Cyclin-dependent kinase 4 degraders

Abstract

The present disclosure relates to pyrrolo-pyrimidine compounds, or pharmaceutically acceptable salts thereof, of Formula (I"): Compounds of the disclosure are useful for degrading cyclin-dependent kinase 4 (CDK4), and methods of making the same are provided.

Description

CYCLIN-DEPENDENT KINASE 4 DEGRADERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of US Provisional Application No. 63 / 643.328, filed on May 6, 2024, US Provisional Application No. 63 / 722,470, filed on November 19, 2024, and US Provisional Application No. 63 / 761,757, filed on February 21, 2025, each of which is incorporated herein by reference in its entirety for any purpose.BACKGROUND

[0002] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that have a central role in cell cycle progression. CDK levels remain relatively constant throughout the cell cycle, and it is the selective activation of specific CDKs which allows for the proper ordering of the steps in cell cycle progression. Cyclins and their binding partner CDKs are key regulatory enzymes driving the cell cycle and cell proliferation. The catalytic activities of CDKs are regulated by their interactions with cyclins (including cyclin A, cyclin B, D-type cyclins, and cyclins E), and with CDK inhibitors (Ding, L. et al., Int. J. Mol. Sci. (2020) 21(6): 1960). In mammals there is one mitotic CDK (CDK1) and multiple interphase CDKs, including CDK2, CDK4, and CDK6.

[0003] Cyclin DI is an important cell cycle regulator that activates CDK4 / 6. CDK4 and closely related CDK6 play key roles in mammalian cell proliferation, where they help to drive the progression of cells into the DNA synthetic (S) phase of the cell-division. The enzymatic activities of CDK4 and CDK6 in the first gap phase (Gl) of the cycle are governed by D-type cyclins expressed in response to various extracellular signals, including stimulatory' mitogens (Sherr, C.J. etal., Cancer Discov. (2016) Cancer Disc. 6(4): 353-367)). Upon activation, CDK4 / 6 phosphory late the retinoblastomas tumor suppressor protein (Rb), leading to the release of its repression on the transcription factor E2F1, which is then free to induce the expression of proteins involved in Gl to S phase transition. This fluctuation in cyclin expression results in the oscillation in CDK activity7and the tightly regulated cell cycle. In cancer cells, the cell cycle is often dysregulated, and such cells then develop dependencies on individual cyclins or CDKs, such as CDK4 or CDK6. providing opportunities for therapeutic targeting (Suski, J.M. et al.. Cancer Cell (2021) 39(6): 759-778).

[0004] Given multiple nodes of oncogenic signals converge on cyclin D-CDK4 / 6 in multiple cancer ty pes, particularly breast cancers, CDK4 / 6 thus have been targeted by small moleculeinhibitors for cancer therapy. There are three Cyclin D isoforms, but only Cyclin DI is required for the maintenance of ER+ breast cancer cell lines. Targeted overexpression of cyclin DI in mammary glands of transgenic mice led to development of mammary carcinomas (Wang, T.C. et al., Nature (1994) 369: 6482), while induced deletion of cyclin DI in adult mice with ErbB2- driven breast cancer halted tumor grow th in vivo (Choi, Y.J. et al., Cancer Cell (2012) 22(4): 438-451). CDK4 / 6 inhibitors are established therapeutics for hormone receptor positive (HR+) / human epidermal growth factor receptor-2 negative (HER2-) breast cancers (Goel, S. et al., Nat. Rev. Cancer (2022) 22(6): 356-372: Sherr, C.J. et al.. Cancer Discov. (2016) Cancer Disc. 6(4): 353-367). In fact, CDK4 / 6 inhibitors have revolutionized the treatment of hormonepositive metastatic breast cancers (mBCs), and they are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC patients (Asghar, U.S. et al., JCO Precis. Oncol. (2022) 6: e210002). Although CDK4 / 6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are associated with severe side effects (Asghar (2022); Braal. C.L. et al., Drugs (2021) 81(3): 317-331). Frequently observed side effects include hematological abnormalities including reduced numbers of neutrophils, erythroid cells and platelets that are associated with anemia, bleeding and a higher risk of infections (Braal (2021)). Recapitulated with these clinical side effects, inducible deletion of CDK6 in adult mice hematopoiesis was accompanied by neutropenia, while that was not the case in the induced deletion of CDK.4 (Maurer, B. et al., Haematologica (2021) 106(10): 2624- 2632). Thus, anti-CDK4 therapies by sparing CDK6 may reduce dose-limiting hematological adverse events, and maximize CDK4 target coverage in HR+HER- breast cancer, which may allow a completely block aberrant Gl-S phase transition and tumor growth.

[0005] However, the effects of CDK4 / 6 inhibitors are limited by intrinsic or acquired resistance to CDK4 / 6 inhibitors, and almost all patients progress after treatment (Y uan, K. et al. , Acta Pharm. Sin. B (2021) 11(1): 30-54, Epub 2000). Multiple mechanisms of resistance to CDK4 / 6 inhibitors have been previously identified, including loss of Rb and amplification and / or overexpression of pl6, CDK6, cyclin DI, and cyclin E, where activation of the cyclin E- CDK2 pathway compensates for CDK.4 / 6 inhibition via a bypass mechanism. Cell line models that rendered resistance to palbociblib demonstrated amplification of the CDK6 locus or increased CDK6 mRNA / protein level, while knockdown of CDK6 restored sensitivity to CDK4 / 6 inhibition, indicating that drug resistance was attributable to increased levels of CDK6 activity (Schoningen S.F. and Blain. S.W., Mol. Cancer Ther. (2020) 19(1): 3-12; Yang, C. et al.. Oncogene (2017) 36: 2255-2264). Recent research has identified the aberrant activation ofcyclin E / CDK2 as a key mechanism by which tumors can evade CDK4 / 6 blockade (Freeman-Cook, K. et al., Cancer Cell (2021) 39: 1404-1421, Wang, B. et al., Front. Oncol. (2021) 11 : 405).

[0006] Targeted protein degradation (TPD) has emerged recently as an attractive novel therapeutic approach, due to the potential benefits including improved selectivity' and catalytic nature hence less stringent requirement on exposure compared to traditional small-molecule inhibitors (Bekes, M. et al., Nat. Rev. Drug Discov. (2022) 21(3): 181-200). Heterobifunctional degraders, or proteolysis-targeting chimeras (PROTAC), are a commonly used therapeutic modality' to achieve targeted protein degradation (Lai, A.C. and Crews, C.M., Nat. Rev. Drug Discov. (2017) 16(2): 101-114). PROTACs are bifunctional degraders that include 2 binding moieties. i.e. the warheads and the E3 ubiquitin ligase-binding moi eties. The warheads bind to the target protein of interest with high affinity. The E3 ubiquitin ligase-binding moieties recruit E3 ligases that ubiquitinate the target protein and prompt the target protein to be recognized and subsequently degraded by 26S proteasome. The two ligands are connected by linkers of various flavors.

[0007] No CDK4 or CDK6 degrader has been approved by FDA so far. Intnguingly, CDK.4 alone, but not CDK6, is required for the maintenance of ER+ breast cancer cell lines in DepMap. Despite the importance of cyclin DI in cancers, it is largely dispensable for normal physiology' as mice deficient in cyclin DI were viable with minor and restricted developmental defects (Choi, Y.J. et al.. Cancer Cell (2012) 22(4): 438-451; Fantl. V. et l., Genes & Dev. (1995) 9(19): 2364-2372), suggesting that degradation or inhibition of cyclin DI may be well-tolerated in patients. Xiong has reported degradation of cyclin DI via a bridged PROTAC that recruits the CDK4 / 6-cyclin DI complex by binding cyclin Dl’s partner with a CDK4 / 6 targeting ligand (Xiong, Y. et l.. J. Am. Chem. Soc. (2022) 144(49): 22622-22632).

[0008] Therefore, there is an unmet medical need to develop new CDK4-specific degraders for cancer patients that may have better efficacy7by degrading CDK4 or cyclin DI via CDK4- binding while avoiding CDK6 mediated heme toxicity'.SUMMARY

[0009] Disclosed herein are compounds of Formulae (I’), (I”), and (I), methods of making the same, and methods of treating a disease or disorder mediated by CDK4.

[0010] The present disclosure relates to compounds of Formula (I’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and CiX alkyl:L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, -(C(Ral)2)P-C*(=O)-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-. -NRa2-. and -C(=O)-:X2is selected from a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rc2, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb2;L3is selected from a covalent bond, -O-, -(C(Ra3)2)P-, -C2-C4alkynyl-, -(*C(Rdl)2)P-C(=O)-, -*O- (C(Rdl)2)P-C(=O)-, and -*N(Rb3)-(C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that if L ’ is not a covalent bond, X2is a covalent bond; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S. N, and NRb4; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb5;Ring B is selected from:JWV 2I on the Ring B moiety denotes the point of attachment to L and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;Y1are each independently selected from C(Re2)2, NRb7, and -*N(Rb7)-C(=O)-, wherein * denotes the point of attachment of Y1to W;R3is selected from H, D, and Ci-C4alkyl;Y2is C(Re3)2or C(=O);W is CH or N;Ral, Ra2, and Ra3are each independently selected from H, D, halo, OH, Ci-C4alkyl, and monocyclic C3-C6 cycloalkyl;RbiRb2, pt.3^ Rb4 Rb5, R’>6_ Rb7Rbs. and Rb9are each independently selected from H, D, Ci- C4alkyl, and monocyclic Cs-Cecycloalkyl;Rcl, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7are each independently selected from D, halo, OH, CN, Ci- C4alkyl, or two Rcl, Rc2, Rc3, Rc4, Rc5, Rc6, or Rc7attached to the same atom, form a =0;Rdlare each independently selected from H, D, halo, OH, CN, N(Rb8)2, Ci-C+alkyl, and Ci- C4alkoxy;Rel, Re2, and Re3are each independently selected from H, D, halo, and Ci-C4alkyl: or two Reltogether with the carbon atom to which they are attached form a monocyclic C-- Cecycloalkyl; or two Re2together with the carbon atom to which they are attached form a =0; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2; provided that:(i) when both R1and R2are methyl; both L1and L3are a covalent bond; X1is piperazine; and X2is 3- to 6-membered heterocyclyl, then the following moieties are not covalently bonded to X2:(ii) when L1, L3, and X2are each a covalent bond; X1is piperazine; L2is -(C(Ra2)2)P; and p is 1, then the following moieties are not covalently bonded to L2:(iii) when L1, L2, and X2are each a covalent bond; X1is piperazine; L3is -*O-(C(Rdl)2)P- C(=O)- or -*NH-(C(Rdl)2)P-C(=O)-; and the following moiety is covalently bonded to L3: j,, then p is 1 or 2 and at least one R is not H; and(iv) when L1. L3. and X2are each a covalent bond; X1is piperidine or piperazine; L2is - (C(Ra2)2)P, then the following moiety is not covalently bonded to L2:

[0011] The present disclosure also relates to compounds of Formula (I”):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Cialkyl:L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, -(C(Ral)2)P-C*(=O)-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently- selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-. -NRa2-. and -C(=O)-:X2is selected from a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rc2, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb2;L3is selected from a covalent bond, -O-, -(C(Ra3)2)P-, -C2-C4alkynyl-, -(*C(Rdl)2)P-C(=O)-, - *O-(C(Rdl)2)P-C(=O)-, and -*N(Rb3)-(C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that if L ’ is not a covalent bond, X2is a covalent bond; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S. N, and NRb4; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb5;Ring B is selected from:t of attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;Y1are each independently selected from C(Re2)2, NRb7. and -*N(Rb7)-C(=O)-, wherein * denotes the point of attachment of Y1to W;R3is selected from H, D, and Ci-C4alkyl;W is CH or N;Ral, Ra2, and Ra3are each independently selected from H, D, halo, OH, Ci-C4alkyl, and monocyclic C3-C6 cycloalkyl;Rbl, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, Rb8, and Rb9are each independently selected from H, D, Ci- C4alkyl, and monocyclic Cs-Cecycloalkyl;Rcl, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7are each independently selected from D, halo, OH, CN, Ci- C4alkyl, or two Rcl, Rc2, Rc3, Rc4, Rc5, Rc6, or Rc7attached to the same atom, form a =0;Rdlare each independently selected from H, D, halo, OH, CN, N(Rb8)2, Ci-C4alkyl, and Ci- C4alkoxy;Reland Re2are each independently selected from H, D, halo, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl; or two Re2together with the carbon atom to which they are attached form a =0; m is 0, 1 , or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2; provided that when Ringthe compound of Formula (I”) is not:

[0012] The present disclosure also relates to compounds of Formula (I):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and C i-C+alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond or -(C(Ra2)2)P-;X2is a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rc2, or 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently- selected from O, S, N, and NRb2;L3is selected from a covalent bond, -O-, -C2-C4alkynyl-, -*O-(C(Rdl)2)P-C(=O)-, and -*N(Rb3)- (C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that if L3is not a covalent bond, X2is a covalent bond; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl or a 7- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4, wherein the 5- to 12- membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb4; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb5;Ring B is selected from:the Ring B moiety denotes the point of attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;Y1are each independently selected from C(Re2)2 and NRb7;R3is selected from H, D, and Ci-C4 lkyl;Y2is C(Re3)2or C(=O);W is CH or N;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;RbiRb2, gb3 j^b4 Rbs, pb6 Rb7;and Rb8are each independently selected from H, D, Ci-C4alkyl, and monocyclic Cs-Cecycloalkyl;Rcl, Rc2, Rc3, Rc4, Rc5, and Rc6are each independently selected from D, halo, OH. CN, Ci- C4alkyl, or two Rcl, Rc2, Rc3. Rc4, Rc5, or Rc6attached to the same atom, form a =0:Rdlare each independently selected from D, halo, OH, CN, N(Rb8)2, Ci-C4alkyl, and Ci- C4alkoxy;Rel, Re2, and Re3are each independently selected from H, D, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cgcycloalkyl; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2; provided that:(i) when both L1and L3are a covalent bond, X1is piperazine, and X2is 3- to 6- membered heterocyclyl, then the following moieties are not covalently bonded to X2:(ii) when L1, L3, and X2are each a covalent bond, X1is piperazine, L2is -(C(Ra2)2)p, and p is 1, then the following moieties are not covalently bonded to L2:(iii) when L1, L2, and X2are each a covalent bond, X1is piperazine, and L3is -*O- (C(Rdl)2)P-C(=O)- or -*NH-(C(Rdl)2)P-C(=O)-, then p is 1 or 2, and at least one Rdlis not H.

[0013] The present disclosure further relates to compounds of Table I, or pharmaceutically acceptable salts thereof.

[0014] The present disclosure furthermore relates to pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of a compound of Formula (I"):and at least one pharmaceutically acceptable excipient

[0015] The present disclosure also relates to a method of treating a disease or disorder mediated by cyclin-dependent kinase 4 (CDK4), comprising providing to a subject in need thereof a compound of Formula (I'’):or a pharmaceutically acceptable salt thereof.DETAILED DESCRIPTIONDefinitions

[0016] Unless otherw ise defined, all tenns of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art. Standard techniques may be used for chemical synthesis and chemical analysis. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0017] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version. Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell. University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, T, John Wiley & Sons, New York: 2001.

[0018] Unless otherw ise indicated, the following terms have the following meanings:

[0019] The term “additional anticancer agent"' as used herein refers to any one or more therapeutic agent, other than a compound described herein (e.g., Formulae (I’), (I”), (I), (IT) to (XX’), and (II) to (XII), or sub-formulae thereof), or a pharmaceutically acceptable salt thereof, that is or can be used in the treatment of cancer.

[0020] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action.

[0021] The expressions “administered in combination with,” “co-administration,” and their grammatical equivalents, refer to administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.

[0022] The term “alkyl” used alone or as part of a larger moiety, such as “alkoxyl” and the like, refers to a saturated aliphatic straight-chain or branched monovalent or bivalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1, 2, 3, or 4 carbon atoms, i.e. Ci-C4alkyl. As used herein, a “Ci-C4alkyl” group means a radical having 1, 2, 3, or 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, sec-butyl, tert-butyl, and the like. In some embodiments, an alkyl group is an unsaturated alkyl group, also termed an alkenyl or alkynyl group. An “alkenyl” group refers to an alkyl group that contains one or more carbon-carbon double bonds. An “alkynyl” group refers to an alkyl group that contains one or more carbon-carbon triple bonds.

[0023] The term “alkoxy” refers to an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, “Ci-C4alkoxy” includes methoxy, ethoxy, propoxy, and butoxy.

[0024] The term “aryl” refers to a radical of a 6- to 12-membered aromatic hydrocarbon nng system. An aryl group can either be monocyclic (“monocyclic aryl”) or polycyclic (e.g., a fused system (“fused ary 1”). Non-limiting examples of aryls include phenyl, cyclooctatetraene, indene, and naphthyl. Substituents may be present on one or more rings in the aryl. Substituents on the aryl do not count towards the number of atoms of the aryl. The aryl itself may be linked to the compound via every suitable position of the ring system.

[0025] The expression “CDK4 degrader” refers to a compound that selectively and catalytically degrades CDK4 over other CDKs and other proteins. Said another way, a CDK4 degrader shows no or low degradation of other CDKs and other proteins. A CDK4 degrader degrades CDK4 to a greater extent (e.g. , in terms of DC50 value, which can be nanomolar) whencompared with the degradation of other CDKs and other proteins. Degradation can be measured using known biochemical assays.

[0026] The term '‘cell” refers to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0027] The term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” CDK4, or “contacting” a cell with a compound of the disclosure, includes the administration of a compound of the present disclosure to a subject or patient, such as a human, having CDK4, as well as, for example, introducing a compound of the disclosure into a sample containing a cellular or purified preparation containing CDK4.

[0028] The term “cycloalkyl” refers to a radical of a 3- to 10-membered non-aromatic hydrocarbon ring system. A cycloalkyl group can either be monocyclic (“monocyclic cycloalkyl”) or polycyclic (e.g, a fused system (“fused cycloalkyl”), bridged system (“bridged cycloalkyl”), or spiro system (“spirocycloalkyl”)). When a cycloalkyl group is a polycyclic ring system, said ring system includes at least one non-aromatic ring. Non-limiting examples of monocyclic C3-C10 cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Polycyclic cycloalkyl may include fused, bridged, and / or spirocyclic rings. Non-limiting examples of fused or bridged cycloalkyls include: indanyl, tetrahydronaphthyl, bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclofl. 1.0]pentane, bicyclo[3.1.0]hexane, bi cyclo [2. 1.1] hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g, spirocyclic bicycle wherein two rings share one ring atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.5]octane, spiro[3.5]nonane, spiro[2.6]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro [3.6] decane, spiro [5.5] undecane, and the like. Substituents may be present on one or more rings in the cycloalkyl. Substituents on the cycloalkyl do not count towards the number of atoms of the cycloalkyl. The cycloalkyl itself may be linked to the compound via every suitable position of the ring system.

[0029] The terms “degrade”, “degrading”, or “degradation” refer to the partial or full breakdown of CDK4 proteins, which reduces or eliminates the biological activity of CDK4, as compared to the amount of that proteins in the absence of the degrader (e.g. , beforeadministration of the degrader). In some alternatives, the term “degrade” means a decrease in the levels of CDK4 protein of at least 5%. at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% (e.g., before administration of the degrader or at two different timepoints during treatment with the degrader). In other alternatives, inhibit means a decrease in the levels of CDK2 and / or CDK4 of 5% to 25%, 25% to 50%, 50 to 70%, 75 to 100%. In some embodiments, degrade means a decrease in the levels of CDK4 of about 95% to 100%, e.g.. a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreases can be measured using a variety of techniques that would be recognizable by one of skill in the art, including in vitro degradation assays. The DCso value refers to the concentration at which 50% maximal degradation was observed.

[0030] The term “degrader” refers to a compound, or a pharmaceutically acceptable salt thereof, that degrades a target protein.

[0031] The expression “E3 ubiquitin ligase-binding moiety” refers to a chemical group that binds to an E3 ubiquitin ligase.

[0032] The expression “effective amount” refers to an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the disease, condition, or cancer being treated in the subject as compared to a control.

[0033] The term “halo” as used herein refers to halogen and includes chloro, fluoro, bromo and iodo.

[0034] The term “heteroaryl” refers to a radical of a 4- to 12-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. Representative heteroary l groups include ring systems where each ring comprises a heteroatom and is aromatic, e.g. imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indoyl, indolizinyl, benzothiophenyl, purinyl, pyrido[4,3-d]pyrimidine, napthyl, naphthyridinyl, quinazolinyl, oxadiazolyl, thiadiazolyl, cinnolinyl, indazyl, and pteridinyl. Substituents may be present on one or more rings in the heteroaryl. Substituents on the heteroaryl do not count towards the number of atoms or heteroatoms of the heteroaryl. The heteroaryl itself may be linked to the compound via every suitable position of the ring system.

[0035] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g.,NO), substituted nitrogen, oxygen, and sulfur, including sulfoxide and sulfone (“3-12 membered heterocyclyf’). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e g., a bicyclic system (“bicyclic heterocyclyl”) or a tricyclic system (“tricyclic heterocyclyl”)). A polycyclic ring system includes fused, bridged, or spiro ring systems. A “fused heterocyclyl” refers to a polycyclic heterocyclyl, wherein two rings share two adjacent ring atoms and the bond between the two common ring atoms. A “spiroheterocyclyl” refers to a polycyclic heterocyclyl, wherein two rings share one carbon atom. When a heterocyclyl group is a polycyclic ring system, said ring system includes at least one non-aromatic ring. Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl. tetrahydrofuranyl, pyrrolidinyl, pyrrolidin-2-onyl. piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can include heteroatoms in one or more rings in the polycyclic ring system, including polycyclic ring systems having a non-aromatic ring fused to a phenyl or heteroatyl ring. Exemplary polycyclic heterocyclic groups include 2 / / -benzo[b][l,4]oxazin-3(4 / / )-onyl, isoindolin-l-onyl, isoquinolin- l(2H)-onyl, 3-oxabicyclo[3.1.0] hexanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 6-oxa-3-azabicyclo[3. 1. l]heptanyl, tetrahydropyrazolo[l,5-a]pyridinyl, 1,4-oxazepanyl, 5, 6,7,8- tetrahydro-47 / -pyrazolo[l,5-a][l,4]diazepinyl, l,3,7-triazaspiro[4.5]decane-2,4-dionyl, 5, 6,7,8- tetrahydroimidazo[1.5-a]pyrazine. 2,7-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl. 1 ,2,3,5-tetrahydropyrrolo[3,4-c]pyrrolyl, 2,6-diazaspiro[3.3]heptanyl, 3,9- diazaspiro[5.5]undecanyl, l,7-diazaspiro[4.4]nonanyl, 2-azaspiro[3.3]heptanyl, 3- azaspiro[5.5]undecanyl, 3-azaspiro[5.5]undec-8-enyl, l-azaspiro[3.3]heptanyl, 1,6- diazaspiro[3.3]heptanyl, isoindolinyl, 2,3-dihydro-lH-benzo[d]imidazolyl, indolinyl. benzo [djoxazolyl, 1,2-dihydroisoquinolinyL and the like. Substituents may be present on one or more rings in the heterocyclyl. Substituents on the heterocyclyl do not count towards the number of atoms or heteroatoms of the heterocyclyl. The heterocyclyl itself may be linked to the compound via every suitable position of the ring system.

[0036] The term “inhibitor” refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce or down-regulate the biological activity of a gene and / or a protein. Consequently, a “CDK4 inhibitor” refers to a compound that has a biological effect to inhibit or significantly reduce or down-regulate the biological activity of CDK4.

[0037] The expression “linker moiety” and “linker” refer to a bivalent chemical moiety’ that binds (e.g., badges) two separate entities to one another. As used herein, the terms “linkermoiety'’ and "linker" can refer to a bivalent chemical moiety that is covalently bonded to both the pyridine ring of the targeting ligand of the compounds of the disclosure and ring B of the E3 ubiquitin ligase-binding moiety of the compounds of the disclosure.

[0038] The expression “Peak 1” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation / purification that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended product compound is referred to as “peak 2”.

[0039] The expression “pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmacal use.

[0040] The expression “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the pharmaceutical compositions of the disclosure without causing a significant adverse toxicological effect on the subject.

[0041] The term “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0042] The expression “selective degrader” refers to a “CDK4 degrader” that has the ability to selectively degrade CDK4 over another kinase or to selectively reduce target signaling activity relative to off-target signaling activity, via direct or indirect interaction with the target. In one embodiment, the compounds of the present disclosure are selective CDK4 degraders. In some embodiments, the compounds of the present disclosure (e.g, compounds of Formula (F), (I”), (I), (IF), (Ila’), (lib’), (lie’), (lid ), (lie’), (Ilf), (III ), (Illa’), (Illb ), (IIIc ), (Illd’), (Ille’), (Illf ), (Illg’), (Illh ), (Illi’), (IV’), (IVa’), (IVb’), (IVc’), (IVd’), (IVe’), (IVf ), (V’), (Va’), (Vb’), (Vc‘), (Vd’), (Ve‘), (VI’), (Via ), (VIb’), (Vic’), (Vid’), (Vie’), (VIF), (Vila’), (Vllb’), (Vile ), (Vlld’), (VIIF), (Villa’), (Vlllb ), (VIIIc ). (VUId ), (IX ). (IXa’). (IXb’). (IXc’), (IXd’), (IXe’), (IXf ), (IXg’), (X’), (Xa’), (Xb’), (Xc’), (Xd’), (XI’), (Xia'), (Xlb’), (XIc’), (Xld’), (Xie’), (XII’), (Xlla’), (Xllb’), (XIIc’), (Xlld’), (XIII ), (Xllla’), (Xlllb’), (XIIIc’), (Xllld’), (Xllle’), (XIV’), (XFVa’j, (XlVb’), (XIVc’). (XlVd’), (XlVe’), (XV’), (XVa'), (XVb’), (XVc’), (XVd’). (XVe’), (XVF), (XVIa’), (XVIb’), (XVIc’), (XVId’). (XVIe’), (XVII’), (XVIIa’), (XVIIb ), (XVIIc’), (XVIId’), (XVIIe’), (XVIIF), (XVIIIa’), (XVIIIb’),(XVIIIc’), (XVIIId’), (XIX’), (XIXa’), (XlXb’), (XIXc ), (XIXd‘), (XX’), (XXa’), (XXb’), (XXc’), (XXd’), (XXe’). (II), (Ila), (lib), (lie), (lid), (lie), (Ilf). (Ill), (Illa), (Illb), (IIIc). (Illd), (Ille), (Illf), (Illg), (Illh), (Illi), (IV), (IV a), (IVb), (IVc), (IV d), (IVe), (IVf), (V), (Va), (Vb), (Vc), (Vd), (Ve), (VI), (Via), (VIb), (Vic), (Vid), (VII), (Vila), (Vllb), (Vile), (Vlld), (VIII), (Villa), (Vlllb), (VIIIc), (Vllld), (IX), (IXa), (IXb), (IXc), (IXd), (IXe), (IXf), (IXg), (X), (Xa), (Xb), (Xc), (Xd). (XI), (Xia), (Xlb), (XIc), (Xld), (Xie), (XII), (Xlla), (Xllb), (XIIc), (Xlld), and subformulae) are selective for CDK.4 over CDK2, CDK6, and CDK9.

[0043] The term '‘subject” or “patient” refers to a mammal in need of medical treatment, for example, a human, but can also be an animal in need of veterinary' treatment, e.g., companion animals (e.g, dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g, rats, mice, guinea pigs, and the like). In one aspect, the patient is a human. In some embodiments, the patient is an adult human.

[0044] The term “tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0045] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of compounds of Fonnula (I”) are within the scope of the present disclosure.

[0046] The term '‘treating” or “treatment” refers to obtaining a desired pharmacological and / or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or substantially reducing the extent of the disease, condition or cancer; ameliorating or improving a clinical symptom or indicator associated with the disease, disorder, condition or cancer; delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or cancer; or decreasing the likelihood of recurrence of the disease, condition or cancer.Compounds of the Disclosure

[0047] Provided herein, among other things, are compounds and compositions that modulate (e.g., by protein degradation) the activity of CDK4.EMBODIMENTS

[0048] The present disclosure relates to compounds of Formula (I’):(1) or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, -(C(Ral)2)P-C*(=O)-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-, -NRa2-, and -C(=O)-;X2is selected from a covalent bond, C'3-Ciocycloalkyl optionally substituted with 1 to 4 Rc2, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb2;L3is selected from a covalent bond, -O-, -(C(Ra3)2)P-, -C2-C4alkynyl-, -(*C(Rdl)2)P-C(=O)-, -*O- (C(Rdl)2)P-C(=O)-, and -*N(Rb3)-(C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that if L1is not a covalent bond. X2is a covalent bond; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb4; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb5;Ring B is selected from:' ' on the Ring B moiety denotes the point of attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;Y1are each independently selected from C(Re2)2, NRb7, and -*N(Rb7)-C(=O)-, wherein * denotes the point of attachment of Y1to W;R3is selected from H, D, and Ci-C4alkyl;Y2is C(Re3)2or C(=O);W is CH or N;Ral, Ra2, and Ra3are each independently selected from H, D, halo, OH, Ci-C4alkyl, and monocyclic C3-C6 cycloalkyl;RblRb2 Rb3 Rb4 pb5 Rb6 Rb7 pbyanJ pb9are eac|1indepencJently selected from H, D, Cl- C4alkyl, and monocyclic Cs-Cecycloalkyl;Rcl, Rc2, Rc3, Rc4, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, CN, Ci- C4alkyl, or two Rcl, Rc2, Rc3, Rc4, Rc3, Rc6, or Rc7attached to the same atom, form a =0;Rdlare each independently selected from H, D, halo, OH, CN, N(Rb8)2, Ci-C4alkyl, and Ci- C4alkoxy;R61, Re2, and Re3are each independently selected from H, D, halo, and CiXUalkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic C-. Cr,cycloalkyl: or two Re2together with the carbon atom to which they are attached form a =0; m is 0, 1. or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2; provided that:(i) when both R1and R2are methyl; both L1and L3are a covalent bond; X1is piperazine: and X2is 3- to 6-membered heterocyclyl, then the following moieties are not covalently bonded to X2:(ii) when L1, L3, and X2are each a covalent bond; X1is piperazine; L2is -(C(Ra2)2)P; and p is 1, then the following moieties are not covalently bonded to L2:(iii) when L1, L2, and X2are each a covalent bond; X1is piperazine; L3is -*O-(C(Rdl)2)P- C(=O)- or -*NH-(C(Rdl)2)P-C(=O)-; and the following moiety is covalently bonded to L3:, then p is 1 or 2 and at least one Rdlis not H; and(iv) when L1, L3, and X2are each a covalent bond; X1is piperidine or piperazine; L2is - (C(Ra2)2)P, then the following moiety is not covalently bonded to L2:

[0049] In addition to embodiment (1) in the preceding paragraphs, the compounds of Formula (I’), or pharmaceutically acceptable salts thereof, include the compound of Formula (I”):(2) (A) or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Cralkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, -(C(Ral)2)P-C*(=O)-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-, -NRa2-. and -C(=O)-;X2is selected from a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rc2, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb2;L3is selected from a covalent bond, -O-, -(C(Ra3)2)P-, -C2-C4alkynyl-, -(*C(Rdl)2)P-C(=O)-, -*O- (C(Rdl)2)P-C(=O)-, and -*N(Rb3)-(C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that if L3is not a covalent bond, X2is a covalent bond; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6-to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently- selected from O, S. N, and NRb4; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb5;Ring B is selected from:t of attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;Y1are each independently selected from C(Re2)2, NRb7, and -*N(Rb7)-C(=O)-, wherein * denotes the point of attachment of Y1to W;R3is selected from H, D, and Ci-C4alkyl;W is CH or N;Rai pa2anc| ga3indepen(ientiy selected from H, D, halo, OH, Ci-C4alkyl, and monocyclic C3-C6 cycloalkyl;Rb1Rb2, Rb3Rb4Rb5, Rb6. Rb7, Rb8, and Rb9are each indepencjently selected from H, D, C1- C4alkyl, and monocyclic Cs-Cecycloalkyl;Rcl, Rc2, Rc3, Rc4, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, CN, Ci- C4alkyl, or two Rcl, Rc2, Rc3, Rc4, Rc3, Rc6, or Rc7attached to the same atom, form a =0;Rdlare each independently selected from H, D, halo, OH, CN, N(Rb8)2, C1-C4alkyl, and C1- C4alkoxy;R61and Re2are each independently selected from H, D, halo, and Ci-C4alkyl: or two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cgcycloalkyl; or two Re2together with the carbon atom to which they are attached form a =0; m is 0, 1, or 2; n is 0, 1, 2. 3, or 4; and p is 0, 1, or 2; provided that when Ringthe compound of Formula (I”) is not:(B)the compound is represented by Formula (I”):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, -(C(Ral)2)P-C*(=O)-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S. N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O-, and -C(=O)-;X2is selected from a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rc2, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb2;L3is selected from a covalent bond, -O-, -(C(Ra3)2)P-, -C2-C4alkynyl-, -*O-(C(Rdl)2)P-C(=O)-, and -*N(Rb3)-(C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that if L3is not a covalent bond. X2is a covalent bond; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S. N, and NRb4; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb5;Ring B is selected from:on theRing B moiety denotes the point of attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;Y1are each independently selected from C(Re2)2, NRb7, and -*N(Rb7)-C(=O)-, wherein * denotes the point of attachment of Y1to W;R3is selected from H, D, and Ci-C4alkyl;W is CH or N;Ral, Ra2, and Ra3are each independently selected from H, D, halo, OH, Ci-C4alkyl, and monocyclic C3-C6 cycloalkyl;Rbipb2 Rb3 Rb4, Rb5, Rb6, Rb7, Rb8, and Rb9are each independently selected from H, D, Ci- C4alkyl, and monocyclic Cs-Cecycloalkyl;Rcl, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7are each independently selected from D, halo, OH, CN, Ci- C4alkyl, or two Rcl, Rc2, Rc3. Rc4, Rc5, Rc6, or Rc7attached to the same atom, form a =0;Rdlare each independently selected from H, D, halo, OH, CN, N(Rb8)2, Ci-C4alkyl, and Ci- C4alkoxy;Reland Re2are each independently selected from H, D, halo, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyk or two Re2together with the carbon atom to which they are attached form a =0; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2; provided that when Ringthe compound of Formula (I”) is not:(C)the compound is represented by Formula (I’'):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and C , -Ctial ky I;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a nng carbon with 1 to 3 Rcl. wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond or -(C(Ra2)2)P-;X2is selected from a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;L3is selected from a covalent bond, -O-, -C2-C4alkynyl-, -*O-(C(Rdl)2)P-C(=O)-. and -*N(Rb3)- (C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that if L3is not a covalent bond, X2is a covalent bond; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 7- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb5;Ring B is selected from:on the Ring B moiety denotes the point of attachment to L3and the other denotes the point of attachment to W;R3is H;W is CH or N;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl:RbiRb2, pt.3^ pb4 Rb55Rb6_ and Rb8are each independently selected from H, D, CnC4alkyl, and monocyclic Cs-Cecycloalkyl;Rcl, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7are each independently selected from D, halo, OH, CN, Ci- C4alkyl, or two Rcl, Rc2, Rc3, Rc4, Rc5, Rc6, or Rc7attached to the same atom, form a =0;Rdlare each independently selected from H, D, halo, OH, CN, N(Rb8)2, Ci-C4alkyl, and Ci- C4alkoxy;Relare each independently selected from H, D, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached fonn a monocyclic Cs-Cgcycloalkyl; m is 0; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

[0050] In addition to embodiment (1) in the preceding paragraphs, the compounds ofFormula (I'), or pharmaceutically acceptable salts thereof, include the compound of Formula (I):(3) or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and CiX alkyl:L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond or -(C(Ra2)2)P-;X2is a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rc2, or 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently- selected from O, S, N, and NRb2;L3is selected from a covalent bond, -O-, -C2-C4alkynyl-, -*O-(C(Rdl)2)P-C(=O)-, and -*N(Rb3)- (C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that if L3is not a covalent bond, X2is a covalent bond; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl or a 7- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4, wherein the 5- to 12- membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb4; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb5;Ring B is selected from:wherein one I on the Ring B moiety denotes the point of attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;Y1are each independently selected from C(Re2)2 and NRb7;R3is selected from H, D, and Ci-C4alkyl;Y2is C(Re3)2or C(~O):W is CH or N;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;RbiRb2pb3 Rb4 pbsselected from H, D, Ci.C4alkyl, and monocyclic Cs-Cecycloalkyl;Rcl, Rc2, Rc3, Rc4, Rc5, and Rc6are each independently selected from D, halo, OH, CN, Ci- C4alkyl, or two Rcl, Rc2, Rc3, Rc4, Rc5, or Rc6attached to the same atom, form a =0;Rdlare each independently selected from D, halo, OH, CN, N(Rb8)2, Ci-C4alkyl, and Ci- C4alkoxy;Rel, Re2, and Re3are each independently selected from H, D, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyk m is 0, 1. or 2; n is 0, 1 , 2, 3, or 4; and p is 0, 1, or 2; provided that:(i) when both L1and L3are a covalent bond. X1is piperazine, and X2is 3- to 6- membered heterocyclyl, then the following moieties are not covalently bonded to X2:(ii) when L1, L3, and X2are each a covalent bond, X1is piperazine, L2is -(C(Ra2)2)P, and p is 1, then the following moieties are not covalently bonded to L2:(iii) when L1, L2, and X2are each a covalent bond, X1is piperazine, and L3is -*O-then p is 1 or 2, and at least one Rdlis not H.

[0051] In addition to embodiments (1) through (3) in the preceding paragraphs, the compounds of Formulae (I’), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(4) (A)R1is H;(B) R1is D;(C) R1is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl.

[0052] In addition to embodiments (1) through (4) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(5) (A)R2is H;(B) R2is D;(C) R2is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl.

[0053] In addition to embodiments (1) through (5) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(6) (A)L1is a covalent bond;(B) L1is -(C(Ral)2)p-;(OLHs -O-;(D)L1is -(C(Ral)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;(E) L1is -(C(Ral)2)P-N(Rb9)C*(=O)- , wherein * denotes the point of attachment of L1to X1;(F) L1is -(C(Ral)2)P-C(=O)N*(Rb9)- , wherein * denotes the point of attachment of L1to X1.

[0054] In addition to embodiments (1) through (6) in the preceding paragraphs, the compounds of Formulae (F), (F ), (I), or pharmaceutically acceptable salts thereof, include those in which:(7) (A)X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRbl; for example,(B) X1is 4- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rcl, wherein the 4- to 10-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRbl;(C)X1is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;(D)X1is 5- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 5- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;(E) X1is 6-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 2 Rcl, wherein the 6-membered heterocyclyl has 1 to 2 ring heteroatoms each independently selected from O, S, N, and NRbl; such as(F) X1is piperidinyl or piperazinyl;(G)X1is Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rcl; for example,(H)X1is Cs-Cscycloalkyl optionally substituted with 1 to 3 Rcl;(I) X1is Cs-Cecycloalkyl optionally substituted with 1 to 2 Rcl;(J) X1is C4cycloalkyl optionally substituted with 1 Rcl;(K)Xxis cyclobutyl.

[0055] In addition to embodiments (1) through (7) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(8) (A)L2is a covalent bond;(B) L2is -(C(Ra2)2)P-;(C) L2is -O(C(Ra2)2)p-;(D)L2IS -O-;(E) L2is -NRa2-;(F) L2is -C(=O)-.

[0056] In addition to embodiments (1) through (8) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(9) (A)X2is a covalent bond;(B)X2is Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rc2; for example,(C)X2is Cs-Cscycloalkyl optionally substituted with 1 to 4 Rc2;(D)X2is Cs-Cecycloalkyl optionally substituted with 1 to 4 Rc2;(E) X2is C4cycloalkyl optionally substituted with 1 to 4 Rc2;(F) X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb2; for example,(G)X2is a 4- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc, wherein the 4- to 10-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb2;(H)X2is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;(I) X2is 5- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 5- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;(J) X2is 4- to 6-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 2 Rc3, wherein the 4- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms each independently selected from O, S, N, and NRb2; such as(K)X2is azetidinyl, piperidinyl, or piperazinyl;(L) X2is Ci-Ciobridged-cycloalkyl optionally substituted with 1 to 4 Rc2; for example,(M) X2is Cs-Cvbridged-cycloalkyl optionally substituted with 1 to 4 Rc2.

[0057] In addition to embodiments (1) through (9) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(10) (A) L3is a covalent bond;(B) L3is -O-, provided that X2is a covalent bond;(C) L3is -C2-C4alkynyl-, provided that X2is a covalent bond;(D)L3is -(*C(Rdl)2)P-C(=O)- , w herein * denotes the point of attachment of L3to RingB, provided that X2is a covalent bond;(E) L3is -*O-(C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that X2is a covalent bond:(F) L3is -*N(Rb3)-(C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that X2is a covalent bond;(G) L3is -(C(Ra3)2)P-, provided that X2is a covalent bond.

[0058] In addition to embodiments (1) through (10) in the preceding paragraphs, the compounds of Formulae (I’), (I"). (I), or pharmaceutically acceptable salts thereof, include those in which:(11) (A) Ring B is selected from:i on the Ring B moiety denotes the point of attachment to L and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0; for example(B) Ring B is selected from:(xix), wherein “ * ” indicates the point of attachment to (Y1^;(C) Ring B is selected from:the Ring B moiety denotes the point of attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;(D) Ring B is selected from:attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is0; for example(E) Ring B is selected from:wherein “ * ” indicates the point of attachment to (Y1^;(F) Ring B is selected from:attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;(G)Ring B is selected from:wherein “ * indicates the point of attachment to (Y1)m.

[0059] In addition to embodiments (1) through (11) in the preceding paragraphs, the compounds of Formulae (I’), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(12) (A)Y1are each independently selected from C(Re2)2;(B) Y1are each independently selected fromNRb7;(C) Y1are each independently selected from -*N(Rb7)-C(=O)-, wherein * denotes the point of attachment of Y1to W.

[0060] In addition to embodiments (1) through (12) in the preceding paragraphs, the compounds of Formulae (I’), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(13) (A)R3IS H;(B) R3is D;(C) R3is selected from Cialkyl, Czalkyl, Csalkyl, and C4alkyl.

[0061] In addition to embodiments (1) and (3) through (13) in the preceding paragraphs, the compounds of Formulae (I’), (I), or pharmaceutically acceptable salts thereof, include those in which:(14) (A)Y2is C(Re3)2;(B) Y2is C(=O).

[0062] In addition to embodiments (1) through (14) in the preceding paragraphs, the compounds of Formulae (I’), (I"). (I), or pharmaceutically acceptable salts thereof, include those in which:(15) (A) W is CH;(B)W is N.

[0063] In addition to embodiments (1) through (15) in the preceding paragraphs, the compounds of Formulae (I’), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(16) (A)Ralis H;(B) Ralis D;(C) Ralis halo;(D)Ralis OH;(E) Ralis selected from Cialkyl, C2alkyl, Csalkyl, and Cralkyl;(F) Ralis selected from monocyclic Cscycloalkyl, monocyclic Crcycloalkyl, monocyclic Cscycloalkyl. and monocyclic Cecycloalkyl.

[0064] In addition to embodiments (1) through (16) in the preceding paragraphs, the compounds of Formulae (I’), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(17) (A)Ra2is H;(B) Ra2is D;(C) Ra2is halo;(D)Ra2is OH;(E) Ra2is selected from Cialkyl, Czalkyl, Csalkyl, and Cralkyl;(F) Ra2is selected from monocyclic Cscycloalkyl, monocyclic C4cycloalkyl, monocyclic CscycloalkyL and monocyclic Cecycloalkyl.

[0065] In addition to embodiments (1), (2), and (4) through (17) in the preceding paragraphs, the compounds of Formulae (F), (I”), or pharmaceutically acceptable salts thereof, include those in which:(18) (A)Ra3is H;(B) Ra3is D;(C) Ra3is halo;(D)Ra3is OH;(E) Ra3is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) Ra3is selected from monocyclic Cscycloalkyl, monocyclic C4cycloalkyl, monocyclic Cscycloalkyl. and monocyclic Cgcycloalkyl.

[0066] In addition to embodiments (1) through (18) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(19) (A)Rblis H;(B) Rblis D;(C) Rblis selected from Cialkyl, C2alkyl, Csalkyl, and C4 lkyl;(D)Rblis selected from monocyclic Cscycloalkyl, monocyclic C4cycloalkyl, monocyclic Cscycloalkyl, and monocyclic Cgcycloalkyl.

[0067] In addition to embodiments (1) through (19) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(20) (A)Rb2is H;(B) Rb2is D;(C) Rb2is selected from Cialkyl, C2alkyl, Cialkyl, and C4alkyl;(D)Rb2is selected from monocyclic Cscycloalkyl, monocyclic C4cycloalkyl, monocyclic Cscycloalkyl, and monocyclic Cgcycloalkyl.

[0068] In addition to embodiments (1) through (20) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(21) (A)Rb3is H;(B) Rb3is D;(C) Rb3is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D)Rb3is selected from monocyclic Cscycloalkyl, monocyclic C4cycloalkyl, monocyclic Cscycloalkyl, and monocyclic Cgcycloalkyl.

[0069] In addition to embodiments (1) through (21) in the preceding paragraphs, the compounds of Formulae (F), (F ), (I), or pharmaceutically acceptable salts thereof, include those in which:(22) (A)Rb4is H;(B) Rb4is D;(C) Rb4is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D)Rb4is selected from monocyclic Cscycloalkyl, monocyclic C4cycloalkyl, monocyclic Cscycloalkyl, and monocyclic Cgcycloalkyl.

[0070] In addition to embodiments (1) through (22) in the preceding paragraphs, the compounds of Formulae (I’), (I"). (I), or pharmaceutically acceptable salts thereof, include those in which:(23) (A)Rb5is H;(B)Rb5is D;(C) Rb5is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D)Rb5is selected from monocyclic CscycloalkyL monocyclic C4cycloalkyl, monocyclic Cgcycloalkyl, and monocyclic Cgcycloalkyl.

[0071] In addition to embodiments (1) through (23) in the preceding paragraphs, the compounds of Formulae (I’), (F ), (I), or pharmaceutically acceptable salts thereof, include those in which:(24) (A)Rb6is s H;(B) Rb6is D;(C) Rb6is selected from Cialkyl, Czalkyl, Csalkyl, and Cralkyl;(D)Rb6is selected from monocyclic Cscycloalkyl, monocyclic C4cycloalkyl, monocyclic Cgcycloalkyl, and monocyclic Cgcycloalkyl.

[0072] In addition to embodiments (1) through (24) in the preceding paragraphs, the compounds of Formulae (I’), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(25) (A)Rb7is H;(B) Rb7is D;(C) Rb7is selected from Cialkyl, C2alkyl, Csalkyl, and Cralkyl;(D)Rb7is selected from monocyclic Cscycloalkyl, monocyclic Crcycloalkyl, monocyclic Cgcycloalky l. and monocyclic Cgcycloalkyl.

[0073] In addition to embodiments (1) through (25) in the preceding paragraphs, the compounds of Formulae (I’), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(26) (A)Rb8is H;(B) Rb8is D;(C) Rb8is selected from Cialkyl, C2alkyl, Csalkyl, and C4 lkyl;(D)Rb8is selected from monocyclic Cscycloalkyl, monocyclic C4cycloalkyl, monocyclic Cgcycloalky l, and monocyclic Cgcycloalkyl.

[0074] In addition to embodiments (1), (2), and (4) through (26) in the preceding paragraphs, the compounds of Formulae (F), (I”), or pharmaceutically acceptable salts thereof, include those in which:(27) (A)Rb9is H;(B)Rb9is D;(C) Rb9is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D)Rb9is selected from monocyclic CscycloalkyL monocyclic C4cycloalkyl, monocyclic Cscycloalkyl, and monocyclic Cgcycloalkyl.

[0075] In addition to embodiments (1) through (27) in the preceding paragraphs, the compounds of Formulae (F), (F ), (I), or pharmaceutically acceptable salts thereof, include those in which:(28) (A)Rclis D;(B) Rclis halo;(C) RC1is OH;(D)RC1is CN;(E) Rclis selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) two Rclattached to the same atom form a =0.

[0076] In addition to embodiments (1) through (28) in the preceding paragraphs, the compounds of Formulae (F), (F ), (I), or pharmaceutically acceptable salts thereof, include those in which:(29) (A)Rc2is D;(B) Rc2is halo;(C) Rc2is OH;(D)Rc2is CN;(E) Re2is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) two Rc2attached to the same atom form a =0.

[0077] In addition to embodiments (1) through (29) in the preceding paragraphs, the compounds of Formulae (F), (F ), (I), or pharmaceutically acceptable salts thereof, include those in which:(30) (A)Rc3is D;(B) Rc3is halo;(C) Rc3is OH;(D)Rc3is CN;(E) Rc3is selected from Cialkyl, C2alkyl, Cialkyl, and C4alkyl;(F) two Rc?attached to the same atom form a =0.

[0078] In addition to embodiments (1) through (30) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(31) (A)Rc4is D;(B) Rc4is halo;(C) Rc4is OH;(D)Rc4is CN;(E) Rc4is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) two Rc4attached to the same atom fonri a =0.

[0079] In addition to embodiments (1) through (31) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(32) (A)Rc5is D;(B) Rc5is halo;(C) Rc5is OH;(D)Rc5is CN;(E) Rc5is selected from Cialkyl, C2alkyl, Csalky l, and C4alkyl;(F) two Rc5attached to the same atom form a =0.

[0080] In addition to embodiments (1) through (32) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(33) (A)Rc6is D;(B) Rc6is halo;(C) Re6is OH;(D)Rc6is CN;(E) Rc6is selected from Cialkyl, Csalkyl, Csalkyl, and C4alkyl;(F) two Rc6attached to the same atom form a =0.

[0081] In addition to embodiments (1), (2), and (4) through (33) in the preceding paragraphs, the compounds of Formulae (I’), (I”), or pharmaceutically acceptable salts thereof, include those in which:(34) (A)Rc7is D;(B) Rc7is halo;(C) Rc7is OH;(D)Rc7is CN;(E) Rc7is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) two Rc7attached to the same atom form a =0.

[0082] In addition to embodiments (1) through (34) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(35) (A) Rdlis H;(B) Rdlis D;(C) Rdlis halo;(D)Rdlis OH;(E) Rdlis CN;(F) Rdlis N(Rb8)2;(G)Rdlis selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(H)Rdlis selected from Cialkoxyl, C2alkoxyl, Csalkoxyl, and C4alkoxyl.

[0083] In addition to embodiments (1) through (35) in the preceding paragraphs, the compounds of Formulae (F), (I”), (1), or pharmaceutically acceptable salts thereof, include those in which:(36) (A)Relis H;(B)Re1is D;(C) Relis selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D)two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyd selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;(E) Relis halo.

[0084] In addition to embodiments (1) through (36) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(37) (A)Re2is H;(B)Re2is D;(C) Rc2is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D)Re2is halo;(E) two Re2together with the carbon atom to which they are attached form a =0.

[0085] In addition to embodiments (1) and (3) through (37) in the preceding paragraphs, the compounds of Formulae (F), (I), or pharmaceutically acceptable salts thereof, include those in which:(38) (A)Re3is H;(B) Re3is D;(C) Re3is selected from Cialkyl, C2alkyl, Cbalkyl, and C4alkyk(D)Re3is halo.

[0086] In addition to embodiments (1) through (38) in the preceding paragraphs, the compounds of Formulae (I’), (F ), (I), or pharmaceutically acceptable salts thereof, include those in which:(39) (A) m is 0;(B) m is 1;(C) m is 2.

[0087] In addition to embodiments (1) through (39) in the preceding paragraphs, the compounds of Formulae (I’), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(40) (A)n is 0;(B)n is 1;(C)n is 2;(D)n is 3;(E) n is 4.

[0088] In addition to embodiments (1) through (40) in the preceding paragraphs, the compounds of Formulae (F), (I”), (I), or pharmaceutically acceptable salts thereof, include those in which:(41) (A) p is 0;(B) p is 1;(C) p is 2.

[0089] In addition to embodiments (1), (2), and (4) through (41) in the preceding paragraphs, the compounds of Formulae (F), (I”), or pharmaceutically acceptable salts thereof, include those in which:(42) (A)the compound is represented by Formula (IF):or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (III’):or a pharmaceutically acceptable salt thereof;(C)the compound is represented by Formula (IV’):or a pharmaceutically acceptable salt thereof;(D)the compound is represented by Formula (V’):or a pharmaceutically acceptable salt thereof;(E) the compound is represented by Formula (VI’):or a pharmaceutically acceptable salt thereof;(F) the compound is represented by Formula (VIE):or a pharmaceutically acceptable salt thereof;(G)the compound is represented by Formula (VIII’):or a pharmaceutically acceptable salt thereof;(H)the compound is represented by Formula (IX’):or a pharmaceutically acceptable salt thereof;(I) the compound is represented by Formula (X’):or a pharmaceutically acceptable salt thereof;(J) the compound is represented by Formula (XI’):or a pharmaceutically acceptable salt thereof;(K)the compound is represented by Formula (XII'):or a pharmaceutically acceptable salt thereof;(L) the compound is represented by Formula (XIIF):or a pharmaceutically acceptable salt thereof;(M) the compound is represented by Formula (XIV’):or a pharmaceutically acceptable salt thereof;(N)the compound is represented by Formula (XV):or a pharmaceutically acceptable salt thereof;(O)the compound is represented by Formula (XVF):or a pharmaceutically acceptable salt thereof;(P) the compound is represented by Formula (XVIF):or a pharmaceutically acceptable salt thereof;(Q)the compound is represented by Formula (XVIIF):or a pharmaceutically acceptable salt thereof;(R)the compound is represented by Formula (XIX'):or a pharmaceutically acceptable salt thereof;(S) the compound is represented by Formula (XX‘):or a pharmaceutically acceptable salt thereof.

[0090] In addition to embodiments (3) through (17), (19) through (26), (28) through (33),(35) through (41) in the preceding paragraphs, the compounds of Formula (I) or pharmaceutically acceptable salts thereof, include those in which:(43) (A) the compound is represented by Formula (II):or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (III):or a pharmaceutically acceptable salt thereof;(C)the compound is represented by Formula (IV):or a pharmaceutically acceptable salt thereof;(D)the compound is represented by Formula (V):or a pharmaceutically acceptable salt thereof;(E) the compound is represented by Formula (VI):or a pharmaceutically acceptable salt thereof;(F) the compound is represented by Formula (VII):or a pharmaceutically acceptable salt thereof;(G)the compound is represented by Formula (VIII):or a pharmaceutically acceptable salt thereof;(H)the compound is represented by Formula (IX):or a pharmaceutically acceptable salt thereof;(I) the compound is represented by Formula (X):or a pharmaceutically acceptable salt thereof;(J) the compound is represented by Formula (XI):or a pharmaceutically acceptable salt thereof;(K)the compound is represented by Formula (XII):or a pharmaceutically acceptable salt thereof.

[0091] In addition to embodiments (1) through (43) in the preceding paragraphs, the compounds of Formulae (I’), (F‘), (I), or pharmaceutically acceptable salts thereof, include those in which:(44) (A) R1and R2are each independently selected from H, D, and Ci-C4alkyl;(B) L1is a covalent bond;(C)X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;(D)L2is a covalent bond;(E) X2is a covalent bond;(F) L3is a covalent bond;(G)Ring B is selected from:(xiii). wherein one i on the Ring B moiety denotes the point of attachment toL3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;(H) Ring B is selected from:the Ring B moiety denotes the point of attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;(I) R3is selected from H, D. and Ci kyl;(J) Y2is C(Re3)2or C(=O);(K)W is CH orN;(L) Rbland Rb6are each independently selected from H, D, and Ci-C4alkyl;(M) Rcl. Rc6, and Rc7are each independently selected from D, halo, OH, and CN;(N)Reland Re3are each independently selected from H, D, and Ci alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic C-.Cgcycloalkyl;(O)m is 0;(P) n is 0, 1, 2, or 3;(Q)a combination of embodiments (44)(A) through (44)(G) and (44)(I) through (44)(P).

[0092] In addition to embodiments (1) through (44) in the preceding paragraphs, the compounds of Formulae (F), (F ), (I), or pharmaceutically acceptable salts thereof, include those in which:(45) no more than three of L1, L2, X2, and L3are simultaneously a covalent bond.

[0093] In addition to embodiments (1) through (45) in the preceding paragraphs, the compounds of Formulae (I’), (F ), (I), or pharmaceutically acceptable salts thereof, include those in which:(46) (A)X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substitutedon a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;(B) X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S. N, and NRb4;(C) X1- L2- X2is:, denotes the point of attachment to L1and the other denotes the point of attachment to L3; for example,(D)X1- L2- X2is:wherein ” indicates the point of attachment to L3;(E) L1- X1- L2- X2- L3is:wherein “ * ” indicates the point of attachment to Ring B;(F) L1- X1- L2- X2- L3is:wherein ” indicates the point of attachment to Ring B;(G)L1- X1- L2- X2- L3is:wherein “ * ” indicates the point of attachment to Ring B;(H)L1- X1- L2- X2- L3is:wherein “ * ” indicates the point of attachment to Ring B;(I) X2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc5, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12- membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb5;(J) X2- L3is:, denotes the point of attachment to L2and the other denotes the point of attachment to Ring B; for example,(K)X2- L3is:wherein “ * ” indicates the point of attachment to Ring B.

[0094] In addition to embodiments (1), (2), (4) through (42), and (44) through (46) in the preceding paragraphs, the compounds of Formulae (I’), (1”), or pharmaceutically acceptable salts thereof, include those in which:(47) (A)the compound is represented by Formula (Ila’), (lib ), (lie’), (lid’), (lie’), or (Ilf):,or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (Illa’). (Mb’), (IIIc’), (Hid’), (Ille ), (IIIF ).(Illg’), (IHh ), or (Illi’):or a pharmaceutically acceptable salt thereof;(C)the compound is represented by Formula (IVa’X (IVb’X (IVc’X (IVd’), (IVe’), or (IVf):or a pharmaceutically acceptable salt thereof,(D)the compound is represented by Formula (Va’), (Vb’), (Vc’), (Vd’), or (Ve’):or a pharmaceutically acceptable salt thereof;(E) the compound is represented by Formula (Via'). (VIb’). (Vic’), (Vid’), or (Vie’):or a pharmaceutically acceptable salt thereof(F) the compound is represented by Formula (Vila’), (Vllb’), (Vile’), or (VIId‘):or a pharmaceutically acceptable salt thereof;(G)the compound is represented by Formula (Villa'), (Vlllb’), (VIIIc’), or (Vllld’):or a pharmaceutically acceptable salt thereof;(H)the compound is represented by Formula (IXa’), (IXb’), (IXc’), (IXd’), (IXe’),(IXf), or (IXg’):or a pharmaceutically acceptable salt thereof;(I) the compound is represented by Formula (Xa’), (Xb’), (Xc’), or (Xd’):or a pharmaceutically acceptable salt thereof;(J) the compound is represented by Formula (Xia'), (Xlb’), (XIc’), (Xld’), or (Xie’):or a pharmaceutically acceptable salt thereof;(K)the compound is represented by Formula (Xlla’), (XIIb‘), (XIIc’). or (XIId‘):or a pharmaceutically acceptable salt thereof;(L) the compound is represented by Formula (Xllla’), (Xlllb’), (XIIIc'), (Xllld'), or (Xllle’):or a pharmaceutically acceptable salt thereof;(M) the compound is represented by Formula (XIV a’), (XlVb’), (XIVc’), (XlVd’), oror a pharmaceutically acceptable salt thereof;(M) the compound is represented by Formula (XVa’), (XVb’), (XVc’), (XVd’), or (XVe’):or a pharmaceutically acceptable salt thereof;(N)the compound is represented by Formula (XVIa‘), (XVIb’), (XVIc’), (XVId’), or (XVIe’):or a pharmaceutically acceptable salt thereof;(O)the compound is represented by Formula (XVIIa’), (XVIIb’), (XVIIc'), (XVIId’), or (XVIIe’):or a pharmaceutically acceptable salt thereof;(P) the compound is represented by Formula (XVIIIa’X (XVIIIb’), (XVIIIc ), or (XVIITd’):or a pharmaceutically acceptable salt thereof;(Q)the compound is represented by Formula (XIXa‘), (XlXb’), (XIXc’), or (XlXd’):or a pharmaceutically acceptable salt thereof;(R)the compound is represented by Formula (XXa’), (XXb’), (XXc’), (XXd’)5or (XXe’):or a pharmaceutically acceptable salt thereof.

[0095] In addition to embodiments (1), (2), (4) through (42), and (44) through (47) in the preceding paragraphs, the compounds of Formulae (I'), (I”), or pharmaceutically acceptable salts thereof, include those in which:(48) (A)the compound is represented by Formula (Ila’):or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (lie’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci.C4alkyl;L1is selected from a covalent bond and -(C(Ral)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralare each independently selected from H. D, and Ci-C4alkykRb4are each independently selected from H, D, and Ci alkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0 or 1 ; for example,(C)the compound is represented by Formula (lie’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Cgalkyl;L1is -(C(Ral)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Ralare each independently selected from H, D, and Ci-Chalky kRb4are each independently selected from H, D, and Ci-Csalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, or 2; and p is 0 or 1.

[0096] In addition to embodiments (1), (2), (4) through (42), and (44) through (47) in the preceding paragraphs, the compounds of Formulae (I’), (I”), or pharmaceutically acceptable salts thereof, include those in which:(49) (A)the compound is represented by Formula (Illa'):or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (Illg’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and CiXUalkyl:L1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond and -(C(Ra2)2)P-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently- selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl each optionally substituted on a ring carbon with 1 to 3 Rc4. wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;Rbl, Rb2, and Rb4are each independently selected from H. D, and Ci-C4alkykRcl, Rc2, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 1 or 2 provided that:(i) when both R1and R2are methyl; R3is H; L1is a covalent bond; and X2is 3- to 6-membered heterocyclyl, then X1is not piperazine;(ii) when L1and X2are both a covalent bond; L2is -(C(Ra2)2)P; and p is 1, then X1is not piperidine;(iii) when L1, L2, and X2are each a covalent bond; X1is piperazine; L3is -*O-(C(Rdl)2)P-C(=O)-then at least one Rdlis not H; and(iv) when L1and X2are both a covalent bond; and L2is -(C(Ra2)2)P. then X1is not piperidine or piperazine; for example,(C)the compound is represented by Formula (Illg’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and CiXUalkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O);X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl each optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralare each independently selected from H. D, and Ci-Cralkyl;Rb4are each independently selected from H, D, and CiXUalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0 or 1 ; for example,(D)the compound is represented by Formula (Illg’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O);X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Ralare each independently selected from H. D, and Ci-CsalkykRb4are each selected from H, D, and Ci.Csalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0 or 1 ;(E) the compound is represented by Formula (Illb ’ ):or a pharmaceutically acceptable salt thereof;(F) the compound is represented by Formula (Illb’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C+alkyl;L1is selected from a covalent bond and -(C(Ral)2)P-C*(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a nng carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from covalent bond and -(C(Ra2)2)P-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;L3is -O-;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;Rbland Rb2are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc2, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0, 1, or 2;(G)the compound is represented by Formula (Illh’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyhL1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O)-;X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl. wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond and -(C(Ra2)2)P-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently- selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;Rbland Rb2are each independently selected from H, D, and Ci-Cralkyl;Rcl, Rc2, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0 or 1 ; for example,(H)the compound is represented by Formula (Illh’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O)-;X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond and -(C(Ra2)2)P-;X2is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-Csalkyl;Raland Ra2are each independently selected from H, D, and Ci-Chalkyl;Rbland Rb2are each independently selected from H, D, and Ci-Csalkyl;Rcl, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0 or 1 ;(I) the compound is represented by Formula (Illi’):(Illi ), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D. and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O)-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralis independently selected from H, D. and Ci-C4alkyl;Rb4are each independently selected from H. D, and CiXLjalkyl:Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0, 1, or 2; for example,(J) the compound is represented by Formula (Illi’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D. and Ci-Csalkyl;L1is a covalent bond;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Rb4are each independently selected from H, D, and Ci-Csalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; and n is 0, 1, 2, or 3.

[0097] In addition to embodiments (1), (2), (4) through (42), and (44) through (47) in the preceding paragraphs, the compounds of Formulae (I’), (I”), or pharmaceutically acceptable salts thereof, include those in which:(50) (A) the compound is represented by Fonnula (IVb’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is a covalent bond;L3is -C2-C4alkynyl-,X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;Rb4and Rb6are each independently selected from H, D. and Ci-C4alkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; and n is 0, 1, 2, or 3;(B)the compound is represented by Formula (IVe’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and CiX alkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, -(C(Ral)2)P-C(=O)*-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S. N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O- and -C(=O)-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently- selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6-to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently- selected from O, S. N, and NRb4:R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;selected from H, D, and Ci-C4alkyl;Rcl, Rc2, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH. and CN, or two Rc4attached to the same atom form a =0; n is 0, 1 , 2, or 3; and p is 0 or 1 ; for example,(C)the compound is represented by Formula (IVe’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-Csalkyl can be replaced by D;L1is selected from a covalent bond, -(C(Ral)2)P-, -0-, -(C(Ral)2)P-C(=O)*-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Raland Ra2are each independently selected from H, D, and Ci-Csalkyl;Rb4, Rb6, and Rb9are each independently selected from H, D, and Ci-Csalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN, or two Rc4attached to the same atom form a =0; n is 0, 1, 2, or 3; and p is 0 or 1 ;(D)the compound is represented by Formula (IVe’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-Csalkyl can be replaced by D;L1is selected from a covalent bond and -O-;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O- and -C(=O)-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-Csalkyl;Ra2are each independently selected from H, D, and Ci-Csalkykindependently selected from H, D, and Ci-Csalkyl;Rcl, Rc2, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0 or 1 ;(E) the compound is represented by Formula (IVf ):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, -(C(Ral)2)P-C(=O)*-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O- and -C(=O)-;X2is selected from C3-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2: orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S. N, and NRb4;R3is selected from H, D, and Ci-C4alkyl:Raland Ra2are each independently selected from H, D, and CiXUalkyl;Rbl, Rb2, Rb4, and Rb9are each independently selected from H, D, and CiXZUalkyl;Rcl, Rc2, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH. and CN, or two Rc4attached to the same atom form a =0; n is 0, 1, 2, or 3; and p is 0 or 1 ; for example,(F) the compound is represented by Formula (IVf ):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci- alkyl can be replaced by D;L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, and -(C(Ral)2)P-C(=O)*-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, and -O-;X2is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3. wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orR3is selected from H, D, and Ci-Csalkyl;Raland Ra2are each independently selected from H, D, and Ci-C?alkyl:Rbland Rb2are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0 or 1 ;(G)the compound is represented by Formula (IVf ), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-Csalkyl can be replaced by D:L1is a covalent bond;X1is 4- to 6-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 4- to 6-membered monocyclic heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is selected from Cs-Cecycloalkyl optionally substituted with 1 to 3 Rc2and 4- to 6-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 4- to 6-membered monocyclic heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orR3is selected from H, D, and Ci-Csalkyl;Rbland Rb2are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc2, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; and n is 0, 1, 2, or 3;(H)the compound is represented by Formula (IVf ):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, and -(C(Ral)2)P-C(=O)*-, wherein * denotes the point of attachment of L1to X1;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Ralis independently selected from H, D, and Ci-Csalkyl;Rb4are each independently selected from H, D, and Ci-Csalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN, or two Rc4attached to the same atom form a =0; n is 0, 1, 2, or 3; and p is 0 or 1 .

[0098] In addition to embodiments (1), (2), (4) through (42), and (44) through (47) in the preceding paragraphs, the compounds of Formulae (I'), (I”), or pharmaceutically acceptable salts thereof, include those in which:(51) (A) the compound is represented by Formula (Vb’):or a pharmaceutically acceptable salt thereof;(B) the compound is represented by Formula (Vb’), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is a covalent bond;L3is -(C(Ra3)2)P-,X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is H;Ra3are each independently selected from H. D, and Ci-Csalkyl;Rb4and Rb6are each independently selected from H, D, and Ci-Csalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 1 or 2;(C)the compound is represented by Formula (Ve’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and CiXUalkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and -O-;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond or -(C(Ra2)2)P-;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, Ss, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 1 or 2;(D)the compound is represented by Formula (Vf ):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and C i -C4al ky 1;L1is selected from a covalent bond, -(C(Ral)2)P-, and -O-;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond or -(C(Ra2)2)P-:X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;Rbl, Rb2, and Rb4are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 1 or 2; for example,(E) the compound is represented by Formula (Vf ):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is a covalent bond;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Rb4are each independently selected from H, D, and Ci-Csalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; and n is 0, 1 , 2, or 3.

[0099] In addition to embodiments (1), (2), (4) through (42), and (44) through (47) in the preceding paragraphs, the compounds of Formulae (I'), (I”), or pharmaceutically acceptable salts thereof, include those in which:(52) (A)the compound is represented by Formula (IXb’):or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (IXe’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc1and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-, and -NRa2-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Re3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;Rbl, Rb2, and Rb4are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc2, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, CN, and Ci- C4alkyl;R61are each independently selected from H. D, halo, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl;n is 0, 1, 2, or 3; and p is 0, 1, or 2; for example,(C)the compound is represented by Formula (IXe’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci.Csalkyl;L1is a covalent bond;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc1and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-, and -NRa2-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Re3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-Csalkyl;Ra2are each independently selected from H. D, and Ci-Chalky!:Rbland Rb2are each independently selected from H, D, and Ci-Csalkyl;Rcl, Rc2, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN;Relare each independently selected from H, D, halo, and Ci-Csalkyl; or two Reltogether with the carbon atom to which they are attached fonn a monocyclic Cs-Cecycloalkyl; n is 0, 1, 2, or 3; and p is 1 or 2;(D)the compound is represented by Formula (IXf ) or Formula (IXg’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-, and -NRa2-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S. N, and NRb4:R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;RbiRb2,anc| Rb4are each independently selected from H, D, and CiXUalkyl;Rcl, Rc2, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH. CN, and Ci- C4alkyl; n is 0, 1, 2, or 3; and p is 0, 1 , or 2; for example,(E) the compound is represented by Formula (IXF) or Formula (IXg’), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci.Csalkyl;L1is a covalent bond;X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently- selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-Csalkyl;Rbland Rb2are each independently selected from H, D, and Ci-Csalkyl;Rcl, Rc2, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 1 or 2;(F) the compound is represented by Formula (IXF) or Formula (IXg’), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is a covalent bond;X1is 4- to 6-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 4- to 6-membered monocyclic heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S. N, and NRbl;L2is a covalent bond;X2is selected from Cs-Cecycloalkyl optionally substituted with 1 to 3 Rc2and 4- to 6-membered monocyclic heterocy clyl optionally substituted on a ring carbon with 1 to 3 Rc?, wherein the 4- to 6-membered monocyclic heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-Csalkyl;Rbland Rb2are each independently selected from H, D, and Ci-Csalkyl;Rcl, Rc2, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 1 or 2;(G)the compound is represented by Formula (IXg’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently is selected from H, D, and Ci-Csalkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4. wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Ralis independently selected from H, D, and Ci-Csalkyl;Rb4are each independently selected from H, D, and Ci-Csalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

[0100] In addition to embodiments (1), (2), (4) through (42), and (44) through (47) in the preceding paragraphs, the compounds of Formulae (F), (I”), or pharmaceutically acceptable salts thereof, include those in which:(53) (A)the compound is represented by Formula (Xia’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D. and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S. N, and NRb4;R3is selected from H, D, and Ci-Cralkyl:Ralare each independently selected from H, D, and Ci-C4alkyl;Rbij^b2,anc| j^b4are each independently selected from H, D, and CiXUalkyl;Rcl, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, CN, and Ci- C4alkyl; n is 0, 1, 2, or 3; and p is 0, 1 , or 2; for example,(C)the compound is represented by Formula (Xie’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D. and Ci-Csalkyl;L1is a covalent bond;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Rb4are each independently selected from H, D, and Ci-Csalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, CN, and Ci-Csalkyl; and n is 0, 1, 2, or 3.

[0101] In addition to embodiments (1), (2), (4) through (42), and (44) through (47) in the preceding paragraphs, the compounds of Formulae (I’), (I”), or pharmaceutically acceptable salts thereof, include those in which:(54) (A)the compound is represented by Formula (XIIIb‘):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is selected from a covalent bond and -(C(Ral)2)P-;X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond and -(C(Ra2)2)P-;X2is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;R3is selected from H, D, and CiXhalkyl;Raland Ra2are each independently selected from H, D, and Ci-Csalkyl;Rbland Rb2are each independently selected from H, D, and Ci-Csalkyl;Rcl, Rc3, Rc6, and Rc7are each independently selected from D. halo. OH, CN. and Ci-Csalkyl; n is 0, 1, 2, or 3; and p is 0 or 1.

[0102] In addition to embodiments (1), (2), (4) through (42), (44) through (47) in the preceding paragraphs, the compounds of Formulae (I'), (I”), or pharmaceutically acceptable salts thereof, include those in which:(55) (A)the compound is represented by Formula (XIVc’):(B)the compound is represented by Formula (XIVe‘):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci.C4alkyl:L1is selected from a covalent bond and -(C(Ral)2)P-;X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralare each independently selected from H, D, and Ci-C4alkyl;Rbl, Rb2, Rb4are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc3, Rc4. Rc6, and Rc7are each independently selected from D, halo, OH, CN, and Ci- C4alkyl;Relis selected from H, D, halo, and Ci-C4alkyl; n is 0, 1, 2, or 3; and p is 0 or 1 ;(C)the compound is represented by Formula (XlVe’), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Cralkyl;L1is selected from a covalent bond and -(C(Ral)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S. N, and NRb4;R3is selected from H, D, and Ci.C4alkyl;Ralare each independently selected from H, D, and Ci-C4alkyl;Rb4are each independently selected from H, D, and CiXUalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, CN, and CiXUalkyl;Relis selected from H, D, halo, and Ci-C4alkyl;n is 0, 1, 2, or 3; and p is 0 or 1 ;(D)the compound is represented by Formula (XlVe’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is selected from a covalent bond and -(C(Ral)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Ralis each independently selected from H, D, and Ci-Csalkyl;Rb4are each independently selected from H, D, and Ci-Csalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, CN, and Ci-Csalkyl;Relis selected from H, D, halo, and Ci-C4alkyl; n is 0, 1, 2. or 3; and p is 0 or 1.

[0103] In addition to embodiments (1), (2), (4) through (42), (44) through (47) in the preceding paragraphs, the compounds of Formulae (I'), (I”), or pharmaceutically acceptable salts thereof, include those in which:(56) (A)the compound is represented by Formula (XVIb’):(B)the compound is represented by Formula (XVIe‘):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and CiX alkyl:L1is selected from a covalent bond and -(C(Ral)2)P-;X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;W is CH or N;Ralare each independently selected from H, D, and Ci-C4alkyl;Rbl, Rb2, and Rb4are each independently selected from H. D, and Ci-C4alkykRcl, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, CN, and Ci- C4alkyl;Relis selected from H, D, halo, and Ci-C4alkyl; n is 0, 1, 2. or 3; and p is 0 or 1 ;(C)the compound is represented by Formula (XVIe’), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond and -(C(Ral)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;W is CH or N;Ralare each independently selected from H, D, and Ci-C4alkyl;Rb4are each independently selected from H, D, and CiXUalkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, CN, and Ci-C4alkyl:Relis selected from H, D, halo, and Ci-C4alkyl; n is 0, 1, 2, or 3; and p is 0 or 1 ;(D)the compound is represented by Formula (XVIe'), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci.Csalkyl;L1is a covalent bond;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4. wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;W is CH or N;Rb4are each independently selected from H, D, and Ci-Csalkyl;Rc4, Rc6, and Re7are each independently selected from D, halo, OH, CN, and Ci-Csalkyl;Relis selected from H, D, halo, and Ci-Csalkyl; n is 0, 1, 2, or 3; and p is 0 or 1.

[0104] In addition to embodiments (3) through (17), (19) through (26), (28) through (33), (35) through (41), and (43) through (46) in the preceding paragraphs, the compounds of Formula (I) or pharmaceutically acceptable salts thereof, include those in which:(57) (A)the compound is represented by Formula (Ila), (lib), (lie), (lid), (lie), or (Ilf):or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (Illa), (Illb), (IIIc), (Hid), (Ille), (Ulf), (Illg), (Illh), or (Illi):or a pharmaceutically acceptable salt thereof;(C)the compound is represented by Formula (IVa), (IVb). (IV c), (IV d). (IV e), or (IV f):or a pharmaceutically acceptable salt thereof,(D)the compound is represented by Formula (Va), (Vb), (Vc), (Vd), or (Ve):or a pharmaceutically acceptable salt thereof;(E) the compound is represented by Formula (Via), (VIb). (Vic), or (Vid):or a pharmaceutically acceptable salt thereof(F) the compound is represented by Formula (Vila), (Vllb), (Vile), or (Vlld):, or a pharmaceutically acceptable salt thereof;(G)the compound is represented by Formula (Villa), (Vlllb), (VIIIc), or (Vllld):, or a pharmaceutically acceptable salt thereof;(H)the compound is represented by Formula (IXa), (IXb), (IXc), (IXd), (IXe), (IXf), or(IXg):or a pharmaceutically acceptable salt thereof;(I) the compound is represented by Formula (Xa). (Xb), (Xc), or (Xd):or a pharmaceutically acceptable salt thereof;(J) the compound is represented by Formula (Xia), (Xlb), (XIc), (Xld), or (Xie):or a pharmaceutically acceptable salt thereof;(K)the compound is represented by Formula (Xlla), (Xllb), (XIIc), or (Xlld):, or a pharmaceutically acceptable salt thereof.

[0105] In addition to embodiments (3) through (17), (19) through (26), (28) through (33), (35) through (41), (43) through (46). and (57) in the preceding paragraphs, the compounds of Formula (I) or pharmaceutically acceptable salts thereof, include those in which:(58) (A)the compound is represented by Formula (Ila):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and C i -C+al ky 1;L1is selected from a covalent bond and -(C(Ral)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl or a 7- to 12-membered fused heterocyclyl each optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralare each independently selected from H, D, and Ci-C4alkyl;Rb4are each independently selected from H, D, and Ci-C4alkyl;Rc4and Rc6are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0 or 1 ; for example,(C)the compound is represented by Formula (lie):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is -(C(Ral)2)p-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4. wherein the 5- to 12-membered spiroheterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Ralis independently selected from H, D, and Ci-Csalkyl;Rb4are each independently selected from H, D, and Ci-Csalkyl; andRc4and Rc6are each independently selected from D, halo. OH, and CN; n is 0, 1 , or 2; and p is 1 or 2.

[0106] In addition to embodiments (3) through (17), (19) through (26), (28) through (33),(35) through (41), (43) through (46). and (57) in the preceding paragraphs, the compounds of Formula (I) or pharmaceutically acceptable salts thereof, include those in which:(59) (A)the compound is represented by Formula (Illa):or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (Illb):or a pharmaceutically acceptable salt thereof;(C)the compound is represented by Formula (Illb):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and C i-C+alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from covalent bond and -(C(Ra2)2)P-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently- selected from O, S, N, and NRb2;L3is -O-;R3is selected from H, D. and Ci-Csalkyl;Ralis independently selected from H, D, and Ci-Csalkyl;Rbland Rb2are each independently selected from H, D, and Ci-Cralkyl;Rcl, Rc3, and Rc6are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0, 1, or 2;(D)the compound is represented by Formula (111c):or a pharmaceutically acceptable salt thereof;(E) the compound is represented by Formula (Illh):(Illh), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and C i -Chalk I;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond and -(C(Ral)2)P-;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3. wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-C4alkyl;Ralis independently selected from H, D, and Ci-C4alkyl;Rbland Rb2are each independently selected from H, D. and Ci-C4alkyl;Rcl, Rc3, and Rc6are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0, 1 , or 2; for example,(F) the compound is represented by Formula (Illh):(Illh), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D. and Ci-Csalkyl;L1is -(C(Ral)2)P-;X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-Csalkyl;Ralis independently selected from H, D, and Ci-Csalkyl;Rbland Rb2are each independently selected from H, D, and Ci-Csalkyl;Rcl, Rc3, and Rc6are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 1 or 2;(G)the compound is represented by Formula (Illi):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1- L2- X2form a 5- to 12-membered spiroheterocyclyl or a 7- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12- membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralis independently selected from H, D, and Ci-C4alkyl;Rb4are each independently selected from H. D, and Ci alkyl;Rc4and Rc6are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0, 1 , or 2; for example,(H)the compound is represented by Formula (Illi):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is a covalent bond;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Rb4are each independently selected from H, D, and Ci-Csalkyl;Rc4and Rc6are each independently selected from D, halo, OH, and CN; and n is 0, 1, 2, or 3;(I) the compound is represented by Formula (Illj):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and CiX alkyl;L1is selected from a covalent bond and -(C(Ral)2)P-;X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a C3-Ciocycloalkyl optionally substituted with 1 to 4 Rc2;L3is -O-;Rbland Rb2are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc3, and Rc6are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

[0107] In addition to embodiments (3) through (17), (19) through (26), (28) through (33), (35) through (41), (43) through (46), and (57) in the preceding paragraphs, the compounds of Formula (I) or pharmaceutically acceptable salts thereof, include those in which:(60) (A)the compound is represented by Formula (IVb):or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (IVe):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C+alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl or a 7- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12- membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralis independently selected from H, D, and CiX alkyl;Rbl, Rb2, Rb4, and Rb6are each independently selected from H, D, and Ci halkyl;Rcl, Rc3, Rc4, and Rc6are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0, 1, or 2; for example,(C)the compound is represented by Formula (IVe):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is selected from a covalent bond and -(C(Ral)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Ralis independently selected from H, D, and Ci-Csalkyl;Rb4and Rb6are each independently selected from H, D, and Ci-Csalkyl;Rc4and Rc6are each independently selected from D, halo, OH, and CN; n is 0, 1, 2. or 3; and p is 0, 1, or 2;(D)the compound is represented by Formula (IVf):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl or a 7- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12- membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralis independently selected from H, D, and CiXZUalkyl;Rbl, Rb2, and Rb4are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc3, Rc4, and Rc6are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 0, 1 , or 2; for example,(E) the compound is represented by Formula (IVf):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci.Csalkyl;L1is selected from a covalent bond and -(C(Ral)2)P-:X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4. wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Ralis independently selected from H, D, and Ci-Csalkyl;Rb4are each independently selected from H, D, and Ci-Csalkyl;Rc4and Rc6are each independently selected from D, halo, OH, and CN; n is 0, 1 , 2, or 3; and p is 0, 1, or 2.

[0108] In addition to embodiments (3) through (17), (19) through (26), (28) through (33), (35) through (41), (43) through (46). and (57) in the preceding paragraphs, the compounds of Formula (I) or pharmaceutically acceptable salts thereof, include those in which:(61) (A)the compound is represented by Formula (IX):or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (IXb):or a pharmaceutically acceptable salt thereof;(C)the compound is represented by Formula (IXe):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci Lialkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=0);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl or a 7- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12- membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralis independently selected from H, D, and Ci-C4alkyl;Rbl, Rb2, and Rb4are each independently selected from H. D, and Ci-C4alkykRcl, Rc3, Rc4, and Rc6are each independently selected from D, halo, OH, and CN;Relare each independently selected from H, D, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cocycloalkyk n is 0, 1, 2. or 3; and p is 0, 1 , or 2; for example,(D)the compound is represented by Formula (IXe):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-CkalkykL1is a covalent bond;X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl. wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3. wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-Csalkyl;Rbland Rb2is independently selected from H, D, and Ci-Csalkyl;Rcl, Rc3, and Rc6are each independently selected from D, halo, OH, and CN;Relare each independently selected from H, D, and Ci-Csalkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl; and n is 0, 1, 2, or 3;(E) the compound is represented by Formula (IXf) or Formula (IXg):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently is selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl or a 7- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12- membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O. S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralis independently selected from H, D, and Ci-C4alkyl;Rbl, Rb2, and Rb4are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc3, Rc4, and Rc6are each independently selected from D. halo. OH, and CN; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

[0109] In addition to embodiments (3) through (17), (19) through (26), (28) through (33), (35) through (41), (43) through (46). and (57) in the preceding paragraphs, the compounds of Formulae (I) or pharmaceutically acceptable salts thereof, include those in which:(62) (A)the compound is represented by Formula (Xia):or a pharmaceutically acceptable salt thereof;(B)the compound is represented by Formula (Xie):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl. wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl or a 7- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O. S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Ralis independently selected from H, D, and Ci-C4alkyl;RbiRb2,anc| pb4are each inciepenciently selected from H, D, and CiXUalkyl;Rcl, Rc3, Rc4, and Rc6are each independently selected from D. halo, OH, CN, and Ci-C4alkyl; n is 0, 1, 2. or 3; and p is 0, 1 , or 2; for example,(C)the compound is represented by Formula (Xie):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci -Chalky 1;L1is a covalent bond;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D. and Ci-Csalkyl;Rb4are each independently selected from H. D, and CiXLjalkyl;Rc4and Rc6are each independently selected from D, halo, OH, CN, and Ci-Csalkyl; and n is 0, 1, 2, or 3.

[0110] In some embodiments, the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof.Table 1. Selected bifunctional degrader compounds.Compound Synthesis

[0111] The compounds described herein can be made using conventional organic syntheses and commercially available starting materials, or the methods provided herein. By way of example and not limitation, compounds of Formulae (F) or (I) or intermediates for synthesizing compounds of Formulae (I’) or (I) can be prepared as outlined in Scheme(s) 1-10, as well as inthe Examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth in the illustrative schemes and Examples to arrive at the desired products. This includes the use of protecting groups: in some cases certain substituents may interfere with the chemistry in these schemes, in which case appropriate protecting groups can be employed to avoid unwanted reactivity and side products.Scheme 1LG is a suitable leaving group, typically halo and preferably Br; andPG = R3(e g., H), or a suitable protecting group, ty pically PMB (p-methoxybenzyl).

[0112] According to a first process, compounds of Formulae (E) or (I) may be prepared from the compounds of Formulae (II”) and (III”) using a palladium catalyzed, cross-coupling reaction. Typical cross-coupling conditions comprise reaction of the amine compound of Formula (II”) with a compound of Formula (III”), a palladium catalyst in the presence of an inorganic base, in a suitable solvent at between rt and the reflux temperature of the reaction. Preferred conditions comprise, reaction of compounds of Formulae (II”) and (III”), in the presence of Pd-PEPPSI-IHeptCL RuPhos Pd G3 or Brettphos Pd G4 and a suitable base such as CS2CO3 in a suitable solvent such as dioxane at between rt and 100 °C. If a suitable protecting group (PG = PMB) is present in a compound of Formula (III”), a 2-step method involving the above-described Pd catalyzed cross-coupling followed by deprotection using trifluoromethanesulfonic acid and TFA at rt to 40 °C is used to give compounds of Formulae (F) or (I).Scheme 2PG = R3(e g., H), or a suitable protecting group, typically PMB (p-methoxybenzyl).

[0113] According to a second process, compounds of Formulae (I’) or (I), may be prepared from the compounds of Formulae (IV”) and (V”) using a reductive amination process. Typical conditions comprise reaction of the amine compound of Formula (V”) with a carbonyl compound of Fonnula (IV”) in a suitable aprotic solvent, organic base in the presence of a suitable organic acid at a suitable temperature of between rt and reflux in the presence of an appropriate reducing agent. Preferred conditions comprise, reaction of compounds of Formulae (IV”) and (V”), in the presence of TEA and acetic acid in DMSO at rt followed by the addition of STAB at rt for 48 h. If a suitable protecting group (PG = PMB) is present in a compound of Formula (V”), a 2-step method involving the above-described reductive amination followed bydeprotection using trifluoromethanesulfonic acid and TFA at rt to 40 °C is used to give compounds of Formulae (T) or (I).Scheme 3LG is a suitable leaving group, typically halo and preferably Br; andPG = R3(e.g., H), or a suitable protecting group, typically PMB (p-methoxybenzyl).

[0114] According to a third process, compounds of Formulae (I’) or (I), may be prepared from the compounds of Formulae (VI”) and (VII”) using a palladium catalyzed, cross-coupling reaction. Typical cross-coupling conditions comprise reaction of the amine compound of Formula (VII”) with a compound of Formula (VI”), a palladium catalyst in the presence of an inorganic base, in a suitable solvent at between rt and the reflux temperature of the reaction. Preferred conditions comprise, reaction of compounds of Formula (VI”) and (VII”), in the presence of Brettphos Pd G4 and a suitable base such as KO Ac in a suitable solvent such as dioxane at between rt and 100 °C. If a suitable protecting group (PG = PMB) is present in a compound of Formula (VII”) a 2-step method involving the above-described Pd catalyzed crosscoupling followed by deprotection using trifluoromethanesulfonic acid and TFA at rt to 40 °C is used to give compounds of Formulae (I’) or (I).Scheme 4

[0115] According to a fourth process, compounds of Formulae (F) or (I), may be prepared from the compounds of Formulae (II”) and (VIII”) using an amide bond forming reaction.Typical coupling conditions comprise reaction of the amine compound of Formula (II”) with a carboxylic acid compound of Formula (VIII”), a peptide coupling reagent, an organic base in a suitable aprotic solvent at a suitable temperature between rt and 100 °C. Preferred conditions comprise, reaction of compounds of Formulae (II”) and (VIII”), in the presence of HATU and DIPEA in DMF at rt.Scheme 5L1is C(=O).

[0116] According to a fifth process, compounds of Formulae (F) or (I), may be prepared from the compounds of Formulae (IX”) and (V”) using an amide bond forming reaction. Typical coupling conditions comprise reaction of the amine compound of Formula (V”) with a carboxylic acid compound of Formula (IX”), a peptide coupling reagent, an organic base in a suitable aprotic solvent at a suitable temperature between rt and 100 °C. Preferred conditions comprise, reaction of compounds of Formulae (IX”) and (V”), in the presence of HATU and DIPEA in DMF at rt.Scheme 6

[0117] According to a sixth process, compounds of Formulae (I’) or (I), may be prepared from the compounds of Formulae (X”) and (XI") using a reductive amination process. Typical conditions comprise reaction of the amine compound of Formula (X”) with a carbonyl compound of Formula (XI”) in a suitable aprotic solvent, organic base in the presence of a suitable organic acid at a suitable temperature of between rt and reflux in the presence of an appropriate reducing agent. Preferred conditions comprise, reaction of compounds of Formula (X”) and (XI”), in the presence of TEA and acetic acid in DMSO at rt followed by the addition of STAB at rt for 48 h.Scheme 7

[0118] According to a seventh process, compounds of Formulae (T) or (I), may be prepared from the compounds of Formulae (XII”) and (XIII”) using a reductive amination process, as described in Scheme 2.Scheme 8

[0119] According to an eighth process, compounds of Formulae (I’) or (1), may be prepared from the compounds of Formulae (XIV”) and (XV”) using a reductive amination process, as described in Scheme 2. In some embodiments, L1is a covalent bond, X1- L2- X2is a spiroheterocyclyl, and L3is -(C(Ra3)2)P-.Scheme 9

[0120] According to a ninth process, wherein, L2is -(C(Ra2)2)P-, compounds of Fonnulae (F) or (I), may be prepared from the compounds of Formulae (XVI”) and (XVII”) using a reductive amination process, as described in Scheme 2.Scheme 10

[0121] According to a tenth process, wherein, L2is a covalent bond, compounds ofFormulae (T) or (I), may be prepared from the compounds of Formulae (X”) and (XVIIF’) using a reductive amination process, as described in Scheme 2.

[0122] It will be appreciated by those skilled in the art that it may be necessary7to utilize a suitable protecting group strategy for the preparation of compounds of Formulae (I’) or (I). Typical protecting groups may comprise a carbamate, preferably a Boc or CBz group for the protection of primary7or secondary7aliphatic amines and p-methoxybenzyl for the protection of di oxopiperidines.

[0123] It will be appreciated that it may be necessary7and / or desirable to carry7out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

[0124] Compounds that contain one or more stereocenters may be separated into their separate stereoisomers by typical methods such as chiral SFC or chiral HPLC techniques as indicated in the Examples below.

[0125] The use of stereoisomerically pure forms of the compounds disclosed herein, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.

[0126] Compounds having one or more chiral centers can exist in various stereoisomeric forms, i. e. , each chiral center can have an R or S configuration, or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomersinclude all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

[0127] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R" or “S”) or structure (e.g., the configuration is indicated by '“wedge” bonds), the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% (except when the designation “rac” or “racemate” accompanies the structure or name, as explained in the following two paragraphs).

[0128] When two stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two stereoisomers is intended, but not both.

[0129] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched. diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds disclosed herein.

[0130] “Enantiomerical purity” is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0131] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0132] When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “7?”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the Rconfiguration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.

[0133] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, cry stallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent, as indicated in the Examples below. See also, e.g., Jacques. J., et al., Enantiomers. Racemates and Resolutions (Wiley-Interscience, New York, 1981 ); Wilen, S. El., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S.. Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0134] Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0135] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan.

[0136] It should also be noted the compounds disclosed herein can contain unnatural proportions of atomic isotopes at one or more of the atoms. In some embodiments, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), sulfur-35 (35S), or carbon-14 (14C), or may be isotopically enriched, such as with deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N). As used herein, an “isotopologue” is an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopiccomposition other than the natural isotopic composition of that atom. The term "isotopic composition"’ refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the compounds disclosed herein, for example, the isotopologues are deuterium, carbon-13, and / or nitrogen-15 enriched compounds. As used herein, “deuterated”, means a compound wherein at least one hydrogen (H) has been replaced by deuterium (indicated by D or2H), that is, the compound is enriched in deuterium in at least one position.

[0137] In the compounds of the disclosure, any position specifically designated as “D” or “deuterium” is understood to have deuterium enrichment at least 5, 10, 25, 50, 80, 90, 95, 98 or 99%. “Deuterium enrichment” is a mole percent and is determined by dividing the number of compounds with deuterium at the indicated position by the total number of all of the compounds. When a position is designated as “H” or “hydrogen”, the position has hydrogen at its natural abundance. When a position is silent as to whether hydrogen or deuterium is present, the position has hydrogen at its natural abundance. One specific alternative embodiment is directed to a compound of the disclosure having deuterium enrichment of at least 5, 10, 25, 50, 80, 90, 95, 98 or 99% at one or more positions not specifically designated as “D” or “deuterium”.

[0138] As used herein, many moieties (e.g., alkyl, alkoxy, cycloalkyl or heterocyclyl) are referred to as being either “substituted” or “optionally substituted”. When a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents. Where if more than one substituent is present, then each substituent may be independently selected. Such means for substitution are well-known in the art and / or taught by the instant disclosure. The optional substituents can be any substituents that are suitable to attach to the moiety.Pharmaceutical Compositions and Dosages

[0139] The present disclosure also relates to pharmaceutical compositions comprising compounds or a pharmaceutically acceptable salt of any of the compounds disclosed in this application and at least one pharmaceutically acceptable excipient.

[0140] Non-limiting examples of pharmaceutically acceptable excipients, carriers, and / or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, hydroxymethy cellulose, fatty' acid esters, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity' of the compounds provided herein. One of ordinary' skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds or pharmaceutically acceptable salts thereof.

[0141] The pharmaceutical compositions of the disclosure optionally include one or more pharmaceutically acceptable excipients, carriers and / or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various ty pes of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and / or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0142] The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, such as general the route of administration, the time of administration, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular active ingredient employed, the type and severity of the disease or condition, the rate of excretion of the particular active ingredient being employed, and on the characteristics of the subject, such as the age, sex, body weight, general health and prior medical history' of the patient being treated, tolerance to drugs, and like factors well known in the medical arts. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, an “effective amount” of anyadditional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed., 2003).

[0143] In general, a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.Methods of Treatment

[0144] The disclosure provides methods of modulating (e.g., degrading) CDK4 activity and therefore are useful for treating diseases for which CDK4 are dysregulated, such as cancer. In some embodiments, the method of modulating is a method of degrading CDK4 comprising contacting CDK4 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of modulating is a method of degrading CDK.4 in a subject in need thereof, comprising contacting CDK4 w ith an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0145] Described herein is a method of treating a disease, condition, or cancer mediated by CDK4 comprising providing to a subject in need thereof any of the compounds disclosed in this application, or a pharmaceutically acceptable salt thereof.

[0146] In another aspect, provided herein is a method of treating a cancer in a patient in need thereof comprising administering to a patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0147] In another aspect, provided herein is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of cancers.

[0148] In another aspect, provided herein is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for the treatment of cancers.

[0149] Compounds of the disclosure, or pharmaceutically acceptable salts thereof, are CDK4 degraders with warheads that target CDK4 and inhibit its function with high potency andselectivity compared to traditional small-molecule inhibitors. Some of the compounds of the disclosure selectively and catalytically degrade their target protein (e.g., CDK4) over other CDKs and other proteins. The ability to selectively target CDK4 with a compound of the disclosure provides advantages in terms of targeted degradation of CDK4 with little to no off- target activity, and an increased probability of clinical success in comparison with traditional small-molecule inhibitors.

[0150] A CDK.4 degrader may show degradation that is at least 2-fold relative to another target protein (e g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40- fold selectivity; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90- fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200-fold).

[0151] In some alternatives, a CDK4 degrader exhibits at least 15-fold selectivity over another CDK, e.g., CDK1, CDK2, and CDK.6. In some embodiments, the compounds of the disclosure are selective against CDK4 versus CDK2. In some embodiments, compounds show at least 10-fold selectivity' for CDK4 versus CDK2. In some embodiments, compounds show at least 20-fold selectivity for CDK4 versus CDK2. In some embodiments, compounds show at least 30-fold selectivity for CDK4 versus CDK2. In some embodiments, compounds show at least 40-fold selectivity for CDK4 versus CDK2. In some embodiments, compounds show at least 50-fold selectivity for CDK4 versus CDK2. In some embodiments, compounds show at least 100-fold selectivity for CDK4 versus CDK2. For example, compounds show at least 200- fold selectivity for CDK4 versus CDK2.

[0152] In some embodiments, the compounds of the disclosure are selective against CDK4 versus CDK6. In some embodiments, compounds show at least 10-fold selectivity for CDK4 versus CDK6. In some embodiments, compounds show at least 20-fold selectivity for CDK4 versus CDK6. In some embodiments, compounds show at least 30-fold selectivity for CDK4 versus CDK6. In some embodiments, compounds show at least 40-fold selectivity for CDK4 versus CDK6. In some embodiments, compounds show at least 50-fold selectivity for CDK4 versus CDK6.

[0153] In some embodiments, the compounds of the disclosure are selective against CDK4 versus CDK1. In some embodiments, compounds show at least 10-fold selectivity for CDK4 versus CDK1. In some embodiments, compounds show at least 20-fold selectivity for CDK4 versus CDK1. In some embodiments, compounds show at least 30-fold selectivity for CDK4 versus CDK1. In some embodiments, compounds show at least 40-fold selectivity for CDK4 versus CDK1. In some embodiments, compounds show at least 50-fold selectivity for CDK4 versus CDK1.

[0154] Some compounds of the disclosure have the advantage of oral bioavailability. In some embodiments, a compound of the disclosure catalytically degrades its target protein, which may require a lower dose compared to traditional small molecule inhibitor. For example, many CDK4 / 6 inhibitors, including ribociclib, palbociclib, and abemaciclib, bind the adenosine triphosphate (ATP) cleft, which contains the catalytic residues, and compete with ATP to inhibit activity. In some embodiments, a compound of the disclosure is a bifunctional degrader with a warhead that binds to the target protein (e.g., CDK4) linked to an E3 ubiquitin ligase-binding moiety that recruit E3 ligases to ubiquitinate the target protein and prompt the target protein to be recognized and subsequently degraded by 26S proteasome. The compounds of the disclosure can be used repeatedly to trigger this targeted protein degradation. In some embodiments, a compound of the disclosure may eliminate certain side effects, for example, drug-drug interactions and off-target effects, such as CDK6 mediated heme toxicity.

[0155] In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as first line therapy. In other embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy.

[0156] In embodiments of the cancers and the methods provided herein, the cancer is a solid tumor cancer. In embodiments, the solid tumor cancer is a carcinoma or a sarcoma. In embodiments, the solid tumor cancer is an adenocarcinoma, a carcinoma, or a cystadenocarcinoma. In some embodiments, the subject has an advanced and / or relapsed solid tumor.

[0157] In embodiments of the methods provided herein, the cancer is selected from bile duct cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer, esophageal cancer, gastric cancer, head and neck cancer (e.g. , head and neck squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), and prostate cancer.

[0158] In some embodiments, the cancer is a refractory7cancer, which is also referred to as a treatment-resistant cancer.

[0159] In some embodiments of the cancers and methods disclosed herein, the cancer is breast cancer (BC). In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is selected from ductal carcinoma in situ, ER+ breast cancer (estrogen receptor positive breast cancer); ER+ / HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer); HR+ breast cancer (hormone receptor positive breast cancer); HR+ / HER2- breast cancer; HER2- breast cancer;HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer); f IER2-low breast cancer; invasive ductal carcinoma (IDC); invasive lobular carcinoma, lobular carcinoma in situ, PR+ / HER2- breast cancer (progesterone receptor positive, human epidermal growth factor 2 negative breast cancer); triple negative breast cancer (TNBC); and tubular breast carcinoma. In some embodiments, the breast cancer is HR+ / HER2- BC. In some embodiments, the breast cancer is ER+ / HER2- BC. In some embodiments, the breast cancer is PR+ / HER2- BC. In some embodiments, the breast cancer is TNBC.

[0160] In some embodiments, the breast cancer is refractory. In some embodiments, the breast cancer is chemotherapy resistant breast cancer, endocrine resistant breast cancer, radiotherapy resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition.

[0161] In some embodiments, the breast cancer is responsive to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is resistant to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer has progressed despite treatment with a CDK.4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the breast cancer has progressed despite a first treatment with palbociclib, ribociclib, and / or fulvestrant and a second treatment with abemaciclib and / or fulvestrant.

[0162] In some embodiments of the cancers and methods disclosed herein, the cancer is prostate cancer. In some embodiments, the prostate cancer is advanced or metastatic prostate cancer. In some embodiments, the prostate cancer is selected from androgen receptor positive (AR+) prostate cancer, castration-resistant prostate cancer (CRPC), and metastatic castrationresistant prostate cancer. In some embodiments, the prostate cancer is CRPC.

[0163] In one embodiment, the subject has HR+ / HER- breast cancer (including both ER+ / HER2- BC and PR+ / HER2- BC) that has progressed despite treatment with one or more CDK4 / 6 inhibitors. In one embodiment, the subject has TNBC that has progressed despite one or more lines of therapies. In one embodiment, the subject has AR+ prostate cancer that has progressed despite one or more lines of therapies. In one embodiment, the subject has NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib).Methods of Administration

[0164] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease.the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly, etc.) doses over a period of a few days to months, or even years.Combination Therapies

[0165] In addition, a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure can be co-administered with other therapeutic agents, e.g, an additional anticancer agent. In some embodiments the one or more compounds of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure will be co-administered with other agents. These terms encompass administration of two or more agents to the subject so that both agents and / or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and the other agent(s) are administered in a single composition. In some embodiments, compounds described herein and the other agent(s) are admixed in the composition. In some embodiments, the other therapeutic agent(s) or other agent(s) is / are one or more additional anticancer agent(s).

[0166] In some embodiments, the additional anticancer agent is a chemotherapeutic agent including, but not limited to. 5-fluorouracil, abraxane. camptothecin, capecitabine, carboplatin, cisplatin, cyclophosphamide, dacarbazine, docetaxel, doxorubicin, epirubicin, eribulin, etoposide, floxuridine, gemcitabine, ifosfamide, irinotecan, ixabepilone, methotrexate, mitomycin, oxaliplatin, paclitaxel, sabizabulin, temozolomide, thiotepa, topotecan, vinblastine, vinorelbine, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the chemotherapeutic agent is capecitabine, carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, paclitaxel, and vinorelbine or a pharmaceutically acceptable salt thereof. In some embodiments, the chemotherapeutic agent is paclitaxel. In some embodiments, the chemotherapeutic agent is cisplatin, carboplatin or oxaliplatin. In some embodiments, the chemotherapeutic agent is carboplatin.

[0167] In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor (e.g, anastrozole, exemestane, fadrozole, formestane, and letrozole), a luteinizing honnone-releasing hormone (LHRH) receptor agonist (e.g., leuprolide, and leuprorelin), a Selective Estrogen-Receptor Downregulator (SERD) (e.g.. amcenestrant, carmzestrant, elacestrant, fulvestrant, giredestrant, imlunestrant, rintodestrant, taragarestrant, andZB716), or a Selective Estrogen Receptor Modulator (SERM) (e.g., afimoxifene, arzoxifene, bazedoxifene, clomiphene. fispemifene, lasofoxifene, raloxifene, ormeloxifene, ospemifene, tamoxifen, tesmilifene, toremifene, and trilostane). In some embodiments, the endocrine agent is anastrozole, elacestrant, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, toremifene, or a combination thereof. In some embodiments, the additional anticancer agent is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is anastrozole, exemestane, or letrozole. In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the additional anticancer agent is a SERB. In some embodiments, the SERB is elacestrant or fulvestrant. In some embodiments, the SERB is elacestrant. In some embodiments, the SERB is fulvestrant. In some embodiments, the SERB is camizestrant.Biomarkers and Pharmacodynamics Markers

[0168] The disclosure provides predictive markers including, but not limited to, biomarkers and pharmacodynamic markers, which can be monitored based on levels including, but not limited to, BNA (including cBNA), RNA (including messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA)), protein expression (including protein overexpression), enzyme activity’ (e.g., for TK1), gene copy number, gene expression, gene sequence, mutations, and phosphorylation, to identify those subjects having, suspected of having, or at risk of developing a cancer for whom administering a CBK4 degrader is likely to be effective.

[0169] In some embodiments, the biomarker is selected from AR; breast cancer gene 1 (BRCA1); breast cancer gene 2 (BRCA2); cyclin Al (CCNA1); cyclin A2 (CCNA2); cyclin Bl (CCNB1); cyclin Bl (CCNB1); cyclin B2 (CCNB2); cyclin B3 (CCNB3); cyclin El (CCNE1); cyclin E2 (CCNE2); cyclin-dependent kinase 1 (CBK.1); CBK2; cyclin-dependent kinase 3 (CBK3); CBK4; cyclin-dependent kinase 5 (CBK5); CBK6; cyclin-dependent kinase 18 (CBK18); cyclin-dependent kinase inhibitor 1A (CBKN1A); cyclin-dependent kinase inhibitor IB (CBKN1B); cyclin-dependent kinase inhibitor 2A (CBKN2A, also known p!6. cyclin- dependent kinase 4 inhibitor A, multiple tumor suppressor 1, pl6-INK4a, and pl6(INK4)); ER; Harvey rat sarcoma virus proto-oncogene, GTPase (HRAS); HER2; human epidermal growth factor receptor-3 (HER3); KRAS; neuroblastoma rat sarcoma virus oncogene homolog (NRAS); PR; prostate-specific antigen (PSA); RB transcriptional corepressor 1 (RBI, which encodes retinoblastoma 1 protein referred to as Rb. RB, or RBI); retinoblastoma transcriptional corepressor like 1 (RBL1); retinoblastoma transcriptional corepressor like 2 (RBL2); thymidine kinase 1 (TK1), and the corresponding proteins encoded by these genes. In some embodiments,the biomarker is selected from AR; BRCA1; BRCA2; CCND1, CDK4, ER, HER2, p!6 (or CDKN2A), PR, PSA, RBI, TK1, and the corresponding proteins encoded by these genes.

[0170] In some embodiments, the levels of a biomarker are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, a biomarker is absent. In some embodiments, the modulation results in the loss of expression of the corresponding protein, a decrease in the expression of DNA (including cDNA), a decrease in the expression level of RNA (including messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA), a decrease in the expression level of protein, a decrease in gene copy numbers, a decrease in gene expression, a decrease in phosphorylated protein, or a decrease in protein activity as compared to a control sample. In some embodiments, the modulation results in an elevated expression level of DNA, an elevated expression level of RNA, an elevated expression level of protein (including protein overexpression), an increase in gene copy numbers, an increase in gene expression, an increase in phosphorylated protein, or an increase in protein activity as compared to a control sample. In some embodiments, the biomarker has a mutation (e.g., a loss of function mutation). In some embodiments, a biomarker or a biomarker mutant is functional. In some embodiments, a biomarker is intact based on expression level of mRNA or Rb and no loss of function mutations. In some embodiments, a change in the levels of a biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or at two different timepoints during treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is indicative / predictive that a subject having or at risk of developing a cancer has responded to treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, a comparison of the amplification and / or levels of certain biomarkers is made between a biological sample (e.g, the subject’s tumor, plasmas, or other tissue) and a control sample. In some embodiments, the control sample comprises normal tissue. In some embodiments, the control sample is from a subject with a normally functioning pathway. In some embodiments, the control sample provides or a comparison is made to an average expression level (e.g., mRNA or protein) of certain biomarkers in a population of subjects suffering from a solid tumor. In some embodiments, the control sample provides or a comparison is made to an average expression level (e.g, mRNA or protein) of certain biomarkers in a population of subjects suffering from a specific cancer.

[0172] In some embodiments, the levels of a biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by atleast 10%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%. 75%. 80%. 85%. 90%. 95%. or 100%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are increased. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are reduced.

[0173] In some embodiments, the levels of the biomarker at two different timepoints during treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%. In some embodiments, the levels of the biomarker at two different timepoints during treatment are changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%. 50%. 55%. 60%. 65%. 70%. 75%. 80%. 85%. 90%. 95%. or 100%. In some embodiments, the levels of the biomarker at two different timepoints during treatment are changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker at two different timepoints during administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are increased. In some embodiments, the levels of the biomarker at two different timepoints during administration of a compound of the disclosure, or a pharmacally acceptable salt thereof, are reduced.

[0174] In another aspect, provided herein is a method of treating cancer in a subject in need thereof comprising: i. testing, or having tested, a first biological sample obtained from the subject with cancer, thereby measuring levels of one or more biomarkers in the subject’s tumor, plasmas, or other tissue; ii. comparing the levels of the one or more biomarkers in step i. to levels of one or more biomarkers measured in a population of subjects suffering from cancer; iii. determining that the subject’s cancer will be sensitive to a compound of the disclosure, or a pharmacally acceptable salt thereof; iv. administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, thereby treating the cancer.

[0175] In some embodiments, the method further comprises: v. further testing, or having tested, a first biological sample obtained from the subject with cancer, thereby further measuring levels of one or more additional biomarkers in the subject’s tumor, plasmas, or other tissue; vi. testing, or having tested, a second biological sample obtained from the subject, thereby measuring levels of one or more additional biomarkers in the subject's tumor, plasmas, or other tissue; vii. determining whether the subject having or at risk of developing cancer has responded to treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, if the comparison of the second biological sample analysis in step vi. to the first biological sample analysis in step v. shows a changed level of one or more biomarkers, thereby monitoring a response in a subject having or at risk of developing cancer.

[0176] In some embodiments, additional biological samples are obtained from the subject and compared to the levels of the biomarkers measured in a patient with a control level to continue monitoring. In some embodiments, additional biological samples are obtained from the patient and compared to the levels of the biomarkers measured in the first biological sample to continue monitoring.

[0177] In some embodiments, the biomarker is AR. AR, a ligand-dependent nuclear transcription factor and member of the steroid hormone nuclear receptor family, mediates the actions of androgens such as testosterone and dihydrotestosterone. In some embodiments, the cancer is breast cancer or prostate cancer. In some embodiments, the breast cancer or prostate cancer is characterized by the presence of AR or an elevated level of AR and / or AR splice variants, such as AR-V7, compared to a control level of AR. In some embodiments, the levels of AR and / or AR splice variants, such as AR-V7, are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, AR and / or AR splice variants, such as AR-V7, are biomarkers for sensitivity to a compound of the disclosure.

[0178] In some embodiments, the biomarker is BRCA1 or BRCA2. BRCA1 and BRCA2 protein have crucial roles in different cellular processes, including transcriptional regulation, cell cycle checkpoints regulation, mitophagy, and DNA repair, such as regulating homologous recombination-dependent DNA double strand break repair. In some embodiments, mutations in the BRCA1 gene or the BRCA2 gene predispose a subject to cancer. In some embodiments, the cancer is bile duct cancer, breast cancer, or prostate cancer.

[0179] In some embodiments, the biomarker is CCND1. Cyclin DI modulates the transition from G1 to S phase as an allosteric regulator of CDK4 and CDK6. In some embodiments, the cancer is bladder cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, HR+ / HER2- breast cancer, non-small cell lung cancer, or small cell lung cancer. In some embodiments, these cancers are characterized by an elevated level of CCND1 compared to a control level of CCND1.

[0180] In some embodiments, the biomarker is ER and / or PR. Hormone receptor proteins, including ER, which is activated by estrogen, and PR, which is activated by progesterone, are nuclear transcription factors involved in the regulation of many physiological processes, including promoting cell growth. In some embodiments, the breast cancer is characterized by the presence of ER and / or PR. In some embodiments, the breast cancer is characterized by an elevated level of ER and / or PR compared to a control level of ER and / or PR. In some embodiments, the levels of ER and / or PR are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmacally acceptable salt thereof, to a subject. In some embodiments. ER and / or PR are biomarkers for sensitivity to a compound of the disclosure.

[0181] In some embodiments, the biomarker is HER2. HER2 is an epidermal growth factor receptor having tyrosine kinase activity. In some embodiments, the HR+ / HER2- breast cancer or small-cell lung cancer is characterized by the absence of HER2. In some embodiments, the HR+ / HER2- breast cancer or small-cell lung cancer is characterized by a reduced level of HER2 compared to a control level of HER2. In some embodiments, the level of HER2 is modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, HER2 is a biomarker for sensitivity to a compound of the disclosure.

[0182] In some embodiments, the biomarker is pl 6 (also known as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, p!6-INK4a, and p!6(INK4)). The gene CDKN2A encodes p!6, which acts as a negative regulator of the proliferation of nonnal cells by interacting with CDK.4 and CDK6. In some embodiments, the level of p 16 is modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, pl 6 is a biomarker for sensitivity to a compound of the disclosure.

[0183] In some embodiments, the biomarker is retinoblastoma 1 protein (Rb, RB, or TB1), which is encoded by the gene RB transcriptional corepressor 1 (RBI). Rb is a regulator of thecell cycle and acts as a tumor suppressor. In some embodiments, the cancer is characterized by the presence of Rb. In some embodiments, the cancer is characterized by the absence of Rb.

[0184] In some embodiments, the biomarker is phosphorylation of Rb at any phosphorylation site. In some embodiments, the biomarker is phosphorylation at the serine corresponding to amino acid position 780 (Ser780 or S780) and / or the serine corresponding to amino acid position 795 (Ser795 or S795). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the serine corresponding to amino acid position 807 (Ser807 or S807) and / or the serine corresponding to amino acid position 81 1 (Ser81 1 or S81 1). In some embodiments, the contemplated biomarker is phosphory lation of Rb at the threonine corresponding to amino acid position 821 (Thr821 or T821). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the threonine corresponding to amino acid position 826 (Thr826 or T826). Rb is activated upon phosphorylation by cyclin D-CDK4 / 6 at Ser780 and Ser795 and / or at Ser807 and / or Ser811 and by cyclin E / CDK2 at Ser807 and Ser811 and Thr821. In some embodiments, the levels of phosphory lated Rb, Rb, or RB are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, phosphorylated Rb, Rb, or RB is a biomarker for sensitivity to a compound of the disclosure. In some embodiments, the levels of phosphorylated Rb are reduced compared to a control level of phosphorylated Rb.

[0185] In some embodiments, the biomarker is PSA. PSA, which is a serine protease human kallikrein 3, plays a role in the regulation of semen coagulation. In some embodiments, the cancer is prostate cancer characterized by an elevated level of PSA compared to a control level of PSA.

[0186] In some embodiments, the biomarker is TK1. TK1 is a direct downstream target of Rb-E2F pathway. It is involved in cellular proliferation through the recovery of the nucleotide thymidine in the DNA salvage pathway. TK1 is important for DNA repair following DNA damage because TK1 is necessary for the formation of nucleotides outside of the S phase. In some embodiments, the level of TK1 is modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments. TK1 is differentially methylated. In some embodiments, TK1 is serum TK1. In some embodiments, the levels of TK1 protein and / or enzyme activity are reduced compared to a control level of TK1 protein and / or enzyme activity. In some embodiments, TK1 is a biomarker for sensitivity to a compound of the disclosure.EXAMPLES

[0187] The following Examples are presented by way of illustration, not limitation.Compounds are named using the automatic name generating tool provided in ChemBioDraw Ultra (Cambridgesoft), which generates systematic names for chemical structures, with support for the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.

[0188] Salts of the compounds described herein can be prepared by standard methods, such as inclusion of an acid (for example TFA, formic acid, or HC1) in the mobile phases during chromatography purification, or stirring of the products after chromatography purification, with a solution of an acid (for example, aqueous HC1).Abbreviations

[0189] The following abbreviations may be relevant for this application.General Methods

[0190] Proton NMR:!H NMR spectra were obtained with a Varian 400MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 seconds with a 1 second delay; 16 to 64 scans).Where characterized, all protons were reported in DMSO-rfd solvent as parts-per million (ppm) with respect to residual DMSO (2.50 ppm); or where characterized, all protons were reported in CD3OH solvent as parts-per million (ppm) with respect to residual CD3OH (3.31 ppm); or wherecharacterized, all protons were reported in CD3C1 solvent as parts-per million (ppm) with respect to residual CD3C1 (7.27 ppm); or where characterized, all protons were reported in D2O solvent as parts-per million (ppm) with respect to residual D2O (4.79 ppm).

[0191] Silica gel chromatography: Silica gel chromatography was performed on a Biotage® Isolera unit.

[0192] SFC: Chiral SFC was perfonned on a Waters SFC 80Q or Waters SFC 150Mgm or Waters SFC 350 or Hanbon SFC 600 system using Shimadzu LC-30Ads.

[0193] LC-MS: liquid chromatography-mass spectrometry (LC-MS) data (sample analyzed for purity and identity) were obtained with

[0194] A) an Agilent model-1260 LC system using an Agilent model 6120 mass spectrometer utilizing ES-API ionization fitted with a Kinetex EVO Cl 8 30*2.1 mm, 5 pm reverse-phase column at 50 °C. The flow rate was constant at 1.5 mL / min.

[0195] B) Shimadzu LCMS system using a Shimadzu LCMS mass spectrometer utilizing ESI ionization fitted with a Halo 90A C18 30*3.0 mm, 5um or Kinetex EVO C18 30*2.1 mm, 5 pm reverse-phase column at 50 °C. The flow rate was constant at 1.5 mL / min.

[0196] Analytical HPLC: HPLC was performed on a Shimadzu Preparative system fitted with a Kinetex C18 LC Column 4.6 X 50 mm reverse-phase column at 50 °C. The flow rate was constant at 1.5 mL / min.

[0197] Preperative HPLC: HPLC was performed on a Gilson Preparative system fitted with the columns as described below to purify the Intermediates and Examples, where the HPLC conditions were optimized for each compound as required. Conditions reported in the documents as HPLC -code (% MeCN). The flow rate was constant at 25 mL / min.Intermediates

[0198] Intermediate 1. (rac)-3-(7-bromo-l-oxoisoquinolin-2(lH)-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione.

[0199] Step 1. Synthesis of (rac)-l-(4-methoxybenzyl)-2, 6-dioxopiperidin-3-yl trifluoromethanesulfonate .

[0200] To a solution of 3-hydroxy-l-(4-methoxybenzyl)piperidine-2, 6-dione (5.00 g, 20.1 mmol) and pyridine (3.17 g, 40.1 mmol) in DCM (50 mL) at 0 °C was added dropwise trifluoromethanesulfonic anhydride (8.49 g, 30. 1 mmol) and the mixture stirred at 0-10 °C for 1 h under nitrogen. On completion, the mixture was diluted with water (100 mL) and extracted with DCM (3x 100 mL). The combined organics were washed with brine (lOOrnL), dried (Na2SO4) and concentrated under reduced pressure. The residue w as purified by column chromatography (SiO2, 15-50% EtOAc / PE) to give the title compound as a white solid (6.01 g, 79%) as white solid. 'H-NMR (400 MHz, DMSO-d6): 7.21 (d, 2H). 6.87 (d, 2H). 5.46 (dd. 1H), 4.75 (s, 2H), 3.72 (s, 3H), 2.82 (dd, 2H), 2.34-2.24 (m, 1H), 2.23-2.08 (m, 1H).

[0201] Step 2. Synthesis of (rac)-3-(7-bromo-l-oxoisoqumolm-2(lH)-yl)-l-(4- methoxybenzyl)piperldlne-2, 6-dione.

[0202] To a solution of (rac)-l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (Step 1, 511 mg, 1.34 mmol) in tetrahydrofuran (5 mL) was added cesium carbonate (436 mg, 1.34 mmol) and 7-bromoisoquinolin-l(2H)-one (100 mg, 446 pmol) and the mixture stirred at 25 °C for 1 h. On completion, the mixture was diluted with w ater (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (60 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (51% MeCN / ftO (0.1% FA)) to give the title compound as a white solid (0.20 g, 89%). LCMS m / z = 457 [M+H]+.

[0203] Intermediate 2. (rac)-3-(6-bromo-l-oxoisoquinolin-2(lH)-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione.

[0221] The title compound was prepared as a white solid (240 mg, 62%) from 6- bromoisoquinolin-l(2H)-one and (rac)-l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (Intermediate 12) using an analogous procedure to that described for Intermediate 1, Step 2. 'H-NMR (400 MHz, DMSO-d6): 8.11 (d, 1H), 7.99 (d, 1H), 7.68 (dd, 1H), 7.48 (d, 1H), 7.23 (d, 2H), 6.86 (d, 2H), 6.68 (d, 1H), 5.86-5.38 (m, 1H), 4.92-4.82 (m, 1H), 4.77-4.67 (m, 1H), 3.72 (s, 3H), 3.12-2.92 (m, 1H), 2.87-2.76 (m, 1H), 2.76-2.61 (m, 1H), 2.15-2.03 (m, 1H).

[0222] Intermediate 3. 3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione.

[0223] To a solution of dihydropyrimidine-2,4(lH,3H)-dione (10.0 g, 87.6 mmol) in DMF (100 mL) w as added caesium carbonate (57.1 g, 175 mmol) and 1 -(chloromethyl)-4-methoxy- benzene (8.24 g, 52.6 mmol) at 0 °C and the mixture stirred at 20 °C for 6 h. The reaction mixture was partitioned between water (300 mL) and EtOAc (3x 100 ml). The organic phase was separated, w ashed with brine (5x 100 mL), dried (Na2SO4) and concentrated under pressure reduced. The residue w as triturated with EtOAc (20 mL) at 25 °C for 15 min to give the title compound as a white solid (6.00 g, 29%) together with impure title compound as a light yellow solid (4.30 g. crude). 'H-NMR (400 MHz. DMSO-d6): 7.81 (s, 1H), 7.17 (d, 2H). 6.84 (d, 2H). 4.71 (s, 2H), 3.71 (s, 3H), 3.21 (dt, 2H), 2.62 (t, 2H).

[0224] Intermediate 4. l-(7-bromoquinolin-3-yl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione.

[0225] A mixture of 7-bromo-3 -iodoquinoline (500 mg, 1.50 mmol), 3-(4- methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (Intermediate 4, 350 mg, 1.50 mmol), copper iodide (142 mg, 748 pmol), (lR,2R)-Nl,N2-dimethylcyclohexane-l,2-diamine (106 mg, 748 pmol), cesium carbonate (975 mg, 2.99 mmol) and 4A molecular sieve (100 mg, 1.50 mmol) in DMF (10 mL) was degassed and purged with N2 (x3) and then the mixture stirred at 70 °C for 12 hr under N2. The solids were removed by filtration and the filtrate evaporated to dryness. The residue was purified by column chromatography (SiCh, 0-100% EtOAc / PE) to afford the title compound as a yellow solid (480 mg, 65%). LCMS m / z = 440 [M+H]+.

[0226] Intermediate 5. l-(7-bromo-4-chloroquinolin-3-yl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione.

[0227] Step 1. Synthesis of 7-bromo-3-iodoquinolin-4-ol.

[0228] A solution of 7-bromoquinolin-4-ol (8.00 g, 35.7 mmol) and N-iodosuccinimide (9.64 g, 42.9 mmol) in MeCN (80 mL) was stirred at 65 °C for 3 h. The reaction mixture was filtered and the filter cake washed with MeCN (100 mL) to give the title compound as an off- white solid (12.0 g, 96%). 'H-NMR (400 MHz, DMSO-d6): 8.53 (s, 1H), 8.02 (d, 1H), 7.80 (d,1H), 7.52 (dd, 1H)

[0229] Step 2. Synthesis of 7-bromo-4-chloro-3-iodoquinoline.

[0230] To a solution of 7-bromo-3-iodoquinolin-4-ol (Step 1, 12.0 g, 34.3 mmol) in dioxane (120 mL) was added phosphorus oxychloride (15.8 g, 103 mmol) and the mixture stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residuequenched with saturated sodium bicarbonate solution (150 mL) at 25 °C and extracted with EtOAc (3x 50 mL). The combined organics were dried (b^SCL) and concentrated under reduced pressure to give the title compound as a yellow solid (12.5 g, crude). 'H-NMR (400 MHz, DMSO-d6): 9.17 (s, 1H), 8.31-8.27 (m, 1H), 8.14 (d, 1H), 7.89 (dd, 1H)

[0231] Step 3. Synthesis of l-(7-bromo-4-chloroquinolin-3-yl)-3-(4- melhoxybenzyl)dihydropyrimidine-2.4( 1H.3H)-dlone.

[0232] A mixture of 7-bromo-4-chloro-3 -iodoquinoline (Step 2, 2.00 g, 5.43 mmol), 3-(4- methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (Intermediate 4, 1.40 g, 5.97 mmol), cesium carbonate (5.31 g, 16.2 mmol) and Xantphos Pd G4 (522 mg, 543 pmol) in dioxane (40 mL) was degassed and purged with nitrogen (3x) and the mixture was stirred at 100 °C for 8 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue purified by flash silica gel chromatography (ISCO®: 40 g SepaFlash® Silica Flash Column, 45- 47% EtOAc / PE) followed by prep-HPLC-E (60-90% MeCN) to afford the title compound as an off-white solid (350 mg, 13%). 'H NMR (400 MHz, CDCh): 8.79 (s, 1H), 8.35 (d, 1H), 8.12 (d, 1H), 7.78 (dd, 1H). 7.43 (d, 2H). 6.86 (d, 2H). 5.07-4.94 (m, 2H). 3.89-3.82 (m, 1H). 3.80 (s, 3H), 3.79-3.72 (m. 1H), 3.11-2.91 (m. 2H).

[0233] Intermediate 6 and 7. 3-(6-bromo-5-fluoro-2H-indazol-2-yI)-l-(4- methoxybenzyl)piperidine-2, 6-dione and 3-(6-bromo-5-fluoro-lH-indazol-l-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione.

[0234] To a solution of l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (Intermediate 12, 4.61 g, 12.1 mmol) and 5-bromo-6-fluoro-2H- indazole (2.00 g, 9.30 mmol) in THF (40 mL) was added potassium tert-butoxide (1 M, 13.9 mL) at 0 °C and the mixture stirred at 25 °C for 2 h. The reaction was quenched by addition of saturated ammonium chloride solution (100 mL) at 25 °C and extracted with ethyl acetate (3x 100 mL). The combined organics were washed with brine (300 mL), dried (JSteSC ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 10% EtOAc / PE) to give Peak 1, Intermediate 6; (rac)-3-(6-bromo-5-fluoro-2H-indazol-2- yl)-l-(4-methoxybenzyl)piperidine-2,6-dione (1.5 g) and then eluting with 25% EtOAc / PE gave Peak 2, Intermediate 7; 3-(6-bromo-5-fluoro-2H-indazol-2-yl)-l-(4-methoxybenzyl)piperidine- 2, 6-dione (1 g).

[0235] Peak 1 was repurified using reverse-phase chromatography (62% MeCN / f RO (0.1% FA condition)) to afford 3-(6-bromo-5-fluoro-lH-indazol-l-yl)-l-(4-methoxybenzyl)piperidine- 2, 6-dione, Intermediate d as a yellow solid (1.2 g, 28%). LCMS m / z = 446 [M+H]+, 'H NMR (400 MHz, DMSO-d6): 8.21 (d, 1H), 8.16 (s, 1H), 7.73 (d, 1H), 7.17 (d, 2H), 6.85 (d, 2H), 5.98 (dd, 1H), 4.84-4.69 (m, 2H), 3.71 (s, 3H), 3.04-2.88 (m, 2H), 2.84-2.71 (m, 1H), 2.38-2.28 (m, 1H).

[0236] Peak 2 was repurified using reverse-phase chromatography (60% MeCN / H2O (0. 1% FA condition)) to afford 3-(5-bromo-6-fluoro-2H-indazol-2-yl)-l -(4-methoxybenzyl)piperidine- 2, 6-dione, Intermediate 7 as an off-white solid (800 mg, 19%). LCMS m / z = 446 [M+H]+, 'H NMR (400 MHz, DMSO-d6): 8.54 (s, 1H), 8.22 (d, 1H), 7.61 (d, 1H), 7.19 (d, 2H), 6.86 (d, 2H), 5.91 (dd, 1H), 4.78 (s, 2H), 3.72 (s, 3H). 3.08-2.88 (m, 2H). 2.86-2.70 (m, 1H). 2.43-2.34 (m, 1H).

[0237] Intermediate 8. l-(7-broino-4-methylquinolin-3-yl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione.

[0238] Step 1. Synthesis of 2-(2-amino-4-bromophenyl)but-3-yn-2-ol.

[0239] A solution of ethynylmagnesium bromide (0.5 M, 186 mL) was added to l-(2-amino- 4-bromophenyl)ethan-l-one (5.00 g, 23.3 mmol) in anhydrous THF (80 mL) and at 0 °C under N2 and the resulting mixture stirred at 60 °C for 2 h under N2. The reaction mixture was slowly quenched with saturated ammonium chloride solution (200 mL) under N2 and extracted with EtOAc (3x 100 mL) and the combined organics concentrated. The residue was purified by column chromatography (SiC>2, 0-100% EtOAc / PE) to afford the title compound as a yellow solid (3.00g, 50%). LCMS m / z = 240 [M+H]+.

[0240] Step 2. Synthesis ofN-(7-bromo-4-methylquinolin-3-yl)-4- methylbenzenesulfonamide.

[0241] To a solution of 2-(2-amino-4-bromophenyl)but-3-yn-2-ol (Step 1, 2.50 g, 8.33 mmol) in DMSO (50 mL) was added TsNs (5.26 g, 19.9 mmol, 75% purity ) and silver carbonate (91.8 mg, 333 pmol) at 20 °C and the mixture stirred at 50 °C for 12 h. The reaction mixture wasquenched by addition water (200 mL) at 25 °C and then extracted with EtOAc (2x 150 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2. 0-100% EtOAc / PE) to afford the title compound as a yellow solid (1.90 g, 50%). LCMS m / z = 391 [M+H]+.

[0242] Step 3. Synthesis of 7-bromo-4-methylquinolin-3-amine.

[0243] To a solution of N-(7-bromo-4-methylquinolin-3-yl)-4-methylbenzenesulfonamide (Step 2, 1.70 g. 4.34 mmol) in 1. 2-dichloroethane (15 mL) was added trifluoromethanesulfonic acid (3 mL) and the mixture stirred at 90 °C for 12 h. The reaction mixture was quenched by addition sodium bicarbonate (200 mL) at 25 °C and extracted with EtOAc (2x 150 mL). The combined organics were dried (NazSO-i and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-100% EtOAc / PE) to afford the title compound as a light-yellow solid (800 mg, 77%). 'H NMR (400 MHz, DMSO-d6): 8.46 (s, 1H), 7.94 (d, 1H), 7.79 (d, 1H), 7.55-7.51 (m, 1H), 5.61 (s, 2H), 2.31 (s, 3H)

[0244] Step 4. Synthesis of 7-bromo-3-iodo-4-methylquinoline.

[0245] To a solution of 7-bromo-4-methylquinolin-3-amine (Step 3, 100 mg, 421 pmol) in acetone (0.5 mL) was added isopentyl nitrite (123 mg, 1.05 mmol) and trifluoroborane hydrofluoride (148 mg, 1.69 mmol) at -10 °C and the mixture stirred for 1 h. To this was added hen potassium iodide (84.0 mg, 506 pmol) in H2O (0. 1 mL) and the mixture stirred at 25 °C for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2x 40 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, 25% EtOAc / PE) to afford the title compound as a yellow solid (140 mg, 82%). LCMS m / z = 348 [M+H]+.

[0246] Step 5. Synthesis of l-(7-bromo-4-methylquinolin-3-yl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione.

[0247] A mixture of 7-bromo-3-iodo-4-methylquinoline (Step 4, 100 mg, 287 pmol), 3-(4- methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (Intermediate 4, 53.8 mg, 229 pmol), copper iodide (27.3 mg, 143 pmol), cesium carbonate (187 mg, 574 pmol), (1R,2R)- cyclohexane-l,2-diamine (16.4 mg, 143 pmol) and 4A molecular sieve (50 mg) in dioxane (2 mL) was degassed and purged with N2 (x3) and the mixture stirred at 70 °C for 2 h under N2. The mixture was filtered, concentrated and the residue purified by prep-HPLC-A (6-36% MeCN) to afford the title compound as a yellow solid (15.0 mg, 11%). 'H NMR(400MHz, CDCh): 8.69 (s, 1H), 8.31 (d, 1H), 7.90 (d, 1H), 7.80-7.61 (m, 1H), 7.45-7.40 (m, 2H), 6.87-6.83 (m, 2H), 5.00 (s, 2H), 3.90-3.76 (m, 4H), 3.04-2.95 (m, 2H), 2.53 (s, 3H).

[0248] Intermediate 9. (rac)-3-(6-bromo-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2,6- dione.

[0249] Step 1. Synthesis of methyl 3-bromo-2-fluoro-6-methylbenzoate.

[0250] To solution of 3-bromo-2-fluoro-6-methylbenzoic acid (1.00 g, 4.29 mmol) in DMF(10 mb) was added K2CO3 (890 mg. 6.44 mmol) and Mel (914 mg. 6.44 mmol) and the mixture stirred at 25 °C for 2 h. The reaction was quenched by addition water (50 mL) and extracted with EtOAc (2x 50 mL). The combined organics were washed with brine (3x 100 mL), dried (NazSCL) and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column. 0-10% EtOAc / PE to afford the title compound as a white solid (960 mg, 90% yield).(400MHz, CDCh): 7.53-7.46 (m, 1H), 6.91 (d, 1H), 3.96 (s, 3H), 2.36 (s, 3H)

[0251] Step 2. Synthesis of methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate.

[0252] A solution of methyl 3-bromo-2-fluoro-6-methylbenzoate (Step 1, 0.96 g, 3.89 mmol). 1, 3-dibromo-5, 5-dimethyl-imidazolidine-2, 4-dione (1.39 g. 4.86 mmol), TFA (88.6 mg, 777 pmol) and MeCN (20 mL) at 25 °C was prepared as Solution A in flow vessel 1 (FLV1). FLVI flowed with a flow rate of 17.9 mL / min on 455 nm ELD light at 40 °C for 5 minutes. A mixture of 1 -ethoxy phosphonoy 1 oxy ethane (832 mg, 6.02 mmo) and N-ethyl-N- isopropylpropan-2-amine (1.51 g, 11.7 mmol, 2.03 mL) at 25 °C was stirred at 25 °C to prepare Solution B in flow vessel 2 (FLV2). FLV2 flowed with a flow rate of 2.2 mL / min. FLV 1 and FLV2 flowed together at 40 °C for 4 min and the reaction mixture collected. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x 100 mL). The combined organics were washed with brine (2x 200 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash®, 0-15% EtOAc / PE) to afford the title compound as ayellow oil (1.10 g, 86%) as yellow oil. ' H NMR (400MHz, CDCI3): 7.69-7.56 (m, 1H), 7.12 (d, 1H), 4.60 (s, 2H), 4.00 (s, 3H)

[0253] Step 3. Synthesis of (rac)-3-(6-bromo-7-fluoro-l-oxoisoindolm-2-yl)piperidme-2,6- dione.

[0254] To a solution of methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate (Step 2, 900 mg, 2.76 mmol) and 3-aminopiperidine-2, 6-dione hydrochloride (545 mg, 3.31 mmol) in MeCN (20 mb) was added DIPEA (1.07 g, 8.28 mmol) at 25 °C and the mixture stirred at 82 °C for 16 h. On completion, the reaction mixture the mixture was cooled to room temperature and the solids collected by filtration. The filter cake was washed with water, MeCN and EtOAc and dried under reduced pressure to afford the title compound as a purple solid (810 mg, 86%).NMR (400MHz, DMSO-d6): 11.02 (s, 1H), 7.94 (dd, 1H), 7.42 (d, 1H), 5.09 (dd, 1H), 4.55-4.41 (m, 1H), 4.40-4.22 (m, 1H), 2.98-2.84 (m, 1H), 2.60 (d, 1H), 2.38 (dq, 1H), 2.06-1.94 (m, 1H).

[0255] Intermediate 10. (rac)-3-(4-bromo-3,3-dimethyl-2-oxoindolin-l-yl)piperidine- 2, 6-dione.

[0256] Step 1. Synthesis of 4-bromo-3,3-dimethylindolin-2-one.

[0257] To a solution of 4-bromoindolin-2-one (2.00 g, 9.43 mmol) in THF (30 mL) was degassed and purged with nitrogen and cooled to -78°C. To this was added LiHMDS (1 M, 28.3 mL) and the mixture stirred at -78°C for 0.5 hour and Mel (23.5 mmol, 1.47 mL) was added and the mixture stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of NH4CI solution (100 mL) at 25 °C and extracted with EtOAc (3x 100 mL). The combined organics were washed with brine (3x 100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 10-25% EtOAc / PE) to give the title compound as a white solid (1.30 g, 57%). LCMS m / z = 240 [M+H]+.

[0258] Step 2. Synthesis of (rac)-3-(4-bromo-3, 3-dimethyl-2-oxoindolin-l-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione.

[0259] Potassium tert-butoxide (1 M, 7.50 mL) was added to a solution of 4-bromo-3,3- dimethylindolin-2-one (Step 1, 1.20 g, 5.00 mmol) and l-(4-methoxybenzyl)-2,6- dioxopiperidin-3-yl trifluoromethanesulfonate (Intermediate 12, 2.86 g, 7.50 mmol) in THF (20 mL) at 0 °C and the mixture stirred at 25 °C for 2 h. The reaction mixture was quenched by addition NH4CI solution (50 mL) at 25 °C and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine (3x 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 15-50% EtOAc / PE) togive the title compound as a white solid (1.15 g, 48%).JH NMR (400MHz, DMSO-de): 7.24- 7.18 (m, 3H), 7.17-7.10 (m, 1H), 7.02-6.76 (m, 3H), 5.49-5.36 (m, 1H), 4.88-4.71 (m, 2H), 3.72 (s, 3H), 3.02 (d, 1H), 2.79 (dd, 1H), 2.65 (dd, 1H), 2.06-1.95 (m, 1H), 1.44 (s, 6H).

[0260] Step 3. Synthesis of (rac)-3-(4-bromo-3,3-dimethyl-2-oxoindolin-l-yl)piperidine-2,6- dione.

[0261] To a solution of (rac)-3-(4-bromo-3,3-dimethyl-2-oxoindolin-l-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione (Step 2, 300 mg. 636 pmol) in TFA (2 mL) was added TfOH (2.26 mmol, 0.2 mL) and the mixture stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced and the residue purified by reversed-phase chromatography (0.1% FA) to give the title compound as a white solid (120 mg, 34%). 'l l NMR (400MHz, DMSO-ds): 11.10 (s, 1H), 7.28-7.17 (m, 2H), 7.06 (s, 1H). 5.35-5.20 (m, 1H), 2.93-2.79 (m, 1H). 2.72-2.55 (m, 2H), 1.99 (d, 1H), 1.43 (d, 6H).

[0262] Intermediate 11. 2-((5-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-7- cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0263] Step 1. Synthesis of tert-butyl 7-(6-nitropyridm-3-yl)-2, 7-diazaspiro[3.5]nonane-2- carboxylate.

[0264] To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.00 g. 4.42 mmol) and 5-chloro-2-nitropyridine (771 mg, 4.86 mmol) in MeCN (15 mL) was added potassium carbonate (916 mg, 6.63 mmol) and the mixture stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (3x 50 L), dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 65% EtOAc / PE) to give the title compound as a yellow solid (540 mg, 36%). LCMS m / z = 349 [M+H]+.

[0265] Step 2. Synthesis of tert-butyl 7-(6-aminopyridin-3-yl)-2, 7-diazaspiro[3.5]nonane-2- carboxylate.

[0266] To a solution of tert-butyl 7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2- carboxylate (Step 1, 540 mg, 1.55 mmol) in EtOH (3.5 mL) and water (1.5 mL) was added ammonium chloride (829 mg, 15.5 mmol) at 20 °C. The mixture was warmed to 80 °C and iron (433 mg, 7.75 mmol) added portion wise and the reaction mixture stirred at 80 °C for 2 h. The solids were removed by filtration and the filtrate concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (3x 50 mL), dried (JSteSCh), concentrated under reduced pressure and the residue purified by column chromatography (SiCL. 5% MeOH / EtOAc) to give the title compound as a green oil (390 mg. 78%). LCMS m / z = 319 [M+H]+.

[0267] Step 3. Synthesis of tert-butyl 7-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[ 2, 3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-2, 7-diazaspiro[3.5 ]nonane-2-carboxylate.

[0268] A mixture of tert-butyl 7-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2- carboxylate (Step 2, 370 mg. 1.16 mmol), 2-chloro-7-cyclopentyl-N,N-dimethyl-7H- pyrrolo[2,3-d]pyrimidine-6-carboxamide (340 mg, 1.16 mmol), Pd2(dba)s (106 mg, 116 pmol). Xantphos (134 mg, 232 pmol) and cesium carbonate (757 mg, 2.32 mmol) in dioxane (7 mL) was degassed and purged with nitrogen (x3) and the mixture was stirred at 100 °C for 2 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (20 mL) and extracted with DCM (3x 20 mL). The combined organics were washed with brine (3x 50 mL), dried (Na^SCf) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL. 100% EtOAc) to give the title compound as a yellow solid (500 mg, 68%). LCMS m / z = 575 [M+H]+.

[0269] Step 4. Synthesis of2-((5-(2, 7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-7- cyclopentyl-NJS-dimethyl-7H-pyrrolo[2,3-dJpyrimidine-6-carboxamide.

[0270] To a solution of tert-butyl 7-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Step 3, 80.0 mg. 139 pmol) in DCM (2 mL) was added TFA (768 mg, 6.73 mmol) and the mixture stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (82 mg, crude) which was used without further purification. LCMS m / z = 475 [M+H]+.

[0271] Intermediate 12. l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate.

[0272] To a solution of 3-hydroxy-l-(4-methoxybenzyl)piperidine-2, 6-dione (8.00 g, 32.0 mmol) and Py (64.1 mmol, 5.18 mL) in DCM (80 mL) was added dropwise Tf20 (48.1 mmol, 7.94 mL) at 0 °C and the mixture stirred at 0-10 °C for 1 h under N2. The reaction mixture was diluted with water (200 mL) and extracted with DCM (3x 200 mL). The combined organics were washed with brine (3x 200 mL), dried (JSfeSC ), concentrated under reduced pressure and the residue was purified by column chromatography (SiCh, 15-25% EtOAc / PE) to give the title compound as a white solid (9.50 g, 77%). LCMS m / z = 382 [M+H]+.

[0273] Intermediate 13. (rac)-3-(4'-bromo-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)piperidine-2, 6-dione.

[0274] Step 1. Synthesis of 4'-bromospiro[cyclopropane-l, 3'-indolin]-2'-one.

[0275] To solution of 4-bromoindolin-2-one (3.71 g, 17.5 mmol) in DMF (90 mL) was added (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (9.30 g, 21.0 mmol) at 25 °C, and the mixture stirred at 25 °C for 5 min. TEA (5.31 g, 52.4 mmol) was added and the mixture stirred at 25 °C for 4 h. On completion, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2x 100 mL). The combined organics were washed with brine (4x 200 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, 0- 20% EtOAc / PE) followed by reversed phase chromatography (0.1% TFA condition) to afford the title compound as a yellow solid (2.60 g, 62%). LCMS m / z = 238 [M+H]+.

[0276] Step 2. Synthesis of(rac)-3-(4'-bromo-2'-oxospiro[cyclopropane-l,3'-indolin]- -yl)- l-(4-methoxybenzyl)piperidine-2, 6-dione.

[0277] To a solution of 4'-bromospiro[cyclopropane-l,3'-indolin]-2'-one (Step 1, 2.00 g, 8.40 mmol) in THF (100 mL) was added KO‘Bu (1 M in THF, 10. 1 mL) at 0 °C and the mixture stirred at 25 °C for 1 h. l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate(Intermediate 12, 4.00 g, 10.5 mmol) was added at 0 °C and the mixture stirred at 25 °C for 2 h. On completion, the reaction mixture was quenched by addition water (100 mL) and extracted with EtOAc (2x 100 mL). The combined organics were washed with brine (2x 200 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by reversed phase chromatography (0.1% TFA condition) to afford the title compound as a yellow solid (3.00 g, 76%). LCMS m / z = 471 [M+H]+.

[0278] Step 3. Synthesis of (rac)-3-(4'-bromo-2’-oxospiro[cyclopropane-1.3'-indolin]-l'- yl)piperidine-2, 6-dione.

[0279] To a solution of 3-(4'-bromo-2'-oxospiro[cyclopropane-l,3'-indolin]-r-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione (Step 2, 2. 10 g, 4.47 mmol) in TFA (20 mL) was added trifluoromethanesulfonic acid (2.0 mL) at 25 °C and the mixture stirred at 60 °C for 6 h. On completion, the reaction mixture was concentrated under reduced pressure and the residue purified by reverse phase chromatography (0.1% TFA condition) to afford the title compound as a yellow solid (750 mg, 48%). LCMS m / z = 349 [M+H]+.

[0280] Intermediate 14. Benzyl (S)-4-(azetidin-2-yl)piperidine-l-carboxylate or benzyl (R)-4-(azetidin-2-yl)piperidine-l-carboxylate.

[0281] Step 1. Synthesis of benzyl (S)-4-(l-(tert-butoxycarbonyl)azetidin-2-yl)piperidine-l- carboxylate or benzyl (R)-4-( I -( tert-butoxycarbonyl)azetidin-2-yl)piperidine-l -carboxylate.

[0282] A mixture of l-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (6.75 g, 33.5 mmol), benzyl 4-bromopiperidine-l -carboxylate (5.00 g, 16.7 mmol), [5,5'-Bis(trifluoromethyl)-2,2'- bipyridine-Nl,Nl']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (376 mg. 335 pmol). (DME)NiC12 (368 mg. 1.68 mmol), 4-methoxy-2-(4- methoxy-2-pyridyl)pyridine (362 mg, 1.68 mmol), potassium carbonate (9.27 g, 67.0 mmol), water (6.04 g, 335 mmol) in acetonitrile (50 mL) and ethyl acetate (50 mL) was degassed and purged with nitrogen. The reaction mixture was stirred at 25 °C for 16 h irradiated with a 455mn blue LED. The reaction mixture was quenched by addition water (30 ml) and extracted with EtOAc (600 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-100% EtOAc / PE) to afford the title compound as a yellow oil (2.50 g, 31%). Theresidue was further purified by chiral-SFC (Diacel Chirlapak IG, 250 x 50 mm, 10 mm; 35% IPA (0.1% NH4OH) in CO2) to afford the title compound as the first eluting isomer as a yellow solid (0.7 g, 65%). LCMS m / z = 375 [M+H]+.

[0283] Step 2. Synthesis of benzyl (S)-4-(azetidin-2-yl)piperidine-l -carboxylate or benzyl (R)-4-(azetidin-2-yl)piperidine-l -carboxylate.

[0284] To a solution of benzyl (S)-4-(l-(tert-butoxycarbonyl)azetidin-2-yl)piperidine-l- carboxylate or benzyl (R)-4-(l-(tert-butoxycarbonyl)azetidin-2-yl)piperidine-l-carboxylate (Step 1 , 0.85 g, 2.27 mmol) in DCM (7.5 mL) was added TFA (2.45 g, 21.4 mmol) and the mixture stirred at 25 °C for 2 h. The reaction mixture was evaporated to dryness and the residue purified by reverse-phase chromatography (0.1% FA condition) to give the title compound as a yellow oil (0.70 g, 96%). LCMS m / z = 275 [M+H]+.

[0285] Intermediate 15. (R)-3-(l-oxo-4-((S)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2- yl)piperidine-2, 6-dione and (S)-3-(l-oxo-4-((S)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2- yl)piperidine-2, 6-dione or (R)-3-(l-oxo-4-((R)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2- yl)piperidine-2, 6-dione and (S)-3-(l-oxo-4-((R)-2-(piperidin-4-yl)azetidin- l-yl)isoindolin-2- yl)piperidine-2, 6-dione.

[0286] Step 1. Synthesis of (benzyl 4-((S)-l-(2-((R)-2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)azetidm-2-yl)piperidine-l-carboxylate and benzyl 4-((S)-l-(2-((S)-2, 6- dioxopiperidin-3-yl)- 1 -oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l -carboxylate) or (benzyl 4- ((R)-l-(2-((R)-2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l- carboxylate and benzyl 4-((R)-l-(2-((S)-2, 6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)azetidin- 2-yl)piperidine-l-carboxylale).

[0287] A mixture of benzyl (S)-4-(azeti din-2 -yl)piperi dine- 1 -carboxylate or benzyl (R)-4- (azetidin-2-yl)piperidine-l -carboxylate (Intermediate 14, 0.50 g, 1.56 mmol), 3-(4-bromo-l - oxoisoindolin-2-yl)piperidine-2, 6-dione (504 mg, 1.56 mmol), palladium(2+) 1 ,3-bis[2,6- bis(heptan-4-yl)phenyl]-4,5-dichloro-2H-imidazole 3 -chloropyridine dichloride (151 mg, 156 pmol), cesium carbonate (1.02 g, 3. 12 mmol) in dioxane (8 mL) was stirred at 100 °C for 2 h. The reaction mixture was quenched by addition citric acid and the pH to adjusted to 5-6 and extracted with DCM (150 mL). The combined organic layers were washed with brine (30 mL), dried (NazSOi) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 0-100% EtOAc / DCM) to give the title compound as a brown solid (0.25 g, 22%). LCMS m / z = 517 [M+H]+.

[0288] Step 2. Synthesis of (R)-3-(l-oxo-4-((S)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2- yl)piperidine-2, 6-dione and (S)-3-(l-oxo-4-((S)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2- yl)piperidine-2.6-dione or (R)-3-( 1 -oxo-4-( (R)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2- yl)piperidine-2.6-dione and (S)-3-( I -oxo-4-((R)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2- yi')piperidine-2.6-dione.

[0289] To a solution of (benzy l 4-((S)-l-(2-((R)-2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- y l)azetidin-2-yl)piperi dine- 1 -carboxylate and benzyl 4-((S)-l-(2-((S)-2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l -carboxylate) or (benzyl 4-((R)-l-(2-((R)-2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l-carboxylate and benzyl 4- ((R)-l-(2-((S)-2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l- carboxylate) (Step 1, 0.22 g, 425 pmol) in DMF (5 mL) was added Pd(OH)2 (44.0 mg, 156 pmol) and Pd / C (45.3 mg, 42.5 pmol) and the mixture stirred at 25 °C for 2 h under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a white solid (0. 15 g, crude). LCMS m / z = 383 [M+H]+.

[0290] Intermediate 16. 7-cyclopentyl-2-((5-formylpyridin-2-yl)amino)-N,N-dimethyl- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

[0291] A mixture of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide (1.00 g, 3.42 mmol), 6-aminonicotinaldehyde (417 mg, 3.42 mmol), BrettPhos Pd G4 (314 mg, 342 pmol), Brettphos (183 mg, 342 pmol) and potassium acetate (670 mg, 6.83 mmol) in dioxane (20 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 100 °C for 2 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (30 mL) and extracted with DCM (3x 30 mL). The combined organics were washed with brine (3x 60 mL), dried (JSteSCh) and concentrated under reduced pressure and the residue triturated with 25% EtOAc / PE at 25 °C for 30 min to give the title compound as a grey solid (1.32 g, 99%). %). LCMS m / z = 379 [M+H]+.

[0292] Intermediate 17. 6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3- d ] pyrimidin-2-yl)amino)nicotinic acid.

[0293] A mixture of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide (500 mg, 1.71 mmol), 6-aminonicotinic acid (260 mg, 1.88 mmol), BrettPhos Pd G4 (189 mg, 205 pmol), BrettPhos (183 mg, 342 pmol) and potassium acetate (335 mg, 3.42 mmol) in dioxane (20 mL) was degassed and purged with nitrogen (3x) at 25 °C and the mixture stirred at 100 °C for 2 h under nitrogen. The reaction mixture was concentrated under reduced pressure the residue treated with DMF the mixture was filtered. The crude product was purified by prep-HPLC-L (15-45%) to afford the title compound as a white solid (400 mg, 46%). LCMS m / z = 395 [M+H]+.

[0294] Intermediate 18. l-(7-bromo-l-methyl-lH-indazol-3-yl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione.

[0295] Step 1. Synthesis of 7-bromo-3-iodo-l -methyl- IH-indazole.

[0296] To a solution of 7-bromo-l -methyl- IH-indazole (3.30 g, 15.6 mmol) in DMSO (33 mL) was added N-iodosuccinimide (7.04 g, 31.2 mmol) and the resulting mixture stirred at 90 °C for 16 h. The reaction mixture was quenched with water (200 mL) and sodium thiosulfate (20 mL), diluted with ethyl acetate (200 mL) and extracted with ethyl acetate (3x 100 mL). The combined organics were washed with brine, dried (NazSCL) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, EtOAc / PE) followed by prep-HPLC-H (52-82%) to afford the title compound as a white solid (3.65 g, 69%). 'H NMR (400 MHz. CDCh): 7.60-7.53 (m, 2H), 7.43 (d, 2H), 6.99 (t, 1H). 6.84 (d, 2H). 5.01 (s, 2H), 4.36 (s, 3H), 3.97 (t, 2H), 3.79 (s, 3H), 2.95 (t, 2H).

[0297] Step 2. Synthesis of 1 -(7 -bromo- 1 -methyl- lH-indazol-3-yl) -3-(4- methoxybenzyl)dihydropyrimidine-2, 4( 1H, 3H)-dione.

[0298] To a solution of 7-bromo-3-iodo-l-methyl-lH-indazole (Step 1. 400 mg, 1.19 mmol) and 3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (Intermediate 4, 417 mg, 1.78 mmol) in dioxane (40 mL) was added potassium phosphate (629 mg, 2.97 mmol), copper iodide (113 mg, 593 pmol) and (1R, 2R)-cyclohexane-l,2-diamine (67.7 mg, 593 pmol) and the mixture stirred at 100 °C for 12 h under nitrogen. The reaction mixture was quenched by addition formic acid (5 mL) and water (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were washed with saturated brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 0-52% EtOAc / PE) to afford the title compound as a white solid (290 mg, 50%). 'l l NMR (400 MHz, CDCh): 7.60-7.53 (m, 2H), 7.43 (d, 2H), 6.99 (t, 1H). 6.84 (d, 2H). 5.01 (s, 2H), 4.36 (s, 3H), 3.97 (t, 2H), 3.79 (s, 3H), 2.95 (t, 2H).

[0299] Intermediate 19. (rac)-3-(4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine- 2, 6-dione.

[0300] Step 1. Synthesis of tert-butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2, 7- diazaspiro[3.5 nona ne-2-car boxy! ate.

[0301] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (2.00 g, 4.48 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.12 g, 4.93 mmol) , RuPhos Pd G3 (449 mg, 537 pmol), cesium carbonate (2.92 g, 8.96 mmol) in dioxane (40 mL) was degassed and purged with nitrogen (3x) at 25 °C and the mixture stirred at 100 °C for 16 h under nitrogen. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3x 70 mL). The combined organics were washed with brine (2x 20 mL), dried (ISteSC ) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiCh, 2-25% EtOAc / PE) to give the title compound as an orange solid (2.20 g, 73%). 'H-NMR (400 MHz, DMSO-d6): 7.67 (d, 1H). 7.44-7.27 (m, 12H), 6.94 (d. 2H), 6.51 (d. 1H), 5.37 (d, 4H), 3.58 (s, 4H), 3.13 (s, 4H), 1.75 (t, 4H), 1.38 (s, 9H).

[0302] Step 2. Synthesis of tert-butyl (rac)-7-(4-(2, 6-dioxopiperidin-3-yl)phenyl)-2, - diazaspiro[3.5 ]nonane-2-carboxylate.

[0303] tert-Butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2.7-diazaspiro[3.5]nonane-2- carboxylate (Step 1, 1.00 g, 1.69 mmol) was added to Pd / C (269 mg, 253 pmol, 10% purity) and Pd(OH)2 (355 mg, 253 pmol, 10% purity) in THF (15 mL) at 30 °C. The reaction mixture was stirred at 30°C for 16 h under hydrogen (15 psi). The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2. 2-50% EtOAc / PE) to afford the title compound as a white solid (600 mg, 85%). 'H-NMR (400 MHz, DMSO-d6): 10.76 (s, 1H), 7.03 (d, 2H), 6.88 (d, 2H), 3.71 (dd, 1H), 3.58 (s, 4H), 3.18-3.00 (m, 4H), 2.69-2.56 (m, 1H), 2.48-2.41 (m, 1H), 2.18-2.06 (m, 1H), 2.04-1.95 (m, 1H), 1.75 (t, 4H), 1.38 (s, 9H).

[0304] Step 3. Synthesis of (rac)-3-(4-(2, 7 -diazaspiro [3.5 ]nonan-7-yl)phenyl)piperidine- 2, 6-dione trifluoroacetate.

[0305] To a solution of tert-butyl 7-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7- diazaspiro[3.5]nonane-2-carboxylate (Step 2, 50.0 mg, 120 pmol) in DCM (1 mL) was added TFA (2.69 mmol, 0.2 mL) and the reaction mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow oil (50.0 mg, 96%).

[0306] Intermediate 20. (rac)-3-(l-oxo-6-(2,6-diazaspiro[3.3]heptan-2-yl)isoindolin-2- yl)piperidine-2, 6-dione trifluoroacetate.

[0307] Step 1. Synthesis of tert-butyl (rac)-6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin- 5-yl)-2.6-dtazaspiro[3.3 ]heptane-2-carboxylate.

[0308] A mixture of 3-(6-bromo-l -oxoisoindolin-2-yl)piperidine-2, 6-dione (500 mg, 1 .55 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (399 mg, 2.01 mmol), Pd-PEPPSI- IHept (151 mg, 155 pmol) and cesium carbonate (1.01 g, 3.09 mmol) in dioxane (10 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 100 °C for 2 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue purified by reversed-phase chromatography (0.1% TFA condition, 35% MeCN / FLO) to give the title compound as a white solid (150 mg, 16%). LCMS m / z = 441 [M+H]+.

[0309] Step 2. Synthesis of (rac)-3-( 1 -oxo-6-(2, 6-diazasplro[3.3 ]heptan-2-yl)isoindolin-2- yl)piperidine-2.6-dione trifluoroacetate.

[0310] To a solution of tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (Step 1, 40.0 mg, 90.8 pmol) in DCM (1 mL) w as added TFA (768 mg, 6.73 mmol) and the mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil (41.0 mg. 99%). LCMS m / z = 341 [M+H]+.

[0311] Intermediate 21. (rac)-3-(l-oxo-5-(2,6-diazaspiro[3.3]heptan-2-yl)isoindolin-2- yl)piperidine-2, 6-dione trifluoroacetate.

[0312] The title compound was prepared as a white solid (30 mg, 22%) from 3-(5-bromo-l- oxoisoindolin-2-yl)piperidine-2, 6-dione and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate using an analogous 2-step procedure as described for Intermediate 20. LCMS m / z = 341 [M+H]+.

[0313] Intermediate 22. (rac)-3-(l-oxo-4-(l,6-diazaspiro[3.3]heptan-l-yl)isoindolin-2- yl)piperidine-2, 6-dione trifluroacetate.

[0314] The title compound was prepared as a white solid (420 mg, 71%) from 3-(4-bromo- l-oxoisoindolin-2-yl)piperidine-2, 6-dione and tert-butyl l,6-diazaspiro[3.3]heptane-6- carboxylate using an analogous 2-step procedure as described for Intermediate 20. LCMS m / z = 341 [M+H]+.

[0315] Intermediate 23. (rac)-3-(4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)piperidine- 2, 6-dione trifluoroacetate.

[0316] The title compound was prepared as a grey solid (50 mg, 16% over 2 steps) from 3- (4-bromophenyl)piperidine-2,6-dione and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate using an analogous 2-step method as described for Intermediate 20. LCMS m / z = 314 [M+H]+.

[0317] Intermediate 24. (rac)-3-(2-methyl-4-(2,7-diazaspiro[3.5]nonan-7- yl)phenyl)piperidine-2, 6-dione.

[0318] Step 1. Synthesis of 2.6-bis(benzyloxy)-3-(4-bromo-2-methylphenyl)pyridine.

[0319] A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (3.00 g, 7.19 mmol), 4-bromo-l-iodo-2-methylbenzene (2.78 g. 9.35 mmol), Pd(dppf)C12 (526 mg, 719 ymol), sodium carbonate (1.52 g, 14.4 mmol) in dioxane (24 mL) and water (6 mL) was degassed and purged with nitrogen (3x) at 25°C and the mixture stirred at 60 °C for 4 h under nitrogen. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3x 100 mL). The combined organics were washed with brine (2x 30 mL), dried ( teSCL) and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 0-20% EtOAc / PE) to afford the title compound as a white solid (2.50 g, 76%). LCMS m / z = 460 [M+H]+.

[0320] Step 2. Synthesis of tert-butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methylphenyl)-2. 7-diazaspiro[3.5 ]nonane-2-carboxylate.

[0321] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2-methylphenyl)pyridine (Step 1, 2.30 g, 5.00 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.24 g, 5.50 mmol), RuPhos Pd G3 (501 mg, 599 pmol). cesium carbonate (3.26 g, 9.99 mmol) in dioxane (50 mL) was degassed and purged with nitrogen (3x) at 25°C and the mixture stirred at 100 °C for 16 h under nitrogen. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (3x 100 mL). The combined organics were washed with brine (2x 20 mL), dried (NazSCL) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiCh, 0-33% EtOAc / PE) to afford the title compound as a yellow oil(2.50 g, 83%).1H-NMR (400 MHz, CDCI3): 7.47-7.28 (m, 11H), 7.06 (d, 1H), 6.84-6.77 (m, 2H), 6.43 (d, 1H), 5.38 (s, 2H), 5.34 (s, 2H), 3.69 (s, 4H), 3.21-3.11 (m, 4H), 2.12 (s, 3H), 1.94-1.86 (m, 4H), 1.47 (s, 9H).

[0322] Step 3. Synthesis of tert-butyl 7-(4-(2,6-dioxopiperidin-3-yl)-3-methylphenyl)-2, 7- diazcispiro[3.5 ]nonane-2-carboxylate.

[0323] To a solution of tert-butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methylphenyl)-2.7-diazaspiro[3.5]nonane-2-carboxylate (Step 2, 2.50 g, 4.13 mmol) in THF (40 mL) was added Pd / C (439 mg, 413 pmol, 10% purity7) and Pd(OH)2 (580 mg, 413 pmol, 10% purity) under nitrogen. The mixture was degassed and purged with hydrogen (3x) and then the mixture stirred at 30 °C for 16 h under hydrogen. The reaction mixture was filtered and the filtrate purified by column chromatography (SiCh, 0-100% EtOAc / PE) to afford the title compound as a green solid (1.40 g, 79%). 'H-NMR (400 MHz, DMSO-d6): 10.77 (s, 1H), 6.89 (d, 1H), 6.80-6.67 (m, 2H), 3.88 (dd, 1H), 3.57 (d, 4H), 3.07 (s, 4H), 2.75-2.62 (m, 1H), 2.49-2.43 (m, 1H), 2.24-2.03 (m, 4H), 1.97-1.88 (m, 1H), 1.74 (t, 4H), 1.38 (s, 9H).

[0324] Step 4. Synthesis of 3-(2-methyl-4-(2, 7-diazaspiro[3.5]nonan-7- yl)phenyl)piperidine-2.6-dione trifluoroacetate.

[0325] To a solution of tert-butyl 7-(4-(2,6-dioxopiperidin-3-yl)-3-methylphenyl)-2,7- diazaspiro[3.5]nonane-2-carboxylate (Step 3, 60.0 mg, 140 pmol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil (60 mg, crude) which was used without further purification. LCMS m / z = 328 [M+H]+.

[0326] Intermediate 25. 3-(4-(2,8-diazaspiro[4.5]decan-8-yI)phenyl)piperidine-2,6- dione.

[0327] Step 1. Synthesis of tert-butyl 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,8- diazaspiro[4.5 ]decane-2-carboxylate.

[0328] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (2 g, 4.48 mmol), tertbutyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.29 g, 5.38 mmol). RuPhos Pd G3 (374 mg. 448 pmol), cesium carbonate (4.38 g, 13.4 mmol) in dioxane (50 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 100 °C for 16 h under nitrogen. The residue was diluted with H2O (100 mL) and extracted with ethyl acetate (3x 100 mL). The combined organics were washed with sodium chloride solution (2x 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2. 5-20% EtOAc / PE) to afford the title compound as a yellow solid (2.2 g, 81%). LCMS m / z = 606 [M+H]+.

[0329] Step 2. Synthesis of tert-butyl 8-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,8- diazaspiro[4.5 flecane-2-carboxylate.

[0330] To a solution of tert-butyl 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,8- diazaspiro[4.5]decane-2-carboxylate (Step 1, 2.2 g, 3.63 mmol) in THF (30 mL) was added Pd / C (386 mg, 363 pmol, 10% purity) and Pd(OH)2 (510 mg, 363 pmol, 10% purity ) under nitrogen. The suspension was degassed and purged with hydrogen (3x) and the mixture stirredunder H2 (15 Psi) at 30 C for 12 h. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was purified by column chromatography (SiO2, 5-20% EtOAc / PE) to afford the title compound as a white solid (1.2 g, 78%). LCMS m / z = 428 [M+H]+.

[0331] Step 3. Synthesis of tert-butyl 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,8- diazaspiro[4.5 ]decane-2-carboxylate hydrochloride.

[0332] HCl / dioxane (2 M, 2 mL) was added to a solution of tert-butyl 8-(4-(2,6- dioxopiperidin-3-yl)phenyl)-2.8-diazaspiro[4.5]decane-2-carboxylate (Step 2, 300 mg. 701 pmol) in DCM (2 mL) and the reaction mixture stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow solid (250 mg, 97%). LCMS m / z = 328 [M+H]+.

[0333] Intermediate 26. l-(7-bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione.

[0334] Step 1. Synthesis of 7-bromo-l-methyl-lH-indazol-3-amine.

[0335] To a solution of 3-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) and methylhydrazine. sulfuric acid (14.4 g, 100 mmol) in ethanol (100 mL) was added sodium carbonate (15.9 g, 150 mmol) and the mixture stirred at 120 °C for 12 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3x 200 mL). The combined organics were dried (Na2SOr), concentrated under reduced pressure and the residue purified bycolumn chromatography (10-50% EtOAc / PE) to afford the title compound as a white solid (5.5 g, 46%). LCMS m / z = 226 [M+H]+.

[0336] Step 2. Synthesis of 3-((7-bromo-l-methyl-lH-indazol-3-yl)amino)propanoic acid.

[0337] To a solution of 7-bromo-l-methyl-lH-indazol-3-amine (Step 1, 5.0 g, 22.1 mmol) in HC1 (2 M, 50 mL) was added TBAB (713 mg, 2.21 mmol) at 25 °C and the reaction mixture warmed to 55 °C and acrylic acid (1.91 g, 26.5 mmol) added dropwise and stirred for 16 h at 90 °C. The reaction mixture was diluted with sodium bicarbonate (100 mL) and filtered to give a residue. The crude product was triturated with water (5 mL) at 25 °C for 10 min to afford the title compound as a yellow solid (4.80 g, 69%). LCMS m / z = 298 [M+H]+.

[0338] Step 3. Synthesis of l-(7-bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione.

[0339] To a solution of 3-((7-bromo-l-methyl-lH-indazol-3-yl)ainino)propanoic acid (Step 2, 2.80 g. 9.39 mmol) in acetic acid (30 mL) was added sodium cyanate (1.22 g, 18.8 mmol) and the mixture stirred at 65 °C for 12 h. Hydrochloric acid (4 M, 28 mL) was added and the resulting mixture stirred at 65 °C for 4 h. The reaction mixture was diluted with sodium bicarbonate (50 mL) and filtered to give a residue. The crude product was triturated with water (5mL) at 25 °C for 0.5 h to give the title compound as ayellow solid (1.70 g, 53%). LCMS m / z = 323 [M+H]+.

[0340] Intermediate 27. l-(l-methyl-7-(2,7-diazaspiro[3.5]nonan-7-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione trifluoroacetate.

[0341] The title compound was prepared as a white solid (125 mg, 16% over 2-steps) from l-(7-bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (Intermediate 26) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate using an analogous 2-step process as described for Intermediate 20. LCMS m / z = 369 [M+H]+.

[0342] Intermediate 28. (rac)-3-(3-methyl-2-oxo-4-(2,7-diazaspiro[3.5]nonan-7-yl)-2,3- dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0343] The title compound was prepared as a white solid (770 mg, 57% over 2-steps) from 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate using an analogous 2-step process as described for Intermediate 20. LCMS m / z = 384 [M+H]+.

[0344] Intermediate 29. (rac)-3-(4-(2,7-diazaspiro[3.5]nonan-7-yl)-lH-indazol-l- yl)piperidine-2, 6-dione.

[0345] Step 1. Synthesis of (rac)-3-(4-bromo-lH-indazol-l-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione.

[0346] To a solution of 4-bromo-lH-indazole (500 mg, 2.54 mmol) in anhydrous THF (15 mL) was added potassium tert-butoxide (1 M, 3.0 mL) at 0°C and the mixture stirred at 20 °C for 1 h under nitrogen. To this was added (rac)-l -(4-methoxybenzyl)-2,6-dioxopiperi din-3 -yl trifluoromethanesulfonate (Intermediate 12, 1.06 g, 2.79 mmol) and the mixture stirred at 20 °C for 2 h. The reaction was quenched with HC1 (1 mL). diluted with water (100 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, 0-25% EtOAc / PE) to afford the title compound as a white solid (480 mg, 43%). LCMS m / z = 430 [M+H]+.

[0347] Step 2. Synthesis of tert-butyl (rac)-7-(l-(l-(4-methoxybenzyl)-2,6-dioxopiperidin-3- yl)-lH-indazol-4-yl)-2, 7-diazaspiro[3.5 ]nonane-2-carboxylate.

[0348] To a solution of (rac)-3-(4-bromo-l H-indazol-1 -yl)-l -(4-methoxybenzyl)piperidine- 2, 6-dione (Step 1, 400 mg, 933 pmol) in dioxane (10 mL) was added tert-butyl 2,7- diazaspiro[3.5]nonane-2-carboxylate (422 mg, 1.87 mmol). 4A MS (933 pmol), cesium carbonate (608 mg, 1.87 mmol) and Pd-PEPPSLIHept (90.8 mg, 93.4 pmol) and the mixture stirred at 110 °C for 20 h under nitrogen. The mixture was filtered and the filtrate evaporated to dryness. The residue was purified by prep-HPLC-E (65-95% MeCN) to afford the title compound as a white solid (450 mg, 81%). LCMS m / z = 574 [M+H]+.

[0349] Step 3. Synthesis of (rac)-3-(4-(2, 7-diazaspiro[3.5Jnonan-7-yl)-lH-indazol-l- yl)piperidine-2, 6-dione.

[0350] A mixture of tert-butyl (rac)-7-( 1 -( 1 -(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)- lH-indazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Step 2, 400 mg, 697 pmol) in TFA (4 mL) and TfOH (0.4 mL) was stirred at 60 °C for 6 h. The mixture was concentrated and theresidue purified by prep-HPLC-E (7-37% MeCN) to afford the title compound as a yellow solid (220 mg, 89%). LCMS m / z = 354 [M+H]+.

[0351] Intermediate 30. 3-(3-methyl-2-oxo-4-(2,7-diazaspiro[3.5]nonan-2-yl)-2,3- dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.Boc

[0352] Step 1. Synthesis of 4-bromo-3-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l,3- dihydro-2H-benzo[d]imidazol-2-one.

[0353] To a solution of 7-bromo-l-methyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (12.0 g, 53 mmol) in DMF (120 mL) was added dropwise sodium hydride (3.17 g, 79.3 mmol, 60% purity) at 0 °C and the mixture stirred at this temperature for 30 min. SEM-C1 (10.6 g, 63.4 mmol) was added dropwise at 0 °C and the resulting mixture stirred at 25 C for 16 h. The reaction was quenched by addition ammonium chloride (200 mL) and extracted with ethyl acetate (3x 200 mL). The combined organics were dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 5-25% EtOAc / PE) to afford the title compound as a yellow solid (16.5 g, 87%).JH NMR (400 MHz, CDCh): 7.33-7.23 (m, 1H), 7.13 (d, 1H), 7.02-6.94 (m, 1H), 5.33 (s, 2H), 3.79 (s, 3H), 3.63 (t, 2H), 0.94 (t, 2H), 0.00 (s, 9H).

[0354] Step 2. Synthesis of tert-butyl 2-(3-methyl-2-oxo-l-((2- (trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-2, 7- diazaspiro [3.5]nonane-7 -carboxylate.

[0355] A mixture of 4-bromo-3-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro- 2H-benzo[d]imidazol-2-one (Step 1, 4.00 g, 11.2 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7- carboxylate (3.29 g, 14.6 mmol), RuPhos (1.04 g, 2.24 mmol), Pd2(dba)s (1.03 g, 1.12 mmol) and sodium tert-butoxide (3.23 g, 33.6 mmol) in toluene (50 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 80 °C for 12 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (SiCh,9-25% EtOAc / PE) to afford the title compound as a yellow oil. 'l l NMR (400 MHz, CDCE): 7.14-6.96 (m, 1H), 6.87 (d, 1H), 6.72 (d, 1H), 5.31 (s, 2H), 3.73 (s, 3H), 3.68 - 3.60 (m, 6H). 3.54-3.40 (m, 4H), 1.89-1.79 (m, 4H), 1.50 (s, 9H), 0.95 (t, 2H), 0.00 (s, 9H).

[0356] Step 3. Synthesis of tert-butyl 2-(3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol- 4-yl)-2, 7-diazaspiro [3.5]nonane-7 -carboxylate.

[0357] tert-Butyl 2-(3-methyl-2-oxo-l-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (Step 2. 4.00 g. 7.96 mmol) in TBAF (1 M, 80 mL) was stirred at 75 °C for 7 h. The reaction mixture was evaporated to dryness and the residue purified by column chromatography (SiCh, 9-25% EtOAc / PE) to afford the title compound as ayellow solid (1.60 g, 51%). 'H NMR (400 MHz, CDCI3): 8.32 (m, 1H), 6.91 (t, 1H), 6.66 (d, 1H), 6.59 (d, 1H), 3.59 (s, 3H), 3.36-3.30 (m, 6H), 1.80-1.71 (m, 4H), 1.40 (s, 9H)

[0358] Step 4. Synthesis of tert-butyl 2-(l-(l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-2, 7-diazaspiro [3.5]nonane-7 -carboxylate.

[0359] To a solution of tert-butyl 2-(3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4- yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (Step 3, 500 mg, 1.34 mmol) in THF (10 mL) was added dropwise potassium tert-butoxide (1 M, 2.0 mL) at 0 °C and the reaction mixture stirred at this temperature for 3 h. To this was added l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (Intermediate 12, 768 mg, 2.01 mmol) dropwise at 0 °C and the resulting mixture stirred at 30 °C for 12 h. The reaction mixture was quenched by addition ammonium chloride (5 mL) and extracted with ethyl acetate (3x 5 mL). The combined organics were dried (Na2SC>4) and concentrated under reduced pressure and the residue purified by column chromatography (SiCh, 9-100% EtOAc / PE) to afford the title compound as ayellow solid (500 mg, 68%). LCMS m / z = 604 [M+H]+.

[0360] Step 5. Synthesis of 3-(3-methyl-2-oxo-4-(2. 7-diazaspiro[3.5Jnonan-2-yl)-2,3- dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2.6-dione.

[0361] To a solution of tert-butyl 2-(l-(l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (Step 4, 900 mg, 1.49 mmol) in trifluoroacetic acid (36 mL) was added trifluoromethanesulfonic acid (6. 11 g, 40.6 mmol) and the mixture stirred at 60 °C for 2 h. The solution was concentrated and the residue purified by prep-HPLC-F (3-33% MeCN) to afford the title compound as a white solid (240 mg, 32% yield). LCMS m / z = 384 [M+H]+.

[0362] Intermediate 31. (rac)-3-(4-(azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0363] Step 1. Synthesis of tert-butyl (rac)-3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2.3-dihydro-lH-benzo[d ]imidazol-4-yl)azetidine-l -carboxylate.

[0364] A mixture of (rac)-3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2, 6-dione (500 mg, 1.48 mmol), tert-butyl 3-iodoazetidine-l -carboxylate (544 mg, 1.92 mmol), Ir(ppy)2(dtbbpy)PF6 (16.6 mg, 14.8 pmol). 4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine dichloronickel (2.94 mg, 7.39 pmol). bis(trimethylsilyl)silyl-trimethyl-silane (368 mg, 1.48 mmol) and sodium carbonate (313 mg, 2.96 mmol) in DME (18 mL) was degassed and purged with N2 and the mixture stirred at 25 °C for 16 h and irradiated with a 455nm blue LED. The reaction mixture was filtered and the residue purified by reverse-phase chromatography (0.1% FA) to afford the title compound as a yellow solid (350 mg, 57%). LCMS m / z = 415 [M+H]+.

[0365] Step 2. Synthesis of(rac)-3-(4-(azetidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione trifluoroacetate.

[0366] To a solution of tert-butyl (rac)-3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)azetidine-l-carboxylate (Step 1, 100 mg, 241 pmol) in DCM (5 mL) was added TFA (1 mL) and the mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue purified by reversed-phase chromatography (0.1% TFA) to afford the title compound as a yellow solid (100 mg, 97 %).JH NMR (400MHz, DMSO-d6): 11.15 (s, 1H), 7.36 (dd, 1H), 7.24-7.18 (m, 1H), 7.18-7.12 (m, 1H), 5.44 (dd, 1H), 4.87-4.78 (m, 1H), 4.39-4.33 (m, 2H), 4.29-4.24 (m, 2H), 3.99-3.96 (m, 1H), 3.57 (s, 3H), 2.99-2.89 (m, 1H), 2.80-2.72 (m, 1H), 2.70-2.64 (m, 1H), 2.48-2.35 (m, 1H), 2.08-1.97 (m, 1H).

[0367] Intermediate 32. Synthesis of (rac)-3-(l-oxo-6-(piperazin-l-yl)isoindolin-2- yl)piperidine-2, 6-dione.

[0368] The title compound was prepared as a brown solid (200 mg, 29%) from 3-(6-bromo- l-oxoisoindolin-2-yl)piperidine-2, 6-dione and tert-butyl piperazine- 1 -carboxyl ate using an analogous 2-step method as described for Intermediate 31.JH NMR (400 MHz, DMSO-de): 10.97 (s, 1H), 7.48 (s, 1H), 7.32 (d, 1H). 7.27 (d, 1H). 5.15-5.06 (m, 1H), 4.39-4.32 (m, 1H), 4.27-4.20 (m, 1H). 3.46-3.37 (m, 4H). 3.26 (s. 4H), 2.98-2.85 (m. 1H), 2.60 (d. 1H), 2.39 (dq, 2H).

[0369] Intermediate 33. 7-cyclopentyl-N,N-dimethyl-2-((5-(2-oxopiperazin-l- yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0370] Step 1. Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)-3-oxopiperazme-l -carboxylate.

[0371] A mixture of 5-bromo-2-nitropyridine (1.00 g, 4.93 mmol), tert-butyl 3- oxopiperazine-1 -carboxylate (986 mg, 4.93 mmol), Pd2(dba)? (226 mg, 246 ymol), Xantphos (285 mg, 493 pmol) and cesium carbonate (3.53 g, 10.8 mmol) in dioxane (40 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 120 °C for 1 h under nitrogen. The mixture was filtered, concentrated under reduced pressure and the residue purified by column chromatography (SiCh. 33-50% EtOAc / PE) to afford the title compound as a yellow solid (1.4 g, 80%). LCMS m / z = 323 [M+H]+.

[0372] Step 2. Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)-3-oxopiperazine-l- carboxylate.

[0373] To a solution of tert-butyl 4-(6-nitropyridin-3-yl)-3-oxopiperazine-l-carboxylate (Step 1, 0.50 g. 1.55 mmol) in ethanol (5 mL), tetrahydrofuran (5 mL) and water (5 mL) was added iron (866 mg, 15.5 mmol) and ammonium chloride (415 mg, 7.76 mmol) and the mixture stirred at 80 °C for 2 h. The mixture was filtered through celite and the filtrate concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3x 20 mL). The combined organics were washed with brine (60 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a red solid (400 mg, 88%). LCMS m / z = 293 [M+H]+.

[0374] Step 3. Synthesis of tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-oxopiperazine-l-carboxylate.

[0375] A mixture of tert-butyl 4-(6-aminopyridin-3-yl)-3-oxopiperazine-l-carboxylate (Step 2, 200 mg, 684 pmol), 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide (200 mg, 684 pmol), Pd(OAc)2 (15.4 mg, 68.4 pmol), BINAP (85.2 mg, 137 pmol) and cesium carbonate (446 mg, 1.37 mmol) in dioxane (4 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 110 °C for 12 h under nitrogen. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were washed with brine (90 mL), dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (32% MeCN (0.1% FA condition)) to give the title compound as a yellow solid (200 mg, 52%). LCMS m / z = 549 [M+H]+.

[0376] Step 4. Synthesis of7-cyclopentyl-N,N-dimethyl-2-((5-(2-oxopiperazin-l-yl)pyridin- 2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide hydrochloride.

[0377] To a solution of tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-3-oxopiperazine-l -carboxylate (Step 3, 200 mg, 336 pmol) in dichloromethane (2 mL) was added HCl / dioxane (2 M, 2 mL) and the mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (160 mg, 98%). LCMS m / z = 449 [M+H]+.

[0378] Intermediate 34. (rac)-l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)azetidine-3-carbaldehyde.

[0379] Step 1. Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine.

[0380] To a solution of azetidin-3-ylmethanol (2.00 g, 16. 1 mmol) in DCM (15 mL) was added TBSC1 (2.56 g, 16.9 mmol) and TEA (4.91 g, 48.5 mmol) and the solution stirred at 25 °C for 16 h. The reaction mixture was quenched by addition water (30 mL) and extracted with DCM (2x 30 mL). The combined organics were dried (NazSCh) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh. 20-100% EtOH (0.5% NELOH) / EtOAc) to afford the title compound as a yellow oil (2.00 g, 61%).!H NMR (400 MHz, CD3OH-d4): 3.77 (d, 2H), 3.62 (t, 2H), 3.46 (t, 2H), 2.91-2.83 (m, 1H), 0.94 (s, 9H), 0.10 (s, 6H).

[0381] Step 2. Synthesis of (rac)-3-(4-(3-(hydroxymethyl)azetidin-l-yl)-l-oxoisoindolin-2- y!)piperidine-2. 6-dione.

[0382] A mixture of 3-(4-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (0.80 g, 2.48 mmol), 3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine (Step 1, 997 mg, 4.95 mmol), Ir(ppy)2(dtbbpy)PF6 (45.2 mg, 49.5 pmol), dibromonickel. 1 ,2-dimethoxyethane (38.2 mg, 123 pmol) and l,4-diazabicyclo[2.2.2]octane (499 mg, 4.46 mmol) in DMA (20 mL) was degassed and purged with argon. The reaction mixture was stirred at 25 °C for 16 h and irradiated with a 455 nm blue LED. The reaction mixture was poured into water (50 mL) and filtered. The filtrate was concentrated and the residue was purified by prep-HPLC-K (44-74% MeCN) followed by prep-HPLC-F (5-35%) to give the title compound as a pale yellow solid (160 mg, 20%). LCMS m / z = 330 [M+H]+.

[0383] Step 3. Synthesis of (rcic)-l-(2-(2, 6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)azetidine-3-carbaldehyde.

[0384] To a solution of (rac)-3-(4-(3-(hydroxymethyl)azetidin-l-yl)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (Step 2, 0. 10 g, 303 pmol) in DMSO (3 mL) was added 2-iodoxybenzoic acid (425 mg, 1.52 mmol) and the solution stirred at 25 °C for 2 h. The solids were removed by filtration and the filtrate evaporated to dryness. The residue was purified by prep-HPLC-E (9- 39% MeCN) to afford the title compound as a pale yellow pie (40.0 mg, 40%). LCMS m / z = 328 [M+H]+.

[0385] Intermediate 35. (rac)-l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperidine-4-carbaldehyde trifluoroacetate.

[0386] Step 1. Synthesis of (rac)-3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-l-oxoisoindolin- 2-yl)piperidine-2, 6-dione.

[0387] To a solution of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (1.50 g, 4.64 mmol) and 4-(dimethoxymethyl)piperidine (813 mg, 5.11 mmol) in dioxane (22 mL) was added Pd-PEPPSI-IHept (361 mg, 371 pmol) and cesium carbonate (3.02 g, 9.28 mmol) 25°C and the reaction mixture was stirred at 100 °C for 2 h under nitrogen. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by reverse phase chromatography (0.1% FA condition) to give the title compound as a brown solid (700 mg, 37%). 'H NMR (400 MHz, DMSO-dg): 10.93 (s, 1H), 7.49 (d, 1H), 7.07-6.98 (m, 2H), 5.03 (dd, 1H), 4.38-4.15 (m, 2H), 4.07 (d, 1H), 3.89 (d, 2H), 3.27 (s, 6H), 2.95-2.84 (m, 1H), 2.83-2.73 (m, 2H), 2.58 (d, 1H), 2.41-2.30 (m, 1H), 1.99-1.91 (m, 1H), 1.85-1.75 (m, 1H), 1.70 (d, 2H), 1.36-1.24 (m, 2H).

[0388] Step 2. Synthesis of (rac)-l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperidine-4-carbaldehyde trifluoroacetate.

[0389] To a solution of (rac)-3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (Step 1, 50 mg, 124 pmol) in DCM (1.5 mL) was added trifluoroacetic acid (6.73 mmol, 0.5 mL) at 25 °C and the mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (58 mg, 99%). LCMS m / z = 356 [M+H]+.

[0390] Intermediate 36. (rac)-l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidine-3- carbaldehyde.

[0391] Step 1. Synthesis of 2,6-bis(benzyloxy)-3-(4-(3-(((tert- butyldimethylsilyl)oxy)methyl)azetidin-l-yl)phenyl)pyridine.

[0392] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (1.00 g, 2.24 mmol), 3- (((tert-butyldimethylsilyl)oxy)methyl)azetidine (451 mg, 2.24 mmol), RuPhos Pd Gs (187 mg, 224 pmol), cesium carbonate (1.82 g, 5.60 mmol) in dioxane (12 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 100 °C for 2 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash®, 0-10% EtOAc / PE) to afford the title compound as a colourless oil (1.09 g, 86%). LCMS m / z = 567 [M+H]+.

[0393] Step 2. Synthesis of (rac)-3-(4-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidin-l- yl)phenyl)piperidine-2.6-dione.

[0394] To a solution of 2,6-bis(benzyloxy)-3-(4-(3-(((tert- butyldimethylsilyl)oxy)methyl)azetidin-l-yl)phenyl)pyridine (Step 1, 990 mg, 1.75 mmol) inEtOAc (10 mL) was added Pd / C (929 mg, 873 pmol, 10% purity) and Pd(OH)2 (1.23 g, 873 pmol, 10% purity) under nitrogen. The mixture was degassed and purged with hydrogen (3x) and the mixture stirred at 30 °C for 16 h under hydrogen (50 psi). The reaction mixture was concentrated under reduced pressure and the residue purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®, 0-30% EtOAc / PE) to afford the title compound as a white solid (100 mg, 15%). LCMS m / z = 389 [M+H]+.

[0395] Step 3. Synthesis of (rac)-3-(4-(3-(hydroxymethyl)azetidin-l-yl)phenyl)piperidine- 2, 6-dione trifluoroacetate.

[0396] To a solution of (rac)-3-(4-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidin-l - yl)phenyl)piperidine-2, 6-dione (Step 2, 85.0 mg, 218 pmol) in DCM (1 mL) was added TFA (1 mL) and the mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue purified by reversed-phase chromatography (0.1% FA) to afford the title compound as a white solid (37.0 mg, 53%). LCMS m / z = 275 [M+H]+.

[0397] Step 4. Synthesis of (rac)-l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidine-3- carbaldehyde.

[0398] To a solution of (rac)-3-(4-(3-(hydroxymethyl)azetidin-l-yl)phenyl)piperidine-2,6- dione trifluoroacetate (Step 3, 32.0 mg, 99.8 pmol) in DMF (1 mL) was added Dess-Martin Periodinane (84.7 mg, 199 pmol) and the mixture stirred at 25 °C for 16 h. The reaction mixture was evaporated to dryness to afford the title compound as a brown liquid (27 mg, 99%). LCMS m / z = 273 [M+H]+.

[0399] Intermediate 37. (rac)-l-(4-(2,6-dioxopiperidin-3-yl)phenyI)piperidine-4- carbaldehyde.

[0400] Step 1. Synthesis of 2,6-bis(benzyloxy)-3-(4-(4-((benzyloxy)methyl)piperidin-l- yl)phenyl)pyridine.

[0401] A mixture of 4-((benzyloxy)methyl)piperidine (542 mg, 2.24 mmol), 2,6- bis(benzyloxy)-3-(4-bromophenyl)pyridine (1.00 g, 2.24 mmol), RuPhos Pd Gs (188 mg, 224 pmol), cesium carbonate (2.19 g, 6.72 mmol) in dioxane (20 mL) was degassed and purged with nitrogen (3x) at 25°C and the mixture stirred at 100 °C for 16 h under nitrogen. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3x 70 mL). The combined organics were washed with brine (2x 20 mL), dried (Na2SC>4) and concentrated under reduced pressure. The reside was purified by column chromatography (S1O2. 0-25% EtOAc / PE) to afford the title compound as ayellow solid (1.00 g, 78%).(400 MHz, DMSO-dg): 7.67 (d, 1H), 7.49-7.23 (m, 17H), 6.93 (d, 2H), 6.50 (d, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 4.47 (s, 2H), 3.72 (d, 2H), 3.32 (d, 2H), 2.73-2.60 (m, 2H), 1.76 (d, 3H), 1.37-1.22 (m, 2H).

[0402] Step 2. Synthesis of (rac)-3-(4-(4-(hydroxymethyl)piperidin-l-yl)phenyl)piperidine- 2, 6-dione.

[0403] To a solution of 2,6-bis(benzyloxy)-3-(4-(4-((benzyloxy)methyl)piperidin-l- yl)phenyl)pyridine (Step 1, 1.00 g, 1.75 mmol) in ethyl acetate (10 mL) and tetrahydrofuran (20 mL) was added Pd / C (186 mg. 175 pmol, 10% purity) and Pd(OH)2 (246 mg, 175 pmol, 10%purity) under nitrogen. The mixture was degassed and purged with hydrogen (3x) and the mixture stirred at 30 °C for 16 h under hydrogen. The reaction mixture was filtered and the filtrate evaporated to dryness and the residue purified by column chromatography (S1O2. 0-100% EtOAc / PE) to afford the title compound as a white solid (120 mg, 23%).JH NMR (400 MHz, DMSO-d6): 10.76 (s, 1H), 7.02 (d, 2H), 6.88 (d, 2H), 4.47 (t, 1H), 3.76-3.62 (m, 3H), 3.28 (t, 2H), 2.69-2.56 (m, 3H), 2.48-2.42 (m, 1H), 2.18-2.06 (m, 1H), 2.05-1.95 (m, 1H), 1.73 (d, 2H), 1.55-1.44 (m, 1H). 1.30-1.15 (m, 2H).

[0404] Step 3. Synthesis of (rac)-l-(4-(2.6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbaldehyde.

[0405] To a solution of 3-(4-(4-(hydroxymethyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione (Step 2, 100 mg, 331 pmol) in dichloromethane (2 mL) and tetrahydrofuran (2 mL) was added Dess-Martin Periodinane (281 mg, 661 pmol) at 0°C and the mixture stirred at 25 °C for 2 h. The reaction mixture was diluted with saturated aqueous sodium thiosulfate solution. The residue was purified by column chromatography (S1O2. 0-100% EtOAc / PE) to afford the title compound as a white solid (60.0 mg, 60%). 'H NMR (400 MHz, DMSO-de): 10.77 (s, 1H), 9.63 (s, 1H), 7.04 (d. 2H), 6.90 (d. 2H), 3.72 (dd, 1H), 3.62-3.53 (m, 2H), 2.86-2.75 (m, 2H), 2.69-2.57 (m, 1H), 2.48-2.41 (m, 1H), 2.20-2.06 (m, 1H), 2.05-1.97 (m, 1H), 1.96-1.87 (m, 2H), 1.65-1.52 (m, 2H).

[0406] Intermediate 38. (rac)-2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2- azaspiro[3.3]heptane-6-carb aldehyde.

[0407] Step 1. Synthesis of tert-butyl 6-((benzyloxy)methyl)-2-azaspiro[3.3]heptane-2- carboxylate.

[0408] To a solution of tert-buty l 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate(1.00 g, 4.40 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (317 mg, 7.92 mmol, 60% purity) at 0 °C and the mixture stirred at 0 °C for 0.5 hour before benzyl bromide (1.50 g, 8.80 mmol, 1.00 mL) was added and the mixture stirred at 25 °C for 16 h. The reaction was quenched by ammonium chloride (20 mL) at 25 °C and extracted with ethyl acetate (3x 20 mL). The combined organics were washed with brine (2x 10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh. 0-25% EtOAc / PE) to afford the title compound as a colourless oil (1 .20 g, 85%).NMR (400MHz, CDCh): 7.39-7.27 (m, 5H), 4.50 (s, 2H), 3.91 (s, 2H), 3.80 (s, 2H), 3.38 (d, 2H), 2.48-2.39 (m, 1H), 2.29-2.23 (m, 2H), 1.99-1.93 (m, 2H), 1.43 (s, 9H).

[0409] Step 2. Synthesis of 6-((benzyloxy)methyl)-2-azaspiro[3.3]heptane trifluoroacetate.

[0410] To a solution of tert-butyl 6-((benzyloxy)methyl)-2-azaspiro[3.3]heptane-2- carboxylate (Step 1, 500 mg, 1.58 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2.5 mL) and the mixture stirred at 25 °C for 2 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a colourless oil (342 mg, 99%). 'H NMR (400MHz, CDCh): 8.59 (s, 2H). 7.39-7.28 (m, 5H). 6.66 (s. 3H), 4.50 (s. 2H), 4.05 (s, 2H), 3.98 (s, 2H), 3.39 (d, 2H), 2.44-2.33 (m, 3H), 2.13 (s, 2H).

[0411] Steps 3, 4. 5. Synthesis of (rac)-2-(4-(2, 6-dioxopiperidin-3-yl)phenyl)-2- azaspiro[3.3 ]heptane-6-carbaldehyde.

[0412] The title compound was prepared from 6-((benzyloxy)methyl)-2- azaspiro[3.3]heptane trifluoroacetate (Step 2) using an analogous 3-step procedure to that described for Intermediate 37. LCMS m / z = 313 [M+H]+.

[0413] Intermediate 39. (rac)-3-((3-fluoro-4-(4-oxopiperidin-l- yl)phenyl)amino)piperidine-2, 6-dione.

[0414] Step 1. Synthesis of 8-(2-fluoro-4-nitrophenyl)-l, 4-dioxa-8-azaspiro[4.5]decane.

[0415] To a mixture of l,2-difluoro-4-nitrobenzene (10.0 g, 62.9 mmol) and l,4-dioxa-8- azaspiro[4.5]decane (9.90 g, 69. 1 mmol) in acetonitrile (150 mL) was added diisopropylethylamine (17.9 g, 138 mmol) and the mixture stirred at 90 °C for 2 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue triturated with 10: 1 PE / EtOAc to give the title compound as a yellow solid. 'H NMR (400 MHz, CDCh): 7.98-7.90 (m, 1H), 7.89-7.82 (m, 1H), 6.90 (t, 1H), 3.98 (s, 4H). 3.42-3.35 (m, 4H). 1.89-1.80 (m, 4H).

[0416] Step 2. Synthesis of 3-fluoro-4-( 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline.

[0417] To a mixture of 8-(2-fluoro-4-nitrophenyl)-l ,4-dioxa-8-azaspiro[4.5]decane (Step 1, 5.00 g, 17.7 mmol) in methanol (100 mL) was added platinum-vanadium on carbon (436 mg, 1.77 mmol) portion wise and the mixture stirred at 25 °C for 2 h under hydrogen (15 psi). The reaction mixture was slowly filtered and the filtrate concentrated under reduced pressure to afford the title compound as a yellow solid (4.60 g, crude). 'H NMR (400 MHz, CDCh): 6.83 (t, 1H), 6.48-6.29 (m, 2H), 4.97-4.23 (m, 2H), 3.98 (s, 4H), 3.14-3.00 (m, 4H), 1.88 (t, 4H).

[0418] Step 3. Synthesis of (rac)-3-((3-fluoro-4-(l,4-dioxa-8-azaspiro[4.5]decan-8- yl)phenyl)amino)piperidine-2, 6-dione.

[0419] A mixture of 3-fluoro-4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline (Step 3. 1.50 g, 5.95 mmol), 3-bromopiperidine-2, 6-dione (2.28 g, 11.9 mmol) and NaHCO3 (1.5 g, 17.8 mmol) in acetonitrile (30 mL) was stirred at 90 °C for 12 h. The reaction w as quenched with citric acid solution (2M, 60 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2. 25-100% EtOAc / PE) followed by prep-HPLC-N (5-35% MeCN) to afford the title compound as an off-white solid (1.10 g, crude). 'H NMR (400MHz, CDCI3): 7.92-7.73 (m, 1H), 7.10-6.69 (m, 1H), 6.43-6.23 (m, 2H), 4.83-4.24 (m, 1H), 3.98-3.87 (m, 5H), 3.27-2.88 (m, 4H), 2.87-2.75 (m, 1H), 2.74-2.62 (m, 1H), 2.50-2.41 (m, 1H), 1.91-1.75 (m, 4H).

[0420] Step 4. Synthesis of (rac)-3-((3-fluoro-4-(4-oxopiperidin-l- yl)phenyl)amino)piperidine-2, 6-dione.

[0421] To a solution of (rac)-3-((3-fluoro-4-(l,4-dioxa-8-azaspiro[4.5]decan-8- yl)phenyl)amino)piperidine-2, 6-dione (Step 3. 100 mg, 275 pmol) in tetrahydrofuran (2 mL) was added hydrochloride acid (3 M. 2 mL) and the reaction mixture stirred at 70 °C for 2 h. The reaction mixture was basified to pH ~8 with saturated sodium bicarbonate and extracted with ethyl acetate (3x 20 mL). The combined organics w ere w ashed with brine (2x 10 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as a grey solid (60.0 mg, 68%).

[0422] Intermediate 40. (rac)-3-((3-fluoro-4-(piperazin-l-yl)phenyl)amino)piperidine- 2, 6-dione.

[0423] Step 1. Synthesis of tert-butyl (rac)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperazine-l-carboxylate.

[0424] To a solution of 3-bromopiperidine-2, 6-dione (975 mg, 5.08 mmol) and tert-butyl 4- (4-amino-2-fluorophenyl)piperazine-l -carboxylate (1.00 g, 3.39 mmol) in DMF (15 mL) was added sodium bicarbonate (853 mg, 10.2 mmol) and the mixture stirred at 70 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x 30 mL). The combined organics were washed with brine (3x 80 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 35% EtOAc / PE) to give the title compound as a blue solid (720 mg, 44%). LCMS m / z = 407 [M+H]+.

[0425] Step 2. Synthesis of (rac)-3-((3fluoro-4-(piperazin-l-yl)phenyl)amino)piperidine- 2, 6-dione.

[0426] To a solution of tert-butyl (rac)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperazine-l -carboxylate (Step 1, 350 mg. 861 pmol) in DCM (3 mL) was added HCl / dioxane (4 M. 3 mL) and the mixture stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a blue solid (390 mg, crude). LCMS m / z = 307 [M+H]+.

[0427] Intermediate 41. 7-cyclopentyl-N,N-dimethyl-2-((5-(4-oxopiperidin-l- yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0428] Step 1. Synthesis of 8-(6-nitropyridin-3-yl)-l ,4-dioxa-8-azaspiro[4.5]decane.

[0429] To a mixture of l,4-dioxa-8-azaspiro[4.5]decane (3.43 g, 24.0 mmol) and 5-chloro-2- nitropyridine (3.80 g, 24.0 mmol) in DMSO (50 mL) was added DIPEA (6.82 g, 52.7 mmol) and the mixture stirred at 100 °C for 4 h. The mixture was poured into water (200 mL), stirred for 0.5 hour at 25 °C and the solids collected by filtration. The filter cake was washed (50% Toluene / PE) to afford the title compound as a yellow solid (5.20 g, 74%). 'H NMR (400 MHz, CDCh): 8.19-8.09 (m, 2H), 7.20 (dd, 1H), 4.01 (s, 4H), 3.63-3.56 (m, 4H), 1.88-1.80 (m, 4H).

[0430] Step 2. Synthesis of 5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-amine.

[0431] P / V / C (0.20 g, 813 pmol) was added portion wise to a mixture of 8-(6-nitropyridin-3- yl)-1.4-dioxa-8-azaspiro[4.5]decane (Step 1, 1.70 g. 6.41 mmol) in MeOH (30 mL) and the mixture stirred at 25 °C for 2 h under H2 (15 psi). The reaction mixture was slowly filtered and the filtrate concentrated under reduced pressure to give the title compound as a yellow solid (1.56 g, crude). 'H NMR (400 MHz, CDCL): 7.79 (d, 1H), 7.21 (dd, 1H), 6.49 (d, 1H), 4.43- 4.05 (m, 2H), 3.99 (s, 4H). 3.19-3.06 (m, 4H). 1.91-1.82 (m, 4H).

[0432] Step 3. Synthesis of 2-((5-( 1.4-dioxa-8-azaspiro[ 4.5Jdecan-8-yl)pyridin-2-yl)amino)- 7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0433] To a mixture of 2-chloro-7-cyclopentyl-N.N-dimethyl-7H-pyrrolo|2.3-d|pyrimidine- 6-carboxamide (236 mg, 808 pmol) and 5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2 -amine (Step 2, 200 mg, 850 pmol) in dioxane (5 mL) was added KO Ac (417 mg, 4.25 mmol), Brettphos (22.8 mg, 42.5 pmol) and BrettPhos Pd G4) (78.3 mg, 85.0 pmol) and the mixture was stirred at 100 °C for 1 h under nitrogen. The reaction was quenched with water (15 mL) and extracted with EtOAc (6x 25 mL). The combined organics was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-TLC (10%MeOH / DCM) to give the title compound as a yellow solid (450 mg, 94%). LCMS m / z = 492 [M+H]+.

[0434] Step 4. Synthesis of7-cyclopentyl-N,N-dimethyl-2-((5-(4-oxopiperidin-l-yl)pyridin- 2-yl)amino)-7H-pyrrolo[2, 3-d ]pyrimidine-6-carboxamide.

[0435] To a solution of 2-((5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)amino)-7- cyclopentyl-N,N-dirnethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Step 3, 150 mg, 305 pmol) in THF (2 mL) was added hydrochloride acid (2 M, 2 mL) and the mixture stirred at 60 °C for 2 h. The mixture was adjusted to pH=8 with solid sodium bicarbonate and the mixture diluted with water (20 mL) and extracted with EtOAc (2x 30 mL). The combined organics were washed with brine (3x 60 mL), dried (NteSCL) and concentrated under reduced pressure to give the title compound as a brown solid (112 mg, 70%). LCMS m / z = 448 [M+H]+.

[0436] Intermediate 42. (rac)-3-(3-methyl-2-oxo-4-(3-oxoazetidin-l-yl)-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0437] Step 1. Synthesis of (rac)-3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidm-l-yl)-3- methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0438] To a solution of (rac)-3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione (0.70 g, 2.07 mmol) and 3-((tert- butyldimethylsilyl)oxy)azetidine (465 mg, 2.48 mmol) in dioxane (10 mL) was added Pd- PEPPSI-IheptCl (201 mg, 207 pmol), cesium carbonate (2.02 g, 6.21 mmol) and 4A MS (2.07 mmol) and the mixture stirred at 110 °C for 6 h. The mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by reverse-phase (0.1% FA condition) to give the title compound as a yellow solid (130 mg, 14%).JH NMR (400 MHz, DMSO-d6): 11.08 (s, 1H), 7.03-6.90 (m, 1H), 6.76 (d, 1H), 6.70 (d, 1H), 5.43-5.23 (m, 1H), 4.78-4.64 (m, 1H), 4.07-4.02 (m, 2H), 3.56 (s. 3H), 3.53 (s, 2H), 2.95-2.56 (m, 4H), 0.88 (s, 9H), 0.08 (s, 6H).

[0439] Step 2. Synthesis of (rac)-3-(4-(3-hydroxyazetidin-l-yl)-3-methyl-2-oxo-2,3-dihydro- lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0440] To a solution of (rac)-3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidin-l-yl)-3-methyl- 2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (Step 1. 130 mg, 292 pmol) in tetrahydrofuran (3 mL) was added TBAF (1 M, 439 pL) and the mixture stirred at 25 °C for 1 h. The mixture was concentrated under pressure reduced and the residue purified by prep- HPLC-A (18-42%) to afford the title compound as a white solid (60.0 mg, 56%).JH NMR (400 MHz, DMSO-d6): 11.07 (s, 1H), 7.03-6.88 (m, 1H), 6.74 (d, 1H), 6.66 (d, 1H), 5.58 (s, 1H), 5.41-5.21 (m, 1H). 4.50 (d, 1H). 3.99 (t. 2H), 3.56 (s, 3H), 3.54 (s, 2H). 2.96-2.81 (m, 1H). 2.76- 2.56 (m, 2H), 2.06-1.92 (m, 1H).

[0441] Step 3. Synthesis of (rac)-3-(3-methyl-2-oxo-4-(3-oxoazetidin-l-yl)-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0442] To a solution of (rac)-3-(4-(3-hydroxyazetidin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione (Step 3, 50.0 mg, 151 pmol) in dimethylsulfoxide (0.5 mL) was added 2-iodoxybenzoic acid (84.7 mg, 302 pmol) and the mixture stirred at 40 °C for 24 h. The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (3x 5 ml). The combined organics were washed with brine (3x 5 ml), dried (Na2SC>4) and concentrated under reduced pressure to give the title compound as a yellow solid (45.0 mg, 90%). LCMS m / z = 329 [M+H]+.

[0443] Intermediate 43. (rac)-3-(4-(4-oxopiperidin-l-yl)phenyl)piperidine-2, 6-dione.

[0444] Step 1. Synthesis of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-l ,4-dioxa-8- azaspiro[4.5 ] decane.

[0445] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (1.00 g, 2.24 mmol), l,4-dioxa-8-azaspiro[4.5] decane (353 mg. 2.46 mmol), RuPhos Pd G3 (225 mg, 269 pmol), cesium carbonate (2.19 g, 6.72 mmol) in dioxane (20 mL) was degassed and purged with nitrogen (3x) at 25°C and the mixture stirred at 100 °C for 16 h under nitrogen. The reaction mixture was diluted with w ater (150 mL) and extracted with ethyl acetate (3x 70 mL). The combined organics were washed with brine (2x 20 mL), dried (Na2SC>4) and concentrated underreduced pressure. The residue was purified by column chromatography (SiC>2, 0-10% EtOAc / PE) to afford the title compound as a yellow solid (930 mg, 82%).NMR (400MHz, DMSO-de): 7.68 (d, 1H), 7.49-7.30 (m, 12H), 6.96 (d, 2H), 6.51 (d, 1H), 5.37 (d, 4H), 3.91 (s, 4H), 3.31-3.28 (m, 4H), 1.74-1.66 (m, 4H).

[0446] Step 2. Synthesis of (rac)-3-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8- yl)phenyl)piperidine-2, 6-dione.

[0447] To a solution of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-l,4-dioxa-8- azaspiro[4.5]decane (Step 1 , 930 mg, 1.83 mmol) in THF (10 mL) was added Pd / C (292 mg, 274 pmol, 10% purity) and Pd(OH)2 (385 mg, 548 gmol, 20% purity) under nitrogen. The mixture was degassed and purged with hydrogen (3x) and the mixture stirred at 30 °C for 16 h under hydrogen atmosphere (50 Psi). The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was purified by column chromatography (S1O2. 0-100% EtOAc / PE) to afford the title compound as a white solid (350 mg, 58%).JH NMR (400MHz, DMSO-de): 10.76 (s, 1H), 7.03 (d, 2H), 6.90 (d, 2H), 3.90 (s, 4H), 3.72 (dd, 1H), 3.26-3.21 (m, 4H), 2.68-2.58 (m, 1H), 2.47-2.41 (m, 1H), 2.15-1.96 (m, 2H), 1.73-1.66 (m, 4H).

[0448] Step 3. Synthesis of (rac)-3-(4-(4-oxopiperidin-l-yl)phenyl)piperidine-2, 6-dione.

[0449] To a solution of (rac)-3-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine- 2, 6-dione (Step 2, 350 mg, 1.06 mmol) in tetrahydrofuran (5 mL) was added hydrochloride acid (3 M, 5 mL) and the mixture stirred at 70 °C for 5 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with aqueous solution sodium bicarbonate to pH=6~7 and extracted with dichloromethane (3x 30 mL). The combined organics was washed with brine (2x 20 mL), dried (Na2SC>4) and evaporated to diyness to afford the title compound as a yellow solid (150 mg, crude), 'l l NMR (400MHz, DMSO-de): 10.77 (s, 1H), 7.14-7.04 (m, 2H), 7.02-6.95 (m, 2H), 3.74 (dd, 1H). 3.58 (t. 4H), 2.70-2.58 (m, 1H), 2.44-2.38 (m. 4H), 2.21- 2.08 (m, 1H), 2.06-1.97 (m, 1H).

[0450] Intermediate 44. (rac)-3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine- 2, 6-dione hydrochloride.

[0451] Step 1. Synthesis of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5 ]undecane-3-carboxylate.

[0452] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (1.14 g, 4.48 mmol), cesium carbonate (2.92 g, 8.96 mmol) and RuPhos Pd G3 (375 mg, 448 pmol) in dioxane (30 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 100 °C for 16 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were washed with brine (3x 100 mL), dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 20% EtOAc / PE) to afford the title compound as a yellow solid (2.78 g, 76%). LCMS m / z = 620 [M+H]+.

[0453] Step 2. Synthesis of tert-butyl (rac)-9-(4-(2, 6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5 ]undecane-3-carboxylate.

[0454] To a solution of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (Step 1, 2.25 g, 3.63 mmol) in ethanol (15 mL) and ethyl acetate (30 mL) was added Pd / C (600 mg, 564 pmol, 10% purity) and Pd(OH)2 (600 mg, 427 pmol, 10% purity) under nitrogen and the suspension degassed and purged with hydrogen (3x). The reaction mixture was stirred under hydrogen (15 Psi) at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue purified by reverse-phase chromatography (35% MeCN / LLO (0.1% FA condition)) to give the title compound as a white solid (1.37 g. 76%). LCMS m / z = 442 [M+H]+.

[0455] Step 3. Synthesis of (rac)-3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine- 2, 6-dione hydrochloride.

[0456] To a solution of tert-buty l 9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (Step 2, 500 mg, 1.03 mmol) in DCM (5 mL) was added HCl / dioxane (4 M. 5 mL) and the mixture stirred at 20 °C for 5 h. The reaction mixture wasconcentrated under reduced pressure to give the title compound as a white solid (390 mg, crude). LCMS m / z = 342 [M+H]+.

[0457] Intermediate 45. (rac)-3-(l-oxo-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2- yl)piperidine-2, 6-dione.

[0458] Step 1. Synthesis of tert-butyl (rac)-2-(2-(2, 6-dioxopiperidin-3-yl)-l-oxoisoindolm- 5-yl)-2, 7-diazaspiro[3.5]nonane-7-carboxylate.

[0459] A mixture of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (1.00 g, 3.09 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1.40 g, 6.19 mmol), Ir(PPY)2(DtBBPY)PF6(56.6 mg, 61.9 pmol), NiBr2.glyme (47.7 mg, 155 pmol) and DABCO (624 mg, 5.57 mmol) in DMA (60 mL) was degassed and purged with argon and the mixture was stirred at 25 °C for 16 h irradiated with a 455 nm blue LED. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure. The residue was purified by prep-HPLC-M (35-65% MeCN) to afford the title compound as an off-white solid (860 mg, 54%). LCMS m / z = 469 [M+H]+.

[0460] Step 2. Synthesis of (rac)-3-(l-oxo-5-(2, 7-diazaspiro[3.5]nonan-2-yl)isoindolin-2- yl)piperidine-2, 6-dione trifluoroacetate.

[0461] To a solution of tert-butyl (rac)-2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)- 2,7-diazaspiro[3.5]nonane-7-carboxylate (Step 1, 360 mg, 700 pmol) in DCM (10.5 mL) was added trifluoroacetic acid (3.5 mL) and the mixture stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil (500 mg, crude) which was used without further purification. LCMS m / z = 369 [M+H]+.

[0462] Intermediate 46. (rac)-3-(l-oxo-6-(2,7-diazaspiro[3.5]nonan-7-yl)isoindolin-2- yl)piperidine-2, 6-dione trifluoroacetate.

[0463] The title compound was prepared from (rac)-3-(6-bromo-l-oxoisoindolin-2- yl)piperidine-2, 6-dione and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate using an analogous 2-step method as described for Intermediate 45. LCMS m / z = 369 [M+H]+.

[0464] Intermediate 47. (rac)-3-(l-oxo-5-(3,9-diazaspiro[5.5]undecan-3-yl)isoindolin-2- yl)piperidine-2, 6-dione hydrochloride.

[0465] Step 1. Synthesis of tert-butyl (rac)-9-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-3, 9-diazaspiro[5.5 ]undecane-3-carboxylate

[0466] The title compound was prepared as a yellow solid (600 mg, 39%) from (rac)-3-(5- bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione and tert-butyl 3,9-diazaspiro[5.5]undecane-3- carboxylate using an analogous method to that described for Intermediate 45, Step 1. LCMS m / z = 497 [M+H]+.

[0467] Step 2. Synthesis of (rac)-3-(l-oxo-5-(3,9-diazaspiro[5.5]undecan-3-yl)isoindolin-2- yl)piperidine-2.6-dione hydrochloride

[0468] The title compound was prepared as a yellow solid (270 mg) from tert-butyl (rac)-9- (2-(2,6-dioxopiperidin-3-yl)-l -oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 1) using an analogous method to that described for Intermediate 44, Step 3.

[0469] Intermediate 48. (rac)-3-(l-oxo-6-(3,9-diazaspiro[5.5]undecan-3-yl)isoindolin-2- yl)piperidine-2, 6-dione hydrochloride.Boc

[0470] Step 1. Synthesis of tert-butyl (rac)-9-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisomdolin- 5-yl)-3, 9-diazaspiro [5.5]undecane-3-carboxylate.

[0471] A mixture of tert-butyl 3.9-diazaspiro[5.5]undecane-3-carboxylate (1.02 g, 4.02 mmol), (rac)-3-(6-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (1.00 g, 3.09 mmol), PEPPSI-Pd- IHeptC (301 mg, 309 pmol), cesium carbonate (2.02 g, 6.19 mmol) in dioxane (20 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 100 °C for Ih under nitrogen. The residue was diluted with water (90 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were washed with brine (30 mL). dried (Na2SO4) and concentrated under reduced pressure. The residue was treated with DMF (10 mL) and the solids collected by fdtration. The fdter cake was triturated with DMF (10 mL) at 100 °C for 30 min. The combined fdtrates were purified by reverse-phase HPLC (0.1% FA condition) to give the title compound as a white solid (220 mg, 80%). LCMS m / z = 497 [M+H]+.

[0472] Step 2. Synthesis of (rac)-3-(l-oxo-6-(3,9-diazaspiro[5.5]undecan-3-yl)isoindolin-2- yl)piperidine-2, 6-dione hydrochloride.

[0473] To a solution of tert-butyl (rac)-9-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)- 3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 1, 700 mg, 1.41 mmol) in DCM (3 mL) was added HCl / dioxane (2 M, 1 mL) and the mixture stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid (500 mg, 81%) which was used without purification.

[0474] Intermediate 49. 3,4-bis(bromomethyl)-l-tosyl-lH-pyrrole.

[0475] Step 1. Synthesis of diethyl l-tosyl-lH-pyrrole-3,4-dicarboxylate.

[0476] To a solution of diethyl lH-pyrrole-3,4-dicarboxylate (10.0 g, 47.4 mmol) and NaOH (2.84 g, 71.0 mmol) in 1,2-dichloroethane (150 mL) was added 4-methylbenzenesulfonyl chloride (18.1 g, 94.7 mmol) in 1,2-dichloroethane (60 mL) dropwise at 0 °C and the reaction mixture stirred at 0-25 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (4x 100 mL). The combined organics were washed with brine (2x 80 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (10% EtOAc / PE) to give the title compound as a white solid (16.0 g, 92%). LCMS m / z = 366 [M+H]+.

[0477] Step 2. Synthesis of (1 -tosyl- IH-pyrr ole-3, 4-diyl)dimethanol.

[0478] To a solution of lithium aluminum hydride (4.99 g, 131 mmol) in tetrahydrofuran (200 mL) was added a solution of diethyl 1 -tosyl- lH-pyrrole-3.4-dicarboxylate (Step 1, 16.0 g, 43.8 mmol) in tetrahydrofuran (70 mL) dropwise at 0 °C and the reaction mixture stirred at 0 °C for 1 h. The reaction mixture was quenched by water (5 ml), 15% NaOH (5 mL) and water (15 mL) at 0 °C under nitrogen. The mixture was extracted with ethyl acetate (400 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (33% EtOAc / PE) to afford the title compound as a white solid (9.30 g, 76%). LCMS m / z = 282 [M+H]+.

[0479] Step 3. Synthesis of 3,4-bis(bromomethyl)-l-tosyl-lH-pyrrole.

[0480] To a solution of (l-tosyl-lH-pyrrole-3,4-diyl)dimethanol (Step 2, 8.30 g, 29.5 mmol) in DCM (100 mL) was added PBn (20.0 g, 73.8 mmol) at 0 °C and the reaction mixture stirred at 0-25 °C for 2 h. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution (100 mL) at 0 °C and extracted with DCM (4x 90 mL). The combined organics were washed with water (2x 40 mL), dried (Na2SC>4) and concentrated in vacuo. The residue was purified by silica gel chromatography (10% EtOAc / PE) to give the title compound as a white oil (9.00 g, 75%). LCMS m / z = 408 [M+H]+.

[0481] Intermediate 50. 7-cyclopentyl-2-((5-(5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0482] Step 1. Synthesis of 2-(4-methoxybenzyl)-5-tosyl- 1 , 2, 3, 5-tetrahydropyrrolo[ 3, 4- c] pyrrole.

[0483] To a solution of 3,4-bis(bromomethyl)-l -tosyl- IH-pyrrole (Intermediate 49, 8.80 g, 21.6 mmol) in THF (100 mL) was added DIPEA (8.38 g, 64.9 mmol) and 4- methoxybenzylamine (2.97 g, 21.6 mmol) and the reaction mixture stirred at 20 °C for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3x 30 mL). The combined organics were washed with brine (2x 20 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (25% EtOAc / PE) to give the title compound as a white solid (2.70 g, 33%). LCMS m / z = 383 [M+H]+.

[0484] Step 2. Synthesis of 2-(4-methoxybenzyl)-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole.

[0485] To a solution of 2-(4-methoxybenzyl)-5-tosyl-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole (Step 1, 2.70 g, 7.06 mmol) in THF (40 mL) was added sodium methoxide (5 M, 21.2 mL) and the reaction mixture stirred at 70 °C for 0.5 h. The reaction mixture was cooled to 25 °C, acidified with hydrochloride acid (3 N) till pH = 7 and concentrated in vacuo. The residue was purified by reverse phase (0.1% FA) followed by prep-HPLC-G (0-30% MeCN) and followed by reverse phase (0.1% NH4OH) to give the title compound as a yellow gum (1.05 g. 65%). LCMS m / z = 229 [M+H]+.

[0486] Step 3. Synthesis of 2-(4-methoxybenzyl)-5-(6-nitropyridin-3-yl)-l, 2,3,5- tetrahydropyrrolo[3, 4-c]pyrrole.

[0487] To a solution of 2-(4-methoxybenzyl)-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole (Step 2, 270 mg, 1.18 mmol) in THF (6 mL) was added sodium hydride (71.0 mg, 1.77 mmol, 60% purity) at 0 °C. 5-fluoro-2-nitropyridine (252 mg, 1.77 mmol) was added at 0 °C after 10 min and the reaction mixture stirred at 0-40 °C for 2.83 h. The reaction mixture was quenched with water (0. 1 mL), diluted with water (10 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were washed with brine (2x 15 mL), dried (Na2SC>4) and concentrated invacuo. The residue was purified by silica gel chromatography (66% EtOAc / PE) to give the title compound as a yellow solid (250 mg, 60%). LCMS m / z = 351 [M+H]+.

[0488] Step 4. Synthesis of 5-(5-(4-methoxybenzyl)-5, 6-dihydropyrrolo[3, 4-c]pyrrol-2(4H)- yl)pyridin-2-amine.

[0489] To a solution of 2-(4-methoxybenzyl)-5-(6-nitropyridin-3-yl)-l, 2,3,5- tetrahydropyrrolo[3,4-c]pyrrole (Step 3, 250 mg, 714 pmol) and ammonium chloride (191 mg, 3.57 mmol) in ethanol (10 mL) and water (3 mL) was added iron (199 mg, 3.57 mmol) at 80 °C and the reaction mixture stirred at 80 °C for 1 h. The reaction mixture was filtered and the filter cake was washed with methanol (20 mL). The filtrate was concentrated in vacuo and the residue purified by reverse phase (0.1% FA) to give the title compound as a brown solid (210 mg, 85%). LCMS m / z = 321 [M+H]+.

[0490] Step 5. Synthesis of7-cyclopentyl-2-((5-(5-(4-methoxybenzyl)-5.6- dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamide.

[0491] A mixture of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide (170 mg, 581 pmol,), 5-(5-(4-methoxybenzyl)-5,6-dihydropyrrolo[3,4-c]pyrrol- 2(4H)-yl)pyridin-2-amine (Step 4, 186 mg, 581 pmol), BrettPhos Pd Gi (53.5 mg, 58.1 pmol), Brettphos (31.2 mg, 58.1 pmol) and potassium acetate (114 mg, 1.16 mmol) in dioxane (8 mL) was stirred at 100 °C for 2 h. The reaction mixture was filtered and the filter cake washed with methanol (20 mL). The filtrate was concentrated in vacuo and the residue purified by reverse phase (0. 1% FA) to give the title compound as a yellow solid (180 mg, 54%). LCMS m / z = 577 [M+H]+.

[0492] Step 6. Synthesis of7-cyclopentyl-2-((5-(5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)- yl)pyridin-2-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0493] To a solution of 7-cyclopentyl-2-((5-(5-(4-methoxybenzyl)-5,6-dihydropyrrolo[3,4- c]pyrrol-2(4H)-yl)pyri din-2 -yl)amino)-N, N-dimethyl-7H-py rrolo[2,3-d]py rimidine-6- carboxamide (Step 5, 80.0 mg, 139 pmol) in methanol (2 mL) and 1,2-di chloroethane (0.5 mL) was added 1 -chloroethyl carbonochloridate (59.5 mg, 416 pmol) and the reaction mixture stirred at 70 °C for 1 h. The reaction mixture was quenched by water (0. 1 mL) and concentrated in vacuo and the residue purified by reverse phase (0. 1% TFA) to give the title compound as a yellow solid (17 mg, 21%). LCMS m / z = 457 [M+H]+.

[0494] Intermediate 51. (rac)-3-(4-(8-((6-aminopyridin-3-yl)methyl)-2,8- diazaspiro [4.5] decan- 2-yl)phenyl)piperidine-2, 6-dione.

[0495] Step 1. Synthesis of tert-butyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,8- diazaspiro[4.5 ]decane-8-carboxylate.

[0496] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (800 mg, 3.33 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (1.49 g, 3.33 mmol), RuPhos Pd G3 (278 mg, 333 pmol), cesium carbonate (3.25 g, 9.99 mmol) in dioxane (12 mL) was degassed and purged with nitrogen(x3) and the mixture stirred at 100 °C for 16 h under nitrogen. The reaction mixture was fdtered and concentrated under reduced pressure and the residue purified by column chromatography (SiCh, 0-20% EtOAc / PE) to give the title compound as a yellow solid (1.53 g, 72%). LCMS m / z = 606 [M+H]+.

[0497] Step 2. Synthesis of tert-butyl (rac)-2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2.8- diazaspiro[4.5 ]decane-8-carboxylate.

[0498] To a solution of tert-butyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,8- diazaspiro[4.5]decane-8-carboxylate (1.50 g, 2.48 mmol) in tetrahydrofuran (15 mL) was added Pd / C (264 mg, 248 pmol, 10% purity) and Pd(OH)2 (348 mg, 248 pmol, 10% purity) under nitrogen and the suspension degassed and purged with hydrogen (x3). The reaction mixture was stirred under hydrogen (15 Psi) at 25 °C for 16 h. The solids were removed by filtration and the filtrate concentrated under reduced pressure and the residue purified by column chromatography (SiC>2, 0-50% EtOAc / PE) to afford the title compound as a white solid (580 mg, 53%). LCMS m / z = 428 [M+H]+.

[0499] Step 3. Synthesis of (rac)-3-(4-(2,8-diazaspiro[4.5]decan-2-yl)phenyl)piperidine- 2. 6-dione trifluoroacetate.

[0500] To a solution of tert-butyl (rac)-2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,8- diazaspiro[4.5]decane-8-carboxylate (200 mg. 468 pmol) in DCM (4 mL) was added trifluoroacetic acid (2.00 mL) and the mixture stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a colourless oil (200 mg, 99% yield). LCMS m / z = 328 [M+H]+.

[0501] Step 4. Synthesis of (rac)-3-(4-(8-((6-aminopyridin-3-yl)methyl)-2, 8- diazaspiro[4.5 ]decan-2-yl)phenyl)piperidine-2, 6-dione.

[0502] To a solution of (rac)-3-(4-(2,8-diazaspiro[4.5]decan-2-yl)phenyl)piperidine-2,6- dione trifluoroacetate (150 mg, 340 pmol) and 6-aminonicotinaldehyde (46.0 mg, 374 pmol) in DMSO (2 mL) was added TEA (34.0 mg, 340 pmol) and acetic acid (20.0 mg, 340 pmol) and the mixture stirred at 25 °C for 0.5 h. STAB (216 mg, 1.02 mmol) was added and the mixture stirred at 25 °C for 48 h. The reaction mixture was filtered and concentrated under reduced pressure and the residue purified by prep-HPLC-0 (20-50% MeCN) to give the title compound as a white solid (50 mg, 33%). LCMS m / z = 434 [M+H]+.

[0503] Intermediate 52. tert-butyl 3,5-dihydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate.

[0504] Step 1. Synthesis of 2-(3, 4-dimethylbenzyl)-5-tosyl-l , 2, 3, 5-tetrahydropyrrolo[ 3.4- c]pyrrole.

[0505] The title compound was prepared as a yellow oil (4 g, 44%) from 3,4- bis(bromomethyl)-! -tosyl- IH-pyrrole (Intermediate 49) using an analogous method to that described for Intermediate 50, Step 1. LCMS m / z = 381 [M+H]+.

[0506] Step 2. Synthesis of 5-tosyl-l, 2, 3, 5-tetrahydropyrrolo[ 3, 4-c]pyrrole.

[0507] To a solution of 2-(3,4-dimethylbenzyl)-5-tosyl-l,2,3,5-tetrahydropyrrolo[3,4- c]pyrrole (Step 1, 3.50 g, 8.48 mmol) in methanol (50 mL) was added 1-chloroethyl carbonochloridate (2.43 g, 17.0 mmol) and the reaction mixture stirred at 70 °C for 1 h. The mixture was concentrated in vacuo and the residue purified by reverse phase (0.1% TFA) to give the title compound as a yellow solid (1.40 g, 94%). LCMS m / z = 263 [M+H]+.

[0508] Step 3. Synthesis of tert-butyl 5-tosyl-3,5-dihydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate.

[0509] To a solution of 5-tosyl-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole (Step 2, 1.45 g, 3.85 mmol) in dichloromethane (30 mL) was added triethylamine (780 mg, 7.71 mmol) and BOC2O (1.09 g, 5.01 mmol) and the reaction mixture stirred at 25 °C for 0.5 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were washed with brine (2x 20 mL), dried ( feSCL) and concentrated in vacuo. The residue was purified by silica gel chromatography (10% EtOAc / PE) to give the title compound as a white solid (1.30 g. 93% yield). LCMS m / z = 363 [M+H]+.

[0510] Step 4. Synthesis of tert-hutyl 3,5-dihydropyrrolo[3,4-c]pyrrole-2(lH)-carhoxylate.

[0511] To a solution of tert-butyl 5-tosyl-3,5-dihydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate (Step 3, 1.00 g, 2.76 mmol) in tetrahydrofuran (20 mL) was added sodium methylate (5 M, 5.52 mL) and the reaction mixture stirred at 70 °C for 0.5 h. The reaction mixture was cooled to 25 °C, acidified with formic acid till pH = 5~6 and concentrated under reduced pressure. The residue w as purified by reverse phase (0.1% FA) to give the title compound as a yellow solid (450 mg, 78%). LCMS m / z = 209 [M+H]+.

[0512] Intermediate 53. (rac)-3-(5-bromo-l-oxoisoindolin-2-yl)-l-((2...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I”):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, -(C(Ral)2)P-C*(=O)-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-, -NRa2-, and -C(=O)-;X2is selected from a covalent bond, CVC'wcycloalkyl optionally substituted with 1 to 4 Rc2, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb2;L3is selected from a covalent bond, -O-, -(C(Ra3)2)P-, -C2-C4alkynyl-, -(*C(Rdl)2)P-C(=O)-, -*O- (C(Rdl)2)P-C(=O)-, and -*N(Rb3)-(C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that if L1is not a covalent bond. X2is a covalent bond; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb4; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rc5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRb5;Ring B is selected from:t of attachment to L3and the other denotes the point of attachment to Y1if m is 1 or 2 or to W if m is 0;Y1are each independently selected from C(Re2)2, NRb7. and -*N(Rb7)-C(=O)-, wherein * denotes the point of attachment of Y1to W;R3is selected from H, D, and Ci-C4alkyl;W is CH or N;Ral, Ra2, and Ra3are each independently selected from H, D, halo, OH, Ci-C4alkyl, and monocyclic C3-C6 cycloalkyl;Rbl, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, Rb8, and Rb9are each independently selected from H, D, Ci- C4alkyl, and monocyclic Cs-Cecycloalkyl;Rcl, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7are each independently selected from D, halo, OH, CN, Ci- C4alkyl, or two Rcl, Rc2, Rc3, Rc4, Rc5, Rc6, or Rc7attached to the same atom, form a =0;Rdlare each independently selected from H, D, halo, OH, CN, N(Rb8)2, Ci-C4alkyl, and Ci- C4alkoxy;Reland Re2are each independently selected from H, D, halo, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl; or two Re2together with the carbon atom to which they are attached form a =0; m is 0, 1 , or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2; provided that when Ringthe compound of Formula (I”) is not:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and C(=O);X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl. wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond or -(C(Ra2)2)P-;X2is selected from a covalent bond, C3-C wcycloalkyl optionally substituted with 1 to 3 Rc2, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3.wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;L3is selected from a covalent bond, -O-, -C2-C4alkynyl-, -*O-(C(Rdl)2)P-C(=O)-, and -*N(Rb3)- (C(Rdl)2)P-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that if L3is not a covalent bond, X2is a covalent bond; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 7- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 7- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb5;Ring B is selected from:attachment to L3and the other denotes the point of attachment to W;R3is H;W is CH or N;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;independently selected from H, D, Ci-C4alkyl, and monocyclic C's-Cecycloalkyl:Rcl, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7are each independently selected from D. halo, OH, CN, Ci- C4alkyl, or two Rcl, Rc2, Rc3. Rc4, Rc5, Rc6. or Rc7attached to the same atom, form a =0;Rdlare each independently selected from H, D, halo, OH, CN, N(Rb8)2, Ci-C4alkyl, and Ci- C4alkoxy;Relare each independently selected from H, D, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic CNCecycloalkyk m is 0; n is 0, 1, 2, or 3; and p is 0, 1, or 2;3. The compound of claim 1. or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from:wherein “ * ” indicates the point of attachment to (Y1^.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is a covalent bond;X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond;X2is a covalent bond;L3is a covalent bond;Ring B is selected from:the Ring B moiety denotes the point of attachment to L3and the other denotes the point of attachment to W;R3is selected from H, D, and Ci-C4alkyl;Rbland Rb6are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc6, and Rc7are each independently selected from D, halo, OH, and CN;Relare each independently selected from H, D, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic CVCecycloalkyl; m is 0; and n is 0, 1, 2. or 3.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein no more than three of L1, L2, X2, and L3are simultaneously a covalent bond.

6. The compound of claim 1, wherein the compound is represented by Formula (IV’):or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein the compound is represented by Formula (IVb’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D. and Ci-C4alkyl;L1is a covalent bond;L3is -C2-C4alkynyl-,X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6-to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently- selected from O, S. N, and NRb4:Rb4and Rb6are each independently selected from H, D, and Ci-C4alkyl;Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; and n is 0, 1, 2, or 3.

8. The compound of claim 6, wherein the compound is represented by Formula (IVe’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci -Chalky I. wherein one or more H in Ci-Chalkyl can be replaced by D:L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, -(C(Ral)2)P-C(=O)*-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Ch-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently- selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O- and -C(=O)-;X2is selected from Ch-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;Rbl, Rb2, Rb4. Rb6, and Rb9are each independently selected from H, D, and Ci-C4alkyl;Rcl, Rc2, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN, or two Rc4attached to the same atom form a =0; n is 0, 1, 2, or 3; and p is 0 or 1.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci -Chalky I. wherein one or more H in Ci-Csalkyl can be replaced by D:X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4:R3is selected from H, D, and Ci-Csalkyl;Ralare each independently selected from H, D, and Ci-Csalkyl;Rb4, Rb6, and Rb9are each independently selected from H, D, and Ci-Csalkyl; andRc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN, or two Rc4attached to the same atom form a =0.

10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-Csalkyl can be replaced by D:L1is selected from a covalent bond and -0-;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S. N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O- and -C(=O)-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently- selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-Csalkyl;Ra2is independently selected from H, D, and Ci-Csalkyl;Rbl, Rb2, and Rb6are each independently selected from H, D, and Ci-Chalkyl; andRcl, Rc2, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN.

11. The compound of claim 6, wherein the compound is represented by Formula (IVF):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci alkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, -(C(Ral)2)P-C(=O)*-, -(C(Ral)2)P- N(Rb9)C*(=O)-, and -(C(Ral)2)P-C(=O)N*(Rb9)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O- and -C(=O)-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently- selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;Rbl, Rb2, Rb4, and Rb9are each independently selected from H, D, and CiXLialkyl;Rcl, Rc2, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH. and CN; n is 0, 1, 2, or 3; and p is 0 or 1.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D. and Ci-Csalkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, -O-, and -(C(Ral)2)P-C(=O)*-, wherein * denotes the point of attachment of L1to X1;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4. wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-Csalkyl;Ralis independently selected from H, D, and Ci-Csalkyl; andRb4are each independently selected from H. D, and Ci-Csalkyl.

13. The compound of claim 1, wherein the compound is represented by Formula (V’):or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13, wherein the compound is represented by Formula (Vb’):or a pharmaceutically acceptable salt thereof.

15. The compound of claim 13, wherein the compound is represented by Formula (Ve’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyhL1is selected from a covalent bond, -(C(Ral)2)P-, and -O-;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is a covalent bond or -(C(Ra2)2)P-;X2is a 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3. wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the a 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl:Rbl, Rb2, Rb4, and Rb6are each independently selected from H, D, and Ci-Cralkyl;Rcl, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, and CN; n is 0, 1, 2, or 3; and p is 1 or 2.

16. The compound of claim 1, wherein the compound is represented by Formula (IX‘):or a pharmaceutically acceptable salt thereof.

17. The compound of claim 16, wherein the compound is represented by Formula (IXb’):or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17, wherein the compound is represented by Formula (IXe’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb1;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-, and -NRa2-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are independently selected from H, D, and Ci-C4alkykRbij^b2,ancj j^b4are each indepen(ientiy selected from H, D, and Ci-C4alkyl;Rcl, Rc2, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, CN, and Ci- C4alkyl;R61are each independently selected from H, D, halo, and Ci-C4alkyl; or two Reltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;L1is a covalent bond;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rel, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-, and -NRa2-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2;R3is selected from H, D, and Ci-Csalkyl;Ra2are each independently selected from H, D, and Ci-Csalkyl;Rbland Rb2is independently selected from H, D, and Ci-Csalkyl; andRcl, Rc2, Rc3, Rc6, and Rc7are each independently selected from D, halo, OH, and CN;Relare each independently selected from H, D, halo, and Ci-Chalkyl; or two Reltogether with the carbon atom to which they are attached form a Ch-Cecycloalkyl.

20. The compound of claim 16, wherein the compound is represented by Formula (IXT) or Formula (IXg’):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;L1is selected from a covalent bond, -(C(Ral)2)P-, and -(C(Ral)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rcland 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rcl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently- selected from O, S, N, and NRbl;L2is selected from a covalent bond, -(C(Ra2)2)P-, -O(C(Ra2)2)P-, and -NRa2-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rc2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb2; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rc4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRb4;R3is selected from H, D, and Ci-C4alkyl;Raland Ra2are each independently selected from H, D, and Ci-C4alkyl;Rbipb2 and Rb4are each independently selected from H, D, and CiXUalkyl;Rcl, Rc2, Rc3, Rc4, Rc6, and Rc7are each independently selected from D, halo, OH, CN, and Ci- C4alkyl; n is 0, 1, 2. or 3; and p is 0, 1, or 2.

21. The compound of claim 1, wherein the compound is represented by Formula (XT):or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound is represented by Formula (XIII’):or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound is represented by Formula (XVT):or a pharmaceutically acceptable salt thereof.

24. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

26. A method of treating a disease or disorder mediated by cyclin-dependent kinase 4 (CDK4), comprising administering to a patient in need thereof an effective amount of the compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25.

27. The method of claim 26, wherein the disease or disorder mediated by CDK4 is cancer.

28. The method of claim 27, wherein the cancer is selected from bile duct cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer, esophageal cancer, gastric cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), and prostate cancer.

29. The method of claim 27, wherein the cancer is breast cancer.

30. The method of claim 27, wherein the cancer is prostate cancer.

31. The method of claim 27, wherein the cancer is a refractory’ cancer.

32. A compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25 for use in treating a cancer.

33. Use of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25 for the manufacture of a medicament for treating a cancer.

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