Degrader molecules targeting androgen receptor

Abstract

The present invention relates to heterobifunctional compounds which cause androgen receptor degradation and are useful, for example, in the treatment of cancer.

Description

[0001] DEGRADER MOLECULES TARGETING ANDROGEN RECEPTOR CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 63 / 600,190, filed November 17, 2023. The disclosure of the prior application is considered part of the disclosure of this application, and is incorporated in its entirety into this application. FIELD OF THE INVENTION The present invention relates to heterobifunctional compounds which cause degradation of androgen receptor and are useful in the treatment of cancer. BACKGROUND OF THE INVENTION Androgen receptor is a Type I class nuclear hormone transcription factor that may be important in the development of several different types of cancer, including prostate cancer and breast cancer. Inactive forms of androgen receptor are located in the cytoplasm, bound to heat shock proteins, which are responsible for proper protein folding, prevention of misfolding, and maintaining 3D protein structure during events of cellular stress. Androgen receptor is activated by the binding of androgen molecules, resulting in activation and transcription of a variety of downstream genes. Michmerhuizen, A.R.; npj Breast Cancer 6:47 (2020). Binding of androgen receptor may result in the activation of signaling pathways that have been implicated in cancer, including the PI3K / AKT pathway. Michmerhuizen, A.R.; npj Breast Cancer 6:47 (2020). Androgen receptor has been well characterized as a key driver for the development of prostate cancer in men. To this end, androgen deprivation therapy is a first line of therapy for men with metastatic prostate cancer. However, despite its effectiveness, resistance to androgen deprivation therapy is nearly universal. Because targeting androgen receptor as a monotherapy or in combination with other therapies has proven to be an effective clinical strategy in the treatment of prostate cancer, this strategy is increasingly being investigated for the treatment of additional types of cancer, such as, for example, bladder cancer, renal cell carcinoma, salivary gland cancer, colorectal cancer, esophageal cancer, pancreatic cancer, and stomach cancer. Hu, C.; Genomics 112(2):1926-1940 (2020). Data from multiple cancer models suggest that androgen receptor signaling may also be important in the development of breast cancer, glioblastoma, and additional tumor types exhibiting androgen receptor expression. Schweizer, M. T.; Cancers 9, 1–19 (2017). Most clinically used pharmaceutical agents are based upon small-molecule inhibition of protein function. However, alternative approaches that provide for protein degradation, rather than inhibition, also have the potential to provide clinical efficacy. Accordingly, targeted protein degradation through ubiquitination of protein targets has emerged as an effective strategy in drug discovery. Heterobifunctional small molecules, which simultaneously bind to target proteins and recruit an ubiquitin ligase (e.g., ubiquitin E3 ligase) have been shown to result in the target protein’s ubiquitination and degradation (Bondeson, D. P., et al. Nat Chem Biol. 201511(8):611- 617). There is a need for the development of new drugs, such as small molecules that can bind to both androgen receptor and ubiquitin E3 ligase to cause androgen receptor degradation, which are useful in the treatment of various diseases, including cancer. SUMMARY OF THE INVENTION The present invention is directed to a compound of Formula I: or a pharmaceutically are defined herein. The present invention is further directed to a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The present invention is further directed to a method of treating a disease or disorder in a patient in need of treatment, where the disease or disorder is an androgen receptor-related disease, comprising administering to the patient a therapeutically effective amount of a compound Formula I, or a pharmaceutically acceptable salt thereof. The present invention is further directed to a method of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The present invention also provides uses of the compounds described herein in the manufacture of a medicament for use in therapy. The present disclosure also provides the compounds described herein for use in therapy. DETAILED DESCRIPTION The present disclosure provides, inter alia, a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R1, R2, and R3are each independently selected from H, halo, SRA, ORA, C1-4alkyl, C2-4alkenyl, and C1-4 haloalkyl, wherein the C2-4 alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis H, C1-4 alkyl, or C1-4 haloalkyl; R4and R5are each independently selected from H, halo, SRA, ORA, C1-4alkyl, C2-4alkenyl, and C1-4haloalkyl, wherein the C2-4alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis H, C1-4 alkyl, or C1-4 haloalkyl; or R4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl group or a 3-6 membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from H, halo, ORA, C1-4 alkyl, and C1-4 haloalkyl; R6and R7are each independently selected from H, halo, C1-4alkyl, and C1-4haloalkyl; R8is H or C1-4 alkyl; Cy1is selected from C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C3-7cycloalkyl fused with phenyl to form a bicyclic ring, C4-7cycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, and 4-7 membered heterocycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C1-6alkyl-NRcRd, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; Cy2is absent or selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4- 7 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from 5-6 membered heteroaryl, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said 5-6 membered heteroaryl substituent of Cy2is optionally substituted with 1 or 2 substituents independently selected from halo and C1-6 alkyl; L is a linker; and Z is a binder of cereblon E3 ligase; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4haloalkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, or Rcand Rdtogether with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; each Ra3, Rb3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; and each Re, Re1, Re2, and Re3is independently selected from H, C1-4 alkyl, and CN. The present disclosure further provides a compound of Formula I:

[0002] or a pharmaceutically acceptable salt thereof, wherein: R1, R2, and R3are each independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; R4and R5are each independently selected from H, halo, ORA, C1-4 alkyl, and C1-4 haloalkyl, wherein RAis H, C1-4alkyl, or C1-4haloalkyl; or R4and R5together with the carbon atom to which they are attached form a C3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, ORA, C1-4alkyl, and C1-4haloalkyl; R6and R7are each independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; R8is H or C1-4 alkyl; Cy1is selected from C6-10aryl, C3-14cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C3-7cycloalkyl fused with phenyl to form a bicyclic ring, C3-7cycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, and 4-7 membered heterocycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C1-6 alkyl-NRcRd, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, 4- 7 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; L is a linker; and Z is a binder of cereblon E3 ligase; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rcand Rdtogether with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C2- 6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkylamino, di(C1-6alkyl)amino, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; and each Re, Re1, Re2, and Re3is independently selected from H, C1-4alkyl, and CN. In some embodiments, L is a linker having formula II: II wherein CyA, CyB, CyC, and CyDare each independently absent or independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa11, SRa11, C(O)Rb11, C(O)NRc11Rd11, C(O)ORa11, OC(O)Rb11, OC(O)NRc11Rd11, C(=NRe11)NRc11Rd11, NRc11C(=NRe11)NRc11Rd11, NRc11Rd11, NRc11C(O)Rb11, NRc11C(O)ORa11, NRc11C(O)NRc11Rd11, NRc11S(O)Rb11, NRc11S(O)2Rb11, NRc11S(O)2NRc11Rd11, S(O)Rb11, S(O)NRc11Rd11, S(O)2Rb11, and S(O)2NRc11Rd11; and LA, LB, and LCare each independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, -C(O)-, -O-, -O-(C1-6 alkylene)-, -NRc23-, -S-(C1-6 alkylene)-, -C(O)-(C1-6alkylene)-, -C(O)NRc23-(C1-6alkylene)-, -C(O)O-, -C(O)O-(C1-6alkylene)- , -OC(O)-(C1-6 alkylene)-, -OC(O)NRc23-(C1-6 alkylene)-, -NRc23-(C1-6 alkylene)-, -N-(C1-6 alkylene)-C(O)-, -NRc23C(O)-(C1-6 alkylene)-, -NRc23C(O)NRc23-(C1-6 alkylene)-, -NRc23C(O)O- (C1-6alkylene)-, -C(=NRe23)NRc23-(C1-6alkylene)-, -NRc23C(=NRe23)NRc23-(C1-6alkylene)-, - S(O)-(C1-6alkylene)-, -S(O)NRc23-(C1-6alkylene)-, -S(O)2-(C1-6alkylene)-, -NRc23S(O)2-(C1-6alkylene)-, -NRc23S(O)2NRc23-(C1-6 alkylene)-, and -S(O)2NRc23-(C1-6 alkylene)-, wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene is optionally substituted by 1, 2, or 3 substituents independently selected from C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, halo, and OH; each Ra11, Rb11, Rc11, and Rd11is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl of Ra11, Rb11, Rc11, and Rd11is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; Rc23is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6alkylamino, di(C1-6alkyl)amino, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; and Re23is independently selected from H, C1-4 alkyl, and CN. In some embodiments, at least one of LA, LB, LC, CyA, CyB, CyC, and CyDis not absent In some embodiments, R1, R2, and R3are each independently selected from H, F, methyl, and trifluoromethyl. In some embodiments, R1, R2, and R3are each F. In some embodiments, R1, R2, and R3are each selected from methyl and trifluoromethyl. In some embodiments, R1, R2, and R3are each H. In some embodiments, R4and R5are each independently selected from H, halo, SRA, ORA, C1-4alkyl, C2-4alkenyl, and C1-4haloalkyl, wherein the C2-4alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis H, C1-4alkyl, or C1-4 haloalkyl. In some embodiments, R4and R5are each independently selected from halo, SRA, ORA, C1-4 alkyl, C2-4 alkenyl, and C1-4 haloalkyl, wherein the C2-4 alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis H, C1-4alkyl, or C1-4 haloalkyl. In some embodiments, R4and R5are each independently selected from H, SRA, C1- 4 alkyl, and C2-4 alkenyl, wherein the C2-4 alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis H, C1-4alkyl, or C1-4haloalkyl. In some embodiments, R4and R5are each independently selected from SRA, C1-4 alkyl, and C2-4 alkenyl, wherein the C2-4 alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis H, C1-4alkyl, or C1-4haloalkyl. In some embodiments, R4and R5are each independently selected from H, SRA, C1-4alkyl, and C2-4 alkenyl, wherein the C2-4alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis C1-4 alkyl. In some embodiments, R4and R5are each independently selected from SRA, C1-4 alkyl, and C2-4 alkenyl, wherein the C2-4 alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis C1-4 alkyl. In some embodiments, R4and R5are each independently selected from OH, C1-4 alkyl, and C1-4haloalkyl; or R4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, ORA, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R4and R5are each independently selected from OH, C1-4alkyl, and C1-4haloalkyl. In some embodiments, R4and R5are each C1-4alkyl. In some embodiments, R4and R5are each methyl. In some embodiments, R4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, ORA, C1-2 alkyl, and C1-2 haloalkyl. In some embodiments, R4and R5together with the carbon atom to which they are attached form a C3-6 cycloalkyl group optionally substituted with 1 or 2 substituents independently selected from halo and C1-2alkyl. In some embodiments, R4and R5together with the carbon atom to which they are attached form a C3-6 cycloalkyl group optionally substituted with 1 or 2 fluoro. In some embodiments, R6and R7are each H. In some embodiments, R8is H. In some embodiments, Cy1is selected from C3-14 cycloalkyl, 5-14 membered heteroaryl, C4-7 cycloalkyl fused with phenyl to form a bicyclic ring, and 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C1-6 alkyl-NRcRd, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd. In some embodiments, Cy1is selected from C3-6 cycloalkyl, 5-6 membered heteroaryl, C5-6 cycloalkyl fused with phenyl to form a bicyclic ring, and 5-6 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6alkyl, C1-6haloalkyl, CN, C1-6alkyl-NRcRd, C(O)NRcRd, and NRcRd. In some embodiments, Cy1is C3-6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from halo, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Cy1is C3-6 cycloalkyl. In some embodiments, Cy1is cyclopropyl or cyclobutyl. In some embodiments, Cy1is cyclopropyl. In some embodiments, Cy1is 5-6 membered heteroaryl, optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, and C(O)NRcRd. In some embodiments, Cy1is 5 membered heteroaryl, optionally substituted by 1 or 2 substituents independently selected from halo, C1-6alkyl, and C(O)NRcRd. In some embodiments, Cy1is pyrazolyl or pyrrolyl, optionally substituted with C(O)NRcRd. In some embodiments, Cy1is pyrazolyl. In some embodiments, Cy1is pyrazolyl, pyrrolyl, or isoxazolyl, each optionally substituted with C(O)NRcRd. In some embodiments, Cy1is isoxazolyl. In some embodiments, Cy1is pyrazolyl, pyrrolyl, or isoxazolyl. In some embodiments, Cy1is C5-6 cycloalkyl fused with phenyl to form a bicyclic ring, optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, CN, C1-6 alkyl-NRcRd, and NRcRd. In some embodiments, Cy1is cyclopentyl fused with phenyl to form a bicyclic ring, optionally substituted by methyl, CN, Cl, F, -CH2NHRd, and NH2. In some embodiments, Cy1is 5-6 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, Cy1is dihydrobenzofuran, optionally substituted by 1 or 2 substituents independently selected from chloro and methyl. In some embodiments, Cy1is dihydrobenzofuran substituted by 1 chloro. In some embodiments, Cy2is selected from C6-10aryl and 5-10 membered heteroaryl, optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, Cy2is phenyl or 5-6 membered heteroaryl, optionally substituted by 1 or 2 substituents selected from halo and C1-6alkyl. In some embodiments, Cy2is C6-10aryl optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Cy2is phenyl optionally substituted with 1 or 2 substituents each independently selected from C1-6 alkyl. In some embodiments, Cy2is phenyl, methylphenyl, methylchlorophenyl, or dimethylphenyl. In some embodiments, Cy2is phenyl optionally substituted with 1 or 2 substituents selected from methyl and chloro. In some embodiments, Cy2is 5-10 membered heteroaryl optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Cy2is 6 membered heteroaryl optionally substituted by 1 or 2 substituents each independently selected from C1-6alkyl. In some embodiments, Cy2is pyridinyl or methylpyridinyl. In some embodiments, Cy2is pyridinyl or pyrimidinyl, each optionally substituted by 1 or 2 substituents each independently selected from C1-6 alkyl. In some embodiments, Cy2is pyridinyl or pyrimidinyl, each optionally substituted with methyl. In some embodiments, Cy2is pyridinyl, methylpyridinyl, or pyrimidinyl. In some embodiments, Cy2is pyridinyl or pyrimidinyl, each optionally substituted with 1 or 2 methyl groups. In some embodiments, Cy2is C3-7 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, Cy2is bicyclo[1.1.1]pentyl. In some embodiments, CyA, CyB, CyC, and CyDare each independently absent or independently selected from C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyA, CyB, CyC, and CyDare each independently absent or independently selected from phenyl, 5-9 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyAis absent or selected from C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyAis absent or selected from phenyl, 5-9 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyAis absent or selected from phenyl, 5-6 membered heteroaryl, and 6-9 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyAis absent or selected from phenyl, pyrazolyl, pyridinyl, indazolyl, and piperidinyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyAis phenyl or pyridinyl, each optionally substituted by halo or methyl. In some embodiments, CyAis absent. In some embodiments, CyAis selected from C6-10 aryl, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyAis selected from phenyl, 5-9 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyAis selected from phenyl, 5-6 membered heteroaryl, and 6-9 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyAis selected from phenyl, pyrazolyl, pyridinyl, indazolyl, and piperidinyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyAis phenyl or pyridinyl, each optionally substituted by1 or 2 substituents selected from halo and methyl. In some embodiments, CyAis absent or selected from phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indazolyl, 2,3-dihydrobenzofuranyl, and piperidinyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyAis selected from phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indazolyl, 2,3-dihydrobenzofuranyl, and piperidinyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyBis absent or selected from C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyBis absent or selected from phenyl, 5-9 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyBis absent or selected from phenyl, 5 membered heteroaryl, and 6-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyBis absent or selected from phenyl, pyrazolyl, piperazinyl, piperidinyl, and azasprio[3.3]heptanyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyBis piperidinyl or piperazinyl. In some embodiments, CyBis absent. In some embodiments, CyBis selected from C6-10 aryl, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyBis selected from phenyl, 5-9 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyBis selected from phenyl, 5 membered heteroaryl, and 6-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyBis selected from phenyl, pyrazolyl, piperazinyl, piperidinyl, and azasprio[3.3]heptanyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyBis absent or selected from phenyl, cyclohexyl, pyrazolyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, 2-azasprio[3.3]heptanyl, diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 6- azaspiro[3.4]octanyl, and octahydropyrrolo[3,2-b]pyrrolyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyBis selected from phenyl, cyclohexyl, pyrazolyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, 2- azasprio[3.3]heptanyl, diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2- azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 6-azaspiro[3.4]octanyl, and octahydropyrrolo[3,2- b]pyrrolyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyBis absent or selected from phenyl, cyclohexyl, pyrazolyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, azasprio[3.3]heptanyl, diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 6- azaspiro[3.4]octanyl, and octahydropyrrolo[3,2-b]pyrrolyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyBis selected from phenyl, cyclohexyl, pyrazolyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, azasprio[3.3]heptanyl, diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2- azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 6-azaspiro[3.4]octanyl, and octahydropyrrolo[3,2- b]pyrrolyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyBis absent or selected from phenyl, cyclohexyl, pyrazolyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, azasprio[3.3]heptanyl, diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, and azaspiro[3.5]nonanyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyBis selected from phenyl, cyclohexyl, pyrazolyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, azasprio[3.3]heptanyl, diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, and azaspiro[3.5]nonanyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyBis 2-azasprio[3.3]heptanyl. In some embodiments, CyCis absent or selected from C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyCis absent or selected from phenyl, 5-9 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyCis absent or selected from 9 membered heteroaryl and 4-6 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyCis absent or selected from indazolyl, piperidinyl, piperazinyl, azetidinyl, and pyrrolidinyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyCis piperidinyl or piperazinyl. In some embodiments, CyCis absent. In some embodiments, CyCis piperidinyl, piperazinyl, or cyclobutyl. In some embodiments, CyCis cyclobutyl. In some embodiments, CyCis selected from C6-10aryl, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyCis selected from phenyl, 5-9 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyCis selected from 9 membered heteroaryl and 4-6 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyCis selected from indazolyl, piperidinyl, piperazinyl, azetidinyl, and pyrrolidinyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyDis absent or selected from C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyDis absent or selected from phenyl, 5-9 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyDis absent or 5-6 membered heterocycloalkyl optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyDis absent or selected from piperazinyl and piperidinyl. In some embodiments, CyDis absent or 6 membered heterocycloalkyl. In some embodiments, CyDis absent or selected from piperazinyl and piperidinyl. In some embodiments, CyDis absent or piperazinyl. In some embodiments, CyDis absent. In some embodiments, CyDis selected from C6-10 aryl, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6alkyl. In some embodiments, CyDis selected from phenyl, 5-9 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyDis 5-6 membered heterocycloalkyl optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl. In some embodiments, CyDis selected from piperazinyl and piperidinyl. In some embodiments, CyDis 6-membered heterocycloalkyl. In some embodiments, LA, LB, and LCare each independently absent or independently selected from C1-6 alkylene, -C(O)-, -O-, -O-(C1-6 alkylene)-, -NRc23-, -C(O)NRc23-, -C(O)-(C1-6 alkylene)-, -C(O)NRc23-(C1-6 alkylene)-, and -NRc23C(O)-. In some embodiments, LA, LB, and LCare each independently absent or independently selected from C1-6 alkylene, -C(O)-, -O-, -O-(C1-6 alkylene)-, -C(O)-(C1-6 alkylene)-, -C(O)NRc23- (C1-6 alkylene)-, and -NRc23C(O)-. In some embodiments, Rc23is selected from H and C1-6 alkyl. In some embodiments, LA, LB, and LCare each independently absent or independently selected from methylene, -C(O)-, -O-, -O-(C1-3 alkylene)-, -C(O)CH2-, -C(O)NH-(C1-3 alkylene). In some embodiments, LAis absent or selected from methylene, -C(O)-, -C(O)CH2-, - C(O)NH-(C1-3alkylene)-, and -NHC(O)-. In some embodiments, LAis absent or selected from methylene and -NHC(O)-. In some embodiments, LAis absent. In some embodiments, LAis selected from methylene and -NHC(O)-. In some embodiments, LAis methylene. In some embodiments, LAis -NHC(O)-. In some embodiments, LAis absent or selected from methylene, -C(O)-, -C(O)CH2-, - C(O)NH-(C1-3 alkylene)-, -NHC(O)-, -CH(CH3)-, -CH(CH(CH3)2)-, -CH(CH2CH2CH3)-, - CH(CH2OCH3)-, and -O-. In some embodiments, LAis selected from methylene, -C(O)-, - C(O)CH2-, -C(O)NH-(C1-3alkylene)-, -NHC(O)-, -CH(CH3)-, -CH(CH(CH3)2)-, - CH(CH2CH2CH3)-, -CH(CH2OCH3)-, and -O-. In some embodiments, LBis absent or selected from methylene, -C(O)-, -ORa3-, - C(O)CH2-, -C(O)NH-(C1-3alkylene)-, -NHC(O)-, and -O-(C1-6alkylene)-. In some embodiments, LBis absent or methylene. In some embodiments, LBis absent. In some embodiments, LBis selected from methylene, -C(O)-, -ORa3-, -C(O)CH2-, -C(O)NH-(C1-3 alkylene)-, and -NHC(O)-. In some embodiments, LBis methylene. In some embodiments, LBis selected from -C(O)-, -ORa3- , -C(O)CH2-, -C(O)NH-(C1-3alkylene)-, and -NHC(O)-. In some embodiments, LBis absent or selected from methylene, -C(O)-, -ORa3-, - C(O)CH2-, -C(O)NH-(C1-3 alkylene)-, -NHC(O)-, -O-, -O-(C1-6 alkylene)-, and -NRc23-(C1-6 alkylene)-. In some embodiments, LBis selected from methylene, -C(O)-, -ORa3-, -C(O)CH2-, - C(O)NH-(C1-3 alkylene)-, -NHC(O)-, -O-, -O-(C1-6 alkylene)-, and -NRc23-(C1-6 alkylene)-. In some embodiments, LCis absent or selected from methylene, -O-, -C(O)CH2-, and - NHC(O)-. In some embodiments, LCis absent or methylene. In some embodiments, LCis absent. In some embodiments, LCis methylene. Ubiquitin ligase binding moieties and linkers are known and well-described in the art, for example: Bondeson, D. P., et al. Nat Chem Biol. 201511(8):611-617; An S, et al. EBioMedicine 201836:553-562; Paiva S-L. et al, Curr. Op. in Chem. Bio. 2010, 50:111-119; and International Patent Application Publication No. WO 2017 / 197056, each of which is incorporated by reference in its entirety. For example, thalidomide derivatives, such as lenalidomide or pomalidomide, have been reported to recruit potential protein substrates to cereblon, for example: WO 2019 / 099926 and WO 2020 / 023851. In some embodiments, Z is a cereblon E3 ubiquitin ligase binding moiety. In some embodiments, Z is an E3 ubiquitin ligase binding moiety that binds to cereblon. In some embodiments, Z comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide. In some embodiments, Z is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof. In some embodiments, Z is a group having Formula III: wherein ring A is C6-10 aryl, 5-14 membered heteroaryl, C3-7 cycloalkyl fused with phenyl to form a bicyclic ring, 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 alkyl, and C1-6 haloalkyl; L1is absent, CH2, NH, or O; and W is CH or N, wherein the wavy line represents the point of attachment to group L. In some embodiments, ring A is 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, optionally substituted with halo. In some embodiments, ring A is phenyl or pyridinyl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, ring A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6alkyl, and C1-6haloalkyl. In some embodiments, ring A is pyrimidinyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6alkyl, and C1-6haloalkyl. In some embodiments, ring A is phenyl or pyridinyl, each optionally substituted with halo. In some embodiments, ring A is phenyl optionally substituted with halo. In some embodiments, ring A is pyrimidinyl optionally substituted with halo. In some embodiments, ring A is 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, optionally substituted with halo. In some embodiments, ring A is phenyl or pyridinyl. In some embodiments, ring A is phenyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, L1is absent or NH. In some embodiments, L1is absent. In some embodiments, L1is NH. In some embodiments, W is CH. In some embodiments, W is N. In some embodiments, Z is selected from: ;

[0003] ; ; ; 5 Cl, C(CH3), and N; and each V is independently selected from CH, C(CH3), and N. In some embodiments, Z is selected from:

[0004] O UV NH; ; N; and each V is independently selected from CH and N. In some embodiments, Z is selected from: O . A: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has Formula IVA: , In some embodiments, the compound has Formula IVB:

[0005] In some embodiments, Cy1is selected from C3-6 cycloalkyl, 5-6 membered heteroaryl, C5-6 cycloalkyl fused with phenyl to form a bicyclic ring, and 5-6 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, C1-6 alkyl-NRcRd, C(O)NRcRd, and NRcRd; Cy2is selected from C6-10aryl and 5-10 membered heteroaryl, optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; CyA, CyB, CyC, and CyDare each independently absent or independently selected from C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl; and LA, LB, and LCare each independently absent or independently selected from C1-6 alkylene, -C(O)-, -O-, -O-(C1-6alkylene)-, -C(O)-(C1-6alkylene)-, -C(O)NRc23-(C1-6alkylene)-, and -NRc23C(O)-. In some embodiments, the compound has Formula IB: IB or a pharmaceutically acceptable salt thereof; wherein R41is selected from halo, C1-4 alkyl, and C1-4 haloalkyl; and p is 0, 1, or 2. In some embodiments, R41is halo. In some embodiments, R41is chloro. In some embodiments, p is 0 or 1. In some embodiments, R41is chloro and p is 0 or 1. In some embodiments, the compound has Formula IB-1: In some embodiments, the compound has Formula IC: or a pharmaceutically acceptable salt thereof; wherein X1and X2are each independently selected from CH and N; each R42and R43is independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl; and q and r are each independently 0, 1, or 2. In some embodiments, X is CH. In some embodiments, X is N. In some embodiments, R42and R43are each independently C1-4 alkyl. In some embodiments, R42and R43are methyl. In some embodiments, the compound has Formula ID: wherein X is CH or N; and R44is selected from H, halo, C1-4alkyl, and C1-4haloalkyl. In some embodiments, X is CH. In some embodiments, X is N. In some embodiments, R44is halo. In some embodiments, R44is chloro. In some embodiments, the compound has Formula ID-1: In some embodiments, the compound has Formula IE: or a pharmaceutically acceptable salt thereof; wherein each R42and R43is independently selected from halo, C1-4alkyl, and C1-4haloalkyl; X1and X2are each independently selected from CH and N; and q and r are each independently 0, 1, or 2. In some embodiments, the compound has Formula IF: or a wherein each is independently selected from halo, C1-4alkyl, and C1-4haloalkyl; and q is 0, 1, or 2. In some embodiments, the compound has Formula IG: IG, or a pharmaceutically acceptable salt thereof; wherein each R42and R43is independently selected from halo, C1-4alkyl, and C1-4haloalkyl; X1and X2are each independently selected from CH and N; and q and r are each independently 0, 1, or 2. In some embodiments, the compound is selected from: (2R)-5-chloro-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)phenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide; (2R)-5-chloro-6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazine-1-carbonyl)phenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide; (2R)-5-chloro-6-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide; (1S,2S)-2-(4'-(1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-[1,1'-biphenyl]-4-yl)-N- ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)cyclopropane-1- carboxamide; (1S,2S)-2-[4-[4-[1-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]-1-piperidyl]-2-oxo-ethyl]pyrazol-3-yl]phenyl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide hydrochloride; 5-(4-((1-(2-(4-(3-chloro-4'-((1S,2S)-2-(3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)propanoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)acetyl)piperidin- 4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; (1S,2S)-2-(2'-chloro-4'-(1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-[1,1'- biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)cyclopropane-1-carboxamide; (1S,2S)-2-[4-[4-[1-[2-[3-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]azetidin-1-yl]-2-oxo-ethyl]pyrazol-4-yl]phenyl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; 3-chloro-N-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)ethoxy)propyl)-4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-carboxamide; 3-chloro-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4- carboxamide; 2-chloro-N-[1-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]-4-piperidyl]-4-[4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methylcarbamoyl]cyclopropyl]phenyl]benzamide; (1S,2S)-2-[4-[1-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]-1-piperidyl]-2-oxo-ethyl]-3-methyl-indazol-5-yl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-[4-[4-[1-[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]-2-oxo-ethyl]azetidin-3-yl]pyrazol-4-yl]phenyl]phenyl]-N-[[3-(2,2,2-trifluoro- 1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-[4-[4-[1-[[1-[2-[4- [2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl] piperazin-1-yl]-2-oxo-ethyl] -4-piperidyl]methyl]pyrazol-4-yl]phenyl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-[4-[4-[1-[2-[(3S)-3-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo- isoindolin-5-yl]-4-piperidyl] oxy]pyrrolidin-1-yl]-2-oxo-ethyl]pyrazol-4-yl]phenyl]phenyl]-N-[[3- (2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-[4-[1-[4-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]piperidine-1-carbonyl]phenyl]pyrazol-4-yl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-(4'-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)cyclopropane-1-carboxamide; (1S,2S)-2-(4'-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)cyclopropane-1-carboxamide; 1-[3-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]methyl]phenyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[3-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]piperazin-1-yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4'-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)oxy)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)-1,4-diazepan-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((1'-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-[4,4'- bipiperidin]-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)pyrrolidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4-(6-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)piperidin-1-yl)methyl)pyridin-3-yl)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(2'-chloro-4'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(3'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-(1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)piperidin-1-yl)ethyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-1-piperidyl]methyl]-3,5-difluoro-phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4-(1-(1'-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-[1,4'- bipiperidin]-4-yl)-3-methyl-1H-indazol-5-yl)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[6-[[1-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]- 4-piperidyl]oxy]-3-pyridyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin- 1-yl]methyl]-1-piperidyl]ethoxy]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(3'-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)ethoxy)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[1-[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin- 1-yl]-1-piperidyl]-1-methyl-ethyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[5-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-1-piperidyl]methyl]pyrazin-2-yl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[5-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-1-piperidyl]methyl]-2-pyridyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(3'-chloro-4'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[5-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl] piperazin-1- yl]-2-pyridyl]oxy]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-2-oxo-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]cyclohexoxy]-3-pyridyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[1-[[1-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]-4-piperidyl]methyl]pyrazol-4-yl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[6-[[1-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]- 4-piperidyl]amino]-3-pyridyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[2-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-2,7- diazaspiro[3.5]nonan-7-yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)azepan-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-1,4-diazepan-1- yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[8-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]- 3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4'-((3-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-(((1S,4S)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N- ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4- carboxamide; 1-(4'-(((1R,4R)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N- ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4- carboxamide; 1-(4'-((3-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)azetidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[2-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]- 2,6-diazaspiro[3.3]heptan-6-yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-3,3-difluoro-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-4-methyl-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[6-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-2,6- diazaspiro[3.3]heptan-2-yl]-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro- 1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4'-(((2S,4S)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)-2-methylpiperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-(((2S,4R)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)-2-methylpiperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-(((2R,4R)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)-2-methylpiperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-(1-(2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-3- methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)piperidin-1-yl)methyl)-3- methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-1-yl]-1- piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-1-yl]methyl]phenyl]-2-methyl- phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4- carboxamide; 1-[4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1- piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(2-chloro-4'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)piperidin-1-yl)methyl)-5-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[3-[4-[[(3S)-3-[[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]amino]pyrrolidin-1-yl]methyl]phenyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[6-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]oxy]-3-pyridyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[6-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]methyl]piperazin-1-yl]-3-pyridyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(3-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,4-dimethylphenyl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[3-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-1-piperidyl]methyl]phenyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[4-[[4-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]piperazin-1-yl]methyl]phenyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[2-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]methyl]piperazin-1-yl]-4-pyridyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(3-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)pyridin-4-yl)-2,4-dimethylphenyl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[3-[6-[4-[[2-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-2,6- diazaspiro[3.3]heptan-6-yl]methyl]-1-piperidyl]-3-pyridyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[6-[6-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl]-3-pyridyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]methyl]-1-piperidyl]pyrimidin-5-yl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; (2S)-5-chloro-6-[4-[[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-1-yl]methyl]phenyl]-N- [[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl] -2,3-dihydrobenzofuran-2- carboxamide; (2R)-5-chloro-6-(4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide; (2R)-5-chloro-2-cyano-6-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-2,3-dihydro-1H-indene-2-carboxamide; 5-chloro-2-cyano-6-(4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)-2,3-dihydro-1H-indene-2-carboxamide; (2R)-5-chloro-2-cyano-6-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin- 5-yl]piperazin-1-yl]methyl]phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]indane-2-carboxamide; (1S,2S)-2-[4-[6-[[1-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]- 4-piperidyl]methyl]-4-piperidyl]pyrazol-4-yl]amino]-3-pyridyl]phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-(4-(6-((1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-3-yl)phenyl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)cyclopropane-1-carboxamide; 1-[4-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]-1-piperidyl]methyl]- phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[(3S)-2,6-dioxo-3-piperidyl]phenyl]piperazin-1-yl]methyl]phenyl]-2- methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole- 4-carboxamide; 1-[4-[4-[[4-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]piperazin-1-yl]methyl]phenyl]- 2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-(4'-((4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperazin-1-yl)methyl)-3-methyl- [1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)- 1H-pyrazole-4-carboxamide; 1-(4'-((4-(5-((2,6-dioxopiperidin-3-yl)amino)pyrazin-2-yl)piperidin-1-yl)methyl)-3- methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperazin-1- yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]-1-piperidyl]methyl]phenyl]-2- methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole- 4-carboxamide; 1-[4-[4-[[4-[5-(2,6-dioxo-3-piperidyl)-4-fluoro-2-pyridyl]piperazin-1-yl]methyl]phenyl]- 2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1- piperidyl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]piperazin-1- yl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperazin-1- yl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[4-[(2,4-dioxohexahydropyrimidin-1-yl)methyl]-2-fluoro-phenyl]piperazin-1- yl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperazin-1- yl]methyl]phenyl]-2-pyridyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-(5-(5-((4-(5-((2,6-dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)piperazin-1- yl)methyl)pyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(5-(5-((4-(5-((2,6-dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)piperazin-1- yl)methyl)-3-fluoropyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[5-[4-[[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]carbamoyl]-3-fluoro-phenyl]piperazin-1- yl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]carbamoyl]-3-fluoro-phenyl]piperazin-1- yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]pyrazole-4-carboxamide hydrochloride; 1-[4-[4-[[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]carbamoyl]-3-fluoro-phenyl]-1- piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; (S)-N-((3-(1,1-difluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1-(5-(4-((4- (4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-1-yl)methyl)phenyl)pyridin-2- yl)-1H-pyrazole-4-carboxamide; 1-[5-[4-[[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]carbamoyl]-3-fluoro-phenyl]-1-piperidyl]- methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]-1-piperidyl]methyl]phenyl]- pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole- 4-carboxamide; 1-(4-((4-(5-(2,6-dioxopiperidin-3-yl)-3-fluoropyridin-2-yl)piperazin-1-yl)methyl)-2- methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H- pyrazole-4-carboxamide; 1-[4-[[1-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]-4-piperidyl]methyl]-2-methyl- phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4- carboxamide; 1-[4-[[2-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]-2-azaspiro[3.5]nonan-7-yl]oxy]-2- methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole- 4-carboxamide; and 3-[5-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperazin-1- yl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]isoxazole-5-carboxamide, or a pharmaceutically acceptable salt of any of the aforementioned. In some embodiments, the compound is selected from: 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-6- yl)piperazin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrimidin-6- yl)piperazin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperidin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(2-fluoro-4-((6-(3-fluoro-4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)phenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-6- yl)piperidin-1-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-6- yl)piperidin-1-yl)ethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorobenzo[d]isoxazol-6- yl)piperidin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; N-((3-(3,3-difluoro-2-methylbutan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(4-(1-(6-(4- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)ethyl)-2- fluorophenyl)-4-methylpyrimidin-2-yl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro- [3.3]heptan-2-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(3-fluoro-2-methylbut- 3-en-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; N-((3-(1-(1,1-difluoroethyl)cyclopropyl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(4-((6-(4- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)methyl)-2- fluorophenyl)-4-methylpyrimidin-2-yl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1- (trifluoromethyl)cyclobutyl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-[5-[4-[1-[6-[4-(2,4-dioxohexahydropyrimidin-1-yl)-3-fluoro-phenyl]-2- azaspiro[3.3]heptan-2-yl]ethyl]-2-fluoro-phenyl]-4,6-dimethyl-pyrimidin-2-yl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]isoxazole-5-carboxamide; 3-[5-[5-[1-[6-[4- (2,4-dioxohexahydropyrimidin-1-yl)-3-fluoro-phenyl]-2- azaspiro[3.3]heptan-2-yl]ethyl]-3-fluoro-2-pyridyl]-4-methyl-pyrimidin-2-yl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2,5- difluorophenyl)piperidin-1-yl)methyl)phenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperazin-1-yl)-7- azaspiro[3.5]nonan-7-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 1-(4-((2-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluoropyridin-2-yl)-2- azaspiro[3.5]nonan-7-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4-((2-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)-2-azaspiro[3.5]nonan-7- yl)oxy)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[[2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-2-pyridyl]-2- azaspiro[3.5]nonan-7-yl]oxy]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; (R)-1-(4-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-3- methylpiperazin-1-yl)cyclohexyl)oxy)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; (S)-1-(4-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-3- methylpiperazin-1-yl)cyclohexyl)oxy)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(3-(2-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylpyridin-2-yl)-2- azaspiro[3.5]nonan-7-yl)-5-fluoro-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)- 1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 3-(3-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)phenyl)bicyclo[1.1.1]pentan-1-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(2- (methylthio)propan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(2-fluoro-4-((6-(3-fluoro-4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)piperazin-1- yl)methyl)piperidin-1-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2,3-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2,5-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-5-methylphenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluoro-6-methylpyridin-2-yl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)methyl)-3-fluoropyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)pyrazin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; (R)-3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6-yl)- 3-methylpiperazin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-6- yl)piperazin-1-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperidin-1-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)ethyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrimidin-6- yl)piperazin-1-yl)ethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-3-fluoropyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)-2,3-dihydrobenzofuran-6-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)pyridin-2-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; N-((3-(3,3-difluoro-2-methylbutan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(4-(1-(6-(4- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)propyl)-2- fluorophenyl)-4-methylpyrimidin-2-yl)isoxazole-5-carboxamide; 3-(5-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)-2,3-dihydro-1H-inden-5-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)propyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((2-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-6- azaspiro[3.4]octan-6-yl)methyl)-3-fluoropyridin-2-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-4'-methyl-[2,5'-bipyrimidin]-2'-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; N-((3-(3,3-difluoro-2-methylbutan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(1-(6-(4-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)ethyl)-4'-methyl- [2,5'-bipyrimidin]-2'-yl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)butyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)-2-methylpropyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3- (1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)-2-methoxyethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3- (1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(7-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)-5-oxa-2-azaspiro[3.4]octan-2-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; N-((3-(tert-butyl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(4-((6-(4-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)methyl)-2- fluorophenyl)-4-methylpyrimidin-2-yl)isoxazole-5-carboxamide; N-((3-(3,3-difluoro-2-methylbutan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(5-(1-(6-(4- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)ethyl)-3- fluoropyridin-2-yl)-4-methylpyrimidin-2-yl)isoxazole-5-carboxamide; 3-(5-(5-(1-(6-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-3-fluoropyridin-2-yl)-4-methylpyrimidin-2-yl)-N-((3-(3,3- difluoro-2-methylbutan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(1-(6-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-4'-methyl-[2,5'-bipyrimidin]-2'-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 1-(4-((4-(4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyridin-2-yl)piperazin-1- yl)cyclohexyl)oxy)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((((3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5- difluorophenyl)cyclobutyl)methyl)amino)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(((3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5- difluorophenyl)cyclobutyl)amino)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)piperazin-1- yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenoxy)piperidin-1- yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenoxy)azetidin-1- yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenoxy)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(3-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrimidin-6- yl)piperazin-1-yl)methyl)phenyl)bicyclo[1.1.1]pentan-1-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(3-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)methyl)phenyl)bicyclo[1.1.1]pentan-1-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)phenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylphenyl)piperidin-1- yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylphenyl)piperidin-1- yl)methyl)piperidin-1-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-1- yl)methyl)piperidin-1-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(((3aS*,6aS*)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3- fluorophenyl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)- N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5- carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-[2,5'-bipyrimidin]-2'-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; or a pharmaceutically acceptable salt of any of the aforementioned. Intermediates Also provided herein is a compound of Formula (A1): or a pharmaceutically acceptable salt thereof, wherein constituent members are defined herein. Compounds of Formula (A1) can be useful intermediates in the preparation of compounds of Formula (I). Moreover, compounds of Formula (A1) can be useful as binders of androgen receptor. In some embodiments, provided herein is a compound of Formula (A1), or a pharmaceutically acceptable salt thereof, wherein: R1, R2, and R3are each independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; R4and R5are each independently selected from H, halo, ORA, C1-4alkyl, and C1-4haloalkyl, wherein RAis H, C1-4 alkyl, or C1-4 haloalkyl; or R4and R5together with the carbon atom to which they are attached form a C3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from H, halo, ORA, C1-4 alkyl, and C1-4 haloalkyl; R6and R7are each independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; R8is H or C1-4alkyl; Cy1is selected from C6-10aryl, C3-14cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C3-7 cycloalkyl fused with phenyl to form a bicyclic ring, C4-7 cycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, and 4-7 membered heterocycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C1-6alkyl-NRcRd, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; A is selected from H, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4alkyl, C1-4haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, from halo, C1-4alkyl, C1-4haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C2- 6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; and each Re, Re1, Re2, and Re3is independently selected from H, C1-4alkyl, and CN. In some embodiments, R1, R2, and R3are each independently selected from H, F, methyl, and trifluoromethyl. In some embodiments, R1, R2, and R3are each F. In some embodiments, R4and R5are each C1-4 alkyl. In some embodiments, R4and R5are each methyl. In some embodiments, R6and R7are each H. In some embodiments, R8is H. In some embodiments, Cy1is selected from C3-6 cycloalkyl, 5-6 membered heteroaryl, C5-6 cycloalkyl fused with phenyl to form a bicyclic ring, and 5-6 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, C1-6 alkyl-NRcRd, C(O)NRcRd, and NRcRd. In some embodiments, Cy1is cyclopropyl, pyrazolyl, or isoxazolyl. In some embodiments, Cy1is cyclopropyl or pyrazolyl. In some embodiments, Cy1is C5-6cycloalkyl fused with phenyl to form a bicyclic ring, optionally substituted by 1 or 2 substituents independently selected from halo, C1-6alkyl, CN, C1-6alkyl-NRcRd, and NRcRd. In some embodiments, Cy1is cyclopentyl fused with phenyl to form a bicyclic ring, optionally substituted by CN, Cl, and F. In some embodiments, Cy1is 5-6 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6alkyl. In some embodiments, Cy1is dihydrobenzofuran, optionally substituted by 1, 2, or 3 substituents independently selected from Cl and I. In some embodiments, A is selected from H, C6-10aryl and 5-10 membered heteroaryl, optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, A is phenyl or 5-6 membered heteroaryl, optionally substituted by 1, 2, or 3 substituents selected from halo and C1-6 alkyl. In some embodiments, A is phenyl optionally substituted by 1, 2, or 3 substituents selected from methyl, Br, and Cl. In some embodiments, A is H. In some embodiments, the compound of Formula (A1) is selected from: 5-chloro-6-iodo-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]- 2,3-dihydrobenzofuran-2-carboxamide; (1S,2S)-2-(4-bromophenyl)-N-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-3- yl]methyl]cyclopropanecarboxamide; 1-(4-bromo-2-methyl-phenyl)-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]pyrazole-4-carboxamide; 1-(3-bromo-2,4-dimethyl-phenyl)-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4-bromo-5-chloro-2-methyl-phenyl)-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 5,6-dichloro-2-cyano-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]indane-2-carboxamide; 1-[5-(4-formylphenyl)pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(5-bromo-2-pyridyl)-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-(4-formylphenyl)-2-pyridyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; and 1-(5-(3-fluoro-5-formylpyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt of any of the aforementioned. In some embodiments, the compound of Formula (A1) is 3-(4-methylpyrimidin-2-yl)-N- ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide, or a pharmaceutically acceptable salt thereof. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl. At various places in the present specification various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “pyridinyl,” “pyridyl,” or “a pyridine ring” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4- yl ring. The term “n-membered,” where “n” is an integer, typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is “n”. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5- membered heteroaryl ring, and pyridyl is an example of a 6-membered heteroaryl ring. At various places in the present specification, variables defining divalent linking groups may be described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -C(O)NRc23-(C1-6 alkylene)- includes both -C(O)NRc23-(C1-6alkylene)- and -(C1-6alkylene)-NRc23(O)C- and is intended to disclose each of the forms individually. For compounds of the invention in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. As used herein, the term “substituted” means that a hydrogen atom is replaced by a non- hydrogen group. It is to be understood that substitution at a given atom is limited by valency. As used herein, the term “C1-j,” where i and j are integers, employed in combination with a chemical group, designates a range of the number of carbon atoms in the chemical group with i-j defining the range. For example, C1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. As used herein, the term “alkyl,” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl. The term “alkylene” refers to a linking alkyl group. As used herein, “alkenyl,” employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. The term “alkenylene” refers to a linking alkenyl group. As used herein, “alkynyl,” employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms. The term “alkynylene” refers to a linking alkynyl group. As used herein, “halo” or “halogen”, employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl. As used herein, the term “haloalkyl,” employed alone or in combination with other terms, refers to an alkyl group having up to the full valency of halogen atom substituents, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like. As used herein, the term “alkoxy,” employed alone or in combination with other terms, refers to a group of formula -O-alkyl. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. As used herein, “haloalkoxy,” employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example haloalkoxy group is -OCF3. As used herein, “amino,” employed alone or in combination with other terms, refers to NH2. As used herein, the term “alkylamino,” employed alone or in combination with other terms, refers to a group of formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Example alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like. As used herein, the term “dialkylamino,” employed alone or in combination with other terms, refers to a group of formula -N(alkyl)2. Example dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms. As used herein, the term “cycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclohexene, cyclohexane, and the like, or pyrido derivatives of cyclopentane or cyclohexane. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes. The term “cycloalkyl” also includes bridgehead cycloalkyl groups (e.g., non- aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane and the like). In some embodiments, the cycloalkyl group has 3 to 14 ring members, 3 to 10 ring members, 3 to 7 ring members, 3 to 6 ring members, or 5 to 6 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is a C3-7 monocyclic cycloalkyl group. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein, the term “cycloalkylalkyl,” employed alone or in combination with other terms, refers to a group of formula cycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl portion is methylene. In some embodiments, the cycloalkyl portion has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl portion is monocyclic. In some embodiments, the cycloalkyl portion is a C3-7 monocyclic cycloalkyl group. As used herein, the term “heterocycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the non-aromatic heterocycloalkyl ring, for example, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom, such as azaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). In some embodiments, the heterocycloalkyl group has 4 to 14 ring-forming atoms, 3 to 10 ring- forming atoms, 4 to 10 ring-forming atoms, 3 to 8 ring forming atoms, 4 to 7 ring forming atoms, 3 to 6 ring forming atoms, or 5 to 6 ring forming atoms. In some embodiments, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, an N- oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl portion is a C2-7 monocyclic heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, tetrahydropyran ring, tetrahyropyridine, azetidine ring, or tetrahydrofuran ring. As used herein, the term “heterocycloalkylalkyl,” employed alone or in combination with other terms, refers to a group of formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl portion is methylene. In some embodiments, the heterocycloalkyl portion has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl portion is monocyclic. In some embodiments, the heterocycloalkyl portion is a C2-7 monocyclic heterocycloalkyl group. As used herein, the term “aryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl. As used herein, the term “arylalkyl,” employed alone or in combination with other terms, refers to a group of formula aryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl portion is methylene. In some embodiments, the aryl portion is phenyl. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is benzyl. As used herein, the term “heteroaryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, having one or more heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a monocyclic or a bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. Example heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl or the like. The carbon atoms or heteroatoms in the ring(s) of the heteroaryl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized, provided the aromatic nature of the ring is preserved. In some embodiments, the heteroaryl group has from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 5 carbon atoms, from 1 to 5 carbon atoms, or from 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 5 to 14 ring-forming atoms, 5 to 10 ring-forming atoms, 5 to 9 ring-forming atoms, or 5 to 6 ring forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms. As used herein, the term “heteroarylalkyl,” employed alone or in combination with other terms, refers to a group of formula heteroaryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl portion is methylene. In some embodiments, the heteroaryl portion is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl portion has 5 to 10 carbon atoms. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention may be isolated as a mixture of isomers or as separated isomeric forms. Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the invention also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the invention include at least one deuterium atom. The term “compound,” as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified. All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or can be isolated. In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. Synthesis Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H or13C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography. Compounds of the invention can be prepared according to numerous preparatory routes known in the literature. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.

[0006] Scheme 1 of formula 1-A, many of which are commercially available or can be made via routes known to one skill in the art, can be coupled with compounds of Formula 1-B to provide compounds of formula 1-C, wherein X1is halogen. The coupling can be performed under peptide coupling conditions (e.g., EDCI, HOBt, and DIPEA; or HATU, DIPEA). Compounds of formula 1-C can be coupled with compounds of formula 1-D to provide compounds of formula 1-E (e.g., the compounds of the disclosure) under the appropriate palladium cross-coupling conditions, for example, in the presence of Pd(dppf)Cl2. Methods of Use Compounds of the present disclosure can bind to both androgen receptor and ubiquitin E3 ligase to cause androgen receptor degradation, which is useful in the treatment of various diseases including cancer. In some embodiments, the compounds provided herein can degrade androgen receptor in a cell, which comprises contacting the cell with the compound or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, provided herein is a method for degrading androgen receptor in a patient, where the method comprises administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt or a stereoisomer thereof. By “degrading androgen receptor,” it is meant rendering the androgen receptor inactive by, for example, altering its structure or breaking down androgen receptor into multiple peptide or amino acid fragments. The compounds of the invention are useful in the treatment of various diseases associated with abnormal expression or activity of androgen receptor. For example, the compounds of the invention are useful in the treatment of cancer. In some embodiments, the cancers treatable according to the present invention include prostate cancer, breast cancer, glioblastoma, bladder cancer, renal cell carcinoma, salivary gland cancer, colorectal cancer, esophageal cancer, pancreatic cancer, and stomach cancer. In some embodiments, the cancers treatable according to the present invention include quamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor or teratocarcinomas. In certain embodiments, the disease to be treated is cancer, e.g., prostate cancer, or Kennedy's Disease. In some embodiments, the cancers treatable according to the present invention include hematopoietic malignancies such as leukemia and lymphoma. Example lymphomas include Hodgkin’s or non-Hodgkin’s lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkett's lymphoma. Example leukemias include acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML). Other cancers treatable by the administration of the compounds of the invention include liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer, intestinal cancers, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. In some embodiments, the cancer treatable by administration of the compounds of the invention is multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colon cancer, or melanoma. As used herein, the term “cell” is meant to refer 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. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” androgen receptor or “contacting” a cell with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having androgen receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing androgen receptor. As used herein, the term “individual” or “patient,” used interchangeably, refers to mammals, and particularly humans. As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and / or symptomatology). As used herein the term “preventing” or “prevention” refers to preventing the disease in an individual who may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease. As used herein, the term “reducing” is with respect to the level in the patient prior to administration. More specifically, when a biomarker or symptom is reduced in a patient, the reduction is with respect to the level of or severity of the biomarker or symptom in the patient prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. Combination Therapy One or more additional pharmaceutical agents or treatment methods such as, for example, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, immunotherapies, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM- CSF, etc.), and / or kinase (tyrosine or serine / threonine), epigenetic or signal transduction inhibitors can be used in combination with the compounds of the present invention. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. Suitable agents for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies or radiation therapy. Compounds of this invention may be effective in combination with anti- hormonal agents for treatment of breast cancer and other tumors. Suitable examples are anti- estrogen agents including but not limited to tamoxifen and toremifene, aromatase inhibitors including but not limited to letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g. prednisone), progestins (e.g. megastrol acetate), and estrogen receptor antagonists (e.g. fulvestrant). Suitable anti-hormone agents used for treatment of prostate and other cancers may also be combined with compounds of the present invention. These include anti-androgens including but not limited to flutamide, bicalutamide, and nilutamide, luteinizing hormone- releasing hormone (LHRH) analogs including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g. degarelix), androgen receptor blockers (e.g. enzalutamide) and agents that inhibit androgen production (e.g. abiraterone). Angiogenesis inhibitors may be efficacious in some tumors in combination with FGFR inhibitors. These include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept. Inhibitors of VEGFR kinases and other anti-angiogenesis inhibitors include but are not limited to sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethio- phosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. Other anti-cancer agent(s) include antibody therapeutics to costimulatory molecules such as CTLA-4, 4-1BB, PD-1, and PD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Exemplary cancer immunotherapy antibodies include pembrolizumab, alemtuzumab, ipilimumab, nivolumab, ofatumumab and rituximab. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety. EXAMPLES Abbreviations: ACN: acetonitrile; Boc: tert-butyloxycarbonyl; BOP: benzotriazole-1-yl-oxy-tris- (dimethylamino)-phosphoniumhexafluorophosphate; Cbz: benzyloxycarbonyl; DBA: dibenzylideneacetone; DCE: 1,2-dichloroethane; DIEA: N,N-diisopropylethylamine; DiBAl-H: diisobutylaluminum hydride; DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide; DPPF: 1,1’--bis(diphenylphosphino)ferrocene; DTBPF: 1,1’-Bis(di-tert-butylphosphino)ferrocene; EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; FA: formic acid; HATU: 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide; hexafluorophosphate; HPLC: high performance liquid chromatography or high-pressure liquid chromatography; HOBt: 1-Hydroxybenzotriazole hydrate; h: hour(s); LCMS: liquid chromatography mass spectrometer; 2-MeTHF: 2-methyltetrahydrofuran; min: minute(s); MTBE: tert-butyl methyl ether; NCS: N-chlorosuccinimide; NMI: N-methyl imidazole; NMP: N-methyl pyrrolidinone; SFC: supercritical fluid chromatography; TLC: thin layer chromatography; T3P: n- propylphosphonic anhydride; T4P: n-butylphosphonic anhydride; TCFH: chloro-N,N,N′,N′- tetramethylformamidinium hexafluorophosphate; TFA: trifluoroacetic acid Example 1: Synthesis of Intermediate 1 Step – (1a) To a solution of 3,3,3-trifluoro-2,2-dimethyl-propanoic acid (220.0 g, 1.4 mol, 1.0 equiv) and tert-butyl-N-aminocarbamate (204.8 g, 1.5 mol, 1.1 equiv) in DMF (2000 mL) was added HATU (589.4 g, 1.5 mol, 1.1 equiv) and DIEA (728.5 g, 5.6 mol, 981.9 mL, 4.0 equiv). The mixture was stirred at 20°C for 16 h. The reaction mixture was diluted with water (3 L). The solids were collected by vacuum filtration and the filter cake was washed with water and dried under vacuum to afford 1a. LCMS: [M-1] = 269.1;1H NMR (400 MHz, DMSO-d6) δ = 9.75 (br s, 1H), 8.81 (s, 1H), 1.46 - 1.29 (m, 15H). Step B – Synthesis of 3,3,3-trifluoro-2,2-dimethyl-propanehydrazide hydrochloride (1b) Intermediate 1a (210.0 g, 777.0 mmol, 1.0 equiv) was added to a solution of 4M HCl in dioxane (1500 mL). The mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 1b, which was used without further purification.1H NMR (400 MHz, DMSO-d6) δ = 11.37 (br s, 1H), 1.42 (s, 6H). Step C – benzyl ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)carbamate (1c) A mixture of 1b (75.0 g, 363.0 mmol, 1.0 equiv), benzyl-N-(2-amino-2-imino- ethyl)carbamate hydrochloride (88.4 g, 363.0 mmol, 1.0 equiv), NaOH (30.4 g, 762.3 mmol, 2.1 equiv) in 2-MeTHF (1500.0 mL) was three-fold degassed and purged with nitrogen and then the mixture was stirred at 110°C for 16 h under an atmosphere of nitrogen. The reaction mixture was cooled to ambient temperature, diluted with water (500 mL) and extracted with ethyl acetate (2 x 500 m). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane : methanol=100 / 1 to 30 / 1). The crude product was triturated with MTBE (200 mL) at 20°C for 20 min and the solids were collected by vacuum filtration to afford 1c. LCMS [M+1] =343.2;1H NMR (400 MHz, DMSO- d6) δ 13.85 (br s, 1H), 7.92 - 7.84 (m, 1H), 7.41 - 7.27 (m, 5H), 5.05 (s, 2H), 4.31 (br d, J = 3.4 Hz, 2H), 1.52 (br s, 6H). Step D – Synthesis of [3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methanamine (Intermediate 1) To a mixture of 1c (70.0 g, 204.4 mmol, 1.0 equiv) in acetic acid (500.0 mL) was added HBr (300.0 mL, 33% purity). The mixture was stirred at 20°C for 1 h and then concentrated under reduced pressure. The residue was two-fold triturated with MTBE (500 mL) at 20°C for 20 min and the solids were collected by vacuum filtration to afford Intermediate 1 (Int 1). LCMS [M- 1] = 207.2;1H NMR (400 MHz, DMSO-d6) δ = 8.39 (s, 3H), 4.22 - 4.06 (m, 2H), 1.59 (s, 6H). The hydrochloride salt of Intermediate 1 was prepared in the following manner. Either the hydrobromide and hydrochloride salts of Intermediate 1 can be used for the preparation of the following examples.

[0007] Step A – Synthesis of tert-butyl ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)carbamate (1d) A solution of 3,3,3-trifluoro-2,2-dimethyl-propanehydrazide hydrochloride (3.80 g, 18.9 mmol, 1.0 equiv.), tert-butyl (2-amino-2-iminoethyl)carbamate (1.90 g, 18.9 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (30 mL) was treated with NaOH (2.20 g, 56.9 mmol, 3.0 equiv.). The mixture was stirred at 100 °C for 48 h, cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 90% ethyl acetate / petroleum ether) to afford 1d. LCMS [M+1] = 309.1 Step B – Synthesis of [3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methanamine hydrochloride (Int 1•HCl) A mixture of tert-butyl ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)carbamate (1.20 g, 3.9 mmol, 1.0 equiv.) in methanol (3 mL) was cooled to 0 °C and treated with 4 M HCl in dioxane (15 mL). The mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated under reduced pressure to afford Int 1 as the hydrochloride salt, which was used without further purification. LCMS [M+1] = 209.11H NMR (400 MHz, DMSO-d6) δ = 8.62 (br s, 3H), 4.15-4.11 (m, 2H), 1.59 (s, 6H). Example 2: Synthesis of Intermediate 2

[0008] To a solution of methyl 2-hydroxy-4-iodo-benzoate (15.0 g, 53.9 mmol, 1.0 equiv) in acetic acid (150.0 mL), was added NCS (7.20 g, 53.9 mmol, 1.0 equiv) and the mixture was stirred at 110°C for 1 h, cooled to 20°C and poured into 1000 mL water. The solids were collected by vacuum filtration. The filter cake was triturated with MTBE and the solids were collected by vacuum filtration to afford 2a. LCMS [M-1] - =310.9;1H NMR (400 MHz, CHLOROFORM-d) δ 10.59 (br s, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 3.97 (s, 3H). Step B – Synthesis of 4-chloro-2-(hydroxymethyl)-5-iodo-phenol (2b) DIBAL-H (1.0 M, 57.4 mL, 3.0 equiv) was added to the solution of 2a (5.9 g, 19.1 mmol, 1.0 equiv) in toluene (60.0 mL) at -5°C. The mixture was stirred at 20°C for 4 h. The mixture was quenched with saturated aqueous HCl (1M, 100.0 mL) and extracted with ethyl acetate (3 x 60.0 mL). The combined ethyl acetate was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization from MTBE (30 mL) to give 2b. LCMS [M+1] = 284.9;1H NMR (400 MHz, DMSO-d6) δ 9.97 (br s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 5.17 (br s, 1H), 4.40 (s, 2H). Step C – Synthesis of ethyl 2-[4-chloro-2-(hydroxymethyl)-5-iodo-phenoxy]acetate (2c) A mixture of 2b (2.8 g, 9.8 mmol, 1.0 equiv) and K2CO3(1.5 g, 10.8 mmol, 1.1 equiv) in DMF (24.0 mL) at 20°C was treated with ethyl 2-bromoacetate (1.6 g, 9.8 mmol, 1.0 mL, 1.0 equiv). The mixture was stirred at 20 °C for 4 h, diluted with water 15 mL and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=80:1 to 20:1) to afford 2c.1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.40 (s, 1H), 5.27 (t, J = 5.6 Hz, 1H), 4.87 (s, 2H), 4.47 (d, J = 5.6 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H). Step D – Synthesis of ethyl 2-[4-chloro-2-(chloromethyl)-5-iodo-phenoxy]acetate (2d) SOCl2(5.5 g, 46.4 mmol, 3.3 mL, 4.0 equiv) was added to the solution of 2c (4.3 g, 11.6 mmol, 1.0 equiv) in toluene (40 mL) at 20°C and stirred at 20°C for 1 h. The mixture was diluted with water 15 mL at 0°C and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (2 x 15 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=80:1 to 20:1) to give 2d.1H NMR (400 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.55 (s, 1H), 4.96 (s, 2H), 4.70 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H). Step E – Synthesis of ethyl 5-chloro-6-iodo-2,3-dihydrobenzofuran-2-carboxylate (2e) NaH (380.9 mg, 9.5 mmol, 60.0% purity, 1.3 equiv) was added to the solution of 2d (2.8 g, 7.3 mmol, 1.0 equiv) in NMP (25.0 mL) at 0°C. The solution was stirred at 20°C for 3 h. The mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic portions were washed with brine (50 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 80:1 to 20:1) to afford 2e.1H NMR (400 MHz, Methanol-d4) δ 7.34 (s, 2H), 5.29 (dd, J = 6.2, 10.6 Hz, 1H), 4.24 (q, J = 7.2 Hz, 2H), 3.56 (dd, J = 10.6, 16.4 Hz, 1H), 3.27 (br d, J = 6.2 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H). Step F – Synthesis of 5-chloro-6-iodo-2,3-dihydrobenzofuran-2-carboxylic acid (2f) A solution of 2e (3.0 g, 8.5 mmol, 1.0 equiv) in tetrahydrofuran (15.0 mL) was treated with a solution of LiOH•H2O (642.7 mg, 15.3 mmol, 1.8 equiv) in water (15.0 mL) at 20°C. The mixture was stirred at 20°C for 2 h. The pH if the mixture was adjusted to pH=6 with citric acid. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate was washed with brine (15 mL), dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=10 / 1 to 5 / 1) to afford 2f. LCMS [M-1] = 322.9;1H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.41 (s, 1H), 5.28 (dd, J = 6.0 , 10.8 Hz, 1H), 3.52 (dd, J = 10.8, 16.8 Hz, 1H), 3.21 (dd, J = 6.0, 16.8 Hz, 1H) Step G – Synthesis of 5-chloro-6-iodo-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]-2,3-dihydrobenzofuran-2-carboxamide (Intermediate 2) T3P (10.7 g, 16.9 mmol, 10.0 mL, 50% in DMF, 2.5 equiv) was added in one portion to a solution of DIEA (7.0 g, 54.2 mmol, 9.4 mL, 8.0 equiv), 2f (2.2 g, 6.7 mmol, 1.0 equiv), Intermediate 1 (2.5 g, 8.8 mmol, 1.3 equiv) in DMF (27.0 mL) at 20°C. Then the solution was stirred at 20 °C for 2 h. The mixture was quenched by water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL) dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane:methanol =100 / 1 to 5 / 1) to afford Intermediate 2 (Int 2). LCMS [M+1] =515.0, 517.0;1H NMR (400 MHz, DMSO- d6) δ 13.82 (s, 1H), 8.82 (br t, J = 5.6 Hz, 1H), 7.45 (s, 1H), 7.37 (s, 1H), 5.28 (dd, J = 6.0, 10.4 Hz, 1H), 4.50 - 4.42 (m, 1H), 4.33 (dd, J = 5.6, 16.0 Hz, 1H), 3.49 (dd, J = 10.4, 16.8 Hz, 1H), 3.24 (dd, J = 5.6, 16.4 Hz, 1H), 1.50 (s, 6H) Example 3: Synthesis of Intermediate 3 Step A – Synthesis of (1S,2S)-2-(4-bromophenyl)-N-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-3-yl]methyl]cyclopropanecarboxamide (Intermediate 3) To a solution of (1S,2S)-2-(4-bromophenyl)cyclopropanecarboxylic acid (160.0 mg, 663.7 µmol, 1 equiv) and Intermediate 1 (268.6 mg, 929.2 umol, 1.4 equiv) in DMF (1.6 mL) was added DIEA (686.2 mg, 5.3 mmol, 924.8 μL, 8.0 equiv), followed by T3P (844.7 mg, 1.3 mmol, 789.4 μL, 50% in DMF, 2.0 equiv). The solution was stirred at 25°C for 16 h. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether: ethyl acetate = 1:1) to afford Intermediate 3 (Int 3). LCMS: [M+1] = 433.2, 435.2;1H NMR (400 MHz, CHLOROFORM-d) δ 7.38 (d, J = 8.4 Hz, 2H), 7.03 (br s, 1H), 6.92 (d, J = 8.4 Hz, 2H), 4.69 - 4.43 (m, 2H), 2.56 - 2.39 (m, 1H), 1.71 - 1.62 (m, 2H), 1.62 - 1.57 (m, 6H), 1.31 - 1.20 (m, 2H) Example 4: Synthesis of Intermediate 4 – To a solution of methyl 1H-pyrazole-4-carboxylate (125.0 g, 991.1 mmol, 1.0 equiv) and 1-fluoro-2-methyl-4-nitrobenzene (153.7 g, 991.2 mmol, 1 equiv) in acetonitrile (1.5 L) was added potassium carbonate (232.8 g, 1.6 mol, 1.7 equiv). The reaction mixture was stirred at 80°C for 16 h. Water (2 L) was added to the reaction mixture and the solids were collected by vacuum filtration and dried under reduced pressure to afford 4a.1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.35 (s, 1H), 8.25 - 8.13 (m, 2H), 7.75 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H), 2.39 (s, 3H). Step B – Synthesis of methyl 1-(4-amino-2-methylphenyl)pyrazole-4-carboxylate (4b) To a mixture of 4a (110.0 g, 421.0 mmol, 1 equiv) in methanol (2 L) was added a slurry of Pd / C (11.00 g, 10 wt% Pd, 50 wt% in water) in methanol (100 ml). The mixture was stirred at 25°C for 12 h under hydrogen (1 atm). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford methyl 4b.1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.01 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.63 - 6.35 (m, 2H), 5.37 (s, 2H), 3.76 (s, 3H), 1.97 (s, 3H). Step C – Synthesis of methyl 1-(4-bromo-2-methylphenyl)pyrazole-4-carboxylate (4c) To a solution of 4b (110.0 g, 475.6 mmol, 1 equiv) in CH3CN (1.5 L) at 0°C was added t- BuONO (68.6 g, 665.9 mmol, 1.4 equiv). The reaction mixture was stirred at 20 °C for 1 h. CuBr2(148.74 g, 665.95 mmol, 31.18 mL, 1.4 equiv) was added portion wise. The reaction mixture was stirred at 20°C for 3 h. Water (4 L) was added and the mixture was extracted with ethyl acetate (2 x 3 L). The combined organic layers were washed with brine (2 L), dried over anhydrous MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0 to 5 / 1) to afford 4c.1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.13 (s, 1H), 7.69 (s, 1H), 7.56 (m, 1H), 7.37 (m, 1H), 3.78 (s, 3H), 2.19 (s, 3H). Step D – Synthesis of 1-(4-bromo-2-methyl-phenyl) pyrazole-4-carboxylic acid (4d) To a solution of 4c (110.0 g, 372.7 mmol, 1 equiv) in methanol (0.2 L), tetrahydrofuran (0.4 L) and water (0.4 L) at 0°C was added LiOH•H2O (93.8 g, 2.24 mol, 6.0 equiv). The reaction mixture was stirred at 20°C for 18 h. The reaction mixture was concentrated under reduced pressure to remove most of the methanol and tetrahydrofuran. The concentrated mixture was cooled to 0°C and adjusted to pH 5 with 1N aqueous HCl. The precipitate was collected by vacuum filtration and dried under vacuum to afford 4d.1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 2.20 (s, 3H). Step E – Synthesis of 1-(4-bromo-2-methyl-phenyl)-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Intermediate 4) To a mixture of 4d (9.5 g, 33.8 mmol, 1 equiv) and Intermediate 1 (10.7 g, 37.17 mmol, 1.1 equiv) in DMF (90 mL) was added BOP (17.9 g, 40.5 mmol, 1.2 equiv) and triethylamine (10.2 g, 101.3 mmol, 3.0 equiv). The mixture was stirred at 20°C for 1 h. The residue was poured into water (200 mL). The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with brine (3 x 200 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=3 / 1 to 0 / 1) to afford Intermediate 4 (Int 4).1H NMR (400 MHz, Methanol-d4) δ 8.32 (s, 1H), 8.15 (s, 1H), 7.61 (s, 1H), 7.52 (dd, J = 2.0, 8.4 Hz, 1H),7.29 (d, J = 8.4 Hz, 1H), 4.69 (s, 2H), 2.22 (s, 3H), 1.60 (s, 6H). Example 5: Synthesis of Intermediate 5 Step – A mixture of 1,3-dibromo-2,4-dimethyl-benzene (1.00 g, 3.79 mmol, 1.0 equiv), methyl 1H-pyrazole-4-carboxylate (573 mg, 4.5 mmol, 1.2 equiv), (1R,2R)-N1,N2-dimethylcyclohexane- 1,2-diamine (216 mg, 1.5 mmol, 0.4 equiv), iodocopper tetrabutylammonium diiodide (848.3 mg, 0.76 mmol, 0.2 equiv) and cesium carbonate (2.5 g, 7.5 mmol, 2.0 equiv) in dioxane (10.0 mL) was three-fold degassed and purged with argon. The mixture was stirred at 120°C for 16 h under argon. The reaction was cooled to 20°C and partitioned between ethyl acetate (120 mL) and water (120 mL). The organic phase was separated, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=100:0 to 96:4) to afford 5a. LCMS [M+1] = 309.1, 311.1;1H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (s, 1H), 8.04 (s, 1H), 7.20 (app s, 2H), 3.88 (s, 3H), 2.50 (s, 3H), 2.25 (s, 3H). Step B – Synthesis of 1-(3-bromo-2,4-dimethyl-phenyl)pyrazole-4-carboxylic acid (5b) To a solution of 5a (1.0 g, 3.2 mmol, 1.0 equiv) in methanol (4.0 mL), tetrahydrofuran (4.0 mL) and water (2.0 mL) was added LiOH•H2O (407.2 mg, 9.7 mmol, 3.0 equiv). The mixture was stirred at 25°C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and pH adjusted to 3 with 1 M aqueous HCl. The solids were collected by vacuum filtration, the filter cake was dried under reduced pressure to afford 5b. LCMS [M+1] = 295.1, 297.1;1H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (s, 1H), 8.11 (s, 1H), 7.22 (app s, 2H), 2.51 (s, 3H), 2.27 (s, 3H). Step C – Synthesis of 1-(3-bromo-2,4-dimethyl-phenyl)-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Intermediate 5) To a solution of 5b (720 mg, 2.4 mmol, 1.0 equiv) in DMF (6.5 mL) was added DIEA (946 mg, 7.3 mmol, 1.3 mL, 3.0 equiv), HATU (928 mg, 2.4 mmol, 1.0 equiv) and Int 1 (916.8 mg, 3.1 mmol, 1.3 equiv). The mixture was stirred at 25°C for 2 h. The reaction mixture was partitioned between ethyl acetate (300 mL) and water (300 mL). The organic phase was separated, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane:methanol=100 / 0 to 96 / 4) to afford Intermediate 5 (Int 5). LCMS [M+1] = 485.3, 487.2;1H NMR (400 MHz, DMSO-d6) δ 13.88 (br s, 1H), 8.91 (br t, J = 5.4 Hz, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.43 - 7.27 (m, 2H), 4.56 (br d, J = 5.6 Hz, 2H), 2.45 (s, 3H), 2.19 (s, 3H), 1.53 (s, 6H). Example 6: Synthesis of Compound 6

[0009] Step A – Synthesis of tert-butyl (R)-4-(4-(5-chloro-2-(((3-(1,1,1-trifluoro-2-methylpropan-2-yl)- 1H-1,2,4-triazol-5-yl)methyl)carbamoyl)-2,3-dihydrobenzofuran-6-yl)benzyl)piperazine-1- carboxylate (6a) To a solution of Intermediate 2 (200.0 mg, 388.6 μmol, 1 equiv), [4-[(4-tert- butoxycarbonylpiperazin-1-yl)methyl]phenyl]boronic acid (186.6 mg, 582.9 μmol, 1.5 equiv), K3PO4 (247.4 mg, 1.17 mmol, 3.0 equiv) in tetrahydrofuran (4.0 mL) and water (1.0 mL) was three-fold degassed and purged with nitrogen gas and treated with Pd(dppf)Cl2(43 mg, 0.06 mmol, 0.15 equiv). The mixture was stirred at 80°C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and water (10 mL). The organic phase was separated, washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol = 10:1). The enantiomers were separated with SFC (CHIRALCEL-OJ(250 mm x 30mm,10µm, CO2-methanol(0.1%NH3H2O)], gradient:10%-30% over 11 min) to afford 6a as the early eluting enantiomer. LCMS [M+1] = 663.2. Step B – Synthesis of (R)-5-chloro-6-(4-(piperazin-1-ylmethyl)phenyl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide (6b) To a solution of 6a (30.0 mg, 45.24 μmol, 1.0 equiv) in dichloromethane (0.5 mL) was added TFA (45 μmol, 3 μL, 1.0 equiv). The mixture was stirred at 25°C for 2 h and then concentrated to afford 6b that was used without further purification. LCMS [M+1]+= 563.3. Step C – Synthesis of (2R)-5-chloro-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)methyl)phenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)- 1H-1,2,4-triazol-5-yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide (Compound 6) To a solution of 6b (30.0 mg, 44.3 μmol, 1.0 equiv) and 2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (13 mg, 44 μmol, 1.0 equiv) in DMSO (0.5 mL) was added DIEA (17 mg, 133 μmol, 23 μL, 3.0 equiv). The mixture was stirred at 70°C for 16 h. The reaction mixture was partitioned between ethyl acetate (30.0 mL) and water (30.0 mL). The organic phase was separated, washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol = 10:1) to afford Compound 6. LCMS [M+1] = 837.3;1H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (br s, 1H), 7.40 (d, J = 11.0 Hz, 1H), 7.36 - 7.24 (m, 6H), 7.22 (s, 1H), 6.78 (s, 1H), 5.22 - 5.12 (m, 1H), 4.86 (dd, J = 5.4, 12.2 Hz, 1H), 4.59 - 4.43 (m, 2H), 3.63 - 3.54 (m, 3H), 3.39 (dd, J = 6.6, 16.8 Hz, 1H), 3.28 - 3.22 (m, 4H), 2.88 - 2.65 (m, 3H), 2.63 - 2.59 (m, 4H), 2.07 (br dd, J = 4.8, 7.6 Hz, 1H), 1.94 (s, 1H), 1.53 (s, 6H). Example 7: Synthesis of Compound 7 2 and [4-(4-tert-butoxycarbonylpiperazine-1-carbonyl)phenyl]boronic acid. The intermediate corresponding to 6a was resolved by SFC (DAICEL CHIRALPAK IG (250mm x 30mm,10 µm); [CO2-EtOH(0.1% NH3H2O)]; 45% isocratic elution) and the early eluting enantiomer was carried forward to afford (2R)-5-chloro-6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- dioxoisoindolin-5-yl)piperazine-1-carbonyl)phenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)- 1H-1,2,4-triazol-5-yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide (Compound 7). LCMS: [M+1]+= 851.3;1H NMR (400 MHz, DMSO-d6) δ = 14.00 - 13.61 (m, 1H), 11.10 (d, J = 2 Hz, 1H), 8.93 - 8.69 (m, 1H), 7.78 (d, J = 11.2 Hz, 1H), 7.62 - 7.36 (m, 6H), 6.89 (s, 1H), 5.33 - 5.32 (m, 1H), 5.31 (dd, J = 6.4, 10.4 Hz, 1H), 5.19 - 5.01 (m, 1H), 4.56 - 4.41 (m, 1H), 4.39 - 4.28 (m, 1H), 3.90 - 3.71 (m, 1H), 3.68 - 3.49 (m, 3H), 3.37 (s, 1H), 2.95 - 2.81 (m, 1H), 2.71 - 2.56 (m, 2H), 2.54 (s, 3H), 2.09 - 1.96 (m, 1H), 2.11 - 1.95 (m, 1H), 1.52 (s, 6H). Example 8: Synthesis of Compound 8

[0010] carboxylate (8a) To a mixture of 5-bromo-2-fluoro-pyridine (619.4 mg, 3.5 mmol, 362.2 μL, 1.05 equiv) and tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (0.95 g, 3.3 mmol, 1.0 equiv) in DMF (10.0 mL) was added K2CO3 (926.5 mg, 6.7 mmol, 2.0 equiv) in one portion at 20°C under nitrogen The mixture was stirred at 90°C for 12 h. The reaction mixture was cooled to 20°C and the residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate 75 / 25 to 1 / 1) to afford 8a. LCMS [M+1] = 439.1;1H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 2.4, 8.8 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 4.22 (br d, J = 13.2 Hz, 2H), 3.48 - 3.39 (m, 4H), 2.81 (dt, J = 2.4, 12.6 Hz, 2H), 2.42 - 2.29 (m, 4H), 2.20 (d, J = 7.2 Hz, 2H), 1.84 (br d, J = 13.2 Hz, 2H), 1.79 - 1.68 (m, 1H), 1.47 (s, 9H), 1.32 - 1.13 (m, 2H). Step B – Synthesis of [6-[4-[(4-tert-butoxycarbonylpiperazin-1-yl)methyl]-1-piperidyl]-3- pyridyl]boronic acid (8b) To a mixture of 8a (640 mg, 1.4 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.11 g, 4.3 mmol, 3.0 equiv) in dioxane (10.0 mL) was added KOAc (714.7 mg, 7.2 mmol, 5.0 eq) Pd(PPh3)4 (168.3 mg, 145.6 μmol, 0.1 eq) and in one portion at 20°C under nitrogen. The mixture was stirred at 80°C for 12 h, cooled to rt, filtered and the filtrate was concentrated under reduced pressure. The crude product was triturated with ethyl acetate to afford 8b. LCMS: [M+1] = 405.4. Step C – Synthesis of tert-butyl (R)-4-((1-(5-(5-chloro-2-(((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)-2,3-dihydrobenzofuran-6-yl)pyridin-2-yl)piperidin- 4-yl)methyl)piperazine-1-carboxylate (8c) To a solution of 8b (300 mg, 742 μmol, 1.5 equiv), Intermediate 2 (254.6 mg, 495 μmol, 1.0 equiv), Pd(dppf)Cl2(54.3 mg, 74.2 μmol, 0.15 equiv), K3PO4(315.01 mg, 1.48 mmol, 3.0 equiv) in tetrahydrofuran (4.0 mL) and water (1.0 mL) was three-fold degassed and purged with nitrogen, and then the mixture was stirred at 80°C for 12 h under a nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate (40 mL) and water (40 mL). The organic phase was separated, washed with brine (2 x 15 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane / methanol=1 / 0 to 96 / 4) and then the residue was purified by preparative TLC (silica gel, dichloromethane: methanol = 10:1). The enantiomers were resolved by SFC (DAICEL CHIRALPAK IG (250 mm x 30mm, 10µm); [CO2- IPA(0.1%NH3H2O)]; 40% isocratic elution) to afford the early eluting isomer 8c. LCMS [M+1] = 747.3. Step D and Step E were performed in a similar manner to Example 6 to afford (2R)-5-chloro-6- (6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)pyridin-3-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide (Compound 8). LCMS [M+1] = 920.9;1H NMR (400 MHz, CHLOROFORM-d) δ 11.87 - 11.33 (m, 1H), 8.27 - 8.18 (m, 2H), 7.57 (dd, J = 2.4, 8.9 Hz, 1H), 7.48 (d, J = 11.1 Hz, 1H), 7.44 - 7.44 (m, 1H), 7.44 - 7.38 (m, 1H), 7.29 - 7.27 (m, 1H), 6.81 (s, 1H), 6.72 (d, J = 8.9 Hz, 1H), 5.25 (dd, J = 6.4, 10.7 Hz, 1H), 4.95 (dd, J = 5.3, 12.3 Hz, 1H), 4.70 - 4.49 (m, 2H), 4.38 (br d, J = 12.8 Hz, 2H), 3.64 (dd, J = 11.1, 16.4 Hz, 1H), 3.45 (br dd, J = 6.2, 16.7 Hz, 1H), 3.33 - 3.28 (m, 4H), 2.94 - 2.72 (m, 5H), 2.63 (br d, J = 1.1 Hz, 4H), 2.31 (br d, J = 6.8 Hz, 2H), 2.23 - 2.06 (m, 1H), 1.91 (br d, J = 12.1 Hz, 2H), 1.86 - 1.67 (m, 3H), 1.60 (s, 6H). Example 9: Synthesis of Compound 9 Step – carboxylate (9a) To a mixture of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (500 mg, 1.7 mmol, 1.0 equiv) and DIEA (250.8 mg, 1.9 mmol, 338 μL, 1.1 equiv) in dichloromethane (5 mL) was added 2-bromoacetyl bromide (356 mg, 1.7 mmol, 154 μL, 1.0 equiv) dropwise at 0°C. The reaction mixture was agitated at 25ºC for 1 h. The residue was poured into water (10 mL). The aqueous phase was extracted with dichloromethane (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum to afford 9a, which was used without further purification. LCMS: [M+1] = 404.1, 406.1;1H NMR (400 MHz, Methanol-d4) δ 4.46 (d, J = 12.0 Hz, 1H), 4.15 - 3.88 (m, 3H), 3.42 (s, 4H), 3.21 - 3.09 (m, 1H), 2.71 (dt, J = 2.6, 12.8 Hz, 1H), 2.38 (t, J = 4.8 Hz, 4H), 2.23 (d, J = 6.6 Hz, 2H), 1.93 - 1.79(m, 3H), 1.45 (s, 9H), 1.29 (s, 1H), 1.14 - 1.01 (m, 1H). Step B – Synthesis of tert-butyl 4-((1-(2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (9b) To a mixture of 9a (160.0 mg, 395.7 μmol, 1.0 equiv) and 4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-1H-pyrazole (106.9 mg, 395.7 μmol, 1.0 equiv) in DMF (2.0 mL) was added K2CO3(164.1 mg, 1.2 mmol, 3.0 equiv) in one portion at 20°C under nitrogen. The mixture was stirred at 20°C for 16 h. The reaction mixture was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (3 x 10 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate / methanol=0 / 1 to 0 / 1 to give 9b. LCMS: [M+1]+= 594.3;1H NMR (400 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.90 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.4 Hz, 2H), 5.26 - 5.07 (m, 2H), 4.47 (d, J = 14.0 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.42 (s, 4H), 3.22 - 3.11 (m, 1H), 2.79 - 2.67 (m, 1H), 2.38 (s, 3H), 2.23 (d, J = 5.8 Hz, 2H), 1.94 - 1.78 (m, 4H), 1.46 (s, 9H), 1.38 - 1.27 (m, 12H), 1.27 - 1.17 (m, 2H), 1.15 - 1.04 (m, 1H). Step C – Synthesis of tert-butyl 4-((1-(2-(4-(4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1- yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (9c) To a mixture of 9b (140.0 mg, 235.8 μmol, 1.2 equiv) and Intermediate 3 (84.7 mg, 196.5 μmol, 1.0 equiv) in dioxane (1.5 mL) and water (0.2 mL) was added K2CO3 (81.5 mg, 589.6 μmol, 3.0 equiv) and Pd(dppf)Cl2•CH2Cl2 (80.3 mg, 98.3 μmol, 0.5 equiv) in one portion at 20°C under nitrogen. The mixture was stirred at 100°C for 2 h. The mixture was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (silica gel, ethyl acetate / methanol =0 / 1 to 0 / 1) to give 9c. LCMS: [M+1] = 818.4;1H NMR (400 MHz, Methanol-d4) δ 8.00 (s, 1H), 7.89 (s, 1H), 7.67 - 7.51 (m, 6H), 7.21 (d, J = 8.0 Hz, 2H), 5.25 - 5.08 (m, 2H), 4.62 - 4.42 (m, 3H), 4.00 (d, J = 13.2 Hz, 1H), 3.43 (s, 4H), 3.17 (t, J = 12.8 Hz, 1H), 2.73 (t, J = 12.2 Hz, 1H), 2.55 - 2.33 (m, 5H), 2.25 (d, J = 6.4 Hz, 2H), 1.98 (s, 1H), 1.94 - 1.78 (m, 3H), 1.60 (s, 5H), 1.46 (s, 9H), 1.38 - 1.28 (m, 2H), 1.12 (s, 2H), 0.99 - 0.84 (m, 1H). Step D – Synthesis of (1S,2S)-2-(4'-(1-(2-oxo-2-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethyl)-1H- pyrazol-4-yl)-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol- 5-yl)methyl)cyclopropane-1-carboxamide (9d) To a mixture of 9c (150.0 mg, 183.4 μmol, 1.0 equiv) in HCl / dioxane (5.0 mL, 4 M) was stirred at 20°C under nitrogen for 1 h. The reaction mixture was concentrated under reduced pressure to afford 9d which was used into next step without further purification. LCMS: [M+1]+= 718.3;1H NMR (400 MHz, Methanol-d4) δ 8.11 - 8.01 (m, 1H), 7.95 (dt, J = 2.8, 5.5 Hz, 1H), 7.67 - 7.54 (m, 6H), 7.32 - 7.13 (m, 2H), 5.22 - 5.19 (m, 2H), 4.66 - 4.61 (m, 3H), 4.10 - 4.05 (m, 1H), 3.66 (s, 4H), 3.20 (d, J = 4.0 Hz, 1H), 2.82 - 2.79 (m, 1H), 2.65 (d, J = 9.8 Hz, 5H), 2.53 - 2.44 (m, 2H), 2.29 - 2.21 (m, 1H), 2.06 - 1.95 (m, 3H), 1.69 - 1.59 (m, 6H), 1.40 - 1.26 (m, 5H). Step E – Synthesis of (1S,2S)-2-(4'-(1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-[1,1'- biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)cyclopropane-1-carboxamide (Compound 9) To a mixture of 9d (130.0 mg, 181.1 μmol, 1.0 equiv) in DMSO (3.0 mL) was added DIEA (70.2 mg, 543.3 μmol, 94.6 μL, 3.0 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5,6- difluoroisoindoline-1,3-dione (79.9 mg, 271.6 μmol, 1.5 equiv) in one portion at 20°C under nitrogen. The mixture was stirred at 80°C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex C18150mm x 25mm, 10µm; mobile phase: [water( NH4HCO3)-acetonitrile]) to give Compound 9. LCMS: [M+1] = 992.4;1H NMR (400 MHz, Methanol-d4) δ 8.03 (s, 1H), 7.93 (s, 1H), 7.67 - 7.58 (m, 6H), 7.56 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 5.29 - 5.09 (m, 3H), 4.57 (d, J = 2.6 Hz, 3H), 4.10 (d, J = 14.8 Hz, 1H), 3.88 - 3.72 (m, 4H), 3.38 (d, J = 9.0 Hz, 4H), 3.26 (d, J = 12.4 Hz, 1H), 3.21 (d, J = 6.8 Hz, 2H), 2.93 - 2.65 (m, 4H), 2.51 - 2.44 (m, 1H), 2.34 - 2.22 (m, 1H), 2.17 - 2.08 (m, 1H), 2.03 - 1.88 (m, 3H), 1.61 (s, 6H), 1.60 - 1.54 (m, 1H), 1.50 - 1.23 (m, 4H). Example 10: Synthesis of Compound 10 Compound 10 was prepared in a similar manner to Example 9. Final purification by preparative HPLC (Phenomenex Luna C18, 80mm x 30mm, 3 µm; H2O (0.04% HCl)-acetonitrile) afforded (1S,2S)-2-[4-[4-[1-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]-1-piperidyl]-2-oxo-ethyl]pyrazol-3-yl]phenyl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide hydrochloride (Compound 10). LCMS: [M+1]+= 992.5;1H NMR (400MHz, DMSO-d6) δ 11.12 (s, 1H), 8.76 (s, 1H), 7.88 - 7.81 (m, 3H), 7.72 - 7.67 (m, 3H), 7.65 - 7.59 (m, 3H), 7.23 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 2.4 Hz, 1H), 5.27 - 5.09 (m, 3H), 4.41 (d, J = 5.6 Hz, 2H), 4.37 - 4.30 (m, 1H), 4.02 - 3.95 (m, 1H), 3.79 (d, J = 12.8 Hz, 2H), 3.64 (d, J = 12.4 Hz, 2H), 3.26 - 3.19 (m, 2H), 3.14 - 3.08 (m, 2H), 2.93 - 2.84 (m, 1H), 2.71 - 2.55 (m, 4H), 2.35 - 2.30 (m, 1H), 2.15 (s, 1H), 2.07 - 1.98 (m, 3H), 1.85 (t, J =12.4 Hz, 2H), 1.53 (s, 6H), 1.45 - 1.38 (m, 1H), 1.33 - 1.21 (m, 3H), 1.16 - 1.06 (m, 1H). Example 11: Synthesis of Compound 11

[0011] Step A – Synthesis of tert-butyl 4-((1-(2-(4-iodo-1H-pyrazol-1-yl)acetyl)piperidin-4- yl)methyl)piperazine-1-carboxylate (11a) To a solution of 2-(4-iodo-1H-pyrazol-1-yl)acetic acid (1.0 g, 4.0 mmol, 1.1 equiv) and tert-butyl 4-((1-(2-bromoacetyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (1.0 g, 3.6 mmol, 1.0 equiv) in DMF (10.0 mL) was added HATU (1.4 g,3.6 mmol, 1.0 equiv) and DIPEA (2.3 g, 18.0 mmol, 3.1 mL, 5.0 equiv). The mixture was stirred at 25°C for 1 h. The residue was purified by preparative HPLC (Phenomenex Luna C18; 250mm x 70mm, 10µm; water( NH4HCO3)-acetonitrile) to afford 11a. LCMS [M+1] = 518.1;1H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.50 (s, 1H), 5.12 (d, J = 4.2 Hz, 2H), 4.27 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 13.6 Hz, 1H), 3.29 (s, 4H), 2.70 - 2.52 (m, 2H), 2.28 (t, J = 5.0 Hz, 4H), 2.13 (d, J = 7.2 Hz, 2H), 1.81 - 1.67 (m, 3H), 1.39 (s, 9H), 1.15 - 0.87 (m, 2H). Step B – Synthesis of tert-butyl 4-((1-(2-(4-(4-bromo-2-chlorophenyl)-1H-pyrazol-1- yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (11b) A mixture of 11a (500.0 mg, 918.1 μmol, 1.0 equiv), (4-bromo-2-chlorophenyl)boronic acid (216.0 mg, 918.1 μmol, 1.0 equiv), Pd(dppf)Cl2.CH2Cl2 (75.0 mg, 91.8 μmol, 0.1 equiv) and K2CO3(380.6 mg, 2.8 mmol, 3.0 equiv) in water (1.0 mL) and dioxane (5.0 mL) was three-fold degassed and purged with nitrogen. The mixture was stirred at 100°C for 1 h under nitrogen atmosphere. The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine (3x50 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum to give residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=10:1 to 0:1) to afford 11b. LCMS [M+1] = 580.0, 582.0;1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.89 (s, 1H), 7.80 - 7.74 (m, 1H), 7.58 - 7.55 (m, 2H), 5.17 (d, J = 5.9 Hz, 2H), 3.30 (s, 4H), 2.70 - 2.56 (m, 4H), 2.28 (br t, J = 4.4 Hz, 4H), 2.13 (br d, J = 7.0 Hz, 3H), 1.81 - 1.65 (m, 4H), 1.39 (s, 9H). Step C – Synthesis of (4-(1-(2-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4-yl)-3-chlorophenyl)boronic acid (11c) A mixture of 11b (400.0 mg, 688.5 μmol, 1.0 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (262.3 mg, 1.0 mmol, 1.5 equiv), potassium acetate (202.7 mg, 2.1 mmol, 3.0 equiv) and Pd(dppf)Cl2(50.4 mg, 68.9 μmol, 0.1 equiv) in dioxane (4.0 mL) was three-fold degassed and purged with nitrogen. The mixture was stirred at 100°C for 6 h under nitrogen atmosphere, cooled to ambient temperature and poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine (3 x 50 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 150mm x 25mm, 10µm; water(formic acid)-acetonitrile];gradient:23%-53% B over 10 min) to give 11c. LCMS [M+1] = 546.3, 548.3;1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.20 - 8.13 (m, 1H), 7.92 (d, J = 9.6 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.63 - 7.56 (m, 1H), 5.17 (dd, J = 2.5, 5.6 Hz, 2H), 4.34 - 4.25 (m, 1H), 3.96 - 3.84 (m, 1H), 3.05 (br t, J = 11.9 Hz, 2H), 2.52 (br s, 6H), 2.28 (br t, J = 4.8 Hz, 4H), 2.14 (br d, J = 7.0 Hz, 2H), 1.89 - 1.64 (m, 4H), 1.39 (s, 10H). Step D – Synthesis of tert-butyl 4-((1-(2-(4-(3-chloro-4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)- 1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (11d) A mixture of 11c (120.3 mg, 220.3 μmol, 1.0 equiv), Intermediate 3 (95.0 mg, 220.3 μmol, 1.0 equiv), K2CO3 (91.3 mg, 660.9 μmol, 3.0 equiv), Pd(dppf)Cl2•CH2Cl2 (18.0 mg, 22.0 μmol, 0.1 equiv) in dioxane (1.0 mL) and water (0.2 mL) was three-fold degassed and purged with nitrogen, and then the mixture was stirred at 100°C for 2 h. The residue was poured into water (10 mL) and extracted with ethyl acetate (3 x 130 mL). The combined organic phase was washed with brine (3 x 10 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, ethyl acetate) to afford 11d. LCMS [M+1] = 852.4, 853.8;1H NMR (400 MHz, Methanol-d4) δ 8.12 (s, 1H), 7.92 (s, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.66 - 7.61 (m, 1H), 7.59 - 7.53 (m, 3H), 7.24 (d, J = 8.4 Hz, 2H), 5.30 - 5.12 (m, 2H), 4.55 (d, J = 2.4 Hz, 2H), 4.51 - 4.43 (m, 1H), 4.00 (d, J = 13.4 Hz, 1H), 3.42 (s, 4H), 3.17 (s, 1H), 2.73 (t, J = 11.8 Hz, 1H), 2.53 - 2.44 (m, 1H), 2.39 ( t, J = 5.0 Hz, 4H), 2.23 (d, J = 6.6 Hz, 2H), 2.01 - 1.96 (m, 1H), 1.94 - 1.71 (m, 3H), 1.60 (s, 6H), 1.58 - 1.52 (m, 1H), 1.46 (s, 9H), 1.34 (ddd, J = 4.6, 6.3, 8.2 Hz, 1H), 1.22 - 0.97 (m, 2H). Step E – Synthesis of 4-((1-(2-(4-(3-chloro-4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1- yl)acetyl)piperidin-4-yl)methyl)piperazin-1-ium (11e) Intermediate 11d (90.0 mg, 105.6 μmol, 1.0 equiv) was dissolved in HCl / dioxane (2 mL, 4 M). The mixture was stirred at 20°C for 1 h and then concentrated under reduced pressure to afford 11e which was used without further purification. LCMS [M+1] = 752.7, 754.7;1H NMR (400 MHz, Methanol-d4) δ 8.01 (s, 1H), 7.73 - 7.55 (m, 5H), 7.25 (d, J = 7.8 Hz, 2H), 5.39 - 5.12 (m, 2H), 4.70 (s, 3H), 4.62 - 4.49 (m, 1H), 4.14 - 4.00 (m, 1H), 3.75 - 3.56 (m, 10H), 3.27 - 3.16 (m, 3H), 2.94 - 2.74 (m, 1H), 2.53 - 2.42 (m, 1H), 2.35 - 2.23 (m, 1H), 2.12 - 1.94 (m, 3H), 1.68 (s, 6H), 1.61 - 1.54 (m, 1H), 1.43 - 1.23 (m, 3H). Step F – Synthesis of 5-(4-((1-(2-(4-(3-chloro-4'-((1S,2S)-2-(3-(3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)propanoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H- pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6- fluoroisoindoline-1,3-dione (Compound 11) To a solution of 11e (80.0 mg, 106.3 μmol, 1.0 equiv) in DMSO (1.0 mL) was added DIEA (20.6 mg, 159.5 μmol, 27.8 μL, 1.5 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5,6- difluoroisoindoline-1,3-dione (46.9 mg, 159.5 μmol, 1.5 equiv). The mixture was stirred at 80°C for 3 h. The mixture was purified by preparative HPLC (Phenomenex Luna C18150mm x 25mm, 10µm; water(NH4HCO3)-acetonitrile]; gradient:44%-74% B over 10 min) to afford Compound 11. LCMS: [M+1] = 1025.5;1H NMR (400 MHz, DMSO-d6) δ 14.08 - 13.65 (m, 1H), 11.23 - 10.99 (m, 1H), 8.75 (br s, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.76 - 7.60 (m, 5H), 7.45 (d, J = 7.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 5.19 (d, J = 6.8 Hz, 2H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 4.41 (d, J = 5.4 Hz, 2H), 4.33 (d, J = 12.8 Hz, 1H), 4.01 - 3.85 (m, 1H), 3.26 (s, 4H), 3.08 (t, J = 11.6 Hz, 2H), 2.93 - 2.84 (m, 1H), 2.72 - 2.55 (m, 4H), 2.46 - 2.26 (m, 2H), 2.26 - 2.18 (m, 2H), 2.08 - 1.97 (m, 2H), 1.89 - 1.73 (m, 3H), 1.53 (s, 6H), 1.42 (td, J = 4.6, 9.0 Hz, 1H), 1.37 - 1.19 (m, 2H), 1.16 - 0.95 (m, 2H). Example 12: Synthesis of Compound 12 (2'- chloro-4'-(1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)cyclopropane-1-carboxamide (Compound 12). LCMS [M+1, M+3]+= 1026.4, 1028.4;1H NMR (400 MHz, DMSO-d6) δ 14.08 - 13.76 (m, 1H), 11.11 (s, 1H), 8.77 (br s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.73 (d, J = 11.4 Hz, 1H), 7.61 (dd, J = 1.4, 7.8 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.40 - 7.33 (m, 3H), 7.22 (d, J = 8.4 Hz, 2H), 5.18 - 5.06 (m, 3H), 4.41 (br d, J = 5.8 Hz, 2H), 4.32 (br d, J = 12.4 Hz, 1H), 3.93 (br d, J = 12.6 Hz, 1H), 3.25 (br s, 4H), 3.08 (br t, J = 12.2 Hz, 1H), 2.95 - 2.82 (m, 1H), 2.71 - 2.60 (m, 2H), 2.59 - 2.51 (m, 5H), 2.38 - 2.31 (m, 1H), 2.22 (br d, J = 6.6 Hz, 2H), 2.08 - 1.98 (m, 2H), 1.90 - 1.71 (m, 3H), 1.53 (s, 6H), 1.42 (td, J = 4.4, 9.4 Hz, 1H), 1.35 - 1.27 (m, 1H), 1.15 - 0.94 (m, 2H). Example 13: Synthesis of Compound 13 Step A – Synthesis of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazole (13a) To a solution of 4-(4-bromophenyl)-1H-pyrazole (9 g, 40.3 mmol, 1 equiv), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (10.2 g, 40.3 mmol, 1 equiv) in dioxane (90 mL) was added potassium acetate (11.8 g, 121.0 mmol, 3 equiv) and Pd(dppf)Cl2•CH2Cl2 (3.2 g, 4.03 mmol, 0.1 equiv). The mixture was stirred at 80°C for 16 h. The mixture was cooled to ambient temperature and quenched with water (600 mL). The mixture was extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with brine (300 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography silica gel, petroleum ether / ethyl acetate=10 / 1 to 4 / 1) to afford 13a. LCMS [M+1]+= 271.2;1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.26 (s, 1H), 7.96 (d, J = 11.4 Hz, 1H), 7.70 - 7.50 (m, 4H), 1.29 (s, 12H). Step B – Synthesis of tert-butyl 2-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]pyrazol-1-yl]acetate (13b) To a solution of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazole (4 g, 14.8 mmol, 1 equiv) in DMF (40 mL) was added K2CO3(4.09 g, 29.6 mmol, 2 equiv) and tert- butyl 2-bromoacetate (3.47 g, 17.7 mmol, 2.62 mL, 1.2 equiv). The mixture was stirred at 25°C for 3 h under a nitrogen atmosphere. The mixture was poured into saturated ammonium chloride (200 mL). The aqueous phase was extracted with ethyl acetate (3 x 60 mL). The combined organic phase was washed with brine (3 x 60 mL), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to afford 13b.1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.96 (s, 1H), 7.68 - 7.63 (m, 2H), 7.62 - 7.56 (m, 2H), 4.96 (s, 2H), 1.44 (s, 9H), 1.30 (s, 12H). Step C – Synthesis of tert-butyl 2-[4-[4-[4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methylcarbamoyl]cyclopropyl]phenyl]phenyl]pyrazol-1-yl]acetate (13c) A mixture of 13b (3.5 g, 9.0 mmol, 1.3 equiv), Intermediate 3 (3 g, 6.9 mmol, 1 equiv), Pd(DPPF)Cl2 (906.8 mg, 1.3 mmol, 0.2 equiv), Cs2CO3 (6.8 g, 20.8 mmol, 3 equiv) in 2- methylbutan-2-ol (30 mL) and water (7 mL) was 3-fold degassed and purged with nitrogen. The mixture was stirred at 85 °C for 5 h under an atmosphere of nitrogen. The mixture was cooled to ambient temperature and poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) 13c. LCMS [M+1] = 609.4;1H NMR (400 MHz, DMSO-d6) δ 13.87 (s, 1H), 8.75 (s, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.65 (s, 3H), 7.61 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 4.97 (s, 2H), 4.41 (d, J = 5.8 Hz, 2H), 2.38 - 2.29 (m, 1H), 1.53 (s, 6H), 1.44 (s, 9H), 1.42 - 1.35 (m, 1H), 1.32 - 1.21 (m, 2H). Step D – Synthesis of 2-[4-[4-[4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methylcarbamoyl]cyclopropyl]phenyl]phenyl] pyrazol-1-yl]acetic acid (13d) To a solution of 13c (2.2 g, 3.6 mmol, 1 equiv) in dichloromethane (22 mL) was added trifluoroacetic acid (33.7 g, 296.1 mmol, 22.0 mL, 81.9 equiv) at 0°C, the mixture was stirred at 25°C for 1.5 h. The mixture was concentrated under reduced pressure. The mixture was treated with water (20 mL) and the solids were collected by vacuum filtration. The filter cake was wash with water (10 mL x 3) and dried under vacuum to afford 13d, which was used to next step directly. LCMS [M+1]+= 553.2;1H NMR (400 MHz, DMSO-d6) δ 14.37 - 13.44 (m, 1H), 13.41 - 12.79 (m, 1H), 8.75 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.65 (s, 3H), 7.61 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 4.98 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 4.31 - 4.14 (m, 1H), 2.37 - 2.29 (m, 1H), 2.04 - 1.95 (m, 1H), 1.53 (s, 6H), 1.45 - 1.38 (m, 1H), 1.29 (ddd, J = 4.2, 5.8, 8.2 Hz, 1H). Step E – Synthesis of benzyl 4-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]piperazine-1- carboxylate (13e) To a mixture of tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (1 g, 4.0 mmol, 1.0 equiv) and benzyl piperazine-1-carboxylate (880.6 mg, 4.0 mmol, 771.1 μL, 1.0 equiv) in DMF (10.0 mL) was added K2CO3(1.1 g, 8.0 mmol, 2 equiv) and KI (132.7 mg, 799.5 μmol, 0.2 equiv) in one portion at 20°C under nitrogen. The mixture was stirred at 50°C for 4 h, cooled to ambient temperature and poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=9 / 1 to 67 / 33) to afford 13e. LCMS [M+1] = 390.3;1H NMR (400 MHz, CHLOROFORM-d) δ 7.43 - 7.29 (m, 5H), 5.14 (s, 2H), 4.01 (t, J = 8.4 Hz, 2H), 3.59 (dd, J = 5.4, 8.4 Hz, 2H), 3.53 - 3.46 (m, 4H), 2.77 - 2.67 (m, 1H), 2.58 (d, J = 7.6 Hz, 2H), 2.37 (br s, 4H), 1.44 (s, 9H). Step F – Synthesis of tert-butyl 3-(piperazin-1-ylmethyl)azetidine-1-carboxylate (13f) To a solution of 13e (1.0 g, 2.5 mmol, 1.0 equiv) in methanol (10.0 mL) was added Pd / C (1.2 g, 1.1 mmol, 10 wt%) under a nitrogen atmosphere. The suspension was three-fold degassed and purged with H2. The mixture was stirred under hydrogen (1 atm) at 30°C for 2 h, filtered and the filtrate was concentrated to afford 13f. LCMS: [M+1] = 256.3;1H NMR (400 MHz, Methanol- d4) δ 4.03 - 3.92 (m, 2H), 3.60 - 3.51 (m, 2H), 3.27 (td, J = 1.6, 3.2 Hz, 3H), 2.84 - 2.75 (m, 4H), 2.55 (d, J = 7.2 Hz, 2H), 2.39 (br s, 3H), 1.39 (s, 9H). Step G – Synthesis of tert-butyl 3-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]azetidine-1-carboxylate (13g) To a mixture of 13f (0.1 g, 391.6 μmol, 1 equiv) and 2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (115.2 mg, 391.6 μmol, 1 equiv) in DMSO (1.0 mL) was added DIEA (253.0 mg, 1.9 mmol, 341.0 μL, 5.0 equiv) in one portion at 20°C under nitrogen. The mixture was stirred at 70°C for 12 h, cooled to ambient temperature and poured into water (10.0 mL). The aqueous phase was extracted with ethyl acetate (20.0 mL). The combined organic phase was washed with brine (10.0 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol = 10:1) to afford 13g. LCMS [M+1]+= 530.4. Step H – Synthesis of 5-[4-(azetidin-3-ylmethyl)piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)-6- fluoro-isoindoline-1,3-dione (13h) To a mixture of 13g (170 mg, 321.0 μmol, 1.0 eq) in dichloromethane (0.5 mL) was added trifluoroacetic acid (261 mg, 2.2 mmol, 170.0 μL, 7.1 equiv) in one portion at ambient temperature, stirred for 1 h and concentrated under reduced pressure. The residue was triturated with MTBE (5.0 mL) to afford 13h. LCMS [M+1]+= 430.3. Step I – Synthesis of (1S,2S)-2-[4-[4-[1-[2-[3-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo- isoindolin-5-yl]piperazin-1-yl]methyl]azetidin-1-yl]-2-oxo-ethyl]pyrazol-4-yl]phenyl]phenyl]-N- [[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide (Compound 13) To a mixture of 13d (80 mg, 144.7 μmol, 1 equiv) and 13h (118.1 mg, 275.0 μmol, 1.9 equiv) and DIEA (93.5 mg, 723.9 μmol, 126.0 μL, 5.0 equiv) in DMF (0.5 mL) was treated with T4P (156.4 mg, 217.1 μmol, 50% purity, 1.5 equiv) in one portion at 20°C under N2. The mixture was stirred at 20 °C for 1 h, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18100mm x 30mm, 5µm; water (0.2% formic acid)-acetonitrile]) to give Compound 13. LCMS [M+1] =964.3;1H NMR (400 MHz, DMSO-d6) δ 14.05 - 13.53 (m, 1H), 11.11 (s, 1H), 8.75 (br s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.73 (d, J = 11.6 Hz, 1H), 7.69 - 7.57 (m, 6H), 7.46 (br d, J = 6.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 5.11 (dd, J = 5.6, 12.8 Hz, 1H), 4.87 (s, 2H), 4.41 (br d, J = 5.2 Hz, 2H), 4.24 (br t, J = 8.4 Hz, 1H), 4.01 (br t, J = 8.8 Hz, 1H), 3.85 (br d, J = 6.4 Hz, 1H), 3.59 (br s, 1H), 3.48 - 3.36 (m, 2H), 2.96 - 2.82 (m, 2H), 2.67 - 2.53 (m, 6H), 2.36 - 2.28 (m, 1H), 2.09 - 1.94 (m, 2H), 1.90 - 1.58 (m, 1H), 1.53 (s, 6H), 1.49 - 1.36 (m, 2H), 1.36 - 1.22 (m, 2H), 0.90 - 0.81 (m, 1H)

[0012] Example 14: Synthesis of Compound 14 carboxylate (14a) A solution of benzyl (3-bromopropyl)carbamate (3.9 g, 14.5 mmol, 1.1 equiv) and tetrabutylammonium hydrogen sulfate (449.6 mg, 1.3 mmol, 0.1 equiv) in dichloromethane (30.0 mL) was stirred at 25°C for 5 min, then tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (3.0 g, 13.2 mmol, 1.0 equiv) and NaOH (1.6 g, 39.7 mmol, 3.0 equiv) were added. The reaction mixture was stirred at 40°C for 16 h. The mixture was poured into water (100 mL) and the aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with brine (3 x 100 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0, 3 / 2) to 14a. LCMS [M+1] = 422.3;1H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.29 (m, 4H), 7.21 (br s, 1H), 5.00 (s, 2H), 3.45 (br s, 2H), 3.37 (br t, J = 5.8 Hz, 2H), 3.27 (br s, 4H), 3.04 (br d, J = 6.0 Hz, 2H), 2.46 (br d, J = 5.6 Hz, 2H), 2.34 (br s, 4H), 1.66 - 1.57 (m, 2H), 1.39 (s, 9H). Step B – Synthesis of tert-butyl 4-(2-(3-aminopropoxy)ethyl)piperazine-1-carboxylate (14b) To a solution of 14a (550.0 mg, 1.3 mmol, 1.0 equiv) in 2,2,2-trifluoroethanol (5.0 mL) was added Pd / C (694.2 mg, 10.0% Pd on carbon, 50% in water(w / w)). The mixture was stirred at 50°C for 2 h under H2(1 atm). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 14b. LCMS [M+1] = 288.2;1H NMR (400 MHz, DMSO-d6) δ 3.63 - 3.53 (m, 4H), 2.75 - 2.58 (m, 14H), 1.70 (quin, J = 6.6 Hz, 2H), 1.54 (s, 9H). Step C – Synthesis of 3-chloro-4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-carboxylic acid (14c). To a solution of Intermediate 3 (300.0 mg, 695.6 μmol, 1.0 equiv) and 2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (294.8 mg, 1.0 mmol, 1.5 equiv) in dioxane (3.0 mL) and water (0.3 mL) added K2CO3(288.4 mg, 2.1 mmol, 3.0 equiv) and Pd(dppf)Cl2•CH2Cl2 (56.8 mg, 69.5 μmol, 0.1 equiv). The mixture was stirred at 120°C for 2 h. The mixture was cooled to 20°C and poured into water (30 mL), the aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with brine (3 x 30 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate: methanol=1:1) to afford 14c. LCMS [M+1] = 507.1, 509.1;1H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.45 (m, 3H), 7.30 (br s, 2H), 7.18 (br d, J = 7.6 Hz, 2H), 4.62 - 4.52 (m, 1H), 4.42 - 4.33 (m, 1H), 3.16 (br d, J = 4.8 Hz, 2H), 1.53 (s, 6H), 1.39 (br d, J = 4.8 Hz, 1H), 1.25 (br d, J = 4.4 Hz, 2H). Step D – Synthesis of tert-butyl 4-(2-(3-(3-chloro-4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4- carboxamido)propoxy)ethyl)piperazine-1-carboxylate (14d) To a solution of 14c (180.0 mg, 355.1 μmol, 1.0 equiv) in DMF (1.8 mL) was added DIEA (137.6 mg, 1.0 mmol, 185.5 μL, 3.0 equiv), BOP (188.4 mg, 426.1 μmol, 1.2 equiv) and 14b (122.4 mg, 426.1 μmol, 1.2 equiv). The mixture was stirred at 20°C for 2 h. The mixture was poured into water (50 mL) and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine (3 x 50 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC(ethyl acetate : methanol=1:1) to afford 14d. LCMS [M+1] = 776.3, 778.3;1H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.75 (m, 1H), 8.41 (br d, J = 5.8 Hz, 1H), 7.75 (s, 1H), 7.69 - 7.60 (m, 3H), 7.47 (br d, J = 8.0 Hz, 1H), 7.28 - 7.20 (m, 2H), 4.40 (br d, J = 4.8 Hz, 2H), 3.53 - 3.40 (m, 6H), 2.73 (s, 8H), 2.35 (br s, 4H), 1.78 - 1.70 (m, 2H), 1.52 (s, 6H), 1.38 (s, 9H), 1.23 (br s, 2H). Step E – Synthesis of 3-chloro-N-(3-(2-(piperazin-1-yl)ethoxy)propyl)-4'-((1S,2S)-2-(((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'- biphenyl]-4-carboxamide (14e) To a solution of 14d (150.0 mg.0, 193 μmol, 1.0 equiv) in dioxane (0.5 mL) was added HCl (4.0 M, 145 μL, 3.0 equiv). The mixture was stirred at 20°C for 4 h. The reaction mixture was concentrated under reduced pressure to afford 14e, which was used without further purification. LCMS [M+1, M+3]+= 676.3, 678.3;1H NMR (400 MHz, DMSO-d6) δ 8.80 (br t, J = 5.0 Hz, 1H), 8.55 - 8.49 (m, 1H), 7.75 (s, 1H), 7.68 - 7.61 (m, 3H), 7.49 (br d, J = 8.0 Hz, 1H), 7.24 (br d, J = 8.2 Hz, 2H), 4.41 (br d, J = 5.6 Hz, 6H), 3.80 (br s, 2H), 3.39 (br d, J = 3.4 Hz, 5H), 2.73 (s, 5H), 2.35 (br dd, J = 4.8, 9.6 Hz, 2H), 1.82 - 1.73 (m, 2H), 1.53 (s, 6H), 1.41 (br dd, J = 4.4, 9.0 Hz, 2H). Step F – Synthesis of 3-chloro-N-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)propyl)-4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4- carboxamide (Compound 14) To a solution of 14e (70.0 mg, 103.5 μmol, 1.0 equiv) in DMSO (1 mL) was added DIEA (40.1 mg, 310.5 μmol, 54.1 μL, 3.0 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5,6- difluoroisoindoline-1,3-dione (45.7 mg, 155.3 μmol, 1.5 equiv). The mixture was stirred at 120°C for 6 h, cooled to rt and filtered. The filtrate was purified by preparative HPLC (Waters Xbridge 150mm x 25mm 10µm; water( NH4HCO3)-acetonitrile) to afford Compound 14. LCMS [M+1] = 950.3, 952.3;1H NMR (400 MHz, DMSO-d6) δ 11.11 (br d, J = 1.0 Hz, 1H), 8.80 (br d, J = 5.8 Hz, 1H), 8.41 (br t, J = 5.6 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.67 - 7.60 (m, 3H), 7.50 - 7.45 (m, 1H), 7.45 - 7.41 (m, 1H), 7.23 (br d, J = 8.4 Hz, 2H), 5.10 (dd, J = 5.2, 12.8 Hz, 1H), 4.41 (br d, J = 5.6 Hz, 2H), 3.58 - 3.48 (m, 4H), 3.21 (br s, 5H), 2.98 - 2.78 (m, 2H), 2.60 - 2.53 (m, 7H), 2.39 - 2.31 (m, 1H), 2.08 - 1.92 (m, 3H), 1.76 (quin, J = 6.2 Hz, 2H), 1.52 (s, 6H), 1.41 (td, J = 4.6, 9.2 Hz, 1H), 1.32 - 1.21 (m, 2H). Example 15: Synthesis of Compound 15 To a solution of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.0 g, 3.5 mmol, 1.0 equiv), DIEA (1.4 g, 10.6 mmol, 1.9 mL, 3.0 equiv) and tert-butyl glycinate (557.1 mg, 4.2 mmol, 1.2 equiv) in DMF (10.0 mL) was added T4P (3.1 g, 4.3 mmol, 50.0% purity, 1.2 equiv). The reaction mixture was stirred at 25 °C for 1 h, quenched by water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=1:0 to 3:1) to afford 15a. LCMS [M-55] = 340.0;1H NMR (400 MHz, DMSO-d6) δ 8.81 (bs, 1H), 7.70 - 7.60 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 3.87 (d, J = 6.0 Hz, 2H), 1.44 (s, 9H), 1.31 (s, 12H). Step B – Synthesis of (2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)glycine (15b) Intermediate 15a (1.0 g, 2.5 mmol, 1.0 equiv) was dissolved in HCl / dioxane (4.0 M, 10.0 mL, 15.8 equiv) and the reaction was stirred at 25°C for 30 min. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 15b which was used without additional purification. LCMS [M+1] = 340.0;1H NMR (400 MHz, DMSO-d6) δ 8.79 (t, J = 6.0 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 3.91 (d, J = 6.0 Hz, 2H), 1.31 (s, 12H). Step C – Synthesis of tert-butyl 4-((1-((2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoyl)glycyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (15c) To a solution of 15b (600.0 mg, 1.8 mmol, 1.0 equiv), DIEA (685.1 mg, 5.3 mmol, 923.3 μL, 3.0 equiv) and tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (600.9 mg, 2.1 mmol, 1.2 equiv) in DMF (6.0 mL) was added T4P (1.9 g, 2.7 mmol, 50% in DMF, 1.5 equiv). The reaction mixture was stirred at 25 °C for 1 h. The mixture was cooled to 25°C quenched by water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=1:0 to 1:1) to give 15c. LCMS [M+1] = 605.2;1H NMR (400 MHz, DMSO-d6) δ 8.48 (t, J = 5.6 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.51 (d, J = 7.6 Hz, 1H), 4.33 (d, J = 13.2 Hz, 1H), 4.10 (d, J = 6.0 Hz, 2H), 3.84 (d, J = 12.4 Hz, 1H), 3.29 (s, 4H), 3.06 - 2.96 (m, 1H), 2.64 - 2.58 (m, 1H), 2.32 - 2.24 (m, 5H), 2.13 (d, J = 7.2 Hz, 2H), 1.83 - 1.67 (m, 4H), 1.39 (s, 9H), 1.31 (s, 12H). Step D – Synthesis of tert-butyl 4-((1-((3-chloro-4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4- carbonyl)glycyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (15d) To solution of 15c (490.9 mg, 811.6 μmol, 1.4 equiv), Int 3 (250.0 mg, 579.7 μmol, 1.0 equiv) and Pd(dppf)Cl2•CH2Cl2 (47.3 mg, 57.9 μmol, 0.1 equiv) in dioxane (2.5 mL) and water (0.5 mL) was added K2CO3 (240.4 mg, 1.7 mmol, 3.0 equiv) under nitrogen at 25°C. The reaction was stirred at 80°C for 2 h, cooled to ambient temperature quenched by water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate: methanol=1:0 to 10:1) to afford 15d. LCMS [M+1] = 829.4;1H NMR (400 MHz, DMSO-d6) δ 8.75 (br t, J = 4.6 Hz, 1H), 8.49 - 8.41 (m, 1H), 7.76 (s, 1H), 7.72 - 7.62 (m, 3H), 7.57 (br d, J = 8.0 Hz, 2H), 7.28 - 7.20 (m, 2H), 4.44 - 4.30 (m, 3H), 3.95 - 3.80 (m, 2H), 3.07 - 2.95 (m, 2H), 2.38 - 2.24 (m, 9H), 2.14 (br d, J = 6.6 Hz, 3H), 1.84 - 1.66 (m, 5H), 1.52 (s, 6H), 1.39 (s, 9H), 1.07 (s, 3H). Step E – Synthesis of 3-chloro-N-(2-oxo-2-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethyl)-4'- ((1S,2S)-2-(((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-carboxamide (15e) A solution of Intermediate 15d (230.0 mg, 277.3 μmol, 1.0 equiv) in HCl / dioxane (4.0 M, 3.0 mL, 43.2 equiv) was stirred at ambient temperature for 1 h. Concentrated under reduced pressure afforded 15e, which was used without further purification. LCMS [M+1] = 729.3;1H NMR (400 MHz, DMSO-d6) δ 11.53 - 11.31 (m, 1H), 9.88 - 9.60 (m, 1H), 8.78 (br t, J = 5.4 Hz, 1H), 8.53 - 8.48 (m, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.72 - 7.63 (m, 3H), 7.57 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 4.44 - 4.30 (m, 6H), 4.15 - 4.10 (m, 2H), 3.94 - 3.85 (m, 1H), 3.79 - 3.67 (m, 2H), 3.40 - 3.35 (m, 1H), 3.33 - 3.21 (m, 2H), 3.12 - 2.98 (m, 3H), 2.68 - 2.59 (m, 1H), 2.38 - 2.30 (m, 2H), 2.05 - 1.97 (m, 2H), 1.53 (s, 6H), 1.45 - 1.38 (m, 1H), 1.33 - 1.26 (m, 1H), 1.25 - 1.17 (m, 1H), 1.13 - 1.01 (m, 2H). Step F – Synthesis of 3-chloro-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-4'-((1S,2S)-2-(((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'- biphenyl]-4-carboxamide (Compound 15) To a solution of 15e (100.0 mg, 137.1 μmol, 1.0 equiv.) in DMSO (1.0 mL) was added DIEA (17.7 mg, 137.1 μmol, 23.9 μL, 1.0 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5,6- difluoroisoindoline-1,3-dione (60.5 mg, 205.7 μmol, 1.5 equiv). The mixture was stirred at 80°C for 1hr, cooled to ambient temperature and filtered. The filtrate was purified by prep HPLC(Phenomenex Luna C18150mm x 25mm, 10µm; water(formic acid)-acetonitrile) to give Compound 15. LCMS [M+1] = 1003.4;1H NMR (400 MHz, DMSO-d6) δ 14.05 - 13.77 (m, 1H), 11.11 (s, 1H), 8.77 (br s, 1H), 8.47 (t, J = 5.6 Hz, 1H), 8.17 (s, 1H), 7.78 - 7.74 (m, 1H), 7.73 - 7.69 (m, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 5.11 (dd, J = 5.4, 12.8 Hz, 1H), 4.45 - 4.34 (m, 3H), 4.13 (br d, J = 5.8 Hz, 2H), 3.88 (br d, J = 13.4 Hz, 1H), 3.05 (br t, J = 11.8 Hz, 2H), 2.89 (ddd, J = 5.2, 13.8, 17.0 Hz, 1H), 2.69 - 2.60 (m, 2H), 2.59 - 2.53 (m, 5H), 2.40 - 2.31 (m, 2H), 2.22 (br d, J = 6.8 Hz, 2H), 2.11 - 1.96 (m, 3H), 1.89 - 1.73 (m, 3H), 1.54 (s, 6H), 1.47 - 1.40 (m, 1H), 1.34 - 1.28 (m, 1H), 1.20 - 1.04 (m, 2H), 1.04 - 0.92 (m, 1H). Example 16: Synthesis of Compound 16

[0013] Step A – Synthesis of tert-butyl 4-[4-[[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl]amino]-1- piperidyl]piperidine-1-carboxylate (16a) To a solution of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.5 g, 1.77 μmol, 1.0 equiv) in DMF (5 mL) was added DIEA (686.18 mg, 5.31 mmol, 924.77 μL, 3 equiv), HOBt (358.7 mg, 2.65 mmol, 1.5 equiv) and EDCI (508.9 mg, 2.65 mmol, 1.5 equiv) and the mixture was stirred at 25°C for 30 minutes. The mixture was treated with tert-butyl 4-(4- amino-1-piperidyl)piperidine-1-carboxylate (501.6 mg, 1.77 mmol, 1 equiv) and stirred at 25°C for 12 h. The reaction mixture was diluted with water (8 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic portions were washed with brine (5 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane / methanol = 100: 1 to 100: 10) to afford 16a. LCMS: [M+1] = 548.3, 550.3;1H NMR (400MHz, methanol-d4): δ 7.73 (s, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 4.16 (d, J = 13.2 Hz, 2H), 3.85-3.96 (m, 1H), 3.02- 3.12 (m, 2H), 2.69-2.84 (m, 2H), 2.67- 2.57 (m, 1H), 2.50 (t, J = 11.6 Hz, 2H), 1.99 - 2.11 (m, 2H), 1.91 (br d, J = 11.6 Hz, 2H), 1.59-1.74 (m, 2H), 1.46 (s, 9H), 1.39-1.44 (m, 2H), 1.32-1.39 (m, 12H). Step B – Synthesis of tert-butyl 4-[4-[[2-chloro-4-[4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methylcarbamoyl]cyclopropyl]phenyl]benzoyl]amino]-1- piperidyl]piperidine-1-carboxylate (16b) To a solution of Intermediate 3 (104.9 mg, 243.3 μmol, 1 equiv) in dioxane (3 mL) and water (0.5 mL) was added 16a (200 mg, 365.0 μmol, 1.5 equiv), Pd(dppf)Cl2•CH2Cl2 (19.9 mg, 24.3 μmol, 0.1 equiv) and K2CO3 (100.9 mg, 730.0 μmol, 3 equiv) at 25°C. The mixture was three-fold degassed and purged with nitrogen, stirred at 100°C for 16 h under nitrogen. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol = 100: 1 to 100: 10) to afford 16b. LCMS: [M+1] = 772.5, 773.7l;1H NMR (400MHz, methanol-d4): δ 7.69 (d, J = 1.6 Hz, 1H), 7.54-7.64 (m, 3H), 7.48 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 5.49 (s, 2H), 4.55 - 4.50 (m, 2H), 4.16 (d, J = 13.2 Hz, 2H), 3.98 - 3.86 (m, 1H), 3.07 (br d, J = 12.4 Hz, 2H), 2.76 (br s, 2H), 2.65 - 2.56 (m, 1H), 2.42-2.55 (m, 3H), 2.06 (d, J = 11.2 Hz, 2H), 1.96-2.02 (m, 1H), 1.91 (d, J = 11.6 Hz, 2H), 1.64-1.73 (m, 2H), 1.60 (s, 6H), 1.46 (s, 9H), 1.27-1.42 (m, 4H). Step C – Synthesis of 2-chloro-N-[1-(4-piperidyl)-4-piperidyl]-4-[4-[(1S,2S)-2-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methylcarbamoyl]cyclopropyl]phenyl]benzamide (16c) To a solution of 16b (100 mg, 129.5 μmol, 1 equiv) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at 25°C. The mixture was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to give 16c, which was used without further purification. LCMS: [M+1] = 672.5, 674.5;1H NMR (Methanol-d4, 400MHz): δ 7.72 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 4.55 (d, J = 2.0 Hz, 2H), 4.25 - 4.10 (m, 1H), 3.53-3.77 (m, 6H), 3.07-3.16 (m, 2H), 2.45-2.53 (m, 1H), 2.32-2.44 (m, 4H), 1.77-2.17 (m, 6H), 1.60 (s, 6H), 1.39 - 1.27 (m, 2H). Step D – Synthesis of 2-chloro-N-[1-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin- 5-yl]-4-piperidyl]-4-piperidyl]-4-[4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methylcarbamoyl]cyclopropyl]phenyl]benzamide (Compound 16) To a solution of 16c (90 mg, 114.5 μmol, 1 equiv) in DMSO (1 mL) was added DIEA (74.0 mg, 572.4 μmol, 99.7 μL, 5 equiv) and 2-(2,6-dioxo-3-piperidyl)-5,6-difluoro-isoindoline- 1,3-dione (50.5 mg, 171.7 μmol, 1.5 equiv). The mixture was three-fold degassed and purged with nitrogen and then stirred at 70°C for 12 h under a nitrogen atmosphere. The reaction mixture was purified directly by preparative HPLC (Waters Xbridge C18150mm x 50mm, 10µm; H2O (10 mM NH4HCO3) - acetonitrile) to give Compound 16. LCMS: [M+1] = 946.5, 948.5;1H NMR (Methanol-d4, 400MHz): δ 7.70 (d, J = 1.6 Hz, 1H), 7.45-7.65 (m, 6H), 7.25 (d, J = 8.4 Hz, 2H), 5.09 (dd, J = 2.0, 8.4 Hz, 1H), 4.55 (d, J = 2.0 Hz, 2H), 3.98 - 3.87 (m, 1H), 3.76 (d, J = 12.0 Hz, 2H), 3.09 (d, J = 12.0 Hz, 2H), 2.92 (t, J = 11.6 Hz, 2H), 2.81-2.88 (m, 1H), 2.65-2.78 (m, 2H), 2.52-2.62 (m, 1H), 2.40-2.52 (m, 3H), 1.97-2.16 (m, 6H), 1.65-1.80 (m, 4H), 1.60 (s, 6H), 1.58 - 1.54 (m, 1H), 1.32-1.37 (m, 1H). Example 17: Synthesis of Compound 17

[0014] To a solution of 5-bromo-3-methyl-1H-indazole (1.0 g, 4.7 mmol, 1.0 equiv) and tert- butyl-2-bromoacetate (1.3 g, 7.1 mmol, 1.0 mL, 1.5 equiv) in DMF (10.0 mL) was added Cs2CO3(2.3 g, 7.1 mmol, 1.5 equiv). The mixture was stirred at 20°C for 1 h, diluted with water (15 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (2 x 15 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=10:1 to 0:1) to afford 17a. LCMS [M-55] = 269.0, 271.0;1H NMR (400 MHz, CHLOROFORM-d) δ 7.81 (d, J = 1.2 Hz, 1H), 7.46 (dd, J = 1.8, 8.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 4.96 (s, 2H), 2.55 (s, 3H), 1.44 (s, 9H). Step B – Synthesis of tert-butyl 2-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indazol-1-yl]acetate (17b) To a solution of 17a (600.0 mg, 1.8 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (702.7 mg, 2.7 mmol, 1.5 equiv) in dioxane (6.0 mL) was added potassium acetate (543.2 mg, 5.5 mmol, 3.0 equiv) and Pd(dppf)Cl2 (135.0 mg, 184.5 μmol, 0.1 equiv). The mixture was stirred at 100°C for 16 h cooled to ambient temperature, diluted with water (3 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (2 x 2 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane : methanol=100 :1 to 0 :1) to afford 17b. LCMS [M+1] = 373.3;1H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1H), 7.81 (dd, J = 0.6, 8.5 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 2.60 (s, 3H), 1.40 (d, J = 17.2 Hz, 21H). Step C – Synthesis of tert-butyl 2-[3-methyl-5-[4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methylcarbamoyl]cyclopropyl]phenyl]indazol-1-yl]acetate (17c) To a solution of 17b (258.9 mg, 695.6 μmol, 1.5 equiv) and Intermediate 3 (200.0 mg, 463.7 μmol, 1.0 equiv) in tetrahydrofuran (4 mL) and water (1.0 mL) was added K3PO4 (295.3 mg, 1.3 mmol, 3.0 equiv) and Pd(dppf)Cl2 (60.4 mg, 92.7 μmol, 0.2 equiv) under nitrogen. The mixture was stirred at 80°C for 16 h, cooled to ambient temperature, treated with water (3 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (2 x 2 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane : methanol=100 :1 to 0 : 1) afford 17c. LCMS [M+1] = 597.4 Step D – Synthesis of 2-[3-methyl-5-[4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methylcarbamoyl]cyclopropyl]phenyl]indazol-1-yl]acetic acid (17d) To a solution of 17c (200.0 mg, 335.2 μmol, 1.0 equiv) in dichloromethane (2.0 mL) was added trifluoroacetic acid (614.0 mg, 5.3 mmol, 0.4 mL, 16.0 equiv) . The mixture was stirred at 20°C for 16 h. The mixture was concentrated under reduced pressure to afford 17d, which was used without further purification. LCMS [M+1] = 541.4. Step E – Synthesis of (1S,2S)-2-[4-[1-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo- isoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidyl]-2-oxo-ethyl]-3-methyl-indazol-5-yl]phenyl]- N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]cyclopropanecarboxamide (Compound 17) To a solution of 17d (180.0 mg, 333.0 μmol, 1.0 equiv) in DMF (2.0 mL) was added T4P (527.8 mg, 732.6 μmol, 50% purity, 2.2 equiv) and DIEA (215.1 mg, 1.6 mmol, 290.0 μL, 5.0 eq). The reaction was stirred at 20°C for 15 min. Then 2-(2,6-dioxo-3-piperidyl)-5-fluoro-6-[4-(4- piperidylmethyl)piperazin-1-yl]isoindoline-1,3-dione (285.6 mg, 499.5 μmol, 1.5 equiv) was added and the resulting mixture was stirred at 20°C for 1 h. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (2 x 2 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18100mm x 30mm, 5µm; H2O (0.2% formic acid)-acetonitrile) to afford Compound 17. LCMS [M+1] = 980.4;1H NMR (400 MHz, CHLOROFORM-d) δ 8.52 - 8.44 (m, 1H), 8.40 (br s, 1H), 7.75 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.46 - 7.40 (m, 1H), 7.39 - 7.35 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.84 (br s, 1H), 5.30 - 5.12 (dd, J = 16.4, 16.0 Hz, 2H), 4.94 (dd, J = 5.2, 12.2 Hz, 1H), 4.61 - 4.50 (m, 3H), 4.05 (br d, J = 13.4 Hz, 1H), 3.29 (br s, 4H), 3.14 - 3.03 (m, 1H), 2.98 - 2.86 (m, 1H), 2.86 - 2.69 (m, 2H), 2.65 (br s, 4H), 2.61 - 2.53 (m, 4H), 2.30 (br s, 2H), 2.20 - 2.11 (m, 1H), 1.92 - 1.74 (m, 3H), 1.74 - 1.65 (m, 2H), 1.62 (s, 6H), 1.44 - 1.25 (m, 2H), 1.17 - 0.95 (m, 2H), 0.93 - 0.83 (m, 1H). Example 18: Synthesis of Compound 18

[0015] Step A – Synthesis of tert-butyl 3-[4-(4-bromophenyl)pyrazol-1-yl]azetidine-1-carboxylate (18a) To a solution of 4-(4-bromophenyl)-1H-pyrazole (1.2 g, 5.38 mmol, 1.0 equiv) in DMF (15 mL) was added cesium carbonate (3.51 g, 10.76 mmol, 2.0 equiv) and tert-butyl 3- methylsulfonyloxyazetidine-1-carboxylate (2.03 g, 8.07 mmol, 1.5 equiv). The mixture was heated at 70°C for 16 h, cooled to ambient temperature and partitioned between ethyl acetate (60.0 mL) and water (60.0 mL). The organic phase was separated, washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane : methanol=1 / 0 to 95 / 5) to afford 18a. LCMS [M-55] = 322.0, 324.0;1H NMR (400 MHz, CHLOROFORM-d) δ 7.83 (s, 1H), 7.77 (s, 1H), 7.53 - 7.45 (m, 2H), 7.39 - 7.33 (m, 2H), 5.08 (tt, J = 5.5, 7.8 Hz, 1H), 4.45 - 4.29 (m, 4H), 1.47 (s, 9H). Step B – Synthesis of 1-(azetidin-3-yl)-4-(4-bromophenyl)pyrazole (18b) To a solution of 18a (1.8 g, 4.76 mmol, 1.0 equiv) in dichloromethane (25 mL) was added trifluoroacetic acid (3.91 mL). The mixture was stirred at 25°C for 2 h and then concentrated under reduced pressure to afford 18b, which was used without further purification. LCMS [M+1] = 278.0, 280.0;1H NMR (400 MHz, DMSO-d6) δ 9.10 (bs, 2H), 8.36 (s, 1H), 8.16 (s, 1H), 7.57 (s, 4H), 5.44 - 5.34 (m, 1H), 4.46 - 4.34 (m, 4H). Step C – Synthesis of tert-butyl 4-[2-[3-[4-(4-bromophenyl)pyrazol-1-yl]azetidin-1- yl]acetyl]piperazine-1-carboxylate (18c) To a solution of 18b (500 mg, 1.27 mmol, 1.0 eq, TFA) and tert-butyl 4-(2- bromoacetyl)piperazine-1-carboxylate (352.48 mg, 1.15 mmol, 0.9 eq) in acetonitrile (5.0 mL) was added DIEA (329.56 mg, 2.55 mmol, 444.15 μL, 2.0 eq). The mixture was stirred at 20°C for 4 h and then partitioned between ethyl acetate (40 mL) and water (40 mL). The organic phase was separated, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane : methanol=1 / 0 to 97 / 3) to afford 18c. LCMS [M+1] = 504.2, 506.2. Step D – Synthesis of tert-butyl 4-[2-[3-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]pyrazol-1-yl]azetidin-1-yl]acetyl]piperazine-1-carboxylate (18d) To a solution of 18c (200 mg, 396.50 μmol, 1.0 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (141.0 mg, 555.1 μmol, 1.4 equiv), potassium acetate (116.7 mg, 1.19 mmol, 3.0 equiv), Pd(dppf)Cl2(32.4 mg, 39.7 μmol, 0.1 equiv) in dioxane (0.5 mL) was three-fold degassed and purged with nitrogen and then the mixture was stirred at 100°C for 16 h under an atmosphere of nitrogen. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30mL). The organic phase was separated, washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography by preparative TLC (silica gel, dichloromethane: methanol = 10:1) to afford 18d. LCMS [M+1] = 552.3. Step E – Synthesis of tert-butyl 4-[2-[3-[4-[4-[4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methylcarbamoyl]cyclopropyl]phenyl]phenyl]pyrazol-1-yl]azetidin- 1-yl]acetyl]piperazine-1-carboxylate (18e) To a solution of 18d (80 mg, 145 μmol, 1.2 equiv), Intermediate 3 (52.1 mg, 120.9 μmol, 1.0 equiv), Pd(dppf)Cl2(49.4 mg, 60.4 μmol, 0.5 equiv), potassium carbonate (50.1 mg, 362.7 μmol, 3.0 equiv) in dioxane (0.4 mL) and water (0.1 mL) was three-fold degassed and purged with nitrogen. The mixture was stirred at 100°C for 2 h under N2 atmosphere. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phase was separated, washed with brine 30 mL (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (silica gel, dichloromethane: methanol = 10:1) to afford 18e. LCMS [M+1]+= 776.6. Step F – Synthesis of (1S,2S)-2-[4-[4-[1-[1-(2-oxo-2-piperazin-1-yl-ethyl)azetidin-3-yl]pyrazol-4- yl]phenyl]phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]cyclopropanecarboxamide (18f) To a solution of 18e (58.0 mg, 74.8 μmol, 1.0 equiv) in dichloromethane (0.5 mL) was added TFA (171 μL). The mixture was stirred at 20°C for 1 h and then concentrated under reduced pressure to afford 18f, which was used without further purification. LCMS [M+1] = 676.6. Step G – Synthesis of (1S,2S)-2-[4-[4-[1-[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo- isoindolin-5-yl]piperazin-1-yl]-2-oxo-ethyl]azetidin-3-yl]pyrazol-4-yl]phenyl]phenyl]-N-[[3- (2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide (Compound 18) To a solution of 18f (56 mg, 70.91 μmol, 1.0 equiv) and 2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (31.3 mg, 106 μmol, 1.5 equiv) in DMSO (0.5 mL) was added DIEA (27.5 mg, 212 μmol, 37 μL, 3.0 equiv). The mixture was stirred at 70°C for 16 h, cooled to ambient temperature and partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol = 10:1) to afford Compound 18. LCMS [M+1] = 950.4;1H NMR (400 MHz, DMSO-d6) δ 14.04 - 13.79 (br s, 1H), 11.21 - 10.99 (br s, 1H), 8.77 (br s, 1H), 8.42 (s, 1H), 8.00 (s, 1H), 7.77 (d, J = 11.2 Hz, 1H), 7.71 - 7.56 (m, 6H), 7.50 (d, J = 7.4 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 5.16 - 4.97 (m, 2H), 4.41 (br d, J = 5.4 Hz, 2H), 3.85 (t, J = 7.4 Hz, 2H), 3.67 - 3.60 (m, 4H), 3.60 - 3.46 (m, 4H), 3.24 (br s, 3H), 2.96 - 2.81 (m, 1H), 2.70 - 2.54 (m, 2H), 2.33 (br s, 2H), 2.08 - 1.94 (m, 2H), 1.53 (s, 6H), 1.46 - 1.37 (m, 1H), 1.33 - 1.20 (m, 1H). Example 19: Synthesis of Compound 19 tert-butyl 4-(bromomethyl)piperidine-1-carboxylate in Step A to afford (1S,2S)-2-[4-[4-[1-[[1-[2-[4- [2- (2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl] piperazin-1-yl]-2-oxo-ethyl] -4- piperidyl]methyl]pyrazol-4-yl]phenyl]phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide (Compound 19). LCMS: [M+1] = 992.5;1H NMR (400 MHz, DMSO-d6) δ 13.91 (s, 1H), 11.11 (s, 1H), 8.78 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.91 (s, 1H), 7.76 (d, J = 11.2 Hz, 1H), 7.65 - 7.57 (m, 6H), 7.49 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 5.12 (dd, J = 5.2, 12.8 Hz, 1H), 4.41 (d, J = 4.4 Hz, 2H), 4.01 (d, J = 6.8 Hz, 2H), 3.76 - 3.71 (m, 2H), 3.63 - 3.58 (s, 2H), 3.27 - 3.14 (m, 6H), 2.93 - 2.76 (m, 3H), 2.64 - 2.53 (m, 2H), 2.36 - 2.29 (m, 1H), 2.09 - 1.91 (m, 4H), 1.88 - 1.77 (m, 1H), 1.53 (s, 6H), 1.49 (s, 1H), 1.44 - 1.38 (m, 1H), 1.32 - 1.22 (m, 3H). Example 20: Synthesis of Compound 20

[0016] To a solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (5.0 g, 26.7 mmol, 1.0 equiv) in tetrahydrofuran (50.0 mL) was added PPh3 (8.4 g, 32.0 mmol, 1.2 equiv) and pyridin-4- ol (3.0 g, 32.0 mmol, 1.2 equiv). DIAD (6.4 g, 32.0 mmol, 6.2 mL, 1.2 equiv) was added at 0°C. The mixture was stirred at 55°C for 16 h, cooled to ambient temperature and treated with water (5 mL). The mixture was extracted with ethyl acetate (3 x 10 mL) and the combined organic phase was washed with brine (10 mL). Then the organic phase was dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (silica gel, dichloromethane / methanol=15 / 1 to 10 / 1) to afford 20a. LCMS [M+1] =265.0;1H NMR (400 MHz, DMSO-d6) δ = 8.42 - 8.36 (m, 2H), 7.01 - 6.95 (m, 2H), 5.12 (br s, 1H), 3.64 - 3.52 (m, 1H), 3.49 - 3.35 (m, 2H), 3.31 - 3.25 (m, 1H), 2.26 - 1.98 (m, 2H), 1.39 (br d, J = 5.6 Hz, 9H) Step B – Synthesis of tert-butyl (3S)-3-(4-piperidyloxy)pyrrolidine-1-carboxylate (20b) To a solution of 20a (1.0 g, 3.7 mmol, 1.0 equiv) in ethanol (10.0 mL) was added H2SO4 (371.0 mg, 3.7 mmol, 201.6 μL, 1.0 equiv) and PtO2(257.7 mg, 1.1 mmol, 0.3 equiv) under a nitrogen atmosphere. The suspension was three-fold degassed and purged with hydrogen. The mixture was stirred under hydrogen (1 atm) at 25°C for 16 h. The reaction mixture was filtered to remove solids and the filtrate was poured into NaOH (1M). Volatile components were removed under reduced pressure and the resulting mixture was extracted with dichloromethane (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated under reduced pressure to afford 20b. LCMS [M+1] =271.1;1H NMR (400 MHz, DMSO-d6) δ = 4.25 - 4.12 (m, 1H), 3.39 - 3.11 (m, 6H), 2.87 (br d, J = 12.4 Hz, 2H), 2.41 (br t, J = 11.2 Hz, 2H), 1.89 - 1.72 (m, 4H), 1.39 (s, 9H), 1.30 - 1.12 (m, 2H). Step C – Synthesis of tert-butyl (3S)-3-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo- isoindolin-5-yl]-4-piperidyl]oxy]pyrrolidine-1-carboxylate (20c) To a solution of 20b (183.7 mg, 679.7 μmol, 1.0 equiv) in DMSO (3.0 mL) was added 2- (2,6-dioxo-3-piperidyl)-5,6-difluoro-isoindoline-1,3-dione (200.0 mg, 679.7 μmol, 1.0 equiv) and DIEA (439.2 mg, 3.4 mmol, 592.0 μL, 5.0 equiv). The suspension was three-fold degassed and purged with nitrogen, stirred at 70°C for 12 h, cooled to ambient temperature and treated with water (5 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic portions were washed with brine (10 mL). The organic phase was dried by anhydrous sodium sulfate, filtered and filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol = 10:1) to afford 20c. LCMS [M+1] = 545.3;1H NMR (400 MHz, DMSO-d6) δ = 11.20 - 11.03 (m, 1H), 7.71 (d, J = 11.6 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 4.23 (br s, 1H), 3.66 - 3.56 (m, 1H), 3.48 (br d, J = 12.8 Hz, 2H), 3.42 - 3.34 (m, 1H), 3.29 - 3.20 (m, 2H), 3.05 (br t, J = 10.0 Hz, 2H), 2.94 - 2.83 (m, 1H), 2.65 - 2.53 (m, 2H), 2.12 - 1.83 (m, 6H), 1.66 - 1.50 (m, 2H), 1.40 (s, 9H). Step D – Synthesis of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-6-[4-[(3S)-pyrrolidin-3-yl]oxy-1- piperidyl]isoindoline-1,3-dione (20d) The mixture of 20c (190.0 mg, 348.9 μmol, 1 equiv) in trifluoroacetic acid (5 mL) and dichloromethane (1 mL) was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure. The residue was triturated with MTBE (5 mL) at 25°C for 20 min to afford 20d. LCMS [M+1] = 445.3;1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.09 - 8.67 (m, 2H), 7.72 (d, J = 11.6 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 4.40 (br s, 1H), 3.66 - 3.62 (m, 2H), 3.52 - 3.45 (m, 2H), 3.31 - 3.16 (m, 4H), 3.06 - 3.02 (m, 1H), 2.92 - 2.84 (m, 1H), 2.65 - 2.52 (m, 2H), 2.12 - 1.91 (m, 6H), 1.66 - 1.50 (m, 2H). Step E – Synthesis of (1S,2S)-2-[4-[4-[1-[2-[(3S)-3-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3- dioxo-isoindolin-5-yl]-4-piperidyl] oxy]pyrrolidin-1-yl]-2-oxo-ethyl]pyrazol-4-yl]phenyl]phenyl]- N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]cyclopropanecarboxamide (Compound 20) To a solution of 20d (67.5 mg, 152.0 μmol, 1.2 equiv) in DMF (1.5 mL) was added 13d (70.0 mg, 126.6 μmol, 1.0 equiv) and DIEA (81.8 mg, 633.4 μmol, 110.3 μL, 5.0 equiv). The mixture was treated with T4P (136.9 mg, 190.0 μmol, 50% in DMF, 1.5 equiv). The mixture was stirred at 25°C for 1 h. The mixture was treated with water (5 mL), extracted with ethyl acetate (3 x 10 mL). The combined organic portions were washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC Waters Xbridge BEH C18100mm x 30mm, 10µm; water(10mM NH4HCO3)-acetonitrile) to afford Compound 20. LCMS [M+1] = 979.3;1H NMR (400 MHz, Methanol-d4) δ 8.05 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 4.4 Hz, 1H), 7.69 - 7.41 (m, 8H), 7.25 - 7.18 (m, 2H), 5.18 - 5.01 (m, 3H), 4.66 - 4.48 (m, 2H), 4.48 - 4.30 (m, 1H), 3.81 - 3.41 (m, 8H), 3.17 - 2.99 (m, 3H), 2.93 - 2.80 (m, 1H), 2.80 - 2.64 (m, 2H), 2.52 - 2.43 (m, 1H), 2.29 - 1.94 (m, 6H), 1.82 - 1.68 (m, 2H), 1.66 - 1.53 (m, 6H), 1.42 - 1.25 (m, 2H). Example 21: Synthesis of Intermediate 21 (Int 21) a mg, acid (62.3 mg, 695.6 μmol, 3 equiv) in EtOH (1 mL) was added DIEA (299.6 mg, 2.32 mmol, 403.9 μL, 10 equiv) and Pd(dppf)Cl2 (3.02 mg, 4.64 μmol, 0.02 equiv). The mixture was three-fold degassed and purged with nitrogen and stirred at 50°C for 2 h under an atmosphere of nitrogen. The mixture was concentrated under reduced pressure to give [4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methylcarbamoyl]cyclopropyl]phenyl]boronic acid (Intermediate 21), which was used without further purification. Example 22: Synthesis of Compound 22

[0017] S ep – Syn es s o me y -( -bromopyrazo - -y ) benzoa e ( a) To a solution of 4-bromo-1H-pyrazole (980.0 mg, 6.67 mmol, 1.2 equiv), (4- methoxycarbonylphenyl)boronic acid (1 g, 5.56 mmol, 1 equiv) in dichloromethane (20 mL) was added pyridine (879.0 mg, 11.1 mmol, 897.0 μL, 2 equiv) and Cu(OAc)2 (2.02 g, 11.1 mmol, 2 equiv) and purged with oxygen. The mixture was stirred at 20°C for 16 h under oxygen (1 atm). The mixture was quench with water (100 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 0 to 10 / 1) to afford 22a. LCMS [M+1] = 281.2, 283.2;1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.10 - 8.04 (m, 2H), 8.01 - 7.94 (m, 3H), 3.86 (s, 3H). Step B – Synthesis of 4-(4-bromopyrazol-1-yl)benzoic acid (22b) To a solution of 22a (800 mg, 2.85 mmol, 1 equiv) in tetrahydrofuran (4 mL), methanol (4 mL) and water (2 mL) was added LiOH•H2O (358.2 mg, 8.54 mmol, 3 equiv). The mixture was stirred at 20°C for 16 h. The reaction mixture was concentrated under reduced pressure to remove volatile components and then the pH was adjusted to approximately 3 by progressively adding HCl (1 mol / L). The solids were collected by vacuum filtration and the filter cake was dried under vacuum to afford 22b. LCMS [M+1] = 266.9, 268.9;1H NMR (400 MHz, DMSO-d6) δ 13.09 (br s, 1H), 8.92 (s, 1H), 8.08 - 8.03 (m, 2H), 7.98 - 7.94 (m, 3H). Step C – Synthesis of tert-butyl 4-[[1-[4-(4-bromopyrazol-1-yl)benzoyl]-4- piperidyl]methyl]piperazine-1-carboxylate (22c) To a solution of 22b (500 mg, 1.87 mmol, 1 equiv) in DMF (5 mL) was added HATU (783.0 mg, 2.06 mmol, 1.1 equiv) and DIEA (967.8 mg, 7.49 mmol, 1.30 mL, 4 equiv). The reaction was stirred for 5 min at 20°C and then treated with tert-butyl 4-(4- piperidylmethyl)piperazine-1-carboxylate (530.5 mg, 1.87 mmol, 1 equiv). The mixture was stirred at 20°C for 1 h and then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol = 100 / 0 to 96 / 4) to 22c. LCMS [M+1]+= 532.2, 534.2;1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.01 - 7.79 (m, 3H), 7.51 (d, J = 8.5 Hz, 2H), 4.45 (br dd, J = 3.8, 8.3 Hz, 1H), 3.61 (br s, 1H), 3.30 (br s, 4H), 3.20 - 2.95 (m, 2H), 2.31 (br s, 4H), 2.19 (br d, J = 5.5 Hz, 2H), 1.88 - 1.61 (m, 3H), 1.39 (s, 9H), 1.14 - 1.00 (m, 2H). Step D – Synthesis of tert-butyl 4-[[1-[4-[4-[4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methylcarbamoyl]cyclopropyl]phenyl]pyrazol-1-yl]benzoyl]-4- piperidyl]methyl]piperazine-1-carboxylate (22d) To a solution of 22c (134.4 mg, 252.4 μmol, 1 equiv) and Int 21 (100 mg, 252.4 μmol, 1 equiv) in dioxane (2.5 mL) and water (0.5 mL) was added potassium carbonate (104.6 mg, 757.2 μmol, 3 equiv) and Pd(dppf)Cl2(20.6 mg, 25.2 μmol, 0.1 equiv). The mixture was three-fold degassed and purged with nitrogen and stirred at 100°C for 12 h under an atmosphere of nitrogen. The reaction mixture was quenched by addition water (20 mL), and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol = 10: 1) to afford 22d. LCMS [M+1] = 804.5;1H NMR (400 MHz, DMSO-d6) δ 13.87 (br s, 1H), 9.03 (s, 1H), 8.78 (br s, 1H), 8.24 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.41 (br s, 3H), 3.73 - 3.57 (m, 1H), 3.29 (br s, 4H), 3.11 - 2.93 (m, 1H), 2.89 - 2.72 (m, 1H), 2.29 (br d, J = 3.9 Hz, 4H), 2.16 (br d, J = 6.8 Hz, 2H), 1.99 - 1.92 (m, 1H), 2.04 - 1.92 (m, 1H), 1.89 - 1.62 (m, 3H), 1.52 (br s, 6H), 1.39 (s, 9H), 1.33 - 1.20 (m, 2H), 1.14 - 1.00 (m, 2H). Step E – Synthesis of (1S,2S)-2-[4-[1-[4-[4-(piperazin-1-ylmethyl)piperidine-1- carbonyl]phenyl]pyrazol-4-yl]phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl] cyclopropanecarboxamide (22e) To a solution of 22d (80 mg, 99.5 μmol, 1 equiv) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.8 mL), the mixture was stirred at 25°C for 1 h and then concentrated under reduced pressure to afford 22e, which was used without further purification. Step F – Synthesis of (1S,2S)-2-[4-[1-[4-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo- isoindolin-5-yl]piperazin-1-yl]methyl]piperidine-1-carbonyl]phenyl]pyrazol-4-yl]phenyl]-N-[[3- (2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide (Compound 22) To a solution of 22e (0.14 g, 198.9 μmol, 1 equiv) and 2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (87.7 mg, 298.3 μmol, 1.5 equiv) in DMSO (1 mL) was added DIEA (77.1 mg, 596.7 μmol, 103.9 μL, 3 equiv). The mixture was stirred at 70°C for 12 h. The reaction mixture was quenched by addition water (20 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (5 x 10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative-HPLC (column: Phenomenex Luna C18100mm x 30 mm, 5 µm; (H2O (0.2% formic acid)-acetonitrile) to afford Compound 22. LCMS [M+1] = 978.5;1H NMR (400 MHz, DMSO-d6) δ 13.97 - 13.84 (m, 1H), 11.10 (s, 1H), 9.03 (s, 1H), 8.83 - 8.69 (m, 1H), 8.24 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 11.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 7.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 4.40 (d, J = 4.6 Hz, 2H), 3.25 (s, 4H), 3.15 - 2.98 (m, 2H), 2.86 (dd, J = 4.8, 16.6 Hz, 2H), 2.69 - 2.60 (m, 1H), 2.58 - 2.53 (m, 4H), 2.35 - 2.21 (m, 4H), 2.09 - 1.93 (m, 3H), 1.92 - 1.68 (m, 3H), 1.53 (s, 6H), 1.39 (td, J = 4.6, 9.2 Hz, 1H), 1.32 - 1.22 (m, 1H), 1.20 - 1.06 (m, 2H). Example 23: Synthesis of Compound 23 1,2,4-triazol-5-yl]methylcarbamoyl]cyclopropyl]phenyl]phenyl]methyl]piperazine-1-carboxylate (23a) To a solution of Intermediate 3 (200 mg, 463.7 μmol, 1.0 equiv), tert-butyl 4-[[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate (223.9 mg, 556.5 μmol, 1.2 equiv) in dioxane (4.0 mL) and water (1.0 mL) was added potassium carbonate (192.2 mg, 1.3 mmol, 3.0 equiv) and Pd(dppf)Cl2•CH2Cl2(189.3 mg, 231.8 μmol, 0.5 equiv). The mixture was stirred at 100°C for 2 h, cooled to ambient temperature, treated with water 10 mL and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with brine (5 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol = 10:1) to afford 23a. LCMS [M+1] =627.5;1H NMR (400 MHz, DMSO-d6) δ 13.87 (br s, 1H), 8.79 (br s, 1H), 7.58 (t, J = 8.8 Hz, 4H), 7.36 (d, J = 8.2 Hz, 2H), 7.21 (br d, J = 8.2 Hz, 2H), 4.49 - 4.32 (m, 2H), 3.50 (s, 2H), 3.32 - 3.23 (m, 4H), 2.32 (br t, J = 4.6 Hz, 4H), 2.28 - 2.23 (m, 1H), 1.99 (br s, 1H), 1.52 (br s, 6H), 1.39 (s, 9H), 1.33 - 1.21 (m, 2H). Step B – Synthesis of (1S,2S)-2-[4-[4-(piperazin-1-ylmethyl)phenyl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide (23b) A solution of 23a (115 mg, 183.50 μmol, 1.0 equiv) in HCl / dioxane (1.0 mL) was stirred at 25°C for 1 h and then concentrated to dryness to afford 23b, which was used without further purification. LCMS [M+1] = 527.4. Step C – Synthesis of (1S,2S)-2-(4'-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin- 5-yl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)cyclopropane-1-carboxamide (Compound 23) To a solution of 23b (60 mg, 113.9 μmol, 1.0 equiv), 2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (50.2 mg, 170.9 μmol, 1.5 equiv) in DMSO (1.0 mL) was added DIEA (44.1 mg, 341.8 μmol, 59.54 μL, 3.0 equiv). The mixture was stirred at 70°C for 16 h, cooled to ambient temperature and partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol = 10:1) to give Compound 23. LCMS [M+1] = 801.3;1H NMR (400 MHz, DMSO-d6) δ 3.89 (br s, 1H), 11.10 (br s, 1H), 8.76 (br d, J = 2.0 Hz, 1H), 7.72 (d, J = 11.2 Hz, 1H), 7.60 (dd, J = 8.0, 12.4 Hz, 4H), 7.48 - 7.37 (m, 3H), 7.21 (d, J = 8.4 Hz, 2H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 4.41 (br d, J = 4.4 Hz, 2H), 3.58 (s, 2H), 3.27 (br s, 4H), 2.88 (br d, J = 2.0 Hz, 1H), 2.63 - 2.52 (m, 6H), 2.37 - 2.29 (m, 1H), 2.08 - 1.95 (m, 2H), 1.53 (s, 6H), 1.44 - 1.36 (m, 1H), 1.33 - 1.21 (m, 1H). Example 24: Synthesis of Compound 24 was a manner tert-butyl 4-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate in Step A to afford (1S,2S)-2-(4'-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)cyclopropane-1-carboxamide (Compound 24). LCMS [M+1] =801.3;1H NMR (400 MHz, DMSO-d6) δ 13.90 (br s, 1H), 11.10 (br s, 1H), 8.73 (br s, 1H), 7.72 (d, J = 11.2 Hz, 1H), 7.62 - 7.56 (m, 3H), 7.54 (br d, J = 8.0 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 5.10 (dd, J = 5.2, 12.8 Hz, 1H), 4.40 (br d, J = 5.2 Hz, 2H), 3.61 (s, 2H), 3.27 (br s, 4H), 2.94 - 2.82 (m, 1H), 2.58 (br s, 5H), 2.37 - 2.30 (m, 2H), 2.06 - 1.96 (m, 2H), 1.53 (s, 6H), 1.41 (td, J = 4.8, 9.2 Hz, 1H), 1.32 - 1.24 (m, 1H). Example 25: Synthesis of Compound 25 Step A – Synthesis of tert-butyl 4-[[4-[2,6-dimethyl-3-[4-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methylcarbamoyl]pyrazol-1-yl]phenyl]phenyl]methyl]piperazine-1- carboxylate (25a) To a solution of Intermediate 5 (50 mg, 103.0 μmol, 1.0 equiv), tert-butyl 4-[[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate (62.1 mg, 154.5 μmol, 1.5 equiv) in tetrahydrofuran (0.4 mL) and water (0.1 mL) was added K3PO4(65.6 mg, 309.0 μmol, 3 equiv) and Pd(dppf)Cl2(13.4 mg, 20.6 μmol, 0.2 equiv). The mixture was stirred at 80°C for 16 h, cooled to ambient temperature and treated with water (1.0 mL). The mixture was extracted with ethyl acetate (3 x 1 mL). The combined organic portions were washed with brine (1 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol = 10: 1) to afford 25a. LCMS [M+1] = 681.4;1H NMR (400 MHz, DMSO-d6) δ 8.47 - 8.42 (m, 1H), 8.13 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 2.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 4.58 - 4.51 (m, 2H), 3.55 (s, 2H), 3.33 (d, J = 3.6 Hz, 4H), 2.35 (d, J = 4.8 Hz, 4H), 2.02 (s, 3H), 1.76 (s, 3H), 1.51 - 1.50 (m, 1H), 1.53 (s, 6H), 1.39 (s, 9H). Step B – Synthesis of 1-[2,4-dimethyl-3-[4-(piperazin-1-ylmethyl)phenyl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (25b) To a solution of 25a (75 mg, 110.1 μmol, 1.0 equiv) in dichloromethane (0.4 mL) was added trifluoroacetic acid (0.4 mL) the mixture was stirred at ambient temperature for 1 h and then concentrated under reduced pressure to afford 25b, which was used without further purification. LCMS [M+1] = 581.3;1H NMR (400 MHz, DMSO-d6) δ 9.05 (br s, 1H), 8.84 (br s, 1H), 8.46 - 8.39 (s, 1H), 8.14 (s, 1H), 7.60 (s, 2H), 7.36 - 7.29 (m, 4H), 4.54 (d, J = 5.6 Hz, 2H), 4.33 (d, J = 6.4 Hz, 2H), 3.35 - 3.22 (m, 8H), 2.03 (s, 3H), 1.77 (s, 3H), 1.53 (s, 6H). Step C – Synthesis of 1-[3-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]phenyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 25) To a solution of 25b (85.0 mg, 52.9 μmol, 1.0 equiv) in DMSO (1.0 mL) was added 2- (2,6-dioxo-3-piperidyl)-5,6-difluoro-isoindoline-1,3-dione (23.3 mg, 79.3 μmol, 1.5 equiv) and DIEA (68.3 mg, 528.9 μmol, 10.0 equiv) at 100 °C for 16 h. The mixture was cooled to ambient temperature and was purified by preparative HPLC (Waters Xbridge Prep OBD C18150mm x 40 mm, 10 µm; water (10mM NH4HCO3)-acetonitrile;) to afford Compound 25. LCMS [M+1] = 855.4;1H NMR (400 MHz, Methanol-d4) δ 8.30 (s, 1H), 8.14 (s, 1H), 7.57 - 7.48 (m, 4H), 7.28 (d, J = 4.8 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.09 (dd, J = 5.6, 12.4 Hz, 1H), 4.68 (s, 2H), 3.69 (s, 2H), 3.37 - 3.33 (m, 4H), 2.89 - 2.79 (m, 1H), 2.77 - 2.68 (m, 6H), 2.13 (td, J = 2.8, 5.6 Hz, 1H), 2.09 (s, 3H), 1.80 (s, 3H), 1.61 (s, 6H). Example 26: Synthesis of Compound 26 -1H- 1,2,4-triazol-5-yl]methylcarbamoyl]pyrazol-1-yl]phenyl]phenyl]methyl]piperazine-1-carboxylate (26a) A mixture of Intermediate 4 (200.0 mg, 424.3 μmol, 1.0 equiv), tert-butyl 4-[[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate (341.4 mg, 848.7 μmol, 2.0 equiv), Pd(dppf)Cl2.CH2Cl2 (69.3 mg, 84.8 μmol, 0.2 equiv), potassium carbonate (175.9 mg, 1.27 mmol, 3.0 equiv) in dioxane (2.0 mL) and water (0.4 mL) was three-fold degassed and purged with nitrogen. The mixture was stirred at 100°C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature diluted with water (10 mL) and extracted with ethyl acetate (3 x15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane : methanol=50 / 1 to 13 / 1) to afford 26a. LCMS [M+1] = 667.5;1H NMR (400 MHz, CHLOROFORM-d) δ 12.00 (br s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.59 - 7.52 (m, 4H), 7.42 (d, J = 8.0 Hz, 3H), 7.01 - 6.87 (m, 1H), 4.72 (d, J = 5.6 Hz, 2H), 3.57 (s, 2H), 3.46 (s, 4H), 2.44 (s, 4H), 2.30 (s, 3H), 1.63 - 1.60 (m, 6H), 1.47 (s, 9H). Step B – Synthesis of 1-[2-methyl-4-[4-(piperazin-1-ylmethyl)phenyl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (26b) To a solution of 26a (150.0 mg, 224.9 μmol, 1.0 equiv) in dichloromethane (2.0 mL) and trifluoroacetic acid (0.4 mL). The mixture was stirred at ambient temperature for 2 h. The mixture was concentrated under reduced pressure to afford 26b, which was used without further purification. LCMS: [M+1] = 567.4. Step C – Synthesis of 1-[4-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 26) A mixture of 26b (150.0 mg, 220.3 μmol, 1.0 equiv), 2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (129.6 mg, 440.7 μmol, 2.0 equiv) and DIEA (85.4 mg, 661.1 μmol, 115.1 μL, 3.0 equiv) in DMSO (2.0 mL) was three-fold degassed and purged with nitrogen. The mixture was stirred at 100°C for 16 h under a nitrogen atmosphere, cooled to ambient temperature. Purification by reverse-phase HPLC. (Waters Xbridge BEH C18100mm x 30mm, 10µm; H2O(10mM NH4HCO3)-acetonitrile) afforded Compound 26. LCMS: [M+1] = 841.3;1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 8.18 (s, 1H), 7.68 (d, J = 7.2 Hz, 3H), 7.64 - 7.60 (m, 1H), 7.57 - 7.42 (m, 5H), 5.09 (dd, J = 5.4, 12.6 Hz, 1H), 4.70 (s, 2H), 3.68 (s, 2H), 3.36 - 3.32 (m, 4H), 2.91 - 2.80 (m, 1H), 2.79 - 2.64 (m, 6H), 2.31 (s, 3H), 2.17 - 2.09 (m, 1H), 1.66 - 1.54 (m, 6H). Example 27: Synthesis of Compound 27 was a manner tert-butyl 4-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate in Step A to afford 1-[4-[3-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 27). LCMS [M+1] = 841.3;1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H), 11.10 (s, 1H), 9.06 - 8.82 (m, 1H), 8.53 (s, 1H), 8.18 (s, 1H), 7.80 - 7.70 (m, 2H), 7.69 - 7.62 (m, 3H), 7.53 - 7.44 (m, 3H), 7.39 (d, J = 7.6 Hz, 1H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 4.57 (d, J = 4.0 Hz, 2H), 3.64 (s, 2H), 3.27 (s, 4H), 2.94 - 2.82 (m, 1H), 2.64 - 2.55 (m, 6H), 2.31 (s, 3H), 2.10 - 1.94 (m, 1H), 1.64 - 1.47 (m, 6H). Example 28: Synthesis of Compound 28 yl)phenyl]methyl]-4-piperidyl]piperazine-1-carboxylate (28a) To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (215.3 mg, 928.0 μmol, 1.0 equiv) in dichloromethane (4.0 mL) was added tert-butyl-4-(4- piperidyl)piperazine-1-carboxylate (500.0 mg, 1.86 mmol, 2.0 equiv) and acetic acid (55.7 mg, 928.0 μmol, 53.1 μL, 1.0 equiv) the mixture was stirred at 20°C for 1 h and then treated with NaBH(OAc)3(393.3 mg, 1.86 mmol, 2.0 equiv). The resulting mixture was stirred at 20°C for 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3(15 mL), then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane ethanol=15 / 1 to 12 / 1) to afford 28a. LCMS: [M+1] = 486.2. Step B – Synthesis of tert-butyl 4-[1-[[4-[3-methyl-4-[4-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methylcarbamoyl]pyrazol-1-yl]phenyl]phenyl]methyl]-4- piperidyl]piperazine-1-carboxylate (28b) A mixture of 28a (231.7 mg, 477.4 μmol, 1.5 equiv), Intermediate 4 (150.0 mg, 318.2 μmol, 1.0 equiv), potassium carbonate (131.9 mg, 954.8 μmol, 3.0 equiv), Pd(dppf)Cl2•CH2Cl2(51.9 mg, 63.6 μmol, 0.2 equiv) in water (0.2 mL) and dioxane (1.0 mL) was three-fold degassed and purged with nitrogen, and then the mixture was stirred at 100°C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, treated with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic portions were washed with brine (15 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane:methanol=10 / 1) to afford 28b. LCMS: [M+1] = 750.5;1H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (s, 1H), 8.03 (s, 1H), 7.62 - 7.46 (m, 4H), 7.44 - 7.33 (m, 3H), 7.00 (br s, 1H), 4.72 (br d, J = 5.5 Hz, 2H), 3.55 (s, 2H), 3.47 - 3.39 (m, 4H), 3.07 - 2.95 (m, 3H), 2.51 (br s, 4H), 2.36 - 2.25 (m, 3H), 2.02 (br t, J = 10.9 Hz, 2H), 1.78 (br d, J = 11.0 Hz, 2H), 1.68 - 1.55 (m, 6H), 1.51 - 1.43 (m, 9H), 1.38 - 1.29 (m, 2H). Step C – Synthesis of 1-[2-methyl-4-[4-[(4-piperazin-1-yl-1-piperidyl)methyl]phenyl]phenyl]-N- [[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (28c) A solution of 28b (210.0 mg, 280.0 μmol, 1.0 equiv) in trifluoracetic acid (0.2 mL) and dichloromethane (2.0 mL) was stirred at 20°C for 1 h. The mixture was concentrated under reduced pressure to afford 28c. LCMS: [M+1] = 650.6. Step D – Synthesis of 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 28). To a solution of 28c (200.0 mg, 261.8 μmol, 1.0 equiv, TFA) in DMSO (2.0 mL) was added DIEA (101.5 mg, 785.5 μmol, 136.8 μL, 3.0 eq) and 2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (154.0 mg, 523.7 μmol, 2.0 equiv). The mixture was stirred at 100°C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge BEH C18, 100mm x 30mm, 10 µm; water (10mM NH4HCO3)-acetonitrile) to afford Compound 28. LCMS: [M+1] = 924.5;1H NMR (400 MHz, CHLOROFORM-d) δ 12.25 (br s, 1H), 8.46 - 8.36 (m, 1H), 8.24 - 8.13 (m, 1H), 8.02 (s, 1H), 7.59 - 7.53 (m, 3H), 7.52 - 7.45 (m, 2H), 7.44 - 7.34 (m, 4H), 6.94 (br s, 1H), 4.94 (dd, J = 5.2, 12.4 Hz, 1H), 4.72 (d, J = 5.6 Hz, 2H), 3.68 - 3.48 (m, 2H), 3.29 (s, 4H), 3.01 (d, J = 10.4 Hz, 2H), 2.95 - 2.70 (m, 7H), 2.42 - 2.32 (m, 1H), 2.32 - 2.27 (m, 3H), 2.20 - 2.10 (m, 1H), 2.05 (t, J = 10.8 Hz, 2H), 1.84 (d, J = 10.8 Hz, 2H), 1.66 (s, 2H), 1.61 (s, 6H). Example 29: Synthesis of Compound 29 tert-butyl 4-piperazin-1-ylpiperidine-1-carboxylate in Step A to afford 1-[4-[4-[[4-[1-[2-(2,6-dioxo-3- piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]piperazin-1-yl]methyl]phenyl]-2- methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole- 4-carboxamide (Compound 29). LCMS: [M+1] = 924.5;1H NMR (400 MHz, DMSO-d6) δ 13.90 (br s, 1 H), 11.10 (br s, 1 H), 8.87 (br s, 1 H), 8.52 (s, 1 H), 8.17 (s, 1 H), 7.59 - 7.78 (m, 5 H), 7.35 - 7.51 (m, 4 H), 5.10 (m, 1 H), 4.55 (br d, J = 4.8 Hz, 2 H), 3.64 (br d, J = 11.0 Hz, 2 H), 3.50 (br s, 2 H), 2.84 - 2.95 (m, 3 H), 2.61 (br s, 4 H), 2.41 (br d, J = 1.8 Hz, 5 H), 2.30 (s, 4 H), 1.97 - 2.09 (m, 1 H), 1.88 (br d, J = 11.2 Hz, 2 H), 1.54 (s, 9 H). Example 30: Synthesis of Compound 30

[0018] utyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate in Step A to afford 1-(4'-((4-((1-(2-(2,6- dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1- yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide. LCMS [M+1] =938.7;1H NMR (400 MHz, DMSO-d6) δ 13.93 ((br s, 1H), 11.10 (s, 1H), 8.88 (br s, 1H), 8.52 (s, 1H), 8.17 (s, 1H), 7.74 - 7.61 (m, 5H), 7.49 - 7.39 (m, 4H), 5.09 (dd, J = 5.6, 5.2 Hz, 1H), 4.55 (br d, J = 5.6 Hz, 2H), 3.65 - 3.46 (m, 5H), 2.95 - 2.83 (m, 3H), 2.69 - 2.54 (m, 2H), 2.45 - 2.29 (m, 10H), 2.18 (br d, J = 7.2 Hz, 2H), 2.10 - 1.98 (m, 1H), 1.87 - 1.67 (m, 3H), 1.54 (s, 6H), 1.32 - 1.18 (m, 2H). Example 31: Synthesis of Compound 31 butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate in Step A to afford 1-(4'-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide. LCMS [M+1] = 938.7;1H NMR (400 MHz, METHANOL-d4) δ(ppm) = 8.40 (s, 1H), 8.20 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.76 - 7.58 (m, 6H), 7.49 (d, J = 8.3 Hz, 1H), 5.11 (dd, J = 5.5, 12.5 Hz, 1H), 4.75 (s, 2H), 4.42 (s, 2H), 3.89 - 3.72 (m, 4H), 3.62 (br d, J = 12.1 Hz, 2H), 3.51 - 3.43 (m, 2H), 3.42 - 3.35 (m, 2H), 3.27 - 3.21 (m, 2H), 3.16 (br t, J = 11.8 Hz, 2H), 2.93 - 2.81 (m, 1H), 2.79 - 2.65 (m, 2H), 2.33 (s, 4H), 2.26 - 2.17 (m, 2H), 2.13 (br dd, J = 4.8, 10.1 Hz, 1H), 1.79 - 1.58 (m, 8H). Example 32: Synthesis of Compound 32 4-(4-piperidyloxy)piperidine-1-carboxylate in Step A to afford 1-(4'-((4-((1-(2-(2,6- dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)piperidin-1-yl)methyl)- 3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-1H-pyrazole-4-carboxamide. LCMS [M+1] = 939.3;1H NMR (400 MHz, DMSO-d6) δ 13.94 (br s, 1H), 11.10 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 8.18 - 8.15 (m, 1H), 7.74 - 7.62 (m, 5H), 7.48 - 7.39 (m, 4H), 5.10 (dd, J = 5.4, 12.6 Hz, 1H), 4.55 (d, J = 5.0 Hz, 2H), 3.65 (s, 2H), 3.51 (s, 3H), 3.05 (t, J = 10.0 Hz, 3H), 2.95 - 2.81 (m, 2H), 2.75 - 2.66 (m, 2H), 2.61 (s, 1H), 2.56 (s, 1H), 2.30 (s, 3H), 2.13 (t, J = 9.8 Hz, 2H), 2.08 - 2.00 (m, 1H), 1.93 (d, J = 10.8 Hz, 2H), 1.83 (d, J = 9.4 Hz, 2H), 1.61 - 1.57 (m, 1H), 1.54 (s, 6H), 1.47 (d, J = 9.4 Hz, 2H). Example 33: Synthesis of Compound 33

[0019] Compound 33 was prepared in a similar manner to Example 28 by substituting tert-butyl 1,4-diazepane-1-carboxylate in Step A to afford 1-(4'-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-6- fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-1,4-diazepan-1-yl)methyl)-3-methyl-[1,1'- biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H- pyrazole-4-carboxamide. LCMS [M+H] = 938.5;1H NMR (400 MHz, DMSO-d6) δ 13.92 (s, 1H), 11.10 (s, 1H), 8.87 (t, J = 4.4 Hz, 1H), 8.52 (s, 1H), 8.17 (s, 1H), 7.72 - 7.62 (m, 5H), 7.47 - 7.42 (m, 4H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 4.55 (d, J = 6.0 Hz, 2H), 3.66 - 3.64 (m, 4H), 2.91 - 2.84 (m, 3H), 2.80 - 2.77 (m, 4H), 2.66 - 2.58 (m, 6H), 2.30 (s, 3H), 2.07 - 2.01 (m, 2H), 1.83 - 1.80 (m, 2H), 1.73 - 1.70 (m, 2H), 1.63 - 1.57 (m, 2H), 1.54 (s, 6H). Example 34. Synthesis of Compound 34

[0020] Compound 34 was prepared in a similar manner to Example 28 by substituting tert-butyl 4-(4-piperidyl)piperidine-1-carboxylate in Step A to afford 1-(4'-((1'-(2-(2,6-dioxopiperidin-3-yl)- 6-fluoro-1,3-dioxoisoindolin-5-yl)-[4,4'-bipiperidin]-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)- N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4- carboxamide. LCMS [M+1] = 923.3;1H NMR (400 MHz, DMSO-d6) δ 13.92 (br s, 1H), 11.10 (s, 1H), 8.88 (br s, 1H), 8.53 (s, 1H), 8.17 (s, 1H), 7.69 - 7.66 (m, 5H), 7.44 - 7.36 (m, 4H), 5.09 (dd, J = 5.4, 12.7 Hz, 1H), 4.55 (br d, J = 5.4 Hz, 2H), 3.63 (br d, J = 11.2 Hz, 2H), 3.49 (br s, 3H), 2.89 - 2.79 (m, 4H), 2.68 - 2.56 (m, 2H), 2.30 (s, 3H), 2.08 - 1.98 (m, 1H), 1.95 - 1.87 (m, 3H), 1.79 (br d, J = 10.2 Hz, 2H), 1.68 (br d, J = 11.8 Hz, 2H), 1.54 (s, 6H), 1.36 - 1.21 (m, 4H), 1.16 - 1.05 (m, 1H) Example 35: Synthesis of Compound 35-1 and 35-2 Compounds 35-1 and 35-2 were prepared in a similar manner to Example 28 by substituting tert-butyl 4-pyrrolidin-3-ylpiperazine-1-carboxylate in Step A. Chiral resolution of the enantiomers from Step C by SFC (DAICEL CHIRALPAK IG (250mm x 30mm, 10µm), [CO2-MeOH(0.1%NH3.water)]; isocratic elution) afforded the early-eluting isomer that was processed further to afford Compound 35-1, 1-(4'-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro- 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pyrrolidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)- N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4- carboxamide (absolute stereochemistry was not confirmed). LCMS: [M+1] = 910.3;1H NMR (400 MHz, METHANOL-d4) δ 8.36 (s, 1H), 8.18 (s, 1H), 7.70 -7.64 (m, 3H), 7.62 (dd, J = 2.0, 8.0 Hz, 1H), 7.54 (d, J = 11.2 Hz, 1H), 7.51 - 7.41 (m, 4H), 5.08 (dd, J = 5.4, 12.4 Hz, 1H), 4.70 (s, 2H), 3.81 - 3.65 (m, 2H), 3.04 - 2.92 (m, 2H), 2.89 - 2.58 (m, 9H), 2.52 - 2.43 (m, 1H), 2.31 (s, 3H), 2.17 - 2.03 (m, 2H), 1.93 - 1.76 (m, 1H), 1.61 (s, 6H). The late-eluting enantiomer was processed further to afford Compound 35-2, 1-(4'-((3-(4- (2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pyrrolidin-1- yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide (absolute stereochemistry was not confirmed) LCMS: [M+1] = 910.3;1H NMR (400 MHz, METHANOL-d4) δ 8.36 (s, 1H), 8.18 (s, 1H), 7.70 - 7.64 (m, 3H), 7.62 (dd, J = 2.0, 8.0 Hz, 1H), 7.54 (d, J = 11.2 Hz, 1H), 7.51 - 7.41 (m, 4H), 5.08 (dd, J = 5.4, 12.4 Hz, 1H), 4.70 (s, 2H), 3.81 - 3.65 (m, 2H), 3.04 - 2.92 (m, 2H), 2.89 - 2.58 (m, 9H), 2.52 - 2.43 (m, 1H), 2.31 (s, 3H), 2.17 - 2.03 (m, 2H), 1.93 - 1.76 (m, 1H), 1.61 (s, 6H). Example 36: Synthesis of Compound 36 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbaldehyde in Step A to afford 1-(4-(6-((4-(4- (2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1- yl)methyl)pyridin-3-yl)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide. LCMS: [M+1] = 925.5;1H NMR (400 MHz, DMSO-d6) δ 13.90 (br s, 1H), 11.10 (s, 1H), 8.95 - 8.88 (m, 1H), 8.86 (d, J = 2.3 Hz, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 8.12 (dd, J = 2.4, 8.2 Hz, 1H), 7.80 (s, 1H), 7.74 - 7.68 (m, 2H), 7.53 (dd, J = 8.2, 14.4 Hz, 2H), 7.44 (d, J = 7.4 Hz, 1H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 4.55 (br d, J = 2.4 Hz, 2H), 3.64 (s, 2H), 3.24 (br s, 4H), 2.95 - 2.86 (m, 3H), 2.69 - 2.64 (m, 4H), 2.34 - 2.30 (m, 4H), 2.28 - 2.22 (m, 1H), 2.11 - 1.99 (m, 4H), 1.79 (br d, J = 11.0 Hz, 2H), 1.54 (s, 6H), 1.51 - 1.42 (m, 2H). Example 37: Synthesis of Compound 37 3-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde in Step A to afford 1-(2'-chloro-4'-((4- (4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1- yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide. LCMS [M+1] = 958.4;1H NMR (400 MHz, DMSO-d6) δ 14.12 - 13.80 (br s, 1H), 11.10 (br s, 1H), 8.88 (br s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.81 - 7.63 (m, 1H), 7.55 - 7.34 (m, 7H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 4.55 (d, J = 5.8 Hz, 2H), 3.51 (s, 2H), 3.23 (br s, 4H), 2.96 - 2.81 (m, 4H), 2.66 (br d, J = 1.5 Hz, 5H), 2.37 - 2.20 (m, 4H), 2.04 -1.97 (m, 3H), 1.87 - 1.69 (m, 2H), 1.54 (s, 6H), 1.51 - 1.41 (m, 2H) Example 38: Synthesis of Compound 38

[0021] 4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde in Step A to afford 1-(3'-((4-(4-(2-(2,6- dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)methyl)-3- methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-1H-pyrazole-4-carboxamide. LCMS: [M+1] = 924.5;1H NMR (400 MHz, DMSO-d6) δ 13.93 (br s, 1H), 11.09 (s, 1H), 8.88 (s, 1H), 8.53 (s, 1H), 8.18 (br s, 1H), 7.76 - 7.69 (m, 2H), 7.67 - 7.56 (m, 3H), 7.46 (dd, J = 8.4, 16.0 Hz, 3H), 7.34 (d, J = 8.0 Hz, 1H), 5.10 (dd, J = 5.2, 12.8 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 3.54 (s, 2H), 3.23 (s, 5H), 2.96 - 2.82 (m, 3H), 2.68 - 2.55 (m, 5H), 2.31 (s, 3H), 2.26 - 2.12 (m, 1H), 2.08 - 1.92 (m, 3H), 1.78 - 1.75 (m, 2H), 1.54 (s, 6H), 1.50 - 1.36 (m, 2H). Example 39: Synthesis of Compound 39-1 and 39-2 substituting 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethenone in Step A. Separation of enantiomers after Step B by SFC (DAICEL CHIRALPAK AD (250 mm x 30 mm,10µm); [CO2-IPA(0.1%NH3water)]; isocratic elution) afforded the early-eluting enantiomer, which was processed further to afford 39-1 (1-(4'-(1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro- 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)ethyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N- ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4- carboxamide). LCMS [M+1] =938.4;1H NMR (400 MHz, DMSO-d6) δ 13.93 (br s, 1H), 11.10 (s, 1H), 8.88 (br s, 1H), 8.53 (s, 1H), 8.17 (s, 1H), 7.79 - 7.58 (m, 5H), 7.53 - 7.31 (m, 4H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 4.55 (br s, 2H), 3.56 - 3.48 (m, 1H), 3.22 (br s, 4H), 3.04 (br d, J = 9.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.64 (br s, 5H), 2.30 (s, 3H), 2.23 - 2.10 (m, 1H), 2.08 - 1.68 (m, 6H), 1.54 (s, 6H), 1.43 - 1.27 (m, 5H). The late-eluting isomer from the SFC separation was further processed to afford 39-2 LCMS [M+1] = 938.5;1H NMR (400 MHz, DMSO-d6) δ 13.93 (br s, 1H), 11.10 (s, 1H), 8.89 (br s, 1H), 8.53 (s, 1H), 8.17 (s, 1H), 7.76 - 7.58 (m, 5H), 7.52 - 7.35 (m, 4H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 4.55 (br d, J = 5.4 Hz, 2H), 3.55 - 3.46 (m, 2H), 3.22 (br s, 4H), 3.04 (br d, J = 9.0 Hz, 1H), 2.96 - 2.80 (m, 2H), 2.71 - 2.58 (m, 6H), 2.30 (s, 3H), 2.23 - 2.12 (m, 1H), 2.08 - 1.68 (m, 6H), 1.54 (s, 6H), 1.33 (br d, J = 6.6 Hz, 3H). Example 40: Synthesis of Compound 40 carboxylate (40a) A mixture of tert-butyl 4-(4-piperidyl)piperazine-1-carboxylate (792.3 mg, 2.9 mmol, 1.3 equiv.), 4-bromo-2,6-difluoro-benzaldehyde (500 mg, 2.2 mmol, 1.0 equiv.) and acetic acid (135.8 mg, 2.2 mmol, 129.5 μL, 1.0 equiv.) in dichloromethane (5 mL) was stirred at 30°C for 2 h. Then the mixture was added NaBH(OAc)3(959.0 mg, 4.5 mmol, 2.0 equiv.) and the mixture was stirred at 30°C for 16 h under a nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate (100 mL) and aqueous sodium bicarbonate (100 mL). The organic phase was separated, washed with brine 30 mL, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol = 100:0 to 96:4) to afford 40a. LCMS [M+1] =474.2, 476.0;1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 7.0 Hz, 2H), 3.50 (s, 2H), 3.25 (br s, 4H), 2.80 (br d, J = 11.2 Hz, 2H), 2.37 (br t, J = 4.6 Hz, 4H), 2.18 - 2.08 (m, 1H), 1.95 (br t, J = 11.2 Hz, 2H), 1.65 (br d, J = 11.8 Hz, 2H), 1.33-1.40 (m, 11H) Step B – Synthesis of tert-butyl 4-[1-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl]-4-piperidyl]piperazine-1-carboxylate (40b) To a solution of 40a (500 mg, 1.05 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (401.4 mg, 1.5 mmol, 1.5 equiv.) in dioxane (5 mL) was added potassium acetate (310.3 mg, 3.1 mmol, 3.0 equiv.) and Pd(dppf)Cl2.CH2Cl2 (172.1 mg, 210.8 μmol, 0.2 equiv.) under nitrogen. The mixture was stirred at 80°C for 4 h. The reaction mixture was cooled to ambient temperature and quenched with water (100 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol = 100:0 to 0:100) to afford 40b, which was used without further purification. Step C – Synthesis of tert-butyl 4-[1-[[2,6-difluoro-4-[3-methyl-4-[4-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methylcarbamoyl]pyrazol-1-yl]phenyl]phenyl]methyl]-4- piperidyl]piperazine-1-carboxylate (40c) To a solution of Int 4 (100 mg, 212.1 μmol, 1.0 equiv.), 40b (221.2 mg, 424.3 μmol, 2.0 equiv.) in dioxane (2 mL) and water (0.2 mL) was added potassium carbonate (87.9 mg, 636.5 μmol, 3.0 equiv.) and Pd(dppf)Cl2.CH2Cl2(34.6 mg, 42.4 μmol, 0.2 equiv.). The mixture was stirred at 100°C for 2 h., cooled to ambient temperature and quenched with water (80 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative-TLC (silica gel, dichloromethane: MeOH = 10:1) to afford 40c. LCMS [M+1] =786.5;1H NMR (400 MHz, DMSO-d6) δ 13.90 (br s, 1H), 8.89 (br s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.74 (dd, J = 1.8, 8.3 Hz, 1H), 7.59 - 7.45 (m, 3H), 4.56 (br d, J = 3.6 Hz, 2H), 3.58 (s, 2H), 3.26 (br s, 4H), 2.86 (br s, 2H), 2.39 (br s, 4H), 2.31 (s, 3H), 2.17 (br t, J = 11.4 Hz, 1H), 2.01 (br t, J = 11.0 Hz, 2H), 1.68 (br d, J = 11.4 Hz, 2H), 1.54 (s, 6H), 1.34-1.40 (m, 11H). Step D – Synthesis of 1-[4-[3,5-difluoro-4-[(4-piperazin-1-yl-1-piperidyl)methyl]phenyl]-2- methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole- 4-carboxamide (40d) To a solution of 40c (80.0 mg, 101.8 μmol, 1.0 equiv.) in HCl in dioxane (4 M, 1 mL) under nitrogen. The mixture was stirred at 25°C for 1 h. The reaction mixture was concentrated to dryness to afford 40d, which was used without further purification. LCMS [M+1] =686.5. Step E – Synthesis of 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]-1-piperidyl]methyl]-3,5-difluoro-phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 40) To a solution of 40d (75 mg, 109.3 μmol, 1.0 equiv.) ,2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (48.2 mg, 164.0 μmol, 1.5 equiv.) in DMSO (1 mL) was added DIEA (42.4 mg, 328.1 μmol, 57.1 μL, 3.0 equiv.). The mixture was stirred at 70°C for 16 h, cooled t ambient temperature and partitioned between ethyl acetate (40 mL) and water (40 mL). The organic phase was separated, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: MeOH = 10:1) to afford Compound 40. LCMS [M+1] =960.3;1H NMR (400 MHz, DMSO-d6) δ 13.92 (br s, 1H), 11.10 (s, 1H), 8.90 (br s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.79 - 7.67 (m, 2H), 7.63 - 7.38 (m, 4H), 5.10 (dd, J = 5.2, 12.8 Hz, 1H), 4.55 (br d, J = 4.6 Hz, 2H), 3.60 (br s, 2H), 3.27 - 3.16 (m, 4H), 2.88 (br s, 3H), 2.70 - 2.53 (m, 6H), 2.32 (s, 3H), 2.26 - 2.14 (m, 1H), 2.09 - 1.96 (m, 3H), 1.76 (br d, J = 10.8 Hz, 2H), 1.54 (s, 6H), 1.48 - 1.34 (m, 2H) Example 41: Synthesis of Compound 41 Step A – Synthesis of tert-butyl 4-(5-bromo-3-methyl-1H-indazol-1-yl)-[1, 4'-bipiperidine]-1'- carboxylate (41a) To a solution of tert-butyl 4-hydroxy-[1, 4'-bipiperidine]-1'-carboxylate (3.0 g, 10.5 mmol, 1.0 equiv.) and 5-bromo-3-methyl-1H-indazole (2.2 g, 10.5 mmol, 1.0 equiv.) in toluene (30.0 mL) was added 2-(tributyl-phosphanylidene)acetonitrile (5.0 g, 21.1 mmol, 2.0 equiv.). The mixture was stirred at 100°C for 3 h. The mixture was cooled to ambient temperature and poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with brine (3 x 50 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0 to 4 / 1) to give 41a. LCMS [M+1]= 477.2, 479.1;1H NMR (400 MHz, CHLOROFORM-d) δ 7.78 (s, 1H), 7.40 (dd, J = 1.6, 8.9 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 4.34 - 4.25 (m, 1H), 4.23 - 4.17 (m, 1H), 4.15 (m, 1H), 3.17 - 3.07 (m, 2H), 2.67 (m, 3H), 2.52 (s, 3H), 2.46 - 2.27 (m, 4H), 1.99 (m, 2H), 1.90 - 1.75 (m, 4H), 1.72 - 1.67 (m, 2H), 1.47 (s, 9H). Step B – Synthesis of tert-butyl 4-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazol-1-yl)-[1,4'-bipiperidine]-1'-carboxylate (41b) To a solution of 41a (1.5 g, 3.1 mmol, 1.0 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.2 g, 4.7 mmol, 1.5 equiv.) in dioxane (15.0 mL) was added potassium acetate (925.0 mg, 9.4 mmol, 3.0 equiv.) and Pd(dppf)Cl2 (229.8 mg, 314.1 μmol, 0.1 equiv.). The mixture was stirred at 100 °C for 1 h. The mixture was cooled to ambient temperature and poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with brine (3 x 50 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) afford (41b). LCMS [M+1] = 525.2;1H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 4.42 - 4.29 (m, 1H), 4.26 - 4.12 (m, 2H), 3.10 (m, 2H), 2.83 - 2.63 (m, 3H), 2.57 (s, 3H), 2.55 (m, 1H), 2.50 - 2.28 (m, 5H), 2.02 (m, 2H), 1.83 (m, 2H), 1.49 (m, 2H), 1.47 (s, 9H), 1.38 (s, 12H). Step C – Synthesis of tert-butyl 4-(3-methyl-5-(3-methyl-4-(4-(((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)phenyl)-1H- indazol-1-yl)-[1,4'-bipiperidine]-1'-carboxylate (41c) To a solution of Int 4 (250.0 mg, 530.4 μmol, 1.0 equiv.) and 41b (333.88 mg, 636.57 μmol, 1.2 equiv.) in dioxane (2.5 mL) and water (0.4 mL) was added K2CO3 (219.9 mg, 1.5 mmol, 3.0 equiv.) and Pd(dppf)Cl2.CH2Cl2 (43.3 mg, 53.0 μmol, 0.1 equiv.) under a nitrogen atmosphere at ambient temperature. The mixture was stirred at 100°C for 16 h. The mixture was cooled to ambient temperature and poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with brine (3 x 10 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silica gel, dichloromethane: methanol =1 / 0 to 20 / 1) to afford 41c. LCMS [M+1] = 789.5;1H NMR (400 MHz, METHANOL-d4) δ 8.36 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.75 - 7.70 (m, 2H), 7.68 - 7.63 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 4.70 (s, 2H), 4.55 - 4.54 (m, 1H), 4.22 - 4.16 (m, 2H), 3.24- 3.21 (m, 2H), 2.82 – 2.80 (m, 2H), 2.71 - 2.62 (m, 2H), 2.59 (s, 3H), 2.58 - 2.52 (m, 1H), 2.43 - 2.33 (m, 2H), 2.31 (s, 3H), 2.10 - 2.00 (m, 2H), 1.99 - 1.90 (m, 2H), 1.61 (s, 6H), 1.50 - 1.49 (m, 2H), 1.47 (s, 9H). Step D – Synthesis of 1-(4-(1-([1,4'-bipiperidin]-4-yl)-3-methyl-1H-indazol-5-yl)-2- methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H- pyrazole-4-carboxamide (41d) A solution of 41c (230.0 mg, 291.5 μmol, 1.0 equiv.) in HCl / dioxane (4 M, 2.5 mL) was stirred at ambient temperature for 0.5 h. The mixture was concentrated in vacuum to afford 41d, which was used without further purification.LCMS [M+1] = 689.5;1H NMR (400 MHz, DMSO- d6) δ 11.38 (s, 1H), 9.33 - 9.22 (m, 1H), 9.16 - 9.14 (m, 1H), 8.96 (t, J = 5.3 Hz, 1H), 8.58 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.81 (br s, 2H), 7.72 (br d, J = 8.2 Hz, 1H), 7.47 (br d, J = 8.2 Hz, 1H), 5.13 - 5.10 (m, 1H), 5.03 - 4.92 (m, 2H), 4.56 (d, J = 5.5 Hz, 2H), 3.47 - 3.43 (m, 2H), 3.32 - 3.27 (m, 2H), 2.97 - 2.92 (m, 2H), 2.70 - 2.65 (m, 2H), 2.60 - 2.59 (m, 1H), 2.56 (s, 3H), 2.39 - 2.28 (m, 5H), 2.20 - 1.94 (m, 4H), 1.54 (s, 6H). Step E – Synthesis of 1-(4-(1-(1'-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)- [1,4'-bipiperidin]-4-yl)-3-methyl-1H-indazol-5-yl)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide (Compound 41) To a solution of 41d (150.0 mg, 197.0 μmol, 1.0 equiv.) in DMSO (1.5 mL) was added DIEA (84.4 mg, 653.3 μmol, 113.8 μL, 3.3 equiv.) and 2-(2,6-dioxopiperidin-3-yl)-5,6- difluoroisoindoline-1,3-dione (96.1 mg, 326.6 μmol, 1.7 equiv.). The mixture was stirred at 100°C for 1 h. The mixture was diluted with acetonitrile (1 mL) and filtered to remove the insoluble portion. The filtrate was purified by preparative HPLC (Phenomenex Luna C18, 150 mm x 25mm; 10 µm; [water(FA)-ACN]) to give afford Compound 41. LCMS [M+1] = 963.5;1H NMR (400 MHz, DMSO-d6) δ 13.93 (s, 1H), 11.12 (s, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.77 - 7.67 (m, 4H), 7.50 - 7.43 (m, 2H), 5.11 (dd, J = 5.6, 12.6 Hz, 1H), 4.63 - 4.51 (m, 3H), 3.72 - 3.67 (m, 2H), 3.12 - 3.07 (m, 2H), 3.00 - 2.83 (m, 3H), 2.71 - 2.57 (m, 3H), 2.56 - 2.55 (m, 4H), 2.32 (s, 3H), 2.23 - 1.98 (m, 4H), 1.94 - 1.02 (m, 4H), 1.70 - 1.64 (m, 2H), 1.54 (s, 6H). Example 42: Synthesis of Compound 42 (42a) To solution of tert-butyl 4-(4-hydroxycyclohexyl)piperazine-1-carboxylate (969.6 mg, 3.41 mmol, 1.2 equiv.) in DMF (10.0 mL) was added NaH (227.3 mg, 5.68 mmol, 60.0% purity, 2.0 equiv.) at 0°C and the mixture was stirred at 0°C for 1 h. 5-bromo-2-fluoro-pyridine (500.0 mg, 2.84 mmol, 292.40 μL, 1.0 equiv.) was added to the mixture. The mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1: 0 to 0: 1) to afford 42a. LCMS [M+1] = 440.2;1H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 2.8, 8.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 4.96 - 4.82 (m, 1H), 3.97-3.93 (m, 2H), 2.80 - 2.73 (m, 3H), 2.70 - 2.66 (m, 1H), 2.45 - 2.38 (m, 1H), 2.37 - 2.29 (m, 2H), 1.99 - 1.91 (m, 2H), 1.70 (d, J = 12.4 Hz, 2H), 1.64 - 1.54 (m, 2H), 1.38 (s, 9H), 1.31 - 1.21 (m, 2H) Step B – Synthesis of tert-butyl 4-[4-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- pyridyl]oxy]-1-piperidyl]piperidine-1-carboxylate (42b) To a solution of 42a (1.0 g, 1.36 mmol, 1.0 equiv.) and bis(pinacolato)diboron (346.0 mg, 1.36 mmol, 1 equiv.) in dioxane (10.0 mL) was added potassium acetate (267.4 mg, 2.72 mmol, 2.0 equiv.) and Pd(dppf)Cl2 (99.7 mg, 136.25 μmol, 0.1 equiv.) at 25°C under a nitrogen atmosphere. The mixture was stirred at 100°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1: 0 to 0: 1) to afford 42b. LCMS [M+1] = 488.3. Step C – Synthesis of tert-butyl 4-[4-[[5-[3-methyl-4-[4-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methylcarbamoyl]pyrazol-1-yl]phenyl]-2-pyridyl]oxy]-1- piperidyl]piperidine-1-carboxylate (42c) To a solution of 42b (150.0 mg, 184.64 μmol, 1.5 equiv.) and Int 4 (58.0 mg, 123.09 μmol, 1.0 equiv.) in THF (1.0 mL) and water (0.25 mL) was added K3PO4 (78.39 mg, 369.28 μmol, 3.0 equiv.) and PdCl2(DTBPF) (16.05 mg, 24.62 μmol, 0.2 equiv.) at 25°C under a nitrogen atmosphere. .The mixture was stirred at 80°C for 12 h. The reaction mixture was diluted with water (1.0 mL) and extracted with ethyl acetate (1.0 mL x 3). The combined organic layers were washed with brine (1.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether: ethyl acetate= 0: 1) to afford 42c. LCMS [M+1] = 752.2. Step D – Synthesis of 1-[2-methyl-4-[6-[[1-(4-piperidyl)-4-piperidyl]oxy]-3-pyridyl]phenyl]-N- [[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (42d) A solution of 42c (100.0 mg, 79.80 μmol, 1 equiv.) in HCl / MeOH (3 M, 1.0 mL) was stirred at 25°C for 1 h. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to give 42d. Step E – Synthesis of 1-[4-[6-[[1-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]-4-piperidyl]-4-piperidyl]oxy]-3-pyridyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 42) To a solution of 42d (50.0 mg, 69.1 μmol, 1 equiv.) and 2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (22.6 mg, 76.7 μmol, 1.1 equiv.) in DMSO (1.0 mL) was added DIEA (99.1 mg, 767 μmol, 133.6 μL, 11.0 equiv.).The mixture was stirred at 100 °C for 12 h. The solution was filtered to give a residue and the residue purified by preparative HPLC (Phenomenex Luna C18, 100 mm x 40 mm, 5 µm; [water(0.04% HCl)-ACN]) to afford Compound 42. LCMS [M+1] = 926.4;1H NMR (400 MHz, MeOD) δ ppm 8.48 (d, J = 11.2 Hz, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 8.06 (t, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.62 - 7.57 (m, 2H), 7.54 (d, J = 7.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.05 - 6.91 (m, 1H), 5.52 - 5.29 (m, 1H), 5.10 (dd, J = 5.2, 12.4 Hz, 1H), 4.72 (d, J = 3.2 Hz, 2H), 3.87 (d, J = 12.0 Hz, 2H), 3.76 (d, J = 12.4 Hz, 1H), 3.61 (d, J = 11.2 Hz, 1H), 3.50 - 3.35 (m, 4H), 3.02 (t, J = 12.0 Hz, 2H), 2.92 - 2.82 (m, 1H), 2.80 - 2.65 (m, 2H), 2.59 (dd, J = 16.0 Hz, 1H), 2.43 (d, J = 15.2 Hz, 1H), 2.35 (s, 1H) 2.31 (s, 3H), 2.26 - 2.18 (m, 1H), 2.15 - 2.09 (m, 1H), 2.08 - 1.95 (m, 3H), 1.63 (s, 6H). Example 43: Synthesis of Compound 43

[0022] Step A – Synthesis of tert-butyl 4-[[1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]ethyl]-4-piperidyl]methyl]piperazine-1-carboxylate (43a) To a solution of 2-[4-(2-bromoethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2 g, 6.1 mmol, 1 equiv.), tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (1.7 g, 6.1 mmol, 1 equiv.) in DMF (2 mL) was added cesium carbonate (4.0 g, 12.2 mmol, 2 equiv.). The mixture was stirred at 60°C for 2 h. The reaction mixture was cooled to ambient temperature, partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate (2 x 30 mL). The organic phase was combined and washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether : ethyl acetate = 5 / 1 to 0 / 1) to afford 43a.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.74 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 4.24 - 4.11 (m, 2H), 3.44 - 3.39 (m, 4H), 3.07 - 3.00 (m, 2H), 2.84 (br s, 2H), 2.33 (br t, J = 4.5 Hz, 4H), 2.23 - 2.10 (m, 4H), 1.77 (br d, J = 12.4 Hz, 2H), 1.51 - 1.48 (m, 1H), 1.46 (s, 9H), 1.34 (s, 12H) Step B – Synthesis of tert-butyl 4-((1-(2-((3'-methyl-4'-(4-(((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4- yl)oxy)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (43b) To a mixture of 43a (247.2 mg, 466.8 μmol, 1.1 equiv.), Int 4 (0.2 g, 424.4 μmol, 1 equiv.) and potassium carbonate (176.0 mg, 1.3 mmol, 3 equiv.) in dioxane (2 mL) and water (0.4 mL) was added Pd(dppf)Cl2.CH2Cl2 (69.3 mg, 84.9 μmol, 0.2 eq) in one portion at ambient temperature under nitrogen. The mixture was stirred at 100°C for 12 h. The mixture was cooled to ambient temperature, treated with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with brine (5 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative TLC (silica gel, ethyl acetate: methanol = 10:1) to afford 43b. LCMS [M+1] = 794.5;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.12 (s, 1H), 7.99 (s, 1H), 7.55 - 7.45 (m, 4H), 7.34 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 8.6 Hz, 2H), 4.72 (d, J = 5.8 Hz, 2H), 4.19 (br t, J = 5.3 Hz, 2H), 3.41 (br d, J = 4.3 Hz, 4H), 3.11 - 3.00 (m, 2H), 2.93 - 2.82 (m, 2H), 2.33 (br d, J = 4.5 Hz, 4H), 2.30 (s, 3H), 2.19 (br d, J = 7.3 Hz, 4H), 1.84 - 1.74 (m, 3H), 1.62 (s, 6H), 1.47 (s, 9H), 1.37 - 1.30 (m, 2H) Step C – Synthesis of 1-(3-methyl-4'-(2-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethoxy)-[1,1'- biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H- pyrazole-4-carboxamide (43c) To a solution of 43b (130 mg, 163.7 μmol, 1 equiv.) in TFA (0.4 mL)and dichloromethane (2 mL).The mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford 43c. LCMS [M+2H] = 347.9. Step D – Synthesis of 1-[4-[4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin- 5-yl]piperazin-1-yl]methyl]-1-piperidyl]ethoxy]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro- 1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 43) To a solution of 2-(2,6-dioxo-3-piperidyl)-5,6-difluoro-isoindoline-1,3-dione (71.9 mg, 244 μmol, 2.0 equiv.) in DMSO (2 mL) was added 43c (113 mg, 123 μmol, 1 equiv.) and DIEA (105 mg, 814 μmol, 142 μL, 6.6 equiv.) .The mixture was stirred at 70°C for 16 h, cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and water (10 mL) extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C1875mm x 30mm, 3 µm; [water(0.04% HCl)-ACN]). to afford Compound 43. LCMS [M+1] = 968.3;1H NMR (400 MHz, METHANOL-d4) δ = 8.37 (s, 1H), 8.18 (s, 1H), 7.54 - 7.44 (m, 5H), 7.44 - 7.35 (m, 3H), 6.95 (d, J = 8.8 Hz, 2H), 5.08 (dd, J = 5.4, 12.8 Hz, 1H), 4.73 (s, 2H), 4.21 - 4.15 (m, 2H), 3.92 - 3.87 (m, 4H), 3.80 - 3.68 (m, 13H), 3.47 - 3.42 (m, 2H), 3.28 - 3.19 (m, 2H), 2.91 - 2.80 (m, 1H), 2.78 - 2.62 (m, 2H), 2.27 (s, 3H), 2.05 (tdd, J = 2.8, 5.1, 10.3 Hz, 1H), 1.63 (s, 6H) Example 44: Synthesis of Compound 44 Compound 44 was prepared in a similar manner to Example 43 by substituting 2-[3-(2- bromoethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step A to afford 1-(3'-(2-(4-((4- (2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- yl)ethoxy)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide. LCMS: [M+1] =968.6;1H NMR (400 MHz, DMSO-d6) δ 13.93 (br s, 1H), 11.11 (s, 1H), 8.89 (br s, 1H), 8.52 (s, 1H), 8.16 (d, J = 6.2 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.66 (dd, J = 1.6, 8.4 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.41 - 7.35 (m, 1H), 7.32 - 7.21 (m, 2H), 6.98 (d, J = 8.6 Hz, 1H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 4.17 (br t, J = 5.6 Hz, 2H), 3.23 (br s, 5H), 3.01 - 2.81 (m, 3H), 2.79 - 2.66 (m, 2H), 2.63 - 2.52 (m, 2H), 2.52 - 2.50 (m, 4H), 2.30 (s, 3H), 2.18 (br d, J = 7.0 Hz, 2H), 2.13 - 1.96 (m, 3H), 1.70 (br d, J = 11.8 Hz, 2H), 1.53 (s, 6H), 1.20 - 1.07 (m, 2H) Example 45: Synthesis of Intermediate 45 To a solution of Int 4 (500 mg, 1.0 mmol, 1.0 equiv.) in 1,2-dimethoxyethane (9 mL) was added potassium acetate (416.4 mg, 4.2 mmol, 4.0 equiv.) and PdDPPF (86.6 mg, 106.1 μmol, 0.1 equiv.), bis(pinacolato)diboron (538.8 mg, 2.1 mmol, 2 equiv.) under a nitrogen atmosphere. The mixture was stirred at 90°C for 16 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL) extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane : methanol=100 / 1 to 90 / 10) to afford 1-[2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Intermediate 45). LCMS [M+1] = 519.3. Example 46: Synthesis of Compound 46

[0023] Step A – Synthesis of 1-[1-(4-bromophenyl)-1-methyl-ethyl]piperidin-4-one (46a) To a solution of 2-(4-bromophenyl)propan-2-amine (2.0 g, 9.3 mmol, 1.0 equiv.) in EtOH (20 mL) and water (8 mL) was added potassium carbonate (129.1 mg, 934.1 μmol, 0.1 equiv.) and 1-ethyl-1-methyl-piperidin-1-ium-4-one iodide (2.0 g, 7.4 mmol, 0.8 equiv.). The mixture was stirred at 80 °C for 2 h . The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL) extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 80 / 20 to 50 / 50) to afford 46a. LCMS [M+1] = 297.0, 299.0;1H NMR (400 MHz, DMSO-d6) δ = 7.64 - 7.40 (m, 4H), 2.65 (t, J = 6.0 Hz, 4H), 2.30 (t, J = 6.0 Hz, 4H), 1.32 (s, 6H). Step B – Synthesis of tert-butyl 4-[1-[1-(4-bromophenyl)-1-methyl-ethyl]-4-piperidyl]piperazine- 1-carboxylate (46b) To a solution of 46a (1.1 g, 3.7 mmol, 1 equiv.) in dichloromethane (15 mL) was added acetic acid (223.0 mg, 3.7 mmol, 212.6 μL, 1.0 equiv.) and NaBH(OAc)3(3.1 g, 14.8 mmol, 4.0 equiv.), tert-butyl piperazine-1-carboxylate (830.0 mg, 4.4 mmol, 1.2 equiv.). The mixture was stirred at 20°C for 2 h. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL) extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford 46b. LCMS [M+1] = 468.2, 470.2. Step C – Synthesis of tert-butyl 4-[1-[1-methyl-1-[4-[3-methyl-4-[4-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methylcarbamoyl]pyrazol-1-yl]phenyl]phenyl]ethyl]-4- piperidyl]piperazine-1-carboxylate (46c) To a solution of 46b (100.0 mg, 214.3 μmol, 1.0 equiv.) in dioxane (1 mL), water (0.2 mL) was added potassium carbonate (59.2 mg, 428.7 μmol, 2.0 equiv.) and Pd(dppf)Cl2 (15.6 mg, 21.4 μmol, 0.1 equiv.), Int 45 (111.1 mg, 214.3 μmol, 1.0 equiv.) under a nitrogen atmosphere. The mixture was stirred at 90°C for 1 h, cooled to ambient temperature and partitioned between ethyl acetate (20 mL) and water (20 mL) extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 46c. LCMS [M+1] =778.6. Step D – Synthesis of 1-[2-methyl-4-[4-[1-methyl-1-(4-piperazin-1-yl-1-piperidyl)ethyl]phenyl]- phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4- carboxamide (46d) To a solution of 46c (100.0 mg, 128.5 μmol, 1.0 equiv.) in CF3CwaterH (10 mL) was added chlorotrimethylsilane (856.0 mg, 7.8 mmol, 1 mL, 61.2 equiv.). The mixture was stirred at 20 °C for 1 h concentrated under reduced pressure to afford 46d. LCMS [M+1] = 704.5. Step E – Synthesis of 1-[4-[4-[1-[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]-1-piperidyl]-1-methyl-ethyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro- 1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 46) To a solution of 46d (80.0 mg, 88 μmol, 1.0 equiv.) in DMSO (1 mL) was added DIEA (61.0 mg, 472 μmol, 82.2 μL, 5.3 equiv.) and 2-(2,6-dioxo-3-piperidyl)-5,6-difluoro-isoindoline-1,3-dione (52.1 mg, 177 μmol, 2.0 equiv.). The mixture was stirred at 80°C for 4 h. The reaction mixture was cooled to ambient temperature, partitioned between ethyl acetate (10 mL) and water (10 mL), extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge C18150 mm x 50mm, 10µm; [water(10mM NH4HCO3)-ACN]) to afford Compound 46. LCMS [M+1] =952.6;1H NMR (400 MHz, DMSO-d6) δ = 13.91 (br s, 1H), 11.10 (s, 1H), 8.72 (s, 1H), 8.53 (s, 1H), 8.17 (s, 1H), 7.80 - 7.56 (m, 8H), 7.50 - 7.37 (m, 2H), 5.10 (dd, J = 5.2, 12.4 Hz, 1H), 4.56 (s, 2H), 3.23 (s, 4H), 2.94 - 2.78 (m, 3H), 2.72 - 2.56 (m, 2H), 2.37 - 2.25 (m, 4H), 2.25 - 2.14 (m, 1H), 2.12 - 1.98 (m, 4H), 1.77 (d, J = 8.8 Hz, 2H), 1.54 (s, 6H), 1.43 - 1.40 (m, 2H)， 1.34 (s, 2H). Example 47: Synthesis of Compound 47

[0024] carboxylate (47a) To a solution of tert-butyl 4-(4-piperidyl)piperazine-1-carboxylate (1.2 g, 4.5 mmol, 1.3 equiv.) and 5-chloropyrazine-2-carbaldehyde (500.0 mg, 3.5 mmol, 1.0 equiv.) in dichloromethane (5.0 mL) was added acetic acid (210.6 mg, 3.5 mmol, 200.8 μL, 1.0 equiv.). The mixture was stirred at ambient temperature for 1.5 h, treated with NaBH(OAc)3 (1.4 g, 7.0 mmol, 2.0 equiv.) and stirred at ambient temperature for 16 h. The reaction mixture was diluted with water (15.0 mL) and extracted with ethyl acetate (2 x 30.0 mL). The combined organic layers were washed with brine (2 x 10.0 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane : methanol=100:1 to 0:1) to afford 47a. LCMS [M+1] = 396.3, 398.3;1H NMR (400 MHz, CHLOROFORM-d) δ 8.53 (d, J = 1.1 Hz, 1H), 8.44 (d, J = 1.1 Hz, 1H), 3.66 (s, 2H), 3.49 - 3.36 (m, 4H), 2.93 (br d, J = 11.8 Hz, 2H), 2.61 - 2.42 (m, 4H), 2.38 - 2.24 (m, 1H), 2.11 (dt, J = 1.8, 11.6 Hz, 2H), 1.78 (br d, J = 12.2 Hz, 2H), 1.60 (br dd, J = 3.4, 12.0 Hz, 2H), 1.45 (s, 9H). Step B – Synthesis of tert-butyl 4-[1-[[5-[3-methyl-4-[4-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methylcarbamoyl]pyrazol-1-yl]phenyl]pyrazin-2-yl] methyl]-4-piperidyl] piperazine-1-carboxylate (47b) To a solution of 47a (130.7 mg, 330.1 μmol, 1.2 equiv.) and Int 45 (142.6 mg, 275.1 μmol, 1.0 equiv.) in dioxane (2.0 mL) and water (0.4 mL) was added potassium carbonate (114.0 mg, 825.3 μmol, 3.0 equiv.) and Pd(dppf)Cl2 (44.9 mg, 55.0 μmol, 0.2 equiv.). The mixture was threefold degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (5.0 mL), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, Dichloromethane : Methanol=100 :1 to 0 :1) to afford 47b. LCMS [M+1] = 752.7. Step C – Synthesis of 1-[2-methyl-4-[5-[(4-piperazin-1-yl-1-piperidyl)methyl]pyrazin-2- yl]phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4- carboxamide (47c) A solution of 47b (50.0 mg, 66.5 μmol, 1.0 equiv.) in HCl / dioxane (1.0 mL) was stirred at 20°C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 47c, which was used without further purification. LCMS [M+1] = 652.6. Step D – Synthesis of 1-[4-[5-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]-1-piperidyl]methyl]pyrazin-2-yl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 47). To a solution of 47c (50.0 mg, 72.6 μmol, 1.0 equiv) and DIEA (56.3 mg, 435.9 μmol, 75.9 μL, 6.0 equiv.) in DMSO (1.0 mL) was added 2-(2,6-dioxo-3-piperidyl)-5,6-difluoro- isoindoline-1,3-dione (25.6 mg, 87.1 μmol, 1.2 equiv.). The mixture was stirred at 70 °C for 16 h, cooled to ambient temperature, diluted with water (3.0 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (2 x 2mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (Waters Xbridge BEH C18, 100 mm x 30 mm, 10 µm; [water(10mM NH4HCO3)-ACN]) to afford Compound 47. LCMS [M+1] = 926.4;1H NMR (400 MHz, DMSO-d6) δ 13.90 (br s, 1H), 11.10 (br s, 1H), 9.24 (d, J = 1.1 Hz, 1H), 9.00 (br s, 1H), 8.75 (d, J = 1.1 Hz, 1H), 8.58 (s, 1H), 8.25 - 8.16 (m, 2H), 8.12 (dd, J = 1.6, 8.2 Hz, 1H), 7.72 (d, J = 11.4 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 4.56 (br d, J = 4.8 Hz, 2H), 3.71 (s, 2H), 3.24 (br s, 5H), 3.01 - 2.78 (m, 3H), 2.67 (br d, J = 1.8 Hz, 5H), 2.36 (s, 3H), 2.34 - 2.31 (m, 1H), 2.26 (br s, 1H), 2.16 - 1.98 (m, 4H), 1.83 - 1.75 (m, 2H), 1.54 (s, 6H). Example 48: Synthesis of Compound 48 6- bromopyridine-3-carbaldehyde in Step A to afford 1-[4-[5-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6- fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]-1-piperidyl]methyl]-2-pyridyl]-2-methyl- phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4- carboxamide. LCMS [M+1] = 925.2.1H NMR (400 MHz, CHLOROFORM-d) δ 8.63 (s, 1H), 8.38 (br s, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 8.01 (d, J = 12.0 Hz, 2H), 7.94 - 7.79 (m, 2H), 7.79 - 7.69 (m, 1H), 7.48 (d, J = 11.0 Hz, 1H), 7.40 (dd, J = 7.8, 11.8 Hz, 2H), 6.98 (s, 1H), 4.94 (dd, J = 5.2, 12.0 Hz, 1H), 4.73 (d, J = 6.0 Hz, 2H), 3.68 (s, 2H), 3.31 (s, 4H), 3.07 (d, J = 10.8 Hz, 2H), 2.98 - 2.86 (m, 2H), 2.81 (s, 5H), 2.51 - 2.41 (m, 1H), 2.34 (s, 3H), 2.25 - 2.11 (m, 3H), 1.92 (d, J = 11.0 Hz, 2H), 1.81 - 1.69 (m, 2H), 1.62 (s, 6H) Example 49: Synthesis of Compound 49 bromo- 2-chloro-benzaldehyde in Step A to afford 1-(3'-chloro-4'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6- fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4- yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4- carboxamide. LCMS [M+1] = 958.2;1H NMR (400 MHz, DMSO-d6) δ = 13.92 (br s, 1H), 11.11 (s, 1H), 8.90 (br s, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 7.81 - 7.79 (m, 2H), 7.74 - 7.69 (m, 3H), 7.60 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 5.11 (dd, J = 5.6, 12.8 Hz, 1H), 4.56 (d, J = 4.8 Hz, 2H), 3.61 (s, 2H), 3.25 (s, 4H), 2.94 - 2.84 (m, 3H), 2.68 (s, 4H), 2.62 - 2.57 (m, 2H), 2.32 (s, 3H), 2.29 – 2.26 (m, 1H), 2.12 - 2.02 (m, 3H), 1.80 (d, J = 10.8 Hz, 2H), 1.55 (s, 6H), 1.51 - 1.44 (m, 2H). Example 50: Synthesis of Compound 50

[0025] Step A – Synthesis of tert-butyl 4-[6-(4-bromophenoxy)-3-pyridyl] piperazine-1-carboxylate (50a) To a solution of tert-butyl 4-(6-bromo-3-pyridyl)piperazine-1-carboxylate (500.0 mg, 1.5 mmol, 1.0 equiv.) and 4-bromophenol (758.3 mg, 4.4 mmol, 3.0 equiv.) in DMSO (5.0 mL) was added K3PO4 (620.2 mg, 2.9 mmol, 2.0 equiv.), pyridine-2-carboxylic acid (18.0 mg, 146.1 μmol, 0.1 equiv.) and CuI (13.9 mg, 73.1 μmol, 0.05 equiv.). The mixture was three-fold degassed and purged with nitrogen, and then the mixture was stirred at 100°C for 12 h under a nitrogen atmosphere. The reaction mixture was quenched by addition water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge BEH C18100 mm x 30 mm, 10µm; [water (10mM NH4HCO3)-ACN]) to afford 50a. LCMS [M+1] = 434.2, 436.2. Step B – Synthesis of tert-butyl 4-[6-[4-[3-methyl-4-[4-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methylcarbamoyl]pyrazol-1-yl]phenyl]phenoxy]-3-pyridyl] piperazine-1- carboxylate (50b) To a solution of 50a (80.0 mg, 184.2 μmol, 1.0 equiv.) and Int 45 (100.3 mg, 193.4 μmol, 1.05 equiv.) in THF (0.8 mL) and water (0.2 mL) was added K3PO4 (78.2 mg, 368.4 μmol, 2.0 equiv.) and PdCl2(DTBPF) (24.0 mg, 36.8 μmol, 0.2 equiv.). The mixture was three-fold degassed and purged with nitrogen. The mixture was stirred at 80°C for 3 h under a nitrogen atmosphere. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (1 mL x 3). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, ethyl acetate: MeOH = 10: 1) to afford 50b. LCMS [M+1] = 746.5. Step C – Synthesis of 1-[2-methyl-4-[4-[(5-piperazin-1-yl-2-pyridyl) oxy]phenyl]phenyl]-N-[[3- (2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl] methyl]pyrazole-4-carboxamide (50c) To a solution of 50b (60.0 mg, 80.5 μmol, 1.0 equiv.) in dichloromethane (0.6 mL) was added TFA (0.2 mL). The mixture was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to afford 50c, which was used without further purification. LCMS [M+1] = 646.5. Step D – Synthesis of 1-[4-[4-[[5-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl] piperazin-1-yl]-2-pyridyl]oxy]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 50) To a solution of 50c (60.0 mg, 78.9 μmol, 1.0 equiv) and 2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (34.9 mg, 118.5 μmol, 1.5 equiv.) in DMSO (0.5 mL) was added DIEA (153.1 mg, 1.2 mmol, 206.4 μL, 15.0 equiv.). The mixture was stirred at 70°C for 12 h, cooled to ambient temperature and the filtered. Direct purification by preparative HPLC (column: Phenomenex Luna C18100mm x 30mm, 5µm; [water(0.2% FA)-ACN]) to afford Compound 50. LCMS [M+1] = 920.2;1H NMR (400 MHz, METHANOL-d4) δ = 8.36 (s, 1H), 8.18 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.65 - 7.55 (m, 4H), 7.44 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 1H), 5.13 - 5.08 (m, 1H), 4.71 - 4.67 (m, 2H), 3.48 - 3.46 (m, 4H), 3.38 - 3.36 (m, 4H), 2.91 - 2.82 (m, 1H), 2.78 - 2.65 (m, 2H), 2.31 (s, 3H), 2.15 - 2.09 (m, 1H), 1.60 (s, 6H). Example 51: Synthesis of Compound 51 Step A – Synthesis of tert-butyl 4-(6-oxo-2,3-dihydro-1H-pyridin-4-yl)piperazine-1-carboxylate (51a) To a mixture of piperidine-2,4-dione (303.6 mg, 2.6 mmol, 1.0 equiv.) and tert-butyl piperazine-1-carboxylate (500 mg, 2.6 mmol, 1.0 equiv.) in CHCl3 (1.5 mL) was added acetic acid (165.2 mg, 2.7 mmol, 157.5 μL, 1.0 equiv.), the mixture was stirred at 60°C for 16 h. The reaction mixture was quenched with water 5 mL at 25°C, and then extracted with dichloromethane (3 mL x 3). The combined organic portions were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford 51a. LCMS: [M+1] = 282.5;1H NMR (400 MHz, DMSO-d6) δ 6.58 (s, 1H), 4.61 (s, 1H), 3.35 (s, 3H), 3.23 - 3.09 (m, 5H), 2.61 (t, J = 4.8 Hz, 1H), 2.37 (t, J = 6.8 Hz, 2H), 1.47 - 1.34 (m, 9H) Step B – Synthesis of tert-butyl 4-(2-oxo-4-piperidyl)piperazine-1-carboxylate (51b) To a mixture of 51a (700 mg, 2.4 mmol, 1.0 equiv.) in MeOH (7 mL) was added NaBH3CN (781.7 mg, 12.4 mmol, 5.0 equiv.) and the mixture was stirred at 60°C for 16 h. The reaction mixture was filtered to remove the insolubles and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate: methanol=1 / 0 to 1 / 5) to afford 51b. LCMS: [M+1] = 284.5;1H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 3.28 (t, J = 4.4 Hz, 4H), 3.18 - 3.11 (m, 1H), 3.03 (td, J = 4.0, 11.2 Hz, 1H), 2.71 - 2.59 (m, 1H), 2.48 - 2.34 (m, 4H), 2.29 - 2.22 (m, 1H), 2.18 - 2.07 (m, 1H), 1.92 - 1.84 (m, 1H), 1.56 - 1.44 (m, 1H), 1.39 (s, 9H) Step C – Synthesis of tert-butyl 4-[1-[(4-bromophenyl)methyl]-2-oxo-4-piperidyl]piperazine-1- carboxylate (51c) To a solution of 51b (700 mg, 2.4 mmol, 1.0 equiv.) in THF (7 mL) was added NaH (296.4 mg, 7.4 mmol, 60% purity, 3.0 equiv.) at 0°C under nitrogen. The mixture was stirred at 25°C for 0.5 h, then the mixture was treated with 1-bromo-4-(bromomethyl)benzene (679.1 mg, 2.7 mmol, 1.1 equiv.) and the mixture was stirred at 25°C for 2 h, quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, ethyl acetate: methanol=1 / 0 to 1 / 1) to afford 51c. LCMS: [M+1] = 452.2, 454.2;1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 4.55 (d, J = 15.2 Hz, 1H), 4.36 (d, J = 15.2 Hz, 1H), 3.30 - 3.06 (m, 6H), 2.72 - 2.64 (m, 1H), 2.47 - 2.31 (m, 6H), 1.93 (s, 1H), 1.71 - 1.61 (m, 1H), 1.39 (s, 9H). Step D – Synthesis of tert-butyl 4-[1-[[4-[3-methyl-4-[4-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methylcarbamoyl]pyrazol-1-yl]phenyl]phenyl]methyl]-2-oxo-4- piperidyl]piperazine-1-carboxylate (51d) To a mixture of 51c (69.8 mg, 154.3 μmol, 1.0 equiv.) and Int 45 (80.0 mg, 154.3 μmol, 1.0 equiv.) and K2CO3 (63.9 mg, 463.0 μmol, 3.0 equiv.) in dioxane (1 mL) and water (0.2 mL) was three-fold degassed and purged with nitrogen, treated with Pd(DPPF)Cl2 (22.5 mg, 30.8 μmol, 0.2 equiv.) and stirred at 80°C for 16 h. The reaction mixture was cooled to ambient temperature, quenched with water (10 mL) and then extracted with ethyl acetate (5 mL x 3). The combined organic portions were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: MeOH = 10:1) to afford 51d. LCMS: [M+1] = 764.6. Step E – Synthesis of 1-[2-methyl-4-[4-[(2-oxo-4-piperazin-1-yl-1-piperidyl)methyl]phenyl]- phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4- carboxamide (51e) A mixture of 51d (40.0 mg, 52.3 μmol, 1.0 equiv.) in dichloromethane (0.5 mL) and TFA (0.1 mL) was stirred at 25°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford (51e), which was used without further purification. LCMS: [M+1] =664.5. Step F – Synthesis of 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]-2-oxo-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 51) To a mixture of 51e (40.0 mg, 51.4 μmol, 1.0 equiv) and 2-(2,6-dioxo-3-piperidyl)-5,6-difluoro- isoindoline-1,3-dione (18.1 mg, 61.7 μmol, 1.2equiv.) in DMSO (0.5 mL) was added DIEA (33.2 mg, 257.1 μmol, 44.7 μL, 5.0 equiv.) and the mixture was stirred at 70°C for 16 h. The reaction mixture was filtered to remove the insoluble. The residue was purified by preparative HPLC (Phenomenex Luna C18100mm x 30mm, 5 µm, [water(0.2% FA)-ACN]) to afford Compound 51. LCMS: [M+1] = 938.2;1H NMR (400 MHz, DMSO-d6METHANOL-d4) δ 8.49 (s, 1H), 8.16 (s, 1H), 7.72 - 7.66 (m, 4H), 7.61 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 7.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 5.09 (dd, J = 5.2, 12.8 Hz, 1H), 4.69 (dd, J = 4.0, 14.8 Hz, 1H), 4.60 - 4.41 (m, 3H), 3.35 - 3.16 (m, 7H), 3.12 (d, J = 1.6 Hz, 3H), 2.93 - 2.81 (m, 1H), 2.80 - 2.59 (m, 7H), 2.28 (s, 3H), 2.08 - 1.98 (m, 2H), 1.75 (dd, J = 4.8, 9.6 Hz, 1H), 1.53 (s, 6H). Example 52: Synthesis of Compound 52

[0026] Step A – Synthesis of tert-butyl 4-(4-hydroxycyclohexyl) piperazine-1-carboxylate (52a) To a solution of 4-aminocyclohexanol (5 g, 43.41 mmol, 1.05 equiv.) and tert-butyl N,N- bis(2-chloroethyl)carbamate (10.01 g, 41.35 mmol, 1 equiv.) in dioxane (200 mL) was added K2CO3 (17.14 g, 124.04 mmol, 3 equiv.), KI (20.59 g, 124.04 mmol, 3 equiv.) at 20 °C. The mixture was stirred at 115°C for 17 h. The reaction was quenched with NH4Cl (250 mL) and extracted with ethyl acetate (500 mL x 3). The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (silica gel, Dichloromethane: Methanol= 1: 0 to 0: 1) to give (1 g, 3.52 mmol, 8.50% yield) was obtained as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ(ppm) = 3.77 - 3.67 (m, 1H), 3.65 - 3.54 (m, 2H), 3.42 (br d, J = 4.4 Hz, 3H), 2.50 (br s, 4H), 2.29 (br s, 1H), 2.03 (br d, J = 3.8 Hz, 2H), 1.88 (br s, 2H), 1.46 (s, 9H), 1.36 - 1.23 (m, 4H). Step B – Synthesis of tert-butyl 4-[4-[(5-bromo-2-pyridyl)oxy]cyclohexyl]piperazine-1- carboxylate (52b) To a solution of 52a (1 g, 3.52 mmol, 1 equiv.) in THF (10 mL) was added NaH (211 mg, 5.3 mmol, 60% purity, 1.5 equiv.) at 0°C, sequentially, was added 5-bromo-2-fluoro-pyridine (618.81 mg, 3.52 mmol, 361.88 μL, 1 equiv.) in THF (5 mL) at 0°C. The mixture was stirred at 50°C for 16 h, quenched with NH4Cl (50 mL) and extracted with ethyl acetate (250 mL x 3). The combined organic portions were concentrated under reduced pressure. The residue was purified by silica gel chromatography (silica gel, petroleum ether: ethyl acetate = 1: 0 to 0: 1) to afford (52b).1H NMR (400 MHz, CHLOROFORM-d) δ = 8.16 (d, J = 2.6 Hz, 1H), 7.62 (dd, J = 2.4, 8.6 Hz, 1H), 6.59 (d, J = 8.8 Hz, 1H), 4.87 (br s, 1H), 3.44 (br s, 4H), 2.52 (br s, 4H), 2.38 (br d, J = 1.6 Hz, 1H), 2.21 (br s, 2H), 1.94 (br s, 2H), 1.52 - 1.41 (m, 13H). Step C – Synthesis of tert-butyl4-[4-[[5-[3-methyl-4-[4-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methylcarbamoyl]pyrazol-1-yl]phenyl]-2- pyridyl]oxy]cyclohexyl]piperazine-1-carboxylate (52c) To a solution of 52b (220 mg, 499.6 μmol, 1 equiv.) and Int 45 (258.9 mg, 499.6 μmol, 1.0 equiv.) in water (0.2 mL) and THF (0.8 mL) was added K3PO4(318.13 mg, 1.50 mmol, 3 equiv.) at 20°C, sequentially, was added PdCl2(DTBPF) (65.12 mg, 99.92 μmol, 0.2 equiv.) at 20°C. The mixture was stirred at 80°C for 12 h. The mixture was poured into ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (silica gel, petroleum ether: ethyl acetate= 1: 0 to 0: 1) to afford 52c. LCMS [M+1] = 752.5. Step D – Synthesis of 1-[2-methyl-4-[6-(4-piperazin-1-ylcyclohexoxy)-3-pyridyl]phenyl]-N-[[3- (2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (52d) To a solution of 52c (60 mg, 79.8 μmol, 1 equiv.) in TFA (0.4 mL) and dichloromethane (2 mL) at 20°C. The mixture was stirred at 20°C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 52d. LCMS [M+1] = 652.5. Step E – Synthesis of 1-[4-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]cyclohexoxy]-3-pyridyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide (Compound 52) To a solution of 52d (52 mg, 80 μmol, 1 equiv.) and 2-(2,6-dioxo-3-piperidyl)-5,6- difluoro-isoindoline-1,3-dione (35.2 mg, 120 μmol, 1.5 equiv.) in DMSO (5 mL) was added DIEA (51.6 mg, 399 μmol, 70 μL, 5 equiv.) at 20°C. The mixture was stirred at 70°C for 12 h, cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC（Phenomenex Luna C18, 100 mm x 40mm, 3 µm; [water(0.2% FA)-ACN]) to afford Compound 52. LCMS [M+1] = 926.3;1H NMR (400 MHz, METHANOL- d4) δ...

Claims

What is claimed is:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: R1, R2, and R3are each independently selected from H, halo, SRA, ORA, C1-4alkyl, C2-4alkenyl, and C1-4haloalkyl, wherein the C2-4alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis H, C1-4 alkyl, or C1-4 haloalkyl; R4and R5are each independently selected from H, halo, SRA, ORA, C1-4alkyl, C2-4alkenyl, and C1-4haloalkyl, wherein the C2-4alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis H, C1-4 alkyl, or C1-4 haloalkyl; or R4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl group or a 3-6 membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from H, halo, ORA, C1-4 alkyl, and C1-4 haloalkyl; R6and R7are each independently selected from H, halo, C1-4alkyl, and C1-4haloalkyl; R8is H or C1-4alkyl; Cy1is selected from C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C3-7cycloalkyl fused with phenyl to form a bicyclic ring, C4-7cycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, and 4-7 membered heterocycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa, SRa, C1-6 alkyl-NRcRd, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa,Cy2is absent or selected from C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, and 4- 7 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from 5-6 membered heteroaryl, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said 5-6 membered heteroaryl substituent of Cy2is optionally substituted with 1 or 2 substituents independently selected from halo and C1-6 alkyl; L is a linker; and Z is a binder of cereblon E3 ligase; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4haloalkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3,heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3,heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selectedfrom halo, C1-4alkyl, C1-4haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C2-heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; and each Re, Re1, Re2, and Re3is independently selected from H, C1-4alkyl, and CN.

2. A compound of Formula I: or a pharmaceuticallyR1, R2, and R3are each independently selected from H, halo, C1-4alkyl, and C1-4haloalkyl; R4and R5are each independently selected from H, halo, ORA, C1-4 alkyl, and C1-4 haloalkyl, wherein RAis H, C1-4 alkyl, or C1-4 haloalkyl; or R4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl group or a 3-6 membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from H, halo, ORA, C1-4 alkyl, and C1-4 haloalkyl; R6and R7are each independently selected from H, halo, C1-4alkyl, and C1-4haloalkyl; R8is H or C1-4alkyl;Cy1is selected from C6-10aryl, C3-14cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C3-7 cycloalkyl fused with phenyl to form a bicyclic ring, C4-7 cycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, and 4-7 membered heterocycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C1-6alkyl-NRcRd, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; Cy2is absent or selected from C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, and 4- 7 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; L is a linker; and Z is a binder of cereblon E3 ligase; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3,or Rcand Rdtogether with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; each Ra3, Rb3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; and each Re, Re1, Re2, and Re3is independently selected from H, C1-4 alkyl, and CN.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is a linker having Formula II: II wherein CyA, CyB, CyC, and CyDare each independently absent or independently selected from C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa11, SRa11, C(O)Rb11, C(O)NRc11Rd11,C(O)ORa11, OC(O)Rb11, OC(O)NRc11Rd11, C(=NRe11)NRc11Rd11, NRc11C(=NRe11)NRc11Rd11, NRc11Rd11, NRc11C(O)Rb11, NRc11C(O)ORa11, NRc11C(O)NRc11Rd11, NRc11S(O)Rb11, NRc11S(O)2Rb11, NRc11S(O)2NRc11Rd11, S(O)Rb11, S(O)NRc11Rd11, S(O)2Rb11, and S(O)2NRc11Rd11; and LA, LB, and LCare each independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, -C(O)-, -O-, -O-(C1-6 alkylene)-, -NRc23-, -S-(C1-6 alkylene)-, -C(O)-(C1-6alkylene)-, -C(O)NRc23-(C1-6alkylene)-, -C(O)O-, -C(O)O-(C1-6alkylene)- , -OC(O)-(C1-6 alkylene)-, -OC(O)NRc23-(C1-6 alkylene)-, -NRc23-(C1-6 alkylene)-, -N-(C1-6 alkylene)-C(O)-, -NRc23C(O)-(C1-6 alkylene)-, -NRc23C(O)NRc23-(C1-6 alkylene)-, -NRc23C(O)O- (C1-6alkylene)-, -C(=NRe23)NRc23-(C1-6alkylene)-, -NRc23C(=NRe23)NRc23-(C1-6alkylene)-, - S(O)-(C1-6alkylene)-, -S(O)NRc23-(C1-6alkylene)-, -S(O)2-(C1-6alkylene)-, -NRc23S(O)2-(C1-6alkylene)-, -NRc23S(O)2NRc23-(C1-6 alkylene)-, and -S(O)2NRc23-(C1-6 alkylene)-, wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene is optionally substituted by 1, 2, or 3 substituents independently selected from C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, halo, and OH; each Ra11, Rb11, Rc11, and Rd11is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl of Ra11, Rb11, Rc11, and Rd11is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3,alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; and Re23is independently selected from H, C1-4 alkyl, and CN; wherein at least one of LA, LB, LC, CyA, CyB, CyC, and CyDis not absent.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof wherein R1, R2, and R3are each independently selected from H, F, methyl, and trifluoromethyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are each F.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are each H.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each independently selected from SRA, C1-4 alkyl, and C2-4 alkenyl, wherein the C2-4 alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and wherein RAis C1-4alkyl.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each independently selected from OH, C1-4 alkyl, and C1-4 haloalkyl; or R4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, ORA, C1-4 alkyl, and C1-4 haloalkyl.

9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each C1-4 alkyl.

10. The compound of any one of claim 1-6, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each methyl.

11. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R4and R5together with the carbon atom to which they are attached form a C3-6 cycloalkyl group optionally substituted with 1 or 2 substituents independently selected from halo and C1-2alkyl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R6and R7are each H.

13. The compound of any one of claim 1-12, or a pharmaceutically acceptable salt thereof, wherein R8is H.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is selected from C3-14 cycloalkyl, 5-14 membered heteroaryl, C4-7 cycloalkyl fused with phenyl to form a bicyclic ring, and 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C1-6 alkyl- NRcRd, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is selected from C3-6 cycloalkyl, 5-6 membered heteroaryl, C5-6 cycloalkyl fused with phenyl to form a bicyclic ring, and 5-6 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, C1-6 alkyl-NRcRd, C(O)NRcRd, and NRcRd.

16. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is C3-6cycloalkyl.

17. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is cyclopropyl or cyclobutyl.

18. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is cyclopropyl.

19. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is 5-6 membered heteroaryl, optionally substituted by 1 or 2 substituents independently selected from halo, C1-6alkyl, and C(O)NRcRd.

20. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is pyrazolyl, pyrrolyl, or isoxazolyl, each optionally substituted with C(O)NRcRd.

21. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is pyrazolyl.

22. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is C5-6 cycloalkyl fused with phenyl to form a bicyclic ring, optionally substituted by 1 or 2 substituents independently selected from halo, C1-6alkyl, CN, C1-6alkyl-NRcRd, and NRcRd.

23. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is cyclopentyl fused with phenyl to form a bicyclic ring, optionally substituted by methyl, CN, Cl, F, -CH2NHRd, and NH2.

24. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is 5-6 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl.

25. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Cy1is dihydrobenzofuran, optionally substituted by 1 or 2 substituents independently selected from chloro and methyl.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Cy2is selected from C6-10 aryl and 5-10 membered heteroaryl, optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1.

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Cy2is bicyclo[1.1.1]pentyl.

28. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Cy2is phenyl or 5-6 membered heteroaryl, optionally substituted by 1 or 2 substituents selected from halo and C1-6 alkyl.

29. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Cy2is phenyl optionally substituted with 1 or 2 substituents selected from methyl and chloro.

30. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Cy2is pyridinyl or pyrimidinyl, each optionally substituted with methyl.

31. The compound of any one of claims 3-30, or a pharmaceutically acceptable salt thereof, wherein CyA, CyB, CyC, and CyDare each independently absent or independently selected from C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6alkyl.

32. The compound of any one of claims 3-30, or a pharmaceutically acceptable salt thereof, wherein CyA, CyB, CyC, and CyDare each independently absent or independently selected from phenyl, 5-9 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6alkyl.

33. The compound of any one of claims 3-32, or a pharmaceutically acceptable salt thereof, wherein CyAis absent or selected from phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indazolyl, 2,3-dihydrobenzofuranyl, and piperidinyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl.

34. The compound of any one of claims 3-32, or a pharmaceutically acceptable salt thereof, wherein CyAis absent or selected from phenyl, pyrazolyl, pyridinyl, indazolyl, and piperidinyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl.

35. The compound of any one of claims 3-32, or a pharmaceutically acceptable salt thereof, z CyAis phenyl or pyridinyl, each optionally substituted by 1 or 2 substituents selected from halo and methyl.

36. The compound of any one of claims 3-35, or a pharmaceutically acceptable salt thereof, wherein CyBis absent or selected from phenyl, cyclohexyl, pyrazolyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, azasprio[3.3]heptanyl, diazaspiro[3.5]nonanyl, 2,6- diazaspiro[3.3]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8- diazabicyclo[3.2.1]octanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 6- azaspiro[3.4]octanyl, and octahydropyrrolo[3,2-b]pyrrolyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl.

37. The compound of any one of claims 3-35, or a pharmaceutically acceptable salt thereof, wherein CyBis absent or selected from phenyl, cyclohexyl, pyrazolyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, azasprio[3.3]heptanyl, diazaspiro[3.5]nonanyl, 2,6- diazaspiro[3.3]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, and azaspiro[3.5]nonanyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl.

38. The compound of any one of claims 3-35, or a pharmaceutically acceptable salt thereof, wherein CyBis piperidinyl or piperazinyl.

39. The compound of any one of claims 3-35, or a pharmaceutically acceptable salt thereof, wherein CyBis 2-azaspiro[3.3]heptan-2-yl.

40. The compound of any one of claims 3-39, or a pharmaceutically acceptable salt thereof, wherein CyCis absent or selected from indazolyl, piperidinyl, piperazinyl, azetidinyl, and pyrrolidinyl, each optionally substituted by 1 or 2 substituents independently selected from halo and C1-6 alkyl.

41. The compound of any one of claims 3-39, or a pharmaceutically acceptable salt thereof, wherein CyCis piperidinyl, piperazinyl, or cyclobutyl.

42. The compound of any one of claims 3-41, or a pharmaceutically acceptable salt thereof, wherein CyDis absent or selected from piperazinyl and piperidinyl.

43. The compound of any one of claims 3-41, or a pharmaceutically acceptable salt thereof, wherein CyDis absent or piperazinyl.

44. The compound of any one of claims 3-43, or a pharmaceutically acceptable salt thereof, wherein LA, LB, and LCare each independently absent or independently selected from C1-6 alkylene, -C(O)-, -O-, -O-(C1-6 alkylene)-, -NRc23-, -C(O)NRc23-, -C(O)-(C1-6 alkylene)-, - C(O)NRc23-(C1-6alkylene)-, and -NRc23C(O)-.

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein Rc23is selected from H and C1-6alkyl.

46. The compound of any one of claims 3-43, or a pharmaceutically acceptable salt thereof, wherein LA, LB, and LCare each independently absent or independently selected from methylene, -C(O)-, -O-, -O-(C1-3 alkylene)-, -C(O)CH2-, -C(O)NH-(C1-3 alkylene).

47. The compound of any one of claims 3-43, or a pharmaceutically acceptable salt thereof, wherein LAis absent or selected from methylene, -C(O)-, -C(O)CH2-, -C(O)NH-(C1-3 alkylene)-, - NHC(O)-, -CH(CH3)-, -CH(CH(CH3)2)-, -CH(CH2CH2CH3)-, -CH(CH2OCH3)-, and -O-.

48. The compound of any one of claims 3-43, or a pharmaceutically acceptable salt thereof, wherein LAis absent or selected from methylene, -C(O)-, -C(O)CH2-, -C(O)NH-(C1-3alkylene)-, and -NHC(O)-.

49. The compound of any one of claims 3-43, or a pharmaceutically acceptable salt thereof, wherein LAis absent or selected from methylene and -NHC(O)-.

50. The compound of any one of claims 3-49, or a pharmaceutically acceptable salt thereof, wherein LBis absent or selected from methylene, -C(O)-, -ORa3-, -C(O)CH2-, -C(O)NH-(C1-3alkylene)-, -NHC(O)-, -O-, -O-(C1-6 alkylene)-, and -NRc23-(C1-6 alkylene)-.

51. The compound of any one of claims 3-49, or a pharmaceutically acceptable salt thereof, wherein LBis absent or selected from methylene, -C(O)-, -ORa3-, -C(O)CH2-, -C(O)NH-(C1-3alkylene)-, -NHC(O)-, -O-, and -O-(C1-6 alkylene)-.

52. The compound of any one of claims 3-49, or a pharmaceutically acceptable salt thereof, wherein LBis absent or methylene.

53. The compound of any one of claim 3-52, or a pharmaceutically acceptable salt thereof, wherein LCis absent or selected from methylene, -O-, -C(O)CH2-, and -NHC(O)-.

54. The compound of any one of claims 3-52, or a pharmaceutically acceptable salt thereof, wherein LCis absent or methylene.

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein Z is a group having Formula III:wherein ring A is C6-10 aryl, 5-14 membered heteroaryl, C3-7 cycloalkyl fused with phenyl to form a bicyclic ring, 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6alkyl, and C1-6 haloalkyl; L1is absent, CH2, NH, C(O)NH, or O; and W is CH or N, wherein the wavy line represents the point of attachment to group L.

56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, wherein Z is selected from:; ch independently selected from CH, CF, CCl, C(CH3), and N; and each V is independently selected from CH, C(CH3), and N.

57. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, wherein Z is selected from:;from CH , CF, and N; and each V is independently selected from CH and N.

58. The compound of claim any one of claims 1-55, or a pharmaceutically acceptable salt thereof, wherein Z is selected from: Oselected from CH , CF, and N; and each V is independently selected from CH and N.

59. The compound of claim 3, wherein the compound has Formula IA: Zor a pharmaceutically acceptable salt thereof.

60. The compound of claim 3 or 59, or a pharmaceutically acceptable salt thereof, wherein: Cy1is selected from C3-6 cycloalkyl, 5-6 membered heteroaryl, C5-6 cycloalkyl fused with phenyl to form a bicyclic ring, and 5-6 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, C1-6 alkyl-NRcRd, C(O)NRcRd, and NRcRd; Cy2is selected from C6-10aryl and 5-10 membered heteroaryl, optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; CyA, CyB, CyC, and CyDare each independently absent or independently selected from C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl; and LA, LB, and LCare each independently absent or independently selected from C1-6 alkylene, -C(O)-, -O-, -O-(C1-6alkylene)-, -C(O)-(C1-6alkylene)-, -C(O)NRc23-(C1-6alkylene)-, and -NRc23C(O)-.

61. The compound of claim 60, or a pharmaceutically acceptable salt thereof, wherein Z is selected from: O62. The compound of claim 3 or 59-61, wherein the compound has Formula IB:wherein is selected from halo, C1-4 alkyl, and C1-4 haloalkyl; and p is 0, 1, or 2.

63. The compound of claim 62, wherein the compound has Formula IB-1:

64. The compound of claim 3 or 59-61, wherein the compound has Formula IC: Zor a pharmaceutically acceptable salt thereof;wherein X1and X2are each independently selected from CH and N; each R42and R43is independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl; and q and r are each independently 0, 1, or 2.

65. The compound of claim 64, or a pharmaceutically acceptable salt thereof, wherein R42and R43are methyl.

66. The compound of claim 3 or 59-61, wherein the compound has Formula ID:wherein X is CH or N; and R44is selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl.

67. The compound of claim 3 or 59-61, wherein the compound has Formula IE:or a pharmaceutically acceptable salt thereof; wherein each R42and R43is independently selected from halo, C1-4alkyl, and C1-4haloalkyl; X1and X2are each independently selected from CH and N; and q and r are each independently 0, 1, or 2.

68. The compound of claims 3 or 59-61, wherein the compound has Formula IF: or awherein each is independently selected from halo, C1-4alkyl, and C1-4haloalkyl; and q is 0, 1, or 2.

69. The compound of claim 3 or 59-61, wherein the compound has Formula IG: or awherein each R42and R43is independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl; X1and X2are each independently selected from CH and N; and q and r are each independently 0, 1, or 2.

70. The compound of claim 1 or 2, wherein the compound is selected from: (2R)-5-chloro-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)phenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide;(2R)-5-chloro-6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazine-1-carbonyl)phenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide; (2R)-5-chloro-6-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide; (1S,2S)-2-(4'-(1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-[1,1'-biphenyl]-4-yl)-N- ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)cyclopropane-1- carboxamide; (1S,2S)-2-[4-[4-[1-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]-1-piperidyl]-2-oxo-ethyl]pyrazol-3-yl]phenyl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide hydrochloride; 5-(4-((1-(2-(4-(3-chloro-4'-((1S,2S)-2-(3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)propanoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)acetyl)piperidin- 4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; (1S,2S)-2-(2'-chloro-4'-(1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-[1,1'- biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)cyclopropane-1-carboxamide; (1S,2S)-2-[4-[4-[1-[2-[3-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]azetidin-1-yl]-2-oxo-ethyl]pyrazol-4-yl]phenyl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; 3-chloro-N-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)ethoxy)propyl)-4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-carboxamide; 3-chloro-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-4'-((1S,2S)-2-(((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4- carboxamide;2-chloro-N-[1-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]-4-piperidyl]-4-[4-[(1S,2S)-2-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methylcarbamoyl]cyclopropyl]phenyl]benzamide; (1S,2S)-2-[4-[1-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]-1-piperidyl]-2-oxo-ethyl]-3-methyl-indazol-5-yl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-[4-[4-[1-[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]-2-oxo-ethyl]azetidin-3-yl]pyrazol-4-yl]phenyl]phenyl]-N-[[3-(2,2,2-trifluoro- 1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-[4-[4-[1-[[1-[2-[4- [2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl] piperazin-1-yl]-2-oxo-ethyl] -4-piperidyl]methyl]pyrazol-4-yl]phenyl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-[4-[4-[1-[2-[(3S)-3-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo- isoindolin-5-yl]-4-piperidyl] oxy]pyrrolidin-1-yl]-2-oxo-ethyl]pyrazol-4-yl]phenyl]phenyl]-N-[[3- (2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-[4-[1-[4-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]methyl]piperidine-1-carbonyl]phenyl]pyrazol-4-yl]phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-(4'-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)cyclopropane-1-carboxamide; (1S,2S)-2-(4'-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)cyclopropane-1-carboxamide; 1-[3-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]methyl]phenyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]pyrazole-4-carboxamide;1-[4-[3-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]piperazin-1-yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4'-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)oxy)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)-1,4-diazepan-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((1'-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-[4,4'- bipiperidin]-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)pyrrolidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4-(6-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)piperidin-1-yl)methyl)pyridin-3-yl)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide;1-(2'-chloro-4'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(3'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-(1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)piperidin-1-yl)ethyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-1-piperidyl]methyl]-3,5-difluoro-phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4-(1-(1'-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-[1,4'- bipiperidin]-4-yl)-3-methyl-1H-indazol-5-yl)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[6-[[1-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]- 4-piperidyl]oxy]-3-pyridyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin- 1-yl]methyl]-1-piperidyl]ethoxy]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(3'-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)ethoxy)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[1-[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin- 1-yl]-1-piperidyl]-1-methyl-ethyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[5-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-1-piperidyl]methyl]pyrazin-2-yl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide;1-[4-[5-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-1-piperidyl]methyl]-2-pyridyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(3'-chloro-4'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)piperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[5-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl] piperazin-1- yl]-2-pyridyl]oxy]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-2-oxo-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]cyclohexoxy]-3-pyridyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[1-[[1-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]-4-piperidyl]methyl]pyrazol-4-yl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[6-[[1-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]- 4-piperidyl]amino]-3-pyridyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[2-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-2,7- diazaspiro[3.5]nonan-7-yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)azepan-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-1,4-diazepan-1- yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide;1-[4-[4-[[8-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]- 3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4'-((3-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-(((1S,4S)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N- ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4- carboxamide; 1-(4'-(((1R,4R)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N- ((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4- carboxamide; 1-(4'-((3-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)azetidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[2-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]- 2,6-diazaspiro[3.3]heptan-6-yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-3,3-difluoro-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-4-methyl-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide;1-[4-[4-[[4-[6-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-2,6- diazaspiro[3.3]heptan-2-yl]-1-piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro- 1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4'-(((2S,4S)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)-2-methylpiperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-(((2S,4R)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)-2-methylpiperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-(((2R,4R)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)-2-methylpiperidin-1-yl)methyl)-3-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-(1-(2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-3- methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4'-((4-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)piperidin-1-yl)methyl)-3- methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-1-yl]-1- piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-1-yl]methyl]phenyl]-2-methyl- phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4- carboxamide; 1-[4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1- piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(2-chloro-4'-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)piperidin-1-yl)methyl)-5-methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide;1-[3-[4-[[(3S)-3-[[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5- yl]amino]pyrrolidin-1-yl]methyl]phenyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[6-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]oxy]-3-pyridyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[6-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]methyl]piperazin-1-yl]-3-pyridyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(3-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,4-dimethylphenyl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[3-[4-[[4-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]-1-piperidyl]methyl]phenyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)- 1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[4-[[4-[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]piperazin-1-yl]methyl]phenyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[2-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]methyl]piperazin-1-yl]-4-pyridyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(3-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)pyridin-4-yl)-2,4-dimethylphenyl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[3-[6-[4-[[2-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-2,6- diazaspiro[3.3]heptan-6-yl]methyl]-1-piperidyl]-3-pyridyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[3-[6-[6-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl]-3-pyridyl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide;1-[3-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1- yl]methyl]-1-piperidyl]pyrimidin-5-yl]-2,4-dimethyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl- ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; (2S)-5-chloro-6-[4-[[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-1-yl]methyl]phenyl]-N- [[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl] -2,3-dihydrobenzofuran-2- carboxamide; (2R)-5-chloro-6-(4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)-2,3-dihydrobenzofuran-2-carboxamide; (2R)-5-chloro-2-cyano-6-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-2,3-dihydro-1H-indene-2-carboxamide; 5-chloro-2-cyano-6-(4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)-2,3-dihydro-1H-indene-2-carboxamide; (2R)-5-chloro-2-cyano-6-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin- 5-yl]piperazin-1-yl]methyl]phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]indane-2-carboxamide; (1S,2S)-2-[4-[6-[[1-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]- 4-piperidyl]methyl]-4-piperidyl]pyrazol-4-yl]amino]-3-pyridyl]phenyl]-N-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]cyclopropanecarboxamide; (1S,2S)-2-(4-(6-((1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-3-yl)phenyl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)cyclopropane-1-carboxamide; 1-[4-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]-1-piperidyl]methyl]- phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[(3S)-2,6-dioxo-3-piperidyl]phenyl]piperazin-1-yl]methyl]phenyl]-2- methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole- 4-carboxamide;1-[4-[4-[[4-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]piperazin-1-yl]methyl]phenyl]- 2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-(4'-((4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperazin-1-yl)methyl)-3-methyl- [1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)- 1H-pyrazole-4-carboxamide; 1-(4'-((4-(5-((2,6-dioxopiperidin-3-yl)amino)pyrazin-2-yl)piperidin-1-yl)methyl)-3- methyl-[1,1'-biphenyl]-4-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperazin-1- yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]-1-piperidyl]methyl]phenyl]-2- methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole- 4-carboxamide; 1-[4-[4-[[4-[5-(2,6-dioxo-3-piperidyl)-4-fluoro-2-pyridyl]piperazin-1-yl]methyl]phenyl]- 2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1- piperidyl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]piperazin-1- yl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperazin-1- yl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[4-[(2,4-dioxohexahydropyrimidin-1-yl)methyl]-2-fluoro-phenyl]piperazin-1- yl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide;1-[5-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperazin-1- yl]methyl]phenyl]-2-pyridyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-(5-(5-((4-(5-((2,6-dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)piperazin-1- yl)methyl)pyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(5-(5-((4-(5-((2,6-dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)piperazin-1- yl)methyl)-3-fluoropyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H- 1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-[5-[4-[[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]carbamoyl]-3-fluoro-phenyl]piperazin-1- yl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[4-[4-[[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]carbamoyl]-3-fluoro-phenyl]piperazin-1- yl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]pyrazole-4-carboxamide hydrochloride; 1-[4-[4-[[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]carbamoyl]-3-fluoro-phenyl]-1- piperidyl]methyl]phenyl]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; (S)-N-((3-(1,1-difluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1-(5-(4-((4- (4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-1-yl)methyl)phenyl)pyridin-2- yl)-1H-pyrazole-4-carboxamide; 1-[5-[4-[[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]carbamoyl]-3-fluoro-phenyl]-1-piperidyl]- methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-[4-[[4-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]-1-piperidyl]methyl]phenyl]- pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole- 4-carboxamide; 1-(4-((4-(5-(2,6-dioxopiperidin-3-yl)-3-fluoropyridin-2-yl)piperazin-1-yl)methyl)-2- methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H- pyrazole-4-carboxamide;1-[4-[[1-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]-4-piperidyl]methyl]-2-methyl- phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole-4- carboxamide; 1-[4-[[2-[5-(2,6-dioxo-3-piperidyl)-3-fluoro-2-pyridyl]-2-azaspiro[3.5]nonan-7-yl]oxy]-2- methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]pyrazole- 4-carboxamide; and 3-[5-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperazin-1- yl]methyl]phenyl]pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]isoxazole-5-carboxamide, or a pharmaceutically acceptable salt of any of the aforementioned.

71. The compound of claim 1 or 2, wherein the compound is selected from: 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-6- yl)piperazin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrimidin-6- yl)piperazin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide;3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperidin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(2-fluoro-4-((6-(3-fluoro-4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)phenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-6- yl)piperidin-1-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-6- yl)piperidin-1-yl)ethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorobenzo[d]isoxazol-6- yl)piperidin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; N-((3-(3,3-difluoro-2-methylbutan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(4-(1-(6-(4- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)ethyl)-2- fluorophenyl)-4-methylpyrimidin-2-yl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro- [3.3]heptan-2-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(3-fluoro-2-methylbut- 3-en-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; N-((3-(1-(1,1-difluoroethyl)cyclopropyl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(4-((6-(4- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)methyl)-2- fluorophenyl)-4-methylpyrimidin-2-yl)isoxazole-5-carboxamide;3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1- (trifluoromethyl)cyclobutyl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-[5-[4-[1-[6-[4-(2,4-dioxohexahydropyrimidin-1-yl)-3-fluoro-phenyl]-2- azaspiro[3.3]heptan-2-yl]ethyl]-2-fluoro-phenyl]-4,6-dimethyl-pyrimidin-2-yl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]isoxazole-5-carboxamide; 3-[5-[5-[1-[6-[4- (2,4-dioxohexahydropyrimidin-1-yl)-3-fluoro-phenyl]-2- azaspiro[3.3]heptan-2-yl]ethyl]-3-fluoro-2-pyridyl]-4-methyl-pyrimidin-2-yl]-N-[[3-(2,2,2- trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2,5- difluorophenyl)piperidin-1-yl)methyl)phenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperazin-1-yl)-7- azaspiro[3.5]nonan-7-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 1-(4-((2-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluoropyridin-2-yl)-2- azaspiro[3.5]nonan-7-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(4-((2-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)-2-azaspiro[3.5]nonan-7- yl)oxy)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-[4-[[2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-2-pyridyl]-2- azaspiro[3.5]nonan-7-yl]oxy]-2-methyl-phenyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide;(R)-1-(4-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-3- methylpiperazin-1-yl)cyclohexyl)oxy)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; (S)-1-(4-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-3- methylpiperazin-1-yl)cyclohexyl)oxy)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(3-(2-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylpyridin-2-yl)-2- azaspiro[3.5]nonan-7-yl)-5-fluoro-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)- 1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 3-(3-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)phenyl)bicyclo[1.1.1]pentan-1-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(2- (methylthio)propan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(2-fluoro-4-((6-(3-fluoro-4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)piperazin-1- yl)methyl)piperidin-1-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2,3-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2,5-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide;3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-5-methylphenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluoro-6-methylpyridin-2-yl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)methyl)-3-fluoropyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)pyrazin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; (R)-3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6-yl)- 3-methylpiperazin-1-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-6- yl)piperazin-1-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperidin-1-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)ethyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide;3-(5-(4-(1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrimidin-6- yl)piperazin-1-yl)ethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-3-fluoropyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)-2,3-dihydrobenzofuran-6-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)pyridin-2-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; N-((3-(3,3-difluoro-2-methylbutan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(4-(1-(6-(4- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)propyl)-2- fluorophenyl)-4-methylpyrimidin-2-yl)isoxazole-5-carboxamide; 3-(5-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)-2,3-dihydro-1H-inden-5-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)propyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((2-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-6- azaspiro[3.4]octan-6-yl)methyl)-3-fluoropyridin-2-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-4'-methyl-[2,5'-bipyrimidin]-2'-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; N-((3-(3,3-difluoro-2-methylbutan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(1-(6-(4-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)ethyl)-4'-methyl- [2,5'-bipyrimidin]-2'-yl)isoxazole-5-carboxamide;3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)butyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)-2-methylpropyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3- (1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)-2-methoxyethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3- (1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(7-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)-5-oxa-2-azaspiro[3.4]octan-2-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; N-((3-(tert-butyl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(4-((6-(4-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)methyl)-2- fluorophenyl)-4-methylpyrimidin-2-yl)isoxazole-5-carboxamide; N-((3-(3,3-difluoro-2-methylbutan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-3-(5-(5-(1-(6-(4- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2-azaspiro[3.3]heptan-2-yl)ethyl)-3- fluoropyridin-2-yl)-4-methylpyrimidin-2-yl)isoxazole-5-carboxamide; 3-(5-(5-(1-(6-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-3-fluoropyridin-2-yl)-4-methylpyrimidin-2-yl)-N-((3-(3,3- difluoro-2-methylbutan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(1-(6-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-4'-methyl-[2,5'-bipyrimidin]-2'-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 1-(4-((4-(4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyridin-2-yl)piperazin-1- yl)cyclohexyl)oxy)-2-methylphenyl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide;3-(5-(4-(1-(6-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(1-(6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)ethyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((((3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5- difluorophenyl)cyclobutyl)methyl)amino)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(((3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5- difluorophenyl)cyclobutyl)amino)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)piperazin-1- yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenoxy)piperidin-1- yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenoxy)azetidin-1- yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide;3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenoxy)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(3-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrimidin-6- yl)piperazin-1-yl)methyl)phenyl)bicyclo[1.1.1]pentan-1-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(3-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrazin-6- yl)piperazin-1-yl)methyl)phenyl)bicyclo[1.1.1]pentan-1-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)phenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2- yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylphenyl)piperidin-1- yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylphenyl)piperidin-1- yl)methyl)piperidin-1-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((4-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-1- yl)methyl)piperidin-1-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4- triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-(((3aS*,6aS*)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3- fluorophenyl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)methyl)-2-fluorophenyl)pyrimidin-2-yl)- N-((3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5- carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-2-fluorophenyl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1-trifluoro- 2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)-4-methylpyrimidin-2-yl)-N-((3-(1,1,1- trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide;3-(5-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2- azaspiro[3.3]heptan-2-yl)methyl)-[2,5'-bipyrimidin]-2'-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-((6-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2-methylpropan- 2-yl)-1H-1,2,4-triazol-5-yl)methyl)isoxazole-5-carboxamide; or a pharmaceutically acceptable salt of any of the aforementioned.

72. A pharmaceutical composition comprising a compound of any one of claims 1-71, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

73. A method of treating cancer in a patient in need of treatment comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-71, or a pharmaceutically acceptable salt thereof.

74. The method of claim 73, wherein the cancer is selected from prostate cancer, breast cancer, glioblastoma, bladder cancer, renal cell carcinoma, salivary gland cancer, colorectal cancer, esophageal cancer, pancreatic cancer, and stomach cancer.

75. A compound of Formula (A1):or a pharmaceutically acceptable salt thereof, wherein: R1, R2, and R3are each independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; R4and R5are each independently selected from H, halo, ORA, C1-4 alkyl, and C1-4 haloalkyl, wherein RAis H, C1-4alkyl, or C1-4haloalkyl; orR4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl group or a 3-6 membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from H, halo, ORA, C1-4 alkyl, and C1-4 haloalkyl; R6and R7are each independently selected from H, halo, C1-4alkyl, and C1-4haloalkyl; R8is H or C1-4 alkyl; Cy1is selected from C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C3-7cycloalkyl fused with phenyl to form a bicyclic ring, C4-7cycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, 4-7 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, and 4-7 membered heterocycloalkyl fused with 5-6 membered heteroaryl to form a bicyclic ring, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa, SRa, C1-6 alkyl-NRcRd, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; A is selected from H, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4alkyl, C1-4haloalkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, CN, ORa3, SRa3, C(O)Rb3,C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C C NRc3C S S Sfrom halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkylamino, di(C1-6alkyl)amino, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; and each Re, Re1, Re2, and Re3is independently selected from H, C1-4 alkyl, and CN.

76. The compound of claim 75, or a pharmaceutically acceptable salt thereof wherein R1, R2, and R3are each independently selected from H, F, methyl, and trifluoromethyl.

77. The compound of claim 75 or 76, or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are each F.

78. The compound of any one of claims 75-77, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each C1-4 alkyl.

79. The compound of any one of claim 75-77, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each methyl.

80. The compound of any one of claims 75-79, or a pharmaceutically acceptable salt thereof, wherein R6and R7are each H.

81. The compound of any one of claim 75-80, or a pharmaceutically acceptable salt thereof, wherein R8is H.

82. The compound of any one of claims 75-81, or a pharmaceutically acceptable salt thereof, wherein Cy1is selected from C3-6 cycloalkyl, 5-6 membered heteroaryl, C5-6 cycloalkyl fused with phenyl to form a bicyclic ring, and 5-6 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, C1-6 alkyl-NRcRd, C(O)NRcRd, and NRcRd.

83. The compound of any one of claims 75-81, or a pharmaceutically acceptable salt thereof, wherein Cy1is cyclopropyl, pyrazolyl, or isoxazolyl.

84. The compound of any one of claims 75-81, or a pharmaceutically acceptable salt thereof, wherein Cy1is C5-6cycloalkyl fused with phenyl to form a bicyclic ring, optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, CN, C1-6 alkyl-NRcRd, and NRcRd.

85. The compound of any one of claims 75-81, or a pharmaceutically acceptable salt thereof, wherein Cy1is cyclopentyl fused with phenyl to form a bicyclic ring, optionally substituted by CN, Cl, and F.

86. The compound of any one of claims 75-81, or a pharmaceutically acceptable salt thereof, wherein Cy1is 5-6 membered heterocycloalkyl fused with phenyl to form a bicyclic ring, optionally substituted by 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl.

87. The compound of any one of claims 75-81, or a pharmaceutically acceptable salt thereof, wherein Cy1is dihydrobenzofuran, optionally substituted by 1, 2, or 3 substituents independently selected from Cl and I.

88. The compound of any one of claims 75-87, or a pharmaceutically acceptable salt thereof, wherein A is selected from H, C6-10aryl and 5-10 membered heteroaryl, optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1.

89. The compound of any one of claims 75-87, or a pharmaceutically acceptable salt thereof, wherein A is phenyl or 5-6 membered heteroaryl, optionally substituted by 1, 2, or 3 substituents selected from halo and C1-6 alkyl.

90. The compound of any one of claims 75-87, or a pharmaceutically acceptable salt thereof, wherein A is phenyl optionally substituted by 1, 2, or 3 substituents selected from methyl, Br, and Cl.

91. The compound of any one of claims 75-87, or a pharmaceutically acceptable salt thereof, wherein A is H.

92. The compound of claim 75, wherein the compound is selected from: 5-chloro-6-iodo-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5-yl]methyl]- 2,3-dihydrobenzofuran-2-carboxamide;(1S,2S)-2-(4-bromophenyl)-N-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-3- yl]methyl]cyclopropanecarboxamide; 1-(4-bromo-2-methyl-phenyl)-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol- 5-yl]methyl]pyrazole-4-carboxamide; 1-(3-bromo-2,4-dimethyl-phenyl)-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(4-bromo-5-chloro-2-methyl-phenyl)-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 5,6-dichloro-2-cyano-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]indane-2-carboxamide; 1-[5-(4-formylphenyl)pyrimidin-2-yl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H- 1,2,4-triazol-5-yl]methyl]pyrazole-4-carboxamide; 1-(5-bromo-2-pyridyl)-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4-triazol-5- yl]methyl]pyrazole-4-carboxamide; 1-[5-(4-formylphenyl)-2-pyridyl]-N-[[3-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-1,2,4- triazol-5-yl]methyl]pyrazole-4-carboxamide; and 1-(5-(3-fluoro-5-formylpyridin-2-yl)pyrimidin-2-yl)-N-((3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt of any of the aforementioned.

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