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): 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 , -OC(O)SR ^la , -OC(NR ^la )NR ^lb R ^lc , -OC(S)R ^la , -OC(S)OR ^la , -OC(S)NR ^lb R ^lc , -OS(O)R ^la , -OS(O) ₂ R ^ia , -OS(O)NR ^lb R ^k , -OS(O) ₂ NR ^lb R ^k , -NR ^lb R ^k , -NR ^la C(O)R ^ld , ~NR ^la C(O)OR ^ld , -NR ^la C(O)NR ^lb R ^le , -NR ^la C(O)SR ^ld , -NR ^la C(NR ^ld )NR ^lb R ^lc , -NR ^la C(S)R ^ld , -NR ^la C(S)OR ^ld , -NR ^la C(S)NR ^lb R ^lc , -NR ^la S(O)R ^ld , -NR ^!a S(O)2R ^ld , -NR ^la S(O)NR ^lb R ^lc , -NR ^la S(O) ₂ NR ^lb R ^k -SR ^la , -S(O)R ^la , -S(O) ₂ R ^la , -S(O)NR ^lb R ^k , or -S(O) ₂ NR ^lb R ^k ;

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, 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 )-;

Z is -CH2- or --C(O)-; one of Z ¹ , Z ² , Z ³ , and Z ⁴ is -C= and the remaining three of Z ¹ , Z ² , Z ³ , and Z ⁴ are each independently -C(R ^E4a )=; or Z ^! is a bond; one of Z ² , Z ³ , and Z ⁴ is C=, and the remaining two of Z ² , Z ³ , and Z ⁴ are each independently -C(R ^E4a )= or -S-; 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; (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 ^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(O)SR ^la , -OC(NR ^la )NR ^lb R ^lc , -OC(S)R ^la ,

OC(S)OR ^la , -OC(S)NR ^lb R ^lc , -OS(O)R ^la , -OS(O)2R ^la , -OS(O)NR ^lb R ^lc , -OS(O) ₂ NR ^lb R ^ic , -NR ^ib R ^lc , -NR ^la C(O)R ^ld , -NR ^la C(O)OR ^ld , -NR ^la C(O)NR ^lb R ^lc , -NR ^la C(O)SR ^ld , -NR ^la C(NR ^ld )NR ^lb R ^lc , -NR ^la C(S)R ^ld , -NR ^la C(S)OR ^ld , ■~NR ^la C(S)NR ^lb R ^lc , -NR ^la S(O)R ^ld , -NR ^la S(O) ₂ R ^ld , -NR ^la S(O)NR ^lb R ^lc ,

-NR ^la S(O) ₂ NR ^lb R ^lc , -SR ^la , -S(O)R ^la , -S(O) ₂ R ^la , -S(O)NR ^lb R ^lc , or -S(O) ₂ NR ^lb R ^lc ; each R ^E4a is independently hydrogen or R ^E4 ; 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 R ^ia , R ^lb , R ^lc , and R ^ld 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 Q ^a ; and (c) -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(O)SR ^a , -C(NR ^a )NR ^b R ^c , -C(S)R ^a , -C(S)OR ^a , -C(S)NR ^b R ^c , OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(O)SR ^a , -OC(NR ^a )NR ^b R ^c , -OC(S)R ^a , -OC(S)OR ^a , -OC(S)NR ^b R ^c , OP(O)(OR ^b )OR ^c , OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(O)SR ^d , -NR ^a C(NR ^d )NR ^b R ^c , -NR ^a C(S)R ^d , -NR ^a C(S)OR ^d , -NR ^a C(S)NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c , and ~S(O) ₂ NR ^b R ^c , wherein each R ^a , R ^b , R ^c , and R ^d 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 Q ^a ; or (iii) R ^b and R ^c 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 Q ^a ; wherein each Q ^a 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)R ^e , -C(O)OR ^e , -C(O)NR ^f R ^g , -C(O)SR ^e , -C(NR ^e )NR ^f R ^g , -C(S)R ^e , -C(S)OR ^e , -C(S)NR ^f R ^g , -0R ^e , -OC(O)R ^e , -OC(O)OR ^e , -OC(O)NR ^f R ^s , -OC(O)SR ^e , -OC(NR ^e )NR ^f R ^s , -OC(S)R ^e , -OC(S)OR ^e , -OC(S)NR ^f R ⁸ , -OP(O)(OR ^f )OR ^g , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ⁸ , -NR ^f R ^g , -NR ^e C(O)R ^h , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^f R ^g , -NR ^e C(O)SR ^f , ~NR ^e C(NR ^h )NR ^f R ^g , -NR ^e C(S)R ^h , -NR ^e C(S)OR ^f , -NR ^e C(S)NR ⁱ R ^g , -NR ^e S(O)R ^h , ~NR ^e S(O) ₂ R ^h , ~NR ^e S(O)NR ^f R ^g -NR ^e S(O) ₂ NR ^f R ^g , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^f R ^g , and -S(O) ₂ NR ^f R ^g ; wherein each R ^e , R ^f , R ^g , and R ^h 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) R ^f and R ^g 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 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)(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)-.

[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, -CH ₂ NHC(O)CH ₃ and -NHC(O)CH ₂ CH ₃ .

[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,

-(CH ₂ )7O-, ~(CH ₂ ) ₈ O--, -(CH ₂ )9O-, ~(CH ₂ )IOO-, -CH2OCH2-, -CIECIEO-, -(CH ₂ CH ₂ O) ₂ -

(CH2CH ₂ O)3 --(CH ₂ CH ₂ O) ₄ --, (CH ₂ CH ₂ O) ₅ -CH2NH -CH2NHCH2-, CH ₂ CH ₂ NH

- CH ₂ CH ₂ CH ₂ NH- -(CH ₂ ) ₄ NH- -CH ₂ S- -CH2SCH2-, and -CH ₂ CH ₂ S- Examples of 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)CH2.O(CH ₂ CH2O) ₄ , -C(O)CH ₂ O(CH ₂ CH ₂ O)5- -CH ₂ NHC(O)CH ₂ -, -CH ₂ CH ₂ C(O)NH-, -CH ₂ N(CH ₃ )-, -(CH2) ₂ N(CH ₃ )-, -(CH ₂ )3N(CH ₃ )-, or ~(CH ₂ ) ₄ N(CH ₃ )-.

[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 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 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=CHSCH ₂ - -CH-CHCH2S-, or -CH=CHCH ₂ NH-.

[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 (-CH ₂ C=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, 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. 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 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 Q ^a ; and (c) -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(O)SR ^a , -C(NR ^a )NR ^b R ^c , -C(S)R ^a , -C(S)OR ^a , -C(S)NR ^b R ^c , -OR ^a , OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(O)SR ^a , -OC(NR ^a )NR ^b R ^c , -OC(S)R ^a , -OC(S)OR ^a , -OC(S)NR ^b R ^c , -OP(O)(OR ^b )OR ^c , -OS(O)R ^a , ~OS(O) ₂ .R ^a , -OS(O)NR ^b R ^c , ~OS(O) ₂ NR ^b R ^c , ~NR ^b R ^c , -NR ^a C(0)R ^d , -NR ^a C(0)0R ^d , ~NR ^a C(0)NR ^b R ^c , -NR ^a C(O)SR ^d , -NR ^a C(NR ^d )NR ^b R ^c , -NR ^a C(S)R ^d , --NR ^a C(S)OR ^d , -NR ^a C(S)NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , S(O)NR ^b R ^c , and ---S(O) ₂ NR ^b R ^c , wherein each R ^a , R ^b , R ^c , and R ^d is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C ₂ -6 alkenyl, C ₂ -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 Q ^a ; or (iii) R ^b and R ^c 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 Q ^a . As used herein, all groups that can be substituted are “optionally substituted.”

[0044] In one embodiment, 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 ^g , -OC(O)SR ^e , ~OC(NR ^e )NR ^f R ^g , ~OC(S)R ^e , -OC(S)OR ^e , -OC(S)NR ^f R ^g , -OP(O)(OR ^f )OR ^g , -OS(O)R ^e , ~OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(O)R ^h , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^f R ^g , -NR ^e C(O)SR ^f , -NR ^e C(NR ^h )NR ^f R ^g , -NR ^e C(S)R ^h , -NR ^e C(S)OR ^f , -NR ^e C(S)NR ^f R ^g , -NR ^e S(O)R ^h , -NR ^e S(O) ₂ R ^h , -NR ^e S(O)NR ^f R ^g , -NR ^e S(O) ₂ NR ^f R ^s , -SR ^e , -S(O)R ^e , -S(O)2R ^e , -S(O)NR ^f R ^g , and -S(O) ₂ NR ^t R ^g ; wherein each R ^e , R ^f , R ⁸ , and R ^h is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R ¹ and R ⁸ 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 ( 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 ( ^{! 7} O), oxygen-18 ( ¹⁸ O), fluorine-17 ( ^b 'F), fluorine-18 ( ¹⁸ F), phosphorus-31 ( ³¹ P), phosphorus-32 ( ³² P), phosphorus-33 ( ³³ P), sulfur-32 ( ³² S), sulfur-33 ( ³³ S), sulfur-34 ( ³⁴ S), sulfur-35 ( ³⁵ S), sulfur-36 ( ^3o S), chlorine-35 ( ^j5 Cl), chlorine-36 ( ^3o Cl), chlorine-37 ( ³⁷ C1), bromine-79 ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br), iodine-123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), iodine-127 ( ¹²⁷ I), iodine-129 ( ¹²⁹ I), and iodine-131 ( ¹³¹ I). 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 ( 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). 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 ( 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). It will be understood that, in a compound as provided herein, 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.

[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, ³ H 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 ( 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%.

[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 ( 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%.

[0053] The term “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. 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): or an enantiomer, a mixture of 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(O)SR ^la , ~OC(NR ^la )NR ^lb R ^lc , -OC(S)R ^la , -OC(S)OR ^la , -OC(S)NR ^lb R ^lc , -OS(O)R ^la , -OS(O) ₂ R ^ia , -OS(O)NR ^lb R ^lc , -OS(O) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(O)R ^ld , -NR ^la C(O)OR ^ld , -NR ^la C(O)NR ^lb R ^lc , -NR ^la C(O)SR ^ld , -NR ^la C(NR ^ld )NR ^lb R ^lc , -NR ^la C(S)R ^ld , -NR ^la C(S)OR ^ld , -NR ^la C(S)NR ^lb R ^lc , -NR ^la S(O)R ^ld , -NR ^la S(0)2R ^ld , -NR ^la S(O)NR ^lb R ^lc , -NR ^la S(O) ₂ NR ^lb R ^lc , -SR ^la , -S(O)R ^la , -S(O) ₂ R ^la , -S(O)NR ^lb R ^lc , or -S(O) ₂ NR ^lb R ^lc ;

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 )-;

Z is -CH2- or -C(0)-; one of Z ¹ , Z ² , Z ³ , and Z ⁴ is ~C= and the remaining three of Z ^l , Z ² , Z ³ , and Z ⁴ are each independently -C(R ^E4a ) ^::: ; or Z ¹ is a bond; one of Z ² , Z ³ , and the remaining two of Z ² , Z ³ , and Z ⁴ are each independently -C(R ^E4a )= or -S-; 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; (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)R ^la , -C(0)0R ^la , -C(0)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 , -0R ^la , -0C(0)R ^la , -0C(0)0R ^la , -0C(0)NR ^lb R ^lc , -OC(O)SR ^la , ~0C(NR ^la )NR ^ib R ^lc , -OC(S)R ^ia , -OC(S)OR ^la , -0C(S)NR ^lb R ^lc , -OS(O)R ^la , -OS(O) ₂ R ^la , -0S(0)NR ^lb R ^lc , -0S(0) ₂ NR ^lb R ^lc , -NR ^ib R ^lc , ~NR ^la C(0)R ^ld , -NR ^la C(0)0R ^ld , -NR ^la C(0)NR ^lb R ^lc , ~NR ^la C(0)SR ^ld , -NR ^la C(NR ^ld )NR ^lb R ^lc , -NR ^la C(S)R ^ld , -NR ^la C(S)0R ^ld , -NR ^la C(S)NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , - NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0)zNR ^lb R ^lc , -SR ^la , -S(O)R ^la , -S(O) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ; each R ^E4a is independently hydrogen or R ^E4 ; 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 R ^la , R ^lb , R ^lc , and R ^ld 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 Q ^a ; and (c) -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(O)SR ^a , ~C(NR ^a )NR ^b R ^c , -C(S)R ^a , -C(S)OR ^a , -C(S)NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(O)SR ^a , -OC(NR ^a )NR ^b R ^c , -OC(S)R ^a , -OC(S)OR ^a , -OC(S)NR ^b R ^c , -OP(O)(OR ^b )OR ^c , -OS(O)R ^a , ~OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(O)R ^d , ~NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(O)SR ^d , -NR ^a C(NR ^d )NR ^b R ^c , -NR ^a C(S)R ^d , -NR ^a C(S)OR ^d , -NR ^a C(S)NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c , and - S(O) ₂ NR ^b R ^c , wherein each R ^a , R ^b , R ^c , and R ^d 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 Q ^a ; or (iii) R ^b and R ^c 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 Q ^a ; wherein each Q ^a 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)R ^e , -C(O)OR ^e , -C(O)NR ^f R ^s , C(O)SR' , -C(NR ^e )NR ^f R ^g , -C(S)R ^e , -C(S)OR ^e , -C(S)NR ^f R ^g , -OR ^e , -OC(O)R ^e , -OC(O)OR ^e , -OC(O)NR ^f R ^g , OC(O)SR ^e , -OC(NR ^e )NR ^f R ⁸ , -OC(S)R ^e , -OC(S)OR ^e , -OC(S)NR ^f R ^g , -OP(O)(OR ^f )OR ^g , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(O)R ^h , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^f R ^g , -NR ^e C(O)SR ^f , -NR ^e C(NR ^h )NR ^f R ^g , -NR ^e C(S)R ^h , -NR ^e C(S)OR ^f , -NR ^e C(S)NR ^f R ^g , -NR ^e S(O)R ^h , -NR ^e S(O) ₂ R ^b , -NR ^e S(O)NR ^f R ^s , -NR ^e S(O) ₂ NR ^f R ^s , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^f R ^g , and -S(O) ₂ NR ^f R ^g ; wherein each R ^e , R\ R ^g , and R ^h 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) R ^f and R ⁸ 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): 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)NR ^lb R ^lc , -OC(O)SR ^la , -OC(NR ^la )NR ^lb R ^lc , -OC(S)R ^la , -OC(S)OR ^la , -OC(S)NR ^lb R ^lc , -OS(O)R ^la , -OS(O) ₂ R ^la , -OS(O)NR ^ib R ^lc , -OS(O) ₂ NR ^ib R ^lc , -NR ^lb R ^lc , ~NR ^la C(O)R ^ld , ~NR ^la C(O)OR ^ld , -NR ^la C(O)NR ^lb R ^lc , -NR ^la C(O)SR ^ld , -NR ^la C(NR ^ld )NR ^lb R ^lc , -NR ^la C(S)R ^ld , -NR ^la C(S)OR ^ld , -NR ^la C(S)NR ^lb R ^lc , -NR ^la S(O)R ^ld , -NR ^!a S(O) ₂ R ^ld , -NR ^la S(O)NR ^ib R ^lc , -NR ^la S(O) ₂ NR ^ib R ^lc ,

SR ^!a , -S(O)R ^la , -S(O) ₂ R ^la , -S(O)NR ^lb R ^lc , or -S(O) ₂ NR ^lb R ^lc ; a is an integer of 0, 1, 2, or 3; and

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.

[0063] In certain embodiments, in Formula (I) or (II), R ^E is not l,3-dioxo-2-(2,6- dioxopiperidin-3-yl)isoindolinyl, unsubstituted or substituted. In certain embodiments, in Formula (I) or (II), 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. In certain embodiments, in Formula (I) or (II), R ^E 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-y l, 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): 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 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 ^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 , -0R ^la , -OC(O)R ^la , -OC(O)OR ^la , -OC(O)NR ^lb R ^lc , -OC(O)SR ^la , OC(NR ^la )NR ^lb R ^lc , -OC(S)R ^la , -OC(S)OR ^la , -OC(S)NR ^lb R ^lc , -OS(O)R ^la , -OS(O) ₂ R ^la , -OS(O)NR ^lb R ^lc , -OS(O) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(O)R ^ld , -NR ^la C(O)OR ^ld , -NR ^la C(O)NR ^lb R ^lc , -NR ^ia C(O)SR ^ld , ~NR ^la C(NR ^ld )NR ^lb R ^lc , ~NR ^la C(S)R ^ld , ~NR ^la C(S)OR ^id , -NR ^la C(S)NR ^lb R ^lc , -NR ^la S(O)R ^ld , -NR ^la S(O) ₂ R ^ld , -NR ^la S(O)NR ^lb R ^lc , -NR ^la S(O) ₂ NR ^lb R ^lc , -SR ^la , -S(O)R ^la , -S(O) ₂ R ^la , -S(O)NR ^lb R ^lc , or -S(O) ₂ NR ^lb R ^lc ; b is an integer of 0, 1, 2, 3, or 4; and

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.

[0065] In certain embodiments, in any one of the formulae provided herein, R ^E 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, 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-

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-y l, 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): or an enantiomer, a mixture of 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.

[0067] In yet another embodiment, provided herein is 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.

[0068] In yet another embodiment, provided herein is 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.

[0069] In yet another embodiment, provided herein is 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.

[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): or an enantiomer, a mixture of 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.

[0072] In yet another embodiment, provided herein is 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.

[0073] In yet another embodiment, provided herein is 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.

[0074] In yet another embodiment, provided herein is 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.

[0075] In yet another embodiment, provided herein is a compound of Formula (IIIA): or an enantiomer, a mixture of 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 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 , -C(O)SR ^ia , -C(NR ^ia )NR ^lb R ^lc , -C(S)R ^la , -C(S)OR ^la , -C(S)NR ^lb R ^ic , ~OR ^la , -OC(O)R ^la , -OC(O)OR ^la , -OC(O)NR ^lb R ^lc , -OC(O)SR ^la , -OC(NR ^la )NR ^lb R ^lc , -OC(S)R ^la , -OC(S)OR ^la , -OC(S)NR ^lb R ^lc , -OS(O)R ^la , -OS(O) ₂ R ^la , -OS(O)NR ^lb R ^lc , -OS(O) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(O)R ^ld , -NR ^la C(O)OR ^ld , -NR ^la C(O)NR ^lb R ^lc , -NR ^la C(O)SR ^ld , -NR ^la C(NR ^ld )NR ^lb R ^lc , -NR ^la C(S)R ^ld , -NR ^la C(S)OR ^ld , -NR ^la C(S)NR ^lb R ^lc , -NR ^la S(O)R ^ld , -NR ^la S(O) ₂ R ^ld , -NR ^!a S(O)NR ^lb R ^lc , -NR ^la S(O) ₂ NR ^lb R ^lc , -SR ^la , -S(O)R ^la , -S(O) ₂ R ^la , -S(O)NR ^lb R ^lc , or -S(O) ₂ NR ^lb R ^lc ; c is an integer of 0, 1, 2, 3, or 4; and

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.

[0076] In still another embodiment, provided herein is 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.

[0077] In certain embodiments, in any one of the formulae provided 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.

[0078] In certain embodiments, in any one of the formulae provided 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.

[0079] In certain embodiments, in any one of the formulae provided 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.

[0080] In certain embodiments, in any one of the formulae provided herein, R ^E is a moiety having the structure of Formula (EC-I-c):

(EC-I-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 ^E4 , m, and n are each as defined herein.

[0081 ] In certain embodiments, in any one of the formulae provided herein, R ^E is a moiety having the structure of Formula (EC-I-d):

(EC-I-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 ^E4 , m, and n are each as defined herein.

[0082] In certain embodiments, in any one of the formulae provi ded herein, R ^E is a moiety having the structure of Formula (EC-I-e):

(EC-I-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 , m, and n are each as defined herein.

[0083] In certain embodiments, in any one of the formulae provided herein, R ^E is a moiety having the structure of Formula (EC-I-f):

(EC-I-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 , m, and n are each as defined herein.

[0084] In certain embodiments, in any one of the formulae provided herein, R ^E is a moiety having the structure of Formula (EC-I-g):

(EC-I-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 ^E2 , R ^E4 , m, and n are each as defined herein

[0085] In certain embodiments, in any one of the formulae provi ded herein, R ^E is a moiety having the structure of Formula (EC-I-h):

(EC-I-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 A ^E , R ^E1 , R ^E2 , R ^EJ , R ^E4 , m, and n are each as defined herein. [0086] In certain embodiments, in any one of the formulae provided herein, R ^E is a moiety having the structure of Formula (EC-I-i):

(EC-I-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; wherein A ^E , R ^E1 , R ^E2 , R ^E3 , R ^E4 , m, and n are each as defined herein.

[0087] In certain embodiments, in any one of the formulae provided herein, R ^E is a moiety having the structure of Formula (EC-I-j):

(EC-I-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 ^EJ , R ^E4 , m, and n are each as defined herein.

[0088] In certain embodiments, in any one of the formulae provi ded 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.

[0089] In one embodiment, in a compound of any one of the formulae provided 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. In another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In still another embodiment, in a compound of any one of the formulae provided herein, 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.

[0090] In certain embodiments, in any one of the formulae provided 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.

[0091] In one embodiment, in a compound of any one of the formulae provided herein, 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. In another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In still another embodiment, in a compound of any one of the formulae provided herein, 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.

[0092] In certain embodiments, in any one of the formulae provi ded herein, 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.

[0093] In certain embodiments, in any one of the formulae provided 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.

[0094] In certain embodiments, in any one of the formulae provided 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.

[0095] In certain embodiments, in any one of the formulae provided herein, R ^E is a moiety having the structure of Formula (EC-II-c):

(EC-II-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 ^E4 , R ^E5 , m, and n are each as defined herein.

[0096] In certain embodiments, in any one of the formulae provided herein, 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. [0097] In certain embodiments, in any one of the formulae provided 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.

[0098] In certain embodiments, in any one of the formulae provided 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 .

[0099] In certain embodiments, in any one of the formulae provided 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.

[00100] In one embodiment, in a compound of any one of the formulae provided 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. In another embodiment, in a compound of any one of the formulae provided herein, 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. 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, 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.

[00101] Ill certain embodiments, in a compound of any one of the formulae provided 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.

[00102] In one embodiment, in a compound of any one of the formulae provided herein, 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. In another embodiment, in a compound of any one of the formulae provided herein, 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 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, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In still another embodiment, in a compound of any one of the formulae provided herein, 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.

[00103] In certain embodiments, in a compound of any one of the formulae provided 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.

[00104] In one embodiment, in a compound of any one of the formulae provided herein, 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. In another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In still another embodiment, in a compound of any one of the formulae provided herein, 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.

[00105] In certain embodiments, in any one of the formulae provided herein, 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.

[00106] In certain embodiments, in any one of the formulae provided herein, one of Z ¹ , Z ² , Z ³ , and Z ⁴ is -C= and the remaining three of Z ¹ , Z ² , Z ³ , and Z ⁴ are each independently -C(R ^E4a )=, wherein R ^E4a is as defined herein. In certain embodiments, in any one of the formulae provided herein, Z ¹ is -C=; and Z ² , Z ³ , and Z ⁴ are each independently -C(R ^E4a )= w'herein R ^E4a is as defined herein. In certain embodiments, in any one of the formulae provided herein, Z ¹ , Z ³ , and Z ⁴ are each independently ~C(R ^E4a )=, wherein R ^E4a is as defined herein; and In certain embodiments, in any one of the formulae provided herein, Z ¹ , Z ² , and Z ⁴ are each independently -C(R ^E4a )=, wherein R ^E4a is as defined herein; and Z ³ is ~C=. In certain embodiments, in any one of the formulae provided herein, Z ¹ , Z ² , and Z ³ are each independently -C(R ^E4a )=, wherein R ^E4a is as defined herein; and Z ⁴ is -C=. [00107] In certain embodiments, in any one of the formulae provided herein, Z ^! is a bond; one of Z ² , Z ³ , and Z ⁴ is -C=, and the remaining two of Z ² , Z ³ , and Z ⁴ are each independently -C(R ^E4a )= or S . wherein R ^E4a is as defined herein. In certain embodiments, in any one of the formulae provided herein, Z ¹ is a bond; Z ² is -C=; Z ³ is -C(R ^E4a )=, wherein R ^E4a is as defined herein; and Z ⁴ is -S-. In certain embodiments, in any one of the formulae provided herein, Z ¹ is a bond; Z ² is -C=; Z ³ is -S-; and Z ⁴ is -C(R ^E4a )=, wherein R ^E4a is as defined herein. In certain embodiments, in any one of the formulae provided herein, Z ¹ is a bond; Z ² is -C(R ^E4a )=, wherein R ^E4a is as defined herein; Z ³ is C=; and Z ⁴ is -~S~. In certain embodiments, in any one of the formulae provided herein, Z ¹ is a bond; Z ² is -S-; Z ² is -C=; and Z ⁴ is -C(R ^E4a )=, wherein R ^E4a is as defined herein. In certain embodiments, in any one of the formulae provided herein, Z ¹ is a bond; Z ² is -C(R ^E4a )=, wherein R ^E4a is as defined herein; Z ³ is -S-; and Z ⁴ is -C=. In certain embodiments, in any one of the formulae provided herein, Z ¹ is a bond; Z ² is -S-; Z ³ is -C(R ^E4a )=, wherein R ^E4a is as defined herein; and Z ⁴ is -C=.

[00108] In certain embodiments, in Formula (EC -III), 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. In certain embodiments, in Formula (EC-III), 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-y l, 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, 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.

[00110] In certain embodiments, in any one of the formulae provided 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is CH2 .

[00111] In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[001 12] In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[00113] In certain embodiments, in any one of the formulae provided herein, 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.

[00114] In certain embodiments, in any one of the formulae provided 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.

[00115] In certain embodiments, in any one of the formulae provided 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.

[00116] In certain embodiments, in any one of the formulae provided 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.

[00117] In certain embodiments, in any one of the formulae provided herein, R ^E is a moiety having the structure of Formula (EC-III-i):

(EC-III-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 ^E1 , R ^E2 , R ^E4a , Z, and m are each as defined herein.

[00118] In certain embodiments, in any one of the formulae provided herein, 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.

[00119] In certain embodiments, in any one of the formulae provided 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.

[00120] In certain embodiments, in any one of the formulae provided 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.

[00121] In certain embodiments, in any one of the formulae provided 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.

[00122] In certain embodiments, 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.

[00123] In one embodiment, in a compound of any one of the formulae provided 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. In another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In still another embodiment, in a compound of any one of the formulae provided herein, 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.

[00124] In certain embodiments, 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.

[00125] In one embodiment, in a compound of any one of the formulae provided herein, 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. In another embodiment, in a compound of any one of the formulae provided herein, 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. 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, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In yet another embodiment, in a compound of any one of the formulae provided herein, 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 In yet another embodiment, in a compound of any one of the formulae provided herein, 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. In still another embodiment, in a compound of any one of the formulae provided herein, 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.

[00126] In one embodiment, provided herein is 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.

[00127] In another embodiment, provided herein is 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.

[00128] In yet another embodiment, provided herein is 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.

[00129] In yet another embodiment, provided herein is 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.

[00130] In still another embodiment, provided herein is 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.

[00131] In one embodiment, provided herein is 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.

[00132] In another embodiment, provided herein is 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.

[00133] In yet another embodiment, provided herein is 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.

[00134] In yet another embodiment, provided herein is 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.

[00135] In still another embodiment, provided herein is 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.

[00136] In one embodiment, provided herein is 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.

[00137] In another embodiment, provided herein is 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.

[00138] In yet another embodiment, provided herein is 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.

[00139] In yet another embodiment, provided herein is 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.

[00140] In stil l another embodiment, provided herein is a compound of Formula

(XVIII 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’, R ⁴ , R ^3a , R ^E2 , R ^E4 , R ^E5 , A ^E , L, Y, a, m, and n are each as defined herein.

[00141] In one embodiment, provided herein is 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.

[00142] In another embodiment, provided herein is 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.

[00143] In yet another embodiment, provided herein is 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.

[00144] In yet another embodiment, provided herein is 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.

[00145] In still another embodiment, provided herein is 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.

[00146] In one embodiment, provided herein is 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -- CH2-.

[00147] In another embodiment, provided herein is 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. In certain embodiments,

R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[00148] In yet another embodiment, provided herein is 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[00149] In still another embodiment, provided herein is a compound of Formula

(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.

[00150] In one embodiment, provided herein is 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is CH2

[00151] In another embodiment, provided herein 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[00152] In yet another embodiment, provided herein is 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[00153] In still another embodiment, provided herein is 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.

[00154] In one embodiment, provided herein is 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.

[00155] In another embodiment, provided herein is 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.

[00156] In yet another embodiment, provided herein is 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.

[00157] In yet another embodiment, provided herein is 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.

[00158] In still another embodiment, provided herein is 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.

[00159] In one embodiment, provided herein is 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. [00160] In another embodiment, provided herein is 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.

[00161] In yet another embodiment, provided herein is 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.

[00162] In yet another embodiment, provided herein is 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.

[00163] In still another embodiment, provided herein is 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.

[00164] In one embodiment, provided herein is 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.

[00165] In another embodiment, provided herein is 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.

[00166] In yet another embodiment, provided herein is 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.

[00167] In yet another embodiment, provided herein is 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.

[00168] In still another embodiment, provided herein is 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.

[00169] In one embodiment, provided herein is 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.

[00170] In another embodiment, provided herein is 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.

[00171] In yet another embodiment, provided herein is 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.

[00172] In yet another embodiment, provided herein is 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.

[00173] In still another embodiment, provided herein is 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.

[00174] In one embodiment, provided herein is 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[00175] In another embodiment, provided herein is 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -Chh

[00176] in yet another embodiment, provided herein is 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. In certain embodiments,

R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[00177] In still another embodiment, provided herein is a compound of Formula

(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.

[00178] In one embodiment, 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CH?-.

[00179] In another embodiment, provided herein is 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[00180] In yet another embodiment, provided herein is 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. In certain embodiments,

R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[00181] In still another embodiment, provided herein is 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.

[00182] In one embodiment, provided herein is 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.

[00183] In another embodiment, provided herein is 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.

[00184] In yet another embodiment, provided herein is 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.

[00185] In yet another embodiment, provided herein is 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.

[00186] In still another embodiment, provided herein is 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.

[00187] In one embodiment, provided herein is 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.

[00188] In another embodiment, provided herein is 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.

[00189] In yet another embodiment, provided herein is 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.

[00190] In yet another embodiment, provided herein is 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.

[00191] In still another embodiment, provided herein is 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.

[00192] In one embodiment, provided herein is 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CH?.-.

[00193] In another embodiment, provided herein is 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CII2-.

[00194] In yet another embodiment, provided herein is 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. In certain embodiments, R ^E4a is fluoro. In certain embodiments, Z is -CH2-.

[00195] In still another embodiment, provided herein is 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.

[00196] In certain embodiments, in any one of the formulae provided herein, R ^l 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, R ¹ is Ci -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 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, R ¹ is ethyl, isopropyl, or pent-3-yl.

[00197] In certain embodiments, in any one of the formulae provided herein, 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.

[00198] In certain embodiments, in any one of the formulae provided herein, R ¹ 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, 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. In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, R ¹ is cyclopropyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R ¹ is cyclobutyl, 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. 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. In certain embodiments, in any one of the formulae provided herein, 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.

[00199] In certain embodiments, in any one of the formulae provided herein, R ^l is heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R ¹ is monocyclic heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R ¹ 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, R ¹ 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, R ¹ is tetrahydrofuryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R ¹ 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, R ¹ 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, R ¹ is bicyclic heterocyclyl, 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 heterocyclyl, each optionally substituted with one, two, or three substituents Q.

[00200] In certain embodiments, in any one of the formulae provided herein, 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,

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, 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

[00201] In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, R ² is hydrogen. In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, R ² 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, R ² is aralkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, R ² is benzyl. In certain embodiments, in any one of the formulae provided herein, 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.

[00202] In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, R ² is -C(O)R ^la , wherein R ^la is as defined herein. In certain embodiments, in any one of the formulae provided herein, R ² is C(O)R ^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 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. In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, 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. 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 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.

[00203] In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, 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.

[00204] In certain embodiments, in any one of the formulae provided herein, 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.

[00205] In certain embodiments, in any one of the formulae provided herein, R ⁴ is hydrogen.

[00206] In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, 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.

[00207] In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, 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.

[00208] In certain embodiments, in any one of the formulae provided herein, 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.

[00209] In certain embodiments, in any one of the formulae provided herein, 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.

[00210] In certain embodiments, in any one of the formulae provided herein, 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.

[00211] In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, 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.

[00212] In certain embodiments, in any one of the formulae provided herein, 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.

[00213] In certain embodiments, in any one of the formulae provided herein, R ^Es 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 ^E5 is hydrogen. In certain embodiments, in any one of the formulae provided herein, R ^E5 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 ^E5 is methyl.

[00214] In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, A ^E is a bond. In certain embodiments, in any one of the formulae provided herein, A ^E is C2-6 alkynylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, 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. In certain embodiments, in any one of the formulae provided herein, A ^E 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 ^E 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, 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. In certain embodiments, in any one of the formulae provided herein, A ^E 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, A ^E 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, A ^E 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, A ^E 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, A ^E 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,

[00216] In certain embodiments, in any one of the formulae provided herein, A ^E 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, A ^E 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, A ^E 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, 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. In certain embodiments, in any one of the formulae provided herein, 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

[00217] In certain embodiments, in any one of the formulae provided herein, 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 -, -OC(O)S-, -OC(NR ^la )NR ^lb - -OC(S)O- -OC(S)NR ^lb -, -OS(O)-, -OS(O) ₂ -, -OS(O)NR ^lb - -OS(O) ₂ NR ^lb -, -NR ^lb -, -NR ^la C(O)NR ^lb -, -NR ^la C(O)S-, -NR ^la C(NR ^ld )NR ^lb -, -NR ^la C(S)NR ^lb -, -NR ^la S(O)NR ^lb -, -NR ^la S(O) ₂ NR ^!b - -S-, -S(O)-, -S(O) ₂ -, -S(O)NR ^lb -, or -S(O) ₂ NR ^lb --; where each R ^la , R ^lb , and R ^ld 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 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 -, or -■S(O)2NR ^lb -; and z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; where each R ^la , R ^lb , and R ^ld is as defined herein.

[00219] In certain embodiments, 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.

[00220] In certain embodiments, 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,

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 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.

[00221 ] In certain embodiments, 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]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 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, 3, 4, 5, 6, 7, or 8. [00222] In certain embodiments, 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-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 Z ^L is independently a bond or -O-; and z is an integer of 2, 3, 4, or 5.

[00223] In certain embodiments, 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-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 Z ^L 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: wherein each A ^L is independently a bond, -O-, -NH-, or -N(CH3)-.

[00225] In certain embodiments, in any one of the formulae provided herein, L is: wherein each A ^L is independently a bond, -0-, -NH-,

[00226] In certain embodiments, in any one of the formulae provided herein, L is: wherein each A ^L is independently a bond, -0---, or -N(CH3 )---.

[00227] In certain embodiments, in any one of the formulae provi ded herein, 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.

[00228] In certain embodiments, in any one of the formulae provided herein, L is: wherein each A ^L is independently a bond, -O-, -NH-, wherein each amino

(NH) group is optionally substituted with methyl.

[00229] In certain embodiments, in any one of the formulae provided herein, 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.

[00230] In certain embodiments, in any one of the formulae provided herein, 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.

[00231 ] In certain embodiments, in any one of the formulae provi ded herein, L is: wherein each A ^L is independently a bond, -O-, -NH-, or -N(CH3)-.

[00232] In certain embodiments, 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.

[00233] In certain embodiments, in any one of the formulae provided herein, L is: wherein each A ^L is independently a bond, -O-, -NH-, wherein each amino group (NH) is optionally substituted with methyl.

[00234] In certain embodiments, in any one of the formulae provided herein, L is: wherein each A ^L is independently a bond, -0-, -NH-, or -N(CH3)-.

[00235] In certain embodiments, in any one of the formulae provided herein, L is:

wherein each A ^L 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: wherein each A ^L 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:

[00238] In certain embodiments, in any one of the formulae provided herein, L is:

[00239] In certain embodiments, in any one of the formulae provi ded herein, L is:

[00240] In certain embodiments, in any one of the formulae provided herein, L is:

[00241] In certain embodiments, in any one of the formulae provided herein, L is:

[00242] In certain embodiments, in any one of the formulae provided herein, L is:

[00243] In certain embodiments, in any one of the formulae provided herein, L is:

[00244] In certain embodiments, in any one of the formulae provided herein, L is:

[00245] In certain embodiments, in any one of the formulae provided herein, L is:

[00246] In certain embodiments, in any one of the formulae provided herein, L is:

[00247] In certain embodiments, in any one of the formulae provided herein, L is:

- I l l -

[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, 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.

[00250] In certain embodiments, in any one of the formulae provided herein, Y is

C(R ⁵ )=, wherein R ³ 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, 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.

[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)ph enoxy)acetyl)- piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A ^z ,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)-A ^r ,A ^r -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)-A ⁷ ,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-dimeth yl-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)-A ^r ,A’-dimethyl-7//-pyrrolo[2,3-^pyrimidine-6-carboxami de 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-dim ethyl-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,A ^z -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-di methyl-7A ^r -pyrrolo[2,3-d ^r ]- 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'',A ^r -dimethyl-7fi ^r -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)-A ⁷ ,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)-A ^r ,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-c arboxamide A117, 7-cyclopentyl-2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)pi perazin-l-yl)- phenyl)amino)-A",A-dimethyl-7/f-pyrrolo[2,3-J]pyrimidine-6-c arboxaniide A118;

7-cyclopentyl-2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenet hyl)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)phenet hyl)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)phe noxy)ethyl)piperazin-l- yl)phenyl)amino)-A,A ⁷ -dimethyl-7Z/-pyrrolo[2,3-<7]pyrimidine-6-carboxami de A121;

7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- ethyl)phenyl)amino)-A\A’-dimethyl-7/f-pyrrolo[2,3-t/]pyrim idine-6-carboxamide A122;

7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- ethyl)phenyl)amino)-A ^z ,A ^; -dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A123;

7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- ethoxy)phenyl)amino)-A ^z ,A-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6-carboxamid e 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-carbo xamide A125;

7-cyclopentyl-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A,A ^r -dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A126;

7-cyclopentyl-2-((4-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phe nyl)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)ben zyl)piperazin-l-yI)- ethyl)phenyl)amino)-A ^r ,A ^r -dimethyl-7J7-pyrrolo[2,3-«/]pyrimidine-6-carboxamide A128;

7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)ben zyl)piperazin-l-yl)- ethyl)phenyl)amino)-A,A ^r -dimethyl-7H-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A129;

7-cyclopentyl-2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)ben zyl)piperazin-l-yl)- ethoxy)phenyl)amino)-A ^z ,A-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6-carboxamid e A130;

7-cyclopentyl-2-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)ben zyl)piperazin-l-yl)- ethoxy)phenyl)amino)-Ay/V-dimethyl-7H-pyrrolo[2,3-^pyrimidin e-6-carboxamide A131;

7-cyclopentyl-2-((4-((4-(l-(4-(2,6-dioxopiperidin-3-yl)ph enyl)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/]pyr imidine-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,A ⁷ -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'’,A ^r -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)-A ⁷ ,A' ^r -dimethyl-7H-pyrrolo[2,3-</|pyrirnidine-6-carboxami de 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 ^r ,A ^r -dimethyl-77/-pyrrolo[2,3-<7]pyrimidine-6-carboxami de A137;

7-cyclopentyi-2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)ben zyl)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)phe nethyl)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)phe nethyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A,A' ^r -dimethyl-7J7-pyrrolo[2,3-</|pyrimidine-6-carboxami de Al 40;

7-cyclopentyl-2-((4-(4-((l-(3-(2,6-dioxopiperidin-3-yl)ph enyl)piperidin-4-yl)- methyl)piperazin-l-yl)phenyl)amino)-A ^z ,7V-dimethyl-7//-pyrrolo[2,3-<T]pyrimidine-6- carboxamide A141;

7-cyclopentyl-2-((4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)ph enyl)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)-A ^r ,A ^r "dimetliyl-7/Apyrrolo[2,3-<7]pyrimidine-6-carboxami de A143;

7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl) phenyl)piperidin-l-yl)- ethyl)piperazin-l-yl)phenyl)amino)-A ^r _J A ⁷ -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-p yrrolo[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)-A ^r ,A ⁷ -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)-A ⁷ ,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//-p yrrolo[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-77 7-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)-A ^r ,AMimethyl-7 _J H-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//-p yrrolo[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'-dim ethyl-7A ^r -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//-py rrolo[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)-A ^r ,A ⁷ -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)phe nethyl)cyclohexyl)- piperazin-l-yl)pyridin-2-yl)amino)-A ^/ ,A''-dimethyl-7A ^r -pyrrolo[2,3-47]pyrimidine-6-carboxamide A155;

7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phe nethyl)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)-A ^T ,A ^L dimethyl-7//-pyrrolo[2,3-</]pyrimidine-6- carboxamide A157; 7"Cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)ph enyl)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)ph enyl)-[l,4'-bipiperidin]- 4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^r ,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’,A ^r -dimetliyl-7/7-pyrrolo[2,3-d]pyrimidine-6- carboxamide A161;

7-cyclopentyl-2-((5-(4-(r-(4-(2,6-dioxopiperidin-3-yl)phe nyl)-[l,4'-bipiperidin]-

3-yl)piperazin-l-yl)pyridin-2-yl)amino)-/V’,A ⁷ -dimethyl-7 _J H-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)- A ⁷ ,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)-A ⁷ A ^r -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)-A ⁷ ,A ⁷ -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)-A ⁷ A ⁷ -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-dioxopiperidi n-3-yl)phenyl)piperidin-

4-yl)morpholin-2-yl)methyl)piperazin-l-yl)pyridin-2-yl)am ino)-A ⁷ ,A ^r -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-d imethyl-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)-A ^r ,A ⁷ -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,A ^r -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)-A ^r ,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//-py rrolo[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)-A ^r ,A ⁷ -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,A ^L dimethyl-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)-A ⁷ ,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-dimeth yl-72/-pyrrolo[2,3-6Z]pyrimidine-6- carb oxami de A 181 ;

7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenet hyl)-[l,4'-bipiperidin]- r-yl)pyridin-2-yl)amino)-A ^r ,A ^r -dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxami de A182;

7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)pheny l)-[l,4'-bipiperidin]-4- yl)methyl)pyridin-2-yl)amino)-A ⁷ ,A ⁷ -dimethyl-7A ^r -pyiTolo[2,3-t7]pyrimidine-6-carboxamide A183;

7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)pheny l)-[4,4'-bipiperidin]-l- yl)methyl)pyridin-2-yl)amino)-A ^/ ,A’-dimethyl-7/7-pyrrolo[2,3-^pyrimidine-6-carboxami de A184;

7-cyclopentyl-2-((5-((4-(4-(4-(2,6-dioxopiperidin-3-yl)ph enyl)piperazin-l-yl)- piperidin-l-yl)methyl)pyridin-2-yl)amino)-A ⁷ ,A ^L dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A185;

7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)pheny l)-[l,4'-bipiperidin]-4- yl)oxy)pyridin-2-yl)amino)-A',A ⁷ -dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6-carboxamide A186;

7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)pheny l)-[l,4'-bipiperidin]-4- yl)methoxy)pyridin-2-yl)amino)-A ^z ,A-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamid e A187;

7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phe nyl)-[4,4 ^f -bipiperidin]- l-yl)ethyl)pyridin-2-yl)amino)-A ⁷ ,A-dimethyl-7//-pyrrolo[2,3-</|pyrimidine-6-carboxa mide A188;

7-cyclopentyl-2-((5-(2-(l'-(4-(2,6-dioxopiperidin-3-yl)ph enyl)-[l,4'-bipiperidin]- 4-yl)ethyl)pyridin-2-yl)amino)-A ⁷ ,A ^ir "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-py rrolo[2,3-t/]pyrimidine-6- carboxamide A190;

7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phe nyl)-[4,4'-bipiperidin]- l-yl)ethoxy )pyri din-2 -yl)amino)-A'’,jV-dimethyl-7//-pyrrolo[2,3-<7]pyrimidin e-6-carboxamide A191;

7-cyclopentyl-2-((5-(2-(r-(4-(2,6-dioxopiperidin-3-yl)phe nyl)-[l,4'-bipiperidin]- 4-yl)ethoxy)pyri din-2 -yi)amino)-A,A-dimethyi-7//-pyrrolo[2,3-t/]pyrimidine-6-carb oxamide 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)-A ^z ,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)-A ⁷ ,iV-dimethyl-7/f-pyrrolo[2,3-^- pyrimidine-6-carboxamide A194;

7-cyclopentyl-2-((5-(4-(r-(4-(2,6-dioxopiperidin-3-yl)phe nyl)-[l,4'-bipiperidin]-

4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7V,A ^z -dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide Al 95;

7-cyclopentyi-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- [l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-A’,A ^; -dimethyl-7A ^r -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,A ^r -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)-A ^r ,A’-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- arboxamide A199; 7-cyclopentyl-2-((5-((4-(l-(4-(2,6-dioxopiperidin-3-yl)pheny l)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)ph enyl)-[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-p yrrolo[2,3-^pyrimidine-6- carboxamide A204:

7-cyclopentyl-2-((5-(3-(r-(4-(2,6-dioxopiperidin-3-yl)phe nyl)-[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)-A ^r ,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)-A ⁷ ,A’-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A208;

7-cyclopentyl-2-((5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phe nethyl)piperazin-l-yl)- piperidin-l-yl)pyridin-2-yl)amino)-jV,A ^r -dimethyl-77/-pyrrolo[2,3-J]pyrimidine-6-carboxamide A209;

7-cyclopentyl-2-((5-((r-(4-(2,6-dioxopiperidin-3-yl)pheny l)-[l,4'-bipiperidin]-3 yl)oxy)pyridin-2-yl)amino)-A ^r ,7'Z-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carbo xamide A210;

7-cyclopentyl-2-((5-((3-(4-(4-(2,6-dioxopiperidin-3-yl)ph enyl)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)pheny l)-[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,J V-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 ^? ,A ^r -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)-A ^r ,A ⁷ -dimethyl-7J/-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A216;

7-cyclopentyi-2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)ph enyl)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)ph enyl)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)ph enyl)piperazin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)--A’,A ^T "dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A219;

7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)ph enyl)piperidin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-A ^z _r A'-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)ph enyl)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)ph enyl)piperazin-l-yl)- methyl)piperidin-l -yl)pyridin-2-yl)amino)-A _T A-dimethyl-777-pyrrolo[2,3-</]pyrimidine-6- carboxamide A223;

7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)ph enyl)piperidin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-A ⁷ ,A ^r -dimethyl-7//-pyrrolo[2,3-^pyrimidine-6- carboxamide A224;

7-cyclopentyl-2-((5-((4-(4-(2,6-dioxopiperidin-3-yl)pheny l)-[l,4'-bipiperidin]-r- yl)methy])pyridin-2-yl)amino)-A ⁷ ,A ⁷ -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)-A ^r ,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)-A ^T ,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)-A ⁷ ,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)-A ^T , 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)-A ^r ,A ^L dimethyl-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-py rrolo[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)-A ^r ,A ^r -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/-p yrrolo[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-pyr rolo[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)-A ⁷ ,A-dimethyl-777-pyrrolo[2,3-t7]pyrimidine-6- carboxamide A235;

7-cyclopentyl-2-((5-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)-[l,4'-bipiperidin]- r-yl)ethyl)pyridin-2-yl)amino)-A ⁷ ,A ^r -dimetliyl-7/7-pyrrolo[2,3-</]pyriniidine-6-carboxa mide A236;

7-cyclopentyl-2-((5-(r-(4-(2,6-dioxopiperidin-3-yl)phenet hyl)-[4,4'-bipiperidin]- l-yl)pyridin-2-yl)amino)-A ^r ,A' ^r -dimethyl-7/f-pyrrolo[2,3-fi(|pyrimidine-6-carboxamide A237;

7-cyclopentyi-2-((5-(r-(4-(2,6-dioxopiperidin-3-yl)phenet hyl)-[l,4'-bipiperidin]- 4-yl)pyridin-2-yl)amino)-A ^r ,A-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxa mide 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,A ^r -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)phe nyl)-[l,4'-bipiperidin]-

4-yl)ethyl)pyridin-2-yl)amino)-A’,A ^r -dimethyl-7H-pyrrolo[2,3-t(]pyrimidine-6-carboxamide A240;

7-cyclopentyl-2-((5-(2-(r-(3-(2,6-dioxopiperidin-3-yl)phe nyl)-[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)phe nyl)-[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)-A ^T 2V-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)-A ^r ,A ^r -dimethyl -7/7-pyrrol o [2, 3 -<7]py rimi dine-6- carboxamide A244;

7-cyclopentyl-7V,A ^L dimethyl-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)-A ⁷ ,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#-pyr rolo[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/-py rrolo[2,3-tZ]pyrimidine-6- carboxamide A248;

7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- propoxy)pyridin-2-yl)amino)-A ^r ,A-dimethyl-7Af-pyrrolo[2,3-tZ]pyrimidine-6-carboxamid e A249;

7-cyclopentyl-2-((5-(3-(l-(4-(2, 6-dioxopiperi din-3-yl)phenyl)piperidin-4-yl)- propoxy)pyridin-2-yl)amino)-A ^A ,A ^r -dimethyl-7 _J H-pyrrolo[2,3-«7]pyrimidine-6-carboxamide A250;

7-cyclopentyi-2-((5-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- ethoxy)pyridin-2-yl)amino)-A’',A ^r -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)-A ^r ,A-dimethyl-7//-pyrrolo[2,3-i/]pyrimidine-6-carboxamid e A252;

7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)phenet hyl)-4-fluoro-[l,4'- bipiperidin]-r-yl)pyridin-2-yl)amino)-A'//-dimethyl-7/7-pyrr olo[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)phe nyl)piperidin-4-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A ^/ ,A''-dimethyl-7 _J ?/-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A255;

7-cyclopentyl-2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)ph enyl)azetidin-3-yl)- methyl)piperazin-l-yi)pyridin-2-yl)amino)-7V,A ⁷ -dimethyl-7H-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A256;

7-cyclopentyl-2-((5-(4-((l-(3-(2,6-dioxopiperidin-3-yl)ph enyl)azetidin-3-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7Z7-p yrrolo[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,A ^z -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)-A ^r ,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 ^/ ,A ^r "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)-A ^f ,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'’ ,A ⁷ -dimethyl-7 _J H-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)-A ^r 2V-dimethyl-7/f-pyrrolo[2,3-(7]- pyrimidine-6-carboxamide A263;

7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)ben zyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A ^r ,A’-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carb oxamide A264;

7-cyclopentyl-2-((5-(4-(l-(3-(2,6-dioxopiperidin-3-yl)ben zyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A' ^r ,A-dimethyl-7/Z-pyrrolo[2,3-if|pyrimidine-6-carboxamid e A265;

7-cyclopentyl-2-((5-(4-(3-(2,6-dioxopiperidin-3-yl)phenet hyl)-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 ^/ ,A ^r -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//-pyrr olo[2,3-«7]pyrimidine-6- carboxamide A268;

7-cyclopentyl-2-((5-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phe nethyl)-3-fluoro- azetidin-l-yl)piperidin-l-yl)pyridin-2-yl)amino)-A',A ^r "dimetliyl-7/7-pyrrolo[2,3-</]pyriniidine-6- carboxamide A269;

7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)phe nethyl)-3-fluoro- azetidin-l-yl)piperidin-l-yl)pyridin-2-yl)amino)-A,A'’-dim ethyl-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)-A ⁷ ,A ^f -dimethyl-7//-pyrrolo[2,3-tZ]- pyrimidine-6-carboxamide A271 ;

7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phe nethyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A’,A-dimethyl-7/7-pyrrol o[2,3-</jpyrimidine-6-carboxamide A272;

7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phe nethyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A ^T ,A-dimethyl-7/f-pyrrolo[2,3-tf|pyrimidine-6-carboxamid e A273;

7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)ben zyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A7,A’-dimethyl-77Z-pyrro lo[2,3-<7]pyrimidine-6-carboxamide A274;

7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)ben zyl)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)ben zyl)-3-fluoroazetidin-l- yl)piperidin-l-yl)pyridin-2-yl)amino)-A ^r ,AMimethyl-7AApyrrolo[2,3-J]pyrimidine-6- carboxamide A276;

7-cyclopentyl-2-((5-(4-(3-(3-(2,6-dioxopiperidin-3-yl)ben zyl)-3-fluoroazetidin-l- yl)piperidin-l-yl)pyridin-2-yl)amino)-A ⁷ ,A ^L dimethyl-7Z/-pyrrolo[2,3-^pyrimidine-6- carboxamide A277;

7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phe nethyl)piperidin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A’,A-dimethyl-7 _J H ^r -pyrrolo[2,3-t/]pyrimidine-6-carboxamide A278;

7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phe nethyl)-4-fluoro- piperidin- 1 -yl)azetidin- 1 -yl)pyridin-2-yl)amino)-A ^r ,A-dimethyl-7Af-pyrrolo[2,3 - J]pyrimidine-6- carboxamide A279;

7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phe nethyl)piperidin-l-yl)- azetidiii-l-yl)pyridin-2-yl)aniino)-A ^r ,A ⁷ -dimethyl-7J/-pyrrolo[2,3-cf|pyrimidine-6-carboxamide A280;

7-cyclopentyi-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phe nethyl)-4-fluoro- piperidin-l-yl)azetidin-l-yl)pyridin-2-yl)amino)-A’,7V-dim ethyl-7Z/-pyrrolo[2,3-J]pyrimidine-6- carboxamide A281;

7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)ben zyl)-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)ben zyl)-4-fluoropiperidin- l-yl)azetidin-l-yl)pyridin-2-yl)amino)-A^V-dimethyl-77/-pyrr olo[2,3-t7]pyrimidine-6- carboxamide A283;

7-cyclopentyl-2-((5-(4-((3-(4-(2,6-dioxopiperidin-3-yl)ph enyl)azetidin-l-yl)- methyl)-4-fliioropiperidin-l-yl)pyridin-2-yl)amino)-A'',7V-d imethyl-7/7-pyrrolo[2,3-tf|pyrimidine- 6-carboxamide A284; 7-cyclopentyl-2-((5-(4-((3-(3-(2,6-dioxopiperidin-3-yl)pheny l)azetidin-l -yl)- methyl)-4-fluoropiperidin-l-yl)pyri din-2 -yl)amino)-A’,A ^r -dimethyl-7A ^r -pyrrolo[2,3-^]pyrimidine- 6-carboxamide A285,

7-cyclopentyl-2-((5-(l-((l-(3-(2,6-dioxopiperidin-3-yl)ph enyl)-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)ph enyl)-4-fluoropiperidin- 4-yl)methyl)piperidin-4-yl)pyridin-2-yl)amino)-A' ^r ,A ^r -dimethyl-7Af-pyrrolo[2,3-^pyrimidine-6- carboxamide A287;

7-cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)ph enyl)piperidin-l-yl)- methyl)-4-fluoropiperidin-l-yl)pyri din-2 -yl)amino)-A’,A ^r -dimethyl-7//-pyrrolo[2,3-d]pyrimidine- 6-carboxamide A288;

7-cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)ph enyl)piperidin-l-yl)- methyl)-4-fluoropiperi din-1 -yl)pyridin-2-yl)amino)-A ^r _f A ^r -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,A ^r -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 ^/ ,A ^r -dimethyl-7Z/-pyrrolo[2,3-t/j- pyrimidine-6-carboxamide A291;

2-((5-(4-(2-(l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)pheny l)piperidin-4-yl)ethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A ^r ,A-dimethyl-7J ^E /-pyrrolo[2,3-6Z]pyrimidine-6- carboxamide A292:

2-((5-(4-(2-(l-(2-chloro-4-(2,6-dioxopiperidin-3-yl)pheny l)piperidin-4-yl)ethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A,A-dimethy l-7H-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A293;

7-cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazm-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A ^T ,A-dimethyl-7 _J H-pyrrolo[2,3-<7|pyrimidine-6-carboxamide A294;

7-cyclopentyl-2-((5-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phe nyl)azetidin-3-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A ^r ,A’-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carb oxamide A295;

7-cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A ⁷ ,A ^r -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',7 V-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)-A ^r ,A'-dimethyl-7/7-pyrrolo[2,3-i7]- pyrimidine-6-carboxamide A298;

7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-3-flu orophenethyl)-4-fluoro-

[ 1 ,4' -bipiperi din] -■ 1 '-yl)pyridin-2-yl)amino)-A,A ^r -dimethyl-727-pyrrolo[2,3 - J]pyrimidine-6- carboxamide A299; or

7-cyclopentyl-2-((5-((r-(3-(2,6-dioxopiperidin-3-yl)pheny l)-[l,4'-bipiperidin]-4- yl)methoxy)pyridin-2-yl)amino)-A ⁷ ,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-dime thyl-7 _J H-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)-A ^r ,A ^r -dimethyl-7/f-pyrrolo[2,3-d]- pyrimidine-6-carboxamide A352; or

7-cyclopentyl-2-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-2-flu orophenethyl)-4-fluoro- [l,4'-bipiperidin]-l '-yl)pyridin-2-yl)amino)-A ^r ,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-dioxotetrahydropyri midin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)- A ^z ,A ⁷ -dimethyl-7J7-pyrrolo[2,3-6/]- pyrimidine-6-carboxamide A401;

7-cyclopentyl-2-((4-((4-(4-(2-(3-(2,4-dioxotetrahydropyri midin-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-dioxotetrahydropyri midin4(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)- A ^z //-dimethyl-7/7-pyrrolo[2,3- <7]pyrimidine-6-carboxamide A403;

7-cyclopentyl-2-((4-((2-(4-(2-(4-(2,4-dioxotetrahydropyri midin-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)- A ^z ,A ⁷ -dimethyl-7A ^r -pyrrolo[2,3-£/]- pyrimidine-6-carboxamide A404;

7-cyclopentyl-2-((4-((4-(4-(2-(4-(2,4-dioxotetrahydropyri midin-l(2H)-yl)- phenoxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)- A ⁷ ,A ^z -dimethyl-7H-pyrrolo[2,3-

</|pyrimidine-6-carboxamide A405; or

7-cyclopentyl-2-((4-((6-(4-(2-(4-(2,4-dioxotetrahydropyri midin-l(22/)-yl)- phenoxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)- A ^z ,A ^r -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’,A ^r -dimetliyl-7/Apyrrolo[2,3-</]pyrimidine-6-carboxami de 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,A ^r -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-dioxotetrahydropyrimidi n-l(22/)-yl)phenoxy)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^r ,A ^r -dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A411;

7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidi n-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-dioxotetrahydropyrimidi n-l(22/)-yl)phenyl)- piperazin-l-yl)ethyl)phenyl)amino)-A ^r ,A’-dimethyl-7/7-pyrrolo[2,3-tf|pyrimidine-6-carboxa mide A413;

7-cyclopentyl-2-((5-((4-(4-(2,4-dioxotetraliydropyrimidin -l(2//)-yl)phenyl)- piperazin-l-yl)methyl)pyridin-2-yl)amino)-A ^r ,A ^r -dimethyl-727-pyrrolo[2,3-(/]pyrimidine-6- carboxamide A414;

7-cyclopentyl-2-((5-(2-(4-(4-(2,4-dioxotetrahydropyrimidi n-l(2//)-yl)phenyl)- piperazin-l-yl)ethoxy)pyridin-2-yl)amino)-A ^r ,A ⁷ -diniethyl-7/Apyrrolo[2,3-t(|pyrimidine-6- carboxamide A415;

7-cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidi n-l(2J/)-yl)phenyl)- piperazin-l-yl)ethoxy)phenyl)amino)-7V,A ^r -dimethyl-7/f-pyrrolo[2,3-^pyrimidine-6- carboxamide A416;

7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidi n-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-dioxotetrahydropyrimidi n-l(2//)-yl)benzyl)- piperaziii-l-yl)ethoxy)phenyl)amino)"A^V-dimethyl-7//-pyrrol o[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)-A ^r , AMimethy I -7/Apyrrol o[2,3 -d]pyrimi dine-6- carboxamide A419;

7-cyclopentyl-2-((4-(4-( 1 -(4-(2,4-dioxotetrahydropyrimidin- 1 1 )pheny 1)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-A ^r ,A ⁷ -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-dioxotetrahydropyrimidi n-l(27/)-yl)benzyl)- piperazin-l-yl)ethyl)phenyl)amino)-A ^r ,A ⁷ -dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxami de A422;

7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidi n-l(22/)-yl)benzyl)- piperazin-l-yl)ethyl)phenyl)amino)-A ^! ',A’-dimethyl-7//-pyrrolo[2,3--t7]pyrimidine-6-carbo xamide A423;

7-cyclopentyl-2-((4-(2-(4-(3-(2,4-dioxotetrahydropyrirnid in-l(277)-yl)benzyl)- piperazin-l-yl)ethoxy)phenyl)amino)-A ^r ,A-dimethyl-7Z/-pyrrolo[2,3-^]pyrimidine-6- carboxamide A424;

7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrim idin-l(277)-yl)phenyl)- piperaziii-l-yl)piperidin-l-yl)ethyl)phenyl)amino)-A ^r JV-dimetliyl-7H-pyrrolo[2J-J]pyrimidine- 6-carboxamide A425,

7-cyclopentyl-2-((4-(2-(4-(4-(3-(2,4-dioxotetrahydropyrim idin-l(2//)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)amino)-A ^r ,A ^z -dimethyl-7//-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A426;

7-cyclopentyl-2-((4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrim idin-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-dioxotetrahydropyrimidi n-l(21/)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-A,A ^L dimethyl-77f-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A428;

7-cyclopentyl-2-((4-(4-(l-(3-(2,4-dioxotetrahydropyrimidi n-l(22/)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-A ^r ,A ⁷ -dimethyl-7J/-pyrrolo[2,3<(|pyrimidine-6- carboxamide A429;

7-cyclopentyl-2-((5-(4-(l-(4-(2,4-dioxotetrahydropyrimidi n-l(2//)-yl)benzyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A ^r ,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,A ⁷ -dimethyl-72/-pyrrolo[2,3-<Z]pyrimidine- 6-carboxamide A431,

7-cyclopentyl-2-((4-(4-((l-(3-(2,4-dioxotetrahydropyrimid in-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-dioxotetrahydropyrim idin-l(2A ^r )-yl)phenyl)- piperidin-l-yl)ethyl)piperazin-l-yl)phenyl)amino)-A ^r ,A ⁷ -dimethyl-777-pyrrolo[2,3-tZ]pyrimidine- 6-carboxamide A433; or

7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrim idin-l(2H)-yl)phenyl)- piperidin- 1 -yl)ethyl)piperazin- 1 -yl)phenyl)amino)-A ^r ,A ^r -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-dioxotetrahydropyrimidi n-l(2/7)-yl)phenethyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A^A ⁷ -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-A ^f ,A ^r -dimethyl-7H- pyrrolo[2,3-iZ]pyrimidine-6-carboxamide A436;

7-cyclopentyl-2-((5-(4-(( 1 -(4-(2,4-dioxotetrahydropyrimidin- 1 (277 ^r )-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-c yclopentyl-A ^? ,A ^z -dimethyl-7/f- pyrrolo[2,3-J]pyrimidine-6-carboxamide A438;

7-cyclopentyl-2-((5-(4-(l-(4-(2,4-dioxotetrahydropyrimidi n-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)ami no)-7-cyclopentyl-A’,A ⁷ -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-y l)-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-y l)-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-y l)-l-methyl-lAf-indazol-

7-yl)oxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)ami no)-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-y l)-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-y l)-l-methyl-l/7-indazol-

6-yl)oxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)ami no)-A’,A ^r -dimethyl-7//-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A505; or

7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,6-dioxopiperidin-3-y l)-l-methyl-17/-indazol-

6-yl)oxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)ami no)-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-dioxotetrahydropyr imidin-l(2A ^r )-yl)-l- methyl-177-indazol-7-yl)oxy)acetyl)piperazin-l -yl)butyl)carbamoyl)phenyl)amino)-A' ^, ,A ^r - dimethyl-7/7-pyrrolo[2,3-</]pyriniidiiie-6-carboxamide A552;

7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,4-dioxotetrahydropyr imidin-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-dioxotetrahydropyr imidin-l(2//)-yl)-l- methyl-l _J H-indazol-6-yl)oxy)acety4)piperazin-l-yl)ethyl)carbamo yl)phenyl)amino)-A ⁷ ,A ^z - dimethyl-7Zf-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A554;

7-cyclopentyl-2-((4-((4-(4-(2-((3-(2,4-dioxotetrahydropyr imidin-l(2//)-yl)-l- methyl-177-indazol-6-yl)oxy)acetyl)piperazin-l -yl)butyl)carbamoyl)phenyl)amino)-A ⁷ ,A ^r - dimethyl-7/7-pyrrolo[2,3-</|pyrimidine-6-carboxamide A555; or

7-cyclopentyl-2-((4-((6-(4-(2-((3-(2,4-dioxotetrahydropyr imidin-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-dioxotetrahydropyrimidi n-l(22/)-yl)-l-methyl- l//-indazol-6-yl)ethyl)-4-fluoro-[l,4'-bipiperidin]-r-yl)pyr idin-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-dioxotetrahydropyrimidi n-l(2//)-yl)-l-methyl- l// ^r -indazol-7-yl)ethyl)-4-fluoro-[l,4'-bipiperidin]-r-yl) pyridin-2-yl)amino)-A ^r ,AAdimethyl-7/7- pyrrolo[2,3-d]pyrimidine-6-carboxamide A558; or

7-cyclopentyl-2-((5-(4-(2-(l-(3-(2,4-dioxotetrahydropyrim idin-l(2//)-yl)-l- methyl-177-indazol-6-yl)piperidin-4-yl)ethyl)piperazin-l-yl) pyridin-2-yl)amino)-jV,A ^r -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 ,A ^r -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)-A ⁷ ,A ^r -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-ox oisoindolin-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)-MA ^L dimethyl-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',A ^r -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)-A ^r ,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)-A ⁷ ,A ^r -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)pyri din-2-yl)amino)-A ^r jV-dimethyl-7j ^E /- 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)pyrid in-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’,AM imethyl-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-dim ethyl-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)pyri din-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)pyrid in-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-o xo-5,6-dihydro-4/f- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)carbamoyl)phenyl)ami no)-A ^r ,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)carbamoy l)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-4A ^r - thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)amino)butyl)carbamoy l)phenyl)amino)-A ^r ,A ⁷ -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)ami no)-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-oxoethox y)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-oxopropo xy)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;

A ^L (2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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 ^z -(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-di hydropyrido[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;

A ^r -(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;

A ^z -(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;

A ^L (3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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-d ihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)phen yl)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)pheny l)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)phen yl)piperidine-2, 6-dione Bl 13;

3-(3-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3-a ^f ]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)phen yl)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)pheny l)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)phen yl)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)phe nyl)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)phe nyl)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)piper idin-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)piperidi n-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)piperidi n-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)piperidi n-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-methyl cyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-J]pyrimidin-2-yl)aniino)piperidi n-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-hydro xy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-</]pyrimidin-2-yl)amino)piper idin-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-hydro xy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piper idin-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-hydrox y-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tf]pyrimidin-2-yl)amino)piperidi n-l-yl)sulfonyl)ethyl)piperazin-l- yl)phenyl)piperidine-2, 6-dione B132;

3-(4-(4-(2-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydrox y-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piper idin-l-yl)sulfonyl)ethyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione B133;

3-(4-(4-(3-((4-((6-(difluoromethyl)-8-((l/?,27?)-2-hydrox y-2-methylcyclopentyi)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)amino)piper idin-l-yl)sulfonyl)propyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B134;

3-(3-(4-(2-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydrox y-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t7]pyrimidin-2-yl)amino)piperidi n-l-yl)sulfonyl)ethyl)piperazin-l- yl)phenyl)piperidine-2, 6-dione B135;

3-(3-(4-(3-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydrox y-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-i7]pyrimidin-2-yl)aniino)piperid in-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)su lfonyl)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)piperidi n-l-yl)sulfonyl)benzyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B139;

3-(4-(4-(3-((4-((6-(difl _UO romethyl)-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)piper idin-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-hydrox y-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tf]pyrimidin-2-yl)amino)piperidi n-l -yl)sulfonyl)benzyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B142;

3-(4-((4-(4-((4-((6-(difluoromethyl)-8-((l/<2/?)-2-hyd roxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-(7]pyrimidin-2-yl)amino)piperidi n-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-hy droxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-y l)amino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)piperidin e-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)piperid in-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-hydro xy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)aniino)pipe ridin-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-hydrox y-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t(|pyrimidin-2-yl)amino)piperidi n-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-hydro xy-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)p iperidin-l-yl)phenyl)piperidine-2,6- di one Bl 50;

3-(4-(2-(4-(4-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hyd roxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyriniidin-2-yl)am ino)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-hyd roxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)ami no)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-hyd roxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<f|pyrimidin-2-yl)ami no)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-hydrox y-2-methylcyclopentyl)-

7-oxo-7,8-dihydropyrido[2,3-^pyrimidin-2-yl)amino)piperid in-l-yl)sulfbnyl)piperazin-l-yl)- ethoxy)phenyl)piperidine-2, 6-dione B154;

3-(4-(3-(4-((4-((6-(difluoromethyl)-8-((lZ7,2 _J R)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidi n-l-yl)sulfonyl)piperazin-l-yl)- propoxy )phenyl)piperidine-2, 6-dione B155;

3-(3-(3-(4-((4-((6-(difluoromethyl)-8-((l/?,2/?)-2-hydrox y-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyriniidin-2-yl)amino)pipe ridin-l-yl)sulfonyl)piperazin-l-yl)- propoxy )phenyl)piperidine-2, 6-dione Bl 56;

3-(4-(4-(4-((4-((6-(difluoromethyl)-8-((17?,2 _J R)-2-hydroxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t(|pyrimidin-2-yl)amino)piperidi n-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-h ydroxy-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-hyd roxy-2-nietliylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)ami no)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)piper idin-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-methyl cyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-tZ]pyrimidin-2-yl)amino)piperidi n-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-hydro xy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-</]pyrimidin-2-yl)amino)piper idin-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)prop yl)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)piper _a zin-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-o xo-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-cyclop _en tyl-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)pipera zin-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'-bipi peridin]-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)cy clohexyl)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-o xo-7,8-dihydropyrido- [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cycl ohexyl)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)piperazi n-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)met hyl)cyclohexyl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B179;

3-(4-(4-(2-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-o xo-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)cyclohex yl)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)cyclohexy l)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)piperidi n-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'-bipip eridin]-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-cyclop _en tyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)cyclohex yl)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)pipe ridin-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-y l)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-d ihydropyrido[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-d ihydropyrido[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-d ihydropyrido[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'-bipiperi din]-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)pi perazin-l-yl)phenyl)piperidine-2,6- di one B201; 3-(4-(r-(2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)-[4,4'-bipipe ridin]-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)piper idin-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)piper azin-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'-bipipe ridin]-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'-bipiper idin]-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)p iperazin-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)p iperidin-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’-bipiperidi n]-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)p iperazin-l-yl)phenyl)piperidine- 2,6-dione B210;

3-(4-(4-(((5)-4-(6-((6- _aC etyl-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-o xo-7,8-dihydropyrido- [2,3-tf]pyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-yl)met hyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B212;

3-(3-(4-(((5)-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-ox o-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)piper azin-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-y l)ethyl)phenyl)piperidine-2,6-dione B215;

3-(4-((5)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-ox o-7,8-dihydropyrido-

[2,3 -<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)meth yl)morpholino)phenyl)piperi dine- 2,6-dione B216;

3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-o xo-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-d ihydropyrido[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)piperidi n-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)met hyl)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)pi perazin-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)aze tidin-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-y l)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-d ihydropyrido[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)phe nyl)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-y l)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)phe nyl)piperidine-2, 6-dione B237;

3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-tfl- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)p henyl)piperidine-2, 6-dione B238;

3-(4-(r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-(7]~ pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)p henyl)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-d ihydropyrido[2,3-t/j- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)p henyl)piperidine-2, 6-dione B241;

3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)p henyl)piperidine-2, 6-dione B242;

3-(3-(r-(6-((6-acetyl"8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)p henyl)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-d ihydropyrido[2,3-t/j- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)p henyl)piperidine-2, 6-dione B245; 3-(4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)p iperidin-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)pi perazin-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)p iperidin-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)p iperidin-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)p iperidin-l-yl)phenyl)piperidine-2,6- dione B251;

3-(4-(lX(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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)pi peridin-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)pi peridin-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)pi perazin-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)pi peridin-l-yl)phenyl)piperidine-2,6- dione B256;

3-(3-(l -(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydr opyrido[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)ethy l)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)pi perazin-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)pi peridin-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)e thyl)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'-bipiperi din]-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'-bipiper idin]-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)piperidi n-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)pipe razin-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'-bipipe ridin]-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)pip eridin-l-yl)phenyl)piperidine-2,6- dione B272;

( ₁ S)-3-(4-(4-(((5 ^T )-4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dih ydro- pyrido[2,3-Jjpyrimidin-2-yl)amino)pyridin-3-yl)morpholin-2-y l)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)pi peridin-4-yl)phenyl)piperidine-2,6- dione B274;

3-(4-((r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)m ethyl)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'-bipi peridin]-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)az etidin-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'-bipiperi din]-4-yl)ethyl)phenyl)piperidine- 2,6-dione B286;

3-(4-((r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3V|- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidi n]-4-yl)methyl)phenyl)piperidine- 2,6-dione B287; 3-(3-((r-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihy dropyrido[2,3-i/]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidi n]-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-fliior oazetidin-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-fluor oazetidin-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-flu oroazetidin-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)pipera zin-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-fl uoropiperidin-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)methy l)-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-cy _C l _O pentyl-5- _m ethyl-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)et hyl)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)pip erazin-l -yl)phenyl)-3-m ethyl- piperidine-2, 6-dione B309;

(7?)-3-(4-(4-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-ox o-7,8-dihydropyrido- [2,3 -d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazi n-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-dihydrop yrido[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-a _C etyl-8-cy _C l _O pentyl-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)pi peridin-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)pi peridin-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)pip eridin-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)su lfonyl)ethoxy)phenyl)- piperidine-2, 6-dione B353; 3-(4-(4-(((4-((6-(difluoromethyl)-8-((17?,27?)-2-hydroxy-2-m ethylcyclopentyl)-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-hyd roxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)am ino)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-hyd roxy-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidi n-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-hy droxy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-y l)amino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)piperidin e-2, 6-dione B357;

4-(3-(4-((4-(3-((4-((6-(difluoromethyl)-8-((17?,27?)-2-hy droxy-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)piperidin e-2, 6-dione B358;

3-(4-(2-(4-((4-((6-(difluoromethyl)-8-((lZ^,2/?)-2-hydrox y-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidi n-l-yl)sulfonyl)piperazin-l-yl)- ethyl)phenyl)piperidine-2, 6-dione B359;

3-(4-(4-(4-((4-((6-(difluoromethyl)-8-((17?,2/?)-2-hydrox y-2-methylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)aniino)pipe ridin-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-hydro xy-2-methylcyclopentyl)-

7-oxo-7,8-dihydropyrido[2,3-t7jpyrimidin-2-yl)amino)piper idin-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-hydro xy-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-d ihydropyrido[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)pi peridin-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-ox o-7,8-dihydropyrido- [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)meth yl)-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-diazas piro[2.5]octan-4-yl)phenyl)- piperidine-2, 6-dione B370;

(/^)-3-(4-((7?)-2-((4-(6-((6-acetyl-8-cyclopentyl-5-methy l-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-methy l-7-oxo-7,8-dihydro- pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-y l)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)piper idin-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-y l)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)piper idin-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)piperidi n-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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-ac _e tyl-8-cycl _O pentyl-5- _me thyl-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)pi peridin-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)pip erazin-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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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)et hyl)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)et hyl)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)pi peridin-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)et hyl)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)p iperidin-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)et hyl)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-d ihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)p iperidin-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-d ihydropyrido[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-fluor oazeti 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]-pyrimid in-2-yl)amino)pyridin-3- yl)piperazin-l-yl)-2-oxoethoxy)-l-methyl-177-indazol-3-yl)-p iperidine-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-&l t;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-fl uoroazetidin-3-yl)ethyl)-l-methyl-lJ ^c f- 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)ethy l)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)eth yl)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)ethy l)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)pi peridin-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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-di hydropyrido[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-ox o-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-dih ydropyrido-

[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-ox o-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-fluor oazetidin-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-di hydropyrido[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-d ihydropyrido[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-dihydropyrid o[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fluor oazetidin-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-di hydropyrido[2,3- t7jpyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiper idin]-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-di hydropyrido[2,3- t(|pyrimidin-2-yl)aniino)pyridin-3-yl)-4-fluoro-[l,4'-bipipe ridin]-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-di hydropyrido[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)pi perazin“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-d ihydropyrido[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-oxoeth yl)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-d ihydropyrido[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]pyrimidi n-2-yl)amino)pyridin-3- yl)piperazin-l-yl)ethoxy)benzyl)piperidin-4-yl)-l-oxo-isoind olin-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, ¹⁵ N for nitrogen; ¹⁷ O or ¹⁸ O for oxygen, and ³⁴ S, ³⁵ S, or ³⁶ S 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, A ^r ,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/m ² /day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m ² /day to given either the height or weight of a subject or both. For example, a dose of 1 mg/m ² /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>]pyri dinium 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)phosphi ne); 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)-A ^r ,A-dimethyl-7/7-pyrrolo[2,3-d ^r ]pyrimidine- 6-carboxamide A104

[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)pyrro lo- [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-y l]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-carboxami de 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)-A ⁷ ,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-dimet hyl-7rt-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A105

[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-carboxam ide 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,A ^r -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)-A ⁷ ,A ^/ -dimethyl-777-pyrrolo[2,3-i/|pyrimidine- 6-carboxamide A106

[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. ^r H 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-carbo xamide 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. 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-dime thyl-7//-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A107

[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-A ^r ,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-carboxamid e 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)phe n- oxy]acetyl]-4-piperidyl]butyl]piperazin-l-yl]anilino]-A,A-di methylpyrrolo[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. ^r H 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)phe noxy)acetamido)- ethyl)piperazin-l-yl)phenyl)amino)-/V,A ⁷ -dimethyl-7A ^r -pyrrolo[2,3-^]pyrimidine-6-carboxamide

A108

[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’,A ^L 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)phe noxy)- 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. ^r H 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)phe noxy)acetamido)- propyl)piperazin-l-yl)phenyl)amino)-A,A ^r -dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine-6-carboxami de

Alli

[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-A ⁷ ,A ⁷ -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, A ⁷ - 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)phe noxy)- acetamido)-propyl)piperazin-l-yl)phenyl)amino)-7V,A ^z -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)pi perazin-l-yl)- phenyl)amino)-A’,A ^r -dimethyl-7Z7-pyrrolo[2,3-J|pyrimidine-6-carboxamide A117

[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-t Z]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)pyrrol o[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)-A ⁷ ,A-dimethyl-7/7-pyrrolo[2,3-t/]pyrimidine-6-carboxamid e A119

[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-carboxamid e Al 19. To a solution of 7-cyclopentyl-A,iV-dimethyl-2-(4-piperazin-l-ylanilino)pyrro lo[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. 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-carboxa mide A120

[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)-A ^z ,A’-dimethyl-71 ^L /-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-carboxamid e (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

[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-cyclop entyl- 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-pyrrol o[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

[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. ^r H 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- d ₆ ) 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,A ^z -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

[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. 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. ^T H 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. ^l H 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-carboxamid e A128

[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. ^l H 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. ^r H 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)anili no]- 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-pyrrol o[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). ^l H 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]pyri midine-6-carboxamide A130

[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-A ⁷ ,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. ^r H 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-carb oxylate 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. ^L H 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-A ^r ,A ^r -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. (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-pyrrol o[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. ^r H NMR (400 MHz, DMSO-J ₆ ) 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)-A ⁷ ,A-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxa mide A131

[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-A ^r ,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 (SiO ₂ , 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)- ₂ V,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 H ₂ 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. ¹ H 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 Na ₂ SO4, concentrated, and purified by column chromatography (SiO ₂ , 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 (SiO ₂ , 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-c arboxylate 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. ^l H 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)a nilino]- 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. ^r H 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)-A ^r pV -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)pheny l)piperidin-4-yl)- piperazin-l-yl)methyl)phenyl)amino)-A ^r ,A’-dimethyl-77f-pyrrolo[2,3-cf]pyrimidine-6- carboxamide A132

[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)p yridine (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. ^V H 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 H ₂ , 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 Pd ₂ (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 (SiO ₂ , 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)-A ^r ,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. ^L H 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)phe nyl)piperazin-l - yl)piperidin-l-yl)ethoxy)phenyl)amino)-A,A’-dimethyl-777-p yrrolo[2,3-t/]pyrimidine-6- carboxamide A133

[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)phe nyl)- piperazin-l-yl)piperidin-l-yl)ethoxy)phenyl)amino)-A,A ^z -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)phe nyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)phenyl)amino)-A ⁷ ,A’-dimethyl-7/f-pyrrolo[2,3-<7]pyrimidine-6-carb oxamide A134

[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)phe nyl)- piperazin-l-yl)-piperidin-l-yl)ethoxy)phenyl)amino)-A(AMimet hyl-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).

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)phe nyl)piperidin-4-yl)- piperazin-l-yl)ethyl)phenyl)amino)-A ^z ,jV-dimethyl-7H-pyrrolo[2,3-tf|pyrimidine-6-carboxamid e

A135

[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)p yridine (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. ^r H 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-A ^r ^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)phe nyl)- piperidin-4-yl)-piperazin-l-yl)ethyl)phenyl)amino)-jV,A-dime thyl-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. ^r H 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

[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)a mino)-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,A ^z -dimethyl-2-((4-(4-(piperidin-4-yl)piperazin- 1 - yl)phenyl)amino)-727-pyrrolo[2,3-<7]pyrimidine-6-carboxam ide 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)-A ⁷ ,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. ^L H 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

[00506] Compound A139 was prepared as described below.

[00507] Preparation of 7-cyclopentyl-A ^r ,A ^r -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)phenet hyl)- 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-7 ₆ ) 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)phenet hyl)piperidin-4-yl)- piperazin-l-yl)phenyl)amino)-A,7/-dimethyl-7/7-pyrrolo[2,3-t /]pyrimidine-6-carboxamide A140

[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. ^r H 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-J ₆ ) <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)pi peridine-l -carboxylate 22.4. A solution of 7-cyclopentyl-A,jV-dimethyl-2-((4-(piperazin-l-yl)phenyl)ami no)-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,A ⁷ -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)phenet hyl)- piperidin-4-yl)-piperazin-l-yl)phenyl)amino)-A,A ^z -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)pheny l)piperidin-4-yl)- methyl)piperazin-l-yl)phenyl)amino)-ApV-dimethyl-7/7-pyrrolo [2,3-<7]pyrimidine-6- carboxamide Al 41

[00516] Compound A141 was prepared as described below ⁷ .

[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)pheny l)- piperidin-4-yl)-methyl)piperazin-l-yl)phenyl)amino)-7V,A-dim ethyl-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. ^r H 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)pheny l)piperidin-4-yl)- methyl)piperazin-l -yl)phenyl)amino)-A ^r ,A ^r -dimethyl-7/f-pyrrolo[2,3-tf]pyrimidine-6- carboxamide Al 42

[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. ^l H 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. (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-di methyl-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)phe nyl)piperidin-l-yl)- ethyl)piperazin-l-yl)phenyl)amino)-7V,A-dimethyl-7/7-pyrrolo [2,3-d]pyrimidine-6-carboxamide A143

[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 (SiO ₂ , 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. ^l H 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. (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)phe nyl)piperidin-l-yl)- ethyl)piperazin-l-yl)phenyl)amino)-7V,A-dimethyl-7//-pyrrolo [2,3-<7]pyrimidine-6-carboxamide

A144

[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]acetaldeh yde 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)phe nyl)- piperidin-l-yl)-ethyl)piperazin-l-yl)phenyl)amino)-A(,A’-d imethyl-77/-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A144. To a solution of compound 26.6 (40 mg, 127 pmol), 7-cyclopentyl-A ^r ,A ^L 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. 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)ben zyl)piperazin-l-yl)- phenyl)piperazin-l-yl)pyridin-2-yl)aniino)-A ^r ,A-diniethyl-777-pyrrolo[2,3-cf]pyrimidine-6- carboxamide Al 45

[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. ^r H 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,A ⁷ - 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. ^X H 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-c arboxamide 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)ben zyl)- 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)ben zyl)piperazin-l-yl)- phenyl)piperazin-l -yl)pyridin-2-yl)amino)-A _T A-dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A148

[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-c arboxamide 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)ben zyl)- piperazin- l-yl)-phenyl)piperazin-l-yl)pyri din-2 -yl)amino)-A,A ⁷ -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)phe nyl)piperazin-l-yl)- benzyl)piperazin-l-yl)pyridin-2-yl)amino)-ACV-dimethyl-7/f-p yrrolo[2,3-£f]pyrimidine-6- carboxamide A151

[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)phe nyl)- 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-A ^r ,A ^L dimethyl-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- d ₆ ) 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)ph enyl)piperazin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A(A-dimethy l-7F-pyrrolo[2,3-J]pyrimidine- 6-carboxamide A154

[00555] Compound A154 was prepared as described below.

[00556] Preparation of 7-cyclopentyl-2-[[5-[4-(4-formylphenyl)piperazin-l-yl]-2-pyr idyl]- amino]-A ⁷ ,A' ^r -dimethylpyrrolo[2,3-t/]pyrimidine-6-carboxamide 30,1. A mixture of 7-cyclo- pentyl-7V,A ^z -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)ph enyl)- 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. ^L H 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)phenet hyl)cyclohexyl)- piperazin-l-yl)pyridin-2-yl)amino)-A'’,A-dimethyl-7/f-pyrr olo[2,3-d]pyriniidine-6-carboxamide

A155

[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)phenet hyl)- 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-pyrro lo[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. ^r H 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)phenet hyl)piperidin-4-yl)- piperazin-l-yl)pyridin-2-yl)amino)-A,jV-dimethyl-777-pyrrolo [2,3-t/]pyrimidine-6-carboxamide

A156

[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]piperidin e-l -carboxylate 32.1. To a solution of 7-cyclopentyl-A(A-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)am ino]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 w ⁷ ater 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-A ^r ,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)phenet hyl)- piperidin-4-yl)-piperazin-l-yl)pyridin-2-yl)amino)-77,A-dime thyl-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. ^r H 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)phe noxy)ethyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A ^r ,7V-dimethyl-777-pyrrolo[2,3-i7]pyrimidine-6- carboxamide Al 57

[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)phe noxy)- ethyl)-piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-AL& lt;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)pheny l)-[ l,4'-bipiperidin]-

4-yl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-A ⁷ ,A' ^r -dimethyl-7Ef-pyrrolo[2,3-J|-pyrimidine-6- carboxamide Al 59

[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)piperazi n-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,A ^z -dimethyl-2-((5-(4-(piperidin-4-ylmethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7/f-pyrrolo[2,3-</|pyr imidine-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)pheny l)- [l,4'-bipiperidin]-4-yl)methyl)piperazin-l-yl)pyridin-2-yl)a mino)-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. 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)phe noxy)ethyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7V,A ⁷ -dimethyl-7ff-pyrrolo[2,3-</|pyriniidine-6- carboxamide A160

[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)phe noxy)- ethyl)-piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A ^/ ,A ⁷ -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)phe nyl)piperazin-l- yl)propyl)piperazin- 1 -yl)pyridin-2-yl)amino)-A ^r ,AMiniethyl-777-pyrrolo[2, 3 -cZ]pyrimidine-6- carboxamide Al 61

[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-carbox amide 36.1, To a solution of 7- cyclopentyl-A ^r ,A ^T -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)-A ^r ,A ⁷ -dimethyl-7J7-pyrrolo[2,3 -t/]pyrimidine-6- carb oxami de A 162

[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]piperi dine-l -carboxylate 37.1, A mixture of 7-cyclopentyl-jV,A-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)a mino]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-A ^r ,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 ,A ^r -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. ^r H 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)ph enyl)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

[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)-A ^r ,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. ^r H 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)am ino)-A,A'’-dimethyl-7//-pyrrolo[2,3- t/]-pyrimidine-6-carboxamide Al 68

[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)ami no]- 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-A ⁷ ,A’-dimethyl-2-[[5-[4-[[(27?)-morpholin-2-yl]- methyl]piperazin-l-yl]-2-pyridyl]amino]pyrrolo[2,3-t/]pyrimi dine-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)p yridin-2-yl)amino)-A,A ⁷ -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)am ino)-A(A ^r -dimethyl-7H-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A169

[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-A ^r ^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/]pyrimi dine-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)p yridin-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. ^T H 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)ph enyl)piperazin-l-yl)- cyclohexyl)methyl)piperazin-l-yl)pyridin-2-yl)amino)-/V,A-di methyl-7//-pyiTolo[2,3-<7]- pyrimidine-6-carboxamide A170 [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. ^r H 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)ph enyl)- 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'',A ⁷ -dimethyl- 2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-<f|pyrim idine-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,A ^r -dimethyl-7/7-pyrrolo[2,3-tZ]- pyrimidine-6-carboxamide A171

[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. ^T H 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. ^l H 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]cycl o- 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)am ino]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(AMi methyl-777-pyrrolo[2,3</]- pyrimidine-6-carboxamide Al 73

[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)et hyl]- 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). ^L H 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]piperi dine- 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)pyridi n-2-yl)amino)-A ^r ,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 ^/ ',A ⁷ -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. ^r H 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)- A ^T ,Al-dimethyl-7J/-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A174

[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]acetaldeh yde 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)py ridin-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]pyrrol o[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. ^r H 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)ph enyl)-[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

[00627] Compound A175 was prepared as described below.

[00628] Preparation of 7-cyclopentyl-2-[[5-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2-pyridyl] - amino]-A ⁷ ,A' ^r -dimethylpyrrolo[2,3-i/]pyrimidine-6-carboxamide 45.1. To a solution of 7-cyclo- pentyl-A’,A ^z -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-carboxa rnide 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)ph enyl)- [4,4'-bipiperidin]-l-yl)ethyl)piperazin-l-yl)pyridin-2-yl)am ino)-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). ^l H 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)phe nyl)-[l,4'- bipiperidin]-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^/ ,A ^f -dimethyl-7Lf-pyrrolo[2,3-tZ]- pyrimidine-6-carboxamide A176

[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-A ^r ,A ^r -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-A ⁷ ,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)phe nyl)- [ 1 ,4'-bipiperidin]-4-yl)ethyl)piperazin- 1 -yl)py ridin-2-yl)amino)-A ^z ,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

[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. (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]propa n-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. ^r H 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)phe nyl)- piperidin-4-yl)-propyl)piperazin-l-yl)pyridin-2-yl)amino)-A ⁷ ,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,A ⁷ -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. 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)phe nethyl)piperidin-4- yl)cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A ^T -dimethyl-7/7-pyrrolo[2,3-d]pyrimidine-6- carboxamide Al 81

[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-2A ^f - 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)cyclohex yl]- 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)phe n- 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, CD ₃ OD) 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/]pyr imidine-6-carboxamide A182

[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,A ^r -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,A ⁷ - 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)-A ⁷ ,A’-dimethyl-77/-pyrrolo[2,3-<f]pyrimidine-6-carb oxamide A183

[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. ^L H 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 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-carbo xylate 50.2. To a mixture of compound 50.1 (0.5 g, 1.72 mmol), 2-chloro-7-cyclopentyl-A ^r _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-pyrid yl]- 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,A ^z -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. ^S H 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

[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(A ⁷ -dimethyl-7H-pyrrolo[2,3-J]pyriniidine-6-carboxamide A186. [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, (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)pipe ridine-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. ^r H 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)p yridin-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(A ^L dimethyl-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. 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 [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. ^r H NMR (400 MHz, DMSO-d ₆ ) 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'’,A ^T -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

[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]-A ^r ,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]pyrimidin e- 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. (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)pheny l)- [4,4'-bipiperidin]-l-yl)ethyl)pyridin-2-yl)amino)-A,A-dimeth yl-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. ^r H NMR (400 MHz, DMSO-J ₆ ) 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

[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. ^r H 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. ^T H 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-dimeth yl-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-carboxam ide A192

[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. ^r H 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. ^r H 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]piperid ine-l-carboxylate 56.3. To a mixture of compound 56.2 (350 mg, 1.06 mmol), 2-chloro-7-cyclopentyl-A ^r ,A ⁷ -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-A ⁷ ,A ⁷ -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 w ⁷ as 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 w ⁷ ith 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)-A ^r ,jV-dimethyl-7/f-pyrrolo[2,3-t/]- pyrimidine-6-carboxamide A194

[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,A ⁷ -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-c yclo- 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)ph enyl)- piperidin-4-yl)-methyl)azeti din-3 -yl)piperazin- 1 -yl)pyri din-2-yl)amino)-A, A ^r -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. (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)-A ^r ,A-dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A196

[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-pyrid yl]- 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. ^l H NMR (400 MHz, DMSO-7 ₆ ) <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)phe nyl)piperazin-l-yl)- cyclohexyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7 77-pyrrolo[2,3-7]pyrimidine-6- carboxamide A197

[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)phe nyl)- 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)amin o]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)phe nyl)piperazin-l-yl)- cyclohexyl)piperidin-l -yl)pyridin-2-yl)amino)-A,A'’-dimethyl-7/f-pyrrolo[2,3-J]p yrimidine-6- carboxamide Al 98

[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-nitropyr idine

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-a mine 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. ^r H 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. ^X H 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-A ^r ,A-dimethyl-2-[[5-[4-(4-oxocyclohexyl)-l- piperidyl]-2-pyridyl]amino]pyrrolo[2,3-<7]pyrimidine-6-ca rboxamide 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)phe nyl)- 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)pheny l)piperidin-4-yl)- piperazin-l-yl)methyl)pyridin-2-yl)amino)-A ^r ,AMimethyl-7rt-pyrrolo[2,3-r7]pyrimidine-6- carboxamide A200

[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. ^J H 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, 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. (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)pheny l)- piperidin-4-yl)-piperazin-l-yl)methyl)pyridin-2-yl)amino)-A' ',A ^r -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-dimethylpyrrol o[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

[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)a mino)- 7-cyclopentyl-A,A ^; -dimethyl-7//-pyrrolo[2,3-</]pyrimidine-6-carboxami de 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,j V- 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)pheny l)- [4,4'-bipiperidin]-l-yl)propyl)pyridin-2-yl)amino)-A(A-dimet hyl-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,A ^r -dimethyl-7/T-pyrrolo[2,3-J|pyrimidine-6-carboxamide

A205

[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-ca rboxylate 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(A ^r -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-di methyl-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,A ^z -dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A207

[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-ca rboxamide 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,A ^z -dimethyl-7/f-pyrrolo[2,3-J]pyrimidine-6- carboxamide A208

[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(A ^r -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-7/7 ^r -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. ^r H 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)phenet hyl)piperazin-l-yl)- piperidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7#-pyrrolo[2 ,3-7]pyrimidine-6-carboxamide

A209

[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]piperaz ine-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-pipe ridyl)- 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)phenet hyl)- piperazin-l-yl)-piperidin-l-yl)pyridin-2-yl)amino)-A,A-dimet hyl-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. ^T H 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), 1.69-1.79 733.5 [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’,A ^r -dimethyl-7//-pyrrolo[2,3-tf]pyrimidine-6-carboxamide A210

[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. ^l H 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. ^r HNMR (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

[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-pyr rolo[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. ¹ H 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)phe nyl)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

[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]benzaldeh yde 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)phe nyl)- piperidin-l-yl)-benzyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^r ,A ⁷ -dimethyl-7/f-pyrrolo[2,3-J]- pyrimidine-6-carboxamide A215. To a solution of 7-cyclopentyl-A ^f ,A ^r -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. ^r H 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)ph enyI)piperidin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A-dimethy l-7/Z-pyrrolo[2,3-4/]pyrimidine- 6-carboxamide A216

[00764] Compound A216 was prepared as described below.

[00765] Preparation of 7-cyclopentyl-2-[[5-[4-(4-formylphenyl)piperazin-l-yl]-2-pyr idyl]- amino]-A^V-dimethylpyrrolo[2,3- d]pyrimidine-6-carboxamide 70.1, A mixture of 7-cyclo- pentyl-A ⁷ , _J 'V-dimethyl-2-[(5-piperazin-l-yl-2-pyridyl)amino]pyrro lo[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. ^l H 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)ph enyl)- 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. ^r H 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)pheny l)piperazin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-A',iV-dimethyl-7f/ -pyrrolo[2,3-</]pyrimidine-6- carboxamide A223

[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)pyrid in-2- yl)amino)-A\A ⁷ -dimethyl-7//-pyrrolo[2,3-<i]pyrimidine-6-carboxami de 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)- A ^A ,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. ^r H 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)pheny l)- piperazin-l-yl)-methyl)piperidin-l-yl)pyridin-2-yl)amino)-?f ,A ^r -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. ^l H 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)phe nyl)piperidin-4-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A'',A' ^r -dimethyl-7H-pyrrolo[2,3-tf]pyrimidine-6- carboxamide A231

[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. (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-y l)- 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)phe nyl)- piperidin-4-yl)-ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A ⁷ -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-car boxamide (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. ^L H 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)phe nyl)piperazin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-/V,jV-dimethyl-7/f- pyrrolo[2,3-d]pyrimidine-6- carboxamide A235

[00779] Compound A235 was prepared as described below.

[00780] Preparation of 2-[[5-[l-(2-bromoethyl)-4-piperidyl]-2-pyridyl]amino]-7-cycl o- 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]-A ^r //-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)phe nyl)- 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,A ^r -dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6-carboxami de A236

[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. ^L H 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]pyrim idine-6-carboxamide A237 [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]pipe ridine-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-carboxylat e 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. 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)phenethy l)- [4,4'-bipiperidin]-l-yl)pyridin-2-yl)amino)-7V,A ^r -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)phenethy l)-[ 1 ,4 -bipiperidin]-

4-yl)pyridin-2-yl)amino)-A ^/ ,A'-dimethyl-77/-pyrrolo[2,3-<7]pyrimidine-6-carbox amide A238

[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-y l)- 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. ^L H 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'-b ipiperidine]-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-cyclope ntyl- A(A-dimetliyl-7A ^r -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. ^L H 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)phenethy l)- [l,4'-bipiperidin]-4-yl)pyridin-2-yl)amino)-A ^/ ,A ^r -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

[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. ^r H 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. ^r H 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)-A ^r ,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-diox opiperidin-3-yl)- phenethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)- 7H-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A245

[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-d ioxo- piperi din-3 -yl)-phenethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)am ino)-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. (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)phe nyl)piperidin-4-yl)- ethyl)piperi din-1 -yl)pyridin-2-yl)amino)-A ^z ,/V-dimethyl-7//-pyrrolo[2,3-djpyrimidine-6- carboxamide A246

[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)piperid in-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)pipe ridin- 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-dio xo- piperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-l-yl)py ridin-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]pyrimidi ne-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)phe nyl) piperidin-4-yl)-ethyl)piperidin-l-yl)pyridin-2-yl)annno)-A(A Mimethyl-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. ^r H 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)phe nyl)piperazin-l-yl)- ethyl)piperidin-l-yl)pyridin-2-yl)amino)-A(/V-dimethyl-7.H-p yrrolo[2,3-J]pyrimidine-6- carboxamide A247

[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-carbo xamide 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-carboxa mide (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. ^l H 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)phe nyl)- 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 [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',A ⁷ -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]py rimidine-6-carboxamide A250

[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. 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]piperidin e-l-carboxylate 82.3. To a solution of 7-cyclopentyl-2-[(5-hydroxy-2-pyridyl)amino]-A,A ^r -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]ami no]-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). ^r H 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

[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//-pyrro lo[2,3-(7]pyrimidine-6- carboxamide A253

[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-dimet hyl-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-carb oxamide (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. ^l HNMR (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

[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. 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)phe nyl)- 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-A ^r ,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. ^l H 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)phe nyl)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

[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]azetid in-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. (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)phe nyl)- 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)amin o]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. ^r HNMR (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)phe nyl)-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

[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)phe nyl)- 2,2-difluoroethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl )amino)-A ⁷ ,A-dimethyl-7/f-pyrrolo- [2,3<(|pyrimidine-6-carboxamide A260. To a solution of 7-cyclopentyl-A(A ^r -dimethyl-2-((5-(4- (piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-7J7-pyrro lo[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. 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)phe nyl)-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

[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)phe nyl)- 2,2-difluoro-ethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-y l)amino)-A ^r _T A-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]p yrimidine-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/-pyrr olo[2,3-<7]pyrimidine-6- carboxamide A267

[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. ^r H 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)-A ^z ,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. ^r H 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)phenet hyl)-3-fluoro- azeti din-1 -yl)piperi din- l-yl)pyridin-2-yl)amino)-A’,A'-dimethyl-7//-pyrrolo[2,3-&l t;7]pyrimidine-6- carboxamide A269

[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- A ^L (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, (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 (SiO ₂ , EtOAc/PE) to afford compound 90.4 (2.5 g) in 420% yield. ^r H 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)phenet hyl)- 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-A ^r pV-dimethyl-2-[[5-(4-oxo- l-piperidyl)-2-pyridyl]amino]pyrrolo[2,3-iZ]pyrimidine-6-car boxaniide (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)phenet hyl)-3-fluoro- azetidin-l-yl)piperidin-l-yl)pyri din-2 -yl)amino)-jV,Mdimethyl-777-pyrrolo[2,3-d]pyrimidine-6- carboxamide A270

[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. ^r H 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)phenet hyl)- 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-car boxamide (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)phe nyl)-2,2-difluoro- ethyl)piperidin-4-yl)azetidin-l-yl)pyridin-2-yl)amino)-A(A-d imethyl-777-pyrrolo[2,3-d]- pyrimidine-6-carboxamide A271

[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-carbo xamide 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)phe nyl)- 2,2-difluoro— ethyl)piperidin-4-yl)azetidin-l-yl)pyridin-2-yl)amino)-A ^r /V ^r -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-py rrolo[2,3-<7]pyrimidine-6- carboxamide A277

[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)phenet hyl)piperidin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,A ⁷ -dimethyl-7/f-pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A278

[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)-am ino)- 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)phenet hyl)- pi peri din- 1 -yl)-azetidin- 1 -yl)pyridin-2-yl)amino)-A,A ^r -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, 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)pheny l)azetidin-l-yl)- methyl)-4-fluoropiperidin-l-yl)pyridin-2-yl)amino)-A(A-dimet hyl-777-pyrrolo[2,3-</]pyrimidine- 6-carboxamide A284

[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-carboxamid e 95.7. A mixture of compound 95.6 (790 mg, 2.93 mmol), 2-chloro-7-cyclopentyl-A(A ^r -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,A ^T -dimethyl-pyrrolo[2,3-d ^f ]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)pheny l)- azetidin-l-yl)-methyl)-4-fluoropiperidin-l-yl)pyridin-2-yl)a mino)-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. ^l H 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

[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/z ¹ . 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)amin o)-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)amin o]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)-A ^f ,A -dimethyl -7#-pyrrolo[2, 3 -<7]- pyrimidine-6-carboxamide A291

[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)-A ^r ,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)ami no]- 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. ^X H 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)p iperidin-4-yl)ethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A,A ⁷ -dimethyl-77/-pyrrolo[2,3-</|pyrimidine-6- carboxamide A292

[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-c yclopentyl-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. ^r H 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)p iperidin-4-yl)ethyl)- piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-A,A-dimethy l-7//-pyrrolo[2,3-</]pyrirnidine-6- carboxamide A293

[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. ^l H 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-c yclopentyl-A,.V-dimethyl-777- pyrrolo[2,3-c/]pyrimidine-6-carboxamide A293. To a mixture of 7-cyclopen1y4-A,A ^z -dimethyl-2- [(5-piperazin-l-yl-2-pyridyl)amino]pyrrolo[2,3-<Z]pyrimid ine-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-fluoro phenethyl)-4-fluoro- [I,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-ACV-dimethyl-7EL pyrrolo[2,3-J]pyrimidine-6- carboxamide A299 [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]piperidi ne-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)am ino)-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-A ^r ,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. ^L H 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-fluorop henethyl)-4-fluoro- [l,4'-bipiperidin]-r-yl)pyridin-2-yl)amino)-A,iV-dimethyl-7/ /-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A353

[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]piperidi ne-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-pyrid yl]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. 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-dioxotetrahydropyrimid in-l(2/7)-yl)- phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)- AjV-dimethyl-777-pyrrolo[2,3-t7]- pyrimidine-6-carboxamide A401

[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)piper azine-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-A ^r ,A ⁷ -dimethyl-2-((4-((2-(piperazin-l-yl)ethyl)- carbamoyl)phenyl)amino)-7J7-pyrrolo[2,3-7]pyrimidine-6-carbo xamide 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-dioxotetrahydropyrimid in- l(2//)-yl)-phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phe nyl)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)-A _r <V-dimethyl-77/-pyrrolo[2,3 -t/]pyrimidine-6-carboxamide A407

[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 dimethylcyclohexane-l^-diamine (121 mg, 848 pmol), Cui (161 mg, 848 pmol), and 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. ⁱ H 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-di oxo- hexahydropyrimidin-l-yl]phenyl]piperazin-l-yl]anilino]-A(A ^r -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. ^r HNMR (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-py rrolo[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-^+D ₂ O) 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’,A ^r -dimethyl-7H ^r -pyrrolo[2,3-d]pyrimidine-6-carboxamide

A408

[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-pyrid yl]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(A ^r -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. (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 [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,A ^r -dimethyl-2-(4- piperazin-l-ylanilino)pyrrolo[2,3-c/]pyrimidine-6-carboxamid e (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/-pyr rolo[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,A ^r -dimethyl-7//-pyrrolo[2,3-7]pyrimidine-6-carboxamide A410

[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. 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]an ilino]-A,A ^z -dimethyl-pyrrolo[2,3- tZ]pyrimidine-6-carboxamide 106.3. To a solution of compound 106.2 (100 mg, 284 pmol) and 7-cyclopentyl-A ^r ,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. ^r H 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

[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-A ⁷ ,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)-A ^r ,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)-A ^r ,A ⁷ -dimethyl-77f-pyrrolo[2,3-<7|pyrimidine-6- carboxamide A414

[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)-A ^r ,A ⁷ -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. ^l H 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-pyr rolo[2,3-d]pyrimidine-6- carb oxami de A415

[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-jV _r A ^L dimethylpyrrolo[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]-AlA ^z -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-di methyl-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. ^l H 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-pyrrol o[2,3-if]pyrimidine-6- carboxamide A416

[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

[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)-A ^r ,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]pyri midin-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. ¹ H 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)-A ^z ,A-dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A418

[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,A ^L dimethyl-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. ^L H 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

[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)-A ^rl ,A ² - 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. ^r H 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]pyri midine-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. ^r H NMR (400 MHz, DMSO- d ₆ ) 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)-jV _r /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

[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]eth yl]anilino]-A,A ^r -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]benza ldehyde (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)-A ^r ^-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

[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,A ^r -dimethyl-7A ^r - 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-7 7/-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. ^X H 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

[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(A ⁷ -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-dioxotetrahydropyrimidi n- 1 (2#)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethoxy)phenyl)amino)-A,A-dimet hyl-7//-pyrrolo[2,3-7]pyrimidine- 6-carboxamide A427

[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-dioxotetrahydropyrimidi n-

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]pyri midin-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

[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. ⁱ H 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]pipe razin-l-yl]anilino]-/V,iV-dimethyl- pyrrolo[2,3-d]pyrimidine-6-carboxamide 118.3. To a mixture of 7-cyclopentyl-A ^z ,A-dimethyl-2- [4-[4-(4-piperidyl)piperazin-l-yl]anilino]pyrrolo[2,3-c/]pyr imidine-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-7rt ^r -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. ^l H 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-dim ethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6- carboxamide A430

[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(A ^r -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]pipe razin-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) -A ⁷ ,A ⁷ -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)-A ^r ,A ⁷ -dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine- 6-carboxamide A431

[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?)-A ^rl ,A ² -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. ^l H 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]pipe razin-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)pyrrol o[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. ^r H 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)-A ^r ,A ^L dimethyl-7J7-pyrrolo[2,3-t/]pyrimidine-

6-carboxamide A432 [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-A ^r ,A ⁷ - dimethyl-2-(4-piperaziii-l-ylanilino)pyrrolo[2,3-d]pyrimidin e-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. ^r H 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-dioxotetrahydropyrimidi n- 1 (2/7)-yl)phenyl)- piperidin-l -yl)ethyl)piperazin-l-yl)phenyl)amino)-.¥yV-dimethyl-7/f-py rrolo[2,3-<7]pyrimidine- 6-carboxamide A433

[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]piper azin-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-carboxam ide (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-dioxotetrahydropyrimidi n- 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. (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-dioxotetrahydropyrimidi n-l(2//)-yl)phenyl)- piperidin-l-yl)ethyl)piperazin-l-yl)phenyl)amino)-jV,A'-dime thyl-7//-pyrrolo[2,3-(7]pyrimidine- 6-carboxamide A434

[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-carbo xylate 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. 496.2 [M+H] ⁺ . [001046] Preparation of 7-cyclopentyl-2-((4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidi n-

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-dimet hyl-7//-pyrrolo[2,3-£f]pyrimidine-6- carboxamide A435

[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-A ^r ,A ^r - dimethyl-2-[[5-[4-(4-piperidyl)piperazin-l-yl]-2-pyridyl]ami no]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)-A ^r ,A ⁷ -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(2 Z7)-yl)phenyl)- piperidin-4-yl)ethyl)piperazin-l-yl)pyridin-2-yl)amino)-7-cy clopentyl-A,A-dimethyl-7/7- pyrrolo[2,3-d]pyrimidine-6-carboxamide A436

[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. ^L H 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]p iperazin-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-A ^r ,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(2 77)- 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)ami no)-A(A-dimethyl-7H-pyrrolo[2,3-

J|pyrimidine-6-carboxamide A502

[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-meth yl- 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)carb amoyl)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)ami no)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. ^L H 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-dioxotetrahydropyrimidi n-l(2Z/)-yl)-l- methyl-l//-indazol-6-yl)piperidin-4-yl)ethyl)piperazin-l-yl) pyridin-2-yl)amino)-A,A ^L dimethyl- 777-pyrrolo[2,3-</]pyrimidine-6-carboxamide A559

[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]hexahydropy rimidine-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]acetaldeh yde 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-p iperidyl]ethyl]piperazin-l-yl]-2- pyridyl]amino]-A(A-dimethylpyrrolo[2,3-<7]pyrimidine-6-ca rboxamide 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-carboxami de 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. ^l H 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-di oxoisoindolin-4- yl)amino)hexyl)carbamoyl)phenyl)amino)-A ^f ,A-dimethyl-7J/-pyrrolo[2,3-</]pyrimidine-6- carboxamide A601

[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)isoindoli ne- 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-di oxo- isoindolin-4-yl)amino)hexyl)carbamoyl)phenyl)amino)-jV,A-dim ethyl-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. ¹ HNMR (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)ami no)-A,A-dimethyl-7H- pyrrolo[2,3-J)pyrimidine-6-carboxamide A651

[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,A ^r -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)carbamoy l)phenyl)amino)-A,A ⁷ -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-di hydropyrido[2,3-^- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-3-oxopropo xy)phenyl)piperidine-2, 6-dione B102

[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]py rido[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. ^L H 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-dihyd ropyrido[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

[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. ^r H 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)p yridine (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-pyrid yl)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-dih ydro- 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. ^L H 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-dihyd ropyrido[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

[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]acet ic 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 ofA ^r -(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydro- pyrido[2,3-</|-pyrimidin-2-yl)amino)pyridin-3-yl)piperazi n-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]am ino]-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, 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-dihy dropyrido[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

[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-pyrid yl)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. ^r H 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. ^r H 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-dih ydro- 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)piper idin-l-yl)sulfonyl)ethyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione B130

[001097] Compound B130 was prepared as described below.

[001098] Preparation of 6-(difluoromethyl)-8-[(17?,27?)-2-hydroxy-2-methylcyclopenty l]-2-

[(l-vinyl-sulfonyl-4-piperidyl)amino]pyrido[2,3-</]pyr imidin-7-one 134.1, To a mixture of 6-

(difluoromethyl)-8-[(17?,27?)-2-hydroxy-2-methylcyclopent yl]-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)piper idin-l-yl)sulfonyl)ethyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione B131

[001100] Compound B131 was prepared as described below.

[001101] Preparation of 2-[[l-(3-chloropropylsulfonyl)-4-piperidyl]amino]-6-(difluor o- 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-piperidylami no)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]pyrimid in-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. ^r H NMR (400 MHz, CD ₃ OD) 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

[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-ox o-7,8-dihydro- pyrido[2,3-Jjpyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-y l)piperidin-l-yl)methyl)- morpholino)phenyl)piperidi ne-2, 6- di one B 172

[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]piperidin e-

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]meth yl 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. (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-ox o-7,8- dihydro-pyrido[2,3-Jjpyrimidin-2-yl)amino)pyridin-3-yl)piper azin-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-( -2-((4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dih ydro- 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

[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. ^r H 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]meth yl 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-o xo- 7,8-dihydro-pyrido[2,3-J]pyrimidin-2-yl)amino)pyridin-3-yl)p iperazin-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]ami no]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. 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

[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]az etidine-l-carboxylate 139.1. To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-yl-2-pyrid yl)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]a mino]- 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)piper azin-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-di hydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)-[l ,4'-bipiperidin]-4-yl)piperazin-l -yl)phenyl)piperidine- 2,6-dione B188

[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-iZjpyrim idin-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. 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)cyclohex yl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B190 [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. ^r H 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)pipera zin-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-pyrid yl) 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). 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)pi perazin-l-yl)phenyl)piperidine-2,6- dione B201

[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]amin o]-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]amin o]-8- cyclopentyl-6-(l-ethoxyvinyl)-5-methylpyrido[2,3-<7]pyrim idin-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-Bu ₃ P) 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]amin o]-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. 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)piperazi n-l-yl)etliyl)phenyl)piperidine-2,6- di one B214

[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]piperaz ine-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. (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-d ihydropyrido[2,3- d]pyriniidin-2-yl)amino)pyridin-3-yl)methyl)piperidin-3-yl)p iperazin-l-yl)phenyl)piperidine-

2,6-dione B220

[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-carbaldehyd e (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)et hyl)piperazin-l-yl)phenyl)piperidine-2,6- di one B227

[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-piper idyl]- 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-J J- 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)piper idin-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 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

[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. ^X H 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]pheny l]- 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)pi perazin-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-pyrid yl)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-d ihydropyrido[2,3- tf]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione B236

[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]propa n-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)pr opyl)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. ^L H 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-di hydropyrido[2,3-i/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)propoxy)phe nyl)piperidine-2, 6-dione B237

[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]py ridin- 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]pyr imidin-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-piperidy l]-2- pyridyl]amino]-8-cyclopentyl-6-(l-ethoxyvinyl)-5-methylpyrid o[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-piperidy l]-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-t Z]- 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)pipe ridin-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). ^r H 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-dihyd ropyrido[2,3-^Z]- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)p henyl)piperidine-2, 6-dione B239

[001175] Compound B239 was prepared as described below.

[001176] Preparation of 3-[4-[4-[l-[6-[[8-cyclopentyl-6-(l-ethoxyvinyl)-5-methyl-7-o xo- 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]pi peridine-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-piperi dyl]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-dihyd ropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-yl)p henyl)piperidine-2, 6-dione B243

[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. (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-piperidy l]- 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. 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]phen yl]-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-o xo- 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-piperi dyl]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-dihy dro- pyrido[2,3-J|pyriniidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipip eridin]-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. ^r H 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-dihydrop yrido^S-tiO- pyrimidin^-y^amino^yridin-d-y^piperidinM-yllpiperazin-l-y^ph eny^piperidine^, 6-dione

B244

[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-</]pyrim idin-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 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/]pyrim idin-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. ^r H 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. ^r H 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)piper idin-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-d ihydropyrido[2,3-

J]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl )piperidin-l-yl)phenyl)piperidine-2,6- di one B246

[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-ca rboxylate 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. ^r H 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-pyridy l]- 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. ^r H NMR (400 MHz, DMSO-J ₆ ) 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)piperi din-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. ^l H 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-d ihydropyrido[2,3-

J|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)methyl )piperidin-l-yl)phenyl)piperidine-2,6- di one B249

[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]pyrimid in-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 N ₂ . 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 (SiO ₂ , 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-pyridy l]- 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)pi peridin-4-yl)phenyl)piperidine-2,6- di one B253

[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. ^L H 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-py ridyl)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)pi peridin-4-yl)phenyl)piperidine-2,6- di one B254

[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)piperi din-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)p iperazin-l-yl)phenyl)piperidine-2,6- dione B268

[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]amin o]-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-cyclopenty l-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. ^r H 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-d ihydropyrido[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

[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-carbal dehyde 157.1, A solution of 6- acetyl-8-cyclopentyl-2-[[5-[4-(dimethoxymethyl)-4-fluoro-l-p iperidyl]-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-flu oropiperidin-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- 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

[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]pipera zine-l -carboxylate 158.1. To a solution of tert-butyl 4-[l-(6-amino-3-pyridyl)azetidin-3-yl]piperazine-l-carboxyla te ((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-y l]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-ylazeti din-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)az etidin-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-d ihydropyrido[2,3- tZ]pyrimi din-2 -yl)amino)pyridin-3-yl)piperidin-l-yl)methyl)-4-fluoropiperi din-l-yl)phenyl)- piperidine-2, 6-dione B306

[001224] Compound B306 was prepared as described below.

[001225] Preparation of 2,6-dibenzyloxy-3-[4-[4-(dimethoxymethyl)-4-fluoro-l-piperid yl]- 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]piperi dine- 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)piper idin-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-pyridy l]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)pip erazin-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)p iperidin-4-yl)piperazin-l-yl)phenyl)- 3-methyl-piperidine-2, 6-dione B310

[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]a mino]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)pipe ridin-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)pip eridin-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. ^r H 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 ^r H 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-di hydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l -yl)-2-fluorophenyl)piperidine-2,6- di one B313

[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)piper idin-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-py ridyl]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 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-dihydropyri do[2,3-d]- pyrimidin-2-yl)anlino)pyridin-3-yl)piperidin-4-yl)piperazin- l-yl)-3-fluorophenyl)piperidine-2,6- dione B314

[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)pipe ridin-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-di hydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l -yl)-3-chlorophenyl)piperidine-2,6- di one B316

[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)piper idin-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-di hydropyrido[2,3-r7]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)azeti din- l-yl)phenyl)piperidine-2, 6-dione B317

[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)pipe razin-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)pi peridin-l-yl)-5-fluorophenyl)- piperidine-2, 6-dione B318

[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. ^T H 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. ^r H 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)pi perazin-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]pyrimidi n-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. ^r H 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)pip eridin-l-yl)-2-fluorophenyl)- piperidine-2, 6-dione B322

[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 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. ^r H 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)am ino)piperidin-l-yl)sulfonyl)- propyl)piperazin-l-yl)phenyl)dihydropyrimidine-2, 4(127, 3H)-dione B403

[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. ^r H 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. ^T H 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

[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-oxopyrid o- [2,3<dpyrimidin-2-yl)amino]-3-pyridyl]piperazin-l-yl]ethy l]-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-pyrid yl)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)piper azin-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-di hydropyrido[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

[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). ^r H 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)pipe ridin-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]a mino]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. ^r H 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-fl uoroazetidin-3-yl)ethyl)-l-methyl-lJ/- indazol-3-yl)piperidine-2, 6-dione B504

[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. 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 Na ₂ SO4 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)piperi din-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 Na ₂ SC>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

[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]acetaldeh yde 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-oxopyrid o- [2,3-</]pyrimidin-2-yl)amino]-3-pyridyl]piperazin-l-yl]et hyl]-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-d ihydropyrido[2,3- ^pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethy l)amino)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B602 [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. ^l H 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]ac etic 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-pyrid o[2,3- 7]pyrimidin-2-yl)amino]-3-pyridyl]piperazin-l-yl]-2-oxo-ethy l]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)ph enoxy)acetyl)- piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A,JV-dimethyl-7 2/-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] .

[001301] 7-Cyclopentyl-2-((4-((4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)ph enoxy)acetyl)- piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-7V,A ^z -dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide Al 02.

[001302] 7-Cyclopentyl-2-((4-((6-(4-(2-(3-(2,6-dioxopiperidin-3-yl)ph enoxy)acetyl)- piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-jV,A ^z -dimethyl-7//-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A103.

[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. 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

[001304] 7-Cyclopentyl-2-((4-(4-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-4- (trifluoromethyl)- phenoxy)acetamido)ethyl)piperazin-l-yl)phenyl)amino)-<A ^L dimethyl-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] \

[001305] 7-Cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)-4- methylphenoxy)- acetamido)propyl)piperazin-l-yl)phenyl)amino)-A ^/ ,A ⁷ -dimethyl-7/7-pyrrolo[2,3-fcf]pyrimidine-6- carboxamide A112 ^r H 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] ⁺ .

[001306] 7-Cyclopentyl-2-((4-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)-4- (trifluoromethyl)- phenoxy)acetamido)propyl)piperazin-l-yl)phenyl)amiiio)-A ^r ,A ⁷ -dimethyl-7J7-pyrrolo[2,3- ^pyrimidine-6-carboxamide A113 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] \

[001307] 7-Cyclopentyl-2-((4-((2-(4-(2-(4-(2,6-dioxopiperidin-3-yl)ph enoxy)acetyl)- piperazin-l-yl)ethyl)carbamoyl)phenyl)amino)-A’,A ^r -dimethyl-7H-pyrrolo[2,3-iZ]pyrimidine-6- carboxamide Al 14.

[001308] 7-Cyclopentyl-2-((4-((4-(4-(2-(4-(2,6-dioxopiperidin-3-yl)ph enoxy)acetyl)- piperazin-l-yl)butyl)carbamoyl)phenyl)amino)-/V,A ^/ -dimethyl-7 _J H-pyrrolo[2,3-J]pyrimidine-6- carboxamide Al 15.

[001309] 7-Cyclopentyl-2-((4-((6-(4-(2-(4-(2,6-dioxopiperidin-3-yl)ph enoxy)acetyl)- piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)-A(AMimethyl-7H- pynolo[2,3-d]pyrimidine-6- carboxamide Al 16.

[001310] 7-Cyclopentyl-2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)benzyl)-p iperazin-l-yl)- phenyl)amino)-A(A-dimethyl-7/7-pyrrolo[2,3- J|pyrimidine-6-carboxamide Al 18. ^l H 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] ⁺ .

[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. ^l H 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] ⁺ .

[001312] 7-Cyclopentyl-2-((4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenox y)ethyl)piperazin-l- yl)phenyl)amino)-A ⁷ ,A’-dimethyl-7//-pyrrolo[2,3-tZ]pyrimidine-6-carboxa niide 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]\

[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

[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/]pyrimi dine-6-carboxamide A124.

[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-carboxanii de A125. ^r H 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] ⁺

[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

[001317] 7-Cyclopentyl-2-((4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)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] \

[001318] 7-Cyclopentyl-2-((4-(2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- piperidin-l-yl)ethyl)phenyl)amino)-/V,A ^/ -dimethyl-7J7-pyrrolo[2,3-<7]pyrimidine-6-carboxami de 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] ⁺ .

[001319] 7-Cyclopentyl-2-((5-(4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phe n-ethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^r ,i¥-diniethyl-77f-pyrrolo[2,3-c/]pyrimidine-6- carboxamide A146. ^r H 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] ⁺ .

[001320] 7-Cyclopentyl-2-((5-(4-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phe n-ethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A,A'’-dimethy l-7/f-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A147. 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] ⁺ .

[001321] 7-Cyclopentyl-2-((5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phe nethyl)piperazin-l - yl)phenyl)piperazin-l -yl)pyridin-2-yl)amino)-yV,A ^z -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] ⁺ . [001322] 7-Cyclopentyl-2-((5-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phe nethyl)piperazin-l- yl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^r ,A ⁷ -dimethyl-71 ^E Apyrrolo[2,3-t(|pyrimidine-6- carboxamide A150. 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.

[001323] 7-Cyclopentyl-2-((5-(4-(4-((4-(3-(2,6-dioxopiperidin-3-yl)ph enyl)piperazin-l-yl)- methyl)phenyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^T ,A ^L dimethyl-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] ⁺ .

[001324] 7-Cyclopentyl-2-((5-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- benzyl)piperazin-l-yl)pyridin-2-yl)amino)-A ⁷ ,A' ^r -dimethyl-7H-pyrrolo[2,3-J]pyrimidine-6- carboxamide A153. ^r H 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]~.

[001325] 7-Cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)ph enyl)piperidin-4- yl)6methyl)piperidin-4-yl)piperazin- 1 -yl)pyri din-2 -yl)amino)-A’,A ^r -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] ⁺ .

[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',A ⁷ -dimethyl-7A ^r - pyrrolo[2,3-d]pyrimidine-6-carboxamide A164. (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] ⁺ .

[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)pyrid in-2-yl)amino)-A ^r jV-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] ⁺ .

[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)-A ^A ,A-dimethyl-7/7-pyrrolo[2,3-d ^F ]pyrimidiiie-6- carboxamide 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] ⁺ .

[001329] 7-Cyclopentyl-2-((5-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)ph enyl)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]

[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)-A ⁷ ,A ^r -dimethyl-7H-pyrrolo[2,3-J|- pyrimidine-6-carboxamide A172. 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] ⁺ . [001331] 7-Cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l -yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-N,N-dimethyl-7/f-py rrolo[2,3-J]pyrimidine-6- carboxamide A177. 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] ⁺ .

[001332] 7-Cyclopentyl-2-((5-(4-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-4-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A ⁷ ,A'-dimethyl-7J/-pyrrolo[2,3-d ^r ]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] ⁺ .

[001333] 7-Cyclopentyl-2-((5-(4-(l-(3-(4-(2,6-dioxopiperidin-3-yl)phe noxy)propyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A'’,A ^r -dimethyl-7//-pyrrolo[2,3-<f|pyrimidine-6- carboxamide Al 79. 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] ⁺ .

[001334] 7-Cyclopentyl-2-((5-((4-(4-(4-(2,6-dioxopiperidin-3-yl)pheny l)piperazin-l-yl)- piperidin-l -yl)methyl)pyridin-2-yl)amino)-A,A ^L dimethyl-7/7-pyrrolo[2,3-i/]pyrimidine-6- carboxamide A185. ^r H 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] \

[001335] 7-Cyclopentyl-2-((5-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- piperidin-l-yl)ethyl)pyridin-2-yl)amino)-A',A-dimethyl-7//-p yrrolo[2,3-t/]pyrimidine-6- carboxamide Al 90 ^r H 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] ⁺ . [001336] 7-Cyclopentyi-2-((5-(2-(l'-(4~(2,6-dioxopiperidin~3-yl)pheny l)-[4,4'-bipiperidin]- l-yl)ethoxy )pyri din-2 -yl)amino)4VJV-dimethyl-7#-pyrrolo[2,3^pyrimidine-6-carboxam ide

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

[001337] 7-Cyclopentyl-2-((5-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)pyridin-2-yl)amino)-A(A-dimethyl-7H-py rrolo[2,3-</]pyrimidine-6- carboxamide A193. ^r H 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] ⁺

[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-7 _J H-pyn‘olo[2,3-<7]pyrimidine-6- carboxamide Al 95. ^r H 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] ⁺ .

[001339] 7-Cyclopentyl-2-((5-(4-(l-(3-(3-(2,6-dioxopiperidin-3-yl)phe noxy)propyl)- piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)amino)-A,A ^L dimethyl-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] ⁺ .

[001340] 7-Cyclopentyl-2-((5-(2-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-4-yl)- piperazin-l-yl)ethyl)pyridin-2-yl)amino)-A ^r ,A ⁷ -dimethyl-7//-pyrrolo[2,3-£(|pyrimidine-6- carboxamide A201. ^r H 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] ⁺ .

[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] .

[001342] 7-Cyclopentyl-2-((5-(3-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- piperidin-l-yl)propyl)pyridin-2-yl)amino)-jVyV-dimethyl-7/7- pyrrolo[2,3-<7]pyrimidine-6- carboxamide A203. 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] ⁺ .

[001343] 7-Cyclopentyl-2-((5-(3-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-4-yl)- piperazin-l-yl)propyl)pyridin-2-yl)amino)-A,A-dimethyl-7H-py rrolo[2,3-cZ]pyrimidine-6- carboxamide A204. ^r H 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] ⁺ .

[001345] 7-Cyclopentyl-2-((5-((3-(4-(4-(2,6-dioxopiperidin-3-yl)pheny l)piperazin-l-yl)- piperidin-l-yl)methyl)pyridin-2-yl)amino)-A(AMimethyl-7#-pyr rolo[2,3-2]pyrimidine-6- carboxamide A211 ^r H 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] ⁺ .

[001346] 7-Cyclopentyl-2-((5-(2-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- piperidin-l-yl)ethoxy)pyridin-2-yl)amino)-A' ^T ,7V-dimethyl-72/-pyrrolo[2,3-(/]pyrimidine-6- carboxamide A213 ^r H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

[001347] 7-Cyclopentyl-2-((5-(4-((4-(4-(4-(2,6-dioxopiperidin-3-yl)ph enyl)piperazin-l-yl)- piperidin-l-yl)methyl)piperidiri-l-yl)pyridin-2-yl)amino)-7V ,A ^z -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] ⁺ . [001348] 7-Cyclopentyl-2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)pheny l)piperidin-4-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^/ ,A-dimethyl-7ZApyrrolo[2,3-</]pyrimidiiie-6- carboxamide A217. 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] ⁺ .

[001349] 7-Cyclopentyl-2-((5-(l-((l-(4-(2,6-dioxopiperidin-3-yl)pheny l)piperidin-4-yl)- methyl)piperidin-4-yl)pyridin-2-yl)amino)-A ⁷ ,A ^r -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

[001350] 7-Cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)pheny l)piperazin-l-yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-A ^z _r A'-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] ⁺ .

[001351] 7-Cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)pheny l)piperidin-l -yl)- methyl)piperidin-l-yl)pyridin-2-yl)amino)-A ⁷ ,A ^r -dimethyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A220. 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] ⁺ .

[001352] 7-Cyclopentyl-2-((5-(4-((l-(3-(2,6-dioxopiperidin-3-yl)pheny l)piperidin-4-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A(A ⁷ -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] ⁺ .

[001353] 7-Cyclopentyl-2-((5-(l-((l-(3-(2,6-dioxopiperidin-3-yl)pheny l)piperidin-4-yl)- methyl)piperidin-4-yl)pyridin-2-yl)amino)-A^V-dimethyl-777-p yrrolo[2,3-6?]pyrimidine-6- carboxamide A222. 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

[001354] 7-Cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)pheny l)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. ^r H 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] ⁺ . [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-i Z]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] ⁺ .

[001356] 7-Cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^T ,A-dimethyl-7/Apyrrolo[2,3-d ^F ]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] \

[001357] 7-Cyclopentyl-2-((5-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A ^z ,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

[001358] 7-Cyclopentyl-2-((5-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A,A-dimethyl-7H-pyr rolo[2,3-tZ]pyrimidine-6- carboxamide A228. ^r H 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] ⁺ .

[001359] 7-Cyclopentyl-2-((5-(l-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phe nyl)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 [001360] 7-Cyclopentyl-2-((5-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-7V,7V-dimethyl-7//- pyrrolo[2,3-<f|pyrimidine-6- carboxamide A230. ^r H 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] ⁺ .

[001361] 7-Cyclopentyl-2-((5-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phe nyl)piperazin-l-yl)- ethyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^r ,A ⁷ -dimethyl-77f-pyrrolo[2,3-tf]pyrimidine-6- carboxamide A232. 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]\

[001362] 7-Cyclopentyl-2-((5-(l-(2-(4-(3-(2,6-dioxopiperidin-3-yl)phe nyl)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. 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] \

[001363] 7-Cyclopentyl-2-((5-(l-(2-(l-(3-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-4-yl)- ethyl)piperidin-4-yl)pyridin-2-yl)amino)-A ^z ,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] ⁺ .

[001364] 7-Cyclopentyl-2-((5-(2-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-4-yl)- piperazin-l-yl)ethyl)pyridin-2-yl)amino)-A(AMimethyl-7/7-pyr rolo[2,3-t/]pyrimidine-6- carboxamide A239 ^r H 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] ⁺ .

[001365] 7-Cyclopentyl-2-((5-(2-(l'-(3-(2,6-dioxopiperidin-3-yl)pheny l)-[l,4'-bipiperidin]- 4-yl)ethyl)pyridin-2-yl)amino)-A') _i V-dimethyl-7//-pyrrolo[2,3-</]pyrimidine-6-carboxam ide A240 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) 732.5 [M+H] ⁺ .

[001366] 7-Cyclopentyl-2-((5-(2-(r-(3-(2,6-dioxopiperidin-3-yl)phenyl )-[4,4'-bipiperidin]- l-yl)ethyl)pyridin-2-yl)amino)-A ⁷ ,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] ⁺ . [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)-A ^r /» ⁷ -dimethyl-7//-pyrrolo[2, 3 -<Z]pyrimidine-6- carboxamide A243. 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] \

[001368] 7-Cyclopentyl-2-((5-(2-(4-(l-(3-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-4-yl)- piperazin-l-yl)ethoxy)pyridin-2-yl)amino)-?V ^r ,A-dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-6- carboxamide A244. ^r H 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] ⁺ .

[001369] 7-Cyclopentyl-2-((5-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phe nyl)piperidin-l-yl)- ethyl)piperidin-l-yl)pyridin-2-yl)amino)-A(A-dimethyl-7/7-py rrolo[2,3-J]pyrimidine-6- carboxamide A248 ^r H 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.

[001370] 7-Cyclopentyl-2-((5-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl )piperazin-l-yl)- ethoxy)pyridin-2-yl)amino)-/V,A ^r -dimethyl-77f-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A251. ^l H 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] ⁺ .

[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] ⁺ . [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-pyrrol o[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] ⁺ .

[001373] 7-Cyclopentyl-2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)pheny l)azetidm-3-yl)- methyl)piperazin-l-yl)pyridin-2-yl)amino)-A ^; ,A-dimethyl-7A ^r -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] ⁺ .

[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,A ⁷ -dimethyl-7Z/-pyrrolo[2,3-(7]pyrimidine-6- carboxamide A257. ^r H 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]

[001375] 7-Cyclopentyl-2-((5-(4-(l-(2-(4-(2,6-dioxopiperidin-3-yl)phe nyl)-2,2-difluoro- ethyl)azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-MM-di methyl-77/-pyrrolo[2,3-tf|- pyrimidine-6-carboxamide A262. ⁴ HNMR (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] ⁺ .

[001376] 7-Cyclopentyl-2-((5-(4-(l-(2-(3-(2,6-dioxopiperidin-3-yl)phe nyl)-2,2-difluoro- ethyl)azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-A'’ ,A ⁷ -dimethyl-7/f-pyrrolo[2,3-tf]- pyrimidine-6-carboxamide A263. ^r HNMR (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 . [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]~.

[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, CD ₃ OD) 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), 1.76-1.65 691.4 [M+H] ⁺ .

[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] ⁺ .

[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/-pyrr olo[2,3-t/]pyrimidine-6- carboxamide A268 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] ⁺ .

[001381] 7-Cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenet hyl)piperazm- 1 -yl)- azetidin-l-yl)pyridin-2-yl)amino)-A ^r ,A-dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxa mide A272. ^r H 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] ⁺

[001382] 7-Cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenet hyl)piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7/7-pyrrolo[2 ,3-c/]pyrimidine-6-carboxamide

A273. ^T H 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] \

[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/-pyrro lo[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] ⁺ .

[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-7A ^r -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] ⁺ .

[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(A ^L dimethyl-7//-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A276. ^r H 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] ⁺ .

[001386] 7-Cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenet hyl)-4-fluoro- piperidin-l-yl)azetidin-l-yl)pyridin-2-yl)amino)-7V,7V-dimet hyl-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] ⁺ . [001387] 7-Cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenet hyl)piperidin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A,A-dimethyl-7H ^r -pyrrolo[2,3-d ^r ]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 .

[001388] 7-Cyclopentyl-2-((5-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenet hyl)-4-fluoro- piperidin-l-yl)azetidin-l-yl)pyridin-2-yl)amino)-A(A’-dime thyl-7//-pyrrolo[2,3-J]pyrimidine-6- carboxamide A281 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]\

[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. ⁴ H 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] ⁺ .

[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',A ^L dimethyl-7Jf-pyrrolo[2,3-J]pyrimidine-6- carboxamide A283. ^r H 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] \

[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] \

[001392] 7-Cyclopentyl-2-((5-(l-((l-(3-(2,6-dioxopiperidin-3-yl)pheny l)-4-fluoropiperidin- 4-yl)methyl)piperidin-4-yl)pyridin-2-yl)amino)-A ^z ,A ^r -dimethyl-7/f-pyrrolo[2,3-</]pyriniidine-6- carboxamide A286 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] ⁺ .

[001393] 7-Cyclopentyl-2-((5-(l-((l-(4-(2,6-dioxopiperidin-3-yl)pheny l)-4-fluoropiperidin- 4-yl)methyl)piperidin-4-yl)pyridin-2-yl)amino)-AyV-dimethyl- 7H-pyrrolo[2,3-^]pyrimidine-6- carboxamide A287. ^r H 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

[001394] 7-Cyclopentyl-2-((5-(4-((4-(4-(2,6-dioxopiperidin-3-yl)pheny l)piperidin-l-yl)- methyl)-4-fluoropiperidin-l -yl)pyri din-2 -yl)amino)-A ^f ,A ⁷ -dimethyl-777-pyrrolo[2,3-t7]pyrimidine- 6-carboxamide A288. ^T H 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] ⁺ .

[001395] 7-Cyclopentyl-2-((5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)pheny l)piperidin-l-yl)- methyl)-4-fluoropiperidin-l-yl)pyridin-2-yl)amino)-A(A ^/ -dimethyl-77/-pyrrolo[2,3-t7]pyrimidine- 6-carboxamide A289 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

[001396] 7-Cyclopentyl-2-((5-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl )piperazin-l-yl)- azetidin-l-yl)pyridin-2-yl)amino)-A ^T ,77-dimethyi-777-pyrrolo[2,3-(/|pyrimidine-6-carboxami de A294. ^r H 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] ⁺ .

[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

[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 ^r H 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] ⁺ .

[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)-A ^r ,A’-dimethyl-7/7-pyrrolo[2,3-7]- pyrimidine-6-carboxamide A297. ^r HNMR (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] ⁺ .

[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)-A ^r ,A ⁷ -dimetliyl-7//-pyrrolo[2,3-7]- pyrimidine-6-carboxamide A298. ^r H 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] ⁺ .

[001401] 7-Cyclopentyl-2-((5-((r-(3-(2,6-dioxopiperidin-3-yl)phenyl)- [l,4'-bipiperidin]-4- yl)methoxy)pyridin-2-yl)amino)-A ^z ,A-dimethyl-777-pyrrolo[2,3-<7]pyriniidine-6-carbox amide

A300. ^r HNMR (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

[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. 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] ⁺ .

[001403] 7-Cyclopentyl-2-((4-((4-(4-(2-(3-(2,4-dioxotetrahydropyrimid in-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)aniino) -A(A ⁷ -dimethyl-7/f-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A402.

[001404] 7-Cyclopentyl-2-((4-((6-(4-(2-(3-(2,4-dioxotetrahydropyrimid in-l(27/)-yl)- phenoxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)- A7^-dimethyl-7//-pyrrolo[2,3- tZ]pyrimidine-6-carboxamide A403.

[001405] 7-Cyclopentyl-2-((4-((2-(4-(2-(4-(2,4-dioxotetrahydropyrimid in-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)aniino) -AjV-dimethyl-77/-pyrrolo[2,3"^- pyrimidine-6-carboxamide A404.

[001406] 7-Cyclopentyl-2-((4-((4-(4-(2-(4-(2,4-dioxotetrahydropyrimid in-l(2//)-yl)- phenoxy)acetyl)piperazin-l-yl)butyl)carbamoyl)phenyl)amino)- A,jV-dimethyl-77/-pyrrolo[2,3- Jjpyrimidine-6-carboxamide A405.

[001407] 7-Cyclopentyl-2-((4-((6-(4-(2-(4-(2,4-dioxotetrahydropyrimid in-l(277)-yl)- phenoxy)acetyl)piperazin-l-yl)hexyl)carbamoyl)phenyl)amino)- A ^/ 7v ^r -dimethyl-777-pyrrolo[2,3- </|pyrimidine-6-carboxamide A406. [001408] 7-Cyclopentyl-2-((4-(2-(4-(4-(2,4-dioxotetrahydropyrimidm-l( 2£/)-yl)phenyl)- piperazin-l-yl)ethyl)phenyl)amino)-A ^r ,A ^r -dimethyl-7H ^r -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] ⁺ .

[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/-pyr rolo[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] ⁺ .

[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 ^r H 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] ⁺ .

[001411] 7-Cyclopentyl-2-((4-(4-(l -(4-(2,4-dioxotetrahydropyrimidin- 1 (27/)-yl)phenyl)- piperidin-4-yl)piperazin-l-yl)phenyl)amino)-A ⁷ ,A ^z -dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide A420 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

[001412] 7-Cyclopentyl-2-((4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrimidi n- 1 (22/)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)amino)-A ^; , _J V-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 .

[001413] 7-Cyclopentyl-2-((4-(2-(4-(4-(3-(2,4-dioxotetrahydropyrimidi n-l(2//)-yl)phenyl)- piperazin-l-yl)piperidin-l-yl)ethyl)phenyl)amino)-A,A ^r -dimethyl-7Z/-pyrrolo[2,3-t7]pyrimidine- 6-carboxamide A426. ^T H 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] ⁺

[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. 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

[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)ami no)-A ^z ,A ^r -dimethyl-7/f-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A503.

[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)ami no)-ADV-dimethyl-7//-pyrrolo[2,3- d]pyrimidine-6-carboxamide A505.

[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)ami no)-A ^z ,7V-dimethyl-7/?-pyrrolo[2,3- t/]pyrimidine-6-carboxamide A506.

[001418] 7-Cyclopentyl-2-((4-((2-(4-(2-((3-(2,4-dioxotetrahydropyrimi din- 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. 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.

[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.

[001420] 7-Cyclopentyl-2-((4-((6-(4-(2-((3-(2,4-dioxotetrahydropyrimi din-l(2//)-yl)-l- methyl-l//-indazol-7-yl)oxy)acetyd)piperazin-l-yl)hexyl)carb amoyl)phenyl)amino)-A ^A _rI V- dimethyl-7J7-pyrrolo[2,3-6f]pyrimidine-6-carboxamide A553.

[001421] 7-Cyclopentyl-2-((4-((2-(4-(2-((3-(2,4-dioxotetrahydropyrimi din-l(2//)-yl)-l- methyl-l/7-indazol-6-yl)oxy)acetyl)piperazin-l-yl)ethyl)carb amoyl)phenyl)amino)-A^V- dimethyl-7/7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide A554.

[001422] 7-Cyclopentyl-2-((4-((4-(4-(2-((3-(2,4-dioxotetrahydropyrimi din-l(27/)-yl)-l- methyl- l/7-indazol-6-yl)oxy)acetyl)piperazin- 1 -yl)butyl)carbamoyl)phenyl)amino)-A ^z ,/V- dimethyl-777-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A555.

[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.

[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)pyr idin-2-yl)amino)-jV,7V-dimethyl-7J/- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A557.

[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)pyr idin-2-yl)amino)-A’,A-dimethyl-7Z/- pyrrol o[2, 3 -<7]pyrimidine-6-carboxamide A558. [001426] 7-Cyclopentyl-2-((4-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-di oxoisoindolin-4- yl)amino)hexyl)(metliyl)carbanioyl)phenyl)amino)-A^V-dimethy l-72f-pyrrolo[2,3-^pyrimidine-

6-carboxamide A602.

[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)-A ^r ,A ^/ -dimethyl-7Z/-pyrrolo[2,3-t/]pyrimidine-6- carboxamide A603

[001428] 7-Cyclopentyl-2-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxois oindolin-4-yl)- glycyl)piperazin-l-yl)pyri din-2 -yl)amino)-A ⁷ ,A' ^r -dimethyl-7/7-pyrrolo[2,3-t(|pyrimidine-6- carboxamide A611.

[001429] 7-Cyclopentyl-2-((4-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fl uoro-l-oxoisoindolin-

4-yl)piperidin-l-yl)ethyl)carbamoyl)phenyl)amino)-AAV-dim ethyl-7//-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A612.

[001430] 7-Cyclopentyl-2-((4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fl uoro-l-oxoisoindolin-

4-yl)piperidin-l-yl)butyl)carbamoyl)phenyl)amino)-A', _J V-dimethyl-7/7-pyrrolo[2,3-^pyrimidine-

6-carboxamide A613

[001431] 7-Cyclopentyl-2-((4-((6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fl uoro-l-oxoisoindolin-

4-yl)piperidin-l-yl)hexyl)carbamoyl)phenyl)amino)-jV,A ^z -dimethyl-7Z/-pyrrolo[2,3-t/]pyrimidine- 6-carboxamide A614.

[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)-A ^r jV-dimethyl-7J7- pyrrolo[2,3-</]pyrimidine-6-carboxamide A615.

[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’,A ⁷ -dimethyl-7A ^r - pyrrolo[2,3-<7]pyrimidine-6-carboxamide A616.

[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)pyrid in-2-yl)amino)-A ^r /v ^r -dimethyl-77/- pyrrolo[2,3-^pyrimidine-6-carboxamide A617.

[001435] 7-Cyclopentyl-2-((4-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fl uoro-l-oxoisoindolin-

5-yl)piperidin-l-yl)ethyl)carbamoyl)phenyl)amino)-A’^\ ^r -dimethyl-7H-pyrrolo[2,3-<7]pyrimidine-

6-carboxamide A618.

[001436] 7-Cyclopentyl-2-((4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fl uoro-l-oxoisoindolin-

5-yl)piperidin-l-yl)butyl)carbamoyl)phenyl)amino)-/VpV-di methyl-7#-pyrrolo[2,3-47]pyrimidine-

6-carboxamide A619.

[001437] 7-Cyclopentyl-2-((4-((6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fl uoro-l-oxoisoindolin-

5-yl)piperidin-l-yl)hexyl)carbamoyl)phenyl)amino)-A ^r ,A ^/ -dimethyl-7Z/-pyrrolo[2,3-<7]pyrimidine-

6-carboxamide A620.

[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-dimethy l-7J/- pyrrolo[2,3-tZ]pyrimidine-6-carboxamide A621

[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)pyri din-2-yl)amino)-A ⁷ ,jV-dimethyl-7/f- pyrrolo[2,3-iZ]pyrimidine-6-carboxamide A622.

[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)pyrid in-2-yl)amino)-A’,A-dimethyl-7A ^r - pyrrolo[2,3-<7]pyrimidine-6-carboxamide A623.

[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)carbamoy l)phenyl)amino)-A'/Adimethyl- 77/-pyrrolo[2,3-^pyrimidine-6-carboxamide A652.

[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)carbamoy l)phenyl)amino)-A,A-dimethyl- 7//-pyrrolo[2,3-t/]pyrimidine-6-carboxamide A653.

[001443] 7-Cyclopentyl-2-((4-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo- 5,6-dihydro-4 _J ff- thieno[3,4-c]pyrrol-l-yl)methoxy)benzyl)carbamoyl)phenyl)ami no)-A ⁷ ,A-dimethyl-7/7-pyrrolo- [2,3-<7]pyrimidine-6-carboxamide A654. ^v HNMR (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] ⁺ .

[001444] 3-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethox y)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] ⁺ .

[001445] A-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihyd ropyrido[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 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] ⁺ .

[001446] A-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihyd ropyrido[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] ⁺ .

[001447] A-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihyd ropyrido[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 ¹ H 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] \

[001448] A-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihyd ropyrido[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. ^l H 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] .

[001449] A-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihyd ropyrido[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] ⁺ .

[001450] 3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-rnethyl-7-oxo-7,8-dih ydropyrido[2,3-</|- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)phen yl)piperidine-2, 6-dione Bill

[001451] 3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyi-5-methyl-7-oxo-7,8-di hydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)pheny l)piperidine-2, 6-dione Bill.

[001452] 3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-^- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethoxy)phen yl)piperidine-2, 6-dione Bl 13.

[001453] 3-(3-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihy dropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)phen yl)piperidine-2, 6-dione Bl 14.

[001454] 3-(3-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-(7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethyl)pheny l)piperidine-2, 6-dione B115.

[001455] 3-(3-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-^ pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)ethoxy)phen yl)piperidine-2, 6-dione B116.

[001456] 3-(4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propoxy)phe nyl)piperidine-2, 6-dione B117.

[001457] 3-(3-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)propoxy)phe nyl)piperidine-2, 6-dione BUS.

[001458] 3-(4-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-(7]- pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin-l-yl)piperi din- l-yl)phenyl)piperidine-2, 6-dione

B119

[001459] 3-(4-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- tf|pyriinidin-2-yl)amino)pyridin-3-yl)piperazin-l -yl)methyl)piperidin-l-yl)phenyl)piperidine-

2, 6-dione B120.

[001460] 3-(4-((4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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

[001461] 3-(3-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)piperidin-l -yl)phenyl)piperidine-2, 6-dione

B122

[001462] 3-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3-

^pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl) piperidin-l -yl)phenyl)piperidine-

2,6-dione B123.

[001463] 3-(3-((4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyri din-3 -yl)piperazin-l-yl)piperi din- l-yl)methyl)phenyl)piperi dine-

[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 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] ⁺ .

[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.

[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-

[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.

[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)piperidi n-l-yl)sulfonyl)ethyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione B129.

[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)piper idin-l-yl)sulfonyl)ethyl)piperazin-l- yl)phenyl)piperidine-2, 6-dione B132 ^r H 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] ⁺ .

[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)pipe ridin-l-yl)sulfonyl)ethyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione B133.

[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)piperi din-l-yl)sulfonyl)propyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B134.

[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)pi peridin- 1 -yl)sulfonyl)ethyl)piperazin- 1 - yl)phenyl)piperidine-2, 6-dione B135. 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] ⁺ .

[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)piperi din-l-yl)sulfonyl)propyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B136

[001474] 3-(4-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-me thylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)su lfonyl)propoxy)phenyl)- piperidine-2, 6-dione B137.

[001475] 3-(3-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydroxy-2-me thylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidin-l-yl)s ulfonyl)propoxy)phenyl)- piperidine-2, 6-dione B138

[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)pi peridin-l-yl)sulfonyl)benzyl)piperazin-

1 -yl)phenyl)piperi di ne-2, 6-dione B139.

[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)pi peridin-l-yl)sulfonyl)benzyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B141. ¹ H 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.

[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)piper idin-l-yl)sulfonyl)benzyl)piperazin-

1 -yl)phenyl)piperi di ne-2, 6-dione B142.

[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)piperi din-l-yl)sulfonyl)phenyl)piperazin- l-yl)methyl)phenyl)piperidine-2, 6-dione B143.

[001480] 3-(4-(4-((4-(4-((4-((6-(Difluoromethyl)-8-((17?,2/?)-2-hydro xy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-c/]pyrimidin-2-yl)a mino)piperidin-l-yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)piperidin e-2, 6-dione B144.

[001481] 3-(4-((4-((4-((6-(Difluoromethyl)-8-((l/?,27?)-2-hydroxy-2-m ethylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-<7]pyriniidin-2-yl)amino)piperi din-l-yl)sulfonyl)piperazin-l -yl)- methyl)phenyl)piperidine-2, 6-dione B145.

[001482] 3-(3-((4-((4-((6-(Difluoromethyl)-8-((l/?,2Z^)-2-hydroxy-2-m ethylcyclopentyl)-7- oxo-7,8-dihydropyrido[2,3-</jpyrimidin-2-yl)amino)piperid in-l-yl)sulfonyl)piperazin-l -yl)- methyl)phenyl)piperidine-2, 6-dione B146.

[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)piperid in-l-yl)sulfonyl)piperazin-l-yl)- methyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione B147.

[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)piper idin-l-yl)sulfbnyl)propyl)piperazin- l-yl)phenyl)piperidine-2, 6-dione B148

[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)piperidi n-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)piperidine-2, 6-dione Bl 49.

[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] ⁺

[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)ami no)piperidin-l-yl)sulfonyl)phenyl)- piperazin- 1 -yl)ethyl)phenyl)piperidine-2, 6-dione B151. MS (ESI) OT/Z: 417.5 [M/2+H] ⁺ .

[001488] 3-(4-(2-(4-(4-((4-((6-(Difluoromethyl)-8-((l _J R,27?)-2-hydroxy-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-yl)ami no)piperidin-l-yl)sulfonyl)phenyl)- piperazin- l-yl)ethoxy)phenyl)piperidine-2, 6-dione B152. ^r H 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] ⁺ .

[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] ⁺ .

[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)piper idin-l-yl)sulfonyl)piperazin-l-yl)- ethoxy)phenyl)piperi dine-2, 6-dione B154. MS (ESI) m/z: 773.4 [M+H]* .

[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)piperid in-l-yl)sulfonyl)piperazin-l -yl)- propoxy)phenyl)piperidine-2, 6-dione B155. MS (ESI) m/z'. 787.3 [M+H] ⁺ .

[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)piperi din- 1 -yl)sulfonyl)piperazin- 1 -yl)- propoxy)phenyl)piperidine-2, 6-dione Bl 56 MS (ESI) m/z\ 787.4 [M+H] \

[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)pipe ridin-l-yl)sulfonyl)phenethyl)- piperazin- l-yl)phenyl)piperidine-2, 6-dione B157. MS (ESI) m/z'. 417.4 [M/2+H] ⁺ .

[001494] 3-(4-(4-(2-(4-((4-((6-(Difluoromethyl)-8-((l/?,27?)-2-hydrox y-2-methylcyclo- pentyl)-7-oxo-7,8-dihydropyrido[2,3-</|pyriniidin-2-yl)am ino)piperidin-l-yl)sulfonyl)phenoxy)- ethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B158. MS (ESI) m/z'. 849.4 [M+H] ⁺ .

[001495] 3-(4-(4-(2-(3-((4-((6-(Difluoromethyl)-8-((l/?,27?)-2-hydrox y-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] ⁺ .

[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)piper idin-l-yl)sulfonyl)phenyl)piperidin-

4-yl)oxy)phenyl)piperidine-2, 6-dione B160. MS (ESI) m/z: 410.8 [M/2+H] ¹ .

[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)piper idin-l-yl)sulfonyl)phenyl)piperidin-

4-yl)oxy)phenyl)piperidine-2, 6-dione B161. MS (ESI) m/z: 410.9 [M/2+H] \

[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)piper idin-l-yl)sulfonyl)phenyl)piperidin-

4-yl)oxy)phenyl)piperidine-2, 6-dione B162. MS (ESI) m/z'. 410.7 [M/2+H] ⁺ .

[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] ⁺ .

[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 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] ⁺ . [001501] 3-(4-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3-

4/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methy l)-[l,4'-bipiperidin]-l'-yl)phenyl)- piperidine-2, 6-dione Bl 65 MS (ESI) m/z: 815.5 [M+H]t

[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] ⁺ .

[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)et hyl)-[l,4'-bipiperidin]-r-yl)phenyl)- piperidine-2, 6-dione B167 MS (ESI) m/z: 415.5 [M/2+H] ⁺ .

[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)p iperidine-2, 6-dione B168 MS (ESI) m/z: 691.5 [M+H] ⁺ .

[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)piper azin-l-yl)phenyl)piperidine-2,6- dione B169 MS (ESI) m/z: 741.3 [M+H] ⁺ .

[001506] 3-(4-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-[l,4'-bipi peridin]-l'-yl)phenyl)piperidine-2,6- dione B170. MS (ESI) m/z: 801.8 [M+H] ⁺ .

[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]’. [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]’.

[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] ⁺

[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

[001511] 3-(4-(4-((5)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-ox o-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] ⁺ .

[001512] 3-(4-(4-((/?)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-o xo-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] ⁺ .

[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/z ¹ . 815.4 [M+H] ⁺ . [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]’.

[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)cyclohex yl)ethyl)phenyl)piperidine-2,6- dione B181 MS (ESI) m/z: 745.4 [M+H] ⁺ .

[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)cyclohexy l)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B182 ^l H 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] \ [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)p iperidin-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] ⁺ .

[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

[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]“.

[001520] 3-(4-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-c/]- pyrimidm-2yl)amino)pyridin-3-yl)piperazin-l-yl)-[l,4’-bipi peridin]-r-yi)phenyl)piperidine-2,6- dione B187 MS (ESI) m/z: 801.5 [M+H] ⁺ .

[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)cycloh exyl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B189. MS (ESI) m/z: 801.5 [M+Hp.

[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)piperi din-l-yl)ethoxy)phenyl)piperidine- 2,6-dione B191 'H NMR (400 MHz, CD ₃ OD) 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 .

[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 |

[001524] 3-(4-(4-(l-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- t/jpyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperidin-4-yl)p iperazin-l-yl)phenyl)piperidine-

2,6-dione B193. MS (ESI) m/z: 732.2 [M+H] ⁺ .

[001525] 3-(4-(4-(4-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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] ⁺ .

[001526] 3-(4-(l'-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dih ydropyrido[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

[001527] 3-(4-(4-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihy dropyrido[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

[001528] 3-(4-(4-((6-((6-Acetyl-8-cyclopentyl-5-rnethyl-7-oxo-7,8-dih ydropyrido[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

[001529] 3-(4-(4-(2-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001530] 3-(4-(4-(((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dih ydropyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)methyl)-[l,4'-bipiperi din]-l '-yl)phenyl)piperidine-2,6- dione B199. MS (ESI) m/r. 747.3 [M+H] ⁺ .

[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)pi peridin-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] \

[001532] 3-(4-(r-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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] ⁺

[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)pi peridin-4-yi)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B203 MS (ESI) m/z: 762.3 [M+H] 7

[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)pi perazin-l-yl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B204. MS (ESI) m/z: 762.3 [M+Hp.

[001535] 3-(4-(4-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- c/]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)-[l,4'-bipipe ridin]-l'-yl)phenyl)piperidine-2,6- dione B205. MS (ESI) m/z: 761.3 [M+H] ⁺ .

[001536] 3-(4-(l'-(3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)propyl)-[4,4'-bipiperid in]-l-yl)phenyl)piperidine-2, 6-dione

B206 MS (ESI) m/z: 759.8 [M+H]7 [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)p iperazin-l-yl)phenyl)piperidine-2,6- dione B207. MS (ESI) m/z: 760.8 [M+H] ⁺ .

[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)p iperidin-l-yl)phenyl)piperidine-2,6- dione B208. ^J H 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] ⁺ .

[001539] 3-(4-(4-(3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001540] 3-(3-(4-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3-

</|pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)me thyl)piperazin-l-yl)phenyl)piperidine- 2, 6-dione B210 MS (ESI) m/z: 732.3 | M • ! i |

[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] \

[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] \

[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] \ [001544] 3-(4-(2-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-y l)ethyl)phenyl)piperidine-2, 6-dione

B215 MS (ESI) m/z: 745.4 [M+H]t

[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] ⁺ .

[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. ^l H 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] ⁺ .

[001547] 3-(4-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihy dropyrido[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

[001548] 3-(4-(4-(l-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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 ^l H 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), 1.26-1.13 732.3 [M+H] ⁺

[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 ^L H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

[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)piper idin-3-yl)piperazin-l -yl)phenyl)- piperidine-2, 6-dione B222 ^l H NMR (400 MHz, DMSCW ₆ ) 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] \

[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)meth yl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B223 ^! H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

[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)m ethyl)piperidin-4-yl)piperazin-l-yl)- phenyl)piperidine-2, 6-dione B224. MS (ESI) m/z: 815.6 [M+H] ⁺ .

[001553] 3-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-7]- pyrimidin-2-yl)amino)pyri din-3 -yl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B225. ¹ HNMR (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] ⁺ .

[001554] 3-(4-(4-(( 1 -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrid o[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] ⁺ .

[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)et hyl)azetidin-l-yl)phenyl)piperidine-2,6- dione B228 MS (ESI) m/z: 718.5 [M+H] ⁺ .

[001556] 3-(4-(4-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3-

<7]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)propyl)pipera zin-l-yl)phenyl)piperidine-2, 6-dione

B230. MS (ESI) m/z: 693.6 [M+H] ⁺ .

[001557] 3-(4-(l-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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] ⁺ . [001558] 3-(3-(4-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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] ⁺ .

[001559] 3-(3-(l-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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] ⁺ .

[001560] 3-(4-(3-(4-(6-((6-Aceiyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-t/]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-l-yl)propoxy)phe nyl)piperidine-2, 6-dione B234.

MS (ESI) m/z-. 692.4 [M+H] \

[001561] 3-(4-(4-(3-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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

[001562] 3-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihyd ropyrido[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] .

[001563] 3-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-^]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)piperazin-l -yl)phenyl)piperidine-2, 6-dione B240 ^r H 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] ⁺ .

[001564] 3-(4-(lA6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydr opyrido[2,3-d]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)p henyl)piperidine-2, 6-dione B241. ^r H 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] ⁺ .

[001565] 3-(3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihyd ropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)p henyl)piperidine-2, 6-dione B242.

MS (ESI) m/z: 717.5 [M+H]t

[001566] 3-(3-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihyd ropyrido[2,3-7]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)p henyl)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] ⁺ .

[001567] 3-(4-(4-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- <7]pyrimidin-2-yl)ainino)pyridin-3-yl)piperidin-4-yl)meth yl)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] ⁺ .

[001568] 3 -(4-( 1 -(( 1 -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrid o[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)p iperidin-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] ⁺ . [001569] 3-(3-(l-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- tZ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)methyl)p iperidin-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] ⁺

[001570] 3-(3-(4-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3-

<Z]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)me thyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B251 MS (ESI) m/z: 731.4 [M+H] ⁺

[001571] 3-(4-(r-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihy dropyrido[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] \

[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)pi perazin-l-yl)phenyl)piperidine-2,6- dione B255. MS (ESI) m/z: 746.8 [M+H] ⁺ .

[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)pi peridin-l-yl)phenyl)piperidine-2,6- dione B256 MS (ESI) m/z: 745.5 [M+H] ⁺

[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)pi peridin-4-yl)phenyl)piperidine-2,6- dione B257. MS (ESI) m/z: 746.3 [M+H] ⁺ .

[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)p iperidin-4-yl)phenyl)piperidine-2,6- dione B258. MS (ESI) m/z: 745.5 [M+H] ⁺ .

[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] ⁺ .

[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)et hyl)piperidin-l-yl)phenyl)piperidine-2,6- dione B260. MS (ESI) m/z: 745.4 [M+H] ⁺

[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)pi peridin-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]\

[001579] 3-(4-(2-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-[4,4'-bipiperidin]-l-y l)ethyl)phenyl)piperidine-2, 6-dione B262. MS (ESI) m/z: 745.3 [M+H] ⁺ .

[001580] 3-(4-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-</]- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-r-yl)e thyl)phenyl)piperidine-2, 6-dione

B263. MS (ESI) m/z: 745.5 [M+H] ⁺ .

[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)pi peridin-l-yl)phenyl)piperidine-2,6- dione B264. MS (ESI) m/z: 746.8 [ M + H ] ⁺ .

[001582] 3-(3-(4-(2-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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

[001583] 3-(3-(4-(((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dih ydropyrido[2,3-fl(]- pyrimidin-2-yl)amino)pyridin-3-yl)oxy)methyl)-[l,4'-bipiperi din]-l'-yl)phenyl)piperidine-2,6- dione B266. MS (ESI) m/z: 747.5 [M+H] ⁺

[001584] 3-(3-(l'-(2-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- cZ]pyrimidin-2-yl)amino)pyridin-3-yl)ethyl)-[4,4'-bipiperidi n]-l-yl)phenyl)piperidine-2, 6-dione

B267. MS (ESI) m/z: 745.3 [M+H]t

[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)piperid in-4-yl)piperazin-l-yl)phenyl)- piperidine-2, 6-dione B269. MS (ESI) m/z: 762.5 [M+H]~.

[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)pi perazin-l-yl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B270 MS (ESI) m/z: 762.8 [M+H] 2

[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] ⁺ .

[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)et hyl)piperidin-l-yI)phenyl)piperidine-2,6- dione B272. MS (ESI) m/z: 745.4 [M+H] ⁺ .

[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.

[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)pi peridin-4-yl)phenyl)piperidine-2,6- dione B274 MS (ESI) m/z: 745.7 [M+H] ⁺ .

[001591] 3-(4-((r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihy dropyrido[2,3-^- pyrimidin-2-yl)amino)pyridin-3-yl)-[l,4'-bipiperidin]-4-yl)m ethyl)phenyl)piperidine-2, 6-dione

B275. MS (ESI) m/2: 731.3 [M+H]t

[001592] 3-(4-(4-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- t/]-pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperazin-l- yl)phenyl)piperidine-2, 6-dione B276 ^r HNMR (400 MHz, DMSO-J ₆ ) 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]\

[001593] 3-(4-(4-(2-((6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- J]-pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidin-l-y l)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] ⁺ .

[001594] 3-(4-(2-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-

J]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipip eridin]-4-yl)ethyl)phenyl)piperidine- 2,6-dione B278. ^l H 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] ⁺ .

[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] ⁺ .

[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]’

[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 ¹ H NMR (400 MHz, DMSO-<7 ₆ ) <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] \

[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] ⁺ .

[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 ^L H 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] ⁺ ,

[001600] 3-(4-((3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3-

J]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetid in-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] ⁺ .

[001601] 3-(3-((3-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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

[001602] 3-(3-(2-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiper idin]-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

[001603] 3-(4-((r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihy dropyrido[2,3-J]- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidi n]-4-yl)methyl)phenyl)piperidine- 2,6-dione B287. MS (ESI) m/z: 749.3 [M+H] \

[001604] 3-(3-((r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihy dropyrido[2,3-tZj- pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiperidi n]-4-yl)methyl)phenyl)piperidine- 2,6-dione B288 MS (ESI) m/z: 749.4 [M+H] ⁺ .

[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-fluor oazetidin-3-yl)ethyl)phenyl)- piperidine-2, 6-dione B289. MS (ESI) m/z: 735.3 [M+H]t [001606] 3-(3-(2-(l-(l -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrid o[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

[001607] 3-(4-((l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-3-fl uoroazeti din-3 -yl)methyl)phenyl)- piperidine-2, 6-dione B291 ^r H 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] ⁺ .

[001608] 3-(3-((l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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. ^l H 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 .

[001609] 3-(3-(l-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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

[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)pipera zin-l-yl)ethyl)phenyl)piperidine-2,6- dione B295 ^J H 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] ⁺ .

[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]

[001612] 3-(3-((4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- </|pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)pipera zin-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. [001613] 3-(3-(2-(l-(l -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrid o[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-3-yl)piperidin- 4-yl)ethyl)phenyl)piperidine-2,6- dione B299. ^J H 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] ⁺ .

[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-flu oropiperidin-4-yl)ethyl)phenyl)- piperidine-2, 6-dione B300 ^l HNMR (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.

[001615] 3-(3-(8-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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] \

[001616] 3-(3-(3-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3-

<7]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)me thyl)-8-azabicyclo[3.2.1]octan-8-yl)- phenyl)piperidine-2, 6-dione B302. MS (ESI) m/z: 758.6 [M+H] ⁺ .

[001617] 3-(3-(4-((3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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] ⁺ .

[001618] 3-(3-(4-((8-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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] \

[001619] 3-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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]~.

[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]“.

[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] \

[001622] 3-(4-(l-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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

[001623] 3-(3-(l-((l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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] ⁺

[001624] 3-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[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)pi peridin-l -yl)-2-fluorophenyl)- piperidine-2, 6-dione B319. MS (ESI) m/z: 764.4 [M+H] ".

[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]“.

[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)e thyl)piperidin-l -yl)-2-fluorophenyl)- piperidine-2, 6-dione B321 ¹ H 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] \

[001628] 3-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)methyl)- 4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B323 ^L H 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] ⁺ .

[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)pi perazin-l-yl)piperidin-l-yl)phenyl)- piperidine-2, 6-dione B324. MS (ESI) m/z: 762.8 [M+H] 7

[001630] 3-(4-(2-(4-((4-((6-(Difluoromethyl)-8-((lA,2A)-2-hydroxy-2-m ethylcyclopentyl)- 7-oxo-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl)amino)piperidi n-l-yl)sulfonyl)piperazin-l-yl)- ethyl)phenyl)piperidine-2, 6-dione B359. ^l H 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] ⁺ .

[001631] 3-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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 ]“

[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)pi peridin-l-yl)-4-fluorophenyl)- piperidine-2, 6-dione B365 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] ⁺ .

[001633] 3-(4-(7-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-tZ]- pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-4-yl)-4,7-diazas piro[2.5]octan-4-yl)phenyl)- piperidine-2, 6-dione B370 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] ⁺ .

[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)piperi din-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)dihydropyrimidine-2,4(177,377)-dione B401 ^r HNMR (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] ⁺ . [001635] l-(4-(4-(3-((4-((6-(Difluoromethyl)-8-((lA,2R)-2-hydroxy-2-m ethylcyclopentyl)-

7-oxo-7,8-dihydropyrido[2,3-^pyrimidin-2-yl)amino)piperid in-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] ⁺ .

[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)piper idin-l -yl)sulfonyl)propyl)piperazin- l-yl)-2-fluorophenyl)dihydropyrimidine-2,4(lH,3H)-dione B404. MS (ESI) m/z'. 79b A [M+H] ⁺ .

[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)pi peridin-l-yl)sulfonyl)propyl)piperazin- l-yl)-2-methylphenyl)dihydropyrimidine-2,4(lH,3//)-dione B405. MS (ESI) wz: 786.5 [M+H] ⁺ .

[001638] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001639] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001640] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001641] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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

[001642] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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 ^r H NMR (400 MHz, DMSO-7 ₆ ) 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] ⁺ .

[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 .

[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)et hyl)piperidin-l-yl)-2-chl oro-3 -methyl- phenyl)dihydropyrimidine-2, 4(177, 37/)-dione B414. MS (ESI) m/z: 795.4 [M+Hp.

[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)et hyl)piperidin-l-yl)-5-chloro-2-methyl- phenyl)dihydropyrimidine-2,4(17/,37/)-dione B415. MS (ESI) m/z: 795.4 [M+H]’.

[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)pi perazin-l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 3/7)-dione B416 MS (ESI) m/z: 748.4 [M+H] ⁺ .

[001647] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001648] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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. ^r H 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] ⁺ .

[001649] l-(4-(4-(1 -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrid o[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 ^r H 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] ⁺ .

[001650] l-(4-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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 ^r H 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] ⁺ .

[001651] l-(4-(4-(l -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrid o[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 ^r H 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] ⁺

[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)pi peridin-l-yl)-2-chlorophenyl)- dihydropyrimidine-2, 4(1/7, 37/)-dione B458 ^r H 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] ⁺ .

[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)pip eridin-l-yl)-2-fluorophenyl)- dihydropyrimidine-2,4(lJ7,377)-dione B459 ^r H 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] ⁺ .

[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 ^r H 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] ⁺ .

[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 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] ⁺ .

[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)ethy l)piperidin-l-yl)-2-methyiphenyi)- dihydropyrimidine-2, 4(177, 37/)-dione B462. (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] \

[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)pi peridin-l -yl)-2-chlorophenyl)- dihydropyrimidine-2,4(17/,377)-dione B467. (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-

[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)pi perazin-l-yl)-2-chlorophenyl)- dihydropyrimidine-2, 4(177, 377)-dione B468 ^r H 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] \

[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)pi perazin-l-yl)phenyl)dihydro- pyrimidine-2, 4(177, 377)-dione B469 ^r H 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 ( [001660] l-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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. 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

[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] ⁺ .

[001662] 3-(6-(2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3-<7]- pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethox y)-l-methyl-l//-indazol-3-yl)- piperidine-2, 6-dione B501

[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)piper idine-2, 6-dione B502.

[001664] 3-(6-(4-(l-(6-((6-Acetyl-8-cycIopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001665] 3-(6-(4-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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 ^l H 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] ⁺ .

[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]\

[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] ⁺ .

[001668] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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 ^l H 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] ⁺ .

[001669] l-(6-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001670] l-(6-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001671] l-(6-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺

[001672] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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. ^L H 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] ⁺ .

[001673] l-(6-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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 ^L H 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] ⁺ .

[001674] l-(6-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001675] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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] ⁺ .

[001676] -l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido- [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] ⁺ .

[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 ^r H 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 ]’.

[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] ⁺ .

[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-fluor oazetidin-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] ⁺ .

[001680] l-(7-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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. ^r HNMR (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] \

[001681] l-(6-(2-(r-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[2,3- <7]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipi peridin]-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] ⁺ .

[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-oxoet hyl)piperidin-4-yl)-6-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione B601

[001683] 4-((2-(4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihy dropyrido[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

[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] ⁺ .

[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)phe nyl)piperidin-l-yl)- l,l-difluoroethyl)azetidin-l-yl)pyridin-2-yl)amino)-A,A ^r -dimethyl-7/7-pyrrolo[2,3-6?]pyrimidine- 6-carboxamide A351

[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.

[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-c yclopentyl-jV,A ^r -dimethyl-7 _J H- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A438.

[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-dime thyl-7//-pyrrolo[2,3-<7|pyrimidine-6- carboxamide A439.

[001690] 2-((5-(4-(l-(2-(3-Chloro-4-(2,4-dioxotetrahydropyrimidin-l(2 1/)-yl)phenyl)-2,2- difluoroethyl)piperidin-4-yl)piperazin-l-yl)pyridin-2-yl)ami no)-7-cyclopentyl-jV,jV-dimethyl-7/f- pyrrolo[2,3-<7]pyrimidine-6-carboxamide A440.

[001691] 3-(4-(2-((4-((6-(Difluoromethyl)-8-((l/?,2 _J R)-2-hydroxy-2-methylcyclopentyl)-7- oxo-7, 8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-l-yl)su lfonyl)ethoxy)phenyl)- piperidine-2, 6-dione B351.

[001692] 3-(4-(4-(((4-((6-(Difluoromethyl)-8-((17?,2/?)-2-hydroxy-2-m ethylcyclopentyl)-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.

[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

[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 [001695] 3-(4-(4-(l-(2-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydrox y-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-^pyrimidin-2-yl)ami no)piperidin-l-yl)sulfonyl)- ethyl)piperidin-4-yl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B355.

[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)piper idin-l-yl)sulfonyl)phenyl)piperazin-

1 -yl)methyl)phenyl)piperidine-2, 6-dione B356

[001697] 3-(4-(4-((4-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydro xy-2-methyl- cyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-2-y l)amino)piperidin-l -yl)sulfonyl)- phenyl)piperazin-l-yl)methyl)piperi din- l-yl)phenyl)piperidine-2, 6-dione B357.

[001698] 4-(3-(4-((4-(3-((4-((6-(Difluoromethyl)-8-((17?,27?)-2-hydro xy-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)piperidin e-2, 6-dione B358

[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)pi peridin- 1 -yl)sulfonyl)piperazin- 1 -yl)- piperidin-l-yl)phenyl)piperidine-2, 6-dione B360.

[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)piperi din-l-yl)sulfonyl)propyl)piperidin-4-

[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)piper idin-l-yl)sulfonyl)propyl)piperidin-4- yl)oxy)phenyl)-3-methylpiperidine-2, 6-dione B362.

[001702] 3-(3-(4-((3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[2,3-

<7]pyrimidin-2-yl)amino)pyridin-3-yl)azetidin-l-yl)met hyl)-4-fluoropiperidin-l-yl)phenyl)- piperidine-2, 6-dione B363.

[001703] 3-(3-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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.

[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 [001705] (iS)-3-(4-(2-(l-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-ox o-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.

[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.

[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.

[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

[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.

[001710] (S)-3-(4-((A)-2-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-o xo-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.

[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.

[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)p iperidin-l-yl)phenyl)dihydropyrimidine-2, 4(177, 3//)-dione B456

[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

[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.

[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)pi peridin-l-yl)-4-chloro-2-methyl- phenyl)dihy dropyrimidine-2,4( 1 //,3H)-dione B464. [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)pi peridin-l-yl)-2-chloro-4-methyl- phenyl)dihydropyrimidine-2, 4(177, 3/7)-dione B465.

[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)pi peridin-l-yl)-4-chloro-2-methyl- phenyl)dihydropyrimidine-2, 4(177, 3/7)-dione B466.

[001718] l-(3-(4-((3-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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.

[001719] 3-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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.

[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.

[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)pi perazin-l-yl)-l-methyl-l//-indazol-

3 -yl)piperidine-2, 6-dione B508.

[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. [001723] (7?)-3-(6-(4-(2-(l-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-ox o-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.

[001724] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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

[001725] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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

[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.

[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-fluor oazetidin-3-yl)ethyl)-l -methyl-1/7- indazol-3-yl)dihydropyrimidine-2,4( l//,3ZZ)-dione B569.

[001728] l-(7-(2-(l '-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyri do[2,3- t/]pyrimidin-2-yl)amino)pyridin-3-yl)-4-fluoro-[l,4'-bipiper idin]-4-yl)ethyl)-l-methyl-177- indazol-3-yl)dihydropyrimidine-2,4(l//,3/7)-dione B571

[001729] l-(7-(4-(l-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-di hydropyrido[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 [001730] l-(6-(4-(2-(l -(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrid o[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

[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

[001732] l-(6-(4-((4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-d ihydropyrido[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.

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 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.

[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.