparation of 3-(4-(4-(l-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2,6- dione B201
Figure imgf000437_0002
[001134] Compound B201 was prepared as described below.
[001135] Preparation of 5-[2-[ferLbutyl(dimethyl)silyl]oxyethyl]pyridin-2-amine 142.1. A mixture of 2-(6-amino-3-pyridyl)ethanol (780 mg, 5.65 mmol), ferLbutyl(chloro)dimethylsilane (1.70 g, 11.3 mmol), TEA (2.86 g, 28.2 mmol), and imidazole (769 mg, 11.3 mmol) in DMF (10 mL) was stirred for 12 h under N2. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCU, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 142.1 (900 mg) 61% yield.
[001136] Preparation of 2-[[5-[2-[ter/-butyl(dimethyl)silyl]oxyethyl]-2-pyridyl]amino]-8- cyclopentyl-6-iodo-5-methylpyrido[2,3-</|pyrimidin-7-one 142.2. To a solution of compound 142.1 (898 mg, 3.56 mmol) in THF (5 mL) at 0 °C was added dropwise IM LiHMDS (4.04 mL) over 5 min. After the mixture was stirred at 0 °C for 30 min, 2-chloro-8-cyclopentyl-6-iodo-5- methylpyrido[2,3-rf]pyrimidin-7-one (0.63 g, 1.62 mmol) in THE (2 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 2 h, and then concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 142.2 (600 mg) in 58% yield.
[001137] Preparation of 2-[[5-[2-[ZerZ-butyl(dimethyl)silyl]oxyethyl]-2-pyridyl]amino]-8- cyclopentyl-6-(l-ethoxyvinyl)-5-methylpyrido[2,3-<7]pyrimidin-7-one 142.3. A mixture of compound 142.2 (600 mg, 991 pmol), tributyl(l-ethoxyvinyl)stannane (669 mg, 1.85 mmol), and Pd(Z-Bu3P)2 (101 mg, 198 pmol) in NMP (5 mL) was stirred at 80 °C for 12 h under N2. The reaction mixture was then treated with water and an aqueous KF solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford compound 142.3 (440 mg) in 77% yield.
[001138] Preparation of 6-acetyl-8-cyclopentyl-2-[[5-(2-hydroxyethyl)-2-pyridyl]amino]-5- methylpyrido[2,3-t/]pyrimidin7-one 142.4. To a solution of compound 142.3 (440 mg, 800 pmol) in THF (5 mL) was added 4M HC1 (5 mL). After stirring for 2 h, the reaction mixture was treated with NaHCOs and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOr, and concentrated to afford compound 142.4 (310 mg), which was used directly in the next step without further purification.
[001139] Preparation of 2-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido[2,3-i7]- pyrimidin-2-yl)amino]-3-pyridyl]ethyl 4-methylbenzenesulfonate 142.5. To a solution of compound 142.4 (310 mg, 761 pmol), TsCl (290 mg, 1.52 mmol), and DMAP (93 mg, 761 pmol) in DCM (20 mL) was added TEA (231 mg, 2.28 mmol). After stirring for 12 h, the reaction mixture was concentrated and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 142.5 (300 mg) in 70% yield.
[001140] Preparation of 3-(4-(4-(l-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperidin-4-yl)piperazin-l- yl)phenyl)piperidine-2, 6-dione B201 A mixture of compound 142.5 (100 mg, 178 umol), 3-[4- [4-(4-piperidyl)piperazin-l-yl]phenyl]piperidine-2, 6-dione (63.5 mg, 178 pmol), KI (30 mg, 178 pmol), DIEA (69 mg, 534 praol), and K2CO3 (24.6 rag, 178 pmol) in DMF (2 mL) was stirred at 100 °C for 24 h under N2. The reaction mixture was then filtered and purified by reverse phase prep-HPLC to afford compound B201 (4 mg) in 3% yield.
Figure imgf000439_0001
NMR (400 MHz, DMSO-Js) d 11.20-10.92 (m, 1H), 10.76 (s, 1H), 9.13 (s, 1H), 8.57-8.47 (m, 1H), 8.45-8.34 (m, 1H), 8.13 (s, 1H), 7.92-7.81 (m, 1 H), 7.17-7.04 (m, 4H), 6.08 (d, ./ 2.8 Hz, 1H), 3.87-3.71 (m, 5H), 3.68- 3.61 (m, 2H), 3.58-3.50 (m, 2H), 3.40 (s, 2H), 3.36-3.29 (m, 2H), 3.27-3.19 (m, 3H), 3.15-3.09 (m, 2H), 2.71-2.56 (m, 3H), 2.42 (s, 3H), 2 35 (s, 3H), 2.29-2.05 (m, 7H), 2.02-1.94 (m, 3H), 1.83-1.74 (m, 2H), 1.61-1.53 (m, 2H); MS (ESI) m/z: 746.5 [M+H]T
Example 143
Preparation of 3-(4-(2-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- 6/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)etliyl)phenyl)piperidine-2,6- di one B214
Figure imgf000439_0002
[001 141] Compound B214 was prepared as described below.
[001142] Preparation of tert-butyl 4-[l-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido- [2,3-c/]pyrimidin-2-yl)amino]-3-pyridyl]-4-piperidyl]piperazine-l-carboxylate 143.1. To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-oxo-l-piperidyl)-2-pyridyl]amino]pyrido- [2,3-</]pyrimidin-7-one (500 mg, 1.09 mmol) and tert-butyl piperazine-l-carboxylate as an HC1 salt (725 nig, 3.26 mmol) in DMSO (5 mL) were added NaBH(OAc)s (690 mg, 3.26 mmol) and AcOH (65 mg, 1.09 mmol). After stirring at 60 °C for 6 h, the reaction mixture was dropped into water under agitation. The resulting precipitates were collected by filtration to afford compound 143.1 (250 rag) in 35% yield. MS (ESI) m/r. 631.4 [M+H]+.
[001143] Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-piperazin-l-yl-l- piperidyl)-2-pyridyl]amino]pyrido[2,3-J]pyrimidin-7-one 143.2. To a solution of compound 143.1 (250 mg, 396 pmol) in DCM (2 mL) was added 4M HC1 in dioxane (2 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 143.2 as an HC1 salt (200 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 531.4 [M+H]+.
[001144] Preparation of 3-(4-(2-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2, 3 -tZ]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)pi perazin- l-yl)ethyl)~ phenyl)piperidine-2, 6-dione B214 To a solution of compound 143.2 (200 mg, 377 pmol) and 3- [4-(2-bromoethyl)phenyl]piperidine-2, 6-dione (112 mg, 377 pmol) in DMF (4 mL) were added DIEA (487 mg, 3.77 mmol) and KI (63 mg, 377 umol). After stirring at 100 °C for 2 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound B214 as a TFA salt (49 mg) in 16% yield.
Figure imgf000440_0001
(400 MHz, DMSO-sfc) 3 11.54-12,75 (m, 1H), 10,79 (s, 1H), 9.08 (s, 1H), 8.30 (m, 1H), 8.13 (s, 1H), 8.08 (d, J - 2.0 Hz, 1H), 7.81 (d, J - 9.6 Hz, 1H), 7.21-7.28 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.82 (s, 1H), 3.94 (d, J = 10.8 Hz, 2H), 3.83 (m, 4H), 3.61 (s, 5H), 3.32-3.44 (m, 2H), 3.03-3.11 (m, 2H), 2.83-2.93 (m, 2H), 2.62-2.68 (m, 1H), 2.53 (s, HI), 2.47-2.48 (m, 1H), 2.44 (d, J = 4.0 Hz, HI), 2.42 (s, 3H), 2.34 (s, 3H), 2.26 (d, J = 10.4 Hz, 2H), 2.15-2.20 (m, 2H), 2.08-2.14 (m, 1H), 1.93-1.98 (m, 2H), 1.87 (d, J == 10.0 Hz, 2H), 1.76-1.83 (m, 2H), 1.53-1.62 (m, 2H); MS (ESI) m/z: 746.5 [M+H]+.
Example 144
Preparation of 3-(3-(4-(l-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyriniidin-2-yl)amino)pyridin-3-yl)methyl)piperidin-3-yl)piperazin-l-yl)phenyl)piperidine-
2,6-dione B220
Figure imgf000440_0002
[001145] Compound B220 was prepared as described below.
[001146] Preparation of tert-butyl 3-[4-[3-(2,6-dioxo-3-piperidyl)phenyl]piperazin-l-yl]- piperi dine- 1 -carboxylate 144.1. To a solution of 3-(3-piperazin-l-ylphenyl)piperidine-2, 6-dione as an HC1 salt (3 g, 9.68 mmol) and fert-butyl 3 -oxopiperidine- 1 -carboxylate (3.86 g, 19.4 mmol) in DMF (30 mL) were added NaBH(OAc)3 (8.21 g, 38.7 mmol) and NaOAc (2.38 g, 29.1 mmol). After stirring at 60 °C for 12 h, the reaction mixture was concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 144.1 (3.8 g) in 82% yield. MS (ESI) m/z'. 457.3 [M+H]+.
[001147] Preparation of 3-[3-[4-(3-piperidyl)piperazin-l-yl]phenyl]piperidine-2, 6-dione 144.2. To a solution of compound 144.1 (3.8 g, 8.32 mmol) in DCM (5 mL) was added 4M HC1 in dioxane (10 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 144.2 as an HC1 salt (3.2 g), which was used directly in the next step without further purification. MS (ESI) m/z: 357.3 [M+H]+,
[001148] Preparation of 3-(3-(4-(l-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2, 3 -d]pyrimidin-2-yl)amino)pyri din-3 -yl)methyl)piperi din-3 -yl)piperazin-l- yl)phenyl)piperidine-2, 6-dione B220 To a solution of 6-[(6-acetyl-8-cyclopentyl-5-methyl-7- oxopyrido[2,3-tZ]pyrimidin-2-yl)amino]pyridine-3-carbaldehyde (100 mg, 255 iimol) and compound 144.2 (109 mg, 307 pmol) in DCE (2 mL) were added NaOAc (21 mg, 255 pmol) and NaBH(OAc)3 (162 mg, 766 pmol). After stirring for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound B220 (47 mg) in 25% yield. !H NMR (400 MHz, CD3OD) J 9.03 (s, 1 H), 8.40-8.34 (m, 1H), 8.17 (d, J -- 8.8 Hz, 2H), 7.81 (s, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.80 (d, J = 7.6 Hz, 11 1), 5.99 (q, J = 8.8 Hz, 1H), 4.04 (s, 2H), 3.82 (dd, J = 5.6, 10.4 Hz, 1H), 3.45-3.34 (m, 6H), 3.28 (d, J = 4.8 Hz, 4H), 3.13 (d, J = 11.2 Hz, 1H), 2.86 (t, J = 10.4 Hz, 1H), 2.73-2.59 (m, 3H), 2.49 (s, 3H), 2.40 (s, 3H), 2.36-2.28 (m, 2H), 2.25-2.12 (m, 3H), 2.10-2.00 (m, 3H), 1.95- 1.87 (m, 2H), 1.79-1.64 (m, 4H); MS (ESI) m/z: 732.4 [M+Hf.
Example 145
Preparation of 3-(4-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l-yl)phenyl)piperidine-2,6- di one B227
Figure imgf000442_0001
[001149] Compound B227 was prepared as described below.
[001150] Preparation of 5-[4-(2,2-dimethoxyethyl)-l-piperidyl]-2-nitro-pyridine 145.1. To a solution of 5-fluoro-2-nitropyridine (2 g, 14.1 mmol) and 4-(2,2-dimethoxyethyl)piperidine (2.44 g, 14.1 mmol) in DMF (20 mL) was added D1EA (1.82 g, 14.1 mmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (Si(h, EtOAc/PE) to afford compound 145.1 (3.6 g) in 87% yield. [H NMR (400 MHz, DMSO-tfe) d 8.22 (d, ./ 3.2 Hz, 1H), 8.11 (d, ./ 9.2 Hz, 1H), 7.43 (dd, .7 = 3.2, 9.2 Hz, 1H), 4.47 (t, J = 6.0 Hz, 1H), 4.06 (d, J= 13.2 Hz, 2H), 3.22 (s, 6H), 3.03-2.93 (m, 2H), 1.77 (d, J= 13.2 Hz, 2H), 1.67 (ddd, <7= 4.0, 7.2, 10.8 Hz, 1H), 1.48 (t. ./ 6.4 Hz, 2H), 1.28-1.14 (m, 2H); MS (ESI) m/z: 296.4 [M+H]+.
[001151] Preparation of 5-[4-(2,2-dimethoxyethyl)-l -piperidyl]pyridin-2-amine 145.2. To a solution of compound 145.1 (3.6 g, 12.2 mmol) in THF (30 mL) was added 10% Pd/C (2 g) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 145.2 (3 g), which was used directly in the next step without further purification. ^NMR (400 MHz, DMSCMe) d 7.59 (d, J= 2.8 Hz, 1H), 7.13 (dd, J= 2.8, 8.8 Hz, 1H), 6.38 (d, J= 8.8 Hz, 1H), 5.34 (s, 2H), 4.46 (t, J= 5.6 Hz, 1H), 3.33-3.26 (m, 3H), 3.22 (s, 6H), 1.72 (d, ./ 12.4 Hz, 2H), 1.52-1.45 (ra, 2H), 1.43-1.35 (m, 2H), 1.33-1.19 (m, 2H); MS (ESI) m/z: 266.5 [M+H]+.
[001152] Preparation of 6-acetyl-8-cyclopentyl-2-[[5-[4-(2,2-dimethoxyethyl)-l-piperidyl]- 2-pyridyl]amino]-5-methylpyrido[2,3-Jjpyrimidin-7-one 145.3, To a solution of compound 145.2 (500 mg, 1.88 mmol) in THF (5 mL) was added IM LiHMDS (2.07 mL) at 0 °C. After the mixture was stirred at 0 °C for 0.5 h, 6-acetyl-2-chloro-8-cyclopentyl-5-methyl-pyrido[2,3-tfj- pyrimidin-7-one (288 mg, 942 pmol) in THF (5 mL) was added. The reaction mixture was stirred for 12 h, and then diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na?.SO4, concentrated, and triturated with EtOAc to afford compound 145.3 (280 mg) in 56% yield. MS (ESI) m/z: 535.4 [M+H]+
[001153] Preparation of 2-[l-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-pyrido[2,3-JJ- pyrimidin-2-yl)amino]-3-pyridyl]-4-piperidyl]acetaldehyde 145.4. To a solution of compound 145.3 (490 mg, 916 pmol) in DCM (4 mL) was added TFA (6.14 g, 53.9 mmol). After stirring for 0.5 h, the reaction mixture was concentrated to afford compound 145.4 (440 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 489.2 [M+H]+.
[001154] Preparation of 3-(4-(4-(2-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyiido[2,3-J]pyrimidin-2-yl)araino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l- yl)phenyl)piperidine-2, 6-dione B227. To a solution of 3-(4-piperazin-l-ylphenyl)piperidine-2,6- dione as an HC1 salt (127 mg, 409 pmol) in MeOH (1 mL) was added NaOAc (101 mg, 1.23 mmol), followed by addition of compound 145.4 (200 mg, 409 pmol) and NaBHsCN (77 mg, 1.23 mmol). After stirring for 12 h, the reaction mixture was diluted with DMF and purified by reverse phase prep-HPLC to afford compound B227 (51 mg) in 16% yield. !H NMR (400 MHz, DMSO-tfc) 3 10.78 (s, 1H), 10.07 (s, 1H), 8.95 (s, 1H), 8.23 (d, J= 0.8 Hz, 1H), 8.04 (s, 1H), 7.82 (d, ./= 8.8 Hz, 1 H), 7.53-7.39 (m, 1H), 7.04 (d, J= 8.4 Hz, 2H), 6.89 (d, ./= 8.4 Hz, 2H), 5.89-5.74 (m, 1H), 3.77-3.62 (m, 3H), 3.11 (s, 4H), 2.75-2.54 (m, 4H), 2.42 (s, 3H), 2.39 (d, 7.2 Hz, 3H), 2.30 (s, 3H), 2.24 (s, 2H), 2.20-1 .92 (m, 3H), 1.87 (s, 2H), 1.79
Figure imgf000443_0001
10.0 Hz,
5H), 1.57 (d, J= 2.8 Hz, 2H), 1.45 (s, 4H), 1.33-1.21 (m, 2H); MS (ESI) m/z: 746.6 [M+H]+.
Example 146
Preparation of 3-(4-(2-(2-(4-(6-((6-acetyl-8-cyclopemyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yi)amino)pyridin-3-yi)piperazin-l-yl)ethyl)-2,7-diazaspiro[3.5]nonan-7- yl)phenyl)piperidine-2, 6-dione B229
Figure imgf000444_0001
[001155] Compound B229 was prepared as described below.
[001156] Preparation of tert-butyl 7-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-2,7-diazaspiro- [3.5]nonane-2-carboxylate 146.1. A mixture of 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (3 g, 6.72 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate as an HC1 salt (1.77 g, 6.72 mmol), RuPhos (314 mg, 672 pmol), RuPhos Pd G3 (562 mg, 672 pmol), and CS2CO3 (4.38 g, 13.4 mmol) in dioxane (40 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 146.1 (3 g) in 63% yield. MS (ESI) m/z: 592.5 [M+H]+.
[001157] Preparation of tert-butyl 7-[4-(2,6-dioxo-3-piperidyl)phenyl]-2,7-diazaspiro[3.5]- nonane-2-carboxylate 146.2, To a solution of compound 146.1 (3 g, 5.07 mmol) in THF (30 mL) were added 10% Pd/C (0.5 g) and 20% Pd(OH)2 (0.5 g) under N2. After stirring under H2 at 40 °C for 24 h, the reaction mixture was filtered and concentrated to afford compound 146.2 (800 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 414.4 [M+H]+.
[001158] Preparation of 3-[4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl]piperidine-2, 6-dione 146.3, To a solution of compound 146.2 (800 mg, 1.93 mmol) in DCM (6 mL) was added TFA (4.61 g, 40.4 mmol). After stirring for 2 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound 146.3 (280 mg) in 46% yield. XH NMR (400 MHz, DMSO-flfc) cl 7.03 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 3.71 (dd, J = 4.8, 10.8 Hz, 1H), 3.57 (s, 4H), 3.13-3.00 (m, 4H), 2.69-2.56 (m, 1H), 2.48-2.40 (m, 1H), 2.17-2.05 (m, 1H), 2.05-1.92 (m, 1H), 1.77 (s, 4H); MS (ESI) m/z: 314.1 [M+H]L
[001159] Preparation of 3-[4-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]phenyl]- piperidine-2, 6-dione 146.4 To a solution of compound 146.3 (0.2 g, 638 pmol) and 2- bromoethanol (160 mg, 1.28 mmol) in DMF (2 mL) were added KI (53 mg, 319 pmol) and DIEA (165 mg, 1.28 mmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered and purified by prep-TLC (SiO?., MeOH/DCM) to afford compound 146.4 (0.13 g) in 56% yield. ^HNMR (400 MHz, CDsOD) r) 7.07 (d, J = 8.8 Hz, 2H), 6.60-6.55 (m, 2H), 3.89 (s, 1H), 3.84 (d, J - 5.2 Hz, 1H), 3.75 (t, J - 12 Hz, 1H), 3.50-3.43 (m, 2H), 3.42-3.32 (m, 5H), 3.30-3.25 (m, 2H), 3.16-3.12 (m, 1H), 2.70-2.58 (m, 2H), 2.21-2.08 (m, 6H); MS (ESI) m/z: 358.2 [M+H]+.
[001160] Preparation of 3-[4-[2-(2-bromoethyl)-2,7-diazaspiro[3.5]nonan-7-yl]phenyl]- piperidine-2, 6-dione 146.5. A mixture of compound 146.4 (0.1 g, 280 pmol) and PBn (91 mg, 336 pmol) in ACN (1 mL) was stirred at 80 °C for 1 h under N2. The reaction mixture was then filtered and concentrated to afford compound 146.5 (0.1 g), which was used directly in the next step without further purification. MS (ESI) m/z: 420.1 [M i l] ,
[001161] Preparation of 3-(4-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2,7-diazaspiro- [3.5]nonan-7-yl)phenyl)piperidine-2, 6-dione B229. To a solution of compound 146.5 (100 mg, 238 pmol) and 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrido- [2,3-c/]pyrimidin-7-one (107 mg, 238 pmol) in DMF (1 mL) were added KI (39 mg, 238 pmol) and DIEA (307 mg, 2.38 mmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound B229 (9 mg) in 4% yield. 'H NMR (400 MHz, CD3OD) 3 8.92 (s, 1H), 8.50 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.62-7.45 (m, 1 H), 7.06 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 6.01-5.87 (m, 1H), 4.21-4.04 (m, 1H), 3.79-3.62 (m, 2H), 3.45-3.36 (m, 4H), 3.28-3.12 (m, 8H), 2.78-2.73 (m, 5H), 2.72-2.52 (m, 3H), 2.48 (s, 3H), 2.38 (s, 3H), 2.35-2.27 (m, 2H), 2.19-2.08 (m, 5H), 2.04-2.01
(m, 1H), 1.96 (d, J - 5.6 Hz, 2H), 1.86 (s, 2H), 1.39-1.27 (m, 2H); MS (ESI) m/z: 787.4 [M+H]t
Example 147
Preparation of 3-(3-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tf]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B236
Figure imgf000446_0001
[001162] Compound B236 was prepared as described below.
[001163] Preparation of 3-[3-[4-(3-hydroxypropyl)-l-piperidyl]phenyl]piperidine-2, 6-dione 147.1. To a solution of 3-[l-[3-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]propan-l-ol (7 g, 13.8 mmol) in THF (40 mL) and EtOH (40 mL) was added 10% Pd/C (3 g) under N2. After stirred under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 147.1 (4.9 g), which was used directly in the next step without further purification. MS (ESI) m/z: 331.3 [M+H]+.
[001164] Preparation of 3-[l-[3-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]propyl 4- m ethylbenzenesulfonate 147.2, To a solution of compound 147.1 (4.9 g, 14.8 mmol) in DCM (50 mL) were added TsCl (5.65 g, 29.7 mmol) and TEA (4.5 g, 44.5 mmol). After stirring for 12 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 147.2 (3.3 g) in 45% yield. MS (ESI) m/z: 485.3 [M+H]+.
[001165] Preparation of 3-(3-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B236 To a solution of compound 147.2 (400 mg, 825 pmol) and 6-acetyl- 8-cyclopentyl-2-[(5-hydroxy-2-pyridyl)amino]-5-methylpyrido[2,3-d]pyrimidin-7-one (313 mg, 825 pmol) in DMF (3 mL) were added K2CO3 (342 mg, 2.48 mmol) and KI (137 mg, 825 pmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound B236 (9 mg) in 1.5% yield. LH NMR (400 MHz, CD3OD) d 9.07 (s, 1H), 8.06 (s, 1H), 7.91 (d, J= 7.6 Hz, 1H), 7.69 (d, ./= 9.8 Hz, 1H), 7.51-7.61 (m, 3H), 7.43 (d, .7= 6.4 Hz, 1H), 6 00-6 02 (m, 1H), 4.17 (t, 5.8 Hz, 2H), 4.00-4.02 (m, 1H), 3.73 (d, J- 11 .8 Hz, 2H),
3.60 (t, J= 11.6 Hz, 2H), 2.65-2.84 (m, 2H), 2.50 (s, 3H), 2.42 (s, 3H), 2.11-2.38 (m, 7H), 2.02- 2.11 (m, 2H), 1.89-1.98 (m, 4H), 1.84-1.86 (m, 1H), 1.67-1.77 (m, 4H), 1.56-1.67 (m, 3H); MS (ESI) m/z-. 692.3 [M+H]+.
Example 148
Preparation of 3-(4-(3-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-i/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)propoxy)phenyl)piperidine-2, 6-dione B237
Figure imgf000447_0001
[001166] Compound B237 was prepared as described below.
[001167] Preparation of 3-[l-(6-nitro-3-pyridyl)-4-piperidyl]propan-l-ol 148.1. To a solution of 3-(4-piperidyl) propan-l-ol (5 g, 34.9 mmol) in DMSO (100 mL) were added K2.CO3 (14.5 g, 105 mmol) and 5-chloro-2-nitropyridine (5.53 g, 34.9 mmol). After stirring at 80 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S0r, concentrated, and triturated with EtOAc/PE to afford compound 148.1 (6.07 g) in 46% yield. MS (ESI) m/z\ 266.3 [M+H]+.
[001168] Preparation of ferCbutyl-dimethyl-[3-[l-(6-nitro-3-pyridyl)-4-piperidyl]- propoxy]silane 148,2. To a solution of compound 148.1 (6 g, 22.6 mmol) in DCM (60 mL) were added TBSC1 (6.82 g, 45.2 mmol) and EtsN (6.87 g, 67.9 mmol). After stirring for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, concentrated, and purified by column chromatography ( Si 02, EtOAc/PE) to afford compound 148.2 (5 g) in 57% yield. MS (ESI) m/z\ 380.3 [M+H]+.
[001169] Preparation of 5-[4-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-l-piperidyl]pyridin- 2-amine 148.3, To a solution of compound 148.2 (5 g, 13.2 mmol) in EtOH (30 mL) and THF (30 mL) was added 10% Pd/C (2.5 g) under N2. After stirring under H2 for 12 h, the reaction mixture was filtered and concentrated to afford compound 148.3 (4.64 g), which was used directly in the next step without further purification. MS (ESI) m/z: 350.4 [M+H]+.
[001170] Preparation of 2-[[5-[4-[3-[terLbutyl(dimethyl)silyl]oxypropyl]-l-piperidyl]-2- pyridyl]amino]-8-cyclopentyl-6-iodo-5-methylpyrido[2,3-d]pyrimidin-7-one 148.4, To a solution of compound 148.3 (4.64 g, 13.3 mmol) in THF (40 mL) at 0 °C was added dropwise IM LiHMDS (15.1 mL) over 30 min. After the mixture was stirred at 0 °C for 30 min, 2-chloro- 8-cyclopentyl-6-iodo-5-methylpyrido[2,3-d]pyrimidin-7-one (2.35 g, 6.03 mmol) in THF (40 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 2 h, and then diluted with water, filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 148.4 (2.1 g) in 47% yield. MS (ESI) m/z: 703.4 [M+H]+.
[001171] Preparation of 2-[[5-[4-[3-[fert-butyl(dimethyl)silyl]oxypropyl]-l-piperidyl]-2- pyridyl]amino]-8-cyclopentyl-6-(l-ethoxyvinyl)-5-methylpyrido[2,3-J]pyrimidin-7-one 148.5.
A mixture of compound 148.4 (2.1 g, 2.99 mmol), tributyl(l-ethoxyvinyl)stannane (1.08 g, 2.99 mmol), and Pdp-BurPp (153 mg, 299 umol) in NMP (30 mL) was stirred at 60 °C for 12 h under N2. The reaction mixture was then treated with H2O and an aqueous KF solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCU, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 148.5 (1.12 g) in 53% yield. MS (ESI) m/z: 647.5 [M+Hp.
[001172] Preparation of 6-acetyl-8-cyclopentyl-2-[[5-[4-(3-hydroxypropyl)-l-piperidyl]-2- pyridyl]amino]-5-methylpyrido[2,3-J]pyrimidin-7-one 148.6. To a solution of compound 148.5 (1.12 g, 1.73 mmol) in THF (10 mL) was added 4M HC1 (10 mL). After stirring for 2 h, the reaction mixture was neutralized with NaHCCh to pH 7, filtered, and concentrated to afford compound 148.6 (810 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 505.4 [M+H]+.
[001173] Preparation of 3-[l-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-pyrido[2,3-tZ]- pyrimidin-2-yl)amino]-3-pyridyl]-4-piperidyl]propyl 4-methylbenzenesulfonate 148.7. To a solution of compound 148.5 (810 mg, 1.61 mmol) in DCM (20 mL) were added TsCl (612 mg, 3.21 mmol) and EtsN (487 mg, 4.82 mmol). After stirring for 12 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic 'avers were washed with brine, dried over anhydrous NajSCU, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 148.7 (778 mg) in 65% yield. MS (ESI) m/z: 659.4 [M+H]+.
[001174] Preparation of 3-(4-(3-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-tf]-pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)propoxy)phenyl)- piperidine-2, 6-dione B237. To a solution of compound 148.7 (200 mg, 304 pmol) and 3-(4- hydroxyphenyl)piperidine-2, 6-dione (62.3 mg, 304 pmol) in DMF (3 mL) were added K2CO3 (126 mg, 911 pmol) and KI (50.4 mg, 304 pmol). After stirring at 90 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound B237 (1.9 mg). rH NMR (400 MHz, CD3OD) 3 9.11 (s, 1H), 8.13-8.23 (m, 1H), 7.82-7.90 (m, 1H), 7.52 (d, J= 9.6 Hz, 1H), 7.15 (d, J- 8.4 Hz, 2H), 6.90 (d, J- 8.4 Hz, 2H), 6.01 (t, J = 8.4 Hz, 1H), 4.00 (t, J- 6.8 Hz, 2H), 3.76-3.83 (m, 3H), 2.85-2.94 (m, 2H), 2.61-2.72 (m, 2H), 2.50 (s, 3H), 2.44 (s, 3H), 2.32-8.23 (m, 2H), 2.16-2.23 (m, 2H), 2.10 -2.12 (m, 2H), 1.84-1.96 (m, 6H), 1.67-1.74 (m, 2H), 1.55-1.62 (m, 1H), 1.48-1.54 (m, 2H), 1.35-1.44 (m, 2H); MS (ESI) m/z: 692.3 [M+Hf.
Example 149
Preparation of 3-(4-(^-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-^Z]- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione B239
Figure imgf000449_0001
[001175] Compound B239 was prepared as described below.
[001176] Preparation of 3-[4-[4-[l-[6-[[8-cyclopentyl-6-(l-ethoxyvinyl)-5-methyl-7-oxo- pyrido[2,3-tZ]pyrimidin-2-yl]amino]-3-pyridyl]-4-piperidyl]-l-piperidyl]phenyl]-l-[(4-methoxy- phenyl)methyl]piperidine-2, 6-dione 149.1. A mixture of 3-[4-[4-[l-(6-bromo-3-pyridyl)-4- piperidyl]-l-piperidyl]phenyl]-l-[(4-methoxyphenyl)methyl]piperidine-2, 6-dione (50 mg, 79.2 pmol), 2-amino-8-cyclopentyl-6-(l-ethoxyvinyl)-5-methyl-pyrido[2,3-<7]pyriniidiii-7-one (25 mg, 79.2 pmol), CS2CO3 (77.4 mg, 237 pmol), Pdr(dba)3 (3.6 mg, 3.96 pmol), and Xantphos (6.9 mg, 11.9 pmol) in dioxane (1 mL) was stirred at 90 °C for 14 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by prep-TLC (SiOr, EtOAc) to afford compound 149.1 (10 mg) in 12% yield. MS (ESI) m/z~. 865.5 [M+H]+.
[001177] Preparation of 3-[4-[4-[l-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido[2,3- <7]pyrimidin-2-yl)amino]-3-pyridyl]-4-piperidyl]-l-piperidyl]phenyl]-l-[(4-methoxyphenyl)- methyl]piperidine-2, 6-dione 149.2. To a solution of compound 149.1 (156 mg, 180 pmol) in THF (2 mL) was added 2M HC1 (2 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 149.2 (110 mg) which was used directly in the next step without further purification. MS (ESI) m/z'. 837.4 [M-f-H]’.
[001178] Preparation of 3-(4-(l'-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-r/]-pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)phenyl)- piperidine-2, 6-dione B239 To a solution of compound 149.2 (100 mg, 120 pmol) in DCM (I mL) were added TFA (1.54 g, 13.5 mmol) and TfOH (1 .7 g, 11.3 mmol). After stirring for 2 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound B239 (14 mg) in 16% yield. 'H NMR (400 MHz, DMSO-afe) d 10.77 (s, 1H), 10.07 (s, 1H), 8.95 (s, 1H), 8.05 (d, J= 2.8 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.46-7.48 (m, 1H), 7.03 (d, 8.6 Hz, 2H),
6.89 (d, J = 8.6 Hz, 2H), 5.82 (t, 8.8 Hz, 1H), 3.67-3.78 (m, 5H), 2.65-2.68 (m, 1H), 2.57-
2.63 (m, 4H), 2.55 (s, 1H), 2.41-2.44 (m, 4H), 2.33 (s, 1H), 2.30 (s, 3H), 2.25-2.28 (m, 2H), 2.07-2.16 (m, 1H), 1.96-2.04 (m, 1H), 1.87 (d, ./ 4.4 Hz, I H), 1.77-1.82 (m, 4H), 1.57 (d, ./ 5.2 Hz, 2H), 1.22-1.36 (m, 7H); MS (ESI) m/z: 717.4 [M+H]+.
Example 150
Preparation of 3-(3-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione B243
Figure imgf000451_0001
[001179] Compound B243 was prepared as described below.
[001180] Preparation of tert-butyl 4-[l-[3-[l-[(4-methoxyphenyl)methyl]-2,6-dioxo-3- piperidyl]phenyl]-4-piperidyl] piperidine-l-carboxylate 150.1, To a solution of 3-(3-bromo- phenyl)-l-[(4-methoxyphenyl)methyl]piperidine-2, 6-dione (3.62 g, 9.31 mmol) and tert-butyl 4- (4-piperidyl)piperi dine- 1 -carboxylate (2.5 g, 9.31 mmol) in dioxane (25 mL) were added RuPhos (435 mg, 931 pmol), CS2CO3 (6.07 g, 18.6 mmol), and RuPhos Pd G3 (390 mg, 466 pmol).
After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 150.1 (4.88 g) in 86% yield.
Figure imgf000451_0002
(400 MHz, CDCh-tZ) <5 7.42 (d, J = 8.8 Hz, 2H), 7.19 (t, J - 7.6 Hz, 1H), 6.82 (d, J - 8.8 Hz, 3H), 6.62-6.45 (m, 2H), 4.97 (s, 2H), 4.21-4.10 (m, 2H), 3.83 (dd, J = 5.2, 8.0 Hz, 1H), 3,79 (s, 3H), 3.55 (t, J = 9.6 Hz, 2H), 2.66 (ddt, J = 5.2, 8.0, 17.2 Hz, 4H), 2.54 (s, 2H), 2.32-2.19 (m, 1H), 2.18-2.09 (m, 1H), 1.73 (dd, J --- 12.8, 20.0 Hz, 4H), 1.47 (s, 9H), 1.33 (d, J = 13.2 Hz, 2H), 1.23-1.09 (m, 4H); MS (ESI) m/z: 576.5 [M+H]+.
[001181] Preparation of l-[(4-methoxyphenyl)methyl]-3-[3-[4-(4-piperidyl)-l-piperidyl]- phenyl]piperidine-2, 6-dione 150.2. To a solution of compound 150.1 (4.8 g, 8.34 mmol) was added 4M HC1 in dioxane (2.08 mL). After stirring for 1 h, the reaction mixture was concentrated to afford compound 150.2 (3.8 g), which was used directly in the next step without further purification.
Figure imgf000451_0003
NMR (400 MHz, DMSO-rfe) <5 9, 11 (d, J= 8.8 Hz, 1H), 8.99 (d, J= 10.0 Hz, 1H), 7.79 (s, 2H), 7.52 (t, •/ 7.6 Hz, 1H), 7.32 (d, ./ 6.4 Hz, 1H), 7.19 (d, J= 8.4 Hz, 2H), 6.85 (d, 8.4 Hz, 2H), 4.13 (dd, J- 4.8, 11.6 Hz, 1H), 3.71 (s, 3H), 3.51 (s, 4H), 3.26 (d, J =
11.6 Hz, 2H), 2.93-2.71 (m, 4H), 2.34-2.24 (m, 1H), 2.08 (td, J= 4.4, 8.8 Hz, 1H), 1.97 (d, J =
7.6 Hz, 2H), 1.91-1.75 (m, 4H), 1 .55-1 .37 (m, 4H); MS (ESI) m/z: 476.3 [M+H]+. [001182] Preparation of 3-[3-[4-[l-(6-bromo-3-pyridyl)-4-piperidyl]-l-piperidyl]phenyl]-l- [(4-methoxyphenyl)methyl]piperidine-2, 6-dione 150.3. A mixture of 2-bromo-5-iodopyridine (2.79 g, 9.84 mmol), compound 150.2 (3.6 g, 7.57 mmol), CS2CO3 (7.4 g, 22.7 mmol), and XantPhos Pd G3 (359 mg, 378 pmol) in dioxane (20 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then filtered, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford compound 150.3 (0.9 g) in 18% yield. !H NMR (400 MHz, DMSO-Jo) 3 8.05 (d, ./ 3.2 Hz, HI), 7.39-7.34 (m, HI), 7.34-7.29 (m, 1H), 7.22 (d, ./= 8.4 Hz, 2H), 7.12 (t, J= 8.0 Hz, 1H), 6.86 (d, 8.8 Hz, 2H), 6.80 (d, J= 8.4 Hz, 1H), 6.78-
6.78 (m, 1H), 6.62-6.53 (m, 2H), 4.85-4.75 (m, 2H), 3.93 (dd, J= 5.6, 9.2 Hz, 1H), 3.78 (d, J = 11.6 Hz, 2H), 3.72 (s, 3H), 3.58 (d, J= 12.0 Hz, 2H), 2.81 -2.74 (m, 1H), 2.73-2.54 (m, 4H), 2.49-2.44 (m, 1H), 2.20-2.06 (m, 2H), 1.83-1.70 (m, 4H), 1.31-1.21 (m, 5H); MS (ESI) m/z: 631.3 [M+H]+
[001183] Preparation of 3-[3-[4-[l-[6-[[8-cyclopentyl-6-(l-ethoxyvinyl)-5-methyl-7-oxo- pyrido[2,3-J]pyrimidin-2-yl]amino]-3-pyridyl]-4-piperidyl]-l-piperidyl]phenyl]-l-[(4-metlioxy- phenyl)methyl]piperidine-2, 6-dione 150.4. A mixture of compound 150.3 (465 mg, 736 umol), 2-amino-8-cyclopentyl-6-(l -ethoxyvinyl)-5-methylpyrido[2,3-J]pyrimidin-7-one (231 mg, 736 umol), CS2CO3 (480 mg, 1.47 mmol), Xantphos (63.9 mg, 110 pmol), and Pdr(dba)3 (33.7 mg, 36.8 pmol) in dioxane (8 mL) was stirred at 90 °C for 4 h under N2. The reaction mixture was then treated with IM HC1 (10 mL), diluted with H2O, and extracted with EtOAc. The combined organic layers were dried over anhydrous NarSCL, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) and MeOH/DCM to afford compound 150.4 (475 mg) in 75% yield. [H NMR (400 MHz, CDCI3) b' 8.87-8.61 (m, HI), 8.22-7.97 (m, 2H), 7.46-7.35 (m, 2H), 7.21 (t, J - 8.0 Hz, 1H), 6.90-6.79 (m, 2H), 6.59 (d, J - 2.0 Hz, 1H), 5.94-5.81 (m, 1H), 5.31 (s, 2H), 4.13-4.08 (m, 3H), 3.83 (d, J = 6.0 Hz, 1H), 3.79 (s, 2H), 3.74-3.49 (m, 3H), 2.79- 2.58 (m, 4H), 2.55 (d, J ----- 6.4 Hz, 3H), 2.36 (d, J =- 14.0 Hz, 4H), 2.32-2.20 (m, 2H), 2.19-2.07 (m, 2H), 1.93-1.79 (m, 5H), 1.75-1.58 (m, 4H), 1.53-1.31 (m, 4H), 1.27 (t, J = 7.2 Hz, 7H); MS (ESI) m/z: 865.6 [M+H]+.
[001184] Preparation of 3-[3-[4-[l-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido[2,3- </|pyrimidin-2-yl)amino]-3-pyridyl]-4-piperidyl]-l-piperidyl]phenyl]-l-[(4-methoxyphenyl)- methyl]piperidine-2, 6-dione 150.5, To a solution of compound 150.4 (475 mg, 549 pmol) in THF (4 mL) was added 2M HC1 (4 mL). After stirring for 3 h, the reaction mixture was neutralized to pH 7 with IM NaOH, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SCh and concentrated to afford compound 150.5 (560 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 837.6 [M+Hf.
[001185] Preparation of 3-(3-(l'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-J|pyriniidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2,6- dione B243. To a solution of compound 150.5 (460 mg, 550 pmol) in DCM (5 mL) were added TFA (627 mg, 5.5 mmol) and TfOH (412 mg, 2.75 mmol). The mixture was stirred at 40 °C for 12 h, and then concentrated and purified by reverse phase prep-HPLC to afford compound B243 (24 mg) in 6% yield. rH NMR (400 MHz, DMSO-sfe) 3 10,78 (s, 1H), 10.05 (s, 1H), 8,95 (s, 1H), 8.05 (d, J - 2.8 Hz, 1H), 7.82 (d, J - 9.2 Hz, 1H), 7.46 (dd, J - 2.8, 9.2 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.87-6.73 (m, 2H), 6.58 (d, J = 7.6 Hz, 1H), 5.82 (q, J = 9.2 Hz, 1H), 3.79-3.68 (m, 5H), 2.69-2.61 (m, 3H), 2.60 (s, 2H), 2.42 (s, 3H), 2.33 (s, 1H), 2.31 (s, 3H), 2.28-2.16 (m, 3H), 2.02 (qd, J = 4.4, 13.2 Hz, 1H), 1.87 (s, 2H), 1.84-1.70 (m, 6H), 1.63-1.51 (m, 2H), 1.39- 1.21 (m, 6H); MS (ESI) m/z: 717.5 [M+H] \
Example 151
Preparation of SAS-^-fl-ld-^O-acetyl-S-cyclopentyl-S-methyl^-oxo^S-dihydropyrido^S-tiO- pyrimidin^-y^amino^yridin-d-y^piperidinM-yllpiperazin-l-y^pheny^piperidine^, 6-dione
B244
Figure imgf000453_0001
[001186] Compound B244 was prepared as described below.
[001187] Preparation of 8-cyclopentyl-2-[[5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2- pyridyl]amino]-6-iodo-5-methylpyrido[2,3-J|pyrimidin-7-one 151.1. To a solution of 5-(l ,4- dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-amine (6 91 g, 29.4 mmol) in THF (100 mL) at 0 °C under N2 was added IM LiHMDS (33.4 mL) dropwise. After the mixture was stirred at 0 °C for 0.5 h, 2-chloro-8-cyclopentyl-6-iodo-5-methylpyrido[2,3-</]pyrimidin-7-one (5.2 g, 13.4 mmol) in THF (20 mL) was added. The reaction mixture was stirred for 2 h, and then treated with aqueous NH4CI at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh, concentrated, and triturated with MeOH to afford compound 151.1 (6.5 g) in 79% yield
Figure imgf000454_0001
NMR (400 MHz, CDCh) <5 8.85 (s, 1H), 8.15 (d, ./ 9.2 Hz, 1H), 8.09 (d, J= 2.8 Hz, 1H), 7.36 (dd, J= 2.8, 9.2 Hz, 1H), 6.00 (q, J= 8.8 Hz, 1H), 4.01 (s, 4H), 3.45-3.24 (m, 4H), 2.69 (s, 3H), 2.38-2.22 (m, 2H), 2.18-2.05 (m, 2H), 1.97-1.80 (m, 8H).
[001188] Preparation of 8-cyclopentyl-2-[[5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2- pyridyl]amino]-6-(l-ethoxyvinyl)-5-methylpyrido[2,3-t/]pyrimidin-7-one 151.2. A mixture of compound 151.1 (6.5 g, 11.1 mmol), tributyl(l -ethoxy vinyl)stannane (6.36 g, 17.6 mmol), and PdfLBusP)?. (565 mg, 1.1 mmol) in NMP (100 mL) was stirred at 60 °C for 12 h under Nz. The reaction mixture was then treated with water and an aqueous KF solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh, concentrated, and triturated with MeOH to afford compound 151.2 (4.2 g) in 71% yield. rH NMR (400 MHz, CDCh) <5 8.81 (s, 1H), 8.17 (d, J= 9.2 Hz, 1H), 8.10 (d, J= 2.8 Hz, 1H), 7.35 (dd, J= 3.2, 9.2 Hz, 1H), 5.91 (q, J= 8.8 Hz, 1H), 4.52 (d, J= 2.4 Hz, 1H), 4.18 (d, J= 2.4 Hz, 1H), 4.00 (s, 4H), 3.93 (q, J= 7.2 Hz, 2H), 3.36-3.25 (m, 4H), 2.46-2.40 (m, 3H), 2.36 (dt, J = 3.6, 8.4 Hz, 2H), 2.10-2.05 (m, 2H), 1.93-1.80 (m, 7H), 1.72-1.59 (m, 3H), 1.36 (t, ,/= 7.2 Hz, 3H).
[001189] Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-oxo-l-piperidyl)-2- pyridyl]amino]pyrido[2,3-ri]pyrimidin-7-one 151.3. A mixture of compound 151.2 (4.2 g, 7.89 mmol) and 4M HC1 in THF (50 mL) was stirred for 22 h under N2. The reaction mixture was then concentrated and triturated with EtOH to afford compound 151.3 (2.4 g) in 62% yield. rH NMR (400 MHz, CDCh) S 8.85 (s, 1H), 8.25 (d, J= 9.2 Hz, 1H), 8.13 (d, J= 2.8 Hz, 1H), 7.49- 7.36 (m, 1H), 5.97-5.81 (m, 1H), 3.65-3.56 (m, 4H), 2.68-2.60 (m, 4H), 2.56 (s, 3H), 2.39 (s, 3H), 2.08 (s, 6H), 1.95-1.81 (m, 3H), 1.77-1.68 (m, 2H). [001190] Preparation of 3-(3-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B244. A mixture of compound 151.3 (200 mg, 434 pmol), 3-(3-piperazin- l-ylphenyl)piperidine-2, 6-dione (142 mg, 521 pmol), NaOAc (107 mg, 1.3 mmol), and NaBH(OAc)j (184 mg, 869 pmol) in DMSO (1 mL) and THF (2 mL) was stirred for 5 h under N2. The reaction mixture was filtered and purified by reverse phase prep-HPLC to afford compound B244 (75 mg) in 23% yield. ^NMR (400 MHz, DMSO-tfc) d 10.79 (s, 1 H), 10.07 (s, 1H), 8.95 (s, 1H), 8.07 (d, J= 2.0 Hz, 1H), 7.83 (d, J= 9.2 Hz, 1H), 7.54-7.41 (m, 1H), 7.15 (t, J= 7.6 Hz, 1H), 6.85-6.77 (m, 2H), 6.61 (d, J= 7.6 Hz, 1H), 5.88-5.76 (m, 1H), 3.80-3.70 (m, 3H), 3.29 (s, 1H), 3.13 (s, 4H), 2.76-2.58 (m, 8H), 2.42 (s, 5H), 2.31 (s, 3H), 2.28-2.17 (m, 3H), 2.05-1.99 (m, 1H), 1.94-1.83 (m, 4H), 1.76 (d, 3.2 Hz, 2H), 1.57 (d, 9.6 Hz, 4H); MS (ESI) w/z: 718.3 [M+H]+.
Example 152
Preparation of 3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6- di one B246
Figure imgf000455_0001
[001191] Compound B246 was prepared as described below.
[001192] Preparation of tert-butyl 4-[6-[(8-cyclopentyl-6-iodo-5-methyl-7-oxopyrido[2,3- tZ]pyrimidin-2-yl)amino]-3-pyridyl]piperidine-l-carboxylate 152.1. To a solution of tert-butyl 4- (6-amino-3-pyridyl)piperidine-l -carboxylate (47 g, 169 mmol) in THF (300 mL) at 0 °C under N2 was added IM LiHMDS (192 mL) dropwise. After the mixture was stirred at 0 °C for 0.5 h, 2-chloro-8-cyclopentyl-6-iodo-5-methylpyrido[2,3-<7] pyrimidin-7-one (30 g, 77 mmol) in THF (100 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 2 h under N2 and then treated with aqueous NH4CI at 0 °C. The resulting precipitates were collected by filtration to afford compound 152.1 (48 g) in 97% yield. !H NMR (400 MHz, CDCh) d 8.92 (s, 1H), 8.78 (s, 1H), 8.36-8.13 (m, 2H), 7.58 (d, J = 9.2 Hz, 1H), 6.01 (q, J = 8.8 Hz, 1H), 4.41- 4.12 (m, 2H), 2.84 (t, J -- 12.0 Hz, 2H), 2.71 (s, 3H), 2.65 (d, J --- 11.6 Hz, 1H), 2.32 (dd, J - 12, 11.2 Hz, 2H), 2.12 (s, 2H), 1.95-1.81 (m, 4H), 1.74-1.62 (m, 4H), 1.50 (s, 9H); MS (ESI) m/z: 631.1 [M+H]+.
[001193] Preparation of ZeH-butyl 4-[6-[[8-cyclopentyl-6-(l-ethoxyvinyl)-5-methyl-7-oxo- pyrido[2,3-J|pyrimidin-2-yl]amino]-3-pyridyl]piperidine-l-carboxylate 152.2. A mixture of compound 152.2 (24 g, 38.1 mmol), tributyl(l -ethoxy vinyl)stannane (20.9 g, 57.9 mmol), and Pd(M3u3P)2 (1.95 g, 3.81 mmol) in NMP (250 mL) was stirred at 60 °C for 12 h under Nz. The reaction mixture was then treated with water and an aqueous KF solution. The resulting precipitates were collected by filtration and triturated with MeOH to afford compound 152.2 (28 g) in 64% yield. rH NMR (400 MHz, CDCh) 3 8.83 (s, 1H), 8.57 (s, 1H), 8.28 (d, J - 8.4 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 2.4, 8.8 Hz, 1H), 5.99-5.82 (m, 1H), 4.54 (d, J = 2.4 Hz, 1H), 4.28 (s, 2H), 4.19 (d, J - 2.4 Hz, 1H), 3.95 (q, J - 7.2 Hz, 2H), 2.89-2.77 (m, 2H),
2.72-2.63 (ra, 1H), 2.44 (s, 3H), 2.40-2.31 (m, 2H), 2.14-2.03 (m, 2H), 1.85 (d, J = 12.4 Hz, 4H),
1.73-1.65 (m, 4H), 1.49 (s, 9H), 1.37 (t, J = 12 Hz, 3H); MS (ESI) m/z\ 575.6 [M+H]+.
[001194] Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-piperidyl)-2-pyridyl]- amino]pyrido[2,3-t/]pyrimidin-7-one 152,3. To a solution of compound 152.2 (30 g, 52.2 mmol) in THE (150 mL) was added 4M HC1 (150 mL). After stirring for 12 h, the reaction mixture was concentrated and treated with saturated aqueous NaHCCh at 0 °C. The resulting precipitates were collected by filtration and triturated with MeOH to afford compound 152.3 (8.4 g) in 36% yield. rH NMR (400 MHz, DMSO-J6) 3 10.32 (s, 1H), 9.00 (s, 1H), 8.24 (d, J - 2.0 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 2.4, 8.8 Hz, 1H), 5.93-5.69 (m, 1H), 4.11 (s, 2H), 2.98- 2.88 (m, 2H), 2.88-2.80 (m, 1H), 2.42 (s, 3H), 2.32 (s, 3H), 2.29-2.19 (m, 2H), 1.96-1.84 (m, 5H), 1.83-1.72 (m, 3H), 1.64-1.53 (m, 2H); MS (ESI) m/z: 447.4 [M+H]7
[001195] Preparation of 3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-I-yl)methyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione B246 To a solution of compound 152.3 (300 mg, 621 umol) and l-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-4-carbaldehyde (257 mg, 621 pmol) in DMSO (2 mL) and THF (2 mL) was added NaBH(OAc)3 (263 mg, 1.24 mmol). After the mixture was stirred at 60 °C for 0.5 h, NaOAc (102 mg, 1.24 mmol) was added. The reaction mixture was stirred for 2 h, and then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by prep-TLC (SiCh, MeOH/DCM) and reverse phase prep-HPLC to afford compound B246 (29 mg) in 6% yield. lH NMR (400 MHz, DMSO-rfc) <5 11.08-10.91 (m, 1H), 10.88 (s, 1H), 9.10 (s, 1H), 8.43 (s, 1H), 8.36 (d, J - 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 3H), 7.45 (d, J = 8.4 Hz, 2H), 5.87 (q, J 8.8 Hz, 1H), 3.98 (dd, J = 4.8, 12.4 Hz, 1H), 3.71-3.56 (m, 6H), 3.46-3.26 (m, 1H), 3.1 1 (dd, J = 6.8, 19.2 Hz, 4H), 2.77-2.63 (m, 1H), 2.54 (d, J = 3.2 Hz, 1H), 2.44 (s, 3H), 2.37 (s, 3H), 2.33 (s, 1H), 2.30-2.15 (m, 6H), 2.13-1.93 (m, 8H), 1.89-1.77 (m, 2H), 1.68-1.53 (m, 2H); MS (ESI) wz: 731.5 [M+H]+.
Example 153
Preparation of 3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6- di one B249
Figure imgf000457_0001
[001196] Compound B249 was prepared as described below.
[001197] Preparation of fert-butyl 4-[6-[(6-bromo-8-cyclopentyl-5-methyl-7-oxo-pyrido- [2,3 -ii]pyrimidin-2-yl)amino]-3-pyridyl]piperidine-l -carboxylate 153.1, To a solution of tert- butyl 4-(6-amino-3-pyridyl)piperidine-l-carboxylate (4.99 g, 18 mmol) in THF (40 mL) at 0 °C under N?. was added IM LiHMDS (20.4 mL) dropwise. After the mixture was stirred at 0 °C for 0.5 h, 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-tZ]pyrimidin-7-one (2.8 g, 8.17 mmol) in THF (10 mL) was added. After completion, the reaction mixture was treated with aqueous NH4CI at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and triturated with MeOH to afford compound 153.1 (3.3 g) in 69% yield. MS (ESI) m/z: 585.1 [M+H] \
[001198] Preparation of tert-butyl 4-[6-[[8-cyclopentyl-6-(l-ethoxyvinyl)-5-methyl-7-oxo- pyrido[2,3-<7]pyrimidin-2-yl]amino]-3-pyridyl]piperidine-l-carboxylate 153.2. A mixture of compound 153.1 (3.3 g, 5.66 mmol), tributyl(l -ethoxy vinyl)stannane (2.45 g, 6,79 mmol), and Pd(LBu3P)2 (289 mg, 566 pmol) in NMP (50 mL) was stirred at 80 °C for 12 h under N2. The reaction mixture was then treated with water and an aqueous KF solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4, concentrated, and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 153.2 (400 mg) in 11% yield. MS (ESI) m/z: 575.4 [M+H]+.
[001199] Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-piperidyl)-2-pyridyl]- amino]pyrido[2,3-<7]pyrimidin-7-one 153.3. To a solution of compound 153.2 (400 mg, 696 praol) in THF (2 mL) was added 4M HC1 (2.18 mL). After stirring at 20 °C for 2 h, the reaction mixture was concentrated to afford compound 153.3 (300 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 447.3 [M+H]+.
[001200] Preparation of 3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3 -<7]pyrimidin-2-y l)amino)pyri din-3 -y l)piperidin- 1 -yl)methyl)piperidin- 1 - yl)phenyl)piperidine-2, 6-dione B249. To a solution of compound 153.3 (300 mg, 621 pmol) and l-[3-(2,6-dioxo-3-piperidyl)phenyl]piperidine-4-carbaldehyde (224 mg, 745 pmol) in DMF (2 mL) were added NaBH(OAc)3 (263 mg, 1.24 mmol) and NaOAc (153 mg, 1.86 mmol). After stirring for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound B249 (97 mg) in 21% yield. ’HNMR (400 MHz, CDCh) 5 10.80 (s, 1H), 10.29 (s, 1H), 9.00 (s, 1H), 8.25 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.74 (d, 8.8 Hz, 1H), 7 14 (t, J = 7.6 Hz, 1H), 6.90-6.70 (m, 2H), 6.58 (d, .7= 7.6 Hz, 1H), 5.84 (q, <7= 8.8 Hz, 1H), 3.75 (dd, <7= 4.8, 11.2 Hz, 1H), 3.68 (d, J = 10.8 Hz, 2H), 3.27-3. 18 (m, 2H), 2.70-2.58 (m, 4H), 2.46-2.38 (m, 5H), 2.32 (s, 3H), 2.29-2.12 (m, 5H), 2.06-1.96 (m, 2H), 1.89 (d, .7= 4.8 Hz, 2H), 1.85-1.66 (m, 9H), 1.63-1.54 (m, 2H), 1.22 (d, J= 9.6 Hz, 2H); MS (ESI) m/z: 731.5 [M+H]+.
Example 154
Preparation of 3-(4-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- di one B253
Figure imgf000459_0001
[001201] Compound B253 was prepared as described below.
[001202] Preparation of 3-[4-[l-(2-hydroxyethyl)-4-piperidyl]phenyl]piperidine-2, 6-dione
154.1. To a solution of 3-[4-(4-piperidyl)phenyl]piperidine-2, 6-dione (3 g, 11 mmol) and 2- bromoethanol (1.38 g, 1 1 mmol) in DMF (25 mL) were added K2CO3 (3.04 g, 22 mmol) and KI (183 mg, 1.1 mmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound 154.1 (900 mg) in 26% yield. LH NMR (400 MHz, DMSO-fifc) d 1.68-1.82 (m, 4H), 1.97-2.06 (m, 1H), 2.10-2.22 (m, 1H), 2.31 (td, J = 11.4, 3.0 Hz, 2H), 2.43-2.48 (m, 1H), 2.52-2.57 (m, 1H), 2.58-2.63 (m, 2H), 2.63-2.70 (m, 1H), 3.12 (d, J - 11.6 Hz, 2H), 3.58 (t, J - 6.0 Hz, 2H), 3.81 (dd, J - 11.4, 4.8 Hz, 1H), 7.12-7.17 (m, 2H), 7.17-7.22 (m, 2H), 8.25 (s, 1 FI); MS (ESI) m/z\ 317.2 [M+H]+.
[001203] Preparation of 3-[4-[l-(2-bromoethyl)-4-piperidyl]phenyl]piperidine-2, 6-dione
154.2, To a solution of PBn (171 mg, 632 umol) in ACN (1 mL) was added compound 154.1 (200 mg, 632 pmol) in ACN (2 mL) dropwise. After stirring at 80 °C for 1 h, the reaction mixture was treated with saturated aqueous NHrCl at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCE, and concentrated to afford compound 154.2 (200 mg), which was used directly in the next step without further purification. MS (ESI) m 2: 379.1 [M+H] \
[001204] Preparation of 3-(4-(l-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2, 3-</]pyri midin-2 -yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-4- yl)phenyl)piperidine-2, 6-dione B253. To a solution of compound 154.2 (200 mg, 527 pmol) and
6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrido[2,3-d]pyrimidin-
7-one (236 mg, 527 pmol) in DMT (3 mL) were added KI (88 mg, 527 pmol) and DIEA (681 mg, 5.27 mmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound B253 (104 mg) in 26% yield. 'H NMR (400 MHz, DMSO-Je) 8 1.55-1.64 (m, 2H), 1.78-1.85 (m, 2H), 1 .96-2.07 (m, 5H), 2.07- 2.16 (m, 2H), 2.16-2.25 (m, 3H), 2.36 (s, 3H), 2.44 (s, 3H), 2.59-2.72 (m, 1H), 2.83-2.91 (m, 1H), 3.16 (d, J = 8.4 Hz, 2H), 3.25-3.48 (m, 4H), 3.69-3.86 (m, 8H), 3.91-4.05 (m, 2H), 5.84 (J - 8.8 Hz, 1H), 7.16-7.23 (m, 4H), 7.86 (d, J - 9.51 Hz, 1H), 7.98-8.22 (m, 2H), 8.31 (dd, J - 9.63, 2.63 Hz, 1H), 9.09 (s, 1H), 10.81 (s, 1H); MS (ESI) w/z: 746.5 [MHI]+.
Example 155
Preparation of 3-(4-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- di one B254
Figure imgf000460_0001
[001205] Compound B254 was prepared as described below.
[001206] Preparation of 6-acetyl-2-[[5-[l-(2-bromoethyl)-4-piperidyl]-2-pyridyl] amino]-8- cyclopentyl-5-methylpyrido[2,3-</|pyrimidin-7-one 155.1. To a solution of 6-acetyl-8- cyclopentyl-2-[[5-[l-(2-hydroxyethyl)-4-piperidyl]-2-pyridyl]amino]-5-methyl-pyrido[2,3-<f|- pyrimidin-7-one (500 mg, 1.02 mmol) in ACN (4 mL) was added PBn (276 mg, 1.02 mmol) in AON (4 mL) dropwise. After stirring at 80 °C for 1 h, the reaction mixture was treated with saturated aqueous NH4Q (2 mL) at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to afford compound 155.1 (540 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 553.3 [M+H]+.
[001207] Preparation of 3-(4-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperi din-4- yl)phenyl)piperidine-2, 6-dione B254 To a solution of compound 155.1 (540 mg, 976 pmol) and 3-[4-(4-piperidyl)phenyl]piperidine-2, 6-dione (266 mg, 976 pmol) in DMF (6 mL) were added KI (162 mg, 976 pmol) and DIEA (1.26 g, 9.76 mmol). After stirring at 100 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound B254 (26 mg) in 3.5% yield. 4-1 NMR (400 MHz, DMSO-r/e) δ 1.55-1.63 (m, 3H), 1.63-1.70 (m, 3H), 1.71-1.78 (m, 5H), 1.86-1.95 (m, 2H), 1.99-2.09 (m, 5H), 2.11-2.30 (m, 4H), 2.32 (s, 3H), 2.43 (s, 3H), 2.47 (s, 6H), 2.59-2.72 (m, 2H), 3.00 (d, J = 1.8 Hz, 4H), 3.77-3.85 (m, 1H), 5.77-5.92 (m, 1H), 7.10-7.16 (m, 2H), 7.17-7.24 (m, 2H), 7.74 (dd, J 8.6, 2.2 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 9.00 (s, 1H), 10.26 (s, 1H), 10.81 (s, 1H), MS (ESI) m/z: 745.7 [M+H]+.
Example 156
Preparation of 3-(3-(4-(l-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tfJpyrimidin-2-yl)araino)pyridin-3-yl)ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2,6- dione B268
Figure imgf000461_0001
[001208] Compound B268 was prepared as described below.
[001209] Preparation of 2-nitro-5-(2-tetrahydropyran-2-yloxyethyl)pyridine 156.1. A mixture of 5-bromo-2-nitropyridine (15 g, 73.9 mmol), potassium trifluoro(2-((tetrahydro- pyran-2-yl)oxy)ethyl)borate (19.2 g, 81.3 mmol), Pd(dppf)Ch CH2C12 (6.03 g, 7.39 mmol), and K2CO3 (30.6 g, 222 mmol) in dioxane (200 mL) and H2O (50 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then concentrated and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 156.1 (8 g) in 36% yield. 41 NMR (400 MHz, CDCh) 3 8.48 (s, 1H), 8.13 (d, J- 8.4 Hz, 1H), 7.88 (d, ./= 8.4 Hz, 1H), 4.50 (d, J- 3.6 Hz, 2H), 3.84 (d, J= 5.6 Hz, 2H), 3.63-3.55 (m, 3H), 1.70 (s, 2H), 1.48 (d, J= 2.4 Hz, 2H), 1.13- 1.01 (m, 2H). [001210] Preparation of 5-(2-tetrahydropyran-2-yloxyethyl)pyridin-2-amine 156.2. A mixture of compound 156.1 (7.5 g, 29.7 mmol) and 10% Pd/C (0.75 g) in THF (70 mL) was stirred for 12 h under H2. The reaction mixture was then filtered, concentrated, and purified by column chromatography (SiO2, EtOAc/PE and MeOH/DCM) to afford compound 156.2 (5.94 g) in 90% yield. (400 MHz, CDCh) d 7.95 (d, ./ 2.0 Hz, 1H), 7.36 (dd, J= 2.4, 8.4 Hz, 1H), 6.47 (d, J= 8.4 Hz, 1H), 3.99-3.84 (m, 3H), 3.79-3.67 (m, 2H), 3.57-3.49 (m, 2H), 2.77 (t, J - 6.8 Hz, 2H), 1.84-1.76 (m, 2H), 1.76-1.64 (m, 2H), 1.28-1.14 (m, 2FI).
[001211] Preparation of compound 8-cyclopentyl-6-iodo-5-methyl-2-[[5-(2-tetrahydro- pyran-2-yloxyethyl)-2-pyridyl]amino]pyrido[2,3-J]pyrimidin-7-one 156.3. To a solution of compound 156.2 (5.71 g, 25.7 mmol) in THF (50 mL) was added dropwise IM LiHMDS (32 mL) over 5 min at 0 °C. After the mixture was stirred at 0 °C for 30 min, 2-chloro-8-cyclo- pentyl-6-iodo-5-methylpyrido[2,3-tZ]pyrimidin-7-one (5 g, 12.8 mmol) in THF (20 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 2 h, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 156.3 (4.5 g) in 52% yield.
[001212] Preparation of 8-cyclopentyl-6-(l-ethoxyvinyl)-5-methyl-2-[[5-(2-tetrahydro- pyran-2-yloxyethyl)-2-pyridyl]amino]pyrido[2,3-J]pyrimidin-7-one 156.4. A mixture of compound 156.3 (3.5 g, 6.08 mmol), tributyl(l-ethoxyvinyl)stannane (2.86 g, 7.91 mmol), and Pd(/-Bu3P)2 (311 mg, 608 pmol) in NMP (70 mL) was stirred at 60 °C for 12 h under N2. The reaction mixture was then treated with water and an aqueous KF solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 'SO 4, concentrated, and triturated with MeOH at to afford compound 156.4 (3 g) in 57% yield. MS (ESI) m/z: 520.2 [M+H]+.
[001213] Preparation of 6-acetyl-8-cyclopentyl-2-[[5-(2-hydroxyethyl)-2-pyridyl]amino]-5- methylpyrido[2,3-d|pyriniidin-7-one 156.5. A mixture of compound 156.4 (3 g, 5.77 mmol) and 4M HC1 (15 mL) in THF (15 mL) was stirred for 2 h under N2. The reaction mixture was then neutralized with NaHCO3 and extracted with EtOAc. The combined organic layers were concentrated to afford compound 156.5 (1.9 g), which was used directly in the next step without further purification. MS (ESI) m/z: 480.3 [M+H] \
[001214] Preparation of 6-acetyl-2-[[5-(2-chloroethyl)-2-pyridyl]amino]-8-cyclopentyl-5- methylpyrido[2,3-t/]pyrimidin-7-one 156.6 A mixture of compound 156.6 (1.9 g, 4.66 mmol), 4-methylbenzenesulfonyl chloride (2.67 g, 14 mmol), DMAP (570 mg, 4.66 mmol), and TEA (1.42 g, 14 mmol) in DCM (10 mL) was stirred at 40 °C for 12 h under N?.. The reaction mixture was then concentrated and purified by column chromatography (SiCh, EtOAc/PE) and reverse phase prep-HPLC to afford compound 156.6 (500 mg) in 21% yield. !H NMR (400 MHz, CDCh) d 8.86 (s, 1H), 8.37 (d, J= 8.8 Hz, IH), 8.23 (s, IH), 7.67 (d, J= 8.8 Hz, IH), 5.89 (q, J = 8.8 Hz, 1H), 3.75 (t, J= 6.8 Hz, 2H), 3.09 (t, ./= 7.2 Hz, 2H), 2.56 (s, 3H), 2.43-2.40 (m, IH), 2.39-2.31 (m, 2H), 2.15-2.06 (m, 2H), 1.95-1.87 (m, 2H), 1.80-1.62 (m, 3H), 1.61-1.48 (m, 1H).
[001215] Preparation of 3-(3-(4-(l-(2-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-J]pyrimidin-2-yl)araino)pyridin-3-yl)ethyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B268. A mixture of compound 156.6 (80 mg, 188 pmol), 3-[3-[4- (4-piperidyl)piperazin-l-yl]phenyl]piperidine-2, 6-dione as an HC1 salt (74 mg, 188 pmol), DIEA (243 mg, 1.88 mmol), and KI (31 mg, 188 pmol) in NMP (2 mL) was stirred at 100 °C for 12 h under Nz. The reaction mixture was then filtered and purified by reverse phase prep-HPLC to afford compound B268 (19 mg) in 13% yield. rH NMR (400 MHz, DMSO-tA) 3 10.83-10.72 (m, 1H), 10.32-10.20 (m, IH), 9.02-8.93 (m, 1H), 8.23-8.19 (m, 1H), 8.18 (s, IH), 8.03-7.92 (m, IH), 7.74-7.64 (m, 1H), 7.19-7.11 (m, 1H), 6.84-6.76 (m, 2H), 6.65-6.54 (m, IH), 5.92-5.76 (m, IH), 3.75 (dd, 4.4 11.2Hz, IH), 3.10 (s, 4H), 3.00 (d, J = 10.0 Hz, 2H), 2.72 (d, J = 6.8Hz, 2H), 2.62 (s, 5H), 2.43 (s, 3H), 2.35-2.16 (m, 9H), 2.06-1.86 (m, 6H), 1.83-1.74 (m, 4H), 1.59 (s, 2H), 1.48-1.37 (m, 2H); MS (ESI) m/z: 746.6 [M+H]+.
Example 157
Preparation of 3-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimi din-2 -yl)amino)pyri din-3 -yl)-4-fluoropiperidin-4-yl)methyl)azeti din-3 -yl)pheny I)- piperidine-2, 6-dione B293
Figure imgf000464_0001
[001216] Compound B293 was prepared as described below.
[001217] Preparation of l-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-pyrido[2,3-<7]- pyrimidin-2-yl)amino]-3-pyridyl]-4-fluoropiperidine-4-carbaldehyde 157.1, A solution of 6- acetyl-8-cyclopentyl-2-[[5-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-2-pyridyl]amino]-5- methylpyrido[2,3-<7]pyrimidin-7-one (200 mg, 371 pmol) in HCOOH (5 mL) was stirred at 80 °C for 2 h. The reaction mixture was then concentrated to compound 157.1 (180 mg), which was used directly in the next step without further purification.
[001218] Preparation of 3-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)azetidin- 3-yl)phenyl)-piperidine-2, 6-dione B293. To a solution of compound 157.1 (180 mg, 365 pmol) and 3-[4-(azetidin-3-yl)phenyl]piperidine-2, 6-dione as a TFA salt (131 mg, 365 pmol) in DMSO (2 mL) and THF (2 mL) was added NaOAc (90 mg, 1.1 mmol). After the mixture was stirred at 30 °C for 0.5 h, NaBHsCN (46 mg, 731 pmol) was added. The reaction mixture was stirred for 12 h, and then diluted with water and extracted with EtOAc. The combined organic layers were concentrated and purified by revers phase prep-HPLC to afford compound B293 (35 mg) in 13% yield. ]H NMR (400 MHz, DMSO-rfe) J 10.83 (s, 1H), 10.10 (s, 1H), 8.95 (s, 1H), 8.16 (s, 1H), 8.09 (d, ./ ■■■ 2.0 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.55-7.45 (m, 1 H), 7.31 (d, 8.0 Hz, 2H), 7.17 (d, J= 8.0 Hz, 2H), 5.82 (t, .7= 8.4 Hz, 1H), 3.82 (dd, .7= 4,8, 11.2 Hz, 1H), 3.74-3.67 (m, 2H), 3.65-3.58 (m, 1H), 3.50 (d, J= 12.4 Hz, 2H), 3.20 (t, J= 6.0 Hz, 2H), 2.98 (t, J= 10.8 Hz, 2H), 2.73-2.66 (m, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27-2.12 (m, 4H), 2.07-1.99 (m, 1H), 1.89 (d, J= 11.6 Hz, 6H), 1.81-1.73 (m, 3H), 1.58 (s, 2H); MS (ESI) m/z: 721.6 [M+H]+.
Example 158 Preparation of S-
Figure imgf000465_0001
acetyl-S-cyclopentyl-S-methyl-J-oxo^S-dihydropyrido^S- tZJpyrimidin^-y^amino^yri din-3 -yl)azeti din-3 -yl)piperazin-l-yl)methyl)phenyl)piperidine-2, 6- dione B297
Figure imgf000465_0002
[001219] Compound B297 was prepared as described below.
[001220] Preparation of /er/-butyl 4-[l-[6-[(8-cyclopentyl-6-iodo-5-methyl-7-oxo-pyrido- [2, 3-</]pyrimidin-2-yl)amino]-3-pyridyl]azetidin-3-yl]piperazine-l -carboxylate 158.1. To a solution of tert-butyl 4-[l-(6-amino-3-pyridyl)azetidin-3-yl]piperazine-l-carboxylate ((3.42 g, 10.3 mmol) in THF (35 mL) was added dropwise IM LiHMDS (12.83 mL) over 30 min at 0 °C. After the mixture was stirred 0 °C for 30 min, 2-chloro-8-cyclopentyl-6-iodo-5-methylpyrido- [2,3-t/]pyrimidin-7-one (2 g, 5.13 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred at 20 °C for 2 h, and then treated with aqueous NHrCl and extracted with EtOAc, The combined organic layers were concentrated to afford compound 158.1 (1 g), which was used directly in the next step without further purification. MS (ESI) m/z: 687.3 [M+H]+.
[001221] Preparation of tert-butyl 4-[l -[6-[[8-cyclopentyl-6-(l-ethoxyvinyl)-5-methyl-7- oxopyrido[2,3-d]pyrimidin-2-yl]amino]-3-pyridyl]azetidin-3-yl]piperazine-l-carboxylate 158.2, To a solution of compound 158.1 (1.17 g, 1.7 mmol) in NMP (10 mL) were added tributyl(l- ethoxyvinyl)stannane (800 mg, 2.22 mmol) and Pd(/-Bu3P)2 (87 mg, 170 pmol). After stirring at 80 °C for 12 h, the reaction mixture was treated with water and an aqueous KF solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 158.2 (1.1 g) in 91% yield. MS (ESI) m/z'. 631 .5 [M+H]+.
[001222] Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(3-piperazin-l-ylazetidin-l- yl)-2-pyridyl]amino]pyrido[2,3-J]pyrimidin-7-one 158.3. To a solution of compound 158.2 (1 g, 1.59 mmol) in THF (10 mL) was added 4M H2SO4 (10 mL). After stirring for 12 h, the reaction mixture was filtered and concentrated to afford compound 158.3 (490 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 503.3 [M+H]+.
[001223] Preparation of 3-(4-((4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)methyl)- phenyl)piperidine-2, 6-dione B297. To a solution of compound 158.3 (120 mg, 239 pmol), 3-[4- (bromomethyl)phenyl]piperidine-2, 6-dione (67 mg, 239 pmol) in DMF (2 mL) were added DIEA (309 mg, 2.39 mmol) and KI (40 mg, 239 pmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound B297 (22 mg) in 12% yield. ‘H NMR (400 MHz, DMSCWs) <5 10.90-10.77 (m, 1H), 10.08-9.95 (m, 1H), 9.01 - 8.85 (m, 1H), 7.83-7.73 (m, 1H), 7.66-7.57 (m, 1H), 7.30-7.22 (m, 2H), 7.21-7.12 (m, 2H), 7.01- 6,91 (m, 1H), 5.87-5.73 (m, 1H), 4,03-3,92 (m, 2H), 3,89-3,78 (m, 1H), 3,67-3,54 (m, 2H), 3,45 (d, J= 1.6 Hz, 2H), 2.72-2.57 (m, 2H), 2.45-2.44 (m, 1H), 2.43-2.41 (m, 3H), 2.40-2.35 (m, 4H), 2.34-2.30 (m, 3H), 2.30-2.27 (m, 2H), 2.26-2.14 (m, 4H), 2.12-1.96 (m, 2H), 1.89-1.81 (m, 2H), 1.80-1.72 (m, 2H), 1.58 (d, J= 5.6 Hz, 2H); MS (ESI) m/z: 704.5 [M+Hf.
Example 159
Preparation of 3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimi din-2 -yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B306
Figure imgf000466_0001
[001224] Compound B306 was prepared as described below.
[001225] Preparation of 2,6-dibenzyloxy-3-[4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]- phenyl]pyridine 159.1. A mixture of 4-(dimethoxymethyl)-4-fluoropiperidine (1.5 g, 8.46 mmol), 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (4.53 g, 10.2 mmol), RuPhos Pd G3 (354 mg, 423 pmol), RuPhos (197 mg, 423 pmol), and CS2CO3 (8.27 g, 25.4 mmol) in dioxane (30 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaiSCh, concentrated, and purified by column chromatography (SiOz, EtOAc/PE) to afford compound 159.1 (2.99 g) in 64% yield. *HNMR (400 MHz, CDCh) d 7.60 (d, J= 8.0 Hz, 1H), 7.50 (d, J=
8.4 Hz, 2H), 7.47-7.27 (m, 10H), 6.99 (br d, ./ 8.4 Hz, 2H), 6.46 (d, ./ 8.0 Hz, 1H), 5.44 (s, 2H), 5.36 (s, 2H), 4.17 (d, J = 8.4 Hz, 1H), 3.63 (br d, ./= 12.4 Hz, 2H), 3.55 (s, 6H), 3.18-3.02 (m, 2H), 2.09-1.87 (m, 4H); MS (ESI) m/z\ 543.4 [M+H]+.
[001226] Preparation of 3-[4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]phenyl]piperidine- 2, 6-dione 159.2. A mixture of compound 159.1 (2.9 g, 5.34 mmol), AcOH (963 mg, 16 mmol), 10% Pd/C (1.71), and 20% Pd(OH)2 (1.13 g) in THF (30 mL) was stirred at 40 °C for 12 h under H2. The reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 159.2 (1.28 g) in 55% yield. ]H NMR (400 MHz, CDCh) d 7.99 (br s, 1H), 7.09 (d, ./ ■■■ 8.4 Hz, 2H), 6.94 (d, ./ ■■■ 8.4 Hz, 2H), 4. 16 (d, J = 8.4 Hz, 1H), 3.73 (dd, J= 5.2, 9.2 Hz, 1H), 3.61-3.55 (m, 2H), 3.54 (s, 6H), 3.05 (dt, J= 4.0, 12.0 Hz, 2H), 2.76 (br d, ./ 5.2 Hz, 3H), 2.31-2.18 (m, 2H), 1.93 (br d, ./ 18.4 Hz, 3H); MS (ESI) m/z:
365.3 [M+H]+.
[001227] Preparation of 1 -[4-(2,6-dioxo-3-piperidyl)phenyl]-4-fluoropiperidine-4- carbaldehyde 159.3. A solution of compound 159.2 (300 mg, 823pmol) in formic acid (6 mL) was stirred at 95 °C for 12 h. The reaction mixture was then concentrated to afford compound
159.3 (265 mg), which was used directly in the next step without further purification. ’H NMR (400 MHz, DMSO-de) 6 10.76 (br s, 1H), 8.13 (s, 1H), 7.14-6.85 (m, 4H), 3.72 (br dd, J - 4.8,
10.4 Hz, 1H), 3.67-3.52 (m, 2H), 2.85 (br t, ,J= 10.0 Hz, 2H), 2.68-2.57 (m, 1H), 2.44 (br d, J= 2.8 Hz, 1H), 2.20-2.07 (m, 1H), 2.06-1.72 (m, 5H).
[001228] Preparation of 3-(4-(4-((4-(6-((6-acetyl-8-cycIopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)-4-fluoro- piperi din- l-yl)phenyl)-piperidine-2, 6-dione B306. To a solution of compound 159.3 (428 mg, 1.17 mmol) in MeOH (6 mL) was added NaOAc (220 mg, 2.69 mmol), followed by addition of 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-piperidyl)-2-pyridyl]amino]pyrido[2,3-t/]pyrimidin-7- one (200 mg, 448 pmol). After the mixture was stirred for 0.5 h, NaBHsCN (56 mg, 896 pmol) was added. The reaction mixture was stirred at 35 °C for 12 h under N2, and then diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous, NarSCh concentrated, and purified by reverse phase prep-HPLC to afford compound B306 (51 mg) in 15% yield. !H NMR (400 MHz, DMSCWe) d 10.77 (s, 1H), 10.26 (s, 1H), 9.00 (s, 1H), 8.24 (s, 1H), 8.00 (br d, ./ 8.4 Hz, 1H), 7.74 (br d, ./ 8.4 Hz, 1H), 7.05 (br d, ./ 8.4 Hz, 2H), 6.93 (br d, J = 8.4 Hz, 2H), 5.93-5.76 (m, 1H), 3.73 (br dd, J= 4.8, 10.8 Hz, 1H), 3.46 (br d, J= 12.4 Hz, 2H), 3.29 (br s, 2H), 3.08-2.91 (m, 4H), 2.60 (br s, 1H), 2.54 (br s, 1H), 2.43 (s, 3H), 2.32 (s, 3H), 2.29-2.17 (m, 4H), 2.16-2.07 (m, 1H), 2.05-1.85 (m, 6H), 1.85-1.67 (m, 8H), 1.60 (br d, J= 4.0 Hz, 2H); MS (ESI) m/z: 749.5 [M+H]+.
Example 160
Preparation of (5)-3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-c(]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)-3-methyl- piped dine-2, 6-dione B309 and (j?)-3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido-[2,3-<7|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)- 3-methyl-piperidine-2, 6-dione B310
Figure imgf000468_0001
[001229] Compounds B309 and B310 were prepared as described below.
[001230] Preparation of tert-butyl 4-[4-(3-methyl-2,6-dioxo-3-piperidyl)phenyl]piperazine- 1 -carboxylate 160.1. A mixture of 3-(4-bromophenyl)-3-methylpiperidine-2, 6-dione (800 mg, 2.84 mmol), tert-butyl piperazine- 1 -carboxylate (528 mg, 2.84 mmol), CS2CO3 (1.85 g, 5.67 mmol), and Pd-PEPPSI-lPent (122 mg, 142 gmol) in dioxane (2 mL) stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 160.1 (360 mg) in 30% yield. MS (ESI) m/z: 388.2 [M+H]+.
[001231] Preparation of 3-methyl-3-(4-piperazin-l-ylphenyl)piperidine-2, 6-dione 160.2, To a solution of compound 160.1 (360 mg, 929 iimol) in DCM (4 mL) was added 4M HC1 in dioxane (4 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 160.2 as an HC1 salt (349 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 288.3 [M+H]T
[001232] Preparation of 3-[4-[4-[l-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-pyrido[2,3- <7jpyrimidin-2-yl)amino]-3-pyridyl]-4-piperidyl]piperazin-l-yl]phenyl]-3-methyl-piperidine-2,6- dione 160.3. To a solution of compound 160.2 as an HC1 salt (300 mg, 926 pmol) in THF (3 mL) and DMSO (3 mL) was added NaOAc (304 mg, 3.71 mmol), followed by addition 6-acetyl- 8-cyclopentyl-5-methyl-2-[[5-(4-oxo-l-piperidyl)-2-pyridyl]amino]pyrido[2,3-tZ]pyrimidin-7- one (427 mg, 926 pmol). After the mixture was stirred at 60 °C for 12 h, NaBH(OAc)i (589 mg, 2.78 mmol) was added. The reaction mixture was stirred for 4 h, and then diluted with ACN and water, filtered, concentrated, and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 160.3 (237 mg) in 35% yield. MS (ESI) m/z: 732.5 [M+H]t
[001233] Preparation of (A)-3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido-[2,3-t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)- 3-methyl-piperidine-2, 6-dione B309 and (7?)-3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7- oxo-7, 8-dihydropyrido-[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l- yl)phenyl)-3-methyl-piperidine-2, 6-dione B310 Compound 160.3 (237 mg) was resolved by prep-HPLC on a chiral column (CHIRALPAK IH) to afford compounds B309 (6 mg) and B310 (10 mg).
[001234] Compound B309. rH NMR (400 MHz, CD3OD) 8 9.20 (s, IH), 8.31 (m, IH), 8.18 (d, J = 2.4 Hz, IH), 8.09 (s, IH), 7.63 (d, J 9.8 Hz, IH), 7.52-7.57 (m, 2H), 7.44-7.49 (m, 2H), 6.19 (s, IH), 3.96-4.04 (m, 6H), 3.84-3.92 (m, 4H), 3.74-3.82 (m, 2H), 3.15-3.20 (m, 2H), 2.52-2.55 (m, 1H), 2.50 (s, 3H), 2.46-2.49 (m, 2H), 2.45 (s, 3H), 2.26-2.32 (m, 2H), 2.23 (d, J - 4.8 Hz, 1H), 2.20 -2.22 (m, 1H), 2.14-2.17 (m, 1H), 2.13 -2.05 (m, 1H), 2.10 (d, J = 6.8 Hz, 2H), 1.88-1.95 (m, 2H), 1.69 ( d, J 5.6 Hz, 2H), 1.53 (s, 3H); MS (ESI) m/z: 732.5 [M+H]+.
[001235] Compound B310 rH NMR (400 MHz, CD3OD) <5 9.19 (s, 1H), 8.27-8.34 (m, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H), 7.62 (d, J - 9.6 Hz, 1H), 7.49-7.55 (m, 2H), 7.43- 7,49 (m, 2H), 6.00 (d, J = 8.6 Hz, 1H), 4,02 (d, J = 13.2 Hz, 2H), 3,96-3,98(m, 4H), 3,87-3,89 (m, 4H), 3.69-3.81 (m, 2H), 3.15 (t, J - 11.8 Hz, 2H), 2.52-2.58 (m, 1H), 2.50 (s, 3H), 2.48 (d, J = 1.6 Hz, 2H), 2.45 (s, 3H), 2.22-2.35 (m, 3H), 2.03-2.18 (m, 5H), 1.86-1.95 (m, 2H), 1.64-1.75 (m, 2H), 1.53 (s, 3H); MS (ESI) m/r 732.5 [M+H] \
Example 161
Preparation of 3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluorophenyl)piperidine-2,6- di one B313
Figure imgf000470_0001
[001236] Compound B313 was prepared as described below.
[001237] Preparation of tert-butyl 4-[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]piperazine- 1 -carboxylate 161.1, To a solution of methyl 2-(4-bromo-2-fluorophenyl)acetate (2 g, 8.1 mmol) and tert-butyl piperazine- 1 -carboxylate (1.51 g, 8.1 mmol) in dioxane (20 mL) were added RuPhos Pd G3 (338 mg, 405 umol), RuPhos (378 mg, 810 pmol), and CS2CO3 (5.28 g, 16.2 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford compound 161.1 (2.8 g) in 98% yield. MS (ESI) m/z: 353.2 [M+H]T.
[001238] Preparation of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)-3-fluoro-phenyl]piperazine- 1 -carboxylate 161.2. To a solution of compound 161.1 (1.5 g, 4.26 mmol) and prop-2-enamide (303 mg, 4.26 mmol) in THF (15 mL) was added LBuOK (525 mg, 4.68 mmol). After stirring at 50 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous NaaSOr, and concentrated to afford compound 161.2 (920 mg), which was used directly in the next step without further purification.
[001239] Preparation of 3-(2-fluoro-4-piperazin-l-yl-phenyl)piperidine-2, 6-dione 161.3. To a solution of compound 161.2 (920 mg, 2.35 mmol) in DCM (10 mL) was added TFA (15.4 g, 135 mmol ). After stirring for 1 h, the reaction mixture was concentrated to afford compound 161.3 (680 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 292.1 [M+H]+.
[001240] Preparation of 3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluoro- phenyl)piperidine-2, 6-dione B313 To a solution of compound 161.3 (152 mg, 521 umol) and 6- acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-oxo-l-piperidyl)-2-pyridyl]amino]pyrido[2,3-<f]- pyrimidin-7-one (200 mg, 434 pmol) in THF (2 mL) and DMSO (2 mL) were added NaBH(OAc)s (184 mg, 869 pmol), NaOAc (107 mg, 1.3 mmol), and AcOH (26 mg, 434 umol). After stirring for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous NaiSCh, concentrated, and purified by reverse phase prep-HPLC to afford compound B313 (33 mg) in 10% yield. I l NAIR (400 MHz, DMSO-tZe) 9' 10.81 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.07 (d, J= 2.4 Hz, 1H), 7.83 (d, J= 8.8 Hz, 1H), 7.48 (dd, J= 2.4, 8.8 Hz, 1H), 7.21-6.95 (m, 1H), 6.78- 6.66 (m, 2H), 5.82 (t, ./ 8.8 Hz, 1H), 3.89 (dd, J- 4.8, 12.0 Hz, 1H), 3.75
Figure imgf000471_0001
1 1.6 Hz, 2H), 3.15 (s, 4H), 2.75-2.62 (m, 8H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27-2.07 (m, 4H), 1.90 (d, J= 13.6 Hz, 5H), 1.77 (dd, J= 3.6, 5.2 Hz, 2H), 1.57 (d, J= 8.8 Hz, 4H); MS (ESI) m/z: 736.7 [M+H]“.
Example 162
Preparation of 3-(4-(4-(l -(6-((6-acetyl-8-cyclopentyl-5-^lethyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)anlino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3-fluorophenyl)piperidine-2,6- dione B314
Figure imgf000472_0001
[001241] Compound B314 was prepared as described below.
[001242] Preparation of fert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)-2-fluorophenyl]- piperazine-1 -carboxylate 162.1. To a solution of 2,6-dibenzyloxy-3-(4-bromo-3-fluorophenyl)- pyridine (2 g, 4.31 mmol) and fert-butyl piperazine- 1 -carboxylate (802 mg, 4.31 mmol) in dioxane (25 mL) were added RuPhos (101 mg, 215 pmol), RuPhos Pd G3 (180 mg, 215 pmol), and CszCCb (4.21 g, 12.9 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NarSCL, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford 162.1 (2 g) in 82% yield. MS (ESI) m/z'. 570.3 [M+H]+.
[001243] Preparation of Zer/-butyl 4-[4-(2,6-dioxo-3-piperidyl)-2-fluorophenyl]piperazine- 1 -carboxylate 162.2. To a mixture of compound 162.1 (2 g, 3.51 mmol) in THF (20 mL) were added 10% Pd/C (0.25 g) and 20% Pd(OH)2 (0.25 g) under N2. After stirring under H2 at 40 °C for 12 h, the reaction mixture was filtered and concentrated to afford compound 162.2 (1.2 g), which was used directly in the next step without further purification.
[001244] Preparation of 3-(3-fluoro-4-piperazin-l-yl-phenyl)piperidine-2, 6-dione 162.3,
To a solution of compound 162.2 (1.2 g, 3.07 mmol) in DCM (15 mL) was added 4M HC1 in dioxane (3 mL). After stirring for 2 h, the reaction mixture was concentrated to afford compound 162.3 as an HC1 salt (996 mg), which was used directly in the next step without further purification. MS (ESI) m/z'. 292.3 [M+H]+.
[001245] Preparation of 3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-t/]-pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3- fluorophenyl)piperidine-2, 6-dione B314. To a solution of compound 162.3 as an HC1 salt (100 mg, 305 pmol) and in DMSO (2 mL) and THF (2 mL) was added NaOAc (75 mg, 915 pmol. After the mixture was stirred at 60 °C for 1 h, 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-oxo-l- piperidyl)-2-pyridyl]amino]pyrido[2,3-d]pyrimidin-7-one (169 mg, 366 pmol) was added. The mixture was stirred at 60 °C for 12 h, followed by addition of NaBH(OAc)3 (129 mg, 610 pmol). The reaction mixture was stirred for 2 h, and then concentrated and purified by reverse phase prep-HPLC to afford compound B314 (58 mg) in 25% yield. }H NMR (400 MHz, DMSO-ufc) ri 10.81 (s, 1H), 10.07 (s, 1H), 8.95 (s, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.48 (d, ./= 9.2 Hz, 1H), 7.07-6.90 (m, 3H), 5.90-5.75 (m, 1H), 3.92-3.66 (m, 4H), 3.06-2.94 (m, 4H), 2.74-2.61 (m, 6H), 2.42 (s, 5H), 2.31 (s, 3H), 2.25-1.96 (m, 4H), 1.95-1.82 (m, 4H), 1.81- 1.71 (m, 2H), 1.64-1.51 (m, 4H); MS (ESI) wk 736.4 [M H] ,
Example 163
Preparation of 3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3-chlorophenyl)piperidine-2,6- di one B316
Figure imgf000473_0001
[001246] Compound B316 was prepared as described below.
[001247] Preparation of ZerZ-butyl 4-[2-chloro-4-(2-m ethoxy -2-oxoethyl)phenyl]- piperazine-l-carboxylate 163.1 A mixture of methyl 2-(4-bromo-3-chlorophenyl)acetate (500 mg, 1.90 mmol), ZerZ-butyl piperazine- 1 -carboxylate (1.06 g, 5.69 mmol), RuPhos Pd G3 (79 mg, 95 pmol), RuPhos (44 mg, 94.9 pmol), and CS2CO3 (1.85 g, 5.69 mmol) in dioxane (5 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford compound 163.1 (580 mg) in 81% yield. [001248] Preparation of tert-butyl 4-[2-chloro-4-(2,6-dioxo-3-piperidyl)phenyl]piperazine- 1 -carboxylate 163.2. To a solution of compound 163.1 (580 mg, 1.57 mmol) and prop-2- enamide (112 mg, 1.57 mmol) in THF (5 mL) was added t-BuOK (194 mg, 1 .73 mmol) at 0 °C. After stirring at 50 °C for 5 h under N2, the reaction mixture was treated with saturated aqueous NH4Q and extracted with EtOAc. The combined organic layers were dried over anhydrous NarSCh, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 163.2 (400 mg) in 56% yield.
[001249] Preparation of 3-(3-chloro-4-piperazin-l-yl-phenyl)piperidine-2,6-dione 163.3. To a solution of compound 163.2 (400 mg, 981 umol) in DCM (3 mL) was added 4M HCI in dioxane (3.00 mL). After stirring for 2 h, the reaction mixture was concentrated and triturated with PE/EtOAc to afford compound 163.3 as an HO salt (200 mg). MS (ESI) m/z: 308 [M+H]+.
[001250] Preparation of 3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-J|-pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3- chlorophenyl)piperidine-2, 6-dione B316 To a solution of compound 163.3 (200 mg, 650 umol) and 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-oxo-l-piperidyl)-2-pyridyl]amino]pyrido[2,3-£/]- pyrimidin-7-one (449 mg, 975 pmol) in DMSO (2 mL) and THF (2 mL) was added NaOAc (159 mg, 1.95 mmol ). After the mixture was stirred at 60 °C for 12 h, NaBHsCN (82 mg, 1 .3 mmol) was added. The reaction mixture was stirred for 4 h, and then filtered, concentrated, and purified by reverse phase prep-HPLC to afford compound B316 (26 mg) in 5% yield. !H NMR (400 MHz, DMSO-d6 ) 3 10.82 (s, 1H), 10.06 (s, 1H), 8.95 (s, 1H), 8.35 (s, 1H), 8.07 (d, J= 2.8 Hz, 1H), 7.83 (d, 9.2 Hz, 1H), 7.48 (dd, ./ ■ 2.8, 9.2 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.21-7.06
(m, 2H), 5.82 (t, J= 8.8 Hz, 1H), 3.84-3.80 (m, 1H), 3.75 (d, J= 11.6 Hz, 2H), 2.99 (s, 4H), 2.77-2.71 (m, 2H), 2.70-2.61 (m, 5H), 2.58-2.52 (m, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27-2.18 (m, 3H), 2.04-1.97 (m, 1H), 1.95-1.85 (m, 4H), 1.82-1.73 (m, 2H), 1.64-1.54 (m, 4H); MS (ESI) m/z: 752.3 [M+H]+.
Example 164
Preparation of 3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-r7]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)azeti din- l-yl)phenyl)piperidine-2, 6-dione B317
Figure imgf000475_0001
[001251] Compound B317 was prepared as described below.
[001252] Preparation of l-(4-bromophenyl)azetidin-3-ol 164.1. A mixture of l-bromo-4- iodo-benzene (22.7 g, 80.3 mmol), azetidin-3-ol as an HC1 salt (8 g, 73 mmol), Cui (4.17 g, 21.9 mmol), Z-proline (2.52 g, 21.9 mmol), and K2CO3 (30.3 g, 219 mmol) in DMF (100 mL) was stirred at 110 °C for 12 h. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous \'a.:S() 4, concentrated, and purified by column chromatography (S1O2, EtOAc/PE) to afford compound 164.1 (11.7 g) in 70% yield. MS (ESI) m/z: 228 [M+H]+.
[001253] Preparation of l-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]azetidin-3-ol 164.2. To a solution of compound 164.1 (10 g, 43.8 mmol), (2,6-dibenzyloxy-3-pyridyl)boronic acid (17.6 g, 52.6 mmol) in dioxane (100 mL) and H2O (10 mL) were added Pd(dppf)C12-CH2C12 (1.79 g, 2.19 mmol) and K3PO4 (18.6 g, 87.7 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 164.2 (11 .4 g) in 58% yield. MS (ESI) m/z: 439.3 [M+H]+.
[001254] Preparation of 3-[4-(3-hydroxyazetidin-l-yl)phenyl]piperidine-2, 6-dione 164.3. To a solution of compound 164.2 (6 g, 13.7 mmol) in THF (30 mL) and EtOH (30 mL) was added 10% Pd/C (3 g) under N2. After stirring under H2 at 50 °C for 12 h, the reaction mixture was filtered and concentrated to afford compound 164.3 (3.8 g), which was used directly in the next step without further purification. MS (ESI) m/z: 261.1 [M+H]+.
[001255] Preparation of 3-[4-(3-oxoazetidin-l-yl)phenyl]piperidine-2, 6-dione 164.4. To a solution of compound 164.3 (1 g, 3.84 mmol) in DMSO (5 mL) was added TEA (3.23 g, 31.9 mmol) and sulfur trioxide pyridine complex (4.28 g, 26.9 mmol). After stirring at 50 °C for 12 h, the reaction mixture was purified by reverse phase prep-HPLC to afford compound 164.4 (350 mg) in 34% yield. MS (ESI) m/z: 259.0 [M+H]+.
[001256] Preparation of 3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-tfj-pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)phenyl)- piperidine-2, 6-dione B317 To a solution of compound 164.4 (100 mg, 387 pmol), and 6-acetyl- 8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrido[2,3-t7]pyrimidin-7-one (144 mg, 323 umol) in THE' (1 mL) and DMSO (1 mL) were added NaOAc (106 mg, 1 .29 mmol) and NaBH(OAc)3 (274 mg, 1.29 mmol). After stirring at 40 °C for 12 h, the reaction mixture was filtered and purified by prep-TLC (SiO2, MeOHZDCM) to afford compound B317 (44 mg) in 20% yield. [H NMR (400 MHz, DMSO-fifc) 3 10.75 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.06 (d, J - 2.8 Elz, 1H), 7.89-7.82 (m, 1H), 7.48 (dd, J- 2.8, 9.2 Elz, 1H), 7.02 (d, ./ - 8.4 Hz, 2H), 6.42 (d, J= 8.8 Hz, 2H), 5.89-5.75 (m, 1H), 3.94 (t, J= 7.2 Hz, 2H), 3.70 (dd, J= 4.8, 10.8 Hz, 1H), 3.65-3.59 (m, 2H), 3.31-3.27 (m, 4H), 3.23-3.15 (m, 4H), 2.64-2.59 (m, 2H), 2.42 (s, 3H), 2.35- 2.32 (m, 1H), 2.31 (s, 3H), 2.28-2.19 (m, 2H), 2.17-2.07 (m, 1H), 2.05-1.95 (m, 1H), 1.93-1.83 (m, 2H), 1.81-1.71 (m, 2H), 1.64-1.54 (m, 2H); MS (ESI) m/z: 690.5 [M+H]+.
Example 165
Preparation of 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-5-fluorophenyl)- piperidine-2, 6-dione B318
Figure imgf000476_0001
[001257] Compound B318 was prepared as described below.
[001258] Preparation of 2, 6-dibenzyloxy-3-(3-bromo-5-fluorophenyl)pyridine 165.1, To a solution of l-bromo-3-fluoro-5-iodobenzene (4.49 g, 14.9 mmol) and (2, 6-dibenzyloxy-3- pyridyl)boronic acid (5 g, 14.9 mmol) in dioxane (50 mL) and H2O (5 mL) were added Pd(dppf)C12'CH2C12 (609 mg, 746 pmol) and K3PO4 (6.33 g, 29.8 mmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO?., EtOAc/PE) to afford 165.1 (4.9 g) in 57% yield. TH NMR (400 MHz, DMSO-rfc) 3 7.86 (d, ./ 8.4 Hz, 1H), 7.47-7.42 (m, 4H), 7.41-7.36 (m, 5H), 7.36-7.28 (m, 4H), 6.61-6.51 (m, 1H), 5.43 (s, 2H), 5.40 (s, 2H); MS (ESI) mA: 466 [M+H]+.
[001259] Preparation of 2,6-dibenzyloxy-3-[3-[4-(2,2-dimethoxyethyl)-l-piperidyl]-5- fluorophenyl]pyridine 165.2. To a solution of compound 165.1 (4.5 g, 7.75 mmol) and 4-(2,2- dimethoxyethyl)piperidine (1.48 g, 8.53 mmol) in dioxane (40 mL) were added RuPhos Pd G3 (648 mg, 775 pmol), CS2CO3 (5.05 g, 15.5 mmol), and RuPhos (362 mg, 775 pmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2.SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 165.2 (4.3 g) in a quantitative yield. MS (ESI) mA: 577.5 [M+H]+.
[001260] Preparation of 3-[3-[4-(2,2-dimethoxyethyl)-l-piperidyl]-5-fluorophenyl]- piperidine-2, 6-dione 165,3. To a solution of compound 165.2 (3.8 g, 6.83 mmol) in THF (30 mL) was added 10% Pd/C (2 g) under N2. After stirring under H2 at 40 °C for 24 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiOr, EtOAc/PE) to afford compound 165.3 (1.2 g) in 46% yield. rH NMR (400 MHz, DMSO-<&) d 10.81 (s, 1H), 6.66-6.54 (m, 2H), 6.38 (d, J= 9.6 Hz, 1H), 4.48 (t, J= 5.6 Hz, 1H), 3.78 (dd, J= 4.8, 12.0 Hz, 1H), 3.69 (d, J= 12.4 Hz, 2H), 3.23 (s, 6H), 2.70-2.58 (m, 3H), 2.23 (dq, 7 4.4, 12.4 Hz, 1H), 2.05-1.94 (m, 2H), 1.73 (d, J= 12.4 Hz, 2H), 1.50-1.45 (m, 2H), 1.28-1.16 (m, 3H); MS (ESI) m/z: 379.4 [M+H]+.
[001261] Preparation of 2-[l-[3-(2,6-dioxo-3-piperidyl)-5-fhiorophenyl]-4-piperidyl]- acetaldehyde 165,4. To a solution of compound 165.3 (200 mg, 528 pmol) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol). After stirring for 0.5 h, the reaction mixture was neutralized with NaHCOa to pH 8 and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford compound 165.4 (100 mg) which was used directly in the next step without further purification. MS (ESI) m/z: 333.1 [M+H]+.
[001262] Preparation of 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-5- fluorophenyl)-piperidine-2, 6-dione B318 To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2- [(5-piperazin-l-yl-2-pyridyl)amino]pyrido[2,3-<7]pyrimidin-7-one (135 mg, 301 pmol) in MeOH (2 mL) was added AcOH (54 mg, 903 pmol), followed by addition of compound 165.4 (100 mg, 301 nmol). After the mixture was stirred for 1 h, NaBFhCN (13 mg, 211 pmol) was added. The reaction mixture was stirred for 12 h, and then diluted with DMF and purified by reverse phase prep-HPLC to afford compound B318 (92 mg) in 39% yield. rH NMR (400 MHz, DMSO-tfc) b 10.80 (s, 1H), 10.08 (s, 1H), 8,95 (s, 1H), 8, 16 (s, 1H), 8,05 (d, J= 2.4 Hz, 1H), 7,84 (d, J= 8.8 Hz, 1H), 7.46 (dd, J= 2.8, 9.2 Hz, 1H), 6.64-6.57 (m, 2H), 6.38 (d, J= 9.2 Hz, 1H), 5.82 (q, J = 8.8 Hz, 1H), 3.77 (dd, .7 - 4.8, 11.6 Hz, 1H), 3.70 (d, .7 - 12.0 Hz, 2H), 3.16 (s, 4H), 2.72-2.57 (m, 6H), 2.42 (s, 3H), 2.39 (d, J= 7.6 Hz, 4H), 2.31 (s, 3H), 2.24 (dd, J= 8.4, 11.6 Hz, 3H), 2.00 (dt, .7 4.4, 8.8 Hz, 1H), 1 94-1.85 (m, 2H), 1.81-1.71 (m, 4H), 1.62-1.54 (m, 2H), 1.49-1.39 (m, 3H), 1.22 (q, J= 10.4 Hz, 2H); MS (ESI) m/z: 764.6 [M~H] .
Example 166
Preparation of 3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-fluorophenyl)- piperidine-2, 6-dione B322
Figure imgf000478_0001
[001263] Compound B322 was prepared as described below.
[001264] Preparation of 2,6-dibenzyloxy-3-(3-bromo-2-fluorophenyl)pyridine 166.1. A mixture of l-bromo-2-fluoro-3 -iodobenzene (5 g, 16.6 mmol), (2,6-dibenzyloxy-3-pyridyl)- boronic acid (5.57 g, 16.6 mmol), K3PO4 (7.05 g, 33.23 mmol), and Pd(dppf)C12 CH2C>2 (1.36 g, 1.66 mmol) in dioxane (50 mL) and water (10 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 166.1 (6 g) in 68% yield. MS (ESI) m/z: 464 [M+H]+.
[001265] Preparation of 2,6-dibenzyloxy-3-[3-[4-(2,2-dimethoxyethyl)-l-piperidyl]-2- fluorophenyl]pyridine 166,2. A mixture of 4-(2,2-dimethoxyethyl)piperidine (2.09 g, 12.1 mmol), compound 166.1 (5.6 g, 12.1 mmol), RuPhos (563 mg, 1.21 mmol), RuPhos Pd G3 (504 mg, 603 umol), and CS2CO3 (7.86 g, 24.1 mmol) in dioxane (40 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was filtered, concentrated, and purified by column chromatography ( Si
Figure imgf000479_0001
EtOAc/PE) to afford compound 166.2 (1 .8 g) in 22% yield. MS (ESI) m/z: 557.5 [M+H]+.
[001266] Preparation of 3-[3-[4-(2,2-dimethoxyethyl)-l-piperidyl]-2-fluorophenyl]- piperidine-2, 6-dione 166.3. To a solution of compound 166.2 (1.8 g, 3.23 mmol) in THF (20 mL) were added 10% Pd/C (0.5 g) and 20% Pd(OH)2 (0.5 g) under N2. After stirring under H?. at 40 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, EtOAc/PE and MeOH/DCM) to afford compound 166.3 (0.55 g) in 74% yield. MS (ESI) m/z: 379.2 [M+H]4.
[001267] Preparation of 2-[l-[3-(2,6-dioxo-3-piperidyl)-2-fluoro-phenyl]-4-piperidyl]- acetaldehyde 166.4 To a solution of compound 166.4 (0.55 g, 1.45 mmol) in DC'M (5 mL) was added TFA (829 mg, 7.27 mmol). After stirring for 1 h, the reaction mixture was concentrated to afford compound 166.4 (0.48 g), which was used directly in the next step without further purification. MS (ESI) fflA: 333.1 [M+H]+.
[001268] Preparation of 3-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihy dropyrido[2,3 -t/]pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin-l -yl)ethyl)piperidin- 1 -yl)-2- fluorophenyl)-piperidine-2, 6-dione B322 To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2- [(5-piperazin-l-yl-2-pyridyl)amino]pyrido[2,3-J|pyrimidin-7-one (67.3 mg, 150 pmol) and compound 166.4 (50 mg, 150 umol) in THF (1 mL) and DMSO (1 mL) was added NaOAc (12.3 mg, 150 prnol). After the mixture was stirred at 60 °C for 4 h, NaBHsCN (9.45 mg, 150 pmol) was added. The reaction mixture was stirred for 12 h and then purified by reverse phase prep- HPLC to afford compound B322 (16 mg) in 13% yield. rH NMR (400 MHz, CDCh) d 8.83 (s, 1H), 8.58 (s, 1H), 8.43-8.31 (m, 1H), 8.18 (d, J= 9.2 Hz, 1H), 8.08 (d, J= 2.8 Hz, 1H), 7.35 (dd, J= 2.8, 9.2 Hz, 1H), 7.09-7.02 (m, 1H), 6.99-6.91 (m, 1H), 6.78 (t, J= 6.4 Hz, 1H), 5.88 (q, J = 8.8 Hz, 1H), .3.92 (dd, ./ 5.2, 10.8 Hz, 1H), .3.42 (t, J= 8.8 Hz, 2H), 3.27 (s, 4H), 2.83-2.63 (m, 8H), 2.56 (s, 5H), 2.38 (s, 3H), 2.33 (d, J= 6.4 Hz, 2H), 2.31-2.19 (m, 2H), 2.07 (dd, J= 5.2, 7.6 Hz, 2H), 1.93-1.86 (m, 2H), 1.82 (d, ./ 6.0 Hz, 2H), 1.74-1.65 (m, 2H), 1.64-1.56 (m, 2H), 1.49 (s, 3H); MS (ESI) m/z: 764.4 [M+H]+.
Example 167
Preparation of 1 -(2-chloro-4-(4-(3-((4-((6-(difluoromethyl)-8-(( U?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- propyl)piperazin-l-yl)phenyl)dihydropyrimidine-2, 4(127, 3H)-dione B403
Figure imgf000480_0001
[001269] Compound B403 was prepared as described below.
[001270] Preparation of 3-(4-bromo-2-chloro-anilino)propanoic acid 167.1. A solution of 4-bromo-2-chloroaniline (20 g, 96.9 mmol) and acrylic acid (8.38 g, 116 mmol) in toluene (100 mL) was stirred at 100 °C for 48 h under N2. The reaction mixture was then concentrated to afford compound 167.1 (15.6 g), which was used directly in the next step without further purification. ^ NMR (400 MHz, DMSO-r/6) d 12.30 (br s, 1H), 7.45 (d, J= 2.4 Hz, 1H), 7.29 2.4, 8.8 Hz, 1H), 6.71 (d, ,7 = 8.8 Hz, 1H), 5.51 (br t, J= 5.6 Hz, 1H), 3.37-3.35 (m, 1H), 3.32 (br s, 1H), 2.56-2.52 (m, 2H); MS (ESI) m/z. 278 [M+H]t
[001271] Preparation of l-(4-bromo-2-chlorophenyl)hexahydropyrimidine-2, 4-dione 167.2.
A solution of compound 167.1 (15.6 g, 56 mmol) and urea (5.05 g, 84 mmol) in AcOH (150 mL) was stirred at 130 °C for 24 h under N2. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 167.2 (7.8 g) 45% yield. rH NMR (400 MHz, DMSO-d6 ) 8 10.53 (s, 1H), 7.88 (d, J= 2.4 Hz, 1H), 7.64 (dd, J= 2.4, 8.5 Hz, 1H), 7.47 (d, J= 8.6 Hz, 1H), 3.78-3.67 (m, 1H), 3.62-3.53 (m, 1 H), 2.76-2.70 (m, 2H); MS (ESI) m/z\ 303 [M+H]+.
[001272] Preparation of /er/-butyl 4-[3-chloro-4-(2,4-dioxohexahydropyrimidin-l -yl)- phenyl]piperazine-l -carboxylate 167.3. To a solution of compound 167.2 (500 mg, 1.65 mmol) and tert-butyl piperazine- 1 -carboxylate (767 mg, 4.12 mmol) in dioxane (5 mL) were added tBuXPhos Pd G3 (140 mg, 165 pmol) and CS2CO3 (1.61 g, 4.94 mmol). After stirring at 100 °C for 12 h, the reaction mixture was treated with saturated NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSOi, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 167.3 (150 mg) in 21% yield. fflNMR (400 MHz, DMSO-flfe) d 10.38 (s, 1H), 7.28 (d, J- 8.8 Hz, 1H), 7.07 (s, 1H), 6.96 (br d, J= 8.8 Hz, 1H), 3.67-3.59 (m, 1H), 3.54 (br dd, J= 6.4, 12.4 Hz, 1H), 3.44 (br s, 4H), 3.18 (br d? ./ 4.4 Hz, 4H), 2.75-2.66 (m, 2H), 1.42 (s, 9H); MS (ESI) m/z\ 409.1 [M+H]+.
[001273] Preparation of l-(2-chloro-4-piperazin-l-yl-phenyl)hexahydropyrimidine-2,4- dione 167.4. To a solution of compound 167.3 (150 mg, 367 pmol) in DCM (2 mL) was added 4M HC1 in dioxane (1.51 mL). After stirring for 6 h, the reaction mixture was concentrated to afford compound 167.4 as an HC1 salt (138 mg), which was used directly in the next step without further purification. MS (ESI) m/z'. 309.1 [M+H]+.
[001274] Preparation of l-(2-chloro-4-(4-(3-((4-((6-(difluoromethyl)-8-((lA,2A)-2- hydroxy-2-methyl-cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin- l-yl)sulfonyl)propyl)piperazin-l-yl)phenyl)dihydropyrimidine-2, 4(177, 3/7)-dione B403 To a solution of compound 167.4 as an HC1 salt (73 mg, 211 pmol) and TEA (43 mg, 423 pmol) in DMF (1 mL) was added KI (35 mg, 21 1 gmol), followed by addition of 2-[[l-(3-chloropropyl- sulfonyl)-4-piperidyl]amino]-6-(difluoromethyl)-8-[(lA,2A)-2-hydroxy-2-methylcyclopentyl]- pyrido[2,3-tfjpyrimidin-7-one (56 mg, 106 pmol) in DMF (0.5 mL) at 0 °C under N2. After stirring at 80 °C for 12 h, the reaction mixture was filtered and purified by reverse phase prep- HPLC to afford compound B403 (30 mg) in 35% yield. TH NMR (400 MHz, DMSO-tfe) 8 10.32 (s, 1H), 8.78-8.66 (m, 1H), 8.03 (s, 2H), 7.21 (d, 8.8 Hz, 1H), 7.00-6.97 (m, 1H), 6.96-6.65
(m, 2H), 5.89-5.74 (m, 1H), 4.41-4.27 (m, 1H), 4.04-3.87 (m, 1H), 3.65-3.42 (m, 6H), 3.18-3.13 (m, 4H), 3.08-3.02 (m, 2H), 2.95-2.87 (m, 2H), 2.68 (br s, 2H), 2.43-2.36 (m, 4H), 2.22-2.05 (m, 2H), 1.95-1.76 (m, 7H), 1.64-1.38 (m, 3H), 0.97-0.90 (m, 3H); MS (ESI) m/z: 806.5 [M+H]L
Example 168
Preparation of l-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)phenyl)dihydro- pyrimidine-2,4(l//,3J/)-dione B406
Figure imgf000482_0001
[001275] Compound B406 was prepared as described below.
[001276] Preparation of l-[4-[4-(2,2-dimethoxy ethyl)- 1-piperi dyl]phenyl]-3-[(4-methoxy- phenyl)methyl]hexahydropyrimidine-2, 4-dione 168.1. To a solution of 4-(2,2-dimethoxyethyl)- piperidine (1.60 g, 9.25 mmol) and l-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydro- pyrimidine-2, 4-dione (3 g, 7.71 mmol) in dioxane (30 mL) were added RuPhos (360 mg, 771 umol), CS2CO3 (5.02 g, 15,41 mmol) and RuPhos Pd G3 (322 mg, 385 pmol). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiCh, EtOAc/PE) to afford compound 168.1 (3.6 g) in 91% yield. MS (ESI) m/z: 482.3 [M+H]+.
[001277] Preparation of 2-[l-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexahydro- pyrimidin-l-yl]phenyl]-4-piperidyl]acetaldehyde 168.2. To a solution of compound 168.1 (500 mg, 1.04 mmol) in DCM (5 mL) was added TFA (3.84 g, 33.7 mmol). After stirring at 40 °C for 1 h, the reaction mixture was concentrated to afford compound 168.2 (0.45 g), which was used directly in the next step without further purification. MS (ESI) m/z: 436.3 [M+H]+. [001278] Preparation of 1 -[4-[4-[2-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido- [2,3<dpyrimidin-2-yl)amino]-3-pyridyl]piperazin-l-yl]ethyl]-l-piperidyl]phenyl]-3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione 168.3. To a solution of compound 168.2 (0.45 g, 1.03 mmol) and 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]- pyrido[2,3-tZ]pyrimidin-7-one (462.42 mg, 1.03 mmol) in DMSO (3 mL) and THF (3 mL) were added NaOAc (85 mg, 1.03 mmol) and NaBH(OAc)i (438 mg, 2.07 mmol). After stirring at 60 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiCh, MeOH/DCM) to afford compound 168.3 (450 mg) in 41% yield. MS (ESI) m/z: 867.4 [M+H]4.
[001279] Preparation of l-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-z7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)- phenyl)dihydro-pyrimidine-2,4(lET,3/7)-dione B406 To a solution of compound 168.3 (0.35 g, 404 pmol) in DCM (1 mL) were added TFA (460 mg, 4.04 mmol) and TfOH (606 mg, 4.04 mmol). After stirring for 1 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound B406 (67 mg) in 21% yield. ^I NMR (400 MHz, CDCh) 3 8.82 (s, 1H), 8.37 ( s, 1H), 8.30 (s, 1H), 8.18 (d, J 9.2 Hz, 1H), 8.07 (d, J - 2.8 Hz, 1H), 7.99 (s, 1H), 7.35 (dd, J = 2.8, 9.2 Hz, 1H), 7.16 (d, J = 9.2 Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H), 5.88 (q, J - 8.8 Hz, 1H), 3.82 (t, J - 6.8 Hz, 2H), 3.68 (d, J - 12.4 Hz, 2H), 3.32-3.20 (m, 4H), 2.82 (t, J = 6.8 Hz, 2H), 2.78-2.68 (m, 6H), 2.59-2.53 (m, 5H), 2.38 (s, 3H), 2.37-2.31 (m, 2H), 2.12- 2.01 (m, 2H), 1.88 (dd, J --- 5.6, 9.6 Hz, 2H), 1.83 (d, J -- 13.2 Hz, 2H), 1.74-1.64 (m, 2H), 1.61- 1.54 (m, 2H), 1.54-1.47 (m, 1H), 1.46-1.34 (m, 2H); MS (ESI) m/z'. 747.6 [M+H]4.
Example 169
Preparation of l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-(trifluoromethyl)phenyl)- dihydropyrimidine-2, 4(1/7, 3/7)-dione B410
Figure imgf000484_0001
[001280] Compound B410 was prepared as described below.
[001281] Preparation of tert-butyl 4-(4-(3-(4-methoxybenzyl)-2,4-dioxotetrahydro- pyrimidin-l(2/7)-yl)-3-(trifluoromethyl)phenyl)piperazine-l-carboxylate 169.1. A mixture of tert-butyl piperazine- 1 -carboxylate (122 mg, 656 pmol), l-(4-bromo-2-(trifluoromethyl)phenyl)- 3-(4-methoxybenzyl)dihydropyrimidine-2, 4(177, 3//)-dione (0.3 g, 656 pmol), Pd-PEPPSI-IPent (28 mg, 32.8 pmol), and CszCCh (641 mg, 1.97 mmol) in dioxane (3 mL) was stirred at 100 °C for 12 h under Ni The reaction mixture was then concentrated and purifi ed by column chromatography (SiCh, EtOAc/PE) to afford compound 169.1 (350 mg) in 86% yield.
[001282] Preparation of l-[4-piperazin-l-yl-2-(trifluoromethyl)phenyl]hexahydro- pyrimidine-2, 4-dione 169.2. To a solution of compound 169.1 (550 mg, 978 umol) in DCM (5 mL) were added TfOH (734 mg, 4.89 mmol) and TFA (1.1 1 g, 9.78 mmol). After stirring for 2 h, the reaction mixture was concentrated and purified by column chromatography (SiCh, DCM/MeOH) to afford 169.2 (0.2 g) in 57% yield). rH NMR (400 MHz, CDiOD) 3 7.45-7.40 (m, 1H), 7.37 (d, J - 2.8 Hz, 1H), 7.35-7.30 (m, 1H), 3.86 (ddd, J - 4.8, 11.6, 12.4 Hz, 1H), 3.58-3.55 (m, 1H), 3.53 (dd, J = 4.0, 6.4 Hz, 4H), 3.41-3.38 (ra, 4H), 2.91-2.79 (m, 1H), 2.78- 2.68 (m, 1H); MS (ESI) m/z: 343 [M+H]+.
[001283] Preparation of 1 -(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-t/]-pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2- (trifluoromethyl)phenyl)-dihydropyrimidine-2, 4(1/7, 3/7)-dione B410. To a solution of 6-acetyl- 8-cyclopentyl-5-methyl-2-[[5-(4-oxo-l-piperidyl)-2-pyridyl]amino]pyrido[2,3-t/]pyrimidin-7- one (202 mg, 438 pmol) and compound 169.2 (0.15 g, 438 umol) in DMSO (2 mL) and THF (2 mL) was added NaOAc (72 mg, 876. pmol). After the mixture was stirred at 60 °C for 12 h, NaBHsCN (55 mg, 876 gmol) was added. The reaction mixture was stirred for 1 h and then purified by reverse phase prep-HPLC to afford compound B410 (72 mg) in 19% yield. rH MR (400 MHz, CDCh) d 8.83 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 8.16 (d, J -- 9.2 Hz, 1H), 8.09 (d, J - 2.0 Hz, 1H), 7.36 (dd, J - 2.4, 9.2 Hz, 1H), 7.26-7.18 (m, 2H), 7.13-7.04 (m, 1H), 5.88 (t, J - 8.8 Hz, 1H), 3.86-3.76 (m, 1H), 3.73 (d, J - 12.0 Hz, 2H), 3.62-3.54 (m, 1 H), 3.34 (s, 4H), 3.00- 2.89 (m, 1H), 2.81 (s, 4H), 2.80-2.69 (m, 2H), 2.56 (s, 3H), 2.38 (s, 3H), 2.24-2.01 (m, 6H), 1.93-1.85 (m, 2H), 1.82-1.64 (m, 4H); MS (ESI) m/z: 787.6 [M+H]t
Example 170
Preparation of 3-(6-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l-methyl-lJ/- indazol-3-yl)piperidine-2, 6-dione B504
Figure imgf000485_0001
[001284] Compound B504 was prepared as described below.
[001285] Preparation of tert-butyl 3-[2-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methylindazol-6- yl]ethynyl]-3-fluoroazetidine-l-carboxylate 170.1. To a solution of 6-bromo-3-(2,6-dibenzyl- oxy-3-pyridyl)-l -methylindazole (2 g, 4 mmol) in THF (40 mL) and ACN (40 mL) were added tert-butyl 3 -ethynyl-3-fluoroazeti dine- 1 -carboxylate (876 mg, 4.4 mmol), XPhos Pd G3 (338 mg, 400 pmol), and CS2CO3 (3.91 g, 11.9 mmol). After stirring at 60 °C for 12 h under N2, the reaction mixture was concentrated and purified by column chromatography (SiO2, EtOAc/PE) to afford compound 170.1 (1.2 g) in 46% yield.
Figure imgf000485_0002
NMR (400 MHz, DMSO-dfo d 7.99-7.87 (m, 2H), 7.71 (br d, J= 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.44-7.27 (m, 8H), 7.10 (br d, J= 8.4 Hz, 1H), 6.60 (br d, ./ 8.0 Hz, 1H), 5.45 (br d, J- 4.8 Hz, 4H), 4.42-4.21 (m, 4H), 4.10-4.05 (m, 3H), 1.42 (s, 9H); MS (ESI) m/z: 619.5 fol df
[001286] Preparation of tert-butyl 3-[2-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]- ethyl]-3-fluoroazetidine-l-carboxylate 170.2, A mixture of compound 170.1 (1.2 g, 1 .94 mmol), AcOH (349 mg, 5.82 mmol), 10% Pd/C (619 mg), and 20% Pd(OH)2 (409 mg) in THF (25 mL) was stirred at 40 °C under Hr for 12 h. The reaction mixture was then filtered and concentrated to afford compound 170.2 (1 g), which was used directly in the next step without further purification.
[001287] Preparation of 3-[6-[2-(3-fluoroazetidin-3-yl)ethyl]-l-methylindazol-3-yl]- piperidine-2, 6-dione 170.3. To a solution of compound 170.2 (500 mg, 1.12 mmol) in DCM (12 mL) was added TFA (6.14 g, 53.9 mmol). After stirring for 2 h, the reaction mixture was partitioned between DCM and NaHCCh. The organic layer was dried over anhydrous Na2SO4 and concentrated to afford compound 170.3 (160 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 345,2 [M+H]+.
[001288] Preparation of 3-(6-(2-(l-(l -(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-J|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3- yl)ethyl)-l-methyl-W-indazol-3-yl)piperidine-2, 6-dione B504 To a mixture of compound 170.3 (160 mg, 465 pmol) in DCM (6 mL) were added 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-oxo- l-piperidyl)-2-pyridyl]amino]pyrido[2,3-(/]pyrimidin-7-one (110 mg, 239 pmol) and AcOH (43 mg, 717 pmol). After the mixture was stirred for 0.5 h, NaBH(OAc)3 (152 mg, 717 pmol) was added. The reaction mixture was stirred for 12 h and then partitioned between DCM and water. The organic layer was dried over anhydrous Na2SC>4, concentrated, and purified by reverse phase prep-HPLC to afford compound B504 (36 mg) in 19% yield. ’H NMR (400 MHz, DMSO-tZs) b 10.88 (s, 1H), 10.08 (s, 1H), 8.95 (s, I D), 8.05 (br d, ~ 2.0 Hz, 1H), 7.83 (br d, J= 9.2 Hz, 1H), 7.62 (d, J= 8.4 Hz, 1H), 7.54-7.39 (m, 2H), 7.03 (br d, J= 8.4 Hz, 1H), 5.82 (quin, J= 8.8 Hz, 1H), 4.34 (br dd, ./ 5.2, 9.2 Hz, 1H), 3.96 (s, 3H), 3.64-3.49 (m, 2H), 3.42 (br dd, ./ 8.4, 14.8 Hz, 2H), 3.25-3.12 (m, 2H), 2.88-2.73 (m, 4H), 2.68-2.55 (m, 3H), 2.42 (s, 3H), 2.30 (s, 3H), 2.27-2.08 (m, 6H), 1.87 (br s, 2H), 1.76 (br d, J= 8.0 Hz, 4H), 1.57 (br d, J= 4.8 Hz, 2H), 1.37- 1.22 (m, 2H); MS (ESI) m/z: 789.6 [M+H] \
Example 171
Preparation of l-(7-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
Jj-pyrimi din-2 -yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-l-methyl-l//-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B551
Figure imgf000487_0001
[001289] Compound B551 was prepared as described below.
[001290] Preparation of l-(7-bromo-l-methylindazol-3-yl)-3-[(4-methoxyphenyl)methyl]- hexahydropyrimidine-2, 4-dione 171.1. A mixture of 7-bromo-3-iodo-l-methylindazole (5 g, 14.8 mmol), 3-[(4-methoxyphenyl)ethyl]hexahydropyrimidine-2, 4-dione (3.48 g, 14.8 mmol), Cui (565 mg, 2.97 mmol), E-proline (342 mg, 2.97 mmol), and K2CO3 (4.1 g, 29.7 mmol) in DMF (50 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SO4, concentrated, and purified by column chromatography (SiO?., EtOAc) to afford compound 171.1 (1.83 g) in 28% yield. MS (ESI) m/z\ 443 [M+H]+.
[001291] Preparation of 1 -[7-[4-(2,2-dimethoxyethyl)-l -piperidyl]- 1 -methyl -indazol-3-yl]-
3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione 171.2. A mixture of compound
171.1 (1 g, 2.26 mmol), 4-(2,2-dimethoxyethyl)piperidine (782 mg, 4.51 mmol), Pd-PEPSI-IPent (19.4 mg, 22. 6 pmol), and CS2CO3 (1.47 g, 4.51 mmol) in dioxane (10 mL) was stirred at 90 °C for 12 h under N2. The reaction mixture was then diluted with water and extracted with EtOAc.
The combined organic layers were dried over anhydrous NaiSCh, concentrated, and purified by prep-TLC (SiOi, EtOAc/PE) to afford compound 171.2 (230 mg) in 19% yield. MS (ESI) m/z'.
536.2 [M+H]+.
[001292] Preparation of 2-[l-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxohexahydro- pyrimidin-l-yl]-l-methyl-indazol-7-yl]-4-piperidyl]acetaldehyde 171.3. To a solution of compound 171.2 (180 mg, 336 pmol) in DCM (2 mL) was added TFA (3.07 g, 26.9 mmol).
After stirring for 2 h, the reaction mixture was neutralized with NaHCOs, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford compound 171.3 (160 mg), which was used directly in the next step without further purification. MS (ESI) m/z: 490.3 [M+Hp.
[001293] Preparation of 1 -[7-[4-[2-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido- [2,3-</]pyrimidin-2-yl)amino]-3-pyridyl]piperazin-l-yl]ethyl]-l-piperidyl]-l-methyl-indazol-3- yl]-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione 171.4. To a solution of compound 171.3 (160 mg, 327 pmol) and 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl- 2-pyridyl)amino]pyrido[2,3-J]pyrimidin-7-one (146 mg, 327 pmol) in THF (2 mL) and DMSO (2 mL) were added NaBH(OAc)3 (208 mg, 980 ,46mol) and NaOAc (80 mg, 980 ,46mol). After stirring for 16 h, the reaction mixture was concentrated and purified by prep-TLC (SiCh, MeOH/DCM) to afford compound 171.4 (75 mg) in 37% yield. MS (ESI) m/z: 921.5 [M+Hp.
[001294] Preparation of l-(7-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3 -tf|-pyrimidin-2-yl)ammo)pyridin-3 -yl)piperazin- 1 -y l)ethy l)piperi din- 1 -y 1 )- 1 - methyl- 17f-indazoI-3-yl)dihydropyrimidine-2, 4(1 H.3//)-dione B551. To a solution of compound 171.4 (75 mg, 81.4 pmol) in DCM (2 mL) were added TfOH (61 mg, 407 iimol) and TFA (93 mg, 814. pmol). After stirring at 40 °C for 12 h, the reaction mixture was concentrated and purified by reverse phase prep-HPLC to afford compound B551 (30 mg) in 45% yield. ^NMR (400 MHz, CD3OD) d 8.94 (s, 1H), 8.13-8.04 (m, 2H), 7.59 (dd, J= 2.4, 9.2 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.14-7.01 (m, 2H), 5.97 (quin, J= 8.8 Hz, 1H), 4.33 (s, 3H), 4.00 (t, 6.8 Hz,
2H), 3.45 (s, 8H), 3.35 (s, 1H), 3.28-3.18 (m, 3H), 2.88 (t, J= 6.8 Hz, 2H), 2.80 (d, J= 8.0 Hz, 2H), 2.49 (s, 3H), 2.39 (s, 3H), 2.35-2.27 (m, 2H), 2.07-1.99 (m, 2H), 1.97-1.87 (m, 4H), 1.84 (d, 7= 6.0 Hz, 2H), 1.72-1.66 (m, 2H), 1.63 (s, 3H); MS (ESI) m/z: 801.3 [M+H]+.
Example 172
Preparation of 3-(4-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- ^pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethyl)amino)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B602
Figure imgf000488_0001
[001295] Compound B602 was prepared as described below.
[001296] Preparation of tert-butyl 2-[[2-(2,6-dioxo-3-piperidyl)-l -oxo-isoindolin-4-yl]- amino]acetate 172.1. To a solution of 3-(4-amino-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (600 mg, 2.31 mmol) and tert-butyl 2 -bromoacetate (542 mg, 2.78 mmol) in NMP (10 mL) was added DIEA (897 mg, 6.94 mmol). After stirring at 110 °C for 12 h, the reaction mixture was diluted with NMP (1 mL) and purified by reverse phase prep-HPLC to afford compound 172.1 (200 mg) in 22% yield. lH NMR (400 MHz, DMSO-A) S 11.01 (s, 1H), 7.28 (t, J= 7.6 Hz, 1H), 6.98 (d, 7= 7.2 Hz, 1H), 6.63 (d, 7= 8.0 Hz, 1H), 6.13-5.88 (m, 1H), 5.12 (dd, 7 = 5.2, 13.2 Hz, IH), 4.29-4.11 (m, 2H), 3.89 (s, 2H), 2.99-2.86 (m, 1H), 2.62 (d, J= 16.8 Hz, 1H), 2.32 (q, J = 4.4, 13.2 Hz, IH), 2.09-1.98 (m, IH), 1.41 (s, 9H).
[001297] Preparation of 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetic acid 172.2, To a solution of compound 172.1 (100 mg, 268 pmol) in DCM (6 mL) was added TFA (4.62 g, 41 mmol). The reaction mixture was stirred at 20 °C for 2 h and then concentrated to afford compound 172.2 (80 mg), which was used directly in the next step without further purification. MS (ESI) wz/z: 318.2 [M+H]+.
[001298] Preparation of 3-[4-[[2-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-pyrido[2,3- 7]pyrimidin-2-yl)amino]-3-pyridyl]piperazin-l-yl]-2-oxo-ethyl]amino]-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione B602. To a solution of compound 172.2 (50 mg, 158 pmol) and 6- acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrido[2,3-7]pyrimidin-7- one (78 mg, 173 pmol) in DMF (1 mL) were added NMM (35 mg, 347 pmol), EDO (33 mg, 173 pmol), and HOAt (24 mg, 173 pmol). The reaction mixture was stirred for 2 h, and then diluted with DMF (1 mL) and purified by reverse phase prep-HPLC to afford compound B602 (22 mg) in 18% yield. *H NMR (400 MHz, DMSO-^) 3 11.00 (s, IH), 10.14 (s, IH), 8.96 (s, IH), 8.10 (d, 7= 2.8 Hz, I I I ), 7.89 (d. .7 9.2 Hz, IH), 7.53 (dd, 7 3.2, 9.2 Hz, IH), 7.30 (t, 7 7.6 Hz, IH), 6.99 (d, 7= 7.2 Hz, IH), 6.80 (d, J= 8.0 Hz, IH), 5.83 (t, J= 8.8 Hz, IH), 5.62 (t, J = 5.6 Hz, IH), 5.12 (dd, 7= 5.2, 13.2 Hz, IH), 4.36-4.28 (m, IH), 4.23-4.08 (m, 3H), 3.69 (d, 7 = 16.0 Hz, 4H), 3.24 (s, 2H), 3.16 (s, 2H), 2.99-2.88 (m, 2H), 2.64-2.60 (m, IH), 2.42 (s, 3H), 2.31 (s, 3H), 2.28-2.22 (m, 2H), 2.08-2.00 (m, IH), 1.90 (d, J= 7.2 Hz, 2H), 1.78 (dd, J= 4.4, 5.6 Hz, 2H), 1.62-1.54 (m, 2H); MS (ESI) m/z\ 747.5 [M+H]+. [001299] The following compounds were prepared similarly according to the synthetic procedures or methodologies exemplified herein.
[001300] 7-Cyclopentyl-2-((4-((2-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A,JV-dimethyl-72/-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A101. ]H NMR (400 MHz, DMSO-r/c) <5 10.82 (s, 1H), 9.82 (s, 1H), 8.80 (s, 1H), 8.24 (!. ./ 5.6 Hz, 1H), 7.91 (d, J = 9.2 Hz, 2H), 7.79 (d, ./ 8.8 Hz, 2H), 7.23 (t, ./ 8.4 Hz, 1H), 6.82-6.79 (m, 3H), 6.62 (s, 1H), 4.78 (s, 2H), 4.74 (d, J= 8.8 Hz, 1H), 3.82 (dd, J= 4.8 Hz, 11.6 Hz, 1H), 3.47 (t, J = 4.0 Hz, 4H), 3.42-3.39 (m, 4H), 3.06 (s, 7H), 2.68-2.61 (m, 1H), 2.52- 2.50 (m, 1H), 2.46-2.45 (m, 2H), 2.45-2.42 (m, 2H), 2.21 -2.17 (m, 1H), 2.05-2.01 (m, 5H), 1.71- 1.68 (m, 2H); MS (ESI) m/z: 750.5 [M+H] .
Figure imgf000490_0001
[001301] 7-Cyclopentyl-2-((4-((4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-7V,Az-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide Al 02.
Figure imgf000490_0002
[001302] 7-Cyclopentyl-2-((4-((6-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-jV,Az-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A103.
Figure imgf000490_0003
[001303] 7-Cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-4-methylphenoxy)- acetamido)ethyl)piperazin-l-yl)phenyl)amino)-/¥,A-dimethyl-7Z/-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A109.
Figure imgf000491_0001
NMR (400 MHz, DMSO-flfc) 3 10.82 (s, 1H), 9.22 (s, 1H), 8.68 (s, 1H), 8.17 (s, 1H), 7.93 (t, J= 5.6 Hz, 1H), 7.65 (d, J= 9.2 Hz, 2H), 7.09 (d, J= 8.0 Hz, 1H), 6.87 (d, J= 9.2 Hz, 2H), 6.79-6.73 (m, 2H), 6.55 (s, 1H), 4.76-4.64 (m, 1H), 4.42 (s, 2H), 3.98 (dd, J = 4.8, 11.6 Hz, 1H), 3.32-3.25 (m, 3H), 3 08-2.98 (in, 10H), 2.74-2.67 (m, 1H), 2 52 (s, 4H), 2.44 (t, J = 6.8 Hz, 3H), 2.17 (s, 3H), 2.14 (d, J= 4.0 Hz, 1H), 1.99-1.90 (m, 5H), 1.68-1.57 (m, 2H); MS (ESI) rn/z: 736.6
Figure imgf000491_0002
Figure imgf000491_0003
[001304] 7-Cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-4-(trifluoromethyl)- phenoxy)acetamido)ethyl)piperazin-l-yl)phenyl)amino)-<ALdimethyl-7//-pyrrolo[2,3-J|- pyrimidine-6-carboxamide AHO !H NMR (400 MHz, CHCh) 3 7.48-7.42 (m, 2H), 7.41 -7.36 (m, 2H), 7.36-7.30 (m, 7H), 7.30-7.26 (m, 4H), 7.25-7.19 (m, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.83-6.77 (m, 1H), 6.73 (d, J= 2.8 Hz, 1H), 6.44 (d, J= 8.0 Hz, 1H), 5.37 (d, 5.4 Hz, 4H),
5.22 (s, 2H), 4.63 (s, 2H), 2.08 (s, 3H); MS (ESI) m/z: 790.3 [M+H] \
Figure imgf000491_0004
[001305] 7-Cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)-4-methylphenoxy)- acetamido)propyl)piperazin-l-yl)phenyl)amino)-A/,A7-dimethyl-7/7-pyrrolo[2,3-fcf]pyrimidine-6- carboxamide A112 rH NMR (400 MHz, DMSCWG) b 10.83 (s, 1H), 9.22 (s, 1H), 8.68 (s, 1H), 8.17 (s, 1H), 8.10 (t, ./ 5.6 Hz, 1H), 7.64 (d, J= 8.8 Hz, 2H), 7.07 (d, ./ 8.0 Hz, 1H), 6.86 (d, J= 8.8 Hz, 2H), 6.71-6.76 (m, 2H), 6.55 (s, 1H), 4.82-4.62 (m, 1H), 4.40 (s, 2H), 4.06-3.89 (m, 1H), 3.23-3.15 (m, 4H), 3.05 (s, 11H), 2.79-2.65 (m, 2H), 2.57-2,55 (m, 2H), 2.33 (t, J= 6.4 Hz, 3H), 2.17 (s, 3H), 2.16-2.08 (m, 1H), 1.99-1.89 (m, 5H), 1.63 (t, .7= 6.4 Hz, 4H); MS (ESI) m/z'. 750.5 [M+H]+.
Figure imgf000492_0001
[001306] 7-Cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)-4-(trifluoromethyl)- phenoxy)acetamido)propyl)piperazin-l-yl)phenyl)amiiio)-Ar,A7-dimethyl-7J7-pyrrolo[2,3- ^pyrimidine-6-carboxamide A113
Figure imgf000492_0002
NMR (400 MHz, DMSO-de) 3 10.93 (s, 1H), 9.22 (s, 1H), 8.68 (s, 1H), 8.22-8.13 (m, 2H), 7.68-7.59 (m, 3H), 7.06 (s, 1H), 7.01 (dd, J= 2A, 8.8 Hz, 1H), 6.87 (d, J- 9.2 Hz, 2H), 6.55 (s, 1H), 4.71 (q, J- 8.8 Hz, 1H), 4.61-4.49 (m, 2H), 4.05 (dd, , 7= 4.8, 12.4 Hz, 1H), 3.23-3.15 (m, 4H), 3.05 (s, 10H), 2.91-2.74 (m, 1H), 2.53-2.56 (m, 1H), 2.46-2.38 (rn, 3H), 2.37-2.30 (m, 3H), 2.29-2.21 (m, 1H), 1.90-1.98 (m, 5H), 1.68-1.59 (m, 4H); MS (ESI) m/z: 804.2 [M+H] \
Figure imgf000492_0003
[001307] 7-Cyclopentyl-2-((4-((2-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A’,Ar-dimethyl-7H-pyrrolo[2,3-iZ]pyrimidine-6- carboxamide Al 14.
Figure imgf000492_0004
[001308] 7-Cyclopentyl-2-((4-((4-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-/V,A/-dimethyl-7JH-pyrrolo[2,3-J]pyrimidine-6- carboxamide Al 15.
Figure imgf000493_0001
[001309] 7-Cyclopentyl-2-((4-((6-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-A(AMimethyl-7H-pynolo[2,3-d]pyrimidine-6- carboxamide Al 16.
Figure imgf000493_0002
[001310] 7-Cyclopentyl-2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)-piperazin-l-yl)- phenyl)amino)-A(A-dimethyl-7/7-pyrrolo[2,3- J|pyrimidine-6-carboxamide Al 18. lH NMR (400
MHz, DMSO<A) 8 10.83 (s, 1H), 9.21 (s, 1H), 8.68 (s, 1H), 7.64 (d, J= 9.2 Hz, 2H), 7.30 (d, J =
8.0 Hz, 2H), 7.19 (d, ,/= 8.0 Hz, 2H), 6.87 (d, ./= 9.2 Hz, 2H), 6.54 (s, 1H), 4.78-4.63 (m, 1H),
3.85 (dd, J= 4.8, 11.2 Hz, 1H), 3.51 (s, 2H), 3.30-3.27 (m, 1H), 3.14-2.97 (m, 10H), 2.68-2.61
(m, 1H), 2.54-2.52 (m, 3H), 2.48-2.39 (m, 3H), 2.24-2.13 (m, 1H), 2.09-2.01 (m, 1H), 2.00-1.89
(m, 4H), 1.68-1.56 (m, 2H); MS (ESI) m/z: 635 [M+H]+.
Figure imgf000493_0003
[001311] 7-Cyclopentyl-2-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- phenyl)amino)-A(A-dimethyl-7/f-pyrrolo[2,3-</|pyrimidine-6-carboxamide A120. lH NMR (400 MHz, CDaOD) 3 8.61 (s, 1H), 8.46 (s, 1H), 7.62 (d, J = 9.2 Hz, 2H), 7.35-7.29 (m, 1H), 7.24- 7.11 (m, 3H), 6.99 (d, J = 9.2 Hz, 2H), 6.55 (s, 1H), 4.75-4.67 (m, 1H), 3.93-3.80 (m, 1H), 3.25
(d, J= 4.8 Hz, 4H), 3.15 (s, 6H), 2.99 (s, 4H), 2.94 (s, 4H), 2.77-2.62 (m, 2H), 2.59-2.48 (m, 2H), 2.32-2.17 (m, 2H), 2.08-1.96 (m, 4H), 1.76-1.59 (m, 2H); MS (ESI) m/z: 649.5 [M+H]+.
Figure imgf000494_0001
[001312] 7-Cyclopentyl-2-((4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)ethyl)piperazin-l- yl)phenyl)amino)-A7,A’-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6-carboxaniide A121. ^H NMR (400 MHz, DMSO-Je) 3 10.83 (s, 1H), 9.23 (s, 1H), 8.68 (s, 1H), 8.21 (s, 1H), 7.65 (d, J= 9.2
Hz, 2H), 7.24 (t, J= 8.0 Hz, 1H), 6.92-6.81 (m, 4H), 6.79 (d, J= 7.6 Hz, 1H), 6.54 (s, 1H), 4.71
(q, J= 8.8 Hz, 1H), 4.10 (t, J= 5.6 Hz, 2H), 3.88-3.76 (m, 1H), 3.06 (d, J= 3.6 Hz, 9H), 2.75 (t,
J= 5.6 Hz, 2H), 2.70-2.60 (m, 6H), 2.48-2.38 (m, 3H), 2.28-2.16 (m, 1H), 2.08-2.00 (m, 1H),
1.95 (s, 4H), 1.68-1.55 (m, 2H); MS (ESI) m/z: 665.6 [M+H]\
Figure imgf000494_0002
[001313] 7-Cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)phenyl)amino)-A',A;-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A123. ^I NMR (400 MHz, DMSO-tfc) <5 10.79 (s, 1H), 9.42 (s, 1H), 8.72 (s, 1H), 8.15 (s, 2H), 7.74 (d, J= 8.8 Hz, 2H), 7.21-7.12 (m, 3H), 6.86-6.78 (m, 2H), 6.62 (d, J= 7.6 Hz, 1H), 6.57 (s, 1H), 4.76- 4.68 (m, 1H), 3,76 (d, J= 6.4 Hz, 1H), 3.19-3.12 (m, 4H), 3.05 (s, 6H), 2.83-2.69 (m, 3H), 2,67- 2.56 (m, 7H), 2.49-2.39 (m, 2H), 2.30-2.14 (m, 1H), 2.10-1.88 (m, 5H), 1.81-1.52 (m, 2H); MS (ESI) m/z: 649.5 [M+H]t
Figure imgf000494_0003
[001314] 7-Cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethoxy)phenyl)amino)-V,A'-dimethyl-7J7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A124.
Figure imgf000495_0001
[001315] 7-Cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethoxy)phenyl)amino)-A'T,7V-dimethyl-72/-pyrrolo[2,3-J]pyrimidine-6-carboxaniide A125. rH NMR (400 MHz, CD3OD) <5 8.61 (s, 1H), 7.61 (d, ./= 9.2 Hz, 2H), 7.23 (t, J= 8.0 Hz, 1H), 6.95- 6.90 (m, 3H), 6.87 (s, 1H), 6.73 (d, J= 7.6 Hz, 1H), 6.55 (s, 1H), 4.74-4.64 (m, 1H), 4.18 (t, J = 5.6 Hz, 2H), 3.82 (dd, J- 5.6, 10.0 Hz, 1 H), 3.26-3.22 (m, 4H), 3.15 (s, 6H), 2.88 (t, J- 5.6 Hz, 2H), 2.82-2.76 (m, 4H), 2.74-2.61 (m, 2H), 2.59-2.50 (m, 2H), 2.29-2.16 (m, 2H), 2.05-1.97 (m, 4H), 1.72-1.61 (m, 2H); MS (ESI) m/z: 665.6 [M+H]+
Figure imgf000495_0002
[001316] 7-Cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- ethyl)phenyl)amino)-A',A;-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A129. Hl NMR (400 MHz, DMSO-flfc) d 10.83 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 7.71 (d, J= 8.4 Hz, 2H), 7.32-7.25 (m, 1H), 7.19 (d, J= 7.6 Hz, 1H), 7.15-7.08 (m, 4H), 6.57 (s, 1H), 4.72 (t, J = 8.8 Hz, 1H), 3.85 (dd, J= 5.2, 1 1.2 Hz, 1H), 3.44 (s, 2H), 3.05 (s, 6H), 2.69-2.59 (m, 4H), 2.49-2.42 (m, 7H), 2.41-2.31 (m, 4H), 2.21-2.13 (m, 1H), 2.10-2.00 (m, 2H), 1.97 (s, 4H), 1.64 (d, J = 5.6 Hz, 2H); MS (ESI) m/z\ 663.2 [M+H] 7
Figure imgf000495_0003
[001317] 7-Cyclopentyl-2-((4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethyl)phenyl)amino)-A',J'V-dimethyl-7H-pyrrolo[2,3-6?]pyrimidine-6-carboxamide A136. ’H NMR (400 MHz, DMSO-Je) 5 10.76 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 8.28 (s, 1H), 7.72 (d, 8.4 Hz, 2H), 7.13 (d, J- 8.4 Hz, 2H), 7.04 (d, 8.8 Hz, 2H), 6.88 (d, ./- 8.8 Hz,
2H), 6.57 (s, 1H), 4.83-4.63 (m, 1H), 3.72 (dd, J= 4.8, 11.2 Hz, 1H), 3.12-3.02 (m, 11H), 3.01-
2.97 (m, 2H), 2.72-2.64 (m, 4H), 2.62 (d, ./= 4.4 Hz, 6H), 2.22-2.10 (m, 2H), 2.05-1.87 (m, 8H),
1.81-1.73 (m, 2H), 1.71-1.61 (m, 2H), 1.48-1.37 (m, 2H); MS (ESI) m/z: 732.5 [M+H] \
Figure imgf000496_0001
[001318] 7-Cyclopentyl-2-((4-(2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethyl)phenyl)amino)-/V,A/-dimethyl-7J7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A137. }H NMR (400 MHz, DMSO-de) 3 10.78 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.19-7.09 (m, 3H), 6.84-6.77 (m, 2H), 6.63-6.55 (m, 2H), 4.72 (quin, ./ 8.8 Hz, 1H), 3.75 (dd, J= 4.8, 11.2 Hz, 1H), 3.10 (s, 4H), 3.05 (s, 6H), 2.98 (d, J= 11.2 Hz, 2H), 2.70- 2.64 (m, 3H), 2.61 (s, 4H), 2.48-2.41 (m, 4H), 2.24-2.14 (m, 2H), 2.03-1.90 (m, 8H), 1.81-1.73 (m, 2H), 1.69-1.62 (m, 2H), 1.48-1.36 (m, 2H); MS (ESI) m/z: 732.4 [M+H]+.
Figure imgf000496_0002
[001319] 7-Cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phen-ethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,i¥-diniethyl-77f-pyrrolo[2,3-c/]pyrimidine-6- carboxamide A146. rH NMR (400 MHz, DMSO-d6 ) d 10.84 (s, 1H), 9.34 (s, 1H), 8.77 (s, 1H), 8.18 (d, J= 9.2 Hz, 1 H), 8.14 (s, 1H), 8.07 (d, J= 2.8 Hz, 1H), 7.55-7.47 (m, 1H), 7.28-7.24 (m, 2H), 7.20 (d, J= 7.2 Hz, 2H), 7.12 (t, J= 8.0 Hz, 1H), 6.63-6.58 (m, 2H), 6.55-6.47 (m, 2H), 4.75 (t, 8.8 Hz, 1H), 3.91-3.80 (m, 2H), 3.29 (d, ./= 8.8 Hz, 10H), 3.06 (s, 8H), 2.73-2.63 (m,
2H), 2.53-2.52 (m, 2H), 2.49-2.39 (m, 6H), 2.23-2.14 (m, 1H), 2.08-1.93 (m, 6H), 1.70-1.61 (m, 2H); MS (ESI) m/z: 810.3 [M+H]+.
Figure imgf000497_0001
[001320] 7-Cyclopentyl-2-((5-(4-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phen-ethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A'’-dimethyl-7/f-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A147.
Figure imgf000497_0002
NMR (400 MHz, DMSO-t/d) d 10.83 (s, 1H), 9.30 (s, 1H), 8.76 (s, 1H), 8.17 (d, J= 9.2 Hz, 1H), 8.13 (s, 0.27H), 8.06 (d, J= 2.8 Hz, 1H), 7.50 (dd, J= 2.8, 8.8 Hz, 1H), 7.31-7.25 (m, 1H), 7.18 (d, J= 7.6 Hz, 1H), 7.15-7.04 (m, 3H), 6.60 (s, 1H), 6.56 (s, 1H), 6.52- 6.43 (m, 2H), 4.79-4.68 (m, 1H), 3.83 (dd, .7= 4.8, 11.2 Hz, 1H), 3.29-3.21 (m, 10H), 3.06 (s, 8H), 2.94-2.77 (m, 4H), 2.75-2.58 (m, 4H), 2.49-2.37 (m, 4H), 2.24-2.14 (m, 1H), 2.09-2.04 (m, 1H), 2.02-1.93 (m, 4H), 1.72-1.57 (m, 2H); MS (ESI) m/z: 810.6 [M+H]+.
Figure imgf000497_0003
[001321] 7-Cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l - yl)phenyl)piperazin-l -yl)pyridin-2-yl)amino)-yV,Az-dimethyl-7H-pyrro]o[2,3-^pyrimidine-6- carboxamide A149. ]H NMR (400 MHz, DMSO-tfc) 3 10.82 (s, 1H), 9.28 (s, 1H), 8.75 (s, 1H), 8.17 (d, ../ ■■■ 9.2 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J = 2.34 Hz, 1H), 7.50 (dd, ../ ■■■ 2.4, 9.6 Hz, 1H), 7.25-7.18 (m, 2H), 7.14 (d, J= 8.0 Hz, 2H), 6.96-6.85 (m, 4H), 6.60 (s, 1H), 4.85-4.61 (m, 1H), 3.81 (dd, J= 4.8, 11.2 Hz, 1H), 3.18 (d, J= 1.6 Hz, 6H), 3.05 - 3.03 (m, 8H), 2.77 (d, J= 7.6 Hz, 3H), 2.71-2.61 (m, 8H), 2.49-2.48 (m, 6H), 2.06-1.94 (m, 5H), 1.73-1.56 (m, 2H); MS (ESI) m/z: 810.2 [M+H]+.
Figure imgf000497_0004
[001322] 7-Cyclopentyl-2-((5-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-71EApyrrolo[2,3-t(|pyrimidine-6- carboxamide A150.
Figure imgf000498_0001
NMR (400 MHz, DMSO-de) <5 10.82 (s, 1H), 9.30 (s, 1H), 8.76 (s, 1H), 8.19-8.14 (m, 1H), 8.05 (d, J= 2.4 Hz, 1H), 7.53-7.45 (m, 1H), 7.28-7.21 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7. 10 (s, 1H), 7.04 (d, ./ === 7.6 Hz, 1H), 6.90 (q, ./ 9.2 Hz, 4H), 6.60 (s, 1H), 4.73 (t, J= 8.8 Hz, 1H), 3.82 (dd, J = 4.8, 11.2 Hz, 1H), 3.27 (d, J = 4.4 Hz, 3H), 3.20-3.17 (m, 6H), 3.04-3.02 (m, 8H), 2.80-2.73 (m, 2H), 2.70-2.64 (m, 1H), 2.62-2.55 (m, 6H), 2.46-4.39 (s, 41 h, 2.25-2.13 (m, 1H), 2.07-1.93 (m, 5H), 1.73-1.55 (m, 2H); MS (ESI) m/z: 810.2 [M+Hf.
Figure imgf000498_0002
[001323] 7-Cyclopentyl-2-((5-(4-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-AT,ALdimethyl-7//-pyrrolo[2,3-</|pyrimidine- 6-carboxamide A152 ^NMR (400 MHz, DMSO-tA) 5 10.78 (s, 1H), 9.30 (s, 1H), 8.75 (s, 1H), 8.35 (s, 1H), 8.17 (d, J= 9.2 Hz, 1H), 8.06 (d, J= 2.8 Hz, 1H), 7.55-7.46 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.14 (t, J= 8.0 Hz, 1H), 6.98 (d, J= 8.8 Hz, 2H), 6.84-6.74 (m, 2H), 6.64-6.57 (m, 2H), 4.87-4.57 (m, 1H), 3.74 (dd, ./= 4.8, 1 1.2 Hz, 2H), 3.42 (s, 4H), 3.28 (d, J= 2.0 Hz, 8H), 3.13-3.09 (m, 4H), 3.08-3.03 (m, 6H), 2.70-2.55 (m, 2H), 2.44 (d, J= 3.6 Hz, 2H), 2.23- 2.11 (m, 1H), 2.06-1.89 (m, 6H), 1.70-1.58 (m, 2H); MS (ESI) m/z: 796.4 [M+H]+.
Figure imgf000498_0003
[001324] 7-Cyclopentyl-2-((5-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- benzyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A'r-dimethyl-7H-pyrrolo[2,3-J]pyrimidine-6- carboxamide A153. rH NMR (400 MHz, DMSO-fifc) d 10.80 (s, 1H), 9.25 (s, 1H), 8.74 (s, 1H), 8.20 (s, 1H), 8.13 (d, ./= 9.2 Hz, 1H), 7.97 (d, J= 2.8 Hz, 1H), 7.41 (dd, 2.8, 9.2 Hz, 1H),
7.25-7.16 (m, 3H), 6.97 (d, J= 8.8 Hz, 2H), 6.92-6.86 (m, 2H), 6.66 (d, J = 7.2 Hz, 1H), 6.59 (s, 1H), 4.73 (quin, 8.8 Hz, 1H), 3.79 (dd, 4.8, 11.2 Hz, 1H), 3.44 (s, 2H), 3.27 (s, 12H),
3.11 (s, 4H), 3.05 (s, 6H), 2.70-2.59 (m, 2H), 2.46-2.39 (m, 2H), 2.27-2.15 (m, 1H), 2.04 (dd, J=
4.4, 9.2 Hz, 1H), 2.02-1.93 (m, 4H), 1.71-1.55 (m, 2H); MS (ESI) m/z: 796.5 [M+H]~.
Figure imgf000499_0001
[001325] 7-Cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)6methyl)piperidin-4-yl)piperazin- 1 -yl)pyri din-2 -yl)amino)-A’,Ar-dimethyl-7/Apyrrolo[2, 3 -d|- pyrimidine-6-carboxamide A158. !H NMR (400 MHz, DMSO-ds) 6 10.76 (s, 1H), 9.24 (s, 1H), 8.74 (s, 1H), 8.13 (d, J= 9.2 Hz, 1H), 7.98 (d, J= 2.8 Hz, 1H), 7.41 (dd, J= 2.8, 9.2 Hz, 1H), 7.03 (d, J= 8.8 Hz, 2H), 6.88 (d, J= 8.8 Hz, 2H), 6.59 (s, 1H), 4.83-4.64 (m, 1H), 3.71 (dd, J= 5.2, 10.9 Hz, 1H), 3.65 (d, J= 12.8 Hz, 2H), 3.13-3.08 (m, 4H), 3.07-2.99 (m, 6H), 2.94-2.84 (m, 2H), 2.71-2.56 (m, 8H), 2.44-2.38 (m, 2H), 2.17-2.09 (m, 3H), 2.05-1.91 (m, 6H), 1.90-1.81 (m, 2H), 1.81-1.73 (m, 4H), 1.68-1.59 (m, 3H), 1.50-1.38 (m, 2H), 1.25-1.15 (m, 2H); MS (ESI) «z/z: 802.5 [M+H]+.
Figure imgf000499_0002
[001326] 7-Cyclopentyl-2-((5-(4-(l-(((25)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- morpholin-2-yl)methyl)piperidin-4-yl)piperazin-l-y!)pyridin-2-yl)amino)-A',A7-dimethyl-7Ar- pyrrolo[2,3-d]pyrimidine-6-carboxamide A164.
Figure imgf000499_0003
(400 MHz, CD3OD) 9’ 1.67-1.94 (m, 4H), 2.02-2.14 (m, 5H), 2.15-2.22 (m, 2H), 2.47-2.58 (m, 3H), 2.59-2.71 (m, 3H), 2.81-2.92 (m, 6H), 3.05 (s, 2H), 3.16 (s, 6H), 3.25 (s, 4H), 3.46-3.60 (m, 4H), 3.75-3.86 (m, 2H), 3.99-4.11 (m, 2H), 4.71-4.80 (m, 1H), 6.62 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.53 (dd, J - 8.8, 2.4 Hz, 1H), 7.98 (d, J 2.4 Hz, 1H), 8.20 (d, J 9.2 Hz, 1H), 8.46 (s, 1H), 8.74 (s, 1H); MS (ESI) m/z: 804.5 [M+H]+.
Figure imgf000500_0001
[001327] 7-Cyclopentyl-2-((5-(4-(l -(((27?)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- niorpholin-2-yl)metliyl)piperidin-4-yl)piperaziii-l-yl)pyridin-2-yl)amino)-ArjV-dimethyl-7J/- pyrrol o[2, 3 -t/]pyrimidine-6-carboxamide A165. *H NMR (400 MHz, CD3OD-J) <5 8.71 (s, 1H), 8.23 (d, J= 8.8 Hz, 1H), 7.98 (d, J= 2.8 Hz, 1H), 7.49 (dd, J= 2.8, 9.2 Hz, 1H), 7.14 (d, .7 = 8.4 Hz, 2H), 6.97 (d, J - 8.4 Hz, 2H), 6.63-6.59 (m, 1H), 4.79-4.73 (m, 1H), 4.04-3.97 (m, 1H), 3.87-3.74 (m, 3H), 3.58-3.53 (m, 1H), 3.50-3.44 (m, 1H), 3.24-3.20 (m, 4H), 3.17-3.14 (m, 6H), 3.12-3.06 (m, 1H), 2.80 (d, J= 4.4 Hz, 4H), 2.75-2.60 (m, 3H), 2.60-2 39 (m, 61 1). 2.36-2.28 (m, 1H), 2.22-2.13 (m, 4H), 2.10-2.01 (m, 4H), 1.98-1.90 (m, 2H), 1.77-1.62 (m, 4H); MS (ESI) w2: 804.3 [M+H]+.
Figure imgf000500_0002
[001328] 7-Cyclopentyl-2-((5-(4-(3-(l -(4-(2,6-dioxopiperidin-3-yl)benzyl)piperidin-4-yl)- cyclohexyl)piperazin-l-yl)pyridin"2-yl)amino)-AA,A-dimethyl-7/7-pyrrolo[2,3-dF]pyrimidiiie-6- carboxamide
Figure imgf000500_0003
1.26 (m, 5H), 1,29-1.48 (m, 4H), 1.50-1.58 (m, 2H), 1.61-1.69 (m, 4H), 1.94-2.00 (m, 6H), 2.13-2.19 (m, 1H), 2.29-2.32 (m, 1H), 2.42-2.47 (m, 3H), 2.56 (d, J = 7.6 Hz, 5H), 2.62-2.69 (m, 2H), 2.70-2.75 (m, 2H), 3.05 (s, 6H), 3.10-3.14 (m, 4H), 3.78-3.82 (m, 2H), 4.70-4.76 (m, 1H), 6.59 (s, 1H), 7.10-7.13 (m, 2H), 7.15- 7.19 (m, 2H), 7.40-7.42 (m, 1H), 7.99 (d, J = 2.8 Hz, 1H), 8.12-8.16 (m, 1H), 8.21 (s, 2H), 8.75 (s, 1H), 9.29 (s, 1H), 10.82 (s, 1H); MS (ESI) m/z: 801.7 [M+H]+.
Figure imgf000501_0001
[001329] 7-Cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- methyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A,A'r-dimethyl-7/7-pyrrolo[2,3-t7j- pyrimidine-6-carboxamide A167. 'HNMR (400 MHz, DMSO-tfo) <5 10.75 (s, 1H), 9.28 (s, 1H), 8.75 (s, HI), 8,18 (s, 2H), 8,14 (d, J = 9.2 Hz, 1H), 7,98 (d, J = 2.8 Hz, 1H), 7,42 (dd, J = 2.8,
9.2 Hz, 1H), 6.99 (d, .7= 8.4 Hz, 2H), 6.59 (s, 1H), 6.37 (d, .7= 8.4 Hz, 2H), 4.81-4.67 (m, 1H),
3.90 (t, J= 7.2 Hz, 2H), 3.69 (d, J- 5.6 Hz, 2H), 3.43-3.39 (m, 2H), 3.13-3.08 (m, 4H), 3.05 (s,
6H), 2.95-2.86 (m, 3H), 2.65-2.62 (m, 3H), 2.58 (d, 6.4 Hz, 2H), 2.47-2.37 (m, 3H), 2.29-
2.18 (m, 1H), 2.15-2.05 (m, 1H), 2.04-1.92 (m, 7H), 1.77 (dd, J= 0.8, 11.2Hz, 2H), 1.68-1.58
(m, 2H), 1.50-1.37 (m, 2H); MS (ESI) m/z: 774.5 [XI -H]
Figure imgf000501_0002
[001330] 7-Cyclopentyl-2-((5-(4-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- y!)ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A7,Ar-dimethyl-7H-pyrrolo[2,3-J|- pyrimidine-6-carboxamide A172.
Figure imgf000501_0003
3 8.99 (s, 1H), 8.14-7.94 (m, 2H), 7.45 (d, J= 9.6 Hz, 1H), 7.25 (d, .7 = 8.4 Hz, 2H), 7.14 (d, .7 = 7.6 Hz, 2H), 6.83 (s, 1H), 4.79 (s, 1H), 4.11-3.90 (m, 4H), 3.89-3.79 (m, 4H), 3.78-3.68 (m, 5H), 3.68-3.42 (m, 8H), 3.35 (s, 4H), 3.16 (d, 7.2 Hz, 6H), 2.75-2.56 (m, 4H), 2.53-2.33 (m, 4H), 2.31-2.17 (m, 2H), 2.10
(s, 4H), 1.75 (s, 2H); MS (ESI) m/z: 817.5 [M+H]+.
Figure imgf000501_0004
[001331] 7-Cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l -yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-N,N-dimethyl-7/f-pyrrolo[2,3-J]pyrimidine-6- carboxamide A177.
Figure imgf000502_0001
NMR (400 MHz, DMSO-tfc) <5 10.76 (s, 1H), 9.03 (s, 1H), 8.19-8.09 (m, 2H), 8.05 (d, J= 2.4 Hz, 1H), 7.66 (d, J= 9.2 Hz, 1H), 7.14-7.09 (m, 2H), 7.02 (d, J= 8.8 Hz, 2H), 6.84 (s, 1H), 4.82-4.71 (m, 3H), 3.79 (s, 4H), 3.76 (d, ./ 5.0 Hz, 2H), 3.51-3.26 (m, 7H), 3.03 (s, 6H), 2.73-2.56 (m, 2H), 2.49-2.38 (m, 2H), 2.30-2.23 (m, 2H), 2.19-2.03 (m, 2H), 2.02- 1.91 (m, 6H), 1.61 (d, ./ 6.0 Hz, 2H); MS (ESI) m/z: 734.4 [M+H]+.
Figure imgf000502_0002
[001332] 7-Cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A'-dimethyl-7J/-pyrrolo[2,3-dr]pyrimidine-6- carboxamide A178. !H NMR (400 MHz, DMSO-tA) <5 10.78 (s, 1H), 9.45-9.45 (m, 1H), 9.46- 9.34 (m, 1H), 8.88-8.66 (m, 1H), 8.23-8.15 (m, 1H), 8.13 (s, 1H), 8.06 (d, J= 3.2 Hz, 1H), 7.54 (dd, ./= 2.0, 9.6 Hz, 1H), 7.04 (d, ,/ = 8.8 Hz, 2H), 6.90 (d, 8.8 Hz, 2H), 6.61 (s, 1H), 4.84-
4.65 (m, 1H), 3.92-3.76 (m, 2H), 3.76 (s, 6H), 3.26-3.19 (m, 2H), 3.06 (d, J= 1.2 Hz, 6H), 3.01- 2.92 (m, 2H), 2.71-2.57 (m, 4H), 2.46-2.40 (m, 2H), 2.19-2.06 (m, 1H), 2.05-1.90 (m, 6H), 1 .84- 1.73 (m, 2H), 1.72-1.59 (m, 4H), 1.55-1.40 (m, 1H), 1.38-1.27 (m, 2H); MS (ESI) m/z: 733.4 [M+H]+.
Figure imgf000502_0003
[001333] 7-Cyclopentyl-2-((5-(4-(l-(3-(4-(2,6-dioxopiperidin-3-yl)phenoxy)propyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A'’,Ar-dimethyl-7//-pyrrolo[2,3-<f|pyrimidine-6- carboxamide Al 79.
Figure imgf000502_0004
NMR (400 MHz, DMSO-^) 6 10.82-10.77 (m, 1H), 9.25 (s, 1H), 8.75
(s, 1H), 8.16-8.11 (m, 1H), 7.98 (d, J= 2.8 Hz, 1H), 7.42 (dd, J= 2.8, 9.2 Hz, 1H), 7.14-7.11 (m, 2H), 6.89 (d, J= 8.4 Hz, 2H), 6.60 (s, 1H), 4.78-4.69 (m, 1H), 3.99 (t, J= 6.4 Hz, 2H), 3.82-3.76 (m, 1H), 3.12-3.04 (m, 10H), 2.95-2.90 (m, 2H), 2.70-2.61 (m, 6H), 2.46-2.39 (m, 6H), 2.04-1.96 (m, 5H), 1.91-1.84 (m, 4H), 1.80-1.75 (m, 2H), 1.68-1.61 (m, 2H), 1.48-1.39 (m, 2H); MS (ESI) m/z: 763.6 [M+H]+.
Figure imgf000503_0001
[001334] 7-Cyclopentyl-2-((5-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l -yl)methyl)pyridin-2-yl)amino)-A,ALdimethyl-7/7-pyrrolo[2,3-i/]pyrimidine-6- carboxamide A185. rH NMR (400 MHz, CD3OD) 3 9.01 (s, 1H), 8.49 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.19 (d, J- 8.4 Hz, 2H), 7.02 (d, J= 8.8 Hz, 2H), 6.87 (s, 1H), 4.844.77 (m, 3H), 4.25 (s, 2H), 3.81 (dd, J= 5.6, 9.6 Hz, 1H), 3.65-3.44 (m, 9H), 3.17 (d, J= 7.6 Hz, 6H), 2.96 (t, 12.8 Hz, 2H), 2.73-2.58 (m, 2H), 2.53-2.40 (m, 4H), 2.22-2.06 (m, 8H),
1.81-1.71 (m, 2H); MS (ESI) m/z: 719.3 [M+H] \
Figure imgf000503_0002
[001335] 7-Cyclopentyl-2-((5-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethyl)pyridin-2-yl)amino)-A',A-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide Al 90 rH NMR (400 MHz, DMSCWe) <5 10.77 (s, 1H), 9.46 (s, 1H), 8.79 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 2.0, 8.8 Hz, 1H), 7.04 (d, J - 8.8 Hz, 2H), 6,88 (d, J - 8.8 Hz, 2H), 6,62 (s, 1H), 4,80-4,65 (m, 1H), 3,72 (dd, J 4.8, 10.8 Hz, 1H), 3.09 (d, J = 4.4 Hz, 4H), 3.05 (s, 6H), 3.00 (s, 4H), 2.74-2.68 (m, 2H), 2.62 (s, 5H), 2.28-2.19 (m, 2H), 2.19-2.06 (m, 2H), 2.03-1.93 (m, 8H), 1.79 (d, J = 10.4 Hz, 2H), 1.66 (d, J - 4.4 Hz, 2H), 1.48-1.37 (m, 2H); MS (ESI) m/z: 733.5 [M+H]+.
Figure imgf000503_0003
[001336] 7-Cyclopentyi-2-((5-(2-(l'-(4~(2,6-dioxopiperidin~3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)ethoxy )pyri din-2 -yl)amino)4VJV-dimethyl-7#-pyrrolo[2,3^pyrimidine-6-carboxamide
A191. ^H NMR (400 MHz, DMSO-Js) d 10.77 (s, 1H), 9.42 (s, 1H), 8.77 (s, 1H), 8.20 (s, 1H),
8.18 (s, 1H), 8.02 (d, J= 2.8 Hz, 1H), 7.45 (dd, J= 3.2, 9.2 Hz, 1H), 7.02 (d, J= 8.8 Hz, 2H),
6.87 (d, ./ 8.8 Hz, 2H), 6.60 (s, 1H), 4.78-4.67 (m, 1H), 4.20-4.06 (m, 2H), 3.73-3.64 (m, 4H), 3.05 (d, J= 0.8 Hz, 6H), 2.98 (d, J= 11.6 Hz, 2H), 2.67 (t, ./ = 5.6 Hz, 2H), 2.62-2.54 (m, 2H), 2.48-2.38 (m, 4H), 2.18-2.05 (m, 1H), 2.03-1.94 (m, 6H), 1.80-1.59 (m, 6H), 1.30-1.05 (m, 6H);
MS (ESI) m/z: 748.6 [M+H]t
Figure imgf000504_0001
[001337] 7-Cyclopentyl-2-((5-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)pyridin-2-yl)amino)-A(A-dimethyl-7H-pyrrolo[2,3-</]pyrimidine-6- carboxamide A193. rH NMR (400 MHz, DMSO-tfc) 3 10.78 (s, 1H), 9.44 (s, 1H), 8.78 (s, 1H), 8.22 (s, 1H), 8.20 (s, 2H), 8.04 (d, J= 2.8 Hz, 1H), 7.47 (dd, J= 2.8, 9.2 Hz, 1H), 7.04 (d, J= 8.4 Hz, 2H), 6.87 (d, J= 8.4 Hz, 2H), 6.61 (s, 1H), 4.80-4.66 (m, 1H), 4.15 (t, J= 4.8 Hz, 2H), 3.73 (d, ./ 6.4 Hz, 2H), 3.11-3.00 (m, 12H), 2.77-2.69 (m, 2H), 2.63 (s, 4H), 2.45 d, ./ 3.6 Hz, 3H), 2.29-2.19 (m, 1H), 2.16-2.05 (m, 3H), 2.03-1.94 (m, 5H), 1.83-1.73 (m, 2H), 1.71-1.59 (m, 2H), 1.52-1.37 (m, 2H); MS (ESI) m/z: 749.5 [M+H]+
Figure imgf000504_0002
[001338] 7-Cyclopentyl-2-((5-(4-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-
4-yl)piperazin-l-yl)pyridin-2-yl)amino)-/V,A/-dimethyl-7JH-pyn‘olo[2,3-<7]pyrimidine-6- carboxamide Al 95. rH NMR (400 MHz, DMSO-^) 6 10.77 (s, 1H), 9.24 (s, 1H), 8.74 (s, 1H), 8.17 (s, 1H), 8.15-8.09 (m, 1H), 7.97 (br d, J= 1.2 Hz, 1H), 7.45-7.37 (m, 1H), 7.03 (br d, J = 8.8 Hz, 2H), 6.88 (br d, J= 8.4 Hz, 2H), 6.59 (s, 1H), 4.73 (td, ./= 2.4, 7.6 Hz, 1H), 3.75-3.67 (m, 4H), 3.13-3.03 (m, 12H), 2.69-2.61 (m, 6H), 2.45-2.37 (m, 4H), 2.23-2.10 (m, 4H), 2.02-1.92 (m, 5H), 1.86-1.76 (m, 4H), 1.68-1.60 (m, 2H), 1.57-1.48 (m, 2H), 1.46-1.35 (m, 2H); MS (ESI) m/z: 788.5 [M+H]+.
Figure imgf000505_0001
[001339] 7-Cyclopentyl-2-((5-(4-(l-(3-(3-(2,6-dioxopiperidin-3-yl)phenoxy)propyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A,ALdimethyl-7/7-pyrrolo[2,3-£f]pyrimidine-6- arboxamide A199 !H NMR (400 MHz, DMSO-tA) d 10.82 (s, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 8.13 (d, J= 9.2 Hz, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.41 (dd, J= 2.8, 9.2 Hz, 1H), 7.23 (t, J= 8.0 Hz, 1H), 6.83 (dd, J= 1 .6, 8.0 Hz, 1H), 6.80-6.75 (m, 2H), 6.59 (s, 1H), 4.83-4.62 (m, 1H), 3.97 (t, J= 6.4 Hz, 2H), 3.82 (dd, J= 5.2, 11.2 Hz, 1H), 3.09 (d, J= 4.4 Hz, 4H), 3.05 (d, J= 0.8 Hz, 6H), 2.92 (d, J- 10.8 Hz, 2H), 2.64 (d, J= 4.8 Hz, 4H), 2.47-2.37 (m, 6H), 2.24-2.15 (m, 2H), 2.04-1.92 (m, 5H), 1.91-1.82 (m, 4H), 1.79-1.72 (m, 2H), 1.67-1.58 (m, 2H), 1.49-1.36 (m, 2H); MS (ESI) m/z: 763.4 [M+H]+.
Figure imgf000505_0002
[001340] 7-Cyclopentyl-2-((5-(2-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)ethyl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7//-pyrrolo[2,3-£(|pyrimidine-6- carboxamide A201. rH NMR (400 MHz, DMSO<A) <5 10.77 (s, 1H), 9.51 (s, 1H), 8.80 (s, 1H), 8.25 (d, J= 8.4 Hz, 1H), 8.16 (d, J= 2.0 Hz, 1H), 8.14 (s, 1H), 7.66 (dd, J= 2.0, 8.8 Hz, 1H), 7.04 (d, ./= 8.8 Hz, 2H), 6.90 (d, 8.8 Hz, 2H), 6.63 (s, 1H), 4.80-4.69 (m, 1H), 3.72 (dd, J=
5.2, 10.8 Hz, 4H), 3.06 (s, 6H), 2.74 (d, J= 5.6 Hz, 4H), 2.67-2.57 (m, 8H), 2.47-2.38 (m, 4H), 2.19-2.07 (m, 2H), 2.05-1.95 (m, 6H), 1.91 (d, ./ 11.2 Hz, 2H), 1.67 (d, ./ 5.2 Hz, 2H), 1.59- 1.49 (m, 2H); MS (ESI) m/z: 733.7 [M+H]+.
Figure imgf000506_0001
[001341] 7-Cyclopentyl-2-((5-(3-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)propyl)pyridin-2-yr)amino)-A,A-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide
A202. MS (ESI) m/z'. 746.3 [M-H] .
Figure imgf000506_0002
[001342] 7-Cyclopentyl-2-((5-(3-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)propyl)pyridin-2-yl)amino)-jVyV-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A203.
Figure imgf000506_0003
NMR (400 MHz, DMSO-de) <5 10.78 (s, 1H), 9.53 (s, 1H), 8.80 (s, 1H), 8.27 (d, J= 8.0 Hz, 1H), 8.15 (s, 3H), 7.64 (br d, J= 8.0 Hz, 1H), 7.04 (br d, J= 8.0 Hz, 2H), 6.87 (br d, J= 8.4 Hz, 2H), 6.62 (s, 1H), 4.79-4.69 (m, 1H), 3.72 (br dd, J= 4.8, 10.8 Hz, 2H), 3.21 (br d, .7 11 .2 Hz, 2H), 3.10 (br s, 4H), 3,05 (br s, 6H), 2,64 (br s, 6H), 2,59 (br d, .7 5.2 Hz, 1H), 2.57 (br s, 1H), 2.44 (br d, J= 5.2 Hz, 4H), 2.19-2.05 (m, 2H), 2.00 (br d, J= 7.2 Hz, 6H), 1.86 (br s, 4H), 1.71-1.56 (m, 4H); MS (ESI) /M/Z: 747 3 [M+H]+.
Figure imgf000506_0004
[001343] 7-Cyclopentyl-2-((5-(3-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)propyl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyrrolo[2,3-cZ]pyrimidine-6- carboxamide A204. rH NMR (400 MHz, DMSO-d6 ) d 10.78 (s, 1H), 9.54 (s, 1H), 8.81 (s, 1H), 8.26 (d, 8.4 Hz, 1H), 8.15 (s, 2H), 7.65 (dd, 1.6, 8.8 Hz, 1H), 7.04 (d, ./ = 9.2 Hz, 2H),
6.90 (d, J= 9.2 Hz, 2H), 6.63 (s, 1H), 4.81-4.72 (m, 1H), 3.73 (br dd, J= 5.2, 10.8 Hz, 4H), 3.06 (br s, 6H), 2.80 (br d, 2= 2.0 Hz, 3H), 2.76-2.54 (m, 13H), 2.46 (br dd, 2= 5.2, 12.4 Hz, 2H), 2.17-2.08 (m, 1H), 2.05-1.96 (m, 5H), 1.91 (br d, 2= 11.6 Hz, 2H), 1.86-1.76 (m, 2H), 1.66 (br d, 2= 5.6 Hz, 2H), 1.60-1.48 (m, 2H); MS (ESI) m/z: 747.3 [M+H]+.
Figure imgf000507_0001
[001345] 7-Cyclopentyl-2-((5-((3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)methyl)pyridin-2-yl)amino)-A(AMimethyl-7#-pyrrolo[2,3-2]pyrimidine-6- carboxamide A211 rH NMR (400 MHz, CD3OD) d 8.76 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 7.80 (dd, 2= 2.0, 8.8 Hz, 1H), 7.11 (d, 2= 8.4 Hz, 2H), 6.93 (d, 2= 8.4 Hz, 2H), 6.64 (s, 1H), 4.80-4.75 (m, 1H), 3.77 (t, 2= 7.6 Hz, 1H), 3.64-3.54 (m, 2H), 3.16 (s, 10H), 2.89 (d, 2 = 11.2 Hz, 1H), 2.76 (s, 4H), 2.73-2.49 (m, 6H), 2.21-2.15 (m, 2H), 2.12-1.98 (m, 7H), 1.84-1.72 (m, 3H), 1.67-1.55 (m, 1H), 1.37-1.24 (m, 1H); MS (ESI) /M/Z: 719.3 [M+H]+.
Figure imgf000508_0001
[001346] 7-Cyclopentyl-2-((5-(2-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)pyridin-2-yl)amino)-A'T,7V-dimethyl-72/-pyrrolo[2,3-(/]pyrimidine-6- carboxamide A213 rH NMR (400 MHz, CD3OD) 6 1.59-1.80 (m, 4H), 1 .90-2.10 (m, 6H), 2.13- 2.20 (m, 2H), 2.50-2.58 (m, 2H), 2.58-2.71 (m, 3H), 2.75-2.89 (m, 2H), 2.94 (d, J= 4.4 Hz, 4H), 3.16 (s, 6H), 3.22 (d, J- 44 Hz, 6H), 3.33-3.40 (m, 2H), 3.77 (t, J- 7.6 Hz, 1H), 4.34 (d, J- 2.0 Hz, 2H), 4.73-4.80 (m, 1H), 6.63 (s, 1H), 6.94 (d, J= 8.4 Hz, 2H), 7.11 (d, J= 8.4 Hz, 2H), 7.51 (dd, J- 9.2, 2.8 Hz, 1H), 8.06 (d, 2.8 Hz, 1H), 8.32 (d, J= 9.6 Hz, 1H), 8.41 (s, 1H), 8.73 (s, 1H); MS (ESI) m/z: 749.7 [M+H]+.
Figure imgf000508_0002
[001347] 7-Cyclopentyl-2-((5-(4-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)methyl)piperidiri-l-yl)pyridin-2-yl)amino)-7V,Az-dimethyl-7//-pyrrolo[2,3-</|- pyrimidine-6-carboxamide A214. {HNMR (400 MHz, DMSO-Je) d 10.78 (s, 1H), 9.41-9.24 (m, 1H), 8.76 (s, 1H), 8.13 (s, 1H), 8.11 (d, J= 9.2 Hz, 1H), 8.00 (d, J= 2.8 Hz, 1H), 7.49-7.41 (m, 1 H), 7.08 (d, J= 8.4 Hz, 2H), 6.92 (d, J= 8.4 Hz, 2H), 6.64-6.54 (m, 1H), 4.80-4.67 (m, 1H),
3.74 (dd, J = 4.8, 11.2 Hz, 1H), 3.66 (d, J = 12.0 Hz, 2H), 3.20-3.12 (m, 3H), 3.06 (s, 8H), 2.95-
2.75 (m, 5H), 2.73-2.59 (m, 6H), 2.46-2.41 (m, 4H), 2.21-1.90 (m, 10H), 1.84 (d, J = 12.8 Hz, 4H), 1.64 (d, J= 5.6 Hz, 2H), 1.41-1.27 (m, 2H); MS (ESI) m/z: 802.7 [M+H]+.
Figure imgf000508_0003
[001348] 7-Cyclopentyl-2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A/,A-dimethyl-7ZApyrrolo[2,3-</]pyrimidiiie-6- carboxamide A217.
Figure imgf000509_0001
NMR (400 MHz, DMSO-tfc) <5 10.78 (s, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 8.19 (s, 1H), 8.15 (d, J= 9.2 Hz, 1H), 7.99 (d, J= 3.2 Hz, 1H), 7.44 (br d, J= 6.0 Hz, 1H), 7.04 (br d, .7 8.4 Hz, 2H), 6.89 (br d, ./ 9.2 Hz, 2H), 6.62-6.58 (m, 1 H), 4.78-4.67 (m, 1H), 3.75- 3.64 (m, 4H), 3.13 (br d, J= 4.0 Hz, 6H), 3.05 (br d, J= 3.6 Hz, 6H), 2.70-2.59 (m, 4H), 2.26- 2.21 (m, 2H), 2.15-2.08 (m, 1H), 2.04-1.93 (m, 6H), 1.84-1 79 (m, 2H), 1.76-1.70 (m, 1H), 1.69- 1.59 (m, 3H), 1.32-1.09 (m, 3H); MS (ESI) /ra/z: 719.4 [M+H]+.
Figure imgf000509_0002
[001349] 7-Cyclopentyl-2-((5-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperidin-4-yl)pyridin-2-yl)amino)-A7,Ar-dimethyl-7//-pyrrolo[2,3-J)pyrimidine-6- carboxamide A218 !H NMR (400 MHz, DMSO-flfc) <5 10.78 (s, 1 H), 9.60 (s, 1H), 8.81 (s, 1H), 8.30 (d, J= 8.4 Hz, 1H), 8.20 (d, J= 1.2 Hz, 1H), 8.14 (s, 1H), 7.65 (br d, J= 7.6 Hz, 1H), 7.05 (d, J= 8.4 Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 6.63 (s, 1H), 4.75 (br t, J= 8.8 Hz, 1H), 3.75-3.68 (m, 3H), 3.54 (br d, J= 4.0 Hz, 2H), 3.06 (br s, 6H), 3.01-2.90 (m, 3H), 2.86-2.79 (m, 1H), 2.74- 2.58 (m, 4H), 2,45 (br d, J = 4.4 Hz, 2H), 2,19-2.06 (m, 2H), 2,05-1,94 (ra, 10H), 1 ,84 (br d, .7 12.0 Hz, 2H), 1.72-1.63 (m, 2H), 1.33 (br d, J= 9.2 Hz, 2H); MS (ESI) m/z: 718.3 [M+H]t
Figure imgf000509_0003
[001350] 7-Cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-Az rA'-dimethyl-7//-pyrrolo[2,3-£/]pyrimidine-6- carboxamide A219. !H NMR (400 MHz, DMSO-tfc) <5 10.79 (s, 1H), 9.41 (s, 1H), 8.78 (s, 1H), 8.15 (br s, 1H), 8.14 (d, J = 4.0 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.44 (dd, J= 2.8, 9.2 Hz, 1H),
7.07 (d, J= 8.8 Hz, 2H), 6.92 (br d, ./= 8.8 Hz, 2H), 6.60 (s, 1H), 4.74 (quin, J= 8.8 Hz, 1H), 3.74 (dd, J - 4.8, 11 .2 Hz, 1H), 3.64 (br d, 12.0 Hz, 2H), 3.05 (br s, 6H), 2.85 (br s, 4H),
2.72-2.53 (m, 6H), 2.48-2.38 (m, 4H), 2.19-2.08 (m, 1H), 2.07-1.90 (m, 6H), 1.90-1.70 (m, 4H), 1.68-1.61 (m, 2H), 1.31 (q, J= 10.8 Hz, 2H); MS (ESI) m/z: 719.6 [M+H]+.
Figure imgf000510_0001
[001351] 7-Cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l -yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-A7,Ar-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A220.
Figure imgf000510_0002
NMR (400 MHz, DMSO-tfc) d 10.82 (s, 1H), 9.28 (s, 1H), 8.75 (s, 1H), 8.18 (s, 1H), 8.13 (d, J= 9.2 Hz, 1H), 8.00 (d, J= 2.8 Hz, 1H), 7.42 (dd, J= 2.8, 9.2 Hz, 1H), 7.23-7.19 (rn, 2H), 7.15-7.12 (m, 2H), 6.59 (s, 1H), 4.73 (quin, ./ 8.8 Hz, 1H), 3.81 (br dd, ./ 4.8, 11.6 Hz, 1H), 3.62 (br d, J= 12.0 Hz, 2H), 3.05 (br s, 6H), 2.98 (br d, J= 11.2 Hz, 2H), 2.70-2,67 (m, 1H), 2.66-2.61 (m, 2H), 2.46-2.43 (m, 2H), 2.23 (br d, J= 7.2 Hz, 2H), 2.18-2.11 (m, 1H), 2.07-1.93 (m, 8H), 1.82 (br d, ,/= 12.4 Hz, 2H), 1 .78-1 .61 (m, 8H), 1.30-1.21 (m, 2H); MS (ESI) m/z: 718.5 [M+H]+.
Figure imgf000510_0003
[001352] 7-Cyclopentyl-2-((5-(4-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A(A7-dimethyl-7H-pyrrolo[2,3-(/]pyrimidine-6- carboxamide A221. ]H NMR (400 MHz, DMSO-de) 3 10.80 (s, 1H), 9.30 (s, 1H), 8.75 (s, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 7.99 (d, J = 3.2 Hz, 1H), 7.43 (dd, ./ ■■■ 2.8, 9.2 Hz, 1H), 7. 14 (t, ./ ■■■ 8.0 Hz, 1H), 6.85-6.77 (m, 2H), 6.61-6.55 (m, 2H), 4.73 (quin, J= 8.4 Hz, 1H), 3.75 (br dd, J= 5.2, 11 .2 Hz, 2H), 3.67 (br d, ./ 11.2 Hz, 2H), 3 13 (br s, 4H), 3.05 (br s, 6H), 2.68-2.63 (m, 2H), 2.62-2.59 (m, 1H), 2.53 (br s, 4H), 2.45 (br d, J= 4.4 Hz, 2H), 2.23 (br d, J= 6.4 Hz, 2H), 2.20- 2.13 (m, 1H), 2.04 (br d, J= 5.2 Hz, 1H), 1.98 (br s, 4H), 1.81 (br d, J= 12.4 Hz, 2H), 1.73-1.68 (m, 1H), 1.67-1.59 (m, 2H), 1.21 (q, J= 10.8 Hz, 2H); MS (ESI) m/z: 719.3 [M+H]+.
Figure imgf000511_0001
[001353] 7-Cyclopentyl-2-((5-(l-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperidin-4-yl)pyridin-2-yl)amino)-A^V-dimethyl-777-pyrrolo[2,3-6?]pyrimidine-6- carboxamide A222.
Figure imgf000511_0002
NMR (400 MHz, DMSO-fik) J 10.79 (s, 1H), 9.48 (s, 1H), 8.79 (s, 1H), 8.25 (br d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 7.67 (br d, J= 8.8 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.85-6.77 (m, 2H), 6.63-6.56 (m, 2H), 4.79-4.68 (m, 1H), 3.75 (br dd, J = 4.8, 11.2 Hz, 1H), 3.67 (br d, J= 11.6 Hz, 2H), 3.05 (br s, 6H), 2.96 (br d, J= 10.8 Hz, 2H), 2.64 (br t, J= 11.6 Hz, 3H), 2.45 (br d, 7 = 4.0 Hz, 2H), 2. 19 (br d, J 6.4 Hz, 3H), 2.06-1.92 (m, 8H), 1.84-1.62 (m, 10H), 1.25-1.15 (m, 2H); MS (ESI) m/z: 718.4 [M+H]t
Figure imgf000511_0003
[001354] 7-Cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)piperidin-l-yl)pyri din-2 -yl)amino)-A'’,A'r-dimethyl-7//-pyrrolo[2,3-7]pyrimidine-6- carboxamide A224. rH NMR (400 MHz, DMSO-TJ) d 10.82 (s, 1H), 9.27 (s, 1H), 8.75 (s, 1H), 8.18 (s, 1 H), 8.13 (d, .7= 9.2 Hz, 1H), 8.00 (d, J= 2.8 Hz, 1H), 7.42 (dd, .7= 2.8, 9.2 Hz, 1H), 7.28-7.23 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 4.73 (quin, J = 8.8 Hz, 1H), 3.82 (dd, ../ ■■■ 4.8, 11.2 Hz, 1H), 3.62 (br d, J = 12.0 Hz, 2H), 3.05 (br s, 6H), 2.97 (br d, J= 11.2 Hz, 2H), 2.70-2.66 (m, 1H), 2.65-2.61 (m, 2H), 2.47-2.39 (m, 3H), 2.23 (br d, ./ 7.2 Hz, 2H), 2.20-2.13 (m, 1H), 2.07-2.00 (m, 3H), 1.98 (br s, 4H), 1.82 (br d, ./ 12.8 Hz, 2H), 1,78-1.70 (m, 3H), 1.69-1.62 (m, 4H), 1.31-1.21 (m, 2H); MS (ESI) m/z: 718.6 [M+H]+.
Figure imgf000511_0004
[001355] 7-Cyclopentyl-2-((5-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-r- yl)methyl)pyridin-2-yl)amino)-AAV-dimethyl-72f-pyrrolo[2,3-iZ]pyrimidine-6-carboxamide
A225. ^H NMR (400 MHz, DMSO-Je) 6 10.80 (s, 1H), 9.53 (s, 1H), 8.80 (s, 1H), 8.26 (d, .7 =
8.4 Hz, 1H), 8.24-8.23 (m, 1H), 8.16 (s, 1H), 7.66 (dd, J= 1.6, 8.4 Hz, 1H), 7.22-7.16 (m, 2H), 7.15-7.09 (m, 2H), 6.62 (s, 1H), 4.75 (quin, ./ 8.8 Hz, 1H), 3.80 (dd, ./ 4.8, 11.2 Hz, 1H), 3.42 (s, 2H), 3.06 (br s, 6H), 2.95 (br d, J= 10.8 Hz, 2H), 2.87 (br d, J = 10.8 Hz, 2H), 2.68-2.60 (m, 1H), 2.47-2.38 (m, 4H), 2.25-2.10 (m, 4H), 2.04-1.90 (m, 7H), 1.71 (br s, 4H), 1.68-1.53 (m, 4H), 1.52-1.41 (m, 2H); MS (ESI) m/z: 718.4 [M+H]+.
Figure imgf000512_0001
[001356] 7-Cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-AT,A-dimethyl-7/Apyrrolo[2,3-dF]pyrimidine-6- carboxamide A226. !H NMR (400 MHz, DMSO-tA) <5 10.83 (s, 1 H), 9.45-9.30 (m, 1H), 8.76 ( s, 1H), 8.13 (s, 1H), 8.11 (s, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.49 (br d, J= 7.6 Hz, 1H), 7.29-7.12 (m, 4H), 6.61 (s, 1H), 4.74 (quin, J= 8.8 Hz, 1H), 3.83 (br dd, .7 = 4.8, 11.6 Hz, 1H), 3.61 (br d, J= 11.6 Hz, 3H), 3.30 (br s, 3H), 3.20 (br s, 3H), 3.12-3.02 (m, 8H), 2.80 (br d, J= 4.4 Hz, 2H), 2.71 (br s, 4H), 2.67-2.63 (m, 1H), 2,46-2,39 (m, 2H), 2,22-2, 14 (m, 1H), 2,06-1 ,87 (m, 9H),
1.71-1.59 (m, 2H); MS (ESI) m/z: 733.3 [M+H] \
Figure imgf000512_0002
[001357] 7-Cyclopentyl-2-((5-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-Az,A-dimethyl-7.A-pyrrolo[2,3-«7]pyrimidine-6- carboxamide A227. !H NMR (400 MHz, DMSO-tA) 8 10.82 (s, 1H), 9.47 (s, 1H), 8.79 (s, 1H), 8.25 (d, J= 8.8 Hz, 1H), 8.17 (d, J= 2.0 Hz, 1H), 7.66 (dd, J= 2.4, 8.8 Hz, 1H), 7.24-7.17 (m,
2H), 7.16-7.08 (m, 2H), 6.62 (s, 1H), 4.79-4.69 (m, 1H), 3.87-3.75 (m, 1H), 3.09-2.97 (m, 10H), 2.70-2.63 (m, 1H), 2.47 (br s, 8H), 2.20-2.12 (m, 1H), 2.10-1.89 (m, 10H), 1.76-1.57 (m, 10H);
MS (ESI) m/z: 732.5 [M+H]t
Figure imgf000513_0001
[001358] 7-Cyclopentyl-2-((5-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A228. rH NMR (400 MHz, DMSO-t/g) 3 10.77 (s, 1H), 9.47-9.44 (m, 1H), 8.79 (s, 1H), 8.24 (d, 8.4 Hz, 1 H), 8.18-8.15 (m, 1H), 7.68-7.64 (m, 1H), 7 05 (d, ./= 8.8 Hz, 2H),
6.92-6.87 (m, 2H), 6.64-6.60 (m, 1H), 4.79-4.69 (m, 1H), 3.75-3.70 (m, 1H), 3.13-3.08 (m, 4H), 3.06 (br d, ./ 0.8 Hz, 6H), 3.02-2.99 (m, 2H), 2.63-2.59 (m, 1 H), 2.58-2.53 (m, 5H), 2.47-2.39 (m, 5H), 2.16-2.04 (m, 3H), 2.03-1.95 (m, 6H), 1.79-1.70 (m, 3H), 1.70-1.62 (m, 4H); MS (ESI) m/z: 733.4 [M+H]+.
Figure imgf000513_0002
[001359] 7-Cyclopentyl-2-((5-(l-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A'T,7V-dimethyl-72/-pyrrolo[2,3-J]pyrimidine-6- carboxamide A229. ’H NMR (400 MHz, DMSO-tfc) <5 11.14-10.95 (m, 1H), 10.86 (s, 1H), 9.16- 8.97 (m, 1H), 8.32 (s, 1H), 8.20-8.16 (m, 1H), 8.14 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.70 (d, J =
9.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 6.85 (s, 1 H), 4.82-4.76 (tn, 1H), 3.97 (dd, J = 4.8, 12.0 Hz, 1H), 3.70-3.45 (m, 6H), 3.17-3.08 (m, 3H), 3.03 (s, 7H), 2.74-2.63 (m, 1H), 2.55-2.51 (m, 2H), 2.35-2.22 (m, 3H), 2.22-2.12 (m, 2H), 2.10-1.91 (m, 11H), 1.82 (s, 3H), 1.62 (d, J = 5.6 Hz, 2H); MS (ESI) m/z: 733.4 [M+H] t
Figure imgf000513_0003
[001360] 7-Cyclopentyl-2-((5-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-7V,7V-dimethyl-7//-pyrrolo[2,3-<f|pyrimidine-6- carboxamide A230. rH NMR (400 MHz, CD3OD) <5 8.70 (s, 1H), 8.23 (d, J= 9.2 Hz, 1H), 7.98 (d, J= 2.8 Hz, 1H), 7.49 (dd, J= 3.2, 9.2 Hz, 1H), 7.32-7.26 (m, 1H), 7.21-7.07 (m, 3H), 6.61 (s, 1H), 4.79-4.73 (m, 1 H), 3.98-3.66 (m, 2H), 3.64-3.42 (m, 1H), 3.25-3.21 (m, 3H), 3.15 (s, 6H), 3.11 (s, 1H), 3.01-2.86 (m, 1H), 2.77-2.71 (m, 4H), 2.70-2.61 (m, 5H), 2.61-2.49 (m, 3H), 2.31- 2.16 (m, 5H), 2.13-1.99 (m, 4H), 1.90-1.77 (m, 4H), 1.76-1.70 (m, 2H); MS (ESI) wz: 733.7 [M+H]+.
Figure imgf000514_0001
[001361] 7-Cyclopentyl-2-((5-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-77f-pyrrolo[2,3-tf]pyrimidine-6- carboxamide A232.
Figure imgf000514_0002
NMR (400 MHz, CD3OD) 6 8.75 (s, 1H), 8.38 (s, 1H), 8.15 (d, J= 9.2 Hz, 1H), 7.98 (d, 2.4 Hz, 1H), 7.57 (d, J= 9.2 Hz, 1H), 7.25 (t, 7.6 Hz, 1H), 6.96-6.85
(m, 2H), 6.78 (d, J= 7.6 Hz, 1H), 6.63 (s, 1H), 4.79-4.72 (m, 1H), 3.82 (dd, J= 5.6, 10.0 Hz, 1H), 3.34 (d, J= 4.4 Hz, 4H), 3.30-3.27 (m, 3H), 3.15 (s, 6H), 3.11-3.01 (m, 6H), 2.96 (d, 4.8
Hz, 6H), 2.75-2.61 (m, 2H), 2.58-2.45 (m, 2H), 2.28-2.16 (m, 2H), 2.14-1.99 (m, 4H), 1.73 (d, J = 5.6 Hz, 2H); MS (ESI) m/z. 734.6 [M+H]\
Figure imgf000514_0003
[001362] 7-Cyclopentyl-2-((5-(l-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperi din-4-yl)pyri din-2 -yl)amino)-A(A-dimethyl-777-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A233.
Figure imgf000514_0004
NMR (400 MHz, CD3OD) d 8.84 (s, 1H), 8.57 (s, 1H), 8.43 (d, J - 8.4 Hz, 1H), 8.27 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.93 (s, 1H), 6.81 (d, J --- 7.6 Hz, 1H), 6.70 (s, 1H), 4.84 (t, J - 8.8 Hz, 1H), 3.88 (dd, J -
5.6, 9.6 Hz, 1H), 3.72 (d, J - 12.0 Hz, 2H), 3.42-3.35 (m, 2H), 3.33-3.31 (m, 2H), 3.30-3.28 (m, 2H), 3.22 (s, 6H), 3.10 (dt, J === 3.6, 11 .6 Hz, 2H), 2.99-2.88 (m, 3H), 2.87-2.78 (m, 4H), 2.78-
2.66 (m, 2H), 2.65-2.56 (m, 2H), 2.34-2.22 (m, 2H), 2.20-2.03 (m, 8H), 1.80 (d, J = 5.6 Hz, 2H);
MS (ESI) m/z: 733.5 [M+H] \
Figure imgf000515_0001
[001363] 7-Cyclopentyl-2-((5-(l-(2-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-Az,A-dimethyl-7.H-pyrrolo[2,3-«7]pyrimidine-6- carboxamide A234. ]H NMR (400 MHz, DMSO-tA) <5 = 10.78 (s, 1H), 9.44 (s, 1H), 8.79 (s, 1H), 8.25 (d, ./ 8.4 Hz, 1H), 8.16 (s, 1H), 7 66 (dd, ./ 2.0, 8.8 Hz, 1H), 7.14 (t, ./ 8.0 Hz, 1H), 6.84-6.77 (m, 2H), 6.62-6.56 (m, 2H), 4.74 (br t, J= 8.8 Hz, 1H), 3.75 (br dd, J= 5.2, 11.0 Hz, 1H), 3.65 (br d, J= 11.2 Hz, 3H), 3.11-3.07 (m, 2H), 3.05 (br s, 6H), 2.67-2.60 (m, 3H), 2.47 (br s, 1H), 2.45 (br d, .7 = 4.4 Hz, 3H), 2.22-2.09 (m, 3H), 2.05-1.94 (m, 5H), 1.85-1.61 (m, 9H), 1.46 (br s, 3H), 1.31-1.20 (m, 2H); MS (ESI) m/z: 732.5 [M+H]+.
Figure imgf000515_0002
[001364] 7-Cyclopentyl-2-((5-(2-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)ethyl)pyridin-2-yl)amino)-A(AMimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A239 rH NMR (400 MHz, DMSO-fifc) 6 10.79 (s, 1H), 9.46 (s, 1H), 8.79 (s, 1H), 8.23 (d, J= 8.8 Hz, 1H), 8.14 (d, J= 2.0 Hz, 1H), 7.65 (m, 1H), 7.13 (t, J= 7.6 Hz, 1H), 6.80- 6.83 (m, 1H), 6.79 (s, 1H), 6.62 (s, 1H), 6.58 (d, ./ 7 6 Hz, 1H), 4.69-4 80 (m, 1H), 3.75 (m, 1H), 3.69 (d, J= 1 1.6 Hz, 2H), 3.06 (s, 6H), 2.59-2.72 (m, 6H), 2.52 (s, 3H), 2.44-2.48 (s, 8H), 2.24-2.34 (m, 2H), 2.15-2.23 (m, 1H), 2.03 (d, J= 4.8 Hz, 1H), 1.92-2.01 (m, 4H), 1.83 (d, J= 11.2 Hz, 2H), 1.61 -1.70 (m, 2H), 1.43-1.53 (m, 2H); MS (ESI) m/z: 733.5 [M+H]+.
Figure imgf000516_0001
[001365] 7-Cyclopentyl-2-((5-(2-(l'-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 4-yl)ethyl)pyridin-2-yl)amino)-A')iV-dimethyl-7//-pyrrolo[2,3-</]pyrimidine-6-carboxamide A240
Figure imgf000516_0002
10.79 (s, 1H), 9.50 (s, 1H), 8.80 (s, 1H), 8.23 (s, 1H), 8.20-8.22 (m, 1H), 8.13 (d, J= 2.0 Hz, 1H), 7.61 (m, 1H), 7.11-7.15 (m, 1H), 6.81 (d, J= 6.4 Hz, 1H), 6.62 (s, 1H), 6.59 (d, J= 7.6 Hz, 1H), 4.71-4.77 (m, 1H), 3.76 (d, J= 5.2 Hz, 1H), 3.70 (s, 2H), 3.23-3.27 (m, 1H), 3.05 (s, 6H), 2.97 (d, J= 11.2 Hz, 2H), 2.66 (d, J= 5.2 Hz, 1H), 2.61- 2.64 (m, 2H), 2.59 (d, J== 5.2 Hz, 2H), 2.56 (d, 8.0 Hz, 2H), 2.42-2.45 (m, 2H), 2.21-2.27 (m,
2H), 2.13-2.18 (m, 1H), 2.03 (d, .7= 4.8 Hz, 1H), 1.95-2.01 (m, 4H), 1.82-1.84 (s, 1H), 1.74 (d, J - 10.4 Hz, 2H), 1.67-1.71 (m, 2H), 1.48-1 .58 (m, 3H), 1.16-1.26 (m, 3H); MS (ESI)
Figure imgf000516_0003
732.5 [M+H]+.
Figure imgf000516_0004
[001366] 7-Cyclopentyl-2-((5-(2-(r-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)ethyl)pyridin-2-yl)amino)-A7,A'r-dimethyl-777-pyrrolo[2,3-J]pyrimidine-6-carboxamide A241. ^ NMR (400 MHz, DMSO-Js) J 10.79 (s, 1H), 9.46 (s, 1H), 8.79 (s, 1H), 8.24 (s, 1H), 8.21 (d, J= 3.6 Hz, 1H), 8.14 (s, 1H), 7.70-7.59 (m, 1H), 7.12 (d, 8.0 Hz, 1H), 6.78 (s, 2H),
6.64-6.55 (m, 2H), 4.84-4.66 (m, 1H), 3.80-3.64 (m, 4H), 3.05 (br s, 6H), 2.99 (br d, J= 11.2 Hz, 3H), 2.74-2.65 (m, 3H), 2.63-2.56 (m, 2H), 2.44 (br s, HI), 2.21-2.14 (m, 1H), 2.04-1.87 (m, 8H), 1.75 (br d, J= 11.6 Hz, 2H), 1.71-1.64 (m, 4H), 1.33-1.13 (m, 6H), 1.11-1.02 (m, IH); MS (ESI) m/z: 732.6 [M+H]+.
Figure imgf000516_0005
[001367] 7-Cyclopentyl-2-((5-(2-(4-(l -(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin- l-yl)ethoxy)pyridin-2-yl)amino)-Ar/»7-dimethyl-7//-pyrrolo[2, 3 -<Z]pyrimidine-6- carboxamide A243.
Figure imgf000517_0001
NMR (400 MHz, DMSO-tfc) <5 10.77 (s, 1H), 9.42 (s, 1H), 8.77 (s, 1H),
8.19 (d, J= 9.2 Hz, 1H), 8.14 (s, 1H), 8.02 (d, J= 2.8 Hz, 1H), 7.45 (dd, J= 2.8, 9.2 Hz, 1H), 7.03 (d, ./ 8.4 Hz, 2H), 6.88 (d, ./ 8.4 Hz, 2H), 6.60 (s, 1H), 4 73 (t, ./ 8.4 Hz, 1 H), 4.14 (t, J = 5.6 Hz, 2H), 3.74-3.66 (m, 3H), 3.05 (s, 6H), 2.72 (s, 2H), 2.68-2.53 (m, 9H), 2.48-2.45 (m, 2H), 2.45-2.38 (m, 3H), 2.31 (d, J = 16.8 Hz, 1H), 2.16-2.07 (m, 1H), 2.05-1.92 (m, 5H), 1.91- 1.82 (m, 2H), 1.64 (d, J= 4.8 Hz, 2H), 1.57-1.42 (m, 2H); MS (ESI) m/z: 749.6 [M+H] \
Figure imgf000517_0002
[001368] 7-Cyclopentyl-2-((5-(2-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)ethoxy)pyridin-2-yl)amino)-?Vr,A-dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A244. rH NMR (400 MHz, DMSO-rfc) 3 10.80 (s, 1H), 9.44 (s, 1H), 8.77 (s, 1H),
8.20 (br d, J= 9.2 Hz, 1H), 8.14 (s, 1H), 8.03 (br s, 1H), 7.46 (br d, J= 9.2 Hz, 1H), 7.18-7.09 (m, 1H), 6.86-6.77 (m, 2H), 6.62-6.58 (m, 2H), 4.79-4.67 (m, 1H), 4.16 (br s, 2H), 3.74 (br d, J= 5.4 Hz, 4H), 3.05 (br s, 6H), 2.77 (br s, 5H), 2.69-2.56 (m, 8H), 2.44 (br s, 3H), 2.24-2.15 (m, 1H), 1.97 (br s, 4H), 1.92 (br d, J= 14.4 Hz, 3H), 1.64 (br d, J = 3.6 Hz, 2H), 1.57-1.48 (m, 2H); MS (ESI) m/z: 749.8 [M+H]+.
Figure imgf000517_0003
[001369] 7-Cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperidin-l-yl)pyridin-2-yl)amino)-A(A-dimethyl-7/7-pyrrolo[2,3-J]pyrimidine-6- carboxamide A248 rH NMR (400 MHz, DMSO-^) 3 10.81 (s, 1H), 9.27 (s, 1H), 8.76 (s, 1H),
8.20 (s, 1H), 8.13 (d, J= 9.2 Hz, 1H), 8.00 (d, J= 2.4 Hz, 1H), 7.42 (dd, J= 2.4, 8.8 Hz, 1H), 7.25-7.17 (m, 2H), 7.17-7.12 (m, 2H), 6.59 (s, 1H), 4.73 (quin, ./ 8.8 Hz, 1H), 3.81 (dd, ./ 4.8, 11.2 Hz, 2H), 3.13 (d, .7 = 10.0 Hz, 2H), 3.05 (s, 6H), 2.67-2.59 (m, 3H), 2.58-2.54 (m, 2H), 2.47-2.42 (m, 2H), 2.33-2.08 (m, 4H), 2.07-1.88 (m, 6H), 1.79 (s, 4H), 1.73-1.61 (m, 4H), 1.55- 1.39 (m, 4H), 1.33-1.24 (m, 2H); MS (ESI) OT/Z: 732.8 [M+Hf.
Figure imgf000518_0001
[001370] 7-Cyclopentyl-2-((5-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethoxy)pyridin-2-yl)amino)-/V,Ar-dimethyl-77f-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A251. lH NMR (400 MHz, DMSO-Jc) 3 10.78 (s, 1H), 9.48 (s, 1H), 8.78 (s, 1H), 8.23 (d, J= 9.2 Hz, 1H), 8.13 (s, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.51 (dd, ./ 2.8, 9.2 Hz, 1H), 7.08 (d, J - 8.8 Hz, 2H), 6.94 (d, J= 8.8 Hz, 2H), 6.61 (s, 1H), 4.74 (q, J= 8.8 Hz, 1H), 4.31 (s, 2H), 3,74 (dd, J= 4.8, 11.2 Hz, 2H), 3.05 (s, 8H), 2.64 (dd, J- 5.2, 11.6, 17.2 Hz, 2H), 2.49-2.29 (m, 6H), 2.19- 2.09 (m, 1H), 2.08-1.84 (m, 7H), 1.80-1.39 (m, 3H); MS (ESI) m/z: 666.6 [M+H]+.
Figure imgf000518_0002
[001371] 7-Cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)pyridin-2-yl)amino)-AAV-dimethyl-777-pyrrolo[2,3-6f|pyrimidine-6-carboxamide A254. ^ NMR (400 MHz, DMSO-d6 ) d 10.77 (s, 1H), 9.27 (s, 1H), 8.75 (s, 1H), 8.15 (s, 1H), 8.13 (d, J= 2.0 Hz, 1H), 7.99 (d, J= 2.4 Hz, 1H), 7.43 (dd, J= 2.4, 9.2 Hz, 1H), 7.04 (br d, .7=
8.8 Hz, 2H), 6.90 (br d, J= 8.8 Hz, 2H), 6.59 (s, 1H), 4.80-4.66 (m, 1H), 3.72 (br dd, J= 4.4,
10.8 Hz, 3H), 3.17-2.98 (m, 10H), 2.74-2.57 (m, 7H), 2.44 (br d, ./ 4.4 Hz, 4H), 2.18-2.07 (m, 1H), 2.05-1.87 (m, 7H), 1.68-1.48 (m, 4H); MS (ESI) m/z: 705.5 [M+H]+.
Figure imgf000518_0003
[001372] 7-Cyclopentyl-2-((5-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperaziii-l-yl)pyridin-2-yl)amino)-A'jV-dimethyl-7Jf-pyrrolo[2,3-t(|pyrimidine-6-carboxaniide A255. Rl NMR (400 MHz, DMSO-Js) 6 1.18-1.32 (m, 2H), 1.53-1.63 (m, 2H), 1.70-1.92 (m, 7H), 1.97-2.06 (m, 1H), 2.07-2.16 (m, 1H), 2.23 (d, J - 7.0 Hz, 4H), 2.30 (s, 3H), 2.42 (s, 3H), 2.58-2.74 (m, 3H), 3.12 (s, 4H), 3.64-3.77 (m, 3H), 5.82 (t, J = 8.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 7.05 (d, J - 8.4 Hz, 2H), 7.45 (dd, J - 9.0, 2.6 Hz, 1H), 7.82 (d, J - 8.8 Hz, 1H), 8.05 (d, J = 2.4 Hz, HI), 8.95 (s, 1H), 10.06 (s, 1H), 10.77 (s, 1H); MS (ESI) m/z: 705.3 [M+H]+.
Figure imgf000519_0001
[001373] 7-Cyclopentyl-2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidm-3-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A;,A-dimethyl-7Ar-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A256. !H NMR (400 MHz, DMSO-tA) <5 10.74 (s, 1H), 9.24 (s, 1H), 8.75 (s, 1H), 8.14 (d, J= 8.8 Hz, 1H), 8.02-7.92 (m, 1H), 7.43 (dd, J= 2.4, 9.2 Hz, 1H), 7.06-6.94 (m, 2H), 6.59 (s, 1H), 6.39 (d, J= 8.4 Hz, 2H), 4.80-4.67 (m, 1H), 3.93 (t, J= 7.6 Hz, 2H), 3.69 (dd, J = 4.8, 11.2 Hz, 1H), 3.46 (t, J= 6.4 Hz, 2H), 3.15-3.09 (m, 4H), 3.05 (s, 6H), 2.99-2.91 (m, 1H), 2.64-2.62 (m, 2H), 2.55-2.53 (m, 4H), 2.44-2.42 (m, 3H), 2.16-2.05 (m, HI), 2.04-1.91 (m, 6H), 1.69-1.59 (m, 2H); MS (ESI) m/z: 691.4 [M+H]+.
Figure imgf000519_0002
[001374] 7-Cyclopentyl-2-((5-(4-((l -(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A7-dimethyl-7Z/-pyrrolo[2,3-(7]pyrimidine-6- carboxamide A257. rH NMR (400 MHz, DMSO-Je) <5 1.13-1.35 (m, 3H), 1.50-1.64 (m, 2H), 1.66-1.94 (m, 8H), 1.95-2.17 (m, 2H), 2.23 (d, J 7.2 Hz, 3H), 2.30 (s, 3H), 2.40-2.44 (m, 3H), 2.58-2.76 (m, 3H), 3.12 (s, 4H), 3.56-3.80 (m, 3H), 5.69-5.94 (m, 1H), 6.89 (d, J = 8.4 Hz, 2H),
7.05 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 9.2, 2 6 Hz, 1H), 7.82 (d, J = 8.8 Hz, I HI. 8.05 (d, J = 2.5 Hz, 1H), 8.26 (s, IH), 8.95 (s, IH), 10.06 (s, IH), 10.77 (s, IH); MS (ESI) TWA: 691.6 [M+H]
Figure imgf000520_0001
[001375] 7-Cyclopentyl-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-MM-dimethyl-77/-pyrrolo[2,3-tf|- pyrimidine-6-carboxamide A262. 4HNMR (400 MHz, DMSO-tfc) 3 1.63 (d, J= 4.8 Hz, 2H), 1.97 (d, J = 2.0 Hz, 4H), 2.02-2.10 (m, HI), 2.18-2.29 (m, 11 1 ), 2.35-2.36 (m, 4H), 2.39-2.46 (in, 2H), 2.53-2.57 (m, 1H), 2.65-2.74 (m, 1H), 2.89-2.95 (m, 1H), 2.98-3.02 (m, 2H), 3.02-3.07 (m, 6H), 3.10-3.12 (s, 4H), 3.15 (s, 2H), 3.41 (d, ./ 6.2 Hz, 2H), 3.94 (dd, J = 11.6, 5.2 Hz, 1H), 4.73 (t, J= 8.4 Hz, 1H), 6.59 (s, IH), 7.34 (d, J= 8.2 Hz, 2H), 7.4-7.6 (m, 1H), 7.47 (d, J= 8.0 Hz, 2H), 7.97 (d, J = 2.8 Hz, IH), 8.13 (d, J = 9.2 Hz, IH), 8.21 (s, IH), 8.74 (s, IH), 9.24 (s, IH), 10.87 (s, IH); MS (ESI) m/z: 741 .5 [M+H]+.
Figure imgf000520_0002
[001376] 7-Cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-A'’,A7-dimethyl-7/f-pyrrolo[2,3-tf]- pyrimidine-6-carboxamide A263. rHNMR (400 MHz , DMSO-tfc) 3 10.86 (s, 1H), 9.24 (s, IH), 8.74 (s, 1H), 8.13 (d, J= 9.2 Hz, 1H), 7.97 (d, J= 2.4 Hz, 1H), 7.40 (d, J= 15.6 Hz, 5H), 6.59 (s, IH), 4.73 (quin, J = 8.4 Hz, 1H), 3.96 (dd, J= 4.8, 11.6 Hz, 1H), 3.37 (d, J= 6.4 Hz, 2H), 3.19- 3.13 (m, 2H), 3.12-3.06 (m, 4H), 3.05 (s, 6H), 2.99 (t, ./ 6.4 Hz, 2H), 2.95-2.86 (m, 1H), 2.75- 2.59 (m, 2H), 2.46-2.39 (m, 2H), 2.38-2.31 (m, 4H), 2.30-2.20 (m, 1H), 2.09-1.90 (m, 5H), 1.72- 1.56 (m, 2H); MS (ESI) m/z: 741.5 [M+H]4.
Figure imgf000520_0003
[001377] 7-Cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)benzyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A'jV-dimethyl-71!f-pyrrolo[2,3-t(|pyrimidine-6-carboxaniide A264. ^H NMR (400 MHz, DMSO-Je) 6 10.90-10.76 (m, 1H), 9.30-9.19 (m, 1H), 8.74 (s, 1H), 8.12 (d, J= 9.2 Hz, 1H), 7.97 (d, J= 2.8 Hz, 1H), 7.48-7.39 (m, 1H), 7.31-7.24 (m, 2H), 7.18 (d, ./ 8.0 Hz, 2H), 6.59 (s, 1H), 4.72 (q, ./ 8.8 Hz, 1H), 3.85 (dd, 4.8, 11.2 Hz, 1H), 3.59-3.47 (m, 3H), 3.44-3.39 (m, 1H), 3.05 (s, 6H), 2.86-2.60 (m, 7H), 2.33-2.13 (m, 7H), 2.08-1.90 (m, 6H), 1.82 (t, J = 10.4 Hz, 1H), 1.63 (d, 5.2 Hz, 2H); MS (ESI) m/z: 691.4 [M+H]~.
Figure imgf000521_0001
[001378] 7-Cyclopentyl-2-((5-(4-(l-(3-(2,6-dioxopiperidin-3-yl)benzyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A'jV-dimethyl-7//-pyrrolo[2,3-t(|pyrimidine-6-carboxamide A265. !H NMR (400 MHz, CD3OD) cl 8.73 (s, 1H), 8.40 (s, 1H), 8.10 (d, J= 9.2 Hz, 1H), 7.92 (s, 1H), 7.57-7.48 (m, 1H), 7.37-7.27 (m, 3H), 7.22 (d, J= 7.6 Hz, 1H), 6.61 (s, 1H), 4.75 (t, J = 8.8 Hz, 1H), 3.89 (dd, J= 5.6, 10.4 Hz, 1H), 3.77-3.65 (m, 2H), 3.57 (d, J= 11.2 Hz, 1H), 3.47 (d, J= 9.2 Hz, 1H), 3.15 (s, 6H), 3.03-2.86 (m, 5H), 2.77-2.64 (m, 2H), 2.56-2.45 (m, 7H), 2,29- 2.13 (m, 3H), 2.09-2.00 (m, 4H), 1.76-1.65
Figure imgf000521_0002
691.4 [M+H]+.
Figure imgf000521_0003
[001379] 7-Cyclopentyl-2-((5-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-A///-dimethyl-7/7-pyrrolo[2,3-J]pyrimidine-6- carboxamide A266. ]H NMR (400 MHz, DMSO-fife) 3 1.55-1.67 (m, 6H), 1.77-1.87 (m, 6H), 1.83-1.83 (m, 1H), 1.96-197 (m, 6H), 2.14-2.23 (m, 2H), 2.61-2.73 (m, 8H), 3.02-3.05 (m, 6H), 3.31 (s, 2H), 3.68 (d, J= 11.6 Hz, 2H), 3.81 (dd, J- 11.2, 4.8 Hz, 1H), 4.73 (quin, J= 8.8 Hz, 1H), 6.59 (s, 1H), 7.03 ( d, J = 7.6 Hz, 1H), 7.08 (s, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.21-7.27 (m, 1H), 7.43 (dd, J= 8.8, 2.0 Hz, 1H), 7.99 (d, J= 2.2 Hz, 1H), 8.12 (d, J= 9.0 Hz, 1H), 8.75 (s, 1H), 9.28 (s, 1H), 10.83 (s, 1H); MS (ESI) m/z'. 750.4 [M+H]+.
Figure imgf000522_0001
[001380] 7-Cyclopentyl-2-((5-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-A,jV-dimethyl-72/-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A268
Figure imgf000522_0002
NMR (400 MHz, DMSO-tA) J 10.92-10.71 (m, 1H), 9.23 (s, 1H), 8.74 (s, 1H), 8.17-8.06 (m, 1H), 8.00-7.94 (m, 1H), 7.46-7.35 (m, 1H), 7.29-7.20 (m, 1H), 7.18-7.03 (m, 3H), 6.59 (s, 1H), 4.78-4.62 (m, 1H), 3.88-3.76 (m, 1 H), 3.70-3.60 (m, 2H), 3.30 (br s, 2H), 3.05 (br s, 6H), 2.92-2.84 (m, 2H), 2.70-2.59 (m, 9H), 2.17 (br dd, J= 3.2, 12.1 Hz, 1H), 2.08- 2.02 (m, 1H), 1.96 (br d, 2.0 Hz, 4H), 1.86-1.78 (m, 2H), 1.69-1.50 (m, 8H); MS (ESI) m/z: 736.4 [M+H]+.
Figure imgf000522_0003
[001381] 7-Cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazm- 1 -yl)- azetidin-l-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A272. rH NMR (400 MHz, DMSO-de) 3 10.81 (s, 1H), 9.22 (s, 1H), 8.74 (s, 1H), 8.15 (s, 1H), 8.09 (d, J= 8.8 Hz, 1H), 7.59 (d, J= 2.4 Hz, 1H), 7.15-7.21 (m, 2H), 7,08-7,15 (m, 2H), 6,94 (m, 1H), 6.58 (s, 1H), 4.69-4.77 (m, 1H), 3.95 (t, J= 6.8 Hz, 2H), 3.78-3.83 (m, 1H), 3.59 (t, J = 6.4 Hz, 2H), 3.25-3.30 (m, 1H), 3.05 (s, 6H), 2.69-2,73 (m, 2H), 2.61-2.65 (m, 1H), 2.55 (s, 3H), 2.30-2.48 (m, 9H), 2.05-2.29 (m, 2H), 1.91-2.03 (m, 5H), 1.63 (d, J= 4.8 Hz, 2H); MS (ESI) m/z: 705.4 [M+H]+
Figure imgf000522_0004
[001382] 7-Cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7/7-pyrrolo[2,3-c/]pyrimidine-6-carboxamide
A273. TH NMR (400 MHz, DMSO-ak) S 10.87 (s, 1H), 9.39 (s, 1H), 8.77-8.78 (m, 1H), 8.18 (s,
1H), 8.12 (d, J= 8.8 Hz, 1H), 7.62 (d, J= 2.2 Hz, 1H), 7.21-7.28 (m, 1H), 7.13 (d, J= 7.6 Hz, 1H), 7.08 (s, 1H), 7.04 (d, J= 1.6 Hz, 1H), 6.95- 6.97 (m, 1H), 6.60 (s, 1H), 4.70-4.77 (m, 1H), 3.96 (t, J == 6.8 Hz, 2H), 3.82 - 3.84 (m, 1H), 3.60 (t, J = 6.4 Hz, 2H), 3.25-3.32 (m, 1H), 3.06 (s, 6H), 2.70-2.77 (m, 2H), 2.60-2.70 (m, 2H), 2.56 (d, J= 7.2 Hz, 4H), 2.29-2.49 (m, 7H), 2.18 (m, 1H), 1.92-2.05 (m, 5H), 1.64 (d, J = 5.2 Hz, 2H)MS (ESI) m/z: 705.4 [M+H] \
Figure imgf000523_0001
[001383] 7-Cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A’,A'-dimethyl-7J/-pyrrolo[2,3-(/|pyrimidine-6-carboxamide A274. ^H NMR (400 MHz, DMSO-Je) / 10.87 (s, 1H), 9.63-9.37 (m, 1H), 8.90 (s, 1H), 7.69 (s, 1H), 7.56 (s, 1H), 7.47 (s, 2H), 7.35 (d, J= 5.6 Hz, 3H), 6.74 (s, 1H), 4.85-4.71 (m, 1H), 4.36 (s, 2H), 4.08-3.97 (m, 2H), 3.93 (d, J= 8.4 Hz, 1H), 3.67 (s, 2H), 3.53-3.42 (m, 2H), 3.11-3.92 (m, 10H), 2.76-2.63 (m, 1H), 2.56-2.51 (m, 2H), 2.45-2.15 (m, 5H), 2.09-1.89 (m, 5H), 1.71-1.57 (m, 2H); MS (ESI) m/z: 691.5 [M+H]+.
Figure imgf000523_0002
[001384] 7-Cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,A'-dimethyl-7Ar-pyrrolo[2,3-<7jpyrimidine-6-carboxamide A275. ^ NMR (400 MHz, DMSO-Je) 3 10.83 (s, 1H), 9.19 (s, 1H), 8.73 (s, 1H), 8.15 (s, 1H), 8.08 (d, J= 8.8 Hz, 1H), 7.57 (s, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.96-6.88 (m, 1H), 6.58 (s, 1H), 4.81-4.63 (m, 1H), 3.99-3.90 (m, 2H), 3.85 (dd, J- 4.8, 11.2 Hz, 1H), 3.58 (t, J= 6.0 Hz, 2H), 3.46 (s, 2H), 3.33-3.22 (m, 2H), 3.05 (s, 6H), 2.71-2.59 (m, 1H), 2.47-2.26 (m, 10H), 2.23-2.11 (m, 1H), 2.07-2.01 (m, 1H), 2.00-1.90 (m, 4H), 1.71-1.54 (m, 2H); MS (ESI) m/z: 691.5 [M+H]+.
Figure imgf000524_0001
[001385] 7-Cyclopentyl-2-((5-(4-(3-(4-(2,6-dioxopiperidin-3-yl)benzyl)-3-fluoroazetidin-l- yl)piperidin-l-yl)pyridin-2-yl)amino)-A(ALdimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A276. rH NMR (400 MHz, DMSO-Je) 3 10.82 (s, 1H), 9.25 (s, 1H), 8.75 (s, 1H), 8. 12 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 2.6 Hz, 1H), 7.42 (m, 1H), 7.20-7.25 (m, 2H), 7.14-7.18 (m, 2H), 6.59 (s, 1H), 4.67-4.78 (m, 1H), 3.82 (m, I I I ), 3.40-3.51 (m, 4H), 3.11-3.16 (m, 2H), 3.08-3.10(m, 2H), 3.06 (s, 6H), 2.75 (t, J = 10.4 Hz, 2H), 2.65 (m, 1H), 2.45 (m, 3H), 2.21-2.27 (m, 1H), 2.11-2.19 (m, 1H), 1.94-2.03 (m, 5H), 1.75 (d, J = 10.4 Hz, 2H), 1.64 (d, J = 4.8 Hz, 2H), 1.33-1.35 (m, 2H); MS (ESI) m/z: 708,6 [M+H]+.
Figure imgf000524_0002
[001386] 7-Cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro- piperidin-l-yl)azetidin-l-yl)pyridin-2-yl)amino)-7V,7V-dimethyl-7/7-pyrrolo[2,3-J]pyrimidine-6- carboxamide A279. ]H NMR (400 MHz, CDCh) 3 8.64 (s, 1H), 8,32-8,26 (m, 1H), 8,20 (s, 1H), 7.89-7.70 (m, 1H), 7.68-7.59 (m, 1H), 7.24-7.19 (m, 2H), 7.17-7.12 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.43 (s, 1H), 4.85-4.74 (m, 1H), 4.11-4.03 (m, 2H), 3.88-3.70 (m, 3H), 3.57-3.37 (m, 1H), 3.16 (s, 6H), 2.80-2.71 (m, 4H), 2.71-2.65 (m, 1H), 2.65-2.52 (m, 3H), 2.38-2.32 (m, 1H), 2.29- 2.22 (m, 2H), 2.12-2.02 (m, 5H), 2.01-1.94 (m, 3H), 1.90 (dd, ./ 8.0, 9.6 Hz, 2H), 1.75-1.68 (m, 3H); MS (ESI) m/z: 722.6 [M+H]+.
Figure imgf000524_0003
[001387] 7-Cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7Hr-pyrrolo[2,3-dr]pyrimidiiie-6-carboxamide A280. ^H NMR (400 MHz, DMSO-tA) d 10.80 (s, 1H), 9.12 (s, 1H), 8.72 (s, 1H), 8.07 (d, .7 =
8.8 Hz, 1H), 7.57 (d, J= 2.8 Hz, 1H), 7.27-7.18 (m, 1H), 7.09 (d, J= 7.6 Hz, 1H), 7.06-6.99 (m, 2H), 6.93 (dd, ./ 2.8, 8.8 Hz, 1H), 6.58 (s, 1H), 4.78-4.67 (m, 1 H), 3.96 (t, ./ 6.8 Hz, 2H), 3.81 (dd, ./= 5.2, 11.2 Hz, 1H), 3.55 (t, J= 6.4 Hz, 2H), 3.24-3.18 (m, 1H), 3.05 (s, 6H), 2.78 (d, ./=
10.8 Hz, 2H), 2.70-2.61 (m, 1H), 2.61-2.55 (m, 2H), 2.44 (dd, ./ 5.2, 9.6 Hz, 2H), 2.21-2 12 (m, 1H), 2.08-2.01 (m, 1H), 1.96 (s, 4H), 1.78 (t, J= 11.2 Hz, 2H), 1.71 (d, J= 12.0 Hz, 2H), 1.66- 1.60 (m, 2H), 1.54-1.46 (m, 2H), 1.32-1.10 (m, 4H); MS (ESI) m/z: 704.5 [M+H]4.
Figure imgf000525_0001
[001388] 7-Cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro- piperidin-l-yl)azetidin-l-yl)pyridin-2-yl)amino)-A(A’-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A281
Figure imgf000525_0002
NMR (400 MHz, DMSO-r/e) d 10.82 (s, 1H), 9.18 (s, 1H), 8.73 (s, 1H), 8.08 (d, J= 8.8 Hz, 1H), 7.58 (d, J= 2.8 Hz, 1H), 7.26-7.22 (m, 1H), 7.12 (d, J= 8.0 Hz, 1H), 7.08 (s, 1H), 7.03 (d, ./ 7.6 Hz, 1H), 6.94 (dd, ./ 2.8, 8.8 Hz, 1H), 6.58 (s, 1 H), 4.72 (quin, ./
8.8 Hz, 1H), 3.98 (1, 6.8 Hz, 2H), 3.81 (dd, J= 4.8, 11.6 Hz, 1H), 3.58 (t, .7= 6.4 Hz, 2H),
3.05 (br s, 6H), 2.64 (dt, ./ 5.2, 11.2 Hz, 5H), 2.47-2.39 (m, 3H), 2.21-2.10 (m, 3H), 2.05-1.99 (m, 2H), 1.98-1.91 (m, 4H), 1.88-1.78 (m, 4H), 1.77-1.70 (m, 1H), 1.64 (br t, ./ = 10.0 Hz, 3H); MS (ESI) m/z: 722.5 [M+H]\
Figure imgf000525_0003
[001389] 7-Cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoropiperidin-
1 -yl)azetidin- 1 -yl)pyridin-2-yl)amino)-A(A/-dimethyl-7//-pyrrolo[2,3 -<7]pyrimidine-6- carboxamide A282. 4H NMR (400 MHz, DMSO-tfe) <5 10.81 (s, 1H), 9.12 (s, 1H), 8.72 (s, 1H), 8.07 (d, J= 8.8 Hz, 1H), 7.56 (d, J= 2.8 Hz, 1H), 7.32-7.21 (m, 1H), 7.10 (t, J= 7.2 Hz, 2H), 7.06 (s, 1H), 6.92 (dd, J- 2.8, 8.8 Hz, 1H), 6.58 (s, 1H), 4.72 (t, 8.8 Hz, 1H), 3.96 (t, J- 6.8 Hz, 2H), 3.83 (dd, J = 5.2, 11.2 Hz, 1H), 3.55 (t, J= 6.4 Hz, 2H), 3.05 (s, 6H), 2.94-2.86 (m, 2H), 2.69-2.56 (m, 8H), 2.19-2.12 (m, 1H), 2.09-2.04 (m, 2H), 1.95 (s, 4H), 1.73-1.60 (m, 6H); MS (ESI) m/z: 708.7 [M+H]+.
Figure imgf000526_0001
[001390] 7-Cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoropiperidin- l-yl)azetidin-l-yl)pyridin-2-yl)amino)-A',ALdimethyl-7Jf-pyrrolo[2,3-J]pyrimidine-6- carboxamide A283. rH NMR (400 MHz, DMSO-cZe) 6 10.83 (s, IH), 9.20 (s, IH), 8.73 (s, IH), 8.30 (s, 1H), 8.08 (d, J= 8.8 Hz, 1H), 7.57 (d, J= 2.8 Hz, 1H), 7.19-7.11 (m, 4H), 6.93 (dd, J= 2.8, 8.9 Hz, IH), 6.58 (s, IH), 4.79-4.64 (m, 1H), 3.96 (t, J= 6.9 Hz, 2H), 3.82 (dd, J= 4.8, 11.4
Hz, 1H), 3.55 (br t, J - 6.4 Hz, 2H), 3.31-3.22 (m, 2H), 3.05 (br s, 6H), 2.92 (s, 1H), 2.86 (s, IH), 2.68-2.59 (m, 2H), 2.47-2.38 (m, 3H), 2.17 (br dd, J= 3.2, 11.9 Hz, 1H), 2.10-2.00 (m, 3H),
2.00-1.92 (m, 4H), 1.71-1.58 (m, 6H); MS (ESI) m 'z: 708.4 [M+H] \
Figure imgf000526_0002
[001391] 7-Cyclopentyl-2-((5-(4-((3 -(3 -(2,6-dioxopiperidin-3-yl)phenyl)azetidin- 1 -yl)- methyl)-4-fluoropiperidin-l-yl)pyridin-2-yl)amino)-A(A/-dimethyl-7.H-pyrrolo[2,3-</|pyrimidine- 6-carboxamide A285. 'H NMR (400 MHz, DMSO-tfe) ci 10.82 (s, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 8.22 (s, 1H), 8.14 (d, ./ 9.2 Hz, 1H), 8.03 (d, ./ 2.8 Hz, 1H), 7.46 (dd, ./ 3.2, 9.2 Hz, IH), 7.33-7.24 (m, 2H), 7.18 (s, 1H), 7.10-7.02 (m, IH), 6.59 (s, IH), 4.73 (q, J= 8.8 Hz, 1H), 3.84 (dd, J = 5.2, 11.6 Hz, IH), 3.74-3.69 (m, 2H), 3.67-3.59 (m, 2H), 3.19 (t, J = 6.4 Hz, 3H), 3.05 (s, 6H), 2.95 (t, 10.4 Hz, 3H), 2.73-2.62 (m, 4H), 2.47-2.40 (m, 2H), 2.20 (t, J- 8.0, 12.0 Hz, IH), 2.04 (dd, J= 4.4, 9.2 Hz, 1H), 1.98 (s, 3H), 1.90 (d, J= 11.6 Hz, 2H), 1.86-1.71 (m, 2H), 1.69-1.59 (m, 2H); MS (ESI) m/z: 708.4 [M+H] \
Figure imgf000527_0001
[001392] 7-Cyclopentyl-2-((5-(l-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)-4-fluoropiperidin- 4-yl)methyl)piperidin-4-yl)pyridin-2-yl)amino)-Az,Ar-dimethyl-7/f-pyrrolo[2,3-</]pyriniidine-6- carboxamide A286
Figure imgf000527_0002
NMR (400 MHz, DMSO-Je) 6 10.80 (s, 1H), 9.51 (s, 1H), 8.80 (s, 1H), 8.26 (d, J= 8.8 Hz, 1H), 8.18 (d, J= 2.0 Hz, 1H), 8.14 (s, 1H), 7.67 (dd, J= 2.0, 8.8 Hz, 1H), 7.16 (t, J- 7.6 Hz, 1H), 6.87 (br d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 6.64-6.57 (m, 2H), 4.74 (quin, J= 8.8 Hz, 1H), 3.76 (dd, J= 4.8, 11.2 Hz, 1H), 3.47 (br d, J= 12.4 Hz, 2H), 3.09-2.97 (m, 10H), 2.68-2.59 (m, 2H), 2.55 (br s, 1H), 2.48-2.40 (m, 3H), 2.27-2.15 (m, 3H), 2.07-1.85 (m, 8H), 1.83-1.60 (m, 8H); MS (ESI) m/z: 736.7 [M+H]+.
Figure imgf000527_0003
[001393] 7-Cyclopentyl-2-((5-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-fluoropiperidin- 4-yl)methyl)piperidin-4-yl)pyridin-2-yl)amino)-AyV-dimethyl-7H-pyrrolo[2,3-^]pyrimidine-6- carboxamide A287. rH NMR (400 MHz, DMSO-^) d 10.84-10.70 (m, 1H), 9.50-9.38 (m, 1H), 8.83-8,74 (m, 1H), 8,25 (br d, J= 9.2Hz, 1H), 8.16 (br s, 1H), 7.72-7.62 (m, 1H), 7.05 (br d, J = 8.0 Hz, 2H), 6.94 (br d, J= 8.4 Hz, 2H), 6.65-6.58 (m, 1H), 4.82-4.65 (m, 1H), 3.78-3.65 (m, 1H), 3.49-3.44 (m, 2H), 3.08-2.94 (m, 11H), 2.60 (br s, 3H), 2.26-2.18 (m, 3H), 2.16-2.10 (m, 1H), 2.04-1.90 (m, 8H), 1.87-1.82 (m, 1H), 1.78-1.61 (m, 8H); MS (ESI) m/z: 736.5 [M+H]t
Figure imgf000527_0004
[001394] 7-Cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)-4-fluoropiperidin-l -yl)pyri din-2 -yl)amino)-Af,A7-dimethyl-777-pyrrolo[2,3-t7]pyrimidine- 6-carboxamide A288. TH NMR (400 MHz, DMSO-^) 4' 10.80 (s, 1H), 9.25 (s, 1H), 8.75 (s, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 8.04 (d, .7= 2.8 Hz, 1H), 7.47 (dd, J = 2.8, 9.2 Hz, 1H), 7.23-7.18 (m, 2H), 7.16-7.10 (m, 2H), 6.59 (s, 1H), 4.73 (t, .7= 8.8 Hz, 1H), 3.80 (dd, .7= 4.8, 11.2 Hz, 1H), 3.44 (d, ./ 12.4 Hz, 2H), 3.05 (s, 6H), 3.02-2.95 (tn, 3H), 2.70-2.54 (m, 4H), 2.48-2.36 (m, 4H), 2.24 (t, .7 = 10.4 Hz, 2H), 2.19-2.10 (m, 1H), 2.07-1.89 (m, 8H), 1.84-1.76 (m, 1H), 1.75- 1.61 (m, 6H); MS (ESI) m/z: 736.8 [M+H]+.
Figure imgf000528_0001
[001395] 7-Cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)-4-fluoropiperidin-l-yl)pyridin-2-yl)amino)-A(A/-dimethyl-77/-pyrrolo[2,3-t7]pyrimidine- 6-carboxamide A289
Figure imgf000528_0002
NMR (400 MHz, DMSO-^) <5 10.81 (s, 1H), 9.27 (s, 1H), 8.75 (s, 1H), 8.17 (s, 1H), 8.14 (d, J= 9.2 Hz, 1H), 8.04 (d, J= 2.4 Hz, 1H), 7.47 (dd, J= 2.8, 9.2 Hz, 1H), 7.28-7.21 (m, 1H), 7.17-7.09 (m, 2H), 7.03 (d, J= 7.6 Hz, 1H), 6.59 (s, 1H), 4.81-4.65 (m, 1H), 3.82 (dd, J= 4.8, 11.2 Hz, 1H), 3.02-2.93 (m, 4H), 2.70-2.58 (m, 4H), 2.46-2.33 (m, 7H), 2.29-2.13 (m, 4H), 2.06-1.90 (m, 9H), 1.87-1.75 (m, 2H), 1.74-1.61 (m, 7H); MS (ESI) m/z:
736.6 [M+H]A
Figure imgf000528_0003
[001396] 7-Cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-AT,77-dimethyi-777-pyrrolo[2,3-(/|pyrimidine-6-carboxamide A294. rH NMR (400 MHz, DMSO-tA) 3 10.78 (s, 1H), 9.20 (s, 1H), 8.78-8.70 (m, 1H), 8.30 (s, 1H), 8.10 (d, .7= 8.4 Hz, 1H), 7.60 (s, 1H), 7.06 (d, J= 8.8 Hz, 2H), 6.99-6.87 (m, 3H), 6.59 (d, J = 1.2 Hz, 1H), 4.73 (q, ,7= 8.8 Hz, 1H), 4.00 (t, J = 7.2 Hz, 2H), 3.73 (dd, J= 4.8, 11.2 Hz, 1H), 3.67 (t, .7= 6.4 Hz, 2H), 3.15 (s, 4H), 3.06 (s, 6H), 2.70-2.58 (m, 2H), 2.45 (d, J= 4.8 Hz, 6H), 2.19-2.07 (m, IH), 2.07-1.86 (m, 6H), 1.64 (d, 7= 5.2 Hz, 2H); MS (ESI) wz: 677.4 [M+H]+.
Figure imgf000529_0001
[001397] 7-Cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-iV,A-dimethyl-77f-pyrrolo[2,3-tf]pyrimidine-6-carboxamide A295. ‘HNMR (400 MHz, DMSO-Jg) 7 10.76 (s, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 8.37-8.28 (m, IH), 8.14 (d, J= 8.8 Hz, 1H), 7.99 (s, 1H), 7.44 (d, J= 8.4 Hz, 1H), 7.01 (d, 7= 7.6 Hz, 2H), 6.59 (s, IH), 6.41 (d, J= 7.6 Hz, 2H), 4.82-4.65 (m, IH), 3.93 (t, J= 6.4 Hz, 2H), 3.70 (dd, J = 4.4, 10,6 Hz, IH), 3,65-3,56 (m, 2H), 3, 15 (s, 4H), 3,05 (s, 6H), 2,64-2,55 (m, 4H), 2.44-2.35 (m, 4H), 2.18-2.08 (m, IH), 2.04-1.82 (m, 6H), 1.71-1.57 (m, 2H); MS (ESI) m/z'. 677.4 [M+H]t
Figure imgf000529_0002
[001398] 7-Cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,AMimethyl-7J7-pyrrolo[2,3-7|pyrimidine-6-carboxamide
A296 rH NMR (400 MHz, DMSO-tfc) (5 10.80 (s, 1H), 9.21 (s, 1H), 8.74 (s, 1H), 8.19 (s, 1H), 8.10 (d, J= 8.8 Hz, 1H), 7.60 (d, J= 2.8 Hz, 1H), 7.16 (t, J= 8.0 Hz, 1H), 6.96 (dd, J= 2.8, 8.8 Hz, 1H), 6.85-6.79 (m, 2H), 6.62 (d, ./ 7.6 Hz, 1H), 6.58 (s, 1H), 4.78-4.66 (m, 1H), 3.99 (i. 7 7.2 Hz, 2H), 3.76 (dd, J= 4.8, 11.2 Hz, 1H), 3.66 (t, J= 6.4 Hz, 2H), 3.38-3.31 (m, 4H), 3.15 (br s, 4H), 3.05 (br s, 6H), 2.64 (ddd, J= 5.2, 11.6, 17.2 Hz, 1H), 2.46-2.38 (m, 3H), 2.25-2.14 (m, 1H), 2.06-1.91 (m, 6H), 1.68-1.60 (m, 2H); MS (ESI) m 'z: 677.7 [M+H]+.
Figure imgf000529_0003
[001399] 7-Cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)-5-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-7/7-pyrrolo[2,3-7]- pyrimidine-6-carboxamide A297. rHNMR (400 MHz, DMSO-Js) <5 10.80 (s, 1H), 9.24 (s, 1H), 8.75 (s, 1H), 8.14 (d, 7= 2.8 Hz, 1H), 8.13 (s, 1H), 7.99 (d, .7= 2.8 Hz, 1H), 7.42 (dd, 7= 2.8, 9.2 Hz, 1H), 6.61 (d, J= 13.2 Hz, 3H), 6.38 (d, J= 9.6 Hz, 1H), 4.73 (t, J= 8.8 Hz, 1H), 3.77 (dd, ./ 4.8, 11.6 Hz, 1H), 3.70 (d, 7 = 12.0 Hz, 2H), 3.13 (s, 4H), 3.05 (s, 6H), 2.74-2.57 (m, 4H), 2.55 (s, 4H), 2.46-2.36 (m, 4H), 2.23 (dq, 7= 4.4, 12.4 Hz, 1H), 2.06-1.88 (m, 5H), 1.75 (d, J - 12.4 Hz, 2H), 1 64 (d, J - 5.2 Hz, 2H), 1 .45 (t, 7 6.4 Hz, 3H), 1.31-1.14 (m, 2H); MS (ESI) m/z: 751.7 [M+H]+.
Figure imgf000530_0001
[001400] 7-Cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)-4-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimetliyl-7//-pyrrolo[2,3-7]- pyrimidine-6-carboxamide A298. rH NMR (400 MHz, DMSO-de) <5 1.10-1.26 (m, 1H), 1.28- 1.40 (m, 4H), 1.49-1.61 (m, 3H), 1.67-1.74 (m, 2H), 1.75-1.81 (m, 1H), 1.81-1.92 (m, 3H), 2.04- 2.06 (m, 5H), 2.21-2.36 (m, 1H), 2.47-2.52 (m, 2H), 2.64-2.71 (m, 4H), 2.73-2.86 (m, 2H), 3.12- 2.04 (m, 6H), 3.19 (s, 3H), 3.60-3.70 (m, 2H), 4.02 (dd, 7 - 12.4, 5.0 Hz, 1H), 4.81 (t, J 8.4 Hz, 1H), 6.67 (s, 1H), 6.84-6.99 (m, 2H), 7.08 (t, 7 = 9.6 Hz, 1H), 7.52 (d, 7 = 7.8 Hz, 1H), 8.07 (s, 1H), 8,22 (d, 7 - 9.0 Hz, 1H), 8.83 (s, 1H), 9.17-9.63 (m, 1H), 10,91 (s, 1H); MS (ESI) m/z: 751.4 [M+H]+.
Figure imgf000530_0002
[001401] 7-Cyclopentyl-2-((5-((r-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-4- yl)methoxy)pyridin-2-yl)amino)-Az,A-dimethyl-777-pyrrolo[2,3-<7]pyriniidine-6-carboxamide
A300. rHNMR (400 MHz, DMSO-tA) <5 10.78 (s, 1H), 9.36 (s, 1H), 8.76 (s, 1H), 8.18 (d, 7 =
2.4 Hz, 1H), 8.17 (s, 1H), 8.00 (d, 7= 3.2 Hz, 1H), 7.43 (dd, 7= 3.2, 9.2 Hz, 1H), 7.14 (t, 7= 7.6 Hz, 1H), 6.89-6.75 (m, 2H), 6.65-6.53 (m, 2H), 4.81-4.65 (m, 1H), 3.92-3.87 (m, 2H), 3.78-3.69 (m, 3H), 3.05 (s, 6H), 2.96 (d, J= 10.4 Hz, 2H), 2.69-2.61 (m, 4H), 2.43 (s, 4H), 2.35-2.30 (m, 1H), 2.27-2.15 (m, 3H), 2.04-1.95 (m, 4H), 1.88-1.76 (m, 4H), 1.69-1.60 (m, 2H), 1.60-1.47 (m, 2H), 1.38-1.22 (m, 2H); MS (ESI) m/z: 734.5 [M+H]t
Figure imgf000531_0001
[001402] 7-Cyclopentyl-2-((5-(4-(2-(l -(5-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A(A-dimethyl-7Z7-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A352.
Figure imgf000531_0002
NMR (400 MHz, DMSO-tfe) <5 10.80 (s, 1 H ), 9.30 (s, 1H), 8.76 (s, 1H), 8.16 (s, 1H), 8.15-8.13 (m, 1H), 8.01 (d, J= 2.8 Hz, 1H), 7.45 (dd, J= 2.8, 9.2 Hz, 1H), 7.05 (dd, ./ 8.0, 12.4 Hz, 1H), 6.88 (d, ./ 8.6 Hz, 1H), 6.77 (dd, ./ 4.2, 8.1 Hz, 1H), 6.59 (s, 1H), 4.79-4.68 (m, 1H), 3.81 (dd, J= 4.8, 11.6 Hz, 1H), 3.18 (s, 4H), 3.05 (s, 6H), 2.73-2.53 (m, 11H), 2.47-2.39 (m, 3H), 2.20 (dt, J = 8.0, 12.0 Hz, 1H), 2.03-1.94 (m, 5H), 1.78 (d, 11.2
Hz, 2H), 1.68-1.61 (m, 2H), 1.54-1.43 (m, 3H), 1.39-1.28 (m, 2H); MS (ESI) m/z: 751.4 [M+H]+.
Figure imgf000531_0003
[001403] 7-Cyclopentyl-2-((4-((4-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)aniino)-A(A7-dimethyl-7/f-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A402.
Figure imgf000531_0004
[001404] 7-Cyclopentyl-2-((4-((6-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(27/)-yl)- phenoxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-A7^-dimethyl-7//-pyrrolo[2,3- tZ]pyrimidine-6-carboxamide A403.
Figure imgf000532_0001
[001405] 7-Cyclopentyl-2-((4-((2-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)aniino)-AjV-dimethyl-77/-pyrrolo[2,3"^- pyrimidine-6-carboxamide A404.
Figure imgf000532_0002
[001406] 7-Cyclopentyl-2-((4-((4-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-A,jV-dimethyl-77/-pyrrolo[2,3- Jjpyrimidine-6-carboxamide A405.
Figure imgf000532_0003
[001407] 7-Cyclopentyl-2-((4-((6-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)- phenoxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-A/7vr-dimethyl-777-pyrrolo[2,3- </|pyrimidine-6-carboxamide A406.
Figure imgf000532_0004
[001408] 7-Cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidm-l(2£/)-yl)phenyl)- piperazin-l-yl)ethyl)phenyl)amino)-Ar,Ar-dimethyl-7Hr-pyrrolo[2,3-</|pyriniidine-6-carboxamide A412. ^HNMR (400 MHz, DMSO-Js) d 9.43 (s, 1H), 8.59 (s, 1H), 7.90 (s, 1H), 6.91 (d, ./= 8.4 Hz, 2H), 6.33 (dd, J= 3.6, 8.8 Hz, 4H), 6.12 (d, J= 9.2 Hz, 2H), 5.75 (s, 1H), 3.90 (q, ./= 8.8 Hz, 1 H), 2.88 (t, ./ 6.8 Hz, 2H), 2.32 (d, J = 4.4 Hz, 4H), 2.23 (s, 6H), 1 .95-1 .88 (m, 2H), 1.86 (t, J= 6.8 Hz, 2H), 1.81-1.72 (m, 6H), 1.66-1.59 (m, 2H), 1.15 (s, 4H), 0.89-0.77 (m, 2H); MS (ESI) m/z: 650.3 [M+H]+.
Figure imgf000533_0001
[001409] 7-Cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidm-l(2/7)-yl)phenyl)- piperazin-l-yl)ethyl)phenyl)amino)-AyA'’-dimethyl-7.7/-pyrrolo[2,3-tf|pyrimidine-6-carboxamide A413 ^ NMR (400 MHz, DMSO-tfe) <5 10.30 (s, 1H), 9.41 (s, 1H), 8.72 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.24-7.18 (m, 1H), 7.16 (d, J= 8.4 Hz, 2H), 6.89 (s, 1H), 6.82 (d, J= 8.4 Hz, 1H), 6.72 (d, J- 7.6 Hz, 1H), 6.57 (s, 1H), 4.72 (quin, J- 8.8 Hz, 1H), 3.74 (t, J- 6.4 Hz, 2H), 3.20- 3.12 (m, 4H), 3.05 (s, 6H), 2.77-2.71 (m, 2H), 2.68 (t, J= 6.4 Hz, 2H), 2.58 (d, J= 5.2 Hz, 4H), 2.56-2.53 (m, 2H), 2.48-2.40 (m, 2H), 1.97 (s, 4H), 1.71-1.56 (m, 2H); MS (ESI) m/z: 650.4 [M+H]+.
Figure imgf000533_0002
[001410] 7-Cyclopentyl-2-((5-((4-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2//)-yl)phenyl)- piperazin-l-yl)methyl)pyridin-2-yl)amino)-A',7V-dimethyl-7J/-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A419 rH NMR (400 MHz, DMSO-fifc) 6 10.25 (s, 1H), 9.59 (s, 1H), 8.81 (s, 1H), 8.29 (d, J= 8.8 Hz, 1H), 8.21 (d, J= 2.0 Hz, 1H), 8.14 (s, 1H), 7.71 (dd, J= 2.0, 8.8 Hz, 1H), 7.14 (d, ./ 8.8 Hz, 2H), 6.92 (d, ./ 9.2 Hz, 2H), 6.63 (s, 1H), 4.75 (quin, ./ 8.8 Hz, 1H), 3.69 (t, J= 6.8 Hz, 2H), 3.51 (s, 2H), 3.17 3.12 (m, 4H), 3.06 (s, 6H), 2.67 (t, J= 6.8 Hz, 2H), 2.56- 2.52 (m, 4H), 2.44 (dd, J- 8.8, 11.6 Hz, 2H), 2.05-1.92 (s, 4H), 1.71-1.60 (m, 2H); MS (ESI) m/z: 637.4 [M+H]+.
Figure imgf000534_0001
[001411] 7-Cyclopentyl-2-((4-(4-(l -(4-(2,4-dioxotetrahydropyrimidin- 1 (27/)-yl)phenyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-A7,Az-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A420
Figure imgf000534_0002
NMR (400 MHz, DMSO-cfc) 3 10.26 (s, 1H), 9.23 (s, 1H), 8.68 (s, 1H), 8.14 (s, 1H), 7.65 (d, J= 9.0 Hz, 2H), 7.14 (d, J= 8.9 Hz, 2H), 6.94 (d, J= 9.1 Hz, 2H), 6.89 (d, ./= 9.1 Hz, 2H), 6.55 (s, 1H), 4.78-4.64 (m, 1H), 3.81-3.65 (m, 4H), 3.06 (br s, 10H), 2.78-2.61 (m, 8H), 2.47-2.40 (m, 3H), 2.02-1.85 (m, 6H), 1.68-1.49 (m, 4H); MS (ESI) m/z: 705.4 [M H i
Figure imgf000534_0003
[001412] 7-Cyclopentyl-2-((4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrimidin- 1 (22/)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)amino)-A;,JV-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine- 6-carboxamide A425. *H NMR (400 MHz, DMSO-tA) 3 11.18-10 98 (m, 1H), 10.61-10.41 (m, 1H), 10.30 (s, 1H), 9.61 (s, 1H), 8.77 (s, 1H), 7.80 (d, J = 8 4 Hz, 2H), 7.22 (t, 8.0 Hz, 4H),
7.03 (d, J= 8.8 Hz, 2H), 6.61 (s, 1H), 4.80-4.66 (m, 1H), 3.86 (d, J= 9.6 Hz, 2H), 3.79-3.69 (m, 4H), 3.64 (d, J= 7.6 Hz, 2H), 3.17 (d, J= 9.2 Hz, 5H), 3.11-2.94 (m, 10H), 2.69 (t, J= 6.8 Hz, 2H), 2.49-2.37 (m, 6H), 2.24-2.08 (m, 2H), 2.05-1.90 (m, 4H), 1 .67 (d, J = 4.4 Hz, 2H); MS (ESI) m/z: 733.6 [M+H]'f.
Figure imgf000534_0004
[001413] 7-Cyclopentyl-2-((4-(2-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)amino)-A,Ar-dimethyl-7Z/-pyrrolo[2,3-t7]pyrimidine- 6-carboxamide A426. TH NMR (400 MHz, DMSO-d6 ) d' 10.29 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 7.72 (d, J= 8.4 Hz, 2H), 7.20 (t, J= 8.0 Hz, 1H), 7.13 (d, J= 8.4 Hz, 2H), 6.87 (s, 1H), 6.82-6.78 (m, 1H), 6.71 (d, J= 7.6 Hz, 1H), 6.57 (s, 1H), 4.80-4.66 (m, 1H), 3.74 (t, J= 6.4 Hz, 2H), 3.14-3.09 (m, 4H ), 3.05 (s, 6H), 2.98 (d, .7 10.4 Hz, 2H), 2.70-2.65 (m, 4H), 2.63-2.59 (m, 4H), 2.48-2.41 (m, 4H), 2.25-2.12 (m, 1H), 2.02-1.90 (m, 6H), 1.77 (d, J = 10.8 Hz, 2H), 1.70- 1.59 (m, 2H), 1.51-1.35 (m, 2H); MS (ESI) zw/z: 733.2 [M+H]+
Figure imgf000535_0001
[001414] 7-Cyclopentyl-2-((4-(4-(l-(3-(2,4-dioxotetrahydropyrimidin-l(2/7)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)phenyi)amino)-A;,A?-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A429.
Figure imgf000535_0002
NMR (400 MHz, CDCh) d 8.60 (s, 1H), 8.41 (s, 1H), 8.09-7,88 (m, 1H), 7.66 ( s, 1H), 7.62 (d, J= 8.8 Hz, 2H), 7.38-7.33 (m, 1H), 7.22 (s, 1H), 7.19-7.13 (m, 2H), 6.94 (d, J- 8.8 Hz, 2H), 6.41 (s, 1H), 4.81-4.71 (m, 1H), 3.89 (t, J- 6.4 Hz, 2H), 3.33 ( d, J- 1 1.2 Hz, 2H), 3.24 ( s, 4H), 3.16 (s, 6H), 3.03-2.97 (m, 2H), 2.91 ( d, J = 8.4 Hz, 2H), 2.87-2.83 (m, 5H), 2.64-2.54 (m, 4H), 2.53-2.45 (m, 4H), 2.04-1.91 (m, 6H), 1.72-1.64 (m, 2H); MS (ESI) Wz:
733.3 [M+H]A
Figure imgf000535_0003
[001415] 7-Cyclopentyl-2-((4-((6-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-l/7-indazol-
7-yl)oxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-Az,Ar-dimethyl-7/f-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A503.
Figure imgf000536_0001
[001416] 7-Cyclopentyl-2-((4-((4-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-U7-indazol-
6-yl)oxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-ADV-dimethyl-7//-pyrrolo[2,3- d]pyrimidine-6-carboxamide A505.
Figure imgf000536_0002
[001417] 7-Cyclopentyl-2-((4-((6-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-H7-indazol-
6-yl)oxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-Az,7V-dimethyl-7/?-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A506.
Figure imgf000536_0003
[001418] 7-Cyclopentyl-2-((4-((2-(4-(2-((3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-l - methyl- 1 J7-indazol-7-yl)oxy)acetyl)piperazin- 1 -yl)ethyl)carbamoyl)phenyl)amino)-A^V- dimethyl-7H-pyrrolo[2,3-Jjpyrimidine-6-carboxamide A551.
Figure imgf000536_0004
NMR (400 MHz, DMSO-H) d 10.52 (s, 1H), 9.81 (s, 1H), 8.79 (s, 1H), 8.24 (t, J= 6.4 Hz, 1H), 7.91 (d, J= 8.8 Hz, 2H), 7.79 (d, ./ 8.8 Hz, 2H), 7.16 (d, ./ 8.0 Hz, HI), 6.96 (t, 8.0 Hz, HI), 6.86 (d, ./ 7.6 Hz, HI),
6.62 (s, 1H), 5.02 (s, 2H), 4.75 (t, J= 9.2 Hz, 1H), 4.23 (s, 3H), 3.88 (t, ./= 6.8 Hz, 2H), 3.52- 3.46 (m, 4H), 3.42-3.36 (m, 2H), 3.10-3.01 (m, 6H), 2.75 (t, J= 6.8 Hz, 2H), 2.46-2.40 (m, 3H), 2.05-1.94 (m, 8H), 1.73-1.63 (m, 2H), 1.49-1.41 (m, 1H); MS (ESI) m/z: 805.2 [MHTf.
Figure imgf000537_0001
[001419] 7-Cy clopentyl-2-((4-((4-(4-(2-((3 -(2,4-dioxotetrahy dropyrimidin- 1 (27Z)-y 1 ) - 1 - methyl- 17/-indazol-7-yl)oxy)acetyl)piperazin- 1 -yl)butyl)carbamoyl)phenyl)amino)-A', N- dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A552.
Figure imgf000537_0002
[001420] 7-Cyclopentyl-2-((4-((6-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)-l- methyl-l//-indazol-7-yl)oxy)acetyd)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-AA rIV- dimethyl-7J7-pyrrolo[2,3-6f]pyrimidine-6-carboxamide A553.
Figure imgf000537_0003
[001421] 7-Cyclopentyl-2-((4-((2-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)-l- methyl-l/7-indazol-6-yl)oxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A^V- dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A554.
Figure imgf000537_0004
[001422] 7-Cyclopentyl-2-((4-((4-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(27/)-yl)-l- methyl- l/7-indazol-6-yl)oxy)acetyl)piperazin- 1 -yl)butyl)carbamoyl)phenyl)amino)-Az,/V- dimethyl-777-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A555.
Figure imgf000538_0001
[001423] 7-Cy clopentyl-2-((4-((6-(4-(2-((3 -(2,4-dioxotetrahy dropyrimidin- 1 (277)-y 1 ) - 1 - methyl- l//-indazol-6-yl)oxy)acetyl)piperazin- 1 -yl)hexyl)carbamoyl)phenyl)amino)-A, N- dimethyl-7/f-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A556.
Figure imgf000538_0002
[001424] 7-Cyclopentyl-2-((5-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2Z/)-yl)-l-methyl- lJ7-indazol-6-yl)ethyl)-4-fluoro-[l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-jV,7V-dimethyl-7J/- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A557.
Figure imgf000538_0003
[001425] 7-Cyclopentyl-2-((5-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2Z/)-yl)-l-methyl- l//-indazol-7-yl)ethyl)-4-fluoro-[l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-A’,A-dimethyl-7Z/- pyrrol o[2, 3 -<7]pyrimidine-6-carboxamide A558.
Figure imgf000538_0004
[001426] 7-Cyclopentyl-2-((4-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)hexyl)(metliyl)carbanioyl)phenyl)amino)-A^V-dimethyl-72f-pyrrolo[2,3-^pyrimidine-
6-carboxamide A602.
Figure imgf000539_0001
[001427] 7-Cyclopentyl-2-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-l ,3-dioxoisoindolin-4- yl)glycyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A/-dimethyl-7Z/-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A603
Figure imgf000539_0002
[001428] 7-Cyclopentyl-2-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)- glycyl)piperazin-l-yl)pyri din-2 -yl)amino)-A7,A'r-dimethyl-7/7-pyrrolo[2,3-t(|pyrimidine-6- carboxamide A611.
Figure imgf000539_0003
[001429] 7-Cyclopentyl-2-((4-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
4-yl)piperidin-l-yl)ethyl)carbamoyl)phenyl)amino)-AAV-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A612.
Figure imgf000540_0001
[001430] 7-Cyclopentyl-2-((4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
4-yl)piperidin-l-yl)butyl)carbamoyl)phenyl)amino)-A',JV-dimethyl-7/7-pyrrolo[2,3-^pyrimidine-
6-carboxamide A613
Figure imgf000540_0002
[001431] 7-Cyclopentyl-2-((4-((6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
4-yl)piperidin-l-yl)hexyl)carbamoyl)phenyl)amino)-jV,Az-dimethyl-7Z/-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A614.
Figure imgf000540_0003
[001432] 7-Cyclopentyl-2-((5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- i soindolin-4-yl)piperidin- 1 -yl)acetyl)piperazin- 1 -yl)pyridin-2-yl)amino)-ArjV-dimethyl-7J7- pyrrolo[2,3-</]pyrimidine-6-carboxamide A615.
Figure imgf000541_0001
[001433] 7-Cyclopentyl-2-((5-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-4-yl)piperidin-l-yl)propanoyl)piperazin- l-yl)pyridin-2-yl)amino)-A’,A7-dimethyl-7Ar- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A616.
Figure imgf000541_0002
[001434] 7-Cyclopentyl-2-((5-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-4-yl)piperidin-l-yl)butanoyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar/vr-dimethyl-77/- pyrrolo[2,3-^pyrimidine-6-carboxamide A617.
Figure imgf000541_0003
[001435] 7-Cyclopentyl-2-((4-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
5-yl)piperidin-l-yl)ethyl)carbamoyl)phenyl)amino)-A’^\r-dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-
6-carboxamide A618.
Figure imgf000542_0001
[001436] 7-Cyclopentyl-2-((4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
5-yl)piperidin-l-yl)butyl)carbamoyl)phenyl)amino)-/VpV-dimethyl-7#-pyrrolo[2,3-47]pyrimidine-
6-carboxamide A619.
Figure imgf000542_0002
[001437] 7-Cyclopentyl-2-((4-((6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
5-yl)piperidin-l-yl)hexyl)carbamoyl)phenyl)amino)-Ar,A/-dimethyl-7Z/-pyrrolo[2,3-<7]pyrimidine-
6-carboxamide A620.
Figure imgf000542_0003
[001438] 7-Cyclopentyl-2-((5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-5-yl)piperidin- l-yl)acetyl)piperaziii-l-yl)pyridin-2-yl)amino)-7VjV-dimethyl-7J/- pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A621
Figure imgf000542_0004
[001439] 7-Cyclopentyl-2-((5-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-5-yl)piperidin-l-yl)propanoyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,jV-dimethyl-7/f- pyrrolo[2,3-iZ]pyrimidine-6-carboxamide A622.
Figure imgf000543_0001
[001440] 7-Cyclopentyl-2-((5-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-5-yl)piperidin-l-yl)butanoyl)piperazin-l-yl)pyridin-2-yl)amino)-A’,A-dimethyl-7Ar- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A623.
Figure imgf000543_0002
[001441] 7-Cyclopentyl-2-((4-((2-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4/7- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)amino)ethyl)carbamoyl)phenyl)amino)-A'/Adimethyl- 77/-pyrrolo[2,3-^pyrimidine-6-carboxamide A652.
Figure imgf000543_0003
[001442] 7-Cyclopentyl-2-((4-((4-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-477- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)amino)butyl)carbamoyl)phenyl)amino)-A,A-dimethyl- 7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A653.
Figure imgf000543_0004
[001443] 7-Cyclopentyl-2-((4-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4Jff- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)carbamoyl)phenyl)amino)-A7,A-dimethyl-7/7-pyrrolo- [2,3-<7]pyrimidine-6-carboxamide A654. vHNMR (400 MHz, DMSO-cfc) 3 10.96 (s, 1H), 9.82 (s, 1H), 8.79 (t, J= 6.8 Hz, 2H), 8.00 (s, 1H), 7.92 (d, J= 8.8 Hz, 2H), 7.85 (d, J= 8.8 Hz, 2H), 7.26 (d, ./= 8.4 Hz, 2H), 6.99 (d, J= 8.8 Hz, 2H), 6.61 (s, 1H), 5.28 (s, 2H), 5.01 (dd, 4.8, 13.2 Hz, 1H), 4.77-4.70 (m, 1H), 4.41 (d, J= 6.0 Hz, 2H), 4.36-4.20 (m, 2H), 3.06 (s, 6H), 2.92- 2.83 (m, 1H), 2.59-2.54 (m, 1H), 2.46-2.44 (m, 1H), 2.35-2.31 (m, 1H), 2.01-1.96 (m, 5H), 1.70- 1.68 (m, 2H); MS (ESI) m/z: 761.4 [M+H]+.
Figure imgf000544_0001
[001444] 3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethoxy)phenyl)piperidine-2, 6-dione B101 ’HNMR (400 MHz, DMSO-t/c) 3 10.83 (s, 1H), 10.13 (s, 1H), 8.96 (s, 1H), 8.09 (d, J= 2.8 Hz, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.51 (dd, J= 3.2, 9.2 Hz, 1H), 7.29-7.17 (m, 1H), 6.88- 6.76 (m, 3H), 5.83 (s, 1H), 4.86 (s, 2H), 3.82 (d, ./= 6.4 Hz, 1H), 3.64 (s, 4H), 3.26-3.10 (m, 4H), 2.72-2.58 (m, 1H), 2.46 (d, J = 4.4 Hz, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.28-2.13 (m, 3H), 2.11-1.97 (m, 1H), 1.79-1.94 (m, 2H), 1.83-1.71 (m, 2H), 1.66-1.51 (m, 2H); MS (ESI) m/z:
693.5 [M+H]+.
Figure imgf000544_0002
[001445] A-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- methylphenoxy)acetamide B105
Figure imgf000544_0003
NMR (400 MHz, DMSO-de) 3 10.82 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.03 (d, J= 3.2 Hz, 1H), 7.93 (t, J= 5.6 Hz, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.48- 7.42 (m, 1H), 7.08 (d, J- 8.0 Hz, 1H), 6.80-6.71 (m, 2H), 5.88-5.75 (m, 1H), 4.42 (s, 2H), 4.03- 3.93 (m, 1H), 3.30-3.22 (m, 4H), 3.10 (br d, ./= 4.8 Hz, 4H), 2.76-2.65 (m, 1H), 2.55-2.52 (m, 4H), 2.45 (br d, ./= 6.8 Hz, 2H), 2.42 (s, 3H), 2.30 (m, 3H), 2.27-2.19 (m, 2H), 2.17 (s, 3H), 1.98-1.91 (m, 1H), 1.91-1.81 (m, 2H), 1.81-1.70 (m, 2H), 1.64-1.51 (m, 2H); MS (ESI) m/z: 750.4 [M+H]+.
Figure imgf000545_0001
[001446] A-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- (trifluoromethyl)phenoxy)acetamide B106. !H NMR (400 MHz, DMSO-d6 ) 3 10.93 (s, 1H), 10.09 (s, 1H), 8.95 (s, 1H), 8.11-7.98 (m, 2H), 7.85 (d, J = 9.2 Hz, 1H), 7.65 (d, J= 8.8 Hz, 1H), 7.45 (dd, J= 2.8, 9.2 Hz, 1H), 7.07 (s, 1H), 7.05-7.00 (m, 1H), 5.88-5.73 (m, 1H), 4.58 (d, J = 4.8 Hz, 2H), 4.05 (dd, J= 5.2, 12.4 Hz, 1H), 3.29-3.28 (m, 2H), 3.12 (s, 4H), 2.89-2.74 (m, 1H), 2.54 (d, J= 2.4 Hz, 5H), 2.45 (s, 2H), 2.42 (s, 3H), 2.32 (d, J= 2.0 Hz, 1H), 2.31 (s, 3H), 2.27- 2.21 (m, 2H), 2.02-1.93 (m, 1H), 1.87 (d, ./ 5.2 Hz, 2H), 1.82-1.70 (m, 2H), 1.63-1.50 (m, 2H); MS (ESI) m/z: 804.4 [M+H]+.
Figure imgf000545_0002
[001447] A-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- methylphenoxy)acetamide B107 1H NMR (400 MHz, DMSO-d6 ) 3 10.83 (s, 1H), 10.79-10.57 (m, 2H), 9.00 (s, 1H), 8.19 (t, J= 6.0 Hz, 1H), 8.10 (d, J= 2.4 Hz, 1H), 7.91-7.84 (m, 1H), 7.80 (s, 1H), 7.16-7.08 (m, 1H), 6.77 (t, J = 8.4 Hz, 2H), 5.84 (t, ./ 9.2 Hz, 1H), 4.51 (s, 2H), 4.10 (s, 1H), 3.86 (d, J= 11.2 Hz, 2H), 3.56 (d, J= 10.0 Hz, 2H), 3.29-3.08 (m, 8H), 2.80-2.70 (m, 1H), 2.43 (s, 3H), 2.34 (s, 3H), 2.32-2.18 (m, 6H), 2.17-2.11 (m, 1H), 1.99-1.87 (m, 5H), 1.84-1.75 (m, 2H), 1.64-1.56 (m, 2H); MS (ESI) m/z: 764.5 [M+H] \
Figure imgf000546_0001
[001448] A-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- (trifluoromethyl)phenoxy)acetamide B108. lH NMR (400 MHz, DMSO-rZ?) <5 10.87 (br s, 1H), 10.09 (s, 1H), 8.95 (s, 1H), 8.03 (d, J- 2.8 Hz, 1H), 7.84 (br d, J - 9.2 Hz, 2H), 7.55 (s, 1H), 7.49-7.39 (m, 1H), 7.11 (br d, .7= 7.8 Hz, 1H), 7.02 (br d, J= 8.0 Hz, 1H), 5.88-5.76 (m, 1H), 4.62 (s, 2H), 4.32-4.16 (m, 1H), 3.25-3.20 (m, 2H), 3.15 (br d, J= 11.4 Hz, 4H), 2.83-2.71 (m, 1H), 2.63 (br d, J- 3.4 Hz, 1H), 2.54 (br s, 4H), 2.42 (s, 3H), 2.36 (br t, J- 7.0 Hz, 2H), 2.31 (s, 3H), 2.29-2.16 (m, 3H), 2.04-1.94 (m, 1H), 1.88 (br s, 2H), 1.81-1.72 (m, 2H), 1.69-1.52 (m, 4H); MS (ESI) m/z'. 818.2 [M-H] .
Figure imgf000546_0002
[001449] A-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- (trifluoromethyl)phenoxy)acetamide B110 !H NMR (400 MHz, CDsOD) § 8.92 (s, 1H), 8.01 (d, .7= 2.8 Hz, 1H), 7.95 (d, .7= 9.2 Hz, 1H), 7.65 (d, .7= 8.8 Hz, 1H), 7.47 (dd, .7= 2.8, 9.2 Hz, 1H), 7.09-6.97 (m, 2H), 5.95 (q, J= 8.8 Hz, 1H), 4.60 (s, 2H), 4.16 (dd, J= 5.2, 12.4 Hz, 1H), 3.38-3.35 (m, 2H), 3.24-3.19 (m, 4H), 2.84-2.75 (m, 1H), 2.74-2.69 (m, 1H), 2.68-2.60 (m, 4H), 2.50-2.44 (m, 5H), 2.38 (s, 3H), 2.35-2.24 (m, 3H), 2.21-2.13 (m, 1H), 2.02-1.95 (m, 2H), 1.91- 1.84 (m, 2H), 1.83-1.76 (m, 2H), 1.72-1.63 (m, 2H); MS (ESI) m/z: 818.5 [M+H]+.
Figure imgf000547_0001
[001450] 3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-rnethyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)phenyl)piperidine-2, 6-dione Bill
Figure imgf000547_0002
[001451] 3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyi-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2, 6-dione Bill.
Figure imgf000547_0003
[001452] 3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-^- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethoxy)phenyl)piperidine-2, 6-dione Bl 13.
Figure imgf000547_0004
[001453] 3-(3-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)phenyl)piperidine-2, 6-dione Bl 14.
Figure imgf000548_0001
[001454] 3-(3-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2, 6-dione B115.
Figure imgf000548_0002
[001455] 3-(3-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-^ pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethoxy)phenyl)piperidine-2, 6-dione B116.
Figure imgf000548_0003
[001456] 3-(4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propoxy)phenyl)piperidine-2, 6-dione B117.
Figure imgf000548_0004
[001457] 3-(3-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propoxy)phenyl)piperidine-2, 6-dione BUS.
Figure imgf000549_0001
[001458] 3-(4-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(7]- pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin-l-yl)piperi din- l-yl)phenyl)piperidine-2, 6-dione
B119
Figure imgf000549_0002
[001459] 3-(4-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tf|pyriinidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)methyl)piperidin-l-yl)phenyl)piperidine-
2, 6-dione B120.
Figure imgf000549_0003
[001460] 3-(4-((4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)piperi din- l-yl)methyl)phenyl)piperidine-
2,6-dione B121
Figure imgf000549_0004
[001461] 3-(3-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-2, 6-dione
B122
Figure imgf000550_0001
[001462] 3-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
^pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)piperidin-l -yl)phenyl)piperidine-
2,6-dione B123.
Figure imgf000550_0002
[001463] 3-(3-((4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)piperi din- l-yl)methyl)phenyl)piperi dine-
Figure imgf000550_0003
[001464] 3-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -yl)ethyl)piperazin- 1 -yl)phenyl)piperidine-2, 6- dione
Figure imgf000550_0004
10.76 (s, 1H), 9.09 (s, 1H), 8.37-8.26 (m, 1H), 8.15 (d, J= 2.4 Hz, 1H), 7.88 (d, J= 9.6 Hz, 1H), 7.12 (d, J= 8.4 Hz, 2H), 7.01 (d, J= 8.8 Hz, 2H), 5.89-5.78 (m, 1H), 3.79 (s, 3H), 3.76 (d, J= 5.0 Hz, 2H), 3.71-3.24 (m, 13H), 2.72-2.56 (m, 2H), 2.43 (s, 3H), 2.40-2.29 (m, 4H), 2.27-2.08 (m, 4H), 2.05-1.91 (m, 4H), 1.85-1.75 (m, 2H), 1.63-1.52 (m, 2H); MS (ESI) m/z: 747.6 [M+H]+.
Figure imgf000551_0001
[001465] 3-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
</|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-] -yl)ethyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B126.
Figure imgf000551_0002
[001466] 3-(4-(2-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-] -yl)piperidin-l-yl)ethyl)phenyl)piperidine-2,6-
Figure imgf000551_0003
[001467] 3-(3-(2-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)piperi din- l-yl)ethyl)phenyl)piperidine-2,6- dione B128.
Figure imgf000551_0004
[001468] 3-(4-((l-(2-((4-((6-(Difluoromethyl)-8-((lA,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione B129.
Figure imgf000552_0001
[001469] 3 -(4-(4-(2-((4-((6-(Difluoromethyl)-8-(( l/?,2/?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-tf]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperazin-l- yl)phenyl)piperidine-2, 6-dione B132 rH NMR (400 MHz, DMSO-fifc) J 0.94-1.02 (m, 3H), 1.39-1.50 (m, 1H), 1.60-1.70 (m, 2H), 1.84 -1.86(m, 2H), 1.91 -2.02 (m, 3H), 2.13-2.22 (m, 2H), 2.27-2.38 (m, 1H), 2.44 (d, J = 4.4 Hz, 2H), 2.59 -2.62(m, 5H), 2.62-2.69 (m, 2H), 2.74 (d, J = 6.8 Hz, 2H), 2.95-3.03 (m, 2H), 3.13 -3.16(m, 4H), 3.59-3.68 (m, 2H), 3.72 -3.76(m, 1H), 3.88- 4.08 (m, 1H), 4.37-4.38(m, 1H), 5.77-5.91 (m, 1H), 6.84-7.09 (m, 5H), 8.00-8.25 (m, 2H), 8.68- 8.79 (m, 1H), 10.76 (s, 1H); MS (ESI) m/z: 757.3 [M+H]+.
Figure imgf000552_0002
[001470] 3-(4-(4-(2-((4-((6-(Difluoromethyl)-8-((17?,27?)-2 -hydroxy -2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-«7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione B133.
Figure imgf000552_0003
[001471] 3-(4-(4-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2 -hydroxy -2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-Jjpyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B134.
Figure imgf000553_0001
[001472] 3-(3-(4-(2-((4-((6-(Difluoromethyl)-8-(( 17?, 2R)-2 -hydroxy -2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin- 1 -yl)sulfonyl)ethyl)piperazin- 1 - yl)phenyl)piperidine-2, 6-dione B135.
Figure imgf000553_0002
NMR (400 MHz, CDCh) d 8.55 (s, 1H), 8.04 (s, 1H),
7.87 (s, 1H), 7.42-7.29 (m, 1H), 7.30-7.22 (m, 2H), 6.91-6.86 (m, 1H), 6.82-6.73 (m, 2H), 6.76- 6.71 (m, 1H), 6.30-6.02 (m, 1H), 5.87-5.65 (m, 1H), 4. 16-3.95 (m, 1H), 3.95-3.69 (m, 4H), 3.35- 3.17 (m, 7H), 3.11-2.98 (m, 2H), 2.95-2.88 (m, 2H), 2.74-2.60 (m, 8H), 2.32-2.26 (m, 2H), 2.17- 1.97 (rn, 4H), 1.89-1.81 (m, 2H), 1.36 (s, 3H); MS (ESI) m/r. 757.5 [M+H]+.
Figure imgf000553_0003
[001473] 3-(3-(4-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B136
Figure imgf000553_0004
[001474] 3-(4-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propoxy)phenyl)- piperidine-2, 6-dione B137.
Figure imgf000554_0001
[001475] 3-(3-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propoxy)phenyl)- piperidine-2, 6-dione B138
Figure imgf000554_0002
[001476] 3-(4-(4-(4-((4-((6-(Difluoromethyl)-8-((lA,2/?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-<7jpyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)benzyl)piperazin-
1 -yl)phenyl)piperi di ne-2, 6-dione B139.
Figure imgf000554_0003
[001477] 3-(3-(4-(3-((4-((6-(Difluoromethyr)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-</]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)benzyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B141. 1H NMR (400 MHz, DMSO-dfc) d 10.77 (s, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 8.15 (d, J= 6.6 Hz, 1H), 8.05 (s, 1H), 7.79-7.57 (m, 4H), 7.15-7.07 (m, 1H), 6.87-6.69 (m, 3H), 6.60 (d, J= 7.6 Hz, 1H), 5.94-5.56 (m, 1H), 4.35 (s, 1H), 3.74 (dd, J = 4.4, 11.2 Hz, 2H), 3.68-3.62 (m, 4H), 3.11-3.13 (m, 4H), 2.62-2.58 (m, 2H), 2.53-2.54 (m, 4H), 2.45- 2.39 (m, 2H), 2.25-2.06 (m, 3H), 2.01 (td, J= 4.4, 13.2 Hz, 1H), 1.96-1.87 (m, 2H), 1.73 (s, 2H), 1.65-1.55 (m, 2H), 1.53-1.40 (m, 1H), 1.34-1.21 (m, 1H), 1.00-0.86 (m, 3H); MS (ESI) ra/z: 410.3 [M/2+Hf.
Figure imgf000555_0001
[001478] 3-(3-(4-(4-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)benzyl)piperazin-
1 -yl)phenyl)piperi di ne-2, 6-dione B142.
Figure imgf000555_0002
[001479] 3-(4-((4-(4-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-Jjpyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperazin- l-yl)methyl)phenyl)piperidine-2, 6-dione B143.
Figure imgf000555_0003
[001480] 3-(4-(4-((4-(4-((4-((6-(Difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-c/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B144.
Figure imgf000555_0004
[001481] 3-(4-((4-((4-((6-(Difluoromethyl)-8-((l/?,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-<7]pyriniidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l -yl)- methyl)phenyl)piperidine-2, 6-dione B145.
Figure imgf000556_0001
[001482] 3-(3-((4-((4-((6-(Difluoromethyl)-8-((l/?,2Z^)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-</jpyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l -yl)- methyl)phenyl)piperidine-2, 6-dione B146.
Figure imgf000556_0002
[001483] 3-(4-(4-((4-((4-((6-(Difluoromethyl)-8-((lJ?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-^pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B147.
Figure imgf000556_0003
[001484] 3-(4-(4-(3-((4-((6-(Difluoromethyl)-8-((lJ?,2Z?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-i/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfbnyl)propyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B148
Figure imgf000557_0001
[001485] 3-(3-((l-(3-((4-((6-(Difluoromethyl)-8-((lJ?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione Bl 49.
Figure imgf000557_0002
[001486] 3-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
Jjpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B150. NMR (400 MHz, DMSCWe) <5 11.51 (d, J = 2.0 Hz, 1H), 10.86 (s, 1H), 9.09 (s, 1H), 8.32 (d, J= 7.6 Hz, 1H), 8.12 (s, 1H), 7.93-7.80 (m, 3H), 7.43 (d, J= 8.4 Hz, 2H), 5.88- 5.82 (m, 1H), 4.01-3.87 (m, 3H), 3.67-3.48 (m, 6H), 3.36 (d, J = 11.6 Hz, 2H), 3.22 (s, 4H), 2.75-2.63 (m, 1H), 2.43 (s, 3H), 2.35 (s, 3H), 2.26 (s, 4H), 1.97 (s, 7H), 1.81 (s, 5H), 1.58 (d, J =
4.6 Hz, 2H); MS (ESI) m/z'. 746.6 [M+H]+
Figure imgf000557_0003
[001487] 3-(4-(2-(4-(4-((4-((6-(Difluoromethyl)-8-((lA,2A)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<f]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)- piperazin- 1 -yl)ethyl)phenyl)piperidine-2, 6-dione B151. MS (ESI) OT/Z: 417.5 [M/2+H]+.
Figure imgf000558_0001
[001488] 3-(4-(2-(4-(4-((4-((6-(Difluoromethyl)-8-((lJR,27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)- piperazin- l-yl)ethoxy)phenyl)piperidine-2, 6-dione B152. rH NMR (400 MHz, DMSO-de) d 10.79 (s, 1H), 8.77-8.68 (m, 1H), 8.34-7.88 (m, 2H), 7.52 (d, J= 8.8 Hz, 2H), 7.11 (dd, J= 8.8, 18,4 Hz, 4H), 6,98-6,71 (m, 3H), 5,85-5,70 (m, 1H), 4,38-4,32 (m, 1H), 4,12 (br t, J= 6,0 Hz, 2H), 3.81-3.75 (m, 2H), 3.61-3.52 (m, 4H), 2.76 (br t, J= 5.2 Hz, 2H), 2.69-2.60 (m, 6H), 2.46- 2.40 (m, 2H), 2.21-1.95 (m, 5H), 1.95-1.42 (m, 9H), 0.99-0.90 (m, 3H); MS (ESI) m/z: 850.3 [M+H]+.
Figure imgf000558_0002
[001489] 3-(4-(2-(4-(3-((4-((6-(Difluoromethyl)-8-((U?,2J?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)aniino)piperidin-l-yl)sulfonyl)phenyl)- piperazin- l-yl)ethyl)phenyl)piperidine-2, 6-dione B153. MS (ESI) m/z: 833.4 [M+H]+.
Figure imgf000558_0003
[001490] 3 -(3 -(2-(4-((4-((6-(Difluoromethyl)-8-(( lZ?,2/?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- ethoxy)phenyl)piperi dine-2, 6-dione B154. MS (ESI) m/z: 773.4 [M+H]* .
Figure imgf000559_0001
[001491] 3-(4-(3-(4-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-^pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l -yl)- propoxy)phenyl)piperidine-2, 6-dione B155. MS (ESI) m/z'. 787.3 [M+H]+.
Figure imgf000559_0002
[001492] 3-(3-(3-(4-((4-((6-(Difluoromethyl)-8-((17?,2R)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin- 1 -yl)sulfonyl)piperazin- 1 -yl)- propoxy)phenyl)piperidine-2, 6-dione Bl 56 MS (ESI) m/z\ 787.4 [M+H] \
Figure imgf000559_0003
[001493] 3-(4-(4-(4-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-«7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenethyl)- piperazin- l-yl)phenyl)piperidine-2, 6-dione B157. MS (ESI) m/z'. 417.4 [M/2+H]+.
Figure imgf000559_0004
[001494] 3-(4-(4-(2-(4-((4-((6-(Difluoromethyl)-8-((l/?,27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-</|pyriniidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenoxy)- ethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B158. MS (ESI) m/z'. 849.4 [M+H]+.
Figure imgf000560_0001
[001495] 3-(4-(4-(2-(3-((4-((6-(Difluoromethyl)-8-((l/?,27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenoxy)- ethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B159 MS (ESI) m/z: 849.4 [M+H]+.
Figure imgf000560_0002
[001496] 3-(3-((l-(3-((4-((6-(Diiluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin-
4-yl)oxy)phenyl)piperidine-2, 6-dione B160. MS (ESI) m/z: 410.8 [M/2+H]1.
Figure imgf000560_0003
[001497] 3-(4-((l-(3-((4-((6-(Difluoromethyl)-8-((17?,2J?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-iZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin-
4-yl)oxy)phenyl)piperidine-2, 6-dione B161. MS (ESI) m/z: 410.9 [M/2+H] \
Figure imgf000560_0004
[001498] 3-(4-((l-(4-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-niethylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin-
4-yl)oxy)phenyl)piperidine-2, 6-dione B162. MS (ESI) m/z'. 410.7 [M/2+H]+.
Figure imgf000561_0001
[001499] 3-(4-(4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2 -yl)amino)pyri din-3 -yl)piperazin- 1 -yl)propyl)piperazin- 1 -yl)phenyl)piperi dine- 2,6-dione B163. MS (ESI) m/z: 761.2 [M+H]+.
Figure imgf000561_0002
[001500] 3-(4-(4-((4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<y]pyrimidin-2-yl)amino)pyridin-3-yl)piperaz.in-l-yl)piperidin-l-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B164
Figure imgf000561_0003
NMR (400 MHz, DMSO<fc) <5 1.16-1.24 (m, 2H), 1.39- 1.48 (m, 2H), 1.51-1.69 (m, 4H), 1.73-1.80 (m, 6H), 1,83-1.91 (m, 411), 1.93-2.08 (m, 2H), 2.14 (d, J -- 7.6 Hz, 2H), 2.20-2.26 (m, 3H), 2.31 (s, 3H), 2.42 (s, 3H), 2.61-2.68 (m, 7H), 2.86-2.92 (m, 2H), 3.14-3.18 (s, 4H), 3.65 (d, J = 12.6 Hz, 2H), 3.69-3.74 (m, 1H), 5.82 (t, J = 8.8 Hz, 1H), 6.88 (d, J - 8.6 Hz, 2H), 7.03 (d, J -- 8.8 Hz, 2H), 7.42-7.48 (m, 1H), 7.84 (d, ./ = 9.2 Hz, 1H), 8.04 (d, J = 3.0 Hz, 1H), 8.19 (s, 1H), 8.95 (s, 1H), 10.08 (s, 1H), 10.76 (s, 1H); MS (ESI) m/z: 815.5 [M+H]+.
Figure imgf000561_0004
[001501] 3-(4-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
4/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-[l,4'-bipiperidin]-l'-yl)phenyl)- piperidine-2, 6-dione Bl 65 MS (ESI) m/z: 815.5 [M+H]t
Figure imgf000562_0001
[001502] 3-(4-(4-(l-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B166. MS (ESI) m/z: 830.5 [M+H]+.
Figure imgf000562_0002
[001503] 3-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-[l,4'-bipiperidin]-r-yl)phenyl)- piperidine-2, 6-dione B167 MS (ESI) m/z: 415.5 [M/2+H]+.
Figure imgf000562_0003
[001504] 3-(4-(4-(3-((4-((8-Cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)- amino)piperidin-l-yl)sulfonyl)propyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B168 MS (ESI) m/z: 691.5 [M+H]+.
Figure imgf000563_0001
[001505] 3-(4-(4-(3-((4-((8-Cyclopentyl-6-(difluoromethyl)-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B169 MS (ESI) m/z: 741.3 [M+H]+.
Figure imgf000563_0002
[001506] 3-(4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-[l,4'-bipiperidin]-l'-yl)phenyl)piperidine-2,6- dione B170. MS (ESI) m/z: 801.8 [M+H]+.
Figure imgf000563_0003
[001507] 3-(4-(4-((3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7.8-dihydropyrido-
[2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidiii-l-yl)niethyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B171. MS (ESI) m/z: 815.5 [M+H]’.
Figure imgf000563_0004
[001508] 3-(4-((4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3 -cZ]pyrimi din-2 -yl)amino)pyri din-3 -yl)piperazin-l-yl)cyclohexyl)piperidin-l-yl)methyl)- phenyl)piperidine-2, 6-dione B174. MS (ESI) m/z: 814.6 [M+H]’.
Figure imgf000564_0001
[001509] 3-(4-(2-(4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperidin-l-yl)ethyl)- phenyl)piperidine-2, 6-dione B175 !H NMR (400 MHz, DMSO-^) 3 11.16-10.97 (m, 1H),
10.83 (s, 1H), 10.55-10.35 (m, 1H), 9.00 (s, 1H), 8.11 (d, J= 2.0 Hz, 1H), 7.90-7.85 (m, 1H), 7.85-7.78 (m, 1H), 7.29-7.17 (m, 4H), 5.84 (quin, J- 8.8 Hz, 1H), 3.85 (td, 5.6, 11.2 Hz, 4H), 3.36 (br d, J= 11.6 Hz, 4H), 3.29-3.17 (m, 5H), 3.07 (br dd, J= 5.6, 10.9 Hz, 3H), 2.93-
2.80 (m, 2H), 2.71-2.62 (m, 1H), 2.47 (br d, ./= 4.4 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3H), 2.29-2.07 (m, 6H), 2.06-1.83 (m, 6H), 1.82-1.74 (m, 2H), 1.72-1.54 (m, 8H), 1.52-1.34 (m, 4H); MS (ESI) m/z\ 828.5 [M+H]+
Figure imgf000564_0002
[001510] 3-(4-(3-((4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)azetidin-l-yl)- phenyl)piperidine-2, 6-dione B176. MS (ESI) m/z: 787 A [M+H] t
Figure imgf000565_0001
[001511] 3-(4-(4-((5)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)piperidin-l- yl)phenyl)piperidine-2, 6-dione B177. MS (ESI) m/z\ 817.6 [M+H]+.
Figure imgf000565_0002
[001512] 3-(4-(4-((/?)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)piperidin-l- yl)phenyl)piperidine-2, 6-dione B178 MS (ESI) w/z: 817.4 [M+H]+.
Figure imgf000565_0003
[001513] 3-(4-(4-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)cyclohexyl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B179 MS (ESI) m/z1. 815.4 [M+H]+.
Figure imgf000565_0004
[001514] 3-(4-(4-(2-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-cZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)ethyl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B180. MS (ESI) m/z: 830.0 [M+H]’.
Figure imgf000566_0001
[001515] 3-(4-(2-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)ethyl)phenyl)piperidine-2,6- dione B181 MS (ESI) m/z: 745.4 [M+H]+.
Figure imgf000566_0002
[001516] 3-(4-(4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- dJpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B182 lH NMR (400 MHz, DMSO-fife) 4 10.78 (s, 1H), 10,10 (s, 1H), 8.96 (s, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.85 (d, J - 8.8 Hz, 1H), 7.47 (m, 1H), 7.05 (d, J - 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.80-5.86 (m, 1H), 3.73 (m, 1H), 3.17-3.20 (s, 5H), 3.12-3.16(s, 4H), 2.66-2.70 (m, 1H), 2.60 (s, 9H), 2.45 (d, J = 4.0 Hz, 1H), 2.43 (s, 3H), 2.31 (s, 3H), 2.22- 2.28 (m, 2H), 2.11-2.17 (m, 1H), 2.01 (m, 1H), 1.89 (d, J = 7.6 Hz, 2H), 1.71-1.80 (m, 4H), 1.63
(d, J 3.64 Hz, 2H), 1.56 (d, J = 11.6 Hz, 6H); MS (ESI) m/z: 801.6 [M+H] \
Figure imgf000566_0003
[001517] 3-(4-(4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B183 H NMR (400 MHz, CD3OD) <5 9.19 (s, 1H), 8.29 (dd, J = 2.3, 9.6 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.84-7.75 (m, 2H), 7.61 (d, J = 9.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 6.02 (q, J = 8.8 Hz, 1H), 5.37 (s, 2H), 4.03 (d, J = 5.2 Hz, 1H), 4.02-3.96 (m, 2H), 3.84-3.64 (m, 6H), 3.42-3.34 (m, 4H), 2.84-2.74 (m, 1H), 2.72-2.62 (m, 1H), 2.50 (s, 3H), 2.45 (s, 3H), 2.38-2.25
(m, 3H), 2.24-2.14 (m, 3H), 2.10 (s, 2H), 2.02-1 .81 (m, 7H), 1.78-1.63 (m, 2H), 1.54 (s, 2H); MS (ESI) m/z: 760.8 [M+H]+.
Figure imgf000567_0001
[001518] 3-(4-(3-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2 -yl)amino)pyri din-3 -yl)piperazin-l-yl)piperi din- l-yl)propoxy)phenyl)piperidine-
2,6-dione B184 MS (ESI) m/z: 776.5 [M+H]7
Figure imgf000567_0002
[001519] 3-(4-(r-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-[4,4'-bipiperidin]-l-yl)phenyl)- piperidine-2, 6-dione B185. MS (ESI) m/z: 829.8 [M+H]“.
Figure imgf000567_0003
[001520] 3-(4-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-c/]- pyrimidm-2yl)amino)pyridin-3-yl)piperazin-l-yl)-[l,4’-bipiperidin]-r-yi)phenyl)piperidine-2,6- dione B187 MS (ESI) m/z: 801.5 [M+H]+.
Figure imgf000568_0001
[001521] 3-(4-(4-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B189. MS (ESI) m/z: 801.5 [M+Hp.
Figure imgf000568_0002
[001522] 3-(3-(2-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)ethoxy)phenyl)piperidine- 2,6-dione B191 'H NMR (400 MHz, CD3OD) J 9.06 (s, 1H), 8.09-7.95 (m, 2H), 7.77-7.66 (m, 1H), 7.39-7.27 (m, 1H), 7,01-6,89 (m, 3H), 6,00 (q, 7 8.8 Hz, 1H), 4,46-4,36 (m, 2H), 3.87 (dd, .7= 5.6, 10.8 Hz, 3H), 3.64 (s, 2H), 3.59-3.50 (m, 4H), 3.48-3.38 (m, 5H), 3.29-3.21 (m, 2H), 2.76-2.60 (m, 2H), 2.50 (s, 4H), 2.45-2.40 (m, 4H), 2.38-2.27 (m, 3H), 2.26-2.03 (m, 6H), 1.95-
1.86 (m, 2H), 1.74-1.65 (m, 2H); MS (ESI) wk 762.3 [M~ H i .
Figure imgf000568_0003
[001523] 3-(3-(3-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
</|pyrimidiii-2-yl)amino)pyridiii-3-yl)piperazin-l-yl)piperidin-l-yl)propoxy)phenyl)piperidine- 2,6-dione Bl 92 MS (ESI) m/z: 776.5 | \i • ! i |
Figure imgf000569_0001
[001524] 3-(4-(4-(l-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-
2,6-dione B193. MS (ESI) m/z: 732.2 [M+H]+.
Figure imgf000569_0002
[001525] 3-(4-(4-(4-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-
2,6-dione B194 MS (ESI) m/z: 732.4 [M+H]+.
Figure imgf000569_0003
[001526] 3-(4-(l'-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- yrimidin-2-yl)amino)pyridin-3-yl)methyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione
B195. MS (ESI) m/z: 731.5 [M+H]t
Figure imgf000569_0004
[001527] 3-(4-(4-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)methyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione
B196 MS (ESI) wz: 731.3 [M+H]t
Figure imgf000570_0001
[001528] 3-(4-(4-((6-((6-Acetyl-8-cyclopentyl-5-rnethyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione
B197. MS (ESI) m/z\ 733.5 [M+H]t
Figure imgf000570_0002
[001529] 3-(4-(4-(2-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B198 MS (ESI) m/z\ 745.7 [M+H]+.
Figure imgf000570_0003
[001530] 3-(4-(4-(((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)methyl)-[l,4'-bipiperidin]-l '-yl)phenyl)piperidine-2,6- dione B199. MS (ESI) m/r. 747.3 [M+H]+.
Figure imgf000571_0001
[001531] 3-(4-(4-(4-(2-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-2,6- dione B200. NMR (400 MHz, CDsOD) d 8.98 (s, 1H), 8.39 (d, J = 2.4 Hz, 2H), 8.23 (d, J = 1.6 Hz, 1H), 8.15 (d, J 8.4 Hz, 1H), 7.76 (dd, J = 2.4, 8.8 Hz, 1H), 7.12 (t, J = 4.4 Hz, 2H), 7.00-6.97 (m, 2H), 6.00 (t, J - 8.8 Hz, 1H), 3.84 (s, 1H), 3.77 (d, J = 6.4 Hz, 2H), 3.52-3.47 (m, 2H), 3.14-3.09 (m, 2H), 2.86 (dd, J = 5.2, 14.4 Hz, 4H), 2.79 (t, J = 4.8 Hz, 1H), 2.74 (dd, J = 4.8, 10.0 Hz, 4H), 2.67-2.59 (m, 3H), 2.59-2.55 (m, 1H), 2.49 (s, 3H), 2.40 (s, 3H), 2.36-2.29 (m, 2H), 2.19 (d, .7 6 4 Hz, 2H), 2.14-2.08 (m, 2H), 2.06-2.02 (m, 2H), 1.94-1.87 (m, 2H), 1.76- 1.66 (m, 4H); MS (ESI) m/z: 746.5 [M+H] \
Figure imgf000571_0002
[001532] 3-(4-(r-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2,6- dione B202. MS (ESI) w/z: 761.5 [M+H]+
Figure imgf000571_0003
[001533] 3-(4-(4-(l-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<f|pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-4-yi)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B203 MS (ESI) m/z: 762.3 [M+H] 7
Figure imgf000572_0001
[001534] 3-(4-(4-(4-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B204. MS (ESI) m/z: 762.3 [M+Hp.
Figure imgf000572_0002
[001535] 3-(4-(4-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)-[l,4'-bipiperidin]-l'-yl)phenyl)piperidine-2,6- dione B205. MS (ESI) m/z: 761.3 [M+H]+.
Figure imgf000572_0003
[001536] 3-(4-(l'-(3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)propyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione
B206 MS (ESI) m/z: 759.8 [M+H]7
Figure imgf000572_0004
[001537] 3-(4-(4-(l-(3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)propyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2,6- dione B207. MS (ESI) m/z: 760.8 [M+H]+.
Figure imgf000573_0001
[001538] 3-(4-(4-(4-(3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)propyl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-2,6- dione B208. JH NMR (400 MHz, CDsOD) 3 8.98 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.22 (d, J --- 8.0 Hz, 1H), 7.12 (d, J -- 8.8 Hz, 2H), 6.95 (d, J --- 8.8 Hz, 2H), 6.06- 5.87 (m, 1H), 3.82-3.71 (m, 3H), 3.14-2.80 (m, 8H), 2.78-2.67 (m, 6H), 2.67-2.54 (m, 2H), 2.49 (s, 3H), 2.40-2.36 (m, 3H), 2.36-2.28 (m, 3H), 2.22-2.14 (m, 2H), 2.09-1.98 (m, 4H), 1.98-1.84 (m, 4H), 1.77-1.63 (m, 4H); MS (ESI) m/z: 760.5 [M+H]+.
Figure imgf000573_0002
[001539] 3-(4-(4-(3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)propyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione
B209. MS (ESI) m/z: 759.4 [M+H]+.
Figure imgf000573_0003
[001540] 3-(3-(4-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
</|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)piperidine- 2, 6-dione B210 MS (ESI) m/z: 732.3 | M • ! i |
Figure imgf000574_0001
[001541] 3-(4-(4-((ES)-4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B211. MS (ESI) m/z: 734.4 [M+H] \
Figure imgf000574_0002
[001542] 3-(4-(4-(((A)-4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-c/]pyrinudin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyr)- piperidine-2, 6-dione B212. MS (ESI) m/z: 734.5 [M+H] \
Figure imgf000574_0003
[001543] 3-(3-(4-((0S)-4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<7]pyriniidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyr)- piperidine-2, 6-dione B213. MS (ESI) m/z: 734.5 [M+H] \
Figure imgf000574_0004
[001544] 3-(4-(2-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine-2, 6-dione
B215 MS (ESI) m/z: 745.4 [M+H]t
Figure imgf000575_0001
[001545] 3-(4-((5)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3 -t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)methyl)morpholino)phenyl)piperidine- 2,6-dione B216 MS (ESI) m/z: 734.5 [M+H]+.
Figure imgf000575_0002
[001546] 3-(4-((7?)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3 -</]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)methyl)morpholino)phenyl)piperi dine- 2,6-dione B217. lH NMR (400 MHz, DMSO-^) 3 10.77 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.32 (s, 1H), 8.05 (d, .7= 2.8 Hz, 1H), 7.85 (d, .7= 8.8 Hz, 1H), 7.47 (dd, .7= 2.8, 9.2 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.82 (q, J = 8.8 Hz, 1H), 3.99-3.90 (m, 1H), 3.78-3.70 (m, 2H), 3.66-3.55 (m, 2H), 3.48 (d, J= 11.2 Hz, 1H), 3.17 (t, .7= 4.8 Hz, 4H), 2.71- 2.56 (m, 7H), 2.47-2.36 (m, 6H), 2.31 (s, 3H), 2.28-2.21 (m, 2H), 2.16-2.08 (m, 1H), 2.04-1.97 (m, 1H), 1.91-1.84 (m, 2H), 1.81 -1.74 (m, 2H), 1.62-1.54 (m, 2H); MS (ESI) m/z: 734.6 [M+H]+.
Figure imgf000575_0003
[001547] 3-(4-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)-[l ,4'-bipiperidin]-l’-yl)phenyl)piperidine-2, 6-dione
B218 MS (ESI) m/z: 733.5 [M+H]t
Figure imgf000576_0001
[001548] 3-(4-(4-(l-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimi din-2-yl)amino)pyri din-3 -yl)methyl)piperi din-3 -yl)piperazin-l-yl)phenyl)piperi dine- 2,6-dione B219 lH NMR (400 MHz, DMSO-de) <5 10.76 (s, 1H), 10.51-10.19 (m, 1H), 9.01 (s, 1H), 8.25 (s, 1H), 8.11-7.92 (m, 1H), 7.86-7.61 (m, 1H), 7.07-6.96 (m, 2H), 6.85 (d, ./= 5.6 Hz, 2H), 5.92-5.73 (m, 1H), 3.70 (td, J= 4.8, 9.2 Hz, 1H), 3.52-3.47 (m, 2H), 3.11-3.00 (m, 4H), 2.99-2.92 (m, 1H), 2.78-2.71 (m, 1H), 2.69-2.56 (m, 5H), 2.43 (s, 4H), 2.36-2.22 (m, 5H), 2.14- 2.05 (m, 1H), 2.03-1.95 (m, 1H), 1.94-1.74 (m, 7H), 1.73-1.65 (m, 1H), 1.64-1.53 (m, 2H), 1.49- 1.38 (m, 1H), 1.26-1.13
Figure imgf000576_0002
732.3 [M+H]+
Figure imgf000576_0003
[001549] 3-(4-(4-(l-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3 -c/]pyrimi din-2 -yl)amino)pyri din-3 -yl)oxy)ethyl)piperi din-3 -yl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B221 LH NMR (400 MHz, CD3OD) J 8.93 (s, 1H), 8.12-8.02 (m, 2H), 7.51 (dd, J = 3.2, 9.2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.94 (d, J - 8.8 Hz, 2H), 5.96 (q, J - 9.2 Hz, 1H), 4.26 (t, J = 5.2 Hz, 2H), 3.77 (t, J = 7.6 Hz, 1H), 3.23-3. 15 (m, 4H), 3.01 (d, J = 10.8 Hz, 1H), 2.93 (t, J - 5.2 Hz, 2H), 2.86-2.75 (m, 4H), 2.71-2.55 (m, 3H), 2.49 (s, 3H), 2.38 (s, 3H), 2.35-2.27 (m, 2H), 2.23-2.13 (m, 4H), 2.05-1.98 (m, 3H), 1.92-1.80 (m, 3H), 1.67 (dd, J = 5.2, 10.4 Hz, 2H), 1.36-1.29 (m, 4H); MS (ESI) m/z: 762A [M+H]+.
Figure imgf000577_0001
[001550] 3-(3-(4-(l-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</|pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-3-yl)piperazin-l -yl)phenyl)- piperidine-2, 6-dione B222 lH NMR (400 MHz, DMSCW6) 6 10.79 (s, 1H), 10.23 (s, 1H), 8.97 (s, 1H), 8.12 (d, J= 2.8 Hz, 1H), 7.95 (d, 9.2 Hz, 1H), 7.54 (dd, J= 2.8, 9.2 Hz, 1H), 7.16 (t,
7.6 Hz, 1H), 6.87-6.76 (m, 2H), 6.63 (d, J= 7.2 Hz, 1H), 5.83 (quin, J= 8.8 Hz, 1H), 4.44- 4.11 (m, 2H), 3.82-3.69 (m, 1H), 3.26-2.94 (m, 10H), 2.81-2.70 (m, 2H), 2.69-2.58 (m, 2H), 2.45-2.38 (m, 4H), 2.31 (s, 3H), 2.28-2.12 (m, 4H), 2.05-1.97 (m, 1H), 1.89 (s, 4H), 1.83-1.71 (m, 3H), 1.64-1.33 (m, 4H); MS (ESI) m/z: 762.8 [M+H] \
Figure imgf000577_0002
[001551] 3-(3-(4-(l-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B223 !H NMR (400 MHz, CD3OD) 8 8.92 (s, 1H), 8.52-8.37 (m, 1H), 8.04 (s, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.25 (t, J= 8.0 Hz, 1H), 6.92 (d, J= 8.0 Hz, 1H), 6.87 (s, 1H), 6.77 (d, J= 7.6 Hz, 1H), 6.01-5.88 (m, 1H), 3.83 (dd, J= 6.0, 9.6 Hz, 1H), 3.73 (d, J= 12.0 Hz, 2H), 3.46 (d, J= 12.4 Hz, 2H), 3.27 (s, 4H), 2.89 (s, 4H), 2.84-2.76 (m, 4H), 2.76-2.58 (m, 5H), 2.49 (s, 3H), 2.38 (s, 3H), 2.31 (dd, 8.0, 11.2 Hz, 2H), 2.27-2, 18 (m, 2H), 2.18-2.11 (m, 2H), 1.93 (d, ./= 11.6 Hz, 5H), 1.90-1.77 (m, 4H), 1.66 (d, J= 5.2 Hz, 2H), 1.53-1.39 (m, 2H); MS (ESI) m/z: 815.4 [M+H]+.
Figure imgf000578_0001
[001552] 3-(4-(4-(l-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-7|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B224. MS (ESI) m/z: 815.6 [M+H]+.
Figure imgf000578_0002
[001553] 3-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-7]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B225. 1HNMR (400 MHz, DMSO-Je) ^ 11.92-11.44 (m, 1H), 10.77 (s, 1H), 9.08 (s, 1H), 8.31 (dd, 7= 2.4, 9.6 Hz, 1H), 8.13 (s, HI), 8.09 (d, ./ 2.0 Hz, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7. 19- 7.13 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H), 5.84-5.79 (m, 1H), 3.93 (d, .7= 11.6 Hz, 2H), 3.87-3.76 (m, 3H), 3.65 (d, ./ 10.4 Hz, 2H), 3.51 (t, ./ 10.8 Hz, 1H), 3.44-3.33 (m, 2H), 3.28 (d, ./ 10.4 Hz, 2H), 2.87 (t, J= 12.0 Hz, 2H), 2.70-2.57 (m, 1H), 2.48-2.44 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 2.30 (d, J= 11.6 Hz, 2H), 2.24-2.07 (m, 3H), 2.03-1.84 (m, 5H), 1.84-1.74 (m, 2H), 1.63- 1.50 (m, 2H)MS (ESI) m/z: 718.4 [M+H]+.
Figure imgf000578_0003
[001554] 3-(4-(4-(( 1 -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
7]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)methyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B226 MS (ESI) m/z: 704.4 [M+H]+.
Figure imgf000579_0001
[001555] 3-(4-(3-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)azetidin-l-yl)phenyl)piperidine-2,6- dione B228 MS (ESI) m/z: 718.5 [M+H]+.
Figure imgf000579_0002
[001556] 3-(4-(4-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione
B230. MS (ESI) m/z: 693.6 [M+H]+.
Figure imgf000579_0003
[001557] 3-(4-(l-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione
B231 MS (ESI) m/z: 692.6 [M+H]+.
Figure imgf000579_0004
[001558] 3-(3-(4-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2 -yl)amino)pyri din-3 -yl)oxy)propyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione
B232. ^NMR (400 MHz, DMSO-Je) d 10.79 (s, 1H), 10.19 (s, 1H), 8.97 (s, 1H), 8.15 (s, 1H),
8.08 (d, .7= 3.2 Hz, 1H), 7.92 (d, .7= 9.2 Hz, 1H), 7.50 (dd, J= 3.2, 9.2 Hz, 1H), 7.19-7.11 (m,
1H), 6.86-6.76 (m, 2H), 6.61 (d, J = 7.6 Hz, 1 H), 5.82 (t, J = 8.8 Hz, 1H), 4.11 (t, J = 6.4 Hz, 2H), 3.75 (dd, J= 4.8, 11.2 Hz, 1H), 3.16-3.11 (m, 4H), 2.70-2.56 (m, 2H), 2.55-2.52 (m, 5H), 2.42 (s, 3H), 2.33-2.30 (m, 3H), 2.29-2.12 (m, 4H), 2.06-1.97 (m, 1H), 1.96-1.84 (m, 4H), 1.81- 1.73 (m, 2H), 1.63-1.50 (m, 2H); MS (ESI) /ra/z: 693.7 [M+H]+.
Figure imgf000580_0001
[001559] 3-(3-(l-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione
B233 MS (ESI) m/z\ 692.6 [M+H]+.
Figure imgf000580_0002
[001560] 3-(4-(3-(4-(6-((6-Aceiyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)propoxy)phenyl)piperidine-2, 6-dione B234.
MS (ESI) m/z-. 692.4 [M+H] \
Figure imgf000580_0003
[001561] 3-(4-(4-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione
B235. MS (ESI) m/z: 692.5 [M+H]t
Figure imgf000581_0001
[001562] 3-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-l'-yl)phenyl)piperidine-2, 6-dione B238. MS (ESI) m/z: 717.5 [M i l] .
Figure imgf000581_0002
[001563] 3-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-^]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B240 rH NMR (400 MHz, DMSO-Je) 8 ppm 11 .27-12.09 (m, 1H), 10.76 (s, 1H), 9.08 (s, 1H), 8.31 (m, 1H), 8.09 (d, J= 2.4 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.06-7.11 (m, 2H), 5.82 (s, 1H), 3.93 (d, ./= 12.0 Hz, 2H), 3.77-3.85 (m, 3H), 3.60-3.68 (m, 2H), 3.48-3.54 (m, 1H), 3.38 (d, J= 11.2 Hz, 2H), 3.29 (d, J= 10.0 Hz, 2H), 2.88 (t, J= 12.0 Hz, 2H), 2.59-2.65 (m, 1H), 2.46 (s, 2H), 2.42 (s, 3H), 2.34 (s, 3H), 2.30 (d, J = 12 0 Hz, 2H), 2. 16-2.22 (m, 2H ), 2.10- 2.15 (m, 1H), 1.89-2.01 (m, 5H), 1.75-1.83 (m, 2H), 1.53-1.61 (m, 2H).; MS (ESI) m/z: 718.5 [M+H]+.
Figure imgf000581_0003
[001564] 3-(4-(lA6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2, 6-dione B241. rH NMR (400 MHz, DMSO-flfc) <5 10.80 (s, 1H), 10.05 (s, 1H), 8.95 (s, 1H), 8.25 (s, 1H), 8.06
(d, 7= 2.8 Hz, 1H), 7.83 (d, 7= 8.8 Hz, 1H), 7.47 (m, 1H), 7.18-7.22 (m, 2H), 7.13 (d, 7= 8.0
Hz, 2H), 5.82 (t, J= 9.2 Hz, 1H), 3.79-3.84 (m, 1H), 3.76 (d, J= 11.6 Hz, 2H), 3.01 (d, J= 11.2 Hz, 2H), 2.59-2.76 (m, 4H), 2.46-2.48 (s, 1H), 2.42-2.46 (s, 4H), 2.31 (s, 3H), 2.26 (d, 7 = 9.6 Hz, 4H), 2.17-2.20 (m, 1H), 1.99-2.06 (m, 1H), 1.87 (d, 7= 9.2 Hz, 4H), 1.77 (d, 7= 9.2 Hz, 4H), 1.62-1.69 (m, 2H), 1.57-1.62 (m, 4H); MS (ESI) m/z: 717.5 [M+H]+.
Figure imgf000582_0001
[001565] 3-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B242.
MS (ESI) m/z: 717.5 [M+H]t
Figure imgf000582_0002
[001566] 3-(3-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-7]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2, 6-dione B245. *H NMR (400 MHz, DMSO-Ts) <5 10.81 (s, 1H), 10.07 (s, 1H), 8.98-8.92 (m, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.86-7.78 (m, 1H), 7.50-7.41 (m, 1H), 7.29-7.21 (m, 1H), 7.17-7.08 (m, 2H), 7.03 (d, 7= 7.6 Hz, 1H), 5.82 (q, 7 = 8.4 Hz, 1H), 3.88-3.71 (m, 3H), 3.00 (d, 7= 11.2 Hz, 2H), 2.73- 2.60 (m, 3H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27-2.14 (m, 5H), 2.09-1.92 (m, 2H), 1.86 (d, J= 12.0 Hz, 4H), 1.76 (d, 7= 8.8 Hz, 5H), 1.71-1.51 (m, 7H); MS (ESI) m/z: 717.5 [M+H]+.
Figure imgf000583_0001
[001567] 3-(4-(4-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)ainino)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)piperidine-
2,6-dione B247 [H NMR (400 MHz, CDCh) 3 1.67-1.73 (m, 2H), 1.84-1.97 (m, 3H), 2.00-2.14 (m, 4H), 2.18-2.33 (m, 4H), 2.34-2.41 (m, 6H), 2.56 (s, 4H), 2.61-2.70 (m, 2H), 2.69-2.86 (m, 5H), 2.87-3.08 (m, 2H), 3.16-3.48 (m, 3H), 3.57-3.77 (m, 5H), 5.79-5.95 (m, 1H), 6.93 (d,
8.6 Hz, 2H), 7.09-7.16 (m, 2H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 7.93-7.99 (m, 1H), 8.04 (s, 2H), 8.16 (d, J - 9.2 Hz, 1H), 8.80 (s, 1H); MS (ESI) m/z: 732.3 [M+H]+.
Figure imgf000583_0002
[001568] 3 -(4-( 1 -(( 1 -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B248 ^ NMR (400 MHz, DMSO-tZe) 3 10.87-10.76 (m, 1H), 10.06 (s, 1H), 8.95 (s, 1H), 8.18 (s, 1H), 8.05 (d, J= 2.8 Hz, 1H), 7.82 (d, J= 9.2 Hz, 1H), 7.45 (dd, J= 3.2, 9.2 Hz, 1H), 7.24-7.19 (m, 2H), 7.15-7.11 (m, 2H), 5.87-5.77 (m, 1H), 3.81 (dd, J = 4.8, 11.2 Hz, 1H), 3.69 (d, J= 12.0 Hz, 2H), 2.96 (d, J= 11.0 Hz, 2H), 2.72-2.61 (m, 3H), 2.45 (d, J= 3.8 Hz, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.26-2.19 (m, 4H), 2.18-2.09 (m, 1H), 2.04-1.94 (m, 3H), 1.92-1.79 (m, 5H), 1.78-1.71 (m, 4H), 1 .67 (dt, J= 2.8, 11.6 Hz, 3H), 1.62-1.56 (m, 2H), 1.29-1.18 (m, 2H); MS (ESI) m/z-. 731.5 [M+H]+.
Figure imgf000583_0003
[001569] 3-(3-(l-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B250. H NMR (400 MHz, DMSO-^) 3 10.82 (s, 1H), 10.09-10.03 (m, 1H), 8.95 (s, 1H), 8.21 (s, 1H), 8.05 (d, J= 2.8 Hz, 1H), 7.82 (d, J= 9.2 Hz, 1H), 7.49-7.42 (m, 1H), 7.28-7.22 (m, 1H), 7.18-7.09 (m, 2H), 7.03 (d, 7.6 Hz, 1 H), 5.82 (q, ./ 8.8 Hz, 1H), 3.82 (dd, J= 4.8, 11.2
Hz, 1H), 3.69 (d, J = 12.0 Hz, 2H), 2.95 (d, J = 11.2 Hz, 2H), 2.73-2.62 (m, 3H), 2.47-2.44 (m, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27-2.16 (m, 5H), 2 06-1.95 (m, 3H), 1.91-1.63 (m, 12H), 1.61- 1.54 (m, 2H), 1.30-1.17 (m, 2H); MS (ESI) wz: 731.4 [M+H]+
Figure imgf000584_0001
[001570] 3-(3-(4-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<Z]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B251 MS (ESI) m/z: 731.4 [M+H]+
Figure imgf000584_0002
[001571] 3-(4-(r-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ]- pyrirnidin-2-yl)amino)pyridin-3-yl)methyl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2, 6-dione B252. ’HNMR (400 MHz, DMSO-d6 ) <5 11.31 (br s, 1H), 10.80 (s, 1H), 9.12 (s, 1H), 8.75 (s, 1H), 8.56 (d, J- 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7. 18 (s, 4H), 5.87 (q, J:::: 8.8 Hz, 1 H), 4.68-4.57 (m, 1H), 4.49 (s, 2H), 3.82 (dd, J= 4.8, 11.2 Hz, 1H), 3.56 (d, J= 8.8 Hz, 3H), 3.43 (d, J= 10.0 Hz, 2H), 3.14 (d, J = 10.4 Hz, 4H), 2.90-2.80 (m, 1H), 2.65 (dt, J = 5.6, 11.6 Hz, 1H), 2.44 (s, 3H), 2.37 (s, 5H), 2.33-2.10 (m, 7H), 2.07-1.90 (m, 5H), 1.83 (d, J = 4.8 Hz, 2H), 1.60 (d, J= 4.8 Hz, 2H); MS (ESI) m/z: 731.5 [M+H] \
Figure imgf000585_0001
[001572] 3-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B255. MS (ESI) m/z: 746.8 [M+H]+.
Figure imgf000585_0002
[001573] 3-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B256 MS (ESI) m/z: 745.5 [M+H]+
Figure imgf000585_0003
[001574] 3-(3-(l-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B257. MS (ESI) m/z: 746.3 [M+H]+.
Figure imgf000585_0004
[001575] 3-(3-(l-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyriniidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B258. MS (ESI) m/z: 745.5 [M+H]+.
Figure imgf000586_0001
[001576] 3-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B259 MS (ESI) m/z: 746.2 [M+H]+.
Figure imgf000586_0002
[001577] 3-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
</|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B260. MS (ESI) m/z: 745.4 [M+H]+
Figure imgf000586_0003
[001578] 3-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B261 !H NMR (400 MHz, CDCh) 8 8.82 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 8.17 (d, J= 9.2 Hz, 1H), 8.07 (d, ,/= 2.8 Hz, 1 H), 7.34 (dd, J= 2.8, 9.2 Hz, 1 H), 7.26-7.21 (m, 1H), 6.88 (dd, J= 2.0, 8.4 Hz, 1H), 6.76 (s, 1H), 6.66 (d, J= 7.6 Hz, 1H), 5.88 (q, J= 8.8 Hz, 1H), 3.82-3.72 (m, 1H), 3.67 (d, ./ 12.2 Hz, 2H), 3.27 (s, 4H), 2.82-2.68 (m, 6H), 2.68-2.58 (m, 2H), 2.56 (s, 3H), 2.54-2.48 (m, 1H), 2.44-2.38 (m, 1H), 2.38 (s, 3H), 2.35-2.19 (m, 3H), 2.13-2.02 (m, 2H), 1.95-1.86 (m, 2H), 1.83 (d, J- 12.4 Hz, 2H), 1.73-1.67 (m, 2H), 1.59 (s, 3H), 1.53 - 1.48 (m, 1H), 1.46-1.35 (m, 2H); MS (ESI) m/z: 746.3 [M+H]\
Figure imgf000587_0001
[001579] 3-(4-(2-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)ethyl)phenyl)piperidine-2, 6-dione B262. MS (ESI) m/z: 745.3 [M+H]+.
Figure imgf000587_0002
[001580] 3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)ethyl)phenyl)piperidine-2, 6-dione
B263. MS (ESI) m/z: 745.5 [M+H]+.
Figure imgf000587_0003
[001581] 3-(3-(4-(4-(2-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-2,6- dione B264. MS (ESI) m/z: 746.8 [ M + H ]+.
Figure imgf000588_0001
[001582] 3-(3-(4-(2-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)-[l,4'-bipiperidin]-l'-yl)phenyl)piperidine-2, 6-dione
B265 MS (ESI) m/z: 745.4 [M+H]t
Figure imgf000588_0002
[001583] 3-(3-(4-(((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-fl(]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)methyl)-[l,4'-bipiperidin]-l'-yl)phenyl)piperidine-2,6- dione B266. MS (ESI) m/z: 747.5 [M+H]+
Figure imgf000588_0003
[001584] 3-(3-(l'-(2-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- cZ]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione
B267. MS (ESI) m/z: 745.3 [M+H]t
Figure imgf000588_0004
[001585] 3-(3-(4-(l-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-tf]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)etliyl)piperidin-4-yl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B269. MS (ESI) m/z: 762.5 [M+H]~.
Figure imgf000589_0001
[001586] 3-(3-(4-(4-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B270 MS (ESI) m/z: 762.8 [M+H] 2
Figure imgf000589_0002
[001587] 3-(4-(l'-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2,6- dione B271 MS (ESI) m/z: 761.3 [M+H]+.
Figure imgf000589_0003
[001588] 3-(4-(4-(2-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
</|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperidin-l-yI)phenyl)piperidine-2,6- dione B272. MS (ESI) m/z: 745.4 [M+H]+.
Figure imgf000590_0001
[001589] -3-(4-(4-(((5)-4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-</jpyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)-
3-methylpiperidine-2, 6-dione B273.
Figure imgf000590_0002
[001590] 3-(4-(l-(2-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B274 MS (ESI) m/z: 745.7 [M+H]+.
Figure imgf000590_0003
[001591] 3-(4-((r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-^- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine-2, 6-dione
B275. MS (ESI) m/2: 731.3 [M+H]t
Figure imgf000590_0004
[001592] 3-(4-(4-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]-pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B276 rHNMR (400 MHz, DMSO-J6) d 10.76 (s, 1H), 10.19 (s, 1H), 8.97 (s, 1H), 8.11 (d, J = 3.2 Hz, 1H), 7.93 (d, J --- 9.2 Hz, 1H), 7.53 (m, 1H), 7.05 (d, J - 8.8 Hz, 2H), 6.90 (d, J - 8.8 Hz, 2H), 5.83 (t, J - 8.8 Hz, 1H), 4.21 (t, J - 5.6 Hz, 2H), 3.72 (m, 1H), 3.11-3.15 (m, 4H), 2.77 (t, J = 5.6 Hz, 2H), 2.62-2.66 (m, 4H), 2.58-2.62 (m, 1H), 2.47-2.49 (s, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.24 (m, 2H), 2.09-2.16 (m, 1H), 1.97-2.03 (m, 1H), 1.89-1.94 (s, 2H), 1.74-1.81 (m, 2H), 1.52-1.61 (m, 2H); MS (ESI) m/z: 679.5 [M+H]\
Figure imgf000591_0001
[001593] 3-(4-(4-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- J]-pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B277. ^I NMR (400 MHz, CD3OD) J 8.93 (s, 1H), 8.07-7.98 (m, 2H), 7.48 (dd, J- 3.2, 9.2 Hz, 1H), 7.12 (d, J= 8.8 Hz, 2H), 7.03-6.96 (m, 2H), 6.06-5.89 (m, 1H), 4.59 (s, 1H), 4.16 (t, J= 6.4 Hz, 2H), 3.82-3.75 (m, 1H), 3.72-3.64 (m, 2H), 2.76-2.59 (m, 4H), 2.49 (s, 3H), 2.38 (s, 3H), 2.35-2.25 (m, 2H), 2.23-2.16 (m, 2H), 2.04-1.95 (m, 2H), 1.90 (d, 12.8 Hz, 4H), 1.84-1.78
(m, 2H), 1.73-1.65 (m, 2H), 1.54-1.42 (m, 2H); MS (ESI) m/z: 678.5 [M+H]+.
Figure imgf000591_0002
[001594] 3-(4-(2-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine- 2,6-dione B278. lH NMR (400 MHz, DMSO-cZe) d 1.51-1.67 (m, 5H), 1.70-1.92 (m, 11H), 1.96- 2.05 (m, 1H), 2.10-2.36 (m, 8H), 2.41-2.43 (m, 5H), 2.57-2.76 (m, 7H), 3.63-3.88 (m, 3H), 5.72- 5.90 (m, 1H), 7.01-7.24 (m, 4H), 7.43-7.53 (m, 1H), 7.82 (d, J= 8.8 Hz, 1H), 8,05 (s, 1H), 8,95 (s, 1H), 10.08 (s, 1H), 10.82 (s, 1H),; MS (ESI) m/z: 763.4 [M+H]+.
Figure imgf000592_0001
[001595] 3-(3-(3-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)azetidin-l-yl)phenyl)piperidine-2,6- dione B279. MS (ESI) m/z: 718.6 [M+H]+.
Figure imgf000592_0002
[001596] 3-(4-(2-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin- 1 -y l)piperi din- 1 -yl)- 1 , 1 -difluoroethyl)phenyl)- piperidine-2, 6-dione B280 MS (ESI) m/z: 782.7 [M+H]’
Figure imgf000592_0003
[001597] 3-(3-(2-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin- 1 -yl)pi peri din- 1 -yl)- 1 , 1 -difluoroethyl)phenyl)- piperidine-2, 6-dione B281 1H NMR (400 MHz, DMSO-<76) <5 10.87 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.03 (d, J= 2.4 Hz, 1H), 7.83 (d, J= 8.8 Hz, 1H), 7.47-7.42 (m, 3H), 7.40 (s, 1H), 7.37- 7.34 (m, 1H), 5.89-5.76 (m, 1H), 3.96 (dd, 7 = 4.8, 11.6 Hz, 1H), 3.16-3.09 (m, 4H), 3.03 (t, J= 14.8 Hz, 2H), 2.81 (d, J = 9.6 Hz, 2H), 2.74-2.64 (m, 1H), 2.63-2.57 (tn, 4H), 2.56-2.52 (m, 1H), 2.42 (s, 3H), 2.30 (s, 3H), 2.28-2.12 (m, 6H), 2.08-2.01 (m, 1H), 1.87 (s, 2H), 1.81-1.71 (m, 2H), 1.65 (d, ./ 12.4 Hz, 2H), 1.60-1.51 (m, 2H), 1.41-1.29 (m, 2H); MS (ESI) m/z: 782.6 [M+H] \
Figure imgf000593_0001
[001598] 3-(4-(2-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- cf|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)azetidin-l -yl)-l, l-difluoroethyl)phenyl)- piperidine-2, 6-dione B282. MS (ESI) m/z: 754.4 [M+H]+.
Figure imgf000593_0002
[001599] 3-(3-(2-(3-(4-(6-((6-/Xcetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin- 1 -y 1 )azeti di n- 1 -yl)- 1 , 1 -difluoroethyl)phenyl)- piperidine-2, 6-dione B283 LH NMR (400 MHz, DMSO-c/e) <5 10.87 (s, 1H), 10.09 (s, 1H), 8.95 (s, 1H), 8.04 (d, J= 2.8 Hz, 1H), 7.84 (d, J= 9.2 Hz, 1H), 7.48-7.41 (m, 3H), 7.41-7.34 (m, 2H), 5.82 (quin, J= 8.8 Hz, 1H), 3.96 (dd, ./ 4.8, 12.0 Hz, 1H), 3.37 (t, J = 6.4 Hz, 2H), 3.19-3.09 (m, 6H), 3.01-2.95 (m, 2H), 2.94-2.87 (m, 1H), 2.73-2.64 (m, 1H), 2.57-2.52 (m, 1H), 2.42 (s, 3H), 2.38-2.32 (m, 4H), 2.30 (s, 3H), 2.28-2.18 (m, 3H), 2.08-1.99 (m, 1H), 1.95-1.83 (m, 2H), 1.81-1 ,72 (m, 2H), 1,64-1,52 (m, 2H),MS (ESI) m/z: 754,3 [M+H]+,
Figure imgf000593_0003
[001600] 3-(4-((3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)methyl)phenyl)piperidine-2,6- dione B284. ^I NMR (400 MHz, CDsOD) cl 8.92 (s, HI), 8.50 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.95 (d, J -- 9.2 Hz, 1H), 7.50 (dd, J -- 2.8, 8.8 Hz, 1H), 7.38-7.33 (m, 2H), 7.31-7.25 (m, 2H), 5.94 (t, J = 8.8 Hz, 1H), 3.89 (s, 2H), 3.73 (t, J - 7.2 Hz, 2H), 3.37 (d, J = 8.0 Hz, 3H), 3.25 (s, 4H), 3.16 (d, J = 6.8 Hz, 1H), 2.70 (dd, J = 6.0, 10.4 Hz, 1H), 2.65 (t, J = 4.8 Hz, 1H), 2.55 (d, J -- 4.4 Hz, 4H), 2.48 (s, 3H), 2.38 (s, 3H), 2.30 (dd, J - 3.2, 8.0 Hz, 2H), 2.23-2.17 (m, 2H), 1.96 (d, J = 6.0 Hz, 2H), 1.89-1.83 (m, 2H), 1.69-1.62 (m, 2H); MS (ESI) m/z: 704.5 [M+H]+.
Figure imgf000594_0001
[001601] 3-(3-((3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)methyl)phenyl)piperidine-2,6- dione B285. ’H NMR (400 MHz, DMSO-tZe) 3 10.85 (s, 1H), 10.09 (s, 1H), 8.95 (s, 1H), 8.25 (s, 1H), 8.04 (d, J= 2.8 Hz, 1H), 7.84 (d, J= 9.2 Hz, 1H), 7.47 (dd, J= 2.8, 9.2 Hz, 1H), 7.33- 7.29 (m, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J= 7.6 Hz, 1H), 5.90-5.75 (m, 1H), 3.88 (dd, J = 5.2, 11.2 Hz, 1H), 3.63 (d, J= 11.6 Hz, 1H), 3.57-3.42 (m, 4H), 2.84 (d, J= 10.8 Hz, 1H), 2.80-2.73 (m, 4H), 2.72-2.61 (m, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.26-2.16 (m, 6H), 2.11-2.03 (m, 1H), 1.91-1.71 (m, 6H), 1.62-1.53 (m, 2H); MS (ESI) m/z: 704.5 [M+H]t
Figure imgf000594_0002
[001602] 3-(3-(2-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine- 2,6-dione B286 [H NMR (400 MHz, CDCh) 3 8.83 (s, 1H), 8.63 (s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.38-7.28 (m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.09-7.02 (m, 2H), 5.88 (q, J = 8.8 Hz, 1H), 3.78 (dd, J = 5.6, 9.2 Hz, 1H), 3.73 (d, J =
11 .6 Hz, 2H), 2.94 (d, J = 10.4 Hz, 2H), 2.85-2.78 (m, 2H), 2.78-2.75 (m, 2H), 2.73 (d, J = 4.8 Hz, 2H), 2.71 -2.67 (m, 2H), 2.67-2.61 (m, 1H), 2.56 (s, 3H), 2.41-2.33 (m, 5H), 2.32-2.22 (m, 2H), 2.06 (d, J = 10.8 Hz, 4H), 2.01-1.92 (m, 4H), 1.92-1.84 (m, 4H), 1.83 (d, J = 2.8 Hz, 2H), 1.73-1.62 (m, 2H); MS (ESI) m/z: 763.4 [M+Hf
Figure imgf000595_0001
[001603] 3-(4-((r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine- 2,6-dione B287. MS (ESI) m/z: 749.3 [M+H] \
Figure imgf000595_0002
[001604] 3-(3-((r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZj- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine- 2,6-dione B288 MS (ESI) m/z: 749.4 [M+H]+.
Figure imgf000595_0003
[001605] 3-(4-(2-(l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)- piperidine-2, 6-dione B289. MS (ESI) m/z: 735.3 [M+H]t
Figure imgf000595_0004
[001606] 3-(3-(2-(l-(l -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3 t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-y l)-3 -fluoroazetidin-3 -yl)ethyl)phenyl)- piperidine-2, 6-dione B290. MS (ESI) m/z'. 735.4 [M+H]t
Figure imgf000596_0001
[001607] 3-(4-((l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazeti din-3 -yl)methyl)phenyl)- piperidine-2, 6-dione B291 rH NMR (400 MHz, DMSO-d6 ) 3 10.84 (s, 1H), 10.09 (s, 1H), 8.96 (s, 1H), 8.37 (s, 1H), 8.05 (s, 1H), 7.84 (d, J= 9.2 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.25-7.12 (m, 4H), 5.90-5.73 (m, 1H), 3.88-3.76 (m, 1H), 3.54 (d, J- 11 .2 Hz, 3H), 3.18-3.03 (m, 6H), 2.80 (t, J= 10.0 Hz, 2H), 2.65 (dt, J= 5.6, 11.6 Hz, 1H), 2.43 (s, 3H), 2.3 i (s, 3H), 2.27-2.14 (m, 4H), 2.07-1 .97 (m, 1 H ), 1.88 (s, 2H), 1.82-1.69 (m, 4H), 1.58 (d, J == 4.4 Hz, 2H), 1.33 (d, J == 9.2 Hz, 2H); MS (ESI) m/z'. 721.6 [M+H]+.
Figure imgf000596_0002
[001608] 3-(3-((l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)-3 -fluoroazeti din-3 -yl)methyl)phenyl)- piperidine-2, 6-dione B292. lH NMR (400 MHz, CDCh) d 8.82 (s, 1H), 8.64 (s, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 8.15 (d, J --- 9.2 Hz, 1H), 8.06 (d, J -- 2.8 Hz, 1H), 7.37-7.31 (m, 2H), 7.25 (s, 1H), 7.17-7.09 (m, 2H), 5.88 (q, J = 8.8 Hz, 1H), 3.80 (dd, J = 5.2, 9.6 Hz, 1H), 3.56 (d, J = 12.0 Hz, 4H), 3.29-3.22 (m, 2H), 3.21-3.15 (m, 2H), 2.89-2.77 (m, 2H), 2.75-2.61 (m, 2H), 2.56 (s, 3H), 2.38 (s, 3H), 2.35-2.19 (m, 4H), 2.07 (dd, J = 5.6, 7.6 Hz, 4H), 1.92-1.86 (m, 2H), 1.74- 1.64 (m, 2H), 1.60-1.50 (m, 2H); MS (ESI) mA: 721.4 [M H i .
Figure imgf000597_0001
[001609] 3-(3-(l-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7jpyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)azetidin-3-yl)phenyl)- piperidine-2, 6-dione B294 'H NMR (400 MHz, DMSO-d6 ) (5 10.82 (s, 1H), 10.07 (s, 1H), 8.95 (s, 1H), 8.28-8.17 (m, 1H), 8.09 (d, J= 3.2 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.50 (dd, J= 2.8, 9.2 Hz, 1H), 7.32-7.25 (m, 2H), 7.18 (s, 1H), 7.07 (d, .7= 6.4 Hz, 1H), 5.90-5.74 (m, 1H), 3.84 (dd, J= 5.2, 11.6 Hz, 1H), 3.75-3.68 (m, 2H), 3.67-3.60 (m, 1H), 3.50 (d, J= 12.0 Hz, 2H), 3.19 (t, J= 6.4 Hz, 2H), 3.03-2.94 (m, 2H), 2.72 (s, 2H), 2.66 (s, 4H), 2.42 (s, 3H), 2.33 (d, J= 2.0 Hz, 1H), 2.31 (s, 3H), 2.23 (dd, J= 2.8, 11.2 Hz, 2H), 2,08-2.00 (m, 1H), 1.93-1.85 (m, 4H), 1.80-1.75 (m, 2H), 1.63-1.52 (m, 2H); MS (ESI) mA: 721.5 [M+H]t
Figure imgf000597_0002
[001610] 3-(4-(2-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2,6- dione B295 JH NMR (400 MHz, CDsOD) 3 8.90 (s, 1H), 8.27-8.55 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.24-7.28 (m, 2H), 7.19-7.23 (m, 2H), 7.01-7.08 (m, 1H), 5.92-5.94 (m, 1H), 4.03-4.12 (m, 2H), 3.85-3.87(m, 1H), 3.76 (t, J - 6.2 Hz, 2H), 3.43-3.50 (m, 1H), 2.93- 2.95(m, 4H), 2.69 (m, 2H ) 2.59-2.65 (m, 2H), 2.48 (s, 3H), 2.37 (s, 3H), 2.28-2.34 (m, 2H), 2.17-2.25 (m, 2H), 1.91-1.98 (m, 2H), 1.82-1.88 (m, 2H), 1.62-1.68 (m, 2H), 1.29-1.31 (m, 4H), 0.82-0.93 (m, 2H); MS (ESI) m/z: 718.5 [M+H]+.
Figure imgf000598_0001
[001611] 3-(3-(2-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2,6- dione B296 !H NMR (400 MHz, CDsOD) d 8.90 (s, 1H), 8.32-8.51 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.27-7.35 (m, 1H), 7.20 (d, J 7.4 Hz, 1H), 7.10-7.17 (m, 2H), 7.01-7.08 (m, 1H), 5.86-5.96 (m, 1H), 4.02-4.13 (m, 2H), 3.86 (m, 1H), 3.71-3.78 (m, 2H), 3.43-3.49 (m, 1H), 2.95-2.97(m, 4H), 2.58-2.71 (m, 4H), 2.48 (s, 3H), 2.37 (s, 3H), 2.26-2.32 (m, 2H), 2.13- 2.24 (m, 2H), 1.95-1.97(m, 2H), 1.79-1.89 (m, 2H), 1.59-1.69 (m, 2H), 1.24-1.38 (m, 4H), 0.73- 0.96 (rn, 2H); MS (ESI) m/z\ 718.5 [M -H]
Figure imgf000598_0002
[001612] 3-(3-((4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </|pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)methyl)phenyl)piperidine-2,6- dione B298. !H NMR (400 MHz, DMSO-flfc) J 10.83 (s, 1 H), 10.01 (s, 1 H), 8.93 (s, 1 H), 8.13 (s, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.61 (d, J= 1.6 Hz, 1H), 7.28 (d, J= 5.6 Hz, 1H), 7.24-7.07 (m, 3H), 6.96 (dd, 1.6, 8.8 Hz, 1H), 5.90-5.71 (m, 1H), 3.96 (t, J 6.8 Hz, 2H), 3.86 (dd, J= 3.6, 10.8 Hz, 1H), 3.66-3.57 (m, 2H), 3.52-3.42 (m, 2H), 3.30 (s, 2H), 2.70-2.60 (m, 2H), 2.47-2.45 (m, 2H), 2.42 (s, 3H), 2.40-2.33 (m, 4H), 2.30 (s, 3H), 2.27-2.11 (m, 4H), 2.09-2.00 (m, 1H), 1.90-1.81 (m, 2H), 1.80-1.69 (m, 2H), 1.63-1.51 (m, 2H); MS (ESI) mk 704.5 [M+Hf.
Figure imgf000598_0003
[001613] 3-(3-(2-(l-(l -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperidin-4-yl)ethyl)phenyl)piperidine-2,6- dione B299. JH NMR (400 MHz, DMSO-^) 3 10.82 (s, 1H), 10.02 (s, 1H), 8.94 (s, 1H), 7.77 (d, J= 8.8 Hz, 1H), 7.62 (s, 1H), 7.29-7.19 (m, 1H), 7.10 (d, J= 8.0 Hz, 1H), 7.06-6.94 (m, 3H), 5.80 (q, ./ 8.8 Hz, 1H), 3.98 (t, 6.8 Hz, 2H), 3.81 (dd, ./ 4.8, 11.2 Hz, 1H), 3.59 (t, ./ 6.4
Hz, 2H), 3.26-3.22 (m, 1H), 2.79 (d, J = 10.0 Hz, 2H), 2.57 (d, J= 8.0 Hz, 4H), 2.42 (s, 3H), 2.33 (d, ./ 1.6 Hz, 1H), 2.31 (s, 3H), 2.27-2.14 (m, 3H), 2.03 (td, J= 4.4, 8.8 Hz, 1H), 1.84 (d, J = 19.2 Hz, 2H), 1.78-1.70 (m, 4H), 1.64-1.55 (m, 2H), 1.54-1.44 (m, 2H), 1.35-1.08 (m, 4H);
MS (ESI) m/z: 717.7 [M+H]+.
Figure imgf000599_0001
[001614] 3-(3-(2-(l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </|pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)-4-fluoropiperidin-4-yl)ethyl)phenyl)- piperidine-2, 6-dione B300 lHNMR (400 MHz, DMSO-i/e) d 10.80 (s, 1H), 9.99 (s, 1H), 8.92 (s, 1H), 8.45 (s, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.62 (d, J = 2.8 Hz, 1H), 7.31-7.18 (m, 1H), 7.14- 7.05 (m, 2H), 7.04-6.93 (m, 2H), 5.85-5.73 (m, 1H), 3.99 (t, J= 7.2 Hz, 2H), 3.80 (dd, J= 4.8, 11 .2 Hz, 1H), 3.64-3.57 (m, 2H), 2.68-2.59 (m, 7H), 2.41 (s, 3H), 2.35-2.31 (m, 1H), 2.29 (s, 3H), 2.25-2.18 (m, 2H), 2.17-2.11 (m, 2H), 2.06-1.97 (m, 1H), 1.85 (d, J = 8.8 Hz, 6H), 1.79- 1.71 (m, 3H), 1.68-1.52 (m, 3H); MS (ESI) m/z: 735.5 [M+Hf.
Figure imgf000599_0002
[001615] 3-(3-(8-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
Jjpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-3-azabicyclo[3.2.1]octan-3-yl)- phenyl)piperidine-2, 6-dione B301 MS (ESI) m/z: 758.4 [M+H] \
Figure imgf000600_0001
[001616] 3-(3-(3-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-8-azabicyclo[3.2.1]octan-8-yl)- phenyl)piperidine-2, 6-dione B302. MS (ESI) m/z: 758.6 [M+H]+.
Figure imgf000600_0002
[001617] 3-(3-(4-((3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1 ]octan-8-yl)methyl)piperidin-l -yl)- phenyl)piperidine-2, 6-dione B303. MS (ESI) m/z: 758.3 [M+H]+.
Figure imgf000600_0003
[001618] 3-(3-(4-((8-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B304. MS (ESI) m/z: 758.3 [M+H] \
Figure imgf000600_0004
[001619] 3-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B305. MS (ESI) m/z'. 749.5 [M+H]~.
Figure imgf000601_0001
[001620] -3-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<i]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)-3-methyl- piperidine-2, 6-dione B307 MS (ESI) m/z'. 760.6 [M+H]“.
Figure imgf000601_0002
[001621] (A)-3-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)-3-m ethyl- piperidine-2, 6-dione B308. MS (ESI) m/z'. 760.8 [M+H] \
Figure imgf000601_0003
[001622] 3-(4-(l-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)phenyl)- piperidine-2, 6-dione B311 [H NAIR (400 MHz, DMSO-r/c) <5 10.80 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.10 (d, ./ 2.8 Hz, 1H), 7.85 (d, ./ 9.2 Hz, 1H), 7.51 (dd, ./ 2.8, 9.2 Hz, 1H), 7.24- 7.16 (m, 2H), 7.16-7.08 (m, 2H), 5.82 (quin, ,/= 8.8 Hz, 1H), 3.80 (dd, 4.8, 11 .2 Hz, 1H), 3.55-3.44 (m, 2H), 3.09-2.95 (m, 4H), 2.70-2.58 (m, 4H), 2.47-2.44 (m, 1H), 2.42 (s, 3H), 2.36- 2.32 (m, 1H), 2.31 (s, 3H), 2.28-2.10 (m, 5H), 2.03 (dt, ./= 4.8, 9.2 Hz, 1 H), 1.98-1.83 (m, 5H), 1.81-1.67 (m, 6H), 1.64-1.52 (m, 2H); MS (ESI) mA: 749.5 [M+H]E
Figure imgf000602_0001
[001623] 3-(3-(l-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)phenyl)- piperidine-2, 6-dione B312 'H NMR (400 MHz, CD3OD) 3 8,97-8,87 (m, 1H), 8,92 (s, 1H),
8.49 (s, 1H), 8.08 (d, J= 2.8 Hz, 1H), 7.94 (d, J= 9.2 Hz, 1H), 7.55 (dd, J= 3.2, 9.2 Hz, 1H), 7.32-7.24 (m, 1H), 7.18 (d, J= 8.0 Hz, 1H), 7.14 (s, 1H), 7.07 (d, .7 = 7.6 Hz, 1H), 6.03-5.87 (m, 1H), 3.85 (dd, J= 6.0, 10.0 Hz, 1H), 3.58-3.45 (m, 2H), 3.17-3.10 (m, 4H), 2.73-2.58 (m, 4H),
2.49 (s, 3H), 2.38 (s, 3H), 2.36-2.25 (m, 4H), 2.25-2.17 (m, 2H), 2.12-2.01 (m, 2H), 2.01-1.93 (m, 3H), 1.88 (dd, J= 3.6, 9.2 Hz, 4H), 1.83-1.72 (m, 4H), 1.71-1.61 (m, 2H); MS (ESI) m/z:
749.6 [M+H]+
Figure imgf000602_0002
[001624] 3-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-chlorophenyl)piperidine-2,6- dione B315. MS (ESI) m/z: 753.2 [M+H]+.
Figure imgf000602_0003
[001625] 3-(5-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l -yl)-2-fluorophenyl)- piperidine-2, 6-dione B319. MS (ESI) m/z: 764.4 [M+H] ".
Figure imgf000603_0001
[001626] 3-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin- 1 -y 1 )ethy l)pi p eri di n- 1 -y 1)- 3 -fluorophenyl)- piperidine-2, 6-dione B320 MS (ESI) m/z: 764.5 [M+H]“.
Figure imgf000603_0002
[001627] 3-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyriniidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l -yl)-2-fluorophenyl)- piperidine-2, 6-dione B321 1H NMR (400 MHz, DMSO-d?) <5 10.79 (s, 1H), 10.07 (s, 1H), 8.95 (s, 1H), 8.23 (s, 1H), 8.05 (d, J= 2.8 Hz, 1H), 7.84 (d, J= 9.2 Hz, 1H), 7.46 (dd, J= 2.8, 9.2 Hz, 1H), 7.06 (t, J = 8.8 Hz, 1H), 6.78-6.63 (m, 2H), 5.82 (q, ./ = 8.8 Hz, 1H), 3.87 (dd, J = 4.8, 12.4 Hz, 1H), 3.70 (d, 12.4 Hz, 2H), 3.16 (s, 4H), 2.72-2.62 (m, 3H), 2.52 (s, 5H), 2.42 (s, 3H),
2.38 (t, ,J= 7.2 Hz, 2H), 2.31 (s, 3H), 2.28-2.19 (m, 2H), 2.18-2.06 (m, 1H), 2.00-1.92 (m, 1H), 1.88 (s, 2H), 1.82-1.72 (m, 4H), 1.63-1.54 (m, 2H), 1.44 (t, •/ 6.4 Hz, 3H), 1.31-1.17 (m, 2H); MS (ESI) m/z: 764.3 [M+H] \
Figure imgf000603_0003
[001628] 3-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B323 LH NMR (400 MHz, DMSO-c/e) <5 10.78 (s, 1H), 10.06 (s, 1H), 8.95 (s, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.84 (d, J= 9.2 Hz, 1H), 7.46 (dd, J= 2.8, 9.2 Hz, 1H), 7.16 (t, J= 7.6 Hz, 1H), 6.92-6.79 (m, 2H), 6.61 (d, J= 7.6 Hz, 1H), 5.82 (quin, J= 8.8 Hz, 1H), 3.76 (dd, ./ 4.8, 11.2 Hz, 1H), 3.46 (br d, ./ 12.4 Hz, 2H), 3.17 (br s, 4H), 3.01 (br t, J = 10.8 Hz, 2H), 2.70-2.57 (m, 7H), 2.49-2.39 (m, 4H), 2.31 (s, 3H), 2.28-2.12 (m, 3H), 2.08-1.83 (m, 6H),
1.82-1.72 (m, 3H), 1.64-1.52 (m, 2H); MS (ESI) m/z: 750.6 [M+H]+.
Figure imgf000604_0001
[001629] 3-(4-(4-(4-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B324. MS (ESI) m/z: 762.8 [M+H] 7
Figure imgf000604_0002
[001630] 3-(4-(2-(4-((4-((6-(Difluoromethyl)-8-((lA,2A)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- ethyl)phenyl)piperidine-2, 6-dione B359. lH NMR (400 MHz, DMSO-tfc) 6 0.94-1.01 (m, 3H), 1.36-1.49 (m, 1H), 1.51-1.71 (m, 3H), 1.79-1.97 (m, 5H), 1.98-2.04 (m, 1H), 2.10-2.23 (m, 3H), 2.40-2.47 (m, 2H), 2.52-2.59 (m, 3H), 2.59-2.76 (m, 4H), 2.88-3.04 (m, 3H), 3.16 (s, 6H), 3.52- 3.67 (m, 3H), 3.79-3.81 (m, 1H), 3.89-4.11 (m, 1H), 4.31-4.51 (m, 1H), 5.85 (t, J = 8.24 Hz, 1H), 6.71 -7.03 (m, 1H), 7.10-7.14 (m, 2H), 7.17-7.21 (m, 2H), 8.08-8.22 (m, 1H), 8.70-8.80 (m, 1H), 10.81 (s, 1H); MS (ESI) m/z: 748.2 [M+H]+.
Figure imgf000605_0001
[001631] 3-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-7]- pyrimi din-2-yl )amino)pyri din-3 -y I )azeti din-3 -yl )pi perazin- 1 -yl)phenyl)piperidine-2, 6-di one
B364. !HNMR (400 MHz, DMSO-7?) 3 10.77 (s, 1H), 10.02 (s, 1H), 8.93 (s, 1H), 7.78 (d, J=
8.8 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.05 (d, ./ 8.8 Hz, 2H), 6.99 (dd, ./ 2.8, 8.8 Hz, 1H), 6.90 (d, J= 8.8 Hz, 2H), 5.88-5.72 (m, 1H), 4.01 (t, J= 7.2 Hz, 2H), 3.79-3.63 (m, 3H), 3.41-
3.33 (m, 4H), 3.15 (s, 4H), 2.72-2.54 (m, 2H), 2.47-2.44 (m, 1H), 2.42 (s, 3H), 2.30 (s, 3H), 2.25
(d, 7= 8.4 Hz, 2H), 2.16-1.95 (m, 2H), 1.87 (d, J= 1.6 Hz, 2H), 1.76 (d, J= 7.2 Hz, 2H), 1.57
(d, J= 4.4 Hz, 2H); MS (ESI) m/z: 690.5 [M + H ]“
Figure imgf000605_0002
[001632] 3-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-4-fluorophenyl)- piperidine-2, 6-dione B365
Figure imgf000605_0003
10.80 (s, 1H), 10.09 (s, 1H), 8.95 (s, 1H), 8.16-8.12 (m, 1H), 8.05 (d, ,7= 2.8 Hz, 1H), 7.85 (d, .7 = 8.8 Hz, 1H), 7.47 (dd, 7= 2.8, 9.2 Hz, 1H), 7.05 (dd, J= 8.0, 12.4 Hz, 1H), 6.88 (d, J= 8.0 Hz, 1H), 6.77 (dd, J= 4.4, 6.0 Hz, 1H), 5.88-5.76 (m, 1H), 3.85-3.76 (m, 1H), 3.17 (s, 4H), 2.70-2.58 (m, 4H), 2.54 (s, 4H), 2.46- 2.36 (m, 6H), 2.31 (s, 3H), 2.27-2.16 (m, 3H), 2.05-1.96 (m, 1H), 1.93-1.83 (m, 2H), 1.78 (d, J= 10.4 Hz, 4H), 1.64-1.54 (m, 2H), 1.46 (s, 3H), 1.40-1.28 (m, 2H); MS (ESI) m/z: 764.4 [M+H] +.
Figure imgf000606_0001
[001633] 3-(4-(7-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-4,7-diazaspiro[2.5]octan-4-yl)phenyl)- piperidine-2, 6-dione B370
Figure imgf000606_0002
d 10.76 (s, 1H), 10.05 (s, 1H), 8.94 (s, 1H), 8.03 (d, .7= 2.8 Hz, 1H), 7.81 (d, .7= 9.2 Hz, 1H), 7.43 (dd, J= 2.8, 9.2 Hz, 1H), 7.04- 6.94 (m, 4H), 5.81 (quin, .7= 8.8 Hz, 1H), 3.76-3.59 (m, 4H), 2.74-2.57 (m, 4H), 2.49-2.40 (m, 5H), 2.33-2.19 (m, 7H), 2. 17-1.94 (m, 3H), 1.94-1.62 (m, 7H), 1.60-1.44 (m, 4H), 0.97-0.58 (m, 4H); MS (ESI) m/z: 744.5 [M+H]+.
Figure imgf000606_0003
[001634] l-(4-((l-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-Jjpyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)dihydropyrimidine-2,4(177,377)-dione B401 rHNMR (400 MHz, CDsOD) J 8.72-8.68 (m, 1H), 8.07 (s, 1H), 7.28-7.26 (m, 2H), 7.04-7.01 (m, 2H), 6.92-6.65 (m, 1H), 5.94- 5.77 (m, 1H), 4.61-4.59 (m, 2H), 4.23-3.97 (m, 1H), 3.82 (t, J= 6.8 Hz, 3H), 3.16 (t, .7= 7.2 Hz, 4H), 3.06-2.92 (m, 6H), 2.81 (t, J= 6.8 Hz, 3H), 2.17-1.73 (m, 15H), 1.37-1.29 (m, 3H); MS (ESI) m/z: 787.5 [M+H]+.
Figure imgf000606_0004
[001635] l-(4-(4-(3-((4-((6-(Difluoromethyl)-8-((lA,2R)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-^pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin-
I-yl)phenyl)dihydropyrimidine-2,4(l/7,3/7)-dione B402. MS (ESI) m/z'. 772.4 [M+H]+.
Figure imgf000607_0001
[001636] l-(4-(4-(3-((4-((6-(Difluoromethyl)-8-((lA,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l -yl)sulfonyl)propyl)piperazin- l-yl)-2-fluorophenyl)dihydropyrimidine-2,4(lH,3H)-dione B404. MS (ESI) m/z'. 79b A [M+H]+.
Figure imgf000607_0002
[001637] l-(4-(4-(3-((4-((6-(Difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-</]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)-2-methylphenyl)dihydropyrimidine-2,4(lH,3//)-dione B405. MS (ESI) wz: 786.5 [M+H]+.
Figure imgf000607_0003
[001638] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridm-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)dihydropyrimidine-
2,4(177,3/7)-dione B407 MS (ESI) m/z-. 719.4 [M+H]+.
Figure imgf000608_0001
[001639] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluorophenyl)dihydropyrimidine-2, 4(177, 377)-dione B408. MS (ESI) m/z: 737.4 [M+H]+.
Figure imgf000608_0002
[001640] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-chlorophenyl)dihydropyrimidine-2, 4(177, 377)-dione B409. MS (ESI) m/z: 753.1 [M+H]+.
Figure imgf000608_0003
[001641] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrirnidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-methylphenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B411 !H NMR (400 MHz, DMSO-de) d' 10.25 (s, 1H), 10.08 (s, 1H), 8.96 (s, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.46-7.51 (m, 1H), 7.07 (d, J 8.4 Hz, 1H), 6.83 (s, 1H), 6.79 (d, J 8.4 Hz, 1H), 5.79-5.86 (m, 1H), 3.72-3.80 (m, 2H), 3.64-3.71 (m, 1H), 3.42-3.51 (m, 2H), 3.14-3.18 (m, 4H), 2.71-2.76 (m, 2H), 2.67 (d, J = 3.2 Hz, 4H), 2.43 (s, 3H), 2.39 -2.41(m, 1H), 2.32 (s, 3H), 2.20-2.28 (m, 2H), 2.13 (s, 3H), 1.86-1.96 (m, 4H), 1.74-1.81 (m, 2H), 1.53-1.63 (m, 4H); MS (ESI) m/z: 733.4 [M+H]t
Figure imgf000609_0001
[001642] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2,3-dimethylphenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B412 rH NMR (400 MHz, DMSO-76) d 10.29 (s, 1H), 10.09 (s, 1H), 8.96 (s, 1H), 8.08 (s, 1H), 7.85 (d, J -- 9.2 Hz, 1H), 7.43-7.55 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.96 (d, ./ 8.6 Hz, 1H), 5.83 -5.86(m, 1H), 3.78 (d, ./ 11.2 Hz, 2H), 3.66-3.72 (m, 1H), 3.43-3.49 (m, 1H), 2.86 (s, 4H), 2.64-2.80 (m, 8H), 2.43 (s, 3H), 2.32 (s, 3H), 2.24 (d, J = 3.2 Hz, 2H), 2.22 (s, 3H), 2.06 (s, 3H), 1.84-2.01 (m, 5H), 1.74-1.81 (m, 2H), 1.55-1.65 (m, 4H); MS (ESI) m/z: 747.4 [M+H]+.
Figure imgf000609_0002
[001643] l-(5-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2,4-dim ethylphenyl)- dihydropyrimidine-2, 4(177, 377)-dione B413. MS (ESI) m/z: 775.4 [M+H]r.
Figure imgf000609_0003
[001644] l-(5-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-chl oro-3 -methyl- phenyl)dihydropyrimidine-2, 4(177, 37/)-dione B414. MS (ESI) m/z: 795.4 [M+Hp.
Figure imgf000610_0001
[001645] l-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-5-chloro-2-methyl- phenyl)dihydropyrimidine-2,4(17/,37/)-dione B415. MS (ESI) m/z: 795.4 [M+H]’.
Figure imgf000610_0002
[001646] l-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperazin-l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 3/7)-dione B416 MS (ESI) m/z: 748.4 [M+H]+.
Figure imgf000610_0003
[001647] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimi din-2-yl )amino)pyri din-3 -yl )pi peri din-4-yl)piperazi n- 1 -yl)-2-chl oro-5 -m ethylphenyl)- dihydropyrimidine-2, 4(177, 377)-dione B451. !H NMR (400 MHz, DMSO-sfc) 3 1.51-1.66 (m, 4H), 1.73-1.81 (m, 2H), 1.83-1.96 (m, 4H), 2.23 (s, 5H), 2.31 (s, 3H), 2.42 (s, 5H), 2.62-2.77 (m, 7H), 2.88 (d, - 3.8 Hz, 4H), 3.51-3.69 (m, 2H), 3.76 (d, J - 12.2 Hz, 2H), 5.82 (m J= 8.8 Hz, 1H), 7.10 (s, 1H), 7.26 (s, 1H), 7.47-7.48 (m, 1H), 7.83 (d, J = 8.8 Hz, 1H), 8.06-8.07 (m, 1H), 8.95 (s, 1H), 10.08 (s, 1H), 10.40 (s, 1H); MS (ESI) m/z: 767.4 [M+H]+.
Figure imgf000611_0001
[001648] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluoro-3-methylphenyl)- dihydropyrimidine-2, 4(1/7, 3/7)-dione B452. rH NMR (400 MHz, DMSO-flfc) 8 = 1.48-1.68 (m, 4H), 1.71 -1.82 (m, 2H), 1.82-1.98 (m, 4H), 2.17 (d, J 2.2 Hz, 3H), 2.25 (t, J -- 7.6, 3.2 Hz, 2H), 2.31 (s, 3H), 2.42 (s, 4H), 2.59-2.80 (m, 8H), 2.87-2.88 (m, 4H), 3.65 (t, J = 6.4 Hz, 2H), 3.74-3.76 (m, 2H), 5.82 (m, ./ 8.8 Hz, HI), 6.89 (d, 8.6 Hz, 1H), 7.18 (t, J = 8.8 Hz, 1H),
7.48 (dd, .7 - 9.0, 3.0 Hz, 1H), 7.83 (d, J - 8.8 Hz, 1H), 8.07 (d, J - 2.8 Hz, 1H), 8.95 (s, 1H), 10.07 (s, 1H), 10.41 (s, 1H); MS (ESI) m/z: 751.4 [M+H]+.
Figure imgf000611_0002
[001649] l-(4-(4-(1 -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluoro-5-methylphenyl)- dihydropyrimidine-2, 4(1/7, 3/7)-dione B453 rH NMR (400 MHz, DMSCWs) 3 10.41 (s, 1H), 10.07 (s, 1H), 8.95 (s, 1H), 8.07 (d, 2.8 Hz, 1H), 7.83 (d, J= 8.8 Hz, 1H), 7.48 (dd, J= 2.8,
9.2 Hz, 1H), 7.19 (d, J= 8.8 Hz, 1H), 6.91 (d, J= 12.4 Hz, 1H), 5.82 (t, J= 8.8 Hz, 1H), 3.76 (d, ,7= 12.0 Hz, 2H), 3.65 (t, J= 6.4 Hz, 2H), 2.87 (s, 4H), 2.77-2.64 (m, 9H), 2.42 (s, 3H), 2.31 (s, 3H), 2.28-2.23 (m, 2H), 2.21 (s, 3H), 1.95-1.84 (m, 4H), 1.82-1.72 (m, 2H), 1.64-1.53 (m, 4H); MS (ESI) m/z: 751.5 [M+H]+.
Figure imgf000612_0001
[001650] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yi)piperidin-4-yl)piperazin-l-yl)-2-chloro-6-methylphenyl)- dihydropyrimidine-2, 4(177, 377)-dione B454 rH NMR (400 MHz, DMSO-t/s) 3 10.36 (s, 1H), 10.06 (s, 1H), 8.95 (s, 1H), 8.15 (s, 1H), 8.07 (d, J= 2.8 Hz, 1H), 7.83 (d, J= 9.2 Hz, 1H), 7.48
(dd, J= 2.8, 9.2 Hz, 1H), 6.92-6.80 (m, 2H), 5.82 (quin, J = 8.8 Hz, 1H), 3.81-3.71 (m, 2H),
3.58-3.47 (m, 2H), 3.18 (s, 4H), 2.78-2.68 (m, 4H), 2.65 (d, 5.2 Hz, 4H), 2.42 (s, 3H), 2.31
(s, 3H), 2.28-2.20 (m, 2H), 2.16 (s, 3H), 1.97-1.80 (m, 5H), 1.80-1.69 (m, 2H), 1.63-1.52 (m,
4H); MS (ESI) m/z\ 767.3 [M+H]+.
Figure imgf000612_0002
[001651] l-(4-(4-(l -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3-fluoro-2-methylphenyl)- dihydropyrimidine-2, 4(177, 377)-dione B455 rH NMR (400 MHz, DMSCWs) 3 10.34 (s, 1H), 10.07 (s, 1H), 8.95 (s, 1H), 8.07 (d, <7= 3.2 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.48 (dd, J = 2.8, 9.2 Hz, 1H), 7.04 (d, J= 8.4 Hz, 1H), 6.90 (t, J= 9.2 Hz, 1H), 5.82 (t, J= 8.8 Hz, 1H), 3.81-3.68 (m, 3H), 3.49 (td, J= 6.4, 12.4 Hz, 1H), 3.02 (d, J= 3.6 Hz, 4H), 2.83-2.60 (m, 8H), 2.42 (s, 4H), 2.31 (s, 3H), 2.28-2.18 (m, 2H), 2.05 (d, J= 2.4 Hz, 3H), 1.96-1.82 (m, 4H), 1.81-1.74 (m, 2H), 1.64-1.52 (m, 4H); MS (ESI) m/z: 751.5 [M+H]+
Figure imgf000613_0001
[001652] l-(5-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-chlorophenyl)- dihydropyrimidine-2, 4(1/7, 37/)-dione B458 rH NMR (400 MHz, DMSO-t/s) 3 10.39 (s, 1H), 10.11 (s, 1H), 8.95 (s, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.53-7.45 (m, 1H), 7.31 (d, J= 8.8 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 6.92 (dd, J- 2.8, 9.2 Hz, 1H), 5.82 (t, J = 8.8 Hz, 1H), 3.75-3.51 (m, 4H), 3.27-2.97 (m, 4H), 2.81-2.60 (m, 6H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27-2.20 (m, 2H), 1.88 (s, 2H), 1.77 (d, J= 9.6 Hz, 4H), 1.65-1.41 (m, 5H), 1.34-1.16 (m, 2H);
MS (ESI) m/z: 781.5 [M+H]+.
Figure imgf000613_0002
[001653] l-(5-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- Jjpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-fluorophenyl)- dihydropyrimidine-2,4(lJ7,377)-dione B459 rH NMR (400 MHz, DMSO-tZe) 3 = 10.53-10.33 (m, 1H), 10.09 (s, 1H), 8.95 (s, 1H), 8.50 (s, 1H), 8.05 (d, J= 2.4 Hz, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.46 (dd, 2.8, 9.0 Hz, 1H), 7.10 (t, ./ 9.2 Hz, 1H), 6.96 (dd, ./ 2.4, 6.4 Hz, 1H), 6.91- 6.85 (m, 1H), 5.82 (t, J= 8.6 Hz, 1H), 3.68 (t, J= 6.4 Hz, 2H), 3.61-3.58 (m, 2H), 3.15 (d, J = 4.0 Hz, 4H), 2.70 (t, J= 6.4 Hz, 2H), 2.65-2.54 (m, 6H), 2.44-2.36 (m, 5H), 2.34-2.29 (m, 3H), 2.28-2.21 (m, 2H), 1.92-1.85 (m, 2H), 1.81-1.72 (m, 4H), 1.61-1.55 (m, 2H), 1.45 (s, 3H), 1.29 (d, J= 8.4 Hz, 2H); MS (ESI) m/z: 765.5 [M+H]+.
Figure imgf000614_0001
[001654] l-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-fluorophenyl)- dihydropyrimidine-2, 4(177, 3J7)-dione B460 rH NMR (400 MHz, DMSO-tfc) 3 10.44 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.25 (s, 1H), 8.05 (d, J= 2.8 Hz, 1H), 7.85 (d, J= 9.2 Hz, 1H), 7.47 (dd, J= 2.8, 9.2 Hz, 1H), 7.16-7.06 (m, 1H), 7.03-6.94 (m, 2H), 5.91-5.75 (m, 1H), 3.68 (t, 7 = 6.4 Hz, 2H), 3.31-3.29 (m, 2H), 3.19-3.14 (m, 4H), 2.74-2.60 (m, 4H), 2.57-2.52 (m, 4H), 2.42 (s, 3H), 2.41-2.36 (m, 2H), 2.31 (s, 3H), 2.28-2.18 (m, 2H), 1.94-1.84 (m, 2H), 1.83-1.71 (m, 4H), 1.64-1.54 (m, 2H), 1.52-1.41 (m, 3H), 1.40-1.27 (m, 2H); MS (ESI) m/z: 765.5 [M+H]+.
Figure imgf000614_0002
[001655] l-(5-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7|pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -y l)ethy l)piperi din- 1 -yl)-2-methylphenyl)- dihydropyrimidine-2, 4(1/7, 3//)-dione B461
Figure imgf000614_0003
NMR (400 MHz, DMSO-tA) ri = 10.26 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.05 (s, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.46 (d, J= 9.2 Hz, 1H), 7.07 (d, J= 8.0 Hz, 1H), 6.87-6.76 (m, 2H), 5.89-5.75 (m, 1H), 3.76-3.70 (m, 1H), 3.64-3.60 (m, 2H), 3.50-3.45 (m, 2H), 3.19-3.10 (m, 4H), 2.70 (d, J= 6.8 Hz, 2H), 2.64-2,53 (m, 5H), 2.45-2.36 (m, 5H), 2.30 (s, 3H), 2.27-2.20 (m, 2H), 2.08-2.04 (m, 3H), 2.02-1.95 (m, 1H), 1.92-1.84 (m, 2H), 1.81-1.73 (m, 4H), 1.62-1.54 (m, 2H), 1.44 (s, 3H), 1.32-1.27 (m, 2H); MS (ESI) m/z: 761.6 [M+H]+.
Figure imgf000615_0001
[001656] l-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)aniino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-methyiphenyi)- dihydropyrimidine-2, 4(177, 37/)-dione B462.
Figure imgf000615_0002
(400 MHz, DMSO-c/s) 8 = 10.29 (s, 1H), 10.07 (s, 1H), 8.95 (s, 1H), 8.32 (s, 2H), 8.05 (d, J= 2.8 Hz, 1H), 7.85 (d, J= 9.2 Hz, 1H), 7.47 (dd, J= 2.8, 9.2 Hz, 1H), 7.22-7.12 (m, 1H), 7.00 (d, J= 7.6 Hz, 1H), 6.95 (d, J= 8.0 Hz, 1H), 5.82 (q, .7= 8.8 Hz, 1H), 3.76-3.70 (m, 1H), 3.53-3.47 (m, 2H), 3.17 (s, 4H), 3.03 (d, 12.0
Hz, 2H), 2.78-2.61 (m, 3H), 2.54 (s, 4H), 2.42 (s, 3H), 2.40 (d, J= 7.2 Hz, 2H), 2.31 (s, 3H), 2.28-2.20 (m, 2H), 2.10 (s, 3H), 1.87 (d, J= 5.6 Hz, 2H), 1.83-1.73 (m, 4H), 1.63-1.55 (m, 2H), 1.53-1.42 (m, 3H), 1.39-1.30 (m, 2H); MS (ESI) m/z: 761.4 [M+H] \
Figure imgf000615_0003
[001657] l-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l -yl)-2-chlorophenyl)- dihydropyrimidine-2,4(17/,377)-dione B467.
Figure imgf000615_0004
(400 MHz, CDCh) <5 8.83 (s, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 8.19 (d, J= 9.2 Hz, 1H), 8.09 (d, J= 2.8 Hz, 2H), 7.35 (dd, 3.2, 9.2 Hz, 1H), 7.17 (d, J= 8.8 Hz, 1H), 6.97 (d, J= 2.8 Hz, 1H), 6.83 (dd, J= 2.8, 8.8 Hz, 1H), 5.88 (q, J = 8.8 Hz, 1H), 3.82-3.63 (m, 4H), 3 31 (s, 4H), 2.99-2.89 (m, 1H), 2.88-2.74 (m, 7H), 2.65 (d, J = 5.6 Hz, 2H), 2.56 (s, 3H), 2.40-2.32 (m, 5H), 2.10-2.03 (m, 2H), 1.95-1.86 (m, 2H), 1.82 (d, J - 12.0 Hz, 2H), 1.76-1.66 (m, 2H), 1.65-1.58 (m, 2H), 1.55 (dt, ./ 3.6, 6.8 Hz, 1H), 1.45-1.31 (m, 2H); MS (ESI) m/z: 781.4 [M+Hf-
Figure imgf000616_0001
[001658] l-(4-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperazin-l-yl)-2-chlorophenyl)- dihydropyrimidine-2, 4(177, 377)-dione B468 rH NMR (400 MHz, DMSO-flfc) 3 10.37 (s, 1H), 10.11 (s, 1H), 8.95 (s, 1H), 8.13 (s, 1H), 8.07 (d, .7= 2.4 Hz, 1H), 7.86 (d, .7= 9.2 Hz, 1H), 7.49 (dd, J= 2.8, 9.2 Hz, 1H), 7.31-7.24 (m, 1H), 7.07 (s, 1H), 6.96 (dd, J= 2.4, 9.2 Hz, 1H), 5.88- 5.76 (m, 1H), 3.68-3.58 (m, 2H), 3.53 (td, J= 6.4, 12.4 Hz, 3H), 3.48-3.36 (m, 9H), 2.80-2.64 (m, 10H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27-2.20 (m, 2H), 1.92-1.83 (m, 2H), 1.80-1.73 (m, 2H), 1.62-1.53 (m, 2H); MS (ESI) m/z\ 782.4 [M+H] \
Figure imgf000616_0002
[001659] l-(4-(4-(2-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B469 rH NMR (400 MHz, DMSO-c/6) 3 10.28 (s, 1H), 10.07 (s, 1H), 8.95 (s, 1H), 8.13 (s, 1H), 8.06 (br d, J = 2.0 Hz, 1H), 7.82 (br d, J = 8.8 Hz, 1 H), 7.47 (br dd, J = 2.8, 9.2 Hz, 1H), 7.19 (br d, J = 7.6 Hz, 2H), 7.04-6.92 (m, 2H), 5.87-5.75 (m, 1H), 3.74- 3.67 (m, 4H), 3.15-2.94 (m, 4H), 2.74-2.63 (m, 5H), 2.42 (s, 5H), 2.31 (s, 4H), 2.28-2.16 (m, 3H), 1.94-1.71 (m, 7H), 1.63-1.43 (m, 5H), 1.37-1.26 (
Figure imgf000616_0003
Figure imgf000616_0004
[001660] l-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)methyl)piperi din- l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 37/)-dione B470.
Figure imgf000617_0001
NMR (400 MHz, DMSO-fifc) 3 10.29 (s, IH), 10.09 (s,
IH), 8.95 (s, IH), 8.05 (br d, J= 2.0 Hz, 1H), 7.84 (br d, J= 9.2 Hz, IH), 7.47 (br dd, J= 2.0,
8.8 Hz, 1H), 7. 19 (t, ./ 8.0 Hz, 1H), 6.87 (br s, IH), 6.81 (br d, J = 7.2 Hz, 1H), 6.68 (br d, J
8.0 Hz, IH), 5.90-5.74 (m, 1H), 3.74 (br t, ./= 6.4 Hz, 2H), 3.69 (br d, J= 11.2 Hz, 2H), 3.17 (br s, 4H), 2.74-2.66 (m, 5H), 2.42 (s, 3H), 2.35-2.29 (m, 4H), 2.23 (br d, ./ 6.8 Hz, 4H), 1.99-1.67
(m, 8H), 1.63-1.54 (m, 2H), 1.26-1.18 (m, 3H); MS (ESI) m/z: 733.5 [M+H]t
Figure imgf000617_0002
[001661] l-(4-(2-(l-(l-(6-((6-Acetyl-8-cydopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- J]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)-3 -fluoroazeti din-3 -yl)ethyl)-2-chloro- phenyl)dihydropyrimidine-2,4(l//,377)-dione B472. ^I NMR (400 MHz, DMSO-Je) O’ 10.45 (s, IH), 10.08 (s, IH), 8.95 (s, IH), 8.43 (br d, J= 2.0 Hz, 1H), 8.06 (d, J= 2.8 Hz, 1H), 7.83 (d, J= 9.2 Hz, IH), 7.50 (d, J = 1.6 Hz, IH), 7.47 (dd, J= 2.8, 9.2 Hz, IH), 7.42-7.37 (m, IH), 7.31 (dd, J= 1.6, 8.0 Hz, IH), 5.82 (t, .7= 8.8 Hz, IH), 3.75-3.64 (m, IH), 3.63-3.51 (m, 3H), 3.40 (br d, J = 15.2 Hz, 3H), 3.23-3.13 (m, 2H), 2.84-2.70 (m, 5H), 2.43 (s, 3H), 2.31 (s, 3H), 2.30-2.19 (m, 3H), 2.18-2.04 (m, 2H), 1,88 (br d, J= 1.6 Hz, 2H), 1 .83-1 .69 (m, 4H), 1.58 (br d, J= 5.6 Hz, 2H), 1.32 (br d, J= 10.0 Hz, 2H); MS (ESI) m/z: 770 A [M+H]+.
Figure imgf000617_0003
[001662] 3-(6-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethoxy)-l-methyl-l//-indazol-3-yl)- piperidine-2, 6-dione B501
Figure imgf000618_0001
[001663] 3-(7-(2-(4-(3-((4-((6-(Difluoromethyl)-8-((17?,25)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-(/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)- piperazin-l-yl)-2-oxoethoxy)-l-methyl-l/7-indazol-3-yl)piperidine-2, 6-dione B502.
Figure imgf000618_0002
[001664] 3-(6-(4-(l-(6-((6-Acetyl-8-cycIopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-i(]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-]J7-indazol-3-yl)- piperidine-2, 6-dione B503 'H NMR (400 MHz, CDCh) 8 8.82 (s, 1H), 8.35 (s, 2H), 8.27 (s, 1H), 8.18 (d, J= 9.2 Hz, 1H), 8.07 (d, J= 2.8 Hz, 1H), 7,55 (d, J= 8.8 Hz, 1H), 7,37 (dd, J = 2.8, 9.2 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 6.66 (s, 1H), 5.89 (q, J = 8.8 Hz, 1H), 4.26 (t, J= 6.0 Hz, 1H), 3.95 (s, 3H), 3.74 (d, J= 12.0 Hz, 2H), 3.39 (s, 4H), 3.08-2.99 (m, 1H), 2.98-2.90 (m, 4H), 2.83 ( t, J = 11.6 Hz, 2H), 2.70-2.63 (m, 2H), 2.56 (s, 3H), 2.53-2.43 (m, 2H), 2.39-2.29 (m, 5H), 2.16-2.01 (m, 4H), 1.96-1.79 (m, 4H), 1.77-1.64 (m, 2H); MS (ESI) m/z: 772A [M+H]+.
Figure imgf000618_0003
[001665] 3-(6-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)-l-methyl-l//-indazol-3-yl)- piperidine-2, 6-dione B507 lH NMR (400 MHz, DMSO-r/e) 8 10.84 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.05 (d, J= 2.8 Hz, 1H), 7.84 (d, ./= 9.2 Hz, 1H), 7.52-7.43 (m, 2H), 6.92 (d, J= 9.2 Hz, 1H), 6.85 (s, 1H), 5.89-5.75 (m, 1H), 4.25 (dd, J= 5.2, 9.0 Hz, 1H), 3.92-3.80 (m, 5H), 3.17 (s, 4H), 2.76 (t, J= 11.6 Hz, 2H), 2.69 (s, 4H), 2.66-2.58 (m, 2H), 2.47-2.40 (m, 4H), 2.31 (s, 3H), 2.30-2.11 (m, 4H), 1.95-1.84 (m, 4H), 1.82-1.72 (m, 2H), 1.66-1.52 (m, 4H); MS (ESI) m/z: 772A [M+H]+.
Figure imgf000619_0001
[001666] 3-(6-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -y l)ethy I)piperi din- 1 -yl)-l -methyl- 1/7-indazol- 3 -yl)piperidine-2, 6-dione B511 M-INMR (400 MHz, CDCh) J 8.80 (s, 1H), 8.17 (d, ./ 8.8 Hz, 1H), 8.05 (s, 2H), 8.00-7.94 (m, 1H), 7.51 (d, J= 8.8 Hz, 1H), 7.35 (d, J= 9.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.63 (s, 1H), 5,95-5.82 (m, 1H), 4.25 (dd, J = 5.2, 6.8 Hz, 1H), 3.94 (s, 3H), 3.81- 3.68 (m, 4H), 3.31-3.21 (m, 3H), 2.99 (dd, .7= 8,8, 13.2 Hz, 1H), 2.79 (t, J = 12.0 Hz, 3H), 2.71- 2.62 (m, 4H), 2.56 (s, 3H), 2.53-2.46 (m, 2H), 2.40-2.32 (m, 6H), 2.12-2.03 (m, 2H), 1.95-1.84 (m, 5H), 1.70 (dd, ./ 5.2, 10.8 Hz, 2H), 1.52-1.48 (m, 2H), 1.32-1.22 (m, 4H); MS (ESI) m/z: 800.6 [M+H]\
Figure imgf000619_0002
[001667] l-(6-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin- 1 -y l)ethy l)piperi din- 1 -y 1)- 1 -methyl- 177-indazol- 3-yl)dihydropyrimidine-2, 4(1//, 3//)-dione B552 ‘H NMR (400 MHz, CDCh) 3 8.83 (s, 1H), 8.52-8.36 (m, 1H), 8.29-8.25 (m, 1H), 8.21 (d, J= 9.2 Hz, 1H), 8.09 (s, 2H), 7.54 (d, J= 9.2 Hz, 1H), 7.36 (dd, ./= 2.8, 9.2 Hz, 1H), 6.92 (d, J= 8.4 Hz, 1H), 6.58 (s, 1H), 5.88 (q, J= 8.8 Hz, 1H), 4.09 (t, J= 6.8 Hz, 2H), 3.93 (s, 3H), 3.76 (d, J= 12.0 Hz, 2H), 3.38 (s, 4H), 2.97 (s, 4H), 2.88 (t, 6.8 Hz, 2H), 2.82-2.75 (m, 4H), 2.56 (s, 3H), 2.39-2.34 (m, 5H), 2.07 (d, J- 4.8 Hz,
2H), 1.92-1.83 (m, 4H), 1.74-1.66 (m, 4H), 1.58-1.42 (m, 3H); MS (ESI) m/z: 801.4 [M+H]+.
Figure imgf000620_0001
[001668] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-l//-indazol-3-yl)- dihydropyrimidine-2, 4(1/7, 3#)-dione B553 lH NMR (400 MHz, DMSO-t/6) d’ 10.53 (s, 1H), 10.06 (s, 1H), 8.95 (s, 1H), 8.43 (s, 1H), 8.08 (d, 2.8 Hz, 1 H ), 7.84 (d, J= 9.2 Hz, 1H), 7.49
(dd, J= 2.8, 9.2 Hz, 1H), 7.31 (d, J= 8.0 Hz, 1H), 7.12-6.92 (m, 2H), 5.82 (quin, J= 8.8 Hz, 1H), 4.24 (s, 3H), 3.88 (t, 6.8 Hz, 2H), 3.77 (d, 11.6 Hz, 2H), 3.22-3.08 (m, 4H), 2.82-
2.70 (m, 6H), 2.67 (s, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.29-2.17 (m, 3H), 1.99-1.83 (m, 5H),
1.82-1,74 (m, 2H), 1.65-1.56 (m, 4H); MS (ESI) m/z: 773.6 [M+H]+.
Figure imgf000620_0002
[001669] l-(6-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-l/Z-indazol-3-yl)- dihydropyrimidine-2,4(lH,3H)-dione B554. MS (ESI) /»/z: 773.5 [M+H]+.
Figure imgf000620_0003
[001670] l-(6-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-fluoro-l-methyl-177-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3//>dione B555 ‘H NMR (400 MHz, DMSCWs) rl 10.53 (s, 1H), 10.09 (s, 1H), 8.96 (s, 1H), 8.08 (d, J= 2.8 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.49 (dd, J = 2.8, 9.2 Hz, 1H), 7.36 (d, J= 12.8 Hz, 1H), 7.10 (d, J= 6. 8 Hz, 1H), 5.91-5.75 (m, 1H), 3.95 (s, 3H), 3.90 (t, J= 6.8 Hz, 2H), 3.81-3.73 (m, 2H), 3.10 (br s, 4H), 2.78-2.69 (m, 8H), 2.43 (s, 3H), 2.32 (s, 3H), 2.29-2.20 (m, 3H), 1.97-1.86 (m, 4H), 1.82-1.74 (m, 2H), 1.65-1.55 (m, 4H); MS (ESI) m/z: 791.5 [M+H]+.
Figure imgf000621_0001
[001671] l-(6-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyriniidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-7-fluoro-l-methyl-17/-indazol-
3-yl)dihydropyrirnidine-2, 4(1 /7, 3//)-dione B556 MS (ESI) m/z'. 791.7 [M+H]+
Figure imgf000621_0002
[001672] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-a[]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-fluoro-l-methyl-l/f-indazol- 3-yl)dihydropyrimidine-2,4(l//,3J/)-dione B557. LH NMR (400 MHz, DMSO-d6 ) 3 10.54 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.35 (s, 1H), 8.08 (d, J- 3.2 Hz, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.49 (dd, J= 2.8, 9.2 Hz, 1H), 7.06 (dd, J= 2.4, 8.4 Hz, 1H), 6.94 (dd, J= 2.4, 10.8 Hz, 1H), 5.82 (quin, ,/ 8.8 Hz, 1H), 4.21 (s, 3H), 3.87 (t, ./ 6.4 Hz, 2H), 3.77 (d, ./ 12.0 Hz, 2H), 2.80-2.70 (m, 5H), 2.69-2.65 (m, 1H), 2.58 (s, 2H), 2.52-2.52 (m, 4H), 2.42 (s, 3H), 2.32 (d, J= 2.0 Hz, 1H), 2.31 (s, 3H), 2.27-2.19 (m, 2H), 1.96-1.84 (m, 4H), 1.81-1.72 (m, 2H), 1.66-1.54 (m, 4H)MS (ESI) m/z: 791.5 [M+H]+.
Figure imgf000622_0001
[001673] l-(6-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yi)piperidin-4-yl)piperazin-l-yl)-5-chloro-l-methyl-lH-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B558 LH NMR (400 MHz, DMSO-t/s) S 10.18-9.98 (m, 1H), 8.95 (s, 1H), 8.07 (br s, 1H), 7.88-7.79 (m, 1H), 7.73 (s, 1H), 7.49 (br dd, ./ 2.4, 8.4 Hz, 1H), 7.28 (s, 1H), 5.91-5.73 (m, 1H), 3.95 (s, 3H), 3.90 (br t, J= 6.4 Hz, 2H), 3.76 (br d, J = 11.6 Hz, 2H), 3.06 (br s, 4H), 2.82-2.67 (m, 8H), 2.47-2.46 (m, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.23 (br d, J- 6.8 Hz, 2H), 1.98-1.84 (m, 4H), 1 .82-1 .72 (m, 2H), 1.68-1.52 (m, 4H); MS (ESI) m/z: 807.5 [M+H]+.
Figure imgf000622_0002
[001674] l-(6-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-7-chloro-l-methyl-l/7-indazol-
3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B559 MS (ESI) m/r. 807.3 [M+H]+.
Figure imgf000622_0003
[001675] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyriniidiii-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-chloro-l-methyl-l//-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 3/7)-dione B560. MS (ESI) m/z\ '&Y13 [M+H]+.
Figure imgf000623_0001
[001676] -l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-y!)-2-methylpiperazin-l-yl)-l-methyl-l//- indazol-3-yl)dihydropyrimidine-2,4(l#,3#)-dione B561. ’H NMR (400 MHz, DMSO-tfo) 3 10.54 (s, 1H), 10.06 (s, 1H), 8.95 (s, 1H), 8.36 (s, 1H), 8.08 (d, ./ 2.4 Hz, 1H), 7.83 (d, J 9.2 Hz, 1H), 7.48 (dd, J= 2.0, 9.2 Hz, 1H), 7.39 (d, J= 8.0 Hz, 1H), 7.27 (d, J= 6.0 Hz, 1H), 7.07 (, J- 7.2 Hz, 1H), 5.82 (t, J- 8.8 Hz, 1H), 4.29 (s, 3 H), 3.89 (t, J = 6.8 Hz, 2H), 3.77 (d, J = 12.8 Hz, 2H), 3.12-3.02 (m, 2H), 2.97-2.89 (m, 1H), 2.84-2.62 (m, 6H), 2.47-2.37 (m, 5H), 2.31 (s, 3H), 2.28-2.06 (m, 3H), 2.00-1.71 (m, 6H), 1.70-1.47 (m, 4H), 0.99-0.67 (m, 3H); MS (ESI) m/z: 787.7 [M+H]+.
Figure imgf000623_0002
[001677] (7?)-l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-tf|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-y!)-2-methylpiperazin-l-yl)-l -methyl-l/f- indazol-3-yl)dihydropyrimidine-2,4(l//,3/7)-dione B562 rH NMR (400 MHz, CDsOD) 3 9.21- 9.16 (m, 1H), 9.03-8.88 (m, 1H), 8.50 (s, 1H), 8.07 (s, 1H), 8.01 -7.86 (m, 1H), 7.65-7.52 (m, 1H), 7.51-7.40 (m, 1H), 7.39-7.28 (m, 1H), 7.18-7.05 (m, 1H), 6.13-5.89 (m, 1H), 4.38 (s, 3H), 4.08-3.93 (m, 2H), 3.86-3.81 (m, 1H), 3.16 (d, ./ 9.2 Hz, 21 1 ), 3.07-2.94 (m, 2H), 2.93-2.76 (m, 4H), 2.76-2.64 (m, 2H), 2.49 (s, 3H), 2.38 (s, 3H), 2.33 (s, 2H), 2.22-2.10 (m, 2H), 2.10-2.00 (m, 3H), 1.99-1.93 (m, 2H), 1.92-1.85 (m, 2H), 1.81-1.65 (m, 4H), 1.38-1.25 (m, 2H), 0.97-0.87 (m, 2H); MS (ESI) m/z: 787.7 [ M+H ]’.
Figure imgf000624_0001
[001678] (A)-l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<^]pyrimidin-2-y])amino)pyridin-3-yl)piperidin-4-yl)-3-methylpiperazin- l-yl)-l -methyl-1//- indazol-3-yl)dihydropyrimidine-2,4(l/7,377)-dione B563. MS (ESI) wk 787.5 [M+H]+.
Figure imgf000624_0002
[001679] l-(6-(2-(l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l-methyl-12/- indazol-3-yl)dihydropyrimidine-2, 4(1/7, 3Z/)-dione B564. MS (ESI) m/z: 790.5 [M+H]+.
Figure imgf000624_0003
[001680] l-(7-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -y l)piperi din- 1 -yl)methy l)-4-fluoropiperidin- 1 -yl)- 1 -methyl - l//-indazol-3-yl)diliydropyrimidine-2,4(l//,3/7)-dione B567. rHNMR (400 MHz, DMSO-tfc) <5 10.55 (s, 1H), 10.27 (s, 1H), 9.00 (s, 1H), 8.26 (d, 2.0 Hz, 1H), 8.19 (s, 1H), 8.06-7.95 (m,
1H), 7.76 (dd, J= 2.4, 8.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.12-7.06 (m, 1H), 7.05-7.00 (m, 1H), 5.92-5.79 (m, 1 H), 4.27 (s, 2H), 3.89 (t, ./ 6.8 Hz, 2H), 3.20-3. 13 (m, 2H), 3.08 (d, 7= 10.4 Hz, 2H), 3.00-2.87 (m, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.67 (d, ./= 2.0 Hz, 1H), 2.61 (s, 1H), 2.43 (s, 6H), 2.32 (s, 3H), 2.29-2.21 (m, 4H), 2.13-2.04 (m, 2H), 1.96-1.85 (m, 3H), 1.83-1.70 (m, 6H), 1.66-1.55 (m, 2H); MS (ESI) m/z: 804.7 [M+H] \
Figure imgf000625_0001
[001681] l-(6-(2-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)-l-methyl-l/7- indazol-3-yl)dihydropyrimidine-2,4(l/7,377)-dione B570. ’H NMR (400 MHz, DMSO-4Z5) 3 10.54 (s, 1H), 10.07 (s, 1H), 8.95 (s, 1H), 8.06 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.40-7.50 (m, 2H), 7.00 (d, J - 8.6 Hz, 1H), 5.82 (m, 1H), 3.96 (s, 3H), 3.91 (t, J - 6.4 Hz, 2H), 3.75 (d, J = 10.8 Hz, 2H), 2.66-2.83 (m, 8H), 2.40-2.48 (m, 6H), 2.31 (s, 3H), 2.23 (d, J -- 8.0 Hz, 2H), 1.90-1.99 (m, 2H), 1.84-1.86 (m, 6H), 1.75 (d, J -- 7.6 Hz, 4H), 1.52-1.62 (m, 4H); MS (ESI) m/z: 818.4 [M+H]+.
Figure imgf000625_0002
[001682] 3-(5-(l-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethyl)piperidin-4-yl)-6-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione B601
Figure imgf000625_0003
[001683] 4-((2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperi din-3 - yl)isoindoline-l, 3-dione B603
Figure imgf000626_0001
[001684] 3-(5-(l-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethoxy)benzyl)piperidin-4-yl)-l-oxo- isoindolin-2-yl)piperidine-2, 6-dione B604. MS (ESI) w/z: 907.5 [M+H]+.
Figure imgf000626_0002
[001685] The following compounds are prepared similarly according to the synthetic procedures or methodologies exemplified herein.
[001686] 7-Cyclopentyl-2-((5-(3-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- l,l-difluoroethyl)azetidin-l-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7/7-pyrrolo[2,3-6?]pyrimidine- 6-carboxamide A351
Figure imgf000626_0003
[001687] 7-Cyclopentyl-2-((5-(4-((l-(4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A^V-dimethyl-7Zf-pyrrolo[2,3-t/]- pyrimidine-6-carboxamide A437.
Figure imgf000627_0001
[001688] 2-((5-(4-((l -(3-Chloro-4-(2,4-dioxotetrahy dropyrimidin- 1 (2#)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yi)pyridin-2-yl)amino)-7-cyclopentyl-jV,Ar-dimethyl-7JH- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A438.
Figure imgf000627_0002
[001689] 7-Cyclopentyl-2-((5-(4-(l -(4-(2,4-dioxotetrahydropyrimidin-l(2Z/)-yl)phenyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7V,TV-dimethyl-7//-pyrrolo[2,3-<7|pyrimidine-6- carboxamide A439.
Figure imgf000627_0003
[001690] 2-((5-(4-(l-(2-(3-Chloro-4-(2,4-dioxotetrahydropyrimidin-l(21/)-yl)phenyl)-2,2- difluoroethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-jV,jV-dimethyl-7/f- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A440.
Figure imgf000627_0004
[001691] 3-(4-(2-((4-((6-(Difluoromethyl)-8-((l/?,2JR)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethoxy)phenyl)- piperidine-2, 6-dione B351.
Figure imgf000628_0001
[001692] 3-(4-(4-(((4-((6-(Difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)methyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione B352.
Figure imgf000628_0002
[001693] 3-(3-(2-((4-((6-(Difluoromethyl)-8-((l/<2/?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethoxy)phenyl)- piperidine-2, 6-dione B353
Figure imgf000628_0003
[001694] 3-(4-(4-(((4-((6-(Difluoromethyl)-8-((l/<2/?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)methyl)-[l,4'- bipiperi din]- l'-yl)phenyl)piperidine-2, 6-dione B354
Figure imgf000628_0004
[001695] 3-(4-(4-(l-(2-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-^pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B355.
Figure imgf000629_0001
[001696] 3-(4-((4-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-(7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperazin-
1 -yl)methyl)phenyl)piperidine-2, 6-dione B356
Figure imgf000629_0002
[001697] 3-(4-(4-((4-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l -yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperi din- l-yl)phenyl)piperidine-2, 6-dione B357.
Figure imgf000629_0003
[001698] 4-(3-(4-((4-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-«7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B358
Figure imgf000630_0001
[001699] 3-(4-(4-(4-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin- 1 -yl)sulfonyl)piperazin- 1 -yl)- piperidin-l-yl)phenyl)piperidine-2, 6-dione B360.
Figure imgf000630_0002
[001700] 3-(3-((l-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperidin-4-
Figure imgf000630_0003
[001701] 3-(4-((l-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)arnino)piperidin-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)-3-methylpiperidine-2, 6-dione B362.
Figure imgf000631_0001
[001702] 3-(3-(4-((3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B363.
Figure imgf000631_0002
[001703] 3-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-l-yl)methyl)-4-fluoropiperi din- l-yl)phenyl)-3- methylpiperidine-2, 6-dione B366.
Figure imgf000631_0003
[001704] -3-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-tfjpyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)-
3-methylpiperidine-2, 6-dione B367
Figure imgf000631_0004
[001705] (iS)-3-(4-(2-(l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<Z]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)-3- methylpiperidine-2, 6-dione B368.
Figure imgf000632_0001
[001706] (A)-3-(4-(2-(l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<i]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)-3- methylpiperidine-2, 6-dione B369.
Figure imgf000632_0002
[001707] (A)-3-(4-((7?)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B371.
Figure imgf000632_0003
[001708] -3-(4-((A)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-d)pyrimidin-2-yl)aniino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B372
Figure imgf000633_0001
[001709] (7?)-3-(4-((7?)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B373.
Figure imgf000633_0002
[001710] (S)-3-(4-((A)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B374.
Figure imgf000633_0003
[001711] (7?)-3-(4-(4-(((5)-4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-t/]pyrimidin-2-yr)amino)pyridin-3-yr)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)- 3 -methylpiperidine-2, 6-dione B375.
Figure imgf000633_0004
[001712] l-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyriniidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)dihydropyrimidine-2, 4(177, 3//)-dione B456
Figure imgf000634_0001
[001713] l-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2-chlorophenyl)- dihydropyrimidine-2,4(l//,3Z/)-dione B457
Figure imgf000634_0002
[001714] l-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2-chloro-6-methyl- phenyl)dihy dropyrimidine-2,4( 1 //,3H)-dione B463.
Figure imgf000634_0003
[001715] l-(5-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- eZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-4-chloro-2-methyl- phenyl)dihy dropyrimidine-2,4( 1 //,3H)-dione B464.
Figure imgf000634_0004
[001716] l-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- eZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-chloro-4-methyl- phenyl)dihydropyrimidine-2, 4(177, 3/7)-dione B465.
Figure imgf000635_0001
[001717] l-(3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-4-chloro-2-methyl- phenyl)dihydropyrimidine-2, 4(177, 3/7)-dione B466.
Figure imgf000635_0002
[001718] l-(3-(4-((3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tf|pyrimidin-2-yl)amino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1 ]octan-8-yl)methyl)piperidin-l-yl)- phenyl)dihydropyrimidine-2,4(177,37/)-dione B471.
Figure imgf000635_0003
[001719] 3-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-l//-indazol-3-yl)-3- methylpiperidine-2, 6-dione B505.
Figure imgf000636_0001
[001720] 3-(7-(2-(l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l-methyl-l//- indazol-3-yl)piperidine-2, 6-dione B506.
Figure imgf000636_0002
[001721] 3-(6-(4-(2-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yT)ethyi)piperazin-l-yl)-l-methyl-l//-indazol-
3 -yl)piperidine-2, 6-dione B508.
Figure imgf000636_0003
[001722] (5)-3-(6-(4-(2-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l-yl)-l-methyl-127- indazol-3-yl)-3-methylpiperidine-2, 6-dione B509.
Figure imgf000636_0004
[001723] (7?)-3-(6-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2, 3 -cZ]pyrimi din-2 -yl)amino)pyri din-3 -yl)piperidin-4-yl)ethyl)piperazin-l-yl)-l -methyl- 1/7- indazol-3-yl)-3-methylpiperidine-2, 6-dione B510.
Figure imgf000637_0001
[001724] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-6-fluoro-l-methyl-l/f-indazol-
3-yl)dihydropyrimidine-2,4(177,3//)-dione B565
Figure imgf000637_0002
[001725] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)piperazin-l-yl)-6-chl oro-1 -methyl- 1/7-indazol- 3-yl)dihydropyrimidine-2,4(177,3//)-dione B566
Figure imgf000637_0003
[001726] (S)-l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7.8-dihydropyrido- [2,3-c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-methylpiperazin-l-yl)-l-methyl-L¥- indazol-3-yl)dihydropyrimidine-2,4(l//,3//)-dione B568.
Figure imgf000638_0001
[001727] l-(7-(2-(l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l -methyl-1/7- indazol-3-yl)dihydropyrimidine-2,4( l//,3ZZ)-dione B569.
Figure imgf000638_0002
[001728] l-(7-(2-(l '-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)-l-methyl-177- indazol-3-yl)dihydropyrimidine-2,4(l//,3/7)-dione B571
Figure imgf000638_0003
[001729] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t(]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-4-chloro-l-methyl-l£7-indazol-
3-yl)dihydropyrimidine-2, 4(1/7, 32f)-dione B572
Figure imgf000638_0004
[001730] l-(6-(4-(2-(l -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,: d]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)ethyl)piperazin- 1 -yl)- 1 -methyl- 177-indazol 3-yl)dihydropyrimidine-2, 4(177, 377)-dione B573
Figure imgf000639_0001
[001731] l-(6-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin- 1 -y l)ethy l)piperi din- 1 -y 1)- 1 -methyl- 177-indazol - 3-yl)dihydropyrimidine-2, 4(177, 377)-dione B574
Figure imgf000639_0002
[001732] l-(6-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)methyl)piperi din- l-yl)-l -methyl- 177- indazol-3-yl)dihydropyrimidine-2, 4(177, 37/)-dione B575.
Figure imgf000639_0003
Example B l
CDK-HiBiT Degradation Assay
[001733] HEK293 cells are engineered to express a HiBiT-tagged endogenous CDK2, CDK4, or CDK6 protein. The cells are cultured in DMEM media supplemented with 10% fetal bovine serum, streptomycin, and penicillin . The cells are seeded in a white-walled 384-well plate at 5,000 cells/well. After incubated at 37 °C under 5% CO2 overnight, the cells are treated with DMSO (control) or a compound for 6 h at 37 °C under 5% CO2 After incubation, the media (25 pL) is removed from each cell and NANO-GLO® lytic detection reagent (25 pL) is added to each well. After a 10 min incubation with shaking, luminescence is measured using a PERKINELMER ENVISION® multimode plate reader.
Example B2 Protein Degradation Assay
[001734] MDA-MB-231 cells were cultured in DMEM media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. The cells were plated in a 6-well plate at 500,000 cells/well in the culturing media. After overnight incubation, the cells were treated with DMSO (control) or a compound at 100 nM and 1 pM for 6 h at 37 °C under 5% CO2. The media was then removed, and the cells were washed with 1 x PBS. The cells were scraped in 1 x PBS and centrifuged to collect the cell pellets, which were lysed with an IP lysis buffer solution and centrifuged. The lysates were stored at -80 °C until protein quantification.
[001735] A protein assay was conducted to determine lysate protein concentration, and loading samples were prepared to run on a JESS SIMPLE WESTERN automated blot system or SDS-PAGE for western blot analysis. For western blot analysis, the whole cell protein extracts were separated on a 4-12% SDS-polyacrylamide gel, transferred to nitrocellulose, blocked with LI-COR INTERCEPT® (PBS) blocking buffer for 1 h at room temperature. Primary antibodies (CDK2 mouse mAb, CDK4 rabbit mAb, CDK6 mouse mAb, [3-actin mouse mAb, RB mouse mAb, and phospho-RB ser 807/811 rabbit mAb) were prepared in an INTERCEPT® (PBS) blocking buffer and added to blots after the blocking step. After overnight incubation at 4 °C with the primary’ antibodies, the blots were washed with 0.1% TWEEN-PBS and treated with secondary' antibody solutions (IRDYE® 680RD goat anti-rabbit and IRDYE® 800CW goat antimouse secondary antibody in the INTERCEPT® (PBS) blocking buffer) for 1 h at room temperature. The blots were washed with 0.1% TWEEN PBS and then imaged with ODYSSEY® CLx.
[001736] For the JESS PROTENSIMPLE analysis, the whole cell protein extracts were analyzed at a concentration of 1 mg/mL and separated using 12-230k Da separation module. The same primary antibodies were used, and JESS anti-rabbit, anti -mouse and anti-mouse NIR detection modules were used. The signal was detected by the JESS machine and analyzed with the COMPASS software.
[001737] The results are summarized in Table 1, where “A” represents a percentage degradation value of no less than 50%; “B” represents a percentage degradation value of less than 50% and no less than 25%; “C” represents a percentage degradation value of less than 25% and no less than 10%; and “D” represents a percentage degradation value of less than 10%.
TABEL 1. Effect on CDK Protein Degradation
Figure imgf000641_0001
Figure imgf000642_0001
Figure imgf000643_0001
Figure imgf000644_0001
Figure imgf000645_0001
Figure imgf000646_0001
Figure imgf000647_0001
Figure imgf000648_0001
Figure imgf000649_0001
Figure imgf000650_0001
Figure imgf000651_0001
Figure imgf000652_0001
Figure imgf000653_0001
Figure imgf000654_0001
Figure imgf000655_0001
Example B3
Cell Cycle Arrest Assay
[001738] MDA-MB-231 or MCF7 cells are plated in a six well dish at 300,000 cells per well. The cells are allowed to adhere overnight and are then treated with DM SO (control) or a compound for 24 h. The cells are then trypsinized, collected, and washed in PBS before being resuspended in cold 70% ethanol. After incubated in cold 70% ethanol at -20 °C overnight, the cells are washed in PBS and resuspended in a FXCYCLE™ PI/RNase staining solution and incubated with agitation at room temperature in the dark before running on an ATTUNE NXT flow cytometer.
Figure imgf000656_0001
[001739] The examples set forth above are provided to give those of ordinary’ skill in the art with a complete disclosure and description of how to make and use the claimed embodiments and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

What is claimed is:
1. A compound of Formula (I):
Figure imgf000657_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
A is a bond, heterocyclylene, or -S(Ch)-;
E is heteroarylene, CG-M arylene, or heterocyclylene;
L is a linker;
X is -C(O)“ or a bond;
R1 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRl c, -C(O)SRla, ~C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, ~C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc;
R2, R3, and R4 are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7.15 aralkyl, heteroaryl, or heterocyclyl; or (iii) C(O)Rla, C(O)ORla, C(O)NRlbRlc, - C(O)SRla, -C(NRia)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2R!a, -OS(O)NRlbRlc, ~OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, ~NRlaC(NRld)NRlbRlc, ~NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc;
Figure imgf000657_0002
Figure imgf000658_0001
wherein: each AE is independently a bond, -0- -N(Rlb)-, -S-, C1-6 alkylene, Ci-6 heteroalkylene, C2-6 alkenylene, C2-6 heteroalkenylene, C2-6 alkynylene, C2-6 heteroalkynylene, C3-10 cycloalkylene, C6-14 arylene, C7-15 aralkylene, heteroarylene, heterocyclylene, C1-6 heteroalkylene-Ce-ii arylene, C1-6 heteroalkylene-heterocyclylene, or C2-6 alkynylene-heterocyclylene; each XE is independently C(RE1) or N;
YE is a bond, C1-6 alkylene, -0-, -S-, -S(0)-, -S(02>-, or --N(RE3)-;
Z is -CH2- or -C(0)-; one of Z1, Z2, Z3, and Z4 is C= and the remaining three of Z1, Z2, Z3, and Z4 are each independently -C(RE4a)=; or Z1 is a bond; one of Z2, Z3, and Z4 is ~C=, and the remaining two of Z2, Z3, and Z4 are each independently -C(RE4a):=: or -S-; each RE1 is independently hydrogen, deuterium, halo, or C1-6 alkyl; each RE2, RE3, and RE5 is independently hydrogen or C1-6 alkyl; each RE4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(0)Rla, -C(0)0Rla, -C(0)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -0Rla, -0C(0)Rla, -0C(0)0Rla, -0C(0)NRlbRlc, -OC(O)SRla, -0C(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -0C(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -0S(0)NRlbRlc, -0S(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, ~NRlaC(0)0Rld, -NRlaC(0)NRlbRlc, -NRlaC(0)SRld, ~NRlaC(NRld)NRlbRlc, ~NRlaC(S)Rld, ~NRlaC(S)0Rld, ~NRlaC(S)NRlbRlc, -NRlaS(0)Rld, ~NRlaS(0)2Rld, -NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; each RE4a is independently hydrogen or RE4; each m is independently an integer of 0, 1, or 2; and each n is independently an integer of 0, 1, 2, or 3; and each Rla, Rlb, Rlc, and Rld is independently hydrogen, deuterium, C1-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C--15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 and, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, ~C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, ~OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, ~NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and - S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C 1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, C(O)NRfRs, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, OC(O)SRe, -OC(NRe)NRfR8, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rb, -NReS(O)NRfRs, -NReS(O)2NRfRs, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, R\ Rg, and Rh is independently (i) hydrogen or deuterium, (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and R8 together with the N atom to which they are attached form heterocyclyl.
2. The compound of claim 1, wherein E is Ce-14 arylene or heteroarylene, each optionally substituted with one or more substituents Q.
3. The compound of claim 1 or 2, wherein E is phenyl or monocyclic heteroarylene, each optionally substituted with one or more substituents Q.
4. The compound of any one of claims 1 to 3, having the structure of Formula (II):
Figure imgf000660_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Y is -C(R> or -N=;
R5 is hydrogen or R5a; each R5a is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRk, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRibRk, -OC(O)SRla, “0C(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRk, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NR!aS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRk, or -S(O)2NRlbRlc; and a is an integer of 0, 1, 2, or 3.
5. The compound of claim 1, wherein E is heterocyclylene, optionally substituted with one or more substituents Q.
6. The compound of claim 1 or 5, wherein E is monocyclic heterocyclylene, each optionally substituted with one or more substituents Q.
7. The compound of claim 1, 5, or 6, wherein E is 6-membered heterocyclylene, optionally substituted with one or more substituents Q.
8. The compound of any one of claims 1 and 5 to 7, wherein E is piperidindiyl, optionally substituted with one or more substituents Q.
9. The compound of any one of claims 1 and 5 to 8, having the structure of Formula
(IIIB):
Figure imgf000661_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: each R6 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, Ci-e heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Ria, -OC(O)ORla, -OC(O)NRlbRlc, ~OC(O)SRla, OC(NRla)NRlbRlc, -OC(S)Ria, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, ~OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRl c, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRle, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc, and b is an integer of 0, 1 , 2, 3, or 4.
10. The compound of any one of claims 1 to 9, X is a bond.
11. The compound of any one of claims 1 to 9, X is --C(O)-
12. The compound of any one of claims 1 to 11, wherein A is a bond or heterocyclylene, optionally substituted with one or more substituents Q.
13. The compound of any one of claims 1 to 12, wherein A is monocyclic heterocyclylene, optionally substituted with one or more substituents Q.
14. The compound of any one of claims 1 to 13, wherein A is 6-membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
15. The compound of any one of claims 1 to 14, wherein A is piperidin-1 ,4-diyl or piperazin- 1,4-diyl, each optionally substituted with one, two, or three substituents Q.
16. The compound of any one of claims 4, 10, and 12, having the structure of Formula (II A):
Figure imgf000662_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
17. The compound of any one of claims 4, 11, and 12, having the structure of Formula (IIB):
Figure imgf000662_0001
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
18. The compound of any one of claims 4, 10, and 12 to 15, having the structure of Formula (IIIA):
Figure imgf000663_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
19. The compound of any one of claims 4 and 11 to 15, having the structure of Formula (IIIB):
Figure imgf000663_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
20. The compound of any one of claims 1 to 11, wherein A is -S(O2)-.
21. The compound of any one of claims 9, 11, and 20, having the structure of Formula (IIIB):
Figure imgf000663_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
22. The compound of any one of claims 1 to 21, wherein RE is a moiety having the structure of Formula (EC-I):
Figure imgf000664_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
23. The compound of any one of claims 1 to 22, wherein RE is a moiety’ having the structure of Formula (EC-I-a):
(EC-I-a)
Figure imgf000664_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
24. The compound of any one of claims 1 to 23, wherein RE is a moiety having the structure of Formula (EC-I-c):
(EC-I-c)
Figure imgf000664_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof.
25. The compound of any one of claims 1 to 23, wherein RE is a moiety having the structure of Formula (EC-I-d): (EC-T-d)
Figure imgf000665_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
26. The compound of any one of claims 1 to 23, wherein RE is a moiety having the structure of Formula (EC-I-f):
(EC-I-f)
Figure imgf000665_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
27. The compound of any one of claims 1 to 23, wherein RE is a moiety having the structure of Formula (EC-I-g):
(EC-I-g)
Figure imgf000665_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
28. The compound of any one of claims 1 to 22, wherein RE is a moiety having the structure of Formula (EC-I-h):
(EC-I-h)
Figure imgf000665_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
29. The compound of claim 27, wherein RE3 is hydrogen.
30. The compound of any one of claims 1 to 23, wherein RE is a moiety having the structure of:
Figure imgf000666_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof.
31. The compound of any one of claims 1 to 23 and 30, wherein RE is a moiety having the structure of:
Figure imgf000666_0002
Figure imgf000667_0001
0 „r1 EC-A16 , or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
32. The compound of any one of claims 1 to 21, wherein RE is a moiety’ having the structure of Formula (EC -II):
Figure imgf000667_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
33. The compound of any one of claims 1 to 21 and 32, wherein RE is a moiety having the structure of Formula (EC-II-b):
(EC-II-b)
Figure imgf000667_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof.
34. The compound of any one of claims 1 to 21 and 32, wherein RE is a moiety having the structure of Formula (EC-II-c):
(EC-II-c)
Figure imgf000667_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
35. The compound of any one of claims 1 to 21 and 32, wherein RE is a moiety having the structure of Formula (EC-II-e):
Figure imgf000668_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
36. The compound of any one of claims 1 to 21 and 32, wherein RE is a moiety having the structure of Formula (EC-II-f):
(EC-II-f)
Figure imgf000668_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
37. The compound of any one of claims 1 to 21 and 32, wherein RE is a moiety having the structure of:
Figure imgf000668_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
38. The compound of any one of claims 1 to 21 , 32, and 37, wherein RE is a moiety having the structure of:
Figure imgf000669_0001
Figure imgf000670_0001
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
39. The compound of any one of claims 1 to 21 , wherein RE is a moiety having the structure of Formula (EC -III):
Figure imgf000670_0002
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
40. The compound of any one of claims 1 to 21 and 39, wherein RE is a moiety having the structure of Formula (EC-III-c):
Figure imgf000670_0003
or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
41. The compound of any one of claims 1 to 21 and 39, wherein RE is a moiety having the structure of Formula (EC-III-d):
Figure imgf000670_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
42. The compound of any one of claims 1 to 21 and 39, wherein RE is a moiety having the structure of Formula (EC-III-e):
Figure imgf000671_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
43. The compound of any one of claims 1 to 21 and 39, wherein RE is a moiety having the structure of Formula (EC-III-h):
Figure imgf000671_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
44. The compound of any one of claims 1 to 21, 39, and 43, wherein RE is a moiety having the structure of Formula (EC-III-i):
(EC-III-i)
Figure imgf000671_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
45. The compound of any one of claims 1 to 21 and 39, wherein RE is a moiety having the structure of Formula (EC-III-k):
Figure imgf000672_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
46. The compound of any one of claims 1 to 21 and 39, wherein RE is a moiety having the structure of
Figure imgf000672_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
47. The compound of any one of claims 1 to 21, 39, and 46, wherein RE is a moiety having the structure of:
Figure imgf000672_0002
Figure imgf000673_0001
EC-C13 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
48. The compound of claim 4 or 10, having the structure of Formula (IVA):
Figure imgf000673_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
49. The compound of any one of claims 4, 10, and 48, having the structure of Formula (VA):
Figure imgf000674_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
50. The compound of any one of claims 4, 10, and 48, having the structure of Formula (VIA):
Figure imgf000674_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
51. The compound of any one of claims 4, 10, and 48, having the structure of
Figure imgf000674_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
52. The compound of any one of claims 4, 10, and 48, having the structure of Formula (VIII A):
Figure imgf000675_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
53. The compound of claim 4 or 10, having the structure of Formula (IXA):
Figure imgf000675_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
54. The compound of any one of claims 4, 10, and 53, having the structure of Formula (XA):
Figure imgf000675_0003
or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
55. The compound of any one of claims 4, 10, and 53, having the structure of Formula (XIA):
Figure imgf000676_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
56. The compound of any one of claims 4, 10, and 53, having the structure of Formula (XII A):
Figure imgf000676_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
57. The compound of any one of claims 4, 10, and 53, having the structure of Formula (XIIIA):
Figure imgf000677_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
58. The compound of claim 4 or 10, having the structure of Formula (XIVA):
Figure imgf000677_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
59. The compound of any one of claim s 4, 10, and 58, having the structure of Formula (XV A):
Figure imgf000677_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
60. The compound of any one of claims 4, 10, and 58, having the structure of Formula (XVIA):
Figure imgf000678_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
61. The compound of any one of claims 4, 10, and 58, having the structure of Formula (XVIIA):
Figure imgf000678_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
62. The compound of any one of claims 4, 10, and 58, having the structure of
Formula (XVIII A):
Figure imgf000678_0003
or an enantiomer, a mixture of enanti omers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
63. The compound of claim 4 or 10, having the structure of Formula (XIXA):
Figure imgf000679_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
64. The compound of any one of claims 4, 10, and 63, having the structure of Formula (XX A):
Figure imgf000679_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
65. The compound of any one of claims 4, 10, and 63, having the structure of
Formula (XXI A):
Figure imgf000679_0003
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
66. The compound of any one of claims 4, 10, and 63, having the structure of Formula (XXII A):
Figure imgf000680_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
67. The compound of any one of claims 4, 10, and 63, having the structure of
Formula (XXIII A):
Figure imgf000680_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
68. The compound of claim 4 or 10, having the structure of Formula (XXV A):
Figure imgf000680_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
69. The compound of claim 4 or 10, having the structure of Formula (XXVIA):
Figure imgf000681_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
70. The compound of claim 4 or 10, having the structure of Formula (XXVIIA):
Figure imgf000681_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
71. The compound of claim 4 or 10, having the structure of Formula (XXIXA):
Figure imgf000681_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
72. The compound of claim 4 or 10, having the structure of Formula (XXXA):
Figure imgf000682_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
73. The compound of claim 4 or 10, having the structure of Formula (XXXIA):
Figure imgf000682_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
74. The compound of claim 9 or 11, having the structure of Formula (IVB):
Figure imgf000682_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
75. The compound of any one of claims 9, 11, and 74, having the structure of Formula (VB):
Figure imgf000683_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
76. The compound of any one of claims 9, 11, and 74, having the structure of Formula (VIB):
Figure imgf000683_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
77. The compound of any one of claims 9, 11, and 74, having the structure of Formula (VIIB):
Figure imgf000683_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
78. The compound of any one of claims 9, 11 , and 74, having the structure of Formula (VIIIB):
Figure imgf000684_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
79. The compound of claim 9 or 11, having the structure of Formula (IXB):
Figure imgf000684_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
80. The compound of any one of claims 9, 11, and 79, having the structure of Formula (XB):
Figure imgf000684_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
81. The compound of any one of claims 9, 11 , and 79, having the structure of
Formula (XIB):
Figure imgf000685_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
82. The compound of any one of claims 9, 11 , and 79, having the structure of Formula (XIIB):
Figure imgf000685_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
83. The compound of any one of claim s 9, 11, and 79, having the structure of Formula (XB1B):
Figure imgf000685_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
84. The compound of claim 9 or 11, having the structure of Formula (XIVB):
Figure imgf000686_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
85. The compound of any one of claim s 9, 11, and 84, having the structure of Formula (XVB):
Figure imgf000686_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
86. The compound of any one of claims 9, 11, and 84, having the structure of Formula (XVIB):
Figure imgf000686_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
87. The compound of any one of claims 9, 11 , and 84, having the structure of Formula (XVIIB):
Figure imgf000687_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
88. The compound of any one of claims 9, 11, and 84, having the structure of
Formula (XVIIIB):
Figure imgf000687_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
89. The compound of claim 9 or 11 , having the structure of Formula (XIXB):
Figure imgf000687_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
90. The compound of any one of claims 9, 11 , and 89, having the structure of
Formula (XXB):
Figure imgf000688_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
91. The compound of any one of claims 9, 11, and 89, having the structure of Formula (XXIB):
Figure imgf000688_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
92. The compound of any one of claims 9, 11, and 89, having the structure of Formula (XXIIB):
Figure imgf000688_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
93. The compound of any one of claims 9, 11 , and 89, having the structure of Formula (XXIIIB):
Figure imgf000689_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
94. The compound of claim 9 or 11, having the structure of Formula (XXVB):
Figure imgf000689_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
95. The compound of claim 9 or 11, having the structure of Formula (XXVIB):
Figure imgf000689_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
96. The compound of claim 9 or 11, having the structure of Formula (XXVIIB):
Figure imgf000690_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
97. The compound of claim 9 or 11, having the structure of Formula (XXIXB):
Figure imgf000690_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
98. The compound of claim 9 or 11, having the structure of Formula (XXXB):
Figure imgf000690_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
99. The compound of claim 9 or 11, having the structure of Formula (XXXIB):
Figure imgf000691_0001
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
100. The compound of any one of claims 21, having the structure of Formula (IIIC):
Figure imgf000691_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
101. The compound of any one of claims 21 or 100, having the structure of Formula
Figure imgf000691_0003
or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
102. The compound of any one of claims 21 or 100, having the structure of Formula
(VC):
Figure imgf000692_0001
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
103. The compound of any one of claims 21 or 100, having the structure of Formula
(VIC):
Figure imgf000692_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
104. The compound of any one of claims 21 or 100, having the structure of Formula
(VIIC):
Figure imgf000692_0003
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
105. The compound of any one of claims 21, having the structure of Formula (VIIIC):
Figure imgf000693_0001
or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
106. The compound of any one of claims 21 or 105, having the structure of Formula
(IXC):
Figure imgf000693_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
107, The compound of any one of claims 21 or 105, having the structure of Formula
(XC):
Figure imgf000693_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
108. The compound of any one of claims 21 or 105, having the structure of Formula
(XIC):
Figure imgf000694_0001
or an enantiomer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
109. The compound of any one of claims 21 or 105, having the structure of Formula
(XIIC):
Figure imgf000694_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
110. The compound of any one of claims 21, having the structure of Formula (XIVC):
Figure imgf000694_0003
or an enanti omer, a mixture of enantiomers, a di astereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
111. The compound of any one of claim s 21 , having the structure of F ormula (XV C) :
Figure imgf000695_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
112. The compound of any one of claims 21, having the structure of Formula (XIVC):
Figure imgf000695_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereom ers, a tautomer, a mi xture of two or more tautomers, or an i sotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
113. The compound of any one of claims 1 to 112, wherein R1 is C1-6 alkyl or C3-10 cycloalkyl, each optionally substituted with one or more substituents Q.
114. The compound of any one of claims 1 to 113, wherein R1 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q.
115. The compound of any one of claims 1 to 114, wherein R1 is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q.
116. The compound of any one of claims 1 to 115, wherein R1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one, two, or three substituents Q.
117. The compound of any one of claims 1 to 113, wherein R1 is cyclopentyl, 2- hydroxy -2-methylcyclopentyl, or
Figure imgf000696_0001
118. The compound of any one of claims 1 to 117, wherein R2 is (i) cyano or halo; (ii) C1-6 alkyl, C7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -ORla, or -NRlbRlc.
119. The compound of any one of claims 1 to 118, wherein R2 is -C(O)Rla
120. The compound of any one of claims 1 to 118, wherein R2 is -C(O)NRlbRlc.
121 . The compound of any one of claims 1 to 118, wherein R2 is cyano, fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, hydroxymethyl, ethoxymethyl, benzyl, oxazol-5-yl, acetyl, hydroxy carbonyl, ethoxycarbonyl, methyl aminocarbonyl, dimethylaminocarbonyl, 2-ethoxy- ethoxy, or amino.
122. The compound of any one of claims 1 to 118, wherein R2 is difluoromethyl, acetyl, or dimethylaminocarbonyl.
123. The compound of any one of claims 1 to 122, wherein R3 is hydrogen, deuterium, or C1-6 alkyl, optionally substituted with one or more substituents Q.
124. The compound of any one of claims 1 to 123, wherein R3 is hydrogen, deuterium, or methyl.
125. The compound of any one of claims 1 to 124, wherein R3 is hydrogen.
126. The compound of any one of claims 1 to 124, wherein R3 is methyl.
127. The compound of any one of claims 1 to 126, wherein R4 is hydrogen.
128. The compound of any one of the preceding claims, wherein Y is ~C(R5)=.
129. The compound of any one of the preceding claims, wherein R3 is hydrogen, deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q.
130. The compound of any one of the preceding claims, wherein R5 is hydrogen, fluoro, chloro, methyl, or ethyl.
131. The compound of any one of the preceding claims, wherein R5 is hydrogen.
132. The compound of any one of the preceding claims, wherein Y is -N=.
133. The compound of any one of the preceding claims, wherein a is an integer of 1.
134. The compound of any one of the preceding claims, wherein R5a is deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q.
135. The compound of any one of the preceding claims, wherein R3a is hydrogen, fluoro, chloro, methyl, or ethyl.
136. The compound of any one of the preceding claims, wherein a is an integer of 0.
137. The compound of any one of the preceding claims, wherein RE1 is hydrogen.
138. The compound of any one of claims 1 to 137, wherein RE2 is hydrogen.
139. The compound of any one of the preceding claims, wherein n is an integer of 1 or 2.
140. The compound of any one of the preceding claims, wherein each RE4 is independently deuterium, halo, or C1-6 alkyl, optionally substituted with one or more substituents Q
141. The compound of any one of the preceding claims, wherein each RE4 is independently fluoro, chloro, methyl, isopropyl, or trifluoromethyl.
142. The compound of any one of the preceding claims, wherein RE4 is methyl or trifluoromethyl.
143. The compound of any one of the preceding claims, wherein n is an integer of 0.
144. The compound of any one of the preceding claims, wherein RE4a is hydrogen, deuterium, or halo.
145. The compound of any one of the preceding claims, wherein RE4a is hydrogen, deuterium, fluoro, or chloro.
146. The compound of any one of the preceding claims, wherein RE4a is fluoro.
147. The compound of any one of the preceding claims, wherein RE3 is hydrogen or Ci- 6 alkyl, optionally substituted with one or more substituents Q.
148. The compound of any one of the preceding claims, wherein RE5 is hydrogen or methyl.
149. The compound of any one of the preceding claims, wherein RE5 is methyl.
150. The compound of any one of the preceding claims, wherein AE is (i) a bond; or (ii) C2-6 alkynylene, heterocyclylene, C1-6 heteroalkylene-Ce-u arylene, C1-6 alkylene- heterocyclylene, or C2-6 alkynylene-heterocyclylene, each of which is optionally substituted with one or more substituents Q.
151. The compound of any one of the preceding claims, wherein AE is (i) a bond; or (ii) heterocyclylene, C1-6 heteroalkylene-Ce-u arylene, or C1-6 alkylene-heterocyclylene, each of which is optionally substituted with one or more substituents Q.
152. The compound of any one of the preceding claims, wherein AE is (i) a bond; or (ii) heterocyclylene, C1-6 heteroalkylene-C6-i4 arylene, or C1-6 alkylene-monocyclic heterocyclylene, each of which is optionally substituted with one or more substituents Q.
153. The compound of any one of the preceding claims, wherein AE is (i) a bond; or (ii) heterocyclylene, C1-6 heteroalkylene-phendiyl, or C1-6 alkylene-(6-membered heterocyclylene), each of which is optionally substituted with one or more substituents Q.
154. The compound of any one of the preceding claims, wherein AE is a bond, piperidin-l,3-diyl, piperidin-l,4-diyl, piperaz-l,4-diyl, (phen-l,4-diyl)oxymethanediyl, (piperidin- 1 ,4-diyl )ethynediyl,
Figure imgf000699_0001
Figure imgf000699_0002
155. The compound of any one of the preceding claims, wherein AE is a bond,
Figure imgf000699_0003
156. The compound of any one of claims 1 to 155, wherein L has the structure of: -ZL-(RL-ZL)z- wh erein: each RL is independently C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more substituents Q; each ZL is independently a bond, -C(O)-, -C(O)O- -C(O)NRlb-, -C(O)S- -C(NRla)NRlb- -C(S)-, -C(S)O-, -C(S)NRlb-, -0- -OC(O)O-, -OC(O)NRlb-, -OC(O)S- -OC(NRla)NRlb-, -OC(S)-, -OC(S)O-, -OC(S)NRlb- -OS(O)-, -OS(O)2-, -OS(O)NRlb- -OS(O)2NRlb-, -NRlb- -NRlaC(O)NRlb- -NRlaC(O)S- -NRlaC(NRld)NRlb- -NRlaC(S)NRlb- -NRlaS(O)NRlb~, -NRlaS(O)2NRlb- -S-, -S(O)-, -S(O)2-, -S(O)NRlb-, or -S(O)2NRlb- and z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
157. The compound of claim 156, wherein each RL is independently Ci-io alkylene, C2- 10 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more substituents Q.
158. The compound of claim 156 or 157, wherein each RL is independently methanediyl, ethane- 1,2-diyl, propane- 1,3 -diyl, butane- 1,4-diyl, pentane-l,5-diyl, hexane-1,6- diyl, heptane-l,7-diyl, octane- 1,8 -diyl, nonane- 1,9-diyl, decane- 1, 10-diyl, undecane- 1 , 1 1 -diyl, dodecane-1,12-diyl, tridecane-1, 13-diyl, ethyne- 1,2-diyl, cyclobutane-1, 3-diyl, cyclopentane- 1, 3-diyl, cyclohexane-1, 3-diyl, cyclohexane-1, 4-diyl, cycloheptane- 1,3 -diyl, cycloheptane- 1,4- diyl, bicyclo[2.2.2]octane-l, 4-diyl, phen-1, 3-diyl, phen-1, 4-diyl, pyrazoi- 1,3 -diyl, pyrazol-1,4- diyl, imidazol-1, 4-diyl, 1, 2, 3-triazol-l, 4-diyl, pyrimidin-2, 4-diyl, pyrimidin-2, 5-diyl, 5, 6, 7, 8, 9, 10-hexahydrocycloocta[d]-pyridazin-l,7-diyl, pyrazoli din- 1,3 -diyl, pyrazolidin-1,4- diyl, l,3-dioxan-2, 5-diyl, piperazin-1, 4-diyl, piperidin-1, 3-diyl, piperidin-1, 4-diyl, or 3,9- diazaspiro[5.5]-undecane-3,9-diyl, each of which is optionally substituted with one or more substituents Q.
159. The compound of any one of claims 156 to 158, wherein each ZL is independently a bond, -C(O)-, -C(O)NRlb- -O-, -OC(O)NRlb-, -NRlb-, or -NRlaC(O)NRlb-.
160. The compound of any one of claims 156 to 159, wherein each ZL is independently a bond, -C(O)-, -C(O)O- -C(O)NH- -OC(O)NH-, -O-, XI I , -N(CH3)~, or -NHC(O)NH-.
161. The compound of any one of claims 156 to 160, wherein z is an integer of 1, 2, 3, or 4.
162. The compound of claim 156, wherein each RL is independently methanediyl, ethane- 1,2-diyl, propane-1, 3-diyl, cyclohex- 1,3 -diyl, cyclohex-1, 4-diyl, phen- 1,3 -diyl, phen-1, 4- diyl, azetidin-1, 3-diyl, piperazin- 1, 4-diyl, piperidin-1 , 3-diyl, piperidin-1, 4-diyl, morpholin-2,4- diyl, 4,7-diazaspiro[2.5]octan-4,7-diyl, 3-azabicyclo[3.2.1]octan-3,8-diyl, 8-azabicyclo[3.2.1]- octan-3,8-diyl, 3,8-diazabicyclo[3.2.1]octan-3,8-diyl, or 2,7-diazaspiro[3.5]nonan-2,7-diyl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro or methyl; each ZL is independently a bond or -O-; and z is an integer of 2, 3, 4, or 5
163. The compound of claim 156 or 162, wherein each RL is independently methanediyl, ethane- 1,2-diyl, 1,1 -difluoroethane- 1,2-diyl, propane-1, 3-diyl, cyclohex- 1,3 -diyl, cy cl ohex-1, 4-diyl, phen- 1,3 -diyl, phen-1, 4-diyl, azetidin-1, 3-diyl, 3-fluoroazetidin-l, 3-diyl, piperazin- 1, 4-diyl, 2-methylpiperazin-l, 4-diyl, piperidin-1, 3 -diyl, piperidin-1, 4-diyl, 4-fluoro- piperi din- 1, 4-diyl, morpholin-2, 4-diyl, 4,7-diazaspiro[2.5]octan-4,7-diyl, 3-azabicyclo[3.2.1]- octan-3,8-diyl, 8-azabi cyclop.2. l]octan-3,8-diyl, 3,8-diazabicyclo[3.2. l]octan-3,8-diyl, or 2,7- diazaspiro[3.5]nonan-2,7-diyl; each ZL is independently a bond or -O-; and z is an integer of 2, 3, 4, or 5.
164. The compound of any one of claims 1 to 156, wherein L is:
Figure imgf000701_0001
165. The compound of any one of claims 1 to 156, wherein L is:
Figure imgf000701_0002
Figure imgf000702_0001
166. The compound of any one of claims 1 to 156, wherein L is:
Figure imgf000703_0001
Figure imgf000704_0001
Figure imgf000705_0001
Figure imgf000706_0001
Figure imgf000707_0001
167. The compound of any one of the preceding claims, wherein Z is -CH2-.
168. The compound of any one of the preceding claims, wherein m is an integer of 1.
169. A compound of:
7-cyclopentyl-2-((4-((2-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-AyV-dimethyl-7H-pyrrolo[2,3-(7]pyrimidine-6- carboxamide A101;
7-cyclopentyl-2-((4-((4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-7V,Az-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6- carboxamide Al 02;
7-cyclopentyl-2-((4-((6-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-A7,A''-dimethyl-7//-pyrrolo[2,3-t(jpyrimidine-6- carboxamide A103;
7-cyclopentyl-2-((4-(4-(2-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)ethyl)piperazin-l-yl)phenyl)amino)-7V,A/r-dimethyl-7H-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A104,
7-cyclopentyl-2-((4-(4-(4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yi)butyl)piperazin-l-yi)phenyi)amino)-Ar,A7-dimethyl-77f-pyrrolo[2,3-J|pyrimidine- 6-carboxamide A105; 7-cyclopentyl-2-((4-(4-(2-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperidin-4-yl)ethyl)piperazin-l-yl)phenyl)amino)-Ar,A'T-dimethyl-7/f-pyrrolo[2,3-^pyrimidine- 6-carboxamide A106, 7-cyclopentyl-2-((4-(4-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperidin-4-yl)butyl)piperazin-l-yl)phenyl)amino)-Ar,Ar-dimethyl-7//-pyrrolo[2,3-^pyrimidine- 6-carboxamide A107;
7-cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamido)- ethyl)piperazin-l-yl)phenyl)amino)-Ar,Ar-dimethyl-7Z/-pyrrolo[2,3-i7]pyrimidine-6-carboxamide A108;
7-cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-4-methylphenoxy)- acetamido)ethyl)piperazin-l-yl)phenyl)amino)-Ar,AMimethyl-7Z/-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A109;
7-cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-4-(trifluoromethyl)- phenoxy)acetamido)ethyl)piperazin-l-yl)phenyl)amino)-A’,A'r-dimethyl-7H-pyrrolo[2,3-tf|- pyrimidine-6-carboxamide A110;
7-cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamido)- propyl)piperazin-l-yl)phenyl)amino)-A7,A/-dimethyl-7H-pyrrolo[2,3-t(|pyrimidine-6-carboxamide Alli;
7-cy cl opentyl-2-(( 4-(4-(3 -(2-(3 -(2, 6-dioxopiperidin-3 -yl)-4-methyl phenoxy)- acetamido)propyl)piperaziii-l-yl)phenyl)amino)-Af,7V-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide Al 12;
7-cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)-4-(trifluoromethyl)- phenoxy)acetamido)propyl)piperazin-l-yl)phenyl)amino)-A',Ar-dimethyl-7//-pyrrolo[2,3-J|- pyrimidine-6-carboxamide Al 13;
7-cyclopentyl-2-((4-((2-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A,A’-dimethyl-7//-pyrrolo[2,3-^]pyrimidine-6- carboxamide Al 14;
7-cyclopentyl-2-((4-((4-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-A',ALdimethyl-7JH-pyrrolo[2,3-J]pyrimidine-6- carboxamide Al 15;
7-cyclopentyl-2-((4-((6-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)- piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-A’,Ar-dimethyl-7/7-pyrrolo[2,3-<7]pyriniidine-6- carboxamide Al 16;
7-cyclopentyl-2-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- phenyl)amino)-A",A-dimethyl-7//-pyrroio[2,3-t7]pyrimidine-6-carboxamide A117;
7-cyclopentyl-2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- plienyl)amino)-7V,A-dimethyl-7/7-pyrrolo[2,3-^pyrimidine-6-carboxamide A118;
7-cyclopentyl-2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- phenyl)aniino)-A7Ar-dimethyl-7Z7-pyrrolo[2,3-J]pyrimidine-6-carboxamide A119;
7-cyclopentyl-2-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- phenyl)amino)-?'/,A'-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide Al 20;
7-cyclopentyi-2-((4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)ethyl)piperazin-l- yl)phenyl)amino)-Ar,Ar-dimethyl-7Z/-pyrrolo[2,3-t(]pyrimidine-6-carboxamide A121;
7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)phenyl)aniino)-A7,A7-dimethyl-7/7-pyiTolo[2,3-J]pyrimidine-6-carboxamide A122;
7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazm-l-yl)- ethyl)phenyl)amiiio)-AT,Ar-dimethyl-727-pyrrolo[2,3-i7]pyrimidine-6-carboxaniide A123;
7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethoxy)phenyl)amino)-AT,A-dimethyl-72/-pyrrolo[2,3-J]pyrimidine-6-carboxaniide A124;
7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethoxy)phenyl)amino)-A7A-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidiiie-6-carboxamide A125;
7-cyclopentyl-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A,Ar-dimetliyl-7JH-pyrrolo[2,3-</]pyrimidine-6-carboxamide A126;
7-cyclopentyl-2-((4-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-AAV-dimethyl-7J7-pyrrolo[2,3-t7]pyrimidine-6-carboxamide A127;
7-cyclopentyi-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- ethyl)phenyl)amino)-A'r,A’-dimethyl-7/Z-pyrrolo[2,3-^]pyrimidine-6-carboxamide A128;
7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- ethyl)phenyl)amino)-A7,A7-dimethyl-7H-pyrrolo[2,3-t7]pyrimidine-6-carboxamide A129;
7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- ethoxy)phenyl)amino)-A,A-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A130;
7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- ethoxy)phenyl)amino)-A'r,A-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A131;
7-cyclopentyl-2-((4-((4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)methyl)phenyl)amino)-A?,Ar-dimethyl-7/7-pyrroIo[2,3-J|pyrimidine-6- carboxamide A132;
7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)phenyl)amino)-Ar r/V-dimethyl-7J7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A133;
7-cyclopentyl-2-((4-(2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l -yl)- piperidin-l-yl)ethoxy)phenyl)amino)-A,Az-dimethyl-7//-pyrrolo[2,3-o0pyrimidine-6-carboxamide A134;
7-cyclopentyl-2-((4-(2-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)piperazin-l-yl)ethyl)phenyl)amino)-A'',7V-dimethyl-7flr-pyrrolo[2,3-J]pyrimidine-6- carboxamide A135;
7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethyl)phenyl)amino)-JV,A7-dimethyl-7/f-pyrrolo[2,3-</|pyrimidine-6-carboxamide A136;
7-cyclopentyl-2-((4-(2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l -yl)- piperidin-l-yl)ethyl)phenyl)amino)-A',jV-dimethyl-777-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A137;
7-cyclopentyi-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperidin-4- yl)piperazin-l-yl)phenyl)amino)-Az,A’-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A138;
7-cyclopentyl-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin- 1 -yl)phenyl)amino)-A^V-dimethyl-7/f-pyrrolo[2,3 -tZ]pyrimidine-6-carboxamide A139;
7-cyclopentyi-2-((4-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-l-yi)phenyl)amino)-A,A/-dimethyl-7/Z-pyrrolo[2,3-^pyrimidine-6-carboxamide A140;
7-cyclopentyl-2-((4-(4-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperazin-l-yl)phenyl)amino)-Ar,7V-dimethyl-7//-pyrrolo[2,3-<T]pyrimidine-6- carboxamide A141;
7-cyclopentyl-2-((4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyi)piperazin-l-yl)phenyl)amino)-A7,Air-dimethyl-7ZZ-pyrrolo[2,3-c(|pyrimidine-6- carb oxami de Al 42;
7-cyclopentyl-2-((4-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)phenyl)amino)-Ar,Ar-dimethyl-77f-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A143;
7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)phenyl)amino)-Ar,A7-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A144;
7-cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- phenyl)piperazin-l-yi)pyridin-2-yl)amino)-Ar,A’-dimethyl-7//-pyrrolo[2,3-dr]pyrimidine-6- carboxamide Al 45;
7-cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,Ar-dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A146;
7-cyclopentyl-2-((5-(4-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A/7-dimethyl-77f-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A147;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidm-3-yl)benzyl)piperazin-l-yl)- phenyl)piperazin-l-yl)pyridin-2-yl)amino)-AT,A’-dimethyl-7//-pyrrolo[2,3-</|pyrimidine-6- carboxamide Al 48;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,Az-dimethyl-77/-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A149;
7-cyclopentyl-2-((5-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,Ar-diniethyl-77f-pyrrolo[2,3-c/]pyrimidine-6- carboxamide A150;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- benzyl)piperazin-l-yl)pyridin-2-yl)amino)-A’,AT-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carb oxami de A 151 ;
7-cyclopentyl-2-((5-(4-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A’,A-dimethyl-7AF-pyiTolo[2,3-J]pyrimidine- 6-carboxamide A152; 7-cy cl opentyl-2-((5 -(4-(4-(4-(3 -(2, 6-dioxopiperidin-3 -yl)pheny l)piperazin- 1 -y I )- benzyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,Ar-dimethyl-7//-pyrrolo[2,3-</]pyrimidine-6- carboxamide A153;
7-cyclopentyl-2-((5-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-7V,Az-dimethyl-7/f-pyrrolo[2,3-^]pyrimidine- 6-carboxamide A154;
7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)cyclohexyl)- piperazin-l-yl)pyridin-2-yl)amino)-A'r,A-dimethyl-7J7-pyrrolo[2,3-tf|pyrimidine-6-carboxamide A155;
7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A'jV-dimethyl-77/-pyrrolo[2,3-t(|pyrimidine-6-carboxamide A156;
7-cy clopentyl-2-((5 -(4-( 1 -(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)ethyl)- piperidin-4-yl)piperazin-l-yl)pyri din-2 -yl)aniino)-7V,7V-dimethy]-7H-pyrrolo[2,3-tf]pyrimidine-6- carboxamide A157:
7-cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A?,ALdimethyl-7H-pyrrolo[2,3-<^|- pyrimidine-6-carboxamide A158;
7-cyclopentyl-2-((5-(4-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-jV,A'’-dimethyl-7//-pyrrolo[2,3-dr]-pyrimidine-6- carboxamide A159;
7-cy clopentyl-2-((5 -(4-( 1 -(2-(3 -(2, 6-dioxopiperidin-3 -yl)phenoxy)ethyl)- piperidin-4-yl)piperazin-l-yl)pyri din-2 -yl)amino)-7V,A'r-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A160:
7-cyclopentyi-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)propyl)piperazin-l-yl)pyridin-2-yl)amino)-A'^V-dimethyl-7H-pyrrolo[2,3-t(]pyrimidine-6- carboxamide A161;
7-cyclopentyl-2-((5-(4-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 3-yl)piperazin-l-yl)pyridin-2-yl)amino)-Af,ALdimethyl-777-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A162;
7-cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4 yl)methyl)piperidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-A’,7V-dimethyl-7/f-pyrrolo[2,3-fiO- pyrimidine-6-carboxamide A163;
7-cyclopentyl-2-((5-(4-(l-(((25)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- niorpholin-2-yl)methyl)piperidin-4-yl)piperaziii-l-yl)pyridin-2-yl)amiiio)-A7,A^-dimethyl-77f- pyrrolo[2,3-t(|pyrimidine-6-carboxamide A164;
7-cyclopentyl-2-((5-(4-(l-(((27?)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)- morpholin-2-yl)methyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A’,A7-dimethyl-7J7- pyrrolo[2,3-d]pyrimidine-6-carboxamide A 165;
7-cyclopentyl-2-((5-(4-(3-(l-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperidin-4-yl)- cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-AAV-dimethyl-777-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A166;
7-cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- methyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-AT,A7-dimethyl-7Z/-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A 167;
7-cyclopentyl-2-((5-(4-(((25)-4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-
4-yl)morpholiii-2-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A’,Ar-dimethyl-71E/-pyrrolo[2,3- tZ]pyrimidine-6-carboxamide A168;
7-cyclopentyl-2-((5-(4-(((2A’)-4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin- 4-yl)morphoHn-2-yl)methyi)piperazin-l-yl)pyridin-2-yl)amino)-Ar,Ar-dimethyl-7/f-pyrrolo[2,3- c/]pyrimidine-6-carboxamide A169;
7-cyclopentyl-2-((5-(4-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- cyclohexyl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A'-dimethyl-7/f-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A170;
7-cyclopentyl-2-((5-(4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)cyclohexyl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7J7-pyrrolo[2,3-</]- pyrimidine-6-carboxamide A171;
7-cyclopentyl-2-((5-(4-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)ethyl)piperidin-4-yl)piperazin-l -yl)pyridin-2-yl)amino)-7V,Ar-dimethyl-7/7-pyrrolo[2,3-</|- pyrimidine-6-carboxamide A172;
7-cyclopentyl-2-((5-(4-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)ethyl)cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-7JH-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A173;
7-cyclopentyl-2-((5-(4-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)ethyl)piperidin-4-yl)piperazin-l-yl)pyri din-2 -yl)amino)-A?,Ar-dimethyl-7/7-pyrrolo[2,3-J|- pyrimidine-6-carboxamide A174;
7-cyclopentyl-2-((5-(4-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'- bipiperi din]- l-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-7V,Ar-dimethyl-7JH-pyrrolo[2, 3-J]- pyrirnidine-6-carboxamide A175;
7-cyclopentyl-2-((5-(4-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'- bipiperidin]-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A^V-dimethyI-7//-pyrrolo[2,3-r/]- pyrimidine-6-carboxamide A176;
7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-N,N-dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A177;
7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-AVV-dimethyl-7/f-pyrrolo[2,3-(f|pyrimidine-6- carboxamide A178;
7-cyclopentyl-2-((5-(4-(l-(3-(4-(2,6-dioxopiperidin-3-yl)phenoxy)propyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-Af,Ar-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6- carboxamide Al 79;
7-cyclopentyi-2-((5-(4-(3-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- propyl)piperazin-l-yl)pyridin-2-yl)amino)-A^,A-dimethyl-777-pyrrolo[2,3-</]pyrimidine-6- carboxamide A180;
7-cyclopentyl-2-((5-(4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4- yl)cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A-dimethyl-7/f-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A181;
7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[l,4'-bipiperidin]- r-yl)pyridin-2-yl)amino)-A’,Ar-dimethyl-7//-pyrrolo[2,3-r7]pyrimidine-6-carboxamide A182;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l ,4'-bipiperidin]-4- yl)methyl)pyridin-2-yl)amino)-Ar,ALdimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A183;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]-l yl)methyl)pyridin-2-yl)amino)-jV,jV-dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-6-carboxamide
A184;
7-cyclopentyl-2-((5-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)methyl)pyridin-2-yl)amino)-A^V-dimethyl-7/7-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide Al 85;
7-cyclopentyl-2-((5-((l'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-4- yl)oxy)pyridin-2-yl)amino)-J¥,A-dimethyl-72/-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A186;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-4- yl)methoxy)pyridin-2-yl)amino)-7V,jV-dimethyl-72/-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A187;
7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)ethyl)pyridin-2-yl)amino)-A'',J'V-dimethyl-7/7-pyrrolo[2,3-^]pyrimidine-6-carboxamide A188;
7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 4-yl)ethyl)pyridin-2-yl)amino)-A^V-dimethyl-777-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A189;
7-cyclopentyl-2-((5-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l -yl)- piperidin-l-yl)ethyl)pyridin-2-yl)amino)-A'r,A-dimetliyl-7/7-pyrrolo[2,3-J]pyrimidine-6- carboxamide Al 90;
7-cyclopentyi-2-((5-(2-(l'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)ethoxy)pyridin-2-yl)amino)-Az,A'’-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A191;
7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 4-yl)ethoxy)pyri din-2 -yl)aniino)-Ar,jV-dimethyl-7/f-pyrrolo[2,3-<f|pyrimidine-6-carboxaniide A192;
7-cyclopentyl-2-((5-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)pyridin-2-yl)amino)-AT,7V-dimethyl-72/-pyrrolo[2,3-t(]pyrimidine-6- carboxamide Al 93;
7-cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)az.etidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-A',A;-dimethyl-7//-pyrrolo[2,3-tZ]- pyrimidine-6-carboxamide A194; 7-cyclopentyl-2-((5-(4-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 4-yl)piperazin- 1 -yllpyri di n-2-y l)amino)-Ar,A-di methy l-77f-pyrrol o[2, 3 -tZ]pyrimidine-6- carboxamide A195;
7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- [l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-7VjV-dimethyl-7H-pyrrolo[2,3-^]pyrimidine-6- carboxamide A196:
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-777-pyrrolo[2,3-<7]pyriniidine-6- carboxamide A197;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- cyclohexyl)piperidin-l-yl)pyridin-2-yl)amino)-Al/7-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A198;
7-cy clopentyl-2-((5 -(4-( 1 -(3 -(3 -(2, 6-dioxopiperi din-3 -yl)phenoxy)propyl)- piperidin-4-yl)piperazin-l-yl)pyri din-2 -yl)amino)-A’,7V-dimethyl-7Ar-pyrrolo[2,3-tf|pyrimidine-6- arboxamide A199;
7-cyclopentyl-2-((5-((4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)methyl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyrrolo[2,3-^pyrimidine-6- carboxamide A200;
7-cyclopentyl-2-((5-(2-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)ethyl)pyridin-2-yl)amino)-7V,A’-dimethyl-7//-pyrrolo[2,3-(/|pyrimidine-6- carboxamide A201;
7-cyclopentyl-2-((5-(3-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)propyl)pyridin-2-yl)amino)-A’,A-diniethyl-7AF-pyrrolo[2,3-Jjpyrimidine-6-carboxamide A202;
7-cyclopentyl-2-((5-(3-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)propyl)pyridin-2-yl)amino)-AVV-dimethyl-7/Z-pyrrolo[2,3-60pyriniidine-6- carboxamide A203;
7-cyclopentyl-2-((5-(3-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)propyl)pyridin-2-yl)amino)-A;A'-dimethyl-7JH-pyiTolo[2,3-t/]pyrimidine-6- carboxamide A204;
7-cyclopentyl-2-((5-(3-(r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin] 4-yl)propyl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7J/-pyrrolo[2,3-t/]pyrimidine-6-carboxamide
A205;
7-cyclopentyl-2-((5-(2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l -yl)- piperidin-l-yl)ethyl)pyridin-2-yl)amino)-A;,A-dimethyl-7JH-pyn'olo[2,3-t/]pyrimidine-6- carboxamide A206;
7-cyclopeiityl-2-((5-((25)-2-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yi)methyl)morpholino)pyridin-2-yl)amino)-A7,A'r-dimethyl-7//-pyrrolo[2,3<7]pyrimidine-6- carboxamide A207;
7-cyclopentyl-2-((5-((27?)-2-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)methyl)morpholino)pyridin-2-yl)amino)-A’,7V-dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A208;
7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- piperidin-l-yl)pyridin-2-yl)amino)-A’,?/-dimethyl-7/f-pyrrolo[2,3-^pyrimidine-6-carboxamide A209;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-3- yl)oxy)pyridin-2-yl)amino)-A’,Ar-dimethyl-7//-pyrrolo[2,3-i/]pyrimidine-6-carboxamide A210;
7-cyclopentyl-2-((5-((3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)methyl)pyridin-2-yl)amino)-A'’,AT-dimethyl-7//-pyrrolo[2,3-<7]pyriniidine-6- carboxamide A211;
7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[3,4'-bipiperidin]-l- yl)methyl)pyridin-2-yI)amino)-Ar,AAdimethyl-7/f-pyrrolo[2,3-£Z]pyrimidine-6-carboxamide A212;
7-cyclopentyl-2-((5-(2-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)pyridin-2-yl)amino)-Ar,A-dimethyl-7/f-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A213;
7-cyclopentyl-2-((5-(4-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- piperidin-l-yl)methyl)piperidin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7J/-pyrrolo[2,3-<f|- pyrimidine-6-carboxamide A214;
7-cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- benzyl)piperazin-l-yl)pyridin-2-yl)amino)-A7,A''-dimethyl-7//-pyiTolo[2,3-<7]pyrin]idine-6- carboxamide A215; 7-cyclopentyl-2-((5-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l -yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A’,A'-dimethyl-7I7-pyrrolo[2,3-</|pyriinidiiie- 6-carboxamide A216,
7-cyclopentyl-2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-7/7-pyrrolo[2,3-c(]pyrimidine-6- carboxamide A217:
7-cyclopentyl-2-((5-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperidin-4-yl)pyridin-2-yl)amino)-ATAr-dimethyl-7/7-pyrrolo[2,3-</]pyrimidine-6- carboxamide A218;
7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-A7,Ar-dimethyl-7//-pyrrolo[2,3-^pyrimidine-6- carboxamide A219;
7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)piperidin-l-yl)pyri din-2 -yl)amino)-A’,A'r-dimethyl-77/-pyrrolo[2,3-t(]pyrimidine-6- carboxamide A220:
7-cyclopentyl-2-((5-(4-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyrrolo[2,3-^pyrimidine-6- carboxamide A221;
7-cy cl opentyl-2-(( 5 -( 1 -(( 1 -(3 -(2, 6-di oxopiperi din-3 -yl )phenyl)piperi din-4-y I )- methyl)piperidin-4-yl)pyridin-2-yl)amino)-A7,Ar-dimethyl-77/-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A222;
7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- methyl)piperidin-l-yl)pyri din-2 -yl)amino)-A',A'r-dimethyl-777r-pyrrolo[2,3-tf|pyrimidine-6- carboxamide A223:
7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-?/,7V-dimethyl-7/Z-pyrrolo[2,3-^pyrimidine-6- carboxamide A224;
7-cyclopentyl-2-((5-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-r- yl)methyl)pyridin-2-yl)amino)-A,A-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A225;
7-cyclopentyl-2-((5-(4-(2-(4-(4-(2, 6-dioxopiperidin-3-yl)phenyl)piperi din-1 -yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)W,?/-dimethyl-7H-pyrrolo[2,3-(7]pyrimidine-6- carboxamide A226;
7-cyclopentyl-2-((5-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A;,A-dimethyl-7JH-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A227;
7-cy cl opentyl-2-((5 -( 1 -(2-(4-(4-(2, 6-dioxopiperi din-3 -yl)pheny l)piperazin- 1 -yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A/7-dimethyl-7#-pyrrolo[2,3-6f]pyrimidine-6- carboxamide A228;
7-cyclopentyl-2-((5-( 1 -(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin- 1 -yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A229;
7-cyclopentyl-2-((5-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7//-pyrrolo[2,3-^pyrimidine-6- carboxamide A 230:
7-cy clopentyl-2-((5 -(4-(2-( 1 -(3 -(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-AT,A'-dimethyl-7//-pyrrolo[2,3-(/|pyrimidine-6- carboxamide A231;
7-cyclopentyl-2-((5-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A232:
7-cyclopentyl-2-((5-(l-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A,A-dimethyl-7JH-pyrrolo[2,3-t/]pyrimidine-6- carb oxami de A233;
7-cy cl opentyl-2-((5 -( 1 -(2-( 1 -(3 -(2, 6-dioxopiperi din-3 -yl)pheny l)piperi din-4-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-Ar,A-dimethyl-72/-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A234;
7-cyclopentyl-2-((5-( 1 -(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin- 1 -yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A235;
7-cyclopentyl-2-((5-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- r-yl)ethyl)pyridin-2-yl)amino)-Ar,AT-dimethyl-77f-pyrrolo[2,3-r/]pyrimidine-6-carboxamide A236;
7-cyclopentyl-2-((5-(r-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[4,4'-bipiperidin]- l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7Z/-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A237;
7-cyclopentyl-2-((5-(r-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-[l,4'-bipiperidin]- 4-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7//-pyrrolo[2,3-t(|pyrimidine-6-carboxamide A238;
7-cy clopentyl-2-((5 -(2-(4-( 1 -(3 -(2, 6-dioxopiperi din-3 -yl)pheny l)pi p eri di n-4 -y 1 )- piperazin-l -yl)ethyl)pyridin-2-yl)amino)-A’,7V-dimethyl-7//-pyrrolo[2,3-6Z]pyrimidine-6- carboxamide A239;
7-cyclopentyl-2-((5-(2-(l'-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- 4-yl)ethyl)pyridin-2-yl)amino)-A,JV-dimethyl-7//-pyrrolo[2;3-<7]pyrimidine-6-carboxamide A240;
7-cyclopentyl-2-((5-(2-(r-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]- l-yl)ethyl)pyridin-2-yl)amino)-Ap\Mimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A241;
7-cyclopentyl-2-((5-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]- r-yl)ethyl)pyridin-2-yl)amino)-Az^V-dimethyl-7/7-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A242;
7-cyclopentyl-2-((5-(2-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)ethoxy)pyridin-2-yl)amino)-A7V-dimethyl-7//-pyrrolo[2,3-<7]pyriniidine-6- carboxamide A243;
7-cyclopentyl-2-((5-(2-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)ethoxy)pyridin-2-yl)amino)-AAV-dimethyl-7J7-pyrrolo[2,3-^pyrimidine-6- carboxamide A244;
7-cyclopentyl-Ar,A-dimethyl-2-((5-(4-(l-(4-(3-methyl-2,6-dioxopiperidin-3-yl)- phenethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A245;
7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethyl)piperidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyrrolo[2,3-</]pyrimidine-6- carboxamide A246;
7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethyl)piperidin-l-yl)pyridin-2-yl)amino)-Air,A-dimethyl-7Jff-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A247;
7-cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- ethy l)piperi din- 1 -yl)pyri din-2 -yl)amino)-AT, A-dimethy I -7/7-pyrrol o [2, 3 -tfjpyrimi dine-6- carboxamide A248;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- propoxy)pyridin-2-yl)amino)-AA,iV-dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A249;
7-cyclopentyl-2-((5-(3-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- propoxy)pyridin-2-yl)amino)-Ar,Ar-dimethyl-7/7-pyrrolo[2,3-(7]pyrimidine-6-carboxamide A250;
7-cyclopentyl-2-((5-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- ethoxy)pyridin-2-yl)amino)-Ar,A-dimethyl-777-pyrrolo[2,3-tf|pyrimidine-6-carboxamide A251;
7-cyclopentyl-2-((5-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- ethoxy)pyridin-2-yl)amino)-/V,7V-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A252;
7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-A^V-dimethyl-72/-pyrrolo[2,3-i(]pyrimidine-6- carboxamide A253:
7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)pyridin-2-yl)amino)-V,A-dimethyl-7J7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A254;
7-cyclopentyl-2-((5-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)- piperazin-l-yl)pyridin-2-yl)amino)-AjV-dimethyl-7//-pyrrolo[2,3-t(|pyrimidine-6-carboxaniide A255;
7-cyclopentyl-2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,Ar-dimethyl-777-pyrrolo[2,3-tflpyrimidine-6- carboxamide A256:
7-cyclopentyi-2-((5-(4-((l-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7Z/-pyrrolo[2,3-(7]pyrimidine-6- carboxamide A257;
7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar7V-dimethyl-7J7-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A258;
7-cy clopenty!-2-((5 -(4-(2-( 1 -(3 -(2, 6-dioxopiperidin-3 -yljpheny l)azetidin-3 -yl) ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyrrolo[2,3-(7]pyrimidine-6- carboxamide A259;
7-cyclopentyl-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,AMimethyl-7//-pyrrolo[2,3-d]- pyrimidine-6-carboxamide A260;
7-cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A',7V-dimethyl-7//-pyrrolo[2,3-cfj- pyrimidine-6-carboxamide A261;
7-cyclopentyl-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,JV-dimethyl-777-pyrrolo[2,3-t(|- pyrimidine-6-carboxamide A262;
7-cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro- ethyl)azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-A,A’-dimethyl-77/-pyrrolo[2,3-t/]- pyrimidine-6-carboxamide A263;
7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)benzyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-AjV-dimethyl-77/-pyrrolo[2,3-i(|pyrimidine-6-carboxaniide A264;
7-cyclopentyl-2-((5-(4-(l-(3-(2,6-dioxopiperidin-3-yl)benzyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7/7-pyrrolo[2,3-</]pyrimidine-6-carboxamide A265;
7-cyclopentyl-2-((5-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7/f-pyrrolo[2,3-t(]pyrimidine-6- carboxamide A266;
7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-A^V-dimethyl-7/Apyrrolo[2,3-tZ]pyrimidine-6- carboxamide A267;
7-cyclopentyl-2-((5-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoro-[l,4'- bipiperidin]-T-yl)pyridin-2-yl)amino)-A^V-dimethyl-777-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A268;
7-cyclopentyl-2-((5-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-3-fluoro- azetidin-l-yl)piperidiii-l-yl)pyridin-2-yl)aniiiio)-Ar,A7-dimethyl-7i7-pyrrolo[2,3-^]pyrimidine-6- carboxamide A269;
7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-3-fluoro- azeti din-1 -yl)piperidin-l-yl)pyridin-2-yl)amino)-A’,Ar-dimethyl-7Z7-pyrrolo[2,3-J|pyrimidine-6- carboxamide A270;
7-cyclopentyl-2-((5-(3-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoro— ethyl)piperidin-4-yl)azetidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7//-pyrrolo[2,3-t/]- py rimidine-6-carboxamide A271 ;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7J/-pyrrolo[2,3-(/]pyrimidine-6-carboxamide A272;
7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,A'-dimethyl-7Ar-pyrrolo[2,3-(7]pyrimidine-6-carboxamide A273;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-77/-pyrrolo[2,3-(7]pyrimidine-6-carboxamide A274;
7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)piperazin-l-yl)- azetidiii-l-yl)pyridin-2-yl)aniino)-Ar,A7-dimethyl-7J/-pyrrolo[2,3-c(|pyrimidine-6-carboxamide A275;
7-cyclopentyi-2-((5-(4-(3-(4-(2,6-dioxopiperidin-3-yl)benzyl)-3-fluoroazetidin-l- yl)piperidin-l-yl)pyridin-2-yl)amino)-A’,A'r-dimethyl-7/7-pyrrolo[2,3-tf|pyrimidine-6- carboxamide A276;
7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)benzyl)-3-fluoroazetidin-l- yl)piperidin-l-yl)pyridin-2-yl)amino)-Af,Ar-dimethyl-7/?-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A277;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-AT,A'-dimethyl-7J/-pyrrolo[2,3-<f|pyrimidine-6-carboxamide A278;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro- piperidin-l-yl)azetidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-77/-pyrrolo[2,3-</]pyrimidine-6- carboxamide A279; 7-cy cl opentyl-2-((5 -(3 -(4-(3 -(2, 6-di oxopiperi din-3 -y 1 )phenethyl)piperidin- 1 -yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7Ar-pyrrolo[2,3-<7|pyrimidine-6-carboxamide A280;
7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenethyl)-4-fluoro- piperidin-l-yl)azetidin-l-yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-7//-pyrrolo[2,3-<^]pyrimidine-6- carboxamide A281:
7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoropiperidin- l-yl)azetidin-l-yl)pyridin-2-yl)amino)-A',7V-dimethyl-7/7-pyrrolo[2,3-</jpyrimidine-6- carboxamide A282;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)-4-fluoropiperidin-
1 -yl)azetidin- 1 -yl)pyridin-2-yl)amino)-A)A-dimethyl-7//-pyrrolo[2,3 -t/]pyrimidine-6- carboxamide A283;
7-cyclopentyl-2-((5-(4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-l-yl)- methyl)-4-fluoropiperidin-l-yl)pyridin-2-yl)amino)-A?’,A-dimethyl-77/-pyrrolo[2,3-'^]pyrin]idine- 6-carboxamide A284;
7-cyclopentyl-2-((5-(4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-l-yl)- methyl)-4-fluoropiperidin-l-yl)pyridin-2-yl)amino)-AAV-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A285;
7-cy cl opentyl-2-(( 5 -( 1 -(( 1 -(3 -(2, 6-di oxopiperi din-3 -yl )phenyl)-4-fluoropiperi din- 4-yl)methyl)piperidin-4-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7jE/-pyrrolo[2,3-d]pyrimidine-6- carboxamide A286;
7-cyclopentyl-2-((5-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-fluoropiperidin- 4-yl)methyl)piperidin-4-yl)pyridin-2-yl)amino)-A'',yV-dimethyl-7Ar-pyiTolo[2,3-J]pyrimidine-6- carboxamide A287:
7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)-4-fluoropiperidin-l-yl)pyridin-2-yl)amino)-AJ\Mimethyl-7H-pyrrolo[2,3-d]pyrimidine- 6-carboxamide A288;
7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- methyl)-4-fluoropiperidin-l-yl)pyri din-2 -yl)amino)-ArALdimethyl-7JH-pyrrolo[2,3-tZ]pyrimidine- 6-carboxamide A289,
7-cy cl opentyl-2-((5 -(4-(2-( 1 -(4-(2, 6-di oxopiperi din-3 -yl)-3 -fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l -yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-7/7-pyrrolo[2,3-<7]- pyrimidine-6-carboxamide A290;
7-cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,ALdimethyl-7//-pyrrolo[2,3-d]- pyrimidine-6-carboxamide A291 ;
2-((5-(4-(2-(l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-Az,A-dimethyl-7//-pyrrolo[2,3-</]pyrimidine-6- carboxamide A292;
2-((5-(4-(2-(l-(2-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A7,A-dimethyl-777-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A293;
7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- azetidin"l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-77f-pyrrolo[2,3-^pyrimidine-6-carboxamide A294;
7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-AjV-dimethyl-77/-pyrrolo[2,3-i(|pyrimidine-6-carboxamide A295;
7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A7,ALdimethyl-777-pyrrolo[2,3-c/]pyrimidine-6-carboxamide A296;
7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)-5-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7/7-pyrrolo[2,3-c/]- pyrimidine-6-carboxamide A297;
7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,6-dioxopiperidin-3-yl)-4-fluorophenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar//-dimethyl-7Z/-pyrrolo[2,3-</]- pyrimidine-6-carboxamide A298;
7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)-4-fluoro- [l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-Ar,Ar-dimethyl-7J7-pyrrolo[2,3-tf|pyrimidine-6- carboxamide A299;
7-cyclopentyl-2-((5-((r-(3-(2,6-dioxopiperidin-3-yl)phenyl)-[l,4'-bipiperidin]-4- yl)methoxy)pyridin-2-yl)amino)-Ar,AMimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A300;
7-cyclopentyl-2-((5-(3-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)- l,l-difluoroethyl)azetidin-l-yl)pyridin-2-yl)amino)-A,ALdimethyl-777-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A351;
7-cyclopentyl-2-((5-(4-(2-(l-(5-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)~ piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A7-dimethyl-77/-pyrrolo[2,3-t/]- pyrimidine-6-carboxamide A352;
7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenethyl)-4-fluoro- [l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-ArpV-dimethyl-777-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A353;
7-cyclopentyi-2-((4-((2-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A/,A7-dimethyl-7J7-pyrrolo[2,3-6f]- pyrimidine-6-carboxamide A401;
7-cyclopentyl-2-((4-((4-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- phenoxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-A’,ALdimethyl-7//-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A402;
7-cyclopentyl-2-((4-((6-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-Az,Ar-dimethyl-7/7-pyrrolo[2,3- tZ]pyrimidine-6-carboxamide A403;
7-cyclopentyi-2-((4-((2-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A/,A;-dimethyl-7Ar-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A404;
7-cyclopentyl-2-((4-((4-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(2/A)-yl)- phenoxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)aniino)-A7,A7-dimethyl-7/f-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A405;
7-cyclopentyl-2-((4-((6-(4-(2-(4-(2,4-dioxotetrahydropvrimidin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-Az,Ar-dimethyl-7/f-pyrrolo[2,3- <7]pyrimidine-6-carboxamide A406;
7-cyclopentyl-2-((4-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2Z7)-yl)phenyl)- piperazin-l-yl)phenyl)amino)-Ar,A’-dimethyl-77/-pyrrolo[2,3-</]pyriniidine-6-carboxamide A407;
7-cyclopentyl-2-((5-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2Z/)-yl)phenyl)- piperazin-l-yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxamide
A408;
7-cyclopentyl-2-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)benzyl)- piperazin- 1 -yl)phenyl)amino)-7Z,A7-dimethyl-7/Z-pyrrolo[2,3 -t/]pyrimidine-6-carboxamide A409;
7-cyclopentyl-2-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2Z/)-yl)phenethyl)- piperazin-l-yl)phenyl)amino)-A^V-dimethyl-7/7-pyrrolo[2,3-t7]pyrimidine-6-carboxamide A410;
7-cyclopentyl-2-((5-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenoxy)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A7-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A411;
7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)phenyl)- piperazin-l-yl)ethyl)phenyl)amino)-Ar,Ar-dimetliyl-7Ar-pyrrolo[2,3-(7]pyrimidine-6-carboxamide A412;
7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2/Z)-yl)phenyl)- piperazin-l-yl)ethyl)phenyl)amino)-Afr,A’-dimethyl-7H-pyrrolo[2,3-i(|pyrirnidine-6-carboxamide A413;
7-cyclopentyl-2-((5-((4-(4-(2,4-dioxotetrahydropyrimidin-l(27/)-yl)phenyl)- piperazin-l-yl)methyl)pyridin-2-yl)amino)-A,ALdimethyl-7H-pyrrolo[2,3-^pyrimidine-6- carboxamide A414;
7-cyclopentyl-2-((5-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(27/)-yl)phenyl)- piperaziii-l-yl)ethoxy)pyridin-2-yl)amiiio)-Ar,A7-diniethyl-7//-pyrrolo[2,3-c(|pyrimidine-6- carboxamide A415;
7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)ethoxy)phenyl)amino)-A',A7-dimethyl-7/7-pyiTolo[2,3-J]pyrimidine-6- carboxamide A416:
7-cyclopentyi-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)ethoxy)phenyl)amino)-A,AMimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A417;
7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(27/)-yl)benzyl)- piperazin-l-yl)ethoxy)phenyl)amino)-A7A-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A418;
7-cyclopentyl-2-((5-((4-(3-(2,4-dioxotetrahydropyrimidin-l(217)-yl)phenyl)- piperazin- 1 -yl)methyl)pyridin-2-yl)amino)-A; A'-dimethy I -7/7-pyrrol o [2, 3 -<7]pyrimi dine-6- carboxamide A419;
7-cyclopentyl-2-((4-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)phenyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-Ar,Ar-dimethyl-7/f-pyrrolo[2,3-^pyrimidine-6- carboxamide A420;
7-cyclopentyl-2-((4-(4-(l-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-/V,A-dimethyl-7Ar-pyrrolo[2,3-<7Jpyrimidine-6- carboxamide A421;
7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)benzyl)- piperazin-l-yl)ethyl)phenyl)amino)-Ar,A'-dimethyl-7/7-pyrrolo[2,3-tf|pyrimidine-6-carboxamide A422;
7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2#)-yl)benzyl)- piperazin-l-yl)ethyl)phenyl)amino)-Ar,AMimethyl-7//-pyrrolo[2,3-d]pyrimidine-6-carboxamide A423;
7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)benzyl)- piperaziii-l-yl)ethoxy)phenyl)amino)-Ar,Ar-dimethyl-7/7-pyrrolo[2,3-i/]pyrimidine-6- carboxamide A424;
7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-l(27/)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)amino)-A’,7V-dimethyl-77/-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A425;
7-cyclopentyl-2-((4-(2-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-l(27/)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)amino)-A,A7-dimethyl-7Z/-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A426;
7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethoxy)phenyl)amino)-7V,Az-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A427,
7-cyclopentyl-2-((4-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(2Jc/)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-A,A-dimethyl-7J7-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A428;
7-cyclopentyl-2-((4-(4-( 1 -(3-(2,4-dioxotetrahydropyrimidin- 1 (2//)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-A^-dimethyl-7/Z-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A429;
7-cyclopentyl-2-((5-(4-( 1 -(4-(2,4-dioxotetrahydropyrimidin- 1 (2/7)-yl)benzyl)- piperidin-4-yl)piperazin-l -yl)pyridin-2-yl)amino)-A,ALdimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A430;
7-cyclopentyl-2-((4-(4-((l-(4-(2,4-dioxotetrahydropyrimidin-l(2Z/)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)-A7,A7-dimethyl-7J/-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A431;
7-cyclopentyl-2-((4-(4-((l-(3-(2,4-dioxotetrahydropyrimidin-l (2/7)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)-A’,A’-dimethyl-7Z/-pyrrolo[2,3-^pyrimidine- 6-carboxamide A432;
7-cyclopentyi-2-((4-(4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-l(27/)-yl)phenyl)- piperidin-l-yl)ethyl)piperazin-l-yl)phenyl)amino)-A7,A'r-dimethyl-7//-pyrrolo[2,3<(|pyrimidine- 6-carboxamide A433;
7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(277)-yl)phenyl)- piperidin- 1 -yl)ethyl)piperazin- 1 -yl)phenyl)amino)-A,AMimethyl-7//-pyrrolo[2,3 -t/]pyrimidine- 6-carboxamide A434, 7-cyclopentyl-2-((5-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A’,Ar-dimethyl-7//-pyrrolo[2,3-</]pyrimidine-6- carboxamide A435;
2-((5-(4-(2-(l-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-Ar,A’-dimethyl-7//- pyrrolo[2,3-c(]pyrimidine-6-carboxamide A436;
7-cyclopentyl-2-((5-(4-((l-(4-(2,4-dioxotetrahydropyrimidin-l(27/)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-Af,Ar-dimethyl-7/f-pyrrolo[2,3-t/]- pyrimidine-6-carboxamide A437;
2-((5-(4-((l -(3 -chloro-4-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)phenyl)- piperidin-4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-Ar,Ar-dimethyl-7Zf- pyrrol o[2, 3 -<7]pyrimidine-6-carboxamide A438;
7-cyclopentyl-2-((5-(4-(l-(4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-Ar,A’-dimethyl-72/-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A439; 2-((5-(4-(l-(2-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)phenyl)-2,2- difluoroethyl)piperidiii-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-Ar,A7-dimethyl-7/f- pyrrolo[2,3-tf]pyrimidine-6-carboxamide A440;
7-cyclopentyl-2-((4-((2-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-l//-indazol-
7-yl)oxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-AAV-dimethyl-7H-pyrrolo[2,3-i/j- pyrimidine-6-carboxamide A501;
7-cyclopentyl-2-((4-((4-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-l//-indazol- 7-yl)oxy)acely4)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-A,A’-dimethyl-7//-pyrrolo[2,3- tZjpyrimidine-6-carboxamide A502;
7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-l/7-indazol- 7-yl)oxy)acety'l)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-jV,Ar-dimethyl-72/-pyrrolo[2,3- <7]pyrimidine-6-carboxamide A503;
7-cyclopentyl-2-((4-((2-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-lZ7-indazol- 6-yl)oxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-Az,A-dimethyl-7H-pyrrolo[2,3-^]- pyrimidine-6-carboxamide A504;
7-cyclopentyl-2-((4-((4-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-l/7-indazol- 6-yl)oxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-A,A7-dimethyl-7//-pyrrolo[2,3- Jjpyrimidine-6-carboxamide A505;
7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-l//-indazol- 6-yl)oxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-jV,?7-dimethyl-72/-pyrrolo[2,3- d]pyrimidine-6-carboxamide A506;
7-cyclopentyl-2-((4-((2-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)-l- methyl- l//-indazol-7-yl)oxy)acetyl)piperazin- 1 -yl)ethyl)carbamoyl)phenyl)amino)-jV,A- dimethyl-7Jff-pyrrolo[2,3-^pyrimidine-6-carboxamide A551;
7-cyclopentyl-2-((4-((4-(4-(2-((3 -(2,4-dioxotetrahydropyrimidin- 1 (27/)-y 1)- 1 - methyl- l//-indazol-7-yl)oxy)acetyl)piperazin- 1 -yl)butyl)carbamoyl)phenyl)amino)-A, A7- dimethyl-7J/-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A552;
7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2/7)-yl)-l- methyl- l//-indazol-7-yl)oxy)acetyl)piperazin- 1 -yl)hexyl)carbamoyl)phenyl)amino)-A^V- dimethyl-7Z/-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A553;
7-cyclopentyl-2-((4-((2-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)-l- methyl-177-indazol-6-yl)oxy)acetyl)piperazin-l -yl)ethyl)carbamoyl)phenyl)amino)-Ar rA’- dimethyl-7/7-pyrrolo[2,3-</]pyrimidine-6-carboxaniide A554;
7-cyclopentyl-2-((4-((4-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)-l- m ethyl- 1 AT-indazol-6-yl)oxy)acetyl)piperazin- 1 -yl)butyl)carbamoyl)phenyl)amino)-A,A- dimethyl-7H-pyrrolo[2,3-^jpyrimidine-6-carboxamide A555;
7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,4-dioxotetrahydropyrimidin-l(2//)-yl)-l- methyl- l//-indazol-6-yl)oxy)acetyl)piperazin- 1 -yl)hexyl)carbamoyl)phenyl)amino)-A^V;- dimethyl-777-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A556;
7-cyclopentyl-2-((5-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(22/)-yl)-l -methyl- l/7-indazol-6-yl)ethyl)-4-fluoro-[l ,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-A',A?-dimethyl-7H- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A557;
7-cyclopentyl-2-((5-(4-(2-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yV)- 1 -methyl- lZ/-indazol-7-yl)ethyl)-4-fluoro-[l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-A,A-dimethyl-77A pyrrolo[2,3-^pynmidine-6-carboxamide A558;
7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,4-dioxotetrahydropyrimidin-l(2/7)-yl)-l- methyl-l//-indazol-6-yl)piperidin-4-yl)etliyl)piperazin-l-yl)pyridin-2-yl)ainino)-Ar,AT-diniethyl- 777-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A559;
7-cyclopentyl-2-((4-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)- amino)hexyl)carbamoyl)phenyl)amino)-AAV-dimethyl-7/7-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A601;
7-cyclopentyl-2-((4-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)- amino)hexyl)(methyl)carbamoyl)phenyl)amino)-A7,Af-dimethyl-7/f-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A602;
7-cyclopentyl-2-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)- glycyl)piperazin-l-yl)pyridin-2-yl)amino)-jV,A/-dimethyl-7/7-pyrrolo[2,3~<7]pyrimidine-6- carboxamide A603;
7-cyclopentyl-2-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)- glycyl)piperazin-l-yl)pyri din-2 -yl)amino)-Ar,A-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A611;
7-cyclopentyl-2-((4-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin- 4-yl)piperi din- l-yl)ethyl)carbamoyl)phenyl)amino)-A’,ALdimethyl-7/7-pyrrolo[2, 3 -^pyrimidine- 6-carboxamide A612;
7-cyclopentyl-2-((4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
4-yl)piperidin-l-yl)butyl)carbamoyl)phenyl)amino)-A’,7V-dimethyl-7/7-pyrrolo[2,3-</]pyrimidine- 6-carboxamide A613;
7-cyclopentyl-2-((4-((6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
4-yl)piperidin-l-yl)hexyl)carbamoyl)phenyl)amino)-77,A/-dimethyl-7Z/-pyrrolo[2,3-«7]pyrimidine- 6-carboxamide A614;
7-cyclopentyl-2-((5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-4-yl)piperidin-l-yl)acetyl)piperazin-l-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7ZA pyrrol o[2, 3 -<7]pyrimidine-6-carboxamide A615;
7-cyclopentyl-2-((5-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-4-yl)piperidin-l-yl)propanoyl)piperazin-l-yl)pyridin-2-yl)amino)-A’,A7-dimethyl-7Ar- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A616;
7-cyclopentyl-2-((5-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-4-yl)piperidin-l-yl)butanoyl)piperazin-l-yl)pyridin-2-yl)amino)-Az,Ar-dimethyl-777- pyrrolo[2,3-<7]pyrimidiiie-6-carboxamide A617;
7-cyclopentyl-2-((4-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l -oxoisoindolin-
5-yl)piperidin-l-yl)ethyl)carbamoyl)phenyl)amino)-A\A/-dimethyl-72/-pyrrolo[2,3-</]pyrimidine-
6-carboxamide A618;
7-cyclopentyl-2-((4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
5-yl)piperidin-l-yl)butyl)carbamoyl)phenyl)amino)-A,A-dimethyl-7//-pyrrolo[2,3-6(|pyrimidine-
6-carboxamide A619;
7-cyclopentyl-2-((4-((6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-
5-yl)piperidin-l-yl)hexyl)carbamoyl)phenyl)amino)-Ar,A7-dimethyl-7/f-pyrrolo[2,3-60pyrimidine-
6-carboxamide A620,
7-cyclopentyl-2-((5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-5-yl)piperidin-l-yl)acetyl)piperazin-l-yl)pyridin-2-yl)amino)-A,Ar-dimethyl-7Ar- pyrrol o[2, 3 -<7]pyrimidine-6-carboxamide A621;
7-cy cl op enty 1 -2 -(( 5 -(4-(3 -(4-(2-(2, 6-dioxopiperidin-3 -yl)-6-fluoro- 1 -oxo- isoindolin-5-yl)piperidin-l-yl)propanoyl)piperazin-l-yl)pyridin-2-yl)amii]o)-A’,A7-dimethyl-7Ar- pyrrolo[2,3-rZ]pyrimidine-6-carboxamide A622; 7-cyclopentyl-2-((5-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxo- isoindolin-5-yl)piperidin-l-yl)butanoyl)piperazin-l-yl)pyridin-2-yl)amino)-ArjV-dimethyl-7Jf- pyrrolo[2,3-tf]pyrimidine-6-carboxamide A623;
7-cyclopentyl-2-((4-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-427- thieno[3,4-c]pyiTol-l-yl)methoxy)benzyl)carbamoyl)phenyl)amino)-?/,JV-dimethyl-777- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A651;
7-cyclopentyl-2-((4-((2-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4/7- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)amino)ethyl)carbamoyl)phenyl)amino)-/V,7V-dimethyl- 7/7-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A652;
7-cyclopentyl-2-((4-((4-((4-((5-(2,6-dioxopiperidm-3-yl)-4-oxo-5,6-dihydro-4Z7- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)aniiiio)butyl)carbamoyl)phenyl)amino)-7V,A7-dimethyl- 7/7-pyrrolo[2,3-<f|pyrimidine-6-carboxamide A653;
7-cyclopentyl-2-((4-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4/f- thieno[3,4-c]pyirol-l-yl)methoxy)benzyl)carbamoyl)phenyl)amino)-Az,ALdimethyl-7H-pyrrolo- [2,3-</]pyrimidine-6-carboxamide A654;
3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethoxy)phenyl)piperidine-2, 6-dione B101;
3-(3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-3-oxopropoxy)phenyl)piperidine-2, 6-dione B102;
A-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- methylphenoxy)acetamide B103; jV-(2-(4-(6-((6-acetyi-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- (trifluoromethyl)phenoxy)acetamide B104;
7V-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- methylphenoxy)acetamide Bl 05;
A7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- (trifluoromethyl)phenoxy)acetamide Bl 06;
Ar-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- methylphenoxy)acetamide B107;
77-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yi)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-2- (tri fluorom ethy 1 )ph en oxy )acetam ide B 108 ;
Az-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- methylphenoxy)acetamide B109;
A'r-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-6f]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)-2-(3-(2,6-dioxopiperidin-3-yl)-4- (trifluoromethyl)phenoxy)acetamide B 110 ;
3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-6/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)phenyl)piperidine-2, 6-dione Bill;
3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2, 6-dione Bl 12;
3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimi din-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethoxy)phenyl)piperidine-2, 6-dione Bl 13;
3-(3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)phenyl)piperidine-2, 6-dione B114;
3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t7|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2, 6-dione B115;
3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yi)piperazin-l-yl)ethoxy)phenyl)piperidine-2, 6-dione B116;
3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propoxy)phenyl)piperidine-2, 6-dione Bl 17;
3-(3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propoxy)phenyl)piperidine-2, 6-dione B118;
3-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-6!0- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B119;
3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)piperi din- l-yl)phenyl)piperi dine-
2,6-dione B120;
3-(4-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-] -yl)piperidin-l-yl)methyl)phenyl)piperidine-
2,6-dione B121;
3-(3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B122;
3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </|pyrimidin-2-yl)aniino)pyridin-3-yl)piperazin-l-yl)methyl)piperi din- l-yl)phenyl)piperi dine-
2,6-dione B123;
3-(3-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyriniidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)piperi din- l-yl)methyl)phenyl)piperidine-
2,6-dione B124;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B125;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t(|pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -yl)ethyl)piperazin- 1 -yl)phenyl)piperidine-2, 6- dione B126;
3-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)piperidine-2,6- dione B127;
3-(3-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)piperidine-2,6- dione B128;
3-(4-((l-(2-((4-((6-(difluoromethyl)-8-((l/^2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperidin-4- y l)oxy )pheny l)pi peri dine-2, 6-dione Bl 29;
3-(3-((l-(2-((4-((6-(difluoromethyl)-8-((17?,22?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperi din-4- yl)oxy)phenyl)piperidine-2, 6-dione B130;
3-(4-((l-(3-((4-((6-(difluoromethyl)-8-((l/?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tf]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione B131;
3-(4-(4-(2-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin- 1 -yl)sulfonyl)ethyl)piperazin- 1 - yl)phenyl)piperi dine-2, 6-dione B132;
3-(4-(4-(2-((4-((6-(difluoromethyl)-8-((l/^,2JR)-2-hydroxy-2-methylcyclopentyi)- 7-oxo-7,8-dihydropyrido[2,3-</]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione B133;
3-(4-(4-(3-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)phenyl)piperi dine-2, 6-dione B134;
3-(3-(4-(2-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)aniino)piperidin- 1 -yl)sulfonyl)ethyl)piperazin- 1 - yl)phenyl)piperi dine-2, 6-dione B135;
3-(3-(4-(3-((4-((6-(difluoromethyl)-8-((l/x',2/?)-2-hydroxy-2-methylcyclopentyi)- 7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- 1 -yl)phenyl)piperi dine-2, 6-dione B136;
3-(4-(3-((4-((6-(difluoromethyl)-8-((12?,22?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propoxy)phenyl)- piperidine-2, 6-dione B137;
3 -(3 -(3 -((4-((6-(difluoromethyl)-8-(( lA,2J?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propoxy)phenyl)- piperidine-2, 6-dione B138;
3-(4-(4-(4-((4-((6-(diflUOrOmethyl)-8-((lJR,2JR)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)benzyl)piperazin- l-yl)phenyl)piperi dine-2, 6-dione B139; 3-(4-(4-(3-((4-((6-(difluoromethyl)-8-((17?,2J?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-^pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)benzyl)piperazin-
1 -yl)phenyl)piperi di ne-2, 6-dione B140;
3-(3-(4-(3-((4-((6-(difluoromethyl)-8-((17?,2JR)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-rf]pyrimidin-2-yl)amino)piperidin-l -yl)sulfonyl)benzyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B141;
3-(3-(4-(4-((4-((6-(difluoromethyl)-8-((l/<27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)sulfbnyl)benzyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B142, 3-(4-((4-(4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperazin- 1 -yl)methyl)phenyl)piperidine-2, 6-dione B143;
3-(4-(4-((4-(4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3<fjpyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B144;
3-(4-((4-((4-((6-(difluoromethyl)-8-((17?,2J?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2, 3-tf|pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- methyl)phenyl)piperidine-2, 6-dione B145;
3-(3-((4-((4-((6-(difluoromethyl)-8-((l/?,2/?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2, 3-t/]pyrimidin-2 -yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- methyl)phenyl)piperidine-2, 6-dione B146;
3-(4-(4-((4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t(|pyrimidin-2-yl)amino)piperidin-l -yl)sulfonyl)piperazin-l-yl)- methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B147;
3-(4-(4-(3-((4-((6-(diflUoromethyl)-8-((l/^2JR)-2-hydroxy-2-methylcyclopentyl)" 7-oxo-7, 8-dihy dropyrido[2, 3 - J]pyrimidin-2-yl)ami no)piperi din- 1 -y l)sulfonyl)propy I )pi perazin- l-yl)phenyl)piperidine-2, 6-dione B148;
3-(3-((l-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-</]pyrimidin-2-yl)amino)piperidin-l-yl)sulfdnyl)propyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione B149;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l -yl)phenyl)piperidine-2,6- dione B150;
3-(4-(2-(4-(4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)- piperazin- 1 -y 1 )ethy l)ph enyl)piperidine-2 , 6-di one B151 ;
3-(4-(2-(4-(4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-c(jpyrimidin-2-yl)amino)piperidin-l-yi)sulfonyl)phenyl)- piperazin- l-yl)ethoxy)phenyl)piperidine-2, 6-dione B152;
3-(4-(2-(4-(3-((4-((6-(difluoromethyl)-8-((17?,22?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyi)- piperazin- 1 -yl)ethyl)phenyl)piperidine-2, 6-dione B153;
3-(3-(2-(4-((4-((6-(difluoromethyl)-8-((l/^,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxO"7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- ethoxy)phenyl)piperidine-2, 6-dione B154;
3-(4-(3-(4-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-</Jpyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- propoxy )phenyl)piperidine-2, 6-dione Bl 55;
3-(3-(3-(4-((4-((6-(difluoromethyl)-8-((lJR,2/^)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3W]pyrimidin-2-yl)amino)piperidin-l-yl)sulfdnyl)piperazin-l-yl)- propoxy )phenyl)piperidine-2, 6-dione B156;
3-(4-(4-(4-((4-((6-(difluoromethyl)-8-((l/^2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenethyl)- piperazin-l-yl)phenyl)piperidine-2, 6-di one B157;
3-(4-(4-(2-(4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)aniino)piperidin-l-yl)sulfonyl)phenoxy)- ethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B158;
3-(4-(4-(2-(3-((4-((6-(difluoromethyl)-8-((17?,2/7)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-t/jpyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenoxy)- ethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B159;
3-(3-((l-(3-((4-((6-(difluoromethyl)-8-((l/^2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-^]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin- 4-yl)oxy)phenyl)piperidine-2, 6-dione B160;
3-(4-((l-(3-((4-((6-(difluoromethyl)-8-((17?,22?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin- 4-yl)oxy)phenyl)piperidine-2, 6-dione B161;
3-(4-((l-(4-((4-((6-(difluoromethyl)-8-((l/?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tf]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin- 4-yl)oxy)phenyl)piperidme-2, 6-dione B162;
3-(4-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZjpyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -yl)propyl)piperazin- 1 -yl)phenyl)piperidine- 2, 6-dione B163;
3-(4-(4-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)aniino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B164;
3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-[l,4'-bipiperidin]-r-yl)phenyl)- piperidine-2, 6-dione B165;
3-(4-(4-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione Bl 66;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyi-5-methyl-7-oxo-7,8-dihydropyrido[2,3~ d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1 -yl)ethyl)-[1 ,4'-bipiperidin]-r-yl)phenyl)- piperidine-2, 6-dione B167;
3-(4-(4-(3-((4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)- amino)piperi din- l-yl)sulfonyl)propyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B168;
3-(4-(4-(3-((4-((8-cyclopentyl-6-(difluoromethyl)-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)aniino)piperidin-l-yl)sulfonyl)propyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B169;
3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(f|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2,6- dione B170;
3-(4-(4-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyi-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B171;
3-(4-((5)-2-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin- 1 -y l)piperi din- 1 -yljmethyl)- morpholino)phenyl)piperidine-2, 6-dione B172;
3-(4-((7?)-2-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-</Jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)- morpholino)phenyl)piperidine-2, 6-dione B173;
3-(4-((4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperidin-l -yl)methyl)- phenyl)piperidine-2, 6-dione B174;
3-(4-(2-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperidin-l-yl)ethyl)- phenyl)piperidine-2, 6-di one Bl 75;
3-(4-(3-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-t(|pyrimidin-2-yl)aniino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)methyl)azetidin-l-yl)- phenyl)piperidine-2, 6-dione Bl 76;
3-(4-(4-((5)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3W]pyriniidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)methyl)morpholino)piperi din-1- yl)phenyl)piperidine-2, 6-dione B177;
3-(4-(4-((/?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-t(]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)piperidin-l- yl)phenyl)piperidine-2, 6-dione B178;
3-(4-(4-(4-((4-(6-((6-acetyl-8-cyclOpentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)cyclohexyl)piperazin-l-yl)- phenyl)piperi dine-2, 6-dione Bl 79;
3-(4-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)ethyl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B180;
3-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)ethyi)phenyi)piperidine-2,6- dione B181;
3-(4-(4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d/pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B182;
3-(4-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B183;
3-(4-(3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZjpyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -yl)piperidin- 1 -yl)propoxy)phenyl)piperidine-
2, 6-dione B184;
3-(4-(r-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-^pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-[4,4'-bipiperidin]-l-yl)phenyl)- piperidine-2, 6-dione Bi 85:
3-(4-(4-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B186;
3-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2yl)amino)pyridin-3-yl)piperazin-l-yl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2,6- dione B187;
3-(4-(4-(r-(6-((6-acetyl-8-CyClOpentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7jpyrimidin-2-yl)amino)pyridin-3-yl)-[l ,4'-bipiperidin]-4-yl)piperazin-l-yl)phenyl)piperidine-
2,6-dione B188;
3-(4-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- cZ]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)cy cl ohexyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B189;
3-(4-(4-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohexyl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B190;
3-(3-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2 -yl)amino)pyridin-3-yl)piperazin-l-yl)piperi din-1 -yl)ethoxy)phenyl)piperidine-
2, 6-dione B191; 3-(3-(3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tflpyrimidin-2 -yl)amino)pyri din-3 -yl)piperazin-l-yl)piperidin-l-yl)propoxy)phenyl)piperi dine-
2, 6-dione B192;
3-(4-(4-(l-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- J]pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-
2, 6-dione B193;
3-(4-(4-(4-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-
2,6-dione B194;
3-(4-(r-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- yrimidin-2-yl)amino)pyridin-3-yl)methyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione B195;
3-(4-(4-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)methyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B196;
3-(4-(4-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J|- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)-[l,4'-bipiperidin]-T-yl)phenyl)piperidine-2, 6-dione B197;
3-(4-(4-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(7]- pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B198;
3-(4-(4-(((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)rnethyl)-[l,4'-bipiperidin]-l'-yl)phenyl)piperidine-2,6- dione B199;
3-(4-(4-(4-(2-(6-((6-acetyl-8-cyclopentyi-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)piperidine-2,6- dione B200;
3-(4-(4-(l-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2,6- di one B201;
3-(4-(r-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3 t/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2,6- dione B202;
3-(4-(4-(l-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B203;
3-(4-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-</]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperazin-l-yl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B204;
3-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)etliyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2,6- dione B205;
3-(4-(r-(3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)propyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2,6-dione B206;
3-(4-(4-(l-(3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)propyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2,6- di one B207;
3-(4-(4-(4-(3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)propyl)piperazin-l-yl)piperidin-l -yl)phenyl)piperidine-2,6- dione B208;
3-(4-(4-(3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)propyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B209;
3-(3-(4-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)piperidine- 2,6-dione B210;
3-(4-(4-(((5)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-t/]pyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B211;
3-(4-(4-(((/?)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B212;
3-(3-(4-(((<S)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)aniino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l -yl)phenyl)- piperidine-2, 6-dione B213;
3-(4-(2-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2,6- dione B214;
3-(4-(2-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZjpyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine-2, 6-dione B215;
3-(4-((5)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)aniino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)phenyl)piperidine- 2,6-dione B216;
3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3 -</]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)methyl)morpholino)phenyl)piperi dine- 2,6-dione B217;
3-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B218;
3-(4-(4-(l-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperidin-3-yl)piperazin-l-yl)phenyl)piperidine- 2,6-dione B219;
3-(3-(4-(l-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- cZ]pyrimi din-2-yl)amino)pyri din-3 -yl)methyl)piperi din-3 -yl)piperazin-l-yl)phenyl)piperi dine- 2,6-dione B220;
3-(4-(4-(l-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-tZjpyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-3-yl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B221;
3-(3-(4-(l-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-3-yl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B222; 3-(3-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3 -cZ]pyrimi din-2 -yl)amino)pyri din-3 -yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B223;
3-(4-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3 -<7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B224;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B225,
3-(4-(4-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- ef|pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)methyl)piperazin-l-yl)plienyl)piperidine-2,6- di one B226;
3-(4-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- iZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B227;
3-(4-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)azetidin-l-yl)phenyl)piperidine-2,6- dione B228;
3-(4-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyriniidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)-2,7-diazaspiro[3.5]nonan-7- yl)phenyl)piperidine-2, 6-dione B229;
3-(4-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B230;
3-(4-(l-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxO"7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)aniino)pyridin-3-yl)oxy)propyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B231;
3-(3-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </]pyrimidin-2 -yl)amino)pyri din-3 -yl)oxy)propyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B232;
3-(3-(l-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3 t/]pyriniidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B233;
3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperi din- l-yl)propoxy)phenyl)piperidine-2, 6-dione B234;
3-(4-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-l-yl)phenyl)piperidine-2,6-dione B235;
3-(3-(4-(3-((6-((6-acetyl-8-cyclopentyl-5-metliyl-7-oxo-7,8-dihydropyrido[2,3- tZjpyrimidin-2-yl)amino)pyridin-3 -yl)oxy)propyl)piperi din- l-yl)phenyl)piperidine-2, 6-dione B236;
3-(4-(3-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)propoxy)phenyl)piperidine-2, 6-dione B237;
3-(4-(4-(6-((6-acetyl-8-cycIopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-£Zj- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B238;
3-(4-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione B239;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B240;
3-(4-(r-(6-((6-aCetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-dF]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2, 6-dione B241;
3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t(]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B242;
3-(3-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione B243;
3-(3-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-60- pyrimidin-2-yl)amino)pyridin-3 -yl)piperidin-4-yl)piperazin- 1 -yl)phenyl)piperidine-2, 6-dione B244;
3-(3-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|" pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2, 6-dione B245;
3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-niethyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B246;
3-(4-(4-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)piperidine- 2,6-dione B247;
3-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- di one B248;
3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B249;
3-(3-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B250;
3-(3-(4-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-l-yl)phenyl)piperidine-2,6- di one B251;
3-(4-(l'-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yI)methyl)-[l ,4'-bipiperidin]-4-yl)phenyl)piperidine-2, 6-dione B252;
3-(4-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tf|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B253;
3-(4-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B254;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperazin-l -yl)phenyl)piperidine-2,6- dione B255;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B256;
3-(3-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- di one B257;
3-(3-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- di one B258;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperazin-l-yl)phenyl)piperidine-2,6- dione B259;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyi-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)ethyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B260;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2 -yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)phenyl)piperidine-2,6- di one B261;
3-(4-(2-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)ethyl)phenyl)piperidine-2, 6-dione B262;
3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)ethyl)phenyl)piperidine-2, 6-dione B263;
3-(3-(4-(4-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- cZ]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperazin-l-yl)piperidin-l-yi)phenyl)piperidine-2,6- dione B264;
3-(3-(4-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)-[l,4'-bipiperidin]-r-yl)phenyl)piperidine-2, 6-dione B265;
3-(3-(4-(((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)methyl)-[l,4'-bipiperidin]-l'-yl)phenyl)piperidine-2,6- dione B266; 3-(3-(r-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)-[4,4'-bipiperidin]-l-yl)phenyl)piperidine-2, 6-dione B267;
3-(3-(4-(l-(2-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7jpyrimidin-2-yl)amino)pyridin-3-yl)ethyl)piperidin-4-yl)piperazin-l -yl)phenyl)piperidine-2,6- dione B268;
3-(3-(4-(l-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-4-yl)piperazin-l-yi)phenyl)- piperidine-2, 6-dione B269;
3-(3-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3 -</]pyrimidin-2-yl)amino)pyri din-3 -yl)oxy)ethyl)piperazin-l-yl)piperi din- l-yl)phenyl)- piperidine-2, 6-dione B270;
3-(4-(r-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
Jjpyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)-[l,4'-bipiperidin]-4-yl)phenyl)piperidine-2,6- dione B271;
3-(4-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperidin-l -yl)phenyl)piperidine-2,6- dione B272;
(S)-3-(4-(4-(((S)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-<7]pyriniidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)niethyl)piperazin-l-yl)phenyl)- 3-methylpiperidine-2, 6-dione B273;
3-(4-(l-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- Jjpyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B274;
3-(4-((r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yi)-[l ,4'-bipiperidin]-4-yi)niethyl)phenyl)piperidine-2!6-dione B275;
3-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B276;
3-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyi)piperidin-l-yl)phenyl)piperidine-2, 6-dione B277; 3-(4-(2-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine- 2,6-dione B278;
3-(3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)azetidin-l-yl)phenyl)piperidine-2,6- dione B279;
3-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin- l-yl)piperidin- 1 -yl)- 1 , 1 -difluoroethyl)phenyl)- piperidine-2, 6-dione B280;
3-(3-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin- 1 -y l)piperi din- 1 -yl)- 1 , 1 -difluoroethyl)phenyl)- piperidine-2, 6-dione B281;
3-(4-(2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)-l, l-difluoroethyl)phenyl)- piperidine-2, 6-dione B282;
3-(3-(2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tf|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)-l,l-difluoroethyl)phenyl)- piperidine-2, 6-dione B283;
3-(4-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)methyl)phenyl)piperidine-2,6- di one B284;
3-(3-((3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidin-l-yl)methyl)phenyl)piperidine-2,6- dione B285;
3-(3-(2-(l'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)phenyl)piperidine- 2,6-dione B286;
3-(4-((r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-tf|- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine- 2,6-dione B287;
3-(3-((r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l ,4'-bipiperidin]-4-yl)methyl)phenyl)piperidine- 2,6-dione B288;
3-(4-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- </]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazeti din-3 -yl)ethyl)phenyl)- piperidine-2, 6-dione B289;
3-(3-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)- piperidine-2, 6-dione B290;
3-(4-((l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyriniidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)methyl)phenyl)- piperidine-2, 6-dione B291;
3-(3-((l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7Jpyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazeti din-3 -yl)methyl)phenyl)- piperidine-2, 6-dione B292;
3-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyriniidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)azetidin-3-yl)phenyl)- piperidine-2, 6-dione B293;
3-(3-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)azetidin-3-yl)phenyl)- piperidine-2, 6-dione B294;
3-(4-(2-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tflpyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2,6- dione B295;
3-(3-(2-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyriniidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)ethyl)phenyl)piperidine-2,6- dione B296;
3-(4-((4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)methyl)phenyl)piperidine-2,6- di one B297;
3-(3-((4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)methyl)phenyl)piperidine-2,6- dione B298;
3-(3-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperidin-4-yl)ethyl)phenyl)piperidine-2,6- dione B299;
3-(3-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)-4-fluoropiperidin-4-yl)ethyl)phenyl)- piperidine-2, 6-dione B300;
3-(3-(8-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t(jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-3-azabicyclo[3.2.1]octan-3-yl)- phenyl)piperidine-2, 6-dione B301;
3-(3-(3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-8-azabicyclo[3.2.1]octan-8-yl)- phenyl)piperidine-2, 6-dione B302;
3-(3-(4-((3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
J]pyrimidin-2-yl)amino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B303;
3-(3-(4-((8-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- Jjpyrimidin-2-yl)amino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)piperidin-l-yl)- phenyl)piperidine-2, 6-dione B304;
3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B305;
3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- cZ]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-l-yl)methyl)-4-fluoropiperi din- l-yl)phenyl)- piperidine-2, 6-dione B306;
(5)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)-3-methyl- piperidine-2, 6-dione B307;
(7?)-3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)ethyl)piperidin-l-yl)phenyl)-3-methyl- piperidine-2, 6-dione B308; -3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2, 3 -t/]pyrimi din-2 -yl)amino)pyri din-3 -yl)piperidin-4-yl)piperazin-l-yl)phenyl)-3 -methyl- piperidine-2, 6-dione B309;
(7?)-3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)-3-methyl- piperidine-2, 6-dione B310;
3-(4-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)phenyl)- piperidine-2, 6-dione B311;
3-(3-(l-((l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)phenyl)- piperidine-2, 6-dione B312;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3 -yl)piperidin-4-yl)piperazin- 1 -yl)-2-fluorophenyl)piperi dine-2,6- dione B313;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)arnino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3-fluorophenyl)piperidine-2,6- dione B314;
3-(4-(4-( l-(6-((6-acetyl-8-cyclOpentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-chlorophenyl)piperidine-2,6- dione B315;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3-chlorophenyl)piperidine-2,6- di one B316;
3-(4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimi din-2-yl)amino)pyri din-3 -yi)pi perazin- 1 -yl)azeti din- 1 -yl)phenyl)piperidine-2, 6-di one B317;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-5-fluorophenyl)- piperidine-2, 6-di one B318;
3-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l -yl)-2-fluorophenyl)- piperidine-2, 6-dione B319;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7]pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 -y 1 )ethy l)pi p eri di n- 1 -yl)-3 -fluorophenyl)- piperidine-2, 6-dione B320;
3-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-] -yl)ethyl)piperidin-l-yl)-2-fluorophenyl)- piperidine-2, 6-dione B321;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyriniidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l -yl)-2-fluorophenyl)- piperidine-2, 6-dione B322;
3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B323;
3-(4-(4-(4-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3 -</|pyrimidin-2-yl)amino)pyri din-3 -yl)oxy)ethyl)piperazin-l-yl)piperi din- l-yl)phenyl)- piperidine-2, 6-dione B324;
3-(4-(2-((4-((6-(difluoromethyl)-8-((17x’,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-J]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethoxy)phenyl)- piperidine-2, 6-dione B351;
3-(4-(4-(((4-((6-(difluoromethyl)-8-((l/?,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)methyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione B352;
3-(3-(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethoxy)phenyl)- piperidine-2, 6-dione B353;
3-(4-(4-(((4-((6-(difluoromethyl)-8-((l/7,27?)-2-hydroxy-2-methylcyciopentyl)-7- oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)methyl)-[l,4'- bipiperi din]- l'-yl)phenyl)piperidine-2, 6-dione B354;
3-(4-(4-(l-(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B355;
3-(4-((4-(3-((4-((6-(difluoromethyl)-8-((lJ?,22?)-2-hydroxy-2-methylcyclopentyl)-
7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperazin- l-yl)methyl)phenyl)piperidine-2, 6-dione B356;
3-(4-(4-((4-(3-((4-((6-(difluoromethyl)-8-((l/?,2/?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B357;
4-(3-(4-((4-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-r/]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l -yl)methyl)piperidin-l -yl)phenyl)piperidine-2, 6-dione B358;
3-(4-(2-(4-((4-((6-(difluoromethyl)-8-((l/^2JR)-2-hydroxy-2-methylcyclopentyi)-
7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)piperazin-l-yl)- ethyl)phenyl)piperidine-2, 6-dione B359;
3-(4-(4-(4-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin- 1 -yl)sulfonyl)piperazin- 1 -yl)- piperi din- l-yl)phenyl)piperidine-2, 6-dione B360;
3-(3-((l -(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)aniino)piperidin-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)-3-methylpiperidine-2, 6-dione B361 ;
3-(4-((l-(3-((4-((6-(difluoroniethyl)-8-((l/7,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)-3-methylpiperidine-2, 6-dione B362;
3-(3-(4-((3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- cZ]pyrimi din-2-yl)amino)pyri din-3 -yl)azeti din- 1 -yl)methyl)-4-fluoropiperi din- 1 -yl)phenyl)- piperidine-2, 6-dione B363;
3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B364;
3-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)ethyl)piperidin-l-yl)-4-fluorophenyl)- piperidine-2, 6-dione B365; 3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-l-yl)methyl)-4-fluoropiperi din- l-yl)phenyl)-3- methylpiperidine-2, 6-dione B366;
(5)-3-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)-4-fluoropiperidin-l-yl)phenyl)- 3 -methylpiperidine-2, 6-dione B367;
(5)-3-(4-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)-3- methylpiperidine-2, 6-dione B368;
(7?)-3-(4-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-cZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)phenyl)-3- methylpiperidine-2, 6-dione B369;
3-(4-(7-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-4,7-diazaspiro[2.5]octan-4-yl)phenyl)- piperidine-2, 6-dione B370; -3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-</|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B371;
(S)-3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-<7]pyriniidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B372;
(7?)-3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B373;
(5)-3-(4-((/^)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)morpholino)phenyl)-3- methylpiperidine-2, 6-dione B374;
(7?)-3-(4-(4-(((lS)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-<7]pyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)methyl)piperazin-l-yl)phenyl)- 3 -methylpiperidine-2, 6-dione B375; l-(4-((l-(3-((4-((6-(difluoro-methyl)-8-((lJR,27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-t7]pyrimidin-2-yl)amino)piperidin-l -yl)sulfonyl)propyl)- piperidin-4-yl)oxy)phenyl)dihydropyrimidine-2, 4(177, 377)-dione B401; l-(4-(4-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)phenyl)dihydropyrimidine-2, 4(177, 377)-dione B402; l-(2-chloro-4-(4-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- propyl)piperazin-l-yl)phenyl)dihydropyrimidine-2, 4(177, 377)-dione B403; l-(4-(4-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-«7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)-2-fluorophenyl)dihydropyrimidine-2, 4(177, 377)-dione B404; l-(4-(4-(3-((4-((6-(difluoromethyl)-8-((177,27?)-2-hydroxy-2-methylcyclopentyl)-
7-oxO"7,8-dihydropyrido[2,3-t7]pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)piperazin- l-yl)-2-methylphenyl)dihydropyrimidine-2, 4(177, 37/)-dione B405; l-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B406; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-€f|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)phenyl)dihydropyrimidine- 2,4(177,377)-dione B407; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluorophenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B408; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyi-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-chlorophenyl)dihydro- pyrimidine-2, 4(177, 37/)-dione B409; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-(trifluoromethyl)phenyi)- dihydropyrimidine-2, 4(177, 377)-dione B410; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yi)piperazin-l-yl)-2-methylphenyl)dihydro- pyrimidine-2, 4(177, 377)-di one B411 ; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2,3-dimethylphenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B412; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2 -yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2,4-dimethylphenyl)- dihydropyrimidine-2,4( 177,377)-dione B413; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7|pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-chl oro-3 -methyl- phenyl)dihydropyrimidine-2,4(177,377)-dione B414; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyi-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-5-chloro-2-methyl- phenyl)dihydropyrimidine-2, 4(177, 377)-dione B415; l-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperazin-l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B416; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-chloro-5-methylphenyl)- dihydropyrimidine-2, 4(177, 37/)-dione B451; l-(4-(4-(l-(6-((6-aCetyl-8-cyClOpentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluoro-3-methylphenyl)- dihydropyrimidine-2,4(177,377)-dione B452; l-(4-(4-(l-
Figure imgf000758_0001
6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-z7|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-fluoro-5-methylphenyl)- dihydropyrimidine-2,4(177,377)-dione B453; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-2-chloro-6-methylphenyl)- dihydropyrimidine-2, 4(177, 37/)-dione B454; l-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-3-fluoro-2-methylphenyl)- dihydropyrimidine-2,4(177,377)-dione B455; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B456; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7jpyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2-chlorophenyl)- dihydropyrimidine-2,4(177,377)-dione B457; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-chlorophenyl)- dihydropyrimidine-2,4(177,377)-dione B458; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-fluorophenyl)- dihydropyrimidine-2,4( 177,377)-dione B459; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-fluorophenyl)- dihydropyrimidine-2,4(177,377)-dione B460; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-methylphenyl)- dihydropyrimidine-2, 4(177, 3//)-dione B461; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2-methylphenyl)- dihydropyrimidine-2,4( 177,377)-dione B462; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
<7jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-chloro-6-methyl- phenyl)dihydropyrimidine-2,4(177,377)-dione B463; l-(5-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-<)xo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-4-chloro-2-methyl- phenyl)dihydropyrimidine-2,4(177,377)-dione B464; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-
^pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)ethyl)piperi din- l-yl)-2-chloro-4-methyl- phenyl)dihy dropyrimidine-2,4( 177,377)-dione B465; l-(3-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-4-chloro-2-methyl- phenyl)dihydropyrimidine-2,4( 177,377)-dione B466; l-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-2-chlorophenyl)- dihydropyrimidine-2,4(177,377)-dione B467; l-(4-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)ethyl)piperazin-l-yl)-2-chlorophenyl)- dihydropyrimidine-2, 4(177, 377)-dione B468; l-(4-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyriniidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l -yl)phenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B469; l-(3-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B470, l-(3-(4-((3-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t7|pyrimidin-2-yl)amino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)piperidin-l-yl)- phenyl)dihydropyrimidine-2, 4(177, 377)-dione B471; l-(4-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-2-chloro- phenyl)dihydropyrimidine-2,4( 17/,377)-dione B472;
3-(6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t7|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethoxy)-l-methyl-177-indazol-3-yl)- piperidine-2, 6-dione B501;
3-(7-(2-(4-(3-((4-((6-(difluoro-methyl)-8-((lJ?,25)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-</|pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)propyl)- piperazin- 1 -yl)-2-oxoethoxy)- 1 -methyl- 177-indazol-3-yl)piperidine-2, 6-dione B502;
3-(6-(4-(l-(6-((6-acetyl-8-cyclo-pentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7j- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-177-indazol-3-yl)- piperidine-2, 6-dione B503;
3-(6-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l-methyl-177- indazol -3 -y l)piperi dine-2, 6-dione B504;
3-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-6/j- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-lJ7-indazol-3-yl)-3- methylpiperidine-2, 6-dione B505;
3-(7-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-y!)ethyl)-l-methyl-l//- indazol-3-yl)piperi dine-2, 6-dione B506;
3-(6-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l-yl)-l-methyl-l//-indazol-3-yl)- piperidine-2, 6-dione B507;
3-(6-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l-yl)-l-methyl-l//-indazol- 3 -yl)piperi dine-2, 6-dione B508;
(5)-3-(6-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2, 3 -</]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)ethyl)piperazin-l-yl)-l -methyl- 1/7- indazol-3-yl)-3 -methylpiperidine-2, 6-dione B509;
(7?)-3-(6-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3 -</jpyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-l-yl)-l -methyl- 1/7- indazol-3-yl)-3-methylpiperidine-2, 6-dione B510;
3-(6-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-l-methyl-l//-indazol- 3 -yl)piperi dine-2, 6-dione B511; l-(7-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]-pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin- 1 -y l)ethy Ijpiperidin- 1 -yl)- 1 -methyl- 1/f-indazol- 3-yl)dihydropyrimidine-2,4(17/,3//)-dione B551, l-(6-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)piperidin-l-yl)-l -methyl- 1/f-indazol- 3 -yl)dihydropyrimi dine-2, 4(1/7, 3//)-dione B552; l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7|- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-l/7-indazol-3-yl)- dihydropyrimidine-2,4(l/7,3/7)-dione B553; l-(6-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t7J- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-l-methyl-177-indazol-3-yl)- dihydropyrimidine-2, 4(177, 377)-dione B554; l-(6-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-fluoro-l-methyl-177-indazol- 3-yl)dihydropyrimidine-2, 4(177, 377)-dione B555; l-(6-(4-(] -(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-7-fluoro-l-methyl-177-indazol- 3-yl)dihydropyrimidine-2, 4(177, 377)-dione B556; l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-t7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-fluoro-l-methyl-177-indazol- 3-yl)dihydropyrimidine-2, 4(177, 377)-dione B557; l-(6-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-chloro-l-methyl-177-indazol- 3-yl)dihydropyrimidine-2, 4(177, 377)-dione B558; l-(6-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-7-chloro-l-methyl-l/7-indazol- 3-yl)dihydropyrimidine-2, 4(177, 377)-dione B559; l-(7-(4-( l-(6-((6-acetyl-8-cycloperityl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-(7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l-yl)-5-chloro-l-methyl-177-indazol- 3-yl)dihydropyrimidine-2, 4(177, 377)-dione B560,
(LS)-l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2,3 -<7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)-2-methy Ipiperazin- 1 -yl)- 1 -methyl- 177- indazol-3-yl)dihydropyrimidine-2,4(177,377)-dione B561;
(77)-l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-2-methylpiperazin-l-yl)-l-methyl-177- indazol-3-yl)dihydropyrimidine-2,4( l//,377)-dione B562;
(7?)-l -(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido-
[2, 3 -<7]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)-3-methylpiperazin-l-yl)-l -methyl- 177- indazol-3-yl)dihydropyrimidine-2, 4(177, 37/)-dione B563; l-(6-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l-methyl-l/7- indazol-3-yl)dihydropyrimidine-2,4(l//,3//)-dione B564; l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)piperazin-l-yl)-6-chl oro-1 -methyl- l//-indazol- 3-yl)dihydropyrimidine-2, 4(177, 3J7)-dione B566; l-(7-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3 -y l)piperidin - l-yl)methyl)-4-fluoropiperidin- 1 -yl)- 1 -methyl- l//-indazol-3-yl)dihydropyrimidine-2,4(l/7,377)-dione B567;
(5)-l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-methylpiperazin-l-yl)-l-methy{-l/7- indazol-3-yl)dihydropyrimidine-2,4(l/7,3Z7)-dione B568; l-(7-(2-(l-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluoroazetidin-3-yl)ethyl)-l-methyl-177- indazol-3-yl)dihydropyrimidine-2,4( 177,377)-di one B569; l-(6-(2-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- r/|pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidin]-4-yl)ethyl)-l-methyl-177- indazol-3-yl)dihydropyrimidine-2, 4(177, 3//)-dione B570; l-(7-(2-(l'-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l ,4'-bipiperidin]-4-yl)ethyl)-l-methyl-l/7- indazol-3-yl)dihydropyrimidine-2,4(177,3/7)-dione B571; l-(7-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)piperazin-l-yl)-4-chl oro-1 -methyl- 1/7-indazol- 3-yl)dihydropyrimidine-2, 4(177, 377)-dione B572; l-(6-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)ethyl)piperazin- 1 -yl)- 1 -methyl- 1/7-indazol- 3-yl)dihydropyrimidine-2, 4(177, 377)-dione B573, l-(6-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin- 1 -yl)ethyl)piperidin- 1 -yl)-l -methyl- 177-indazol- 3-yl)dihydropyrimidine-2, 4(1/7, 377)-dione B574; l-(6-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)piperidin-l-yl)-l -methyl- 177- indazol-3-yl)dihydropyrimidine-2, 4(177, 3/7)-dione B575;
3-(5-(l-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethyl)piperidin-4-yl)-6-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione B601;
3-(4-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethyl)amino)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B602;
4-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperi din-3 - yl)isoindoline-l, 3-dione B603; or
3-(5-(l-(4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido- [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethoxy)benzyl)piperidin-4-yl)-l-oxo- isoindolin-2-yl)piperidine-2, 6-dione B604; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
170. A pharmaceutical composition comprising the compound of any one of claims 1 to 169, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable excipient.
171. The pharmaceutical composition of claim 170, wherein the composition is in single dosage form.
172. The pharmaceutical composition of claim 170 or 171, wherein the composition is in an oral, parenteral, or intravenous dosage form.
173. The pharmaceutical composition of any one of claims 170 to 172, wherein the composition is formulated in an oral dosage form.
174. The pharmaceutical composition of claim 173, wherein the oral dosage form is a tablet or capsule.
175. A method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a CDK in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 169 or a pharmaceutical composition of any one of claims 170 to 174.
176. The method of claim 175, wherein the disorder, disease, or condition mediated by the CDK is mediated by CDK2, CDK4, and/or CDK6.
177. The method of claim 175 or 176, wherein the disorder, disease, or condition mediated by the CDK is a proliferative disease.
178. A method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 169 or a pharmaceutical composition of any one of claims 170 to 174.
179. The method of claim 177 or 178, wherein the proliferative disease is cancer.
180. The method of any one of claims 175 to 179, wherein the subject is a human.
181 . A method of inhibiting the growth of a cell, comprising contacting the cell with an effective amount of a compound of any one of claims 1 to 169 or a pharmaceutical composition of any one of claims 170 to 174.
182. The method of claim 181 , wherein the cell is a cancerous cell.
183. A method of inducing degradation of a CDK, comprising contacting the CDK with an effective amount of a compound of any one of claims 1 to 169 or a pharmaceutical composition of any one of claims 170 to 174
184. The method of claim 183, wherein the CDK is CDK2, CDK4, and/or CDK6.
PCT/US2023/066834 2022-05-10 2023-05-10 Cdk protein degraders, pharmaceutical compositions, and therapeutic applications WO2023220640A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202263364470P 2022-05-10 2022-05-10
US63/364,470 2022-05-10
US202263378671P 2022-10-06 2022-10-06
US63/378,671 2022-10-06
US202363496380P 2023-04-14 2023-04-14
US63/496,380 2023-04-14

Publications (1)

Publication Number Publication Date
WO2023220640A1 true WO2023220640A1 (en) 2023-11-16

Family

ID=86771433

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/066834 WO2023220640A1 (en) 2022-05-10 2023-05-10 Cdk protein degraders, pharmaceutical compositions, and therapeutic applications

Country Status (1)

Country Link
WO (1) WO2023220640A1 (en)

Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4328245A (en) 1981-02-13 1982-05-04 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4409239A (en) 1982-01-21 1983-10-11 Syntex (U.S.A.) Inc. Propylene glycol diester solutions of PGE-type compounds
US4410545A (en) 1981-02-13 1983-10-18 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US5052558A (en) 1987-12-23 1991-10-01 Entravision, Inc. Packaged pharmaceutical product
US5055252A (en) 1989-01-12 1991-10-08 Superior Walls Of America, Ltd. Method of constructing an integrated concrete wall structure
US5525907A (en) 1995-03-17 1996-06-11 Hughes Missile Systems Company Active impulse magnetometer with bipolar magnetic impulse generator and fast fourier transform receiver to detect sub-surface metallic materials
US5612059A (en) 1988-08-30 1997-03-18 Pfizer Inc. Use of asymmetric membranes in delivery devices
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5798119A (en) 1995-06-13 1998-08-25 S. C. Johnson & Son, Inc. Osmotic-delivery devices having vapor-permeable coatings
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US6350458B1 (en) 1998-02-10 2002-02-26 Generex Pharmaceuticals Incorporated Mixed micellar drug deliver system and method of preparation
WO2002017918A3 (en) 2000-08-30 2002-07-25 Pfizer Prod Inc Sustained release formulations for growth hormone secretagogues
WO2018106870A1 (en) * 2016-12-08 2018-06-14 Icahn School Of Medicine At Mount Sinai Compositions and methods for treating cdk4/6-mediated cancer
WO2022068849A1 (en) * 2020-09-30 2022-04-07 Beigene, Ltd. Bifunctional compounds for degradation of egfr and related methods of use
WO2022133285A1 (en) * 2020-12-18 2022-06-23 St. Jude Children's Research Hospital Molecules and methods related to treatmnet of disorders associated with jak-2 signaling dysfunction
WO2022235698A1 (en) * 2021-05-03 2022-11-10 Nurix Therapeutics, Inc. Compounds for inhibiting or degrading target proteins, compositions, comprising the same, methods of their making, and methods of their use
WO2022236058A1 (en) * 2021-05-07 2022-11-10 Kymera Therapeutics, Inc. Cdk2 degraders and uses thereof

Patent Citations (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4410545A (en) 1981-02-13 1983-10-18 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4328245A (en) 1981-02-13 1982-05-04 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4409239A (en) 1982-01-21 1983-10-11 Syntex (U.S.A.) Inc. Propylene glycol diester solutions of PGE-type compounds
US5052558A (en) 1987-12-23 1991-10-01 Entravision, Inc. Packaged pharmaceutical product
US5612059A (en) 1988-08-30 1997-03-18 Pfizer Inc. Use of asymmetric membranes in delivery devices
US5698220A (en) 1988-08-30 1997-12-16 Pfizer Inc. Asymmetric membranes in delivery devices
US5055252A (en) 1989-01-12 1991-10-08 Superior Walls Of America, Ltd. Method of constructing an integrated concrete wall structure
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US5525907A (en) 1995-03-17 1996-06-11 Hughes Missile Systems Company Active impulse magnetometer with bipolar magnetic impulse generator and fast fourier transform receiver to detect sub-surface metallic materials
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US5798119A (en) 1995-06-13 1998-08-25 S. C. Johnson & Son, Inc. Osmotic-delivery devices having vapor-permeable coatings
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US6350458B1 (en) 1998-02-10 2002-02-26 Generex Pharmaceuticals Incorporated Mixed micellar drug deliver system and method of preparation
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
WO2002017918A3 (en) 2000-08-30 2002-07-25 Pfizer Prod Inc Sustained release formulations for growth hormone secretagogues
WO2018106870A1 (en) * 2016-12-08 2018-06-14 Icahn School Of Medicine At Mount Sinai Compositions and methods for treating cdk4/6-mediated cancer
WO2022068849A1 (en) * 2020-09-30 2022-04-07 Beigene, Ltd. Bifunctional compounds for degradation of egfr and related methods of use
WO2022133285A1 (en) * 2020-12-18 2022-06-23 St. Jude Children's Research Hospital Molecules and methods related to treatmnet of disorders associated with jak-2 signaling dysfunction
WO2022235698A1 (en) * 2021-05-03 2022-11-10 Nurix Therapeutics, Inc. Compounds for inhibiting or degrading target proteins, compositions, comprising the same, methods of their making, and methods of their use
WO2022236058A1 (en) * 2021-05-07 2022-11-10 Kymera Therapeutics, Inc. Cdk2 degraders and uses thereof

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
"Drugs and the Pharmaceutical Sciences", 1994, CRC PRESS, article "Multiparticulate Oral Drug Delivery"
"Handbook of Pharmaceutical Additives", 2007, SYNAPSE INFORMATION RESOURCES
"Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2011, JOHN WILEY & SONS
"Modified-Release Drug Delivery Technology", vol. 184, 2008, CRC PRESS
"Pharmaceutical Palletization Technology", 1989, CRC PRESS
"Pharmaceutical Preformulation and Formulation", 2009, CRC PRESS
"Remington: The Science and Practice of Pharmacy", 2020, PHARMACEUTICAL PRESS
ALVAREZ-FERNANDEZMALUMBRES, CANCER CELL, vol. 37, 2020, pages 514 - 29
BERGE ET AL., .L. PHARM. SCI, vol. 66, 1977, pages 1 - 19
DING ET AL., INT. J. MOL. SCI, vol. 21, 2020, pages 1960
MALUMBRES ET AL., CELL BIOL., vol. 11, 2009, pages 1275 - 6
MALUMBRES ET AL., NAT. CELL BIOL., vol. 11, 2009, pages 1275 - 6
MALUMBRESBARBACID, NAT. REV. CANCER, vol. 9, pages 153 - 66
OGATA ET AL., BREAST CANCER, vol. 28, 2021, pages 206 - 15
OTTOSICINSKI, NAL. REV. CANCER, vol. 77, 2017, pages 93 - 115
SANCHEZ-MARTINEZ ET AL., BIOORG. MED. CHEM. LETT, vol. 29, 2019, pages 126637
SANTUSBAKER, J. CONTROLLED RELEASE, vol. 35, 1995, pages 1 - 21
TAKADA ET AL.: "Encyclopedia of Controlled Drug Delivery", vol. 2, 1999, WILEY
TOPACIO ET AL., MOL. CELL, vol. 7-I, 2019, pages 758 - 70
UZBEKOVPRIGENT, CELLS, vol. 11, 2020, pages 704
VERMA ET AL., DRUG DEV. IND PHARM, vol. 26, 2000, pages 695 - 708
VERMA ET AL., J. CONTROLLED RELEASE, vol. 79, 2002, pages 7 - 27
ZHANG ET AL., AM. J. CANCER RES, vol. 11, 2021, pages 1913 - 35

Similar Documents

Publication Publication Date Title
US11939314B2 (en) Quinolin-2-one derivatives
EP3071570B1 (en) 2,6-substituted purine derivatives and their use in the treatment of proliferative disorders
TWI827641B (en) Tlr7/8 antagonists and uses thereof
KR20180021702A (en) TBK / IKK? Inhibitor compounds and uses thereof
JP7266592B2 (en) Pyrimidine TBK/IKKε inhibitor compounds and their uses
CA3129601A1 (en) Indazolyl-isoxazole derivatives for the treatment of diseases such as cancer
WO2023220640A1 (en) Cdk protein degraders, pharmaceutical compositions, and therapeutic applications
CA3148227A1 (en) 4-(imidazo[1,2-a]pyridin-3-yl)-pyrimidine derivatives
JP7284161B2 (en) Pyrimidine TBK/IKKε inhibitor compounds and their uses
CA3176957A1 (en) Aminopyrimidine derivatives and their use as aryl hydrocarbon receptor modulators
OA17768A (en) 2,6-Substituted purine derivatives and their use in the treatment of proliferative disorders

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23731061

Country of ref document: EP

Kind code of ref document: A1