Compounds and methods for treating cancer

Abstract

The present disclosure relates to GSPT1 degrader compounds and pharma- ceutically acceptable salts thereof for the treatment of certain diseases, pharmaceutical compositions containing such compounds or salts, and methods of making and using said compounds or salts. The present disclosure also relates to methods of identifying such compounds.

Description

[Technical Field]

[0001] There is a need in the art for compounds, compositions, and methods of using compounds for the treatment of disease in subjects in need thereof. Summary of the Invention

[0002] The present disclosure relates to compounds (e.g., small molecule compounds), compositions comprising one or more compounds, and methods of using the compounds for the treatment of specific diseases in subjects in need of treatment. The disclosure also relates to methods of identifying or making such compounds.

[0003] In some embodiments, a treatment method is provided that includes administering to a subject in need of treatment a first compound comprising a GSPT1 degrader and a second compound comprising a FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator.

[0004] In some embodiments, Formula (A)

[0005] [ka] Provided herein is a compound of the formula: W is hydrogen or fluorine; Z is absent or -NR 1a -, or -O-, where R 1a is hydrogen or C1-C8 alkyl, L is an optionally substituted C-C 10 Alkylene, or optionally substituted C-C 10 heteroalkylene; or L is

[0006] [ka] wherein: Ring B is an optionally substituted 3- to 7-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl; L 1 is absent or optionally substituted C1-C 10 Alkylene or optionally substituted C-C 10 is heteroalkylene, L 2 is absent or optionally substituted C1-C 10 Alkylene, optionally substituted C-C 10 Alkenylene, optionally substituted C-C 10 Alkynylene or optionally substituted C-C 10 is heteroalkylene, R 1 is absent or is oxo (=O), R 2 and R 4 are each independently hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; R 3 is hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R 2 and R 3 , or R 3 and R 4 together form an optionally substituted 3- to 7-membered partially saturated or unsaturated carbocyclyl, an optionally substituted 4- to 7-membered partially saturated or unsaturated heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered heteroaryl ring; R 5 and R 6 are each independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclylC1-C8 alkyl, optionally substituted 3-10 membered heterocyclylC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; or R 5 and R 6 optionally, together with the atom to which they are attached, form an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl ring.

[0007] Formula (I)

[0008] [ka] Provided herein is a compound of the formula: Z is absent or -NR 1a -, or -O-, where R 1a is hydrogen or C1-C8 alkyl, L is an optionally substituted C-C 10 Alkylene, or optionally substituted C-C 10 heteroalkylene; or L is

[0009] [ka] wherein: Ring B is an optionally substituted 3- to 7-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl; L 1 is absent or optionally substituted C1-C 10 Alkylene or optionally substituted C-C 10 is heteroalkylene, L 2 is absent or optionally substituted C1-C 10 Alkylene, optionally substituted C-C 10 Alkenylene, optionally substituted C-C 10 Alkynylene or optionally substituted C-C 10 is heteroalkylene, R 1 is absent or is oxo (=O), R 2 and R 4 are each independently hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; R 3 is hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R 2 and R 3 , or R 3 and R 4 together form an optionally substituted 3- to 7-membered partially saturated or unsaturated carbocyclyl, an optionally substituted 4- to 7-membered partially saturated or unsaturated heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered heteroaryl ring; R 5 and R 6are each independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclylC1-C8 alkyl, optionally substituted 3-10 membered heterocyclylC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; or R 5 and R 6 are optionally taken together with the atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl.

[0010] In some embodiments of Formula (I), R 2 and R 3 taken together form an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl ring.

[0011] In some embodiments of Formula (I), R 3 and R 4 and together form an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl ring. In some such embodiments, R 3 and R 4 together form ring A to provide the structure of formula (II).

[0012] In some embodiments, the compound of formula (I) has formula (II):

[0013] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , L, and Z are defined as in formula (I), Ring A is phenyl or 5-6 membered heteroaryl; R 11 are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl, and p1 is 0, 1, 2, 3, or 4.

[0014] In some embodiments, the compound of formula (I) has formula (III):

[0015] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , L, and Z are defined as in formula (I), X 4 , X 5 , and X 6 are each independently, CR 8 or N, R 8 are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; or Two R on adjacent carbon atoms 8 together form an optionally substituted partially unsaturated 3- to 7-membered carbocyclyl, an optionally substituted partially unsaturated 4- to 7-membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered heteroaryl, and p2 is 0, 1, 2, 3, 4, or 5.

[0016] In some embodiments, the compound of formula (I) has formula (IV):

[0017] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , L, and Z are defined as in formula (I), X 4 is CR 8a or N, X 5 is CR 8b or N, X 6 is CR 8d or N, R 8a , R 8b , R 8c , R 8d , and R 8e are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; or R 8a and R 8b , R 8b and R 8c , R 8c and R 8d , or R 8d and R 8e together with the atoms to which they are attached form an optionally substituted 3- to 7-membered carbocyclyl, an optionally substituted 4- to 7-membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered heteroaryl.

[0018] In another aspect, provided herein is a pharmaceutical composition comprising a compound of any of the formulae described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0019] In another aspect, provided herein are methods of treatment comprising administering to a subject in need thereof an effective amount of a compound of any of the formulas described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of such a salt as described herein. In some embodiments, the subject has cancer. In some embodiments, the method further comprises administering to the subject a second compound comprising an FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator. In some embodiments, the method further comprises administering to the subject a second compound comprising a chemotherapeutic agent. Further aspects and advantages of the present disclosure will be readily apparent to those skilled in the art from the following detailed description, and only illustrative embodiments of the present disclosure have been shown and described herein. As will be understood, the present disclosure is capable of other and different embodiments, and its various details can be modified in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be considered exemplary in nature and not restrictive.

[0020] Incorporation by Reference All publications, patents, and patent applications mentioned herein are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over such conflicting material. [Brief explanation of the drawings]

[0021] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Figure 1A]Figure 1 shows small molecule-mediated targeted degradation of GSPT1. MOLM-13 cells were treated with compounds GS-729, GS-731, GS-697, and GS-788 at the indicated concentrations for 16 hours, followed by immunoblotting. [Figure 1B] Figure 1 shows small molecule-mediated targeted degradation of GSPT1. MOLM-13 cells were treated with compounds GS-729, GS-731, GS-697, and GS-788 at the indicated concentrations for 16 hours, followed by immunoblotting. [Figure 2A] Figure 3 shows that FLT3 inhibition sensitizes AML cells to GSPT1 degraders GS-707, GS-749, and GS-750. MOLM-13 cells were treated with GSPT1 degraders at the indicated concentrations after 3-fold serial dilutions with or without 20 nM gilteritinib for 3 days. [Figure 2B] Figure 3 shows that FLT3 inhibition sensitizes AML cells to GSPT1 degraders GS-707, GS-749, and GS-750. MOLM-13 cells were treated with GSPT1 degraders at the indicated concentrations after 3-fold serial dilutions with or without 20 nM gilteritinib for 3 days. [Figure 2C] Figure 3 shows that FLT3 inhibition sensitizes AML cells to GSPT1 degraders GS-707, GS-749, and GS-750. MOLM-13 cells were treated with GSPT1 degraders at the indicated concentrations after 3-fold serial dilutions with or without 20 nM gilteritinib for 3 days. [Figure 3] We show that the pancreatic cell line KP-4 is sensitive to the GSPT1 degraders GS-668, GS-676, and GS-766. KP-4 cells were treated with the GSPT1 degraders at the indicated concentrations after 3-fold serial dilutions for 3 days. [Figure 4A] This shows that GSPT1 degraders reduce GSPT1 protein levels in xenograft tumors. Nude mice bearing (Figure 4A) MOLM-13 or (Figure 4B) 22RV1 xenograft tumors were orally treated with 30 mg / kg of GSPT1 degraders or vehicle. Tumors were collected for immunoblotting. [Figure 4B]This shows that GSPT1 degraders reduce GSPT1 protein levels in xenograft tumors. Nude mice bearing (Figure 4A) MOLM-13 or (Figure 4B) 22RV1 xenograft tumors were orally treated with 30 mg / kg of GSPT1 degraders or vehicle. Tumors were collected for immunoblotting. [Figure 5] 1 shows small molecule-mediated targeted degradation of GSPT1. MOLM-13 cells were treated with compounds GS-802 and GS-803 at the indicated concentrations for 16 hours and then immunoblotted. [Figure 6] Figure 1 shows small molecule-mediated targeted degradation of GSPT1. 22RV1 cells were treated with compounds GS-807, GS-813, and -814 at the indicated concentrations for 8 hours, followed by immunoblotting. DETAILED DESCRIPTION OF THE INVENTION

[0022] Translation termination is a GTP-dependent process regulated by two key proteins, eRF1 and eRF3. Translation termination factor eRF3a (also known as eukaryotic peptide chain release factor GTP-binding subunit ERF3A or "GSPT1") is a GTPase that interacts with eRF1 to promote stop codon recognition and release of the nascent peptide from the ribosome (Chauvin, Salhi et al. 2005). GSPT1 activates eRF1 in a GTP-dependent manner, and its GTPase activity requires complex formation with eRF1 and the ribosome (Frolova, Le Goff et al. 1996). GTP-bound GSPT1 and eRF1, together with the ribosome, form a functional translation termination complex (Zhouravleva, Frolova et al. 1995). Through its regulation of translation, GSPT1 plays diverse and important roles in cellular physiology. Increased expression of GSPT1 has been reported in human malignancies, including lung and gastric cancer (Malta-Vacas, Aires et al. 2005; Tian, ​​Tian et al. 2018; Sun, Zhang et al. 2019; Zhang, Zou et al. 2019). Therefore, GSPT1 is considered a novel cancer target whose active translation may be impaired, contributing to the malignant phenotype of cancer cells. Recently, Matyskiela and colleagues reported that the phthalimide-derived molecule CC-885 leads to cereblon-dependent degradation of GSPT1 and other targets, such as IKZF1 and IKZF3 (Matyskiela, Lu et al. 2016). Ishoey et al. also reported that GSPT1 was degraded by a subset of phthalimide-derived heterobiofunctional compounds (Ishoey, Chorn et al. 2018). CC-885 induced significant toxicity in most of the cell lines tested, likely due to degradation of GSTP1 and many other proteins (Matyskiela, Lu et al. 2016). Thus, despite its broad and potent anticancer activity, CC-885 exhibits unacceptable toxicity that hinders further development (Hansen, Correa et al. 2020).

[0023] In certain aspects, compounds are disclosed herein. In some embodiments, the compounds comprise the chemical structures or formulas disclosed herein. The compounds comprise GSPT1 degrading agents. GSPT1 degrading agents can be characterized by their ability to degrade or reduce the cellular protein level of GSPT1.

[0024] While embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It will be understood that various alternatives to the embodiments of the invention described herein may be utilized.

[0025] I. Compounds of the Present Disclosure In some embodiments, compounds are disclosed herein. In some embodiments, the compounds comprise a degradation tag. In some embodiments, the compounds comprise a cereblon-binding moiety. In some embodiments, the degradation tag comprises a cereblon-binding moiety. In some embodiments, the compounds comprise a GSPT1 degrader. For example, the compounds may result in GSPT1 degradation. The compounds may degrade GSPT1 as a result of cereblon modulation via the degradation tag. The compounds may bind to or modulate GSPT1 or cereblon. In some embodiments, the compounds comprise heterobifunctional compounds. In some embodiments, the compounds comprise molecular adhesives. In some embodiments, the compounds may be used as molecular adhesives. In some embodiments, the compounds comprise a linker. In some embodiments, the compounds comprise a truncated Janus kinase (JAK)-binding moiety.

[0026] In one embodiment, the compound of formula (A)

[0027] [ka] Provided herein is a compound of the formula: W is hydrogen or fluorine; Z is absent or -NR 1a -, or -O-, where R 1a is hydrogen or C1-C8 alkyl, L is an optionally substituted C-C 10 Alkylene, or optionally substituted C-C 10 heteroalkylene; or L is

[0028] [ka] wherein: Ring B is an optionally substituted 3- to 7-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl; L 1 is absent or optionally substituted C1-C 10 Alkylene or optionally substituted C-C 10 is heteroalkylene, L 2 is absent or optionally substituted C1-C 10 Alkylene, optionally substituted C-C 10 Alkenylene, optionally substituted C-C 10 Alkynylene or optionally substituted C-C 10 is heteroalkylene, R 1 is absent or is oxo (=O), R 2 and R 4 are each independently hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; R 3 is hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R 2 and R 3 , or R 3 and R 4 together form an optionally substituted 3- to 7-membered partially saturated or unsaturated carbocyclyl, an optionally substituted 4- to 7-membered partially saturated or unsaturated heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered heteroaryl; R 5 and R 6are each independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclylC1-C8 alkyl, optionally substituted 3-10 membered heterocyclylC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; or R 5 and R 6 are optionally taken together with the atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl.

[0029] In some embodiments of Formula (A), W is hydrogen.In some embodiments of Formula (A), W is fluorine.

[0030] In another embodiment, the compound of formula (I)

[0031] [ka] Provided herein is a compound of the formula: Z is absent or -NR 1a -, or -O-, where R 1a is hydrogen or C1-C8 alkyl, L is an optionally substituted C-C 10 Alkylene, or optionally substituted C-C 10 heteroalkylene; or L is

[0032] [ka] wherein: Ring B is an optionally substituted 3- to 7-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl; L 1 is absent or optionally substituted C1-C 10 Alkylene or optionally substituted C-C 10 is heteroalkylene, L 2 is absent or optionally substituted C1-C 10 Alkylene, optionally substituted C-C 10 Alkenylene, optionally substituted C-C 10 Alkynylene or optionally substituted C-C 10 is heteroalkylene, R 1 is absent or is oxo (=O), R 2 and R 4 are each independently hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; R 3 is hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted saturated or partially unsaturated 3- to 10-membered carbocyclyl, or optionally substituted saturated or partially unsaturated 3- to 10-membered heterocyclyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 2 and R 3 , or R 3 and R 4 together form an optionally substituted partially unsaturated 3- to 7-membered carbocyclyl, an optionally substituted partially unsaturated 4- to 7-membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered heteroaryl; R 5 and R 6 are each independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclylC1-C8 alkyl, optionally substituted 3-10 membered heterocyclylC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; or R 5 and R 6 are optionally taken together with the atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl.

[0033] In some embodiments of Formula (A) or Formula (I), R 2 and R 3 and together form an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2 and R 3 are taken together to form an optionally substituted phenyl. In some embodiments, R 2 and R 3 and together form an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2 and R 3 are joined to form an optionally substituted 6-membered heteroaryl containing 1-3 heteroatoms selected from N and O. In some embodiments, the 6-membered heteroaryl is pyridinyl or triazinyl. In some embodiments, the 6-membered heteroaryl is pyridinyl.

[0034] In some such embodiments, R 2 and R 3 together form an optionally substituted partially unsaturated 3- to 7-membered carbocyclyl. In some embodiments, R 2 and R 3 and together form an optionally substituted, partially unsaturated, 4-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S. In some such embodiments, R 2 and R 3 together form an optionally substituted partially unsaturated 3- to 7-membered carbocyclyl. In some embodiments, R 2 and R 3 together form an optionally substituted partially unsaturated 4-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S.

[0035] In some embodiments of Formula (A) or Formula (I), R 3 and R 4and together form an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 3 and R 4 are taken together to form an optionally substituted phenyl. In some embodiments, R 3 and R 4 and together form an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 3 and R 4 are joined to form an optionally substituted 6-membered heteroaryl. In some embodiments, the 6-membered heteroaryl contains 1 to 3 heteroatoms selected from N and O. In some embodiments, the 6-membered heteroaryl is pyridinyl or triazinyl. In some embodiments, the 6-membered heteroaryl is pyrimidinyl, pyrazinyl, or pyridazinyl.

[0036] In some such embodiments, R 3 and R 4 together form an optionally substituted partially unsaturated 3- to 7-membered carbocyclyl. In some embodiments, R 3 and R 4 together form an optionally substituted partially unsaturated 4-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S.

[0037] Embodiments described herein with respect to Formula (A) or Formula (I) are also applicable to any of Formulas (II), (III), or (IV) (including, for clarity, (II-A), (IV-A), (IV-B), (IV-C), or (IV-D)), to the extent such embodiments are not inconsistent.

[0038] In some embodiments of Formula (I), R 3 and R 4When taken together form an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl ring, such ring corresponds to ring A in compounds of formula (II).

[0039] In some embodiments, the compound of formula (I) has formula (II):

[0040] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , L, and Z are defined as in formula (I), Ring A is phenyl or 5-6 membered heteroaryl; R 11 are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl, and p1 is 0, 1, 2, 3, or 4.

[0041] In some embodiments of Formula (II), ring A is phenyl, pyridinyl, or triazinyl. In some embodiments, ring A is phenyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is triazinyl. In some embodiments of Formula (II), ring A is pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyridazinyl.

[0042] Embodiments described herein for formula (II) are also applicable to formula (II-A) to the extent such embodiments are not inconsistent.

[0043] In some embodiments, the compound of formula (II) has the formula (II-A):

[0044] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , L, and Z are defined as in formula (I), and X 1 , X 2 , and X 3 are each independently, CR 11 Or N.

[0045] In some embodiments of Formula (II-A), X 1 , X 2 , and X 3 are each independently CR 11 is.

[0046] In some embodiments of Formula (II-A), X 1 , X 2 , and X 3 are each independently N.

[0047] In some embodiments of Formula (II-A), X 1 is N and X 2 and X 3 are each independently CR 11 is.

[0048] In some embodiments of Formula (II-A), X 1 and X 2 are N and X 3 is CR 11 is.

[0049] In some embodiments of Formula (II-A), X 1 and X 3 are N and X 2 is CR 11 is.

[0050] In some such embodiments, R 11 are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R 5 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl. 11 are each independently hydrogen, halogen, or optionally substituted C1-C8 alkyl. In some embodiments, R 11 are each independently hydrogen. In some embodiments, R 11 are each independently methyl, ethyl, n-propyl, iso-propyl, or tert-butyl. 11 are each independently methyl. In some embodiments, R 11are each independently an optionally substituted 3- to 10-membered carbocyclyl or an optionally substituted 3- to 10-membered heterocyclyl. 11 are each independently optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, R 11 are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 11 are each independently oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, or piperazine. 11 are each independently hydrogen, Cl, F, Br, CN, NO, OH, OCH, methyl, ethyl, or iso-propyl. 11 are each independently hydrogen, Cl, F, Br, CN, NO, NH, OH, OCH, methyl, ethyl, or iso-propyl. 11 are each independently hydrogen, Cl, F, Br, OH, OCH, methyl, or iso-propyl. 11 are each independently hydrogen, Cl, F, Br, NH, OH, OCH, methyl, or iso-propyl. 11 is OCH3. In some embodiments, R 11 is N(R 5 )R 6 In some embodiments, R 11 is NH. In some embodiments, R 11 is N(R 5 )R 6 and R 5 and R 6 are taken together with the N to which they are attached to form a 3- to 10-membered heterocyclyl. In some embodiments, R 11 are N(R 5)R 6 and R 5 and R 6 together with the N to which they are attached to form piperazine.

[0051] In some embodiments of Formula (A) or Formula (I), R 3 is halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted saturated or partially unsaturated 3- to 10-membered carbocyclyl, or optionally substituted saturated or partially unsaturated 3- to 10-membered heterocyclyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0052] In some such embodiments, R 3 is N(R 5 )R 6 , optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R 3 is an optionally substituted 6-10 membered aryl or an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 3 is an optionally substituted phenyl or an optionally substituted 6-10 membered heteroaryl. In some embodiments, R 3 is substituted phenyl. In some embodiments, R 3is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 3 is an optionally substituted 6-10 membered heteroaryl. In some embodiments, R 3 is a substituted 6-10 membered heteroaryl. In some such embodiments, the 6-10 membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some such embodiments, the 6-10 membered heteroaryl is pyridinyl, pyrimidinyl, or pyrazinyl. In some such embodiments, the 6-10 membered heteroaryl is pyridinyl. In some such embodiments, the 6-10 membered heteroaryl is selected from pyrazolopyridinyl, imidazopyridinyl, tetrahydronaphthyridinyl, pyrrolopyridinyl, and dihydrocyclopentapyridinyl. In some such embodiments, the 6-10 membered heteroaryl is pyrazolopyridinyl. In some such embodiments, the 6-10 membered heteroaryl is imidazopyridinyl. In some such embodiments, the 6-10 membered heteroaryl is pyrrolopyridinyl.

[0053] In some embodiments of Formula (A) or Formula (I), R 3 is hydrogen.

[0054] In some embodiments of Formula (A) or Formula (I), R 3 is an optionally substituted C1-C8 alkyl. In some embodiments of Formula (A) or Formula (I), R 3 is an optionally substituted C1-C3 alkyl. In some embodiments of Formula (A) or Formula (I), R3 is optionally substituted methyl. In some embodiments of Formula (A) or Formula (I), R 3 is benzyl.

[0055] In some embodiments of Formula (A) or Formula (I), R 3 is an optionally substituted 3- to 10-membered carbocyclyl. In some embodiments of Formula (A) or Formula (I), R 3 is optionally replaced

[0056] [ka] In some embodiments of Formula (A) or Formula (I), R 3 teeth

[0057] [ka] In some embodiments of Formula (A) or Formula (I), R 3 teeth

[0058] [ka] is.

[0059] In some such embodiments, R 3 is N(R 5 )R 6 In some embodiments, R 3 is NHR 6 In some embodiments, R 3 is NHR 6 and R 6 is an optionally substituted 3- to 10-membered carbocyclyl. In some embodiments, R 3 is optionally replaced

[0060] [ka] In some such embodiments, R 3 teeth

[0061] [ka] In some embodiments, R 3 is NHR 6 and R 6 is an optionally substituted 3-10 membered heterocyclyl. In some embodiments, R 3 is NHR 6 and R 6 is an optionally substituted 6-membered heterocyclyl. In some embodiments, R 3 is optionally replaced

[0062] [ka] In some embodiments, R 3 is optionally replaced

[0063] [ka] In some embodiments, R 3 teeth

[0064] [ka] In some embodiments, R 3 is NHR 6 and R 6 is an optionally substituted 6-10 membered aryl. In some embodiments, R 3 is NHR 6 and R 6 is optionally substituted phenyl. In some embodiments, R 3 is NHR 6 and R 6 is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R3 is NHR 6 and R 6 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 3 is NHR 6 and R 6 is an optionally substituted 5-6 membered heteroaryl containing 1, 2, or 3 nitrogens. In some embodiments, R 3 is NHR 6 and R 6 is an optionally substituted 5-membered heteroaryl. In some embodiments, R 3 is optionally replaced

[0065] [ka] In some embodiments, R 3 teeth

[0066] [ka] In some embodiments, R 3 is NHR 6 and R 6 is an optionally substituted 6-membered heteroaryl. In some embodiments, R 3 is optionally replaced

[0067] [ka] In some embodiments, R 3 is optionally replaced

[0068] [ka] In some embodiments, R 3 is optionally replaced

[0069] [ka] is.

[0070] In some embodiments of Formula (A) or Formula (I), R 4 are hydrogen, halogens, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R 5 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl. 4 is halogen, CN, OR 5 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl. 4 is hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl. 4 is methyl, ethyl, n-propyl, iso-propyl, or tert-butyl. 4 is substituted methyl. In some embodiments, R 4 is benzyl. In some embodiments, R 4 is an optionally substituted 3- to 10-membered carbocyclyl. In some embodiments, R 4 is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, R 4is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 4 is cyclopropyl. In some embodiments, R 4 is cyclobutyl. In some embodiments, R 4 is cyclopentyl. In some embodiments, R 4 is N(R 5 )R 6 In some embodiments, R 4 is NHR 6 In some embodiments, R 4 is NHR 6 and R 6 is an optionally substituted 6-10 membered aryl. In some embodiments, R 4 is NH(optionally substituted phenyl). In some embodiments, R 4 is NH(phenyl). In some embodiments, R 4 is an optionally substituted C-C haloalkyl. In some embodiments, R 4 is CHF2.

[0071] In some such embodiments, R 4 is hydrogen.

[0072] In some such embodiments, R 4 is hydrogen and R 3 is N(R 5 )R 6 , optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0073] In some such embodiments, R 4 is hydrogen and R 3is optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl. In some such embodiments, R 4 is hydrogen and R 3 is optionally substituted phenyl, or optionally substituted pyridinyl. In some such embodiments, R 4 is hydrogen and R 3 is optionally substituted quinoxalinyl, naphthyridinyl, pyrazolopyridinyl, imidazopyridinyl, and pyrrolopyridinyl. In some such embodiments, R 4 is hydrogen and R 3 is optionally substituted quinoxalinyl. In some such embodiments, R 4 is hydrogen and R 3 is optionally substituted naphthyridinyl. In some such embodiments, R 4 is hydrogen and R 3 is optionally substituted pyrazolopyridinyl. In some such embodiments, R 4 is hydrogen and R 3 is optionally substituted imidazopyridinyl. In some such embodiments, R 4 is hydrogen and R 3 is an optionally substituted pyrrolopyridinyl.

[0074] In some embodiments of Formula (A) or Formula (I), R 5 and R 6are each independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclylC1-C8 alkyl, optionally substituted 3-10 membered heterocyclylC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0075] In some embodiments of Formula (A) or Formula (I), R 5 and R 6 optionally forms an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl.

[0076] In one embodiment, the compound of formula (I) is of formula (III)

[0077] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , L, and Z are defined as in formula (I), X 4 , X 5 , and X 6 are each independently, CR 8 or N, R 8 are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5, C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; or Two R on adjacent carbon atoms 8 together form an optionally substituted partially unsaturated 3- to 7-membered carbocyclyl, an optionally substituted partially unsaturated 4- to 7-membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5- to 6-membered heteroaryl, and p2 is 0, 1, 2, 3, 4, or 5.

[0078] In some embodiments of Formula (III), X 4 , X 5 , and X 6 are each independently, CR 8 In some embodiments, X 4 , X 5 , and X 6 are each independently N.

[0079] In some embodiments of Formula (III), X 4 is N and X 5 and X 6 are each independently, CR 8 is.

[0080] In some embodiments of Formula (III), X 5 is N and X 4 and X 6 are each independently, CR 8 is.

[0081] In some embodiments of Formula (III), X 6 is N and X 4 and X5 are each independently, CR 8 is.

[0082] In some embodiments of Formula (III), X 4 is CR 8 and X 5 and X 6 are each independently N.

[0083] In some embodiments of Formula (III), X 5 is CR 8 and X 4 and X 6 are each independently N.

[0084] In some embodiments of Formula (III), X 6 is CR 8 and X 4 and X 5 are each independently N.

[0085] In some embodiments of Formula (III), p2 is 0. In some embodiments, p2 is 1. In some embodiments, p2 is 2. In some embodiments, p2 is 3. In some embodiments, p2 is 4. In some embodiments, p2 is 5.

[0086] In some embodiments of Formula (III), R 8 are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R 5 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl. 8are each independently hydrogen, halogen, or optionally substituted C1-C8 alkyl. In some embodiments, R 8 are each independently hydrogen, halogen, or C1-C4 alkyl. 8 are each independently methyl, ethyl, n-propyl, iso-propyl, or tert-butyl. 8 are each independently hydrogen, halogen, methyl, ethyl, n-propyl, iso-propyl, or tert-butyl. 8 are each independently an optionally substituted 3- to 10-membered carbocyclyl or an optionally substituted 3- to 10-membered heterocyclyl. 8 are each independently optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, R 8 are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 8 are each independently oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, or piperazine. 8 are each independently hydrogen, Cl, F, Br, CN, NO, OH, OCH, methyl, ethyl, or iso-propyl. 8 are each independently OR 5 , N(R 5 )R 6 , optionally substituted C1-C8 haloalkyl. In some embodiments, R 8 are each independently cyclopropoxy, amino, methylamino, dimethylamino, CHF2, and CF3.

[0087] In some such embodiments, R 8are each independently halogen. In some such embodiments, R 8 are each independently F. In some such embodiments, R 8 are each independently Cl.

[0088] In some such embodiments, R 8 are each independently an optionally substituted C1-C8 alkyl. In some such embodiments, R 8 are each independently an optionally substituted C-C alkyl. In some such embodiments, R 8 are each independently C1-C3 haloalkyl. In some such embodiments, R 8 are each independently CH. In some such embodiments, R 8 are each independently CHF2. In some such embodiments, R 8 are each independently CF3.

[0089] In some such embodiments, R 8 are each independently an optionally substituted 3- to 10-membered carbocyclyl. In some embodiments, R 8 are each independently optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, R 8 and each independently is optionally substituted cyclobutyl. In some such embodiments, R 8 are each independently

[0090] [ka] is.

[0091] In some such embodiments, R 8are each independently an optionally substituted 3- to 10-membered heterocyclyl. In some such embodiments, R 8 are each independently an optionally substituted 3-10 membered heterocyclyl containing 1 or 2 nitrogen atoms. In some such embodiments, R 8 are each independently an optionally substituted 3-10 membered heterocyclyl containing 1 nitrogen. In some such embodiments, R 8 are each independently an optionally substituted 4-, 5-, or 6-membered heterocyclyl. In some such embodiments, R 8 are each independently

[0092] [ka] In some such embodiments, R 8 are each independently

[0093] [ka] is.

[0094] In some such embodiments, R 8 are each independently OR 5 In some such embodiments, R 5 is hydrogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl. In some such embodiments, R 5 is an optionally substituted 3- to 10-membered carbocyclyl. In some such embodiments, R 5 is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some such embodiments, R 8 are each independently

[0095] [ka] is.

[0096] In some such embodiments, R 8 are each independently N(R 5 )R 6 In some such embodiments, R 8 are each independently NH. In some such embodiments, R 8 are each independently -NHCH. In some such embodiments, R 8 are each independently -N(CH). In some such embodiments, R 5 and R 6 together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocyclyl. In some such embodiments, R 5 and R 6 together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms. In some such embodiments, R 5 and R 6 together with the nitrogen to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing one nitrogen. In some such embodiments, R 5 and R 6 together with the nitrogen to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing two nitrogens. In some such embodiments, R 5 and R 6 together with the nitrogen to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocyclyl. In some such embodiments, R 8 are each independently

[0097] [ka] In some such embodiments, R 8 are each independently

[0098] [ka] In some such embodiments, R 8 are each independently

[0099] [ka] In some such embodiments, R 8 are each independently

[0100] [ka] In some such embodiments, two R on adjacent carbon atoms are 8 are joined to form an optionally substituted partially unsaturated 3- to 7-membered carbocyclyl, an optionally substituted partially unsaturated 4- to 7-membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered heteroaryl. In some embodiments, two R on adjacent carbon atoms 8 together form an optionally substituted phenyl.

[0101] In some such embodiments, two R on adjacent carbon atoms 8 together form an optionally substituted partially unsaturated 3- to 7-membered carbocyclyl. In some such embodiments, two R on adjacent carbon atoms 8 together form an optionally substituted 5-membered carbocyclyl. In some such embodiments, two R on adjacent carbon atoms 8 together form a 5-membered carbocyclyl substituted with hydroxyl. In some such embodiments, two R on adjacent carbon atoms 8are united,

[0102] [ka] Form.

[0103] In some such embodiments, two R on adjacent carbon atoms 8 together form an optionally substituted partially unsaturated 4- to 7-membered heterocyclyl. In some such embodiments, two R on adjacent carbon atoms 8 and R are joined to form an optionally substituted 6-membered heterocyclyl. In some such embodiments, two R on adjacent carbon atoms are 8 together form an optionally substituted 6-membered heterocyclyl containing 1 or 2 nitrogens. In some such embodiments, two R on adjacent carbon atoms 8 together form an optionally substituted 6-membered heterocyclyl containing one nitrogen. In some such embodiments, two R on adjacent carbon atoms 8 are united and optionally replaced

[0104] [ka] In some such embodiments, two R on adjacent carbon atoms form 8 are united,

[0105] [ka] Form.

[0106] In some embodiments, two R on adjacent carbon atoms 8 together form phenyl. In some embodiments, two R on adjacent carbon atoms 8are joined to form a substituted phenyl. In some embodiments, two R on adjacent carbon atoms 8 are united,

[0107] [ka] In some embodiments, two R on adjacent carbon atoms form a phenyl substituted with 8 are united,

[0108] [ka] In some embodiments, two R on adjacent carbon atoms form a phenyl substituted with 8 are united,

[0109] [ka] In some embodiments, two R on adjacent carbon atoms form a phenyl substituted with 8 are united,

[0110] [ka] In some embodiments, two R on adjacent carbon atoms form a phenyl substituted with 8 are united,

[0111] [ka] In some embodiments, two R on adjacent carbon atoms form a phenyl substituted with 8 are united,

[0112] [ka] In some embodiments, two R on adjacent carbon atoms form a phenyl substituted with 8 are united,

[0113] [ka] In some embodiments, two R on adjacent carbon atoms form a phenyl substituted with 8 are united,

[0114] [ka] In some embodiments, two R on adjacent carbon atoms form a phenyl substituted with 8 are united,

[0115] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0116] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0117] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0118] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0119] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0120] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0121] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0122] [ka] Form.

[0123] In some embodiments, two R on adjacent carbon atoms 8 and R are joined to form an optionally substituted 5-membered heteroaryl. In some embodiments, two R on adjacent carbon atoms are 8 are joined to form an optionally substituted 5-membered heteroaryl containing 1 to 3 nitrogen atoms. In some embodiments, two R on adjacent carbon atoms 8 are joined to form an optionally substituted 5-membered heteroaryl containing one nitrogen atom. In some embodiments, two R on adjacent carbon atoms 8 are joined to form an optionally substituted 5-membered heteroaryl containing two nitrogen atoms. In some embodiments, two R on adjacent carbon atoms 8are joined to form an optionally substituted 5-membered heteroaryl containing three nitrogen atoms. In some embodiments, two R on adjacent carbon atoms are 8 together form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is substituted with methyl. In some embodiments, two R on adjacent carbon atoms 8 together form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is substituted with iso-propyl. In some embodiments, two R 8 together form a substituted 5-membered heteroaryl, and the 5-membered heteroaryl is

[0124] [ka] In some embodiments, two R on adjacent carbon atoms are substituted with 8 together form a substituted 5-membered heteroaryl, and the 5-membered heteroaryl is

[0125] [ka] In some embodiments, two R on adjacent carbon atoms are substituted with 8 together form a substituted 5-membered heteroaryl, and the 5-membered heteroaryl is

[0126] [ka] In some embodiments, two R on adjacent carbon atoms are substituted with 8 together form a substituted 5-membered heteroaryl, and the 5-membered heteroaryl is

[0127] [ka] In some embodiments, two R on adjacent carbon atoms are substituted with 8together form a substituted 5-membered heteroaryl, and the 5-membered heteroaryl is

[0128] [ka] In some embodiments, two R on adjacent carbon atoms are substituted with 8 together form a substituted 5-membered heteroaryl, and the 5-membered heteroaryl is

[0129] [ka] In some embodiments, two R on adjacent carbon atoms are substituted with 8 together form a substituted 5-membered heteroaryl, and the 5-membered heteroaryl is

[0130] [ka] In some embodiments, two R on adjacent carbon atoms are substituted with 8 together form a substituted 5-membered heteroaryl, and the 5-membered heteroaryl is

[0131] [ka] In some embodiments, two R on adjacent carbon atoms are substituted with 8 together form a substituted 5-membered heteroaryl, and the 5-membered heteroaryl is

[0132] [ka] In some embodiments, two R on adjacent carbon atoms are substituted with 8 are united,

[0133] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0134] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0135] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0136] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0137] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0138] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0139] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0140] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0141] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0142] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0143] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0144] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0145] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0146] [ka] In some embodiments, two R on adjacent carbon atoms form 8are united,

[0147] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0148] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0149] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0150] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0151] [ka] In some embodiments, two R on adjacent carbon atoms form 8 are united,

[0152] [ka] Form.

[0153] In some embodiments, two R on adjacent carbon atoms 8 are joined to form an optionally substituted 6-membered heteroaryl. In some embodiments, two R on adjacent carbon atoms are8 are joined to form an optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms. In some embodiments, two R on adjacent carbon atoms 8 are joined together to form an optionally substituted 6-membered heteroaryl containing 1 or 2 nitrogen atoms. In some embodiments, two R on adjacent carbon atoms 8 are joined to form an optionally substituted 6-membered heteroaryl containing one nitrogen atom (i.e., pyridinyl). In some embodiments, two R on adjacent carbon atoms 8 are united and optionally replaced

[0154] [ka] Form.

[0155] In some embodiments, the compound of formula (I) has formula (IV):

[0156] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , L, and Z are defined as in formula (I), X 4 is CR 8a or N, X 5 is CR 8b or N, X 6 is CR 8d or N, R 8a , R 8b , R 8c , R 8d , and R 8e are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; or R 8a and R 8b , R 8b and R 8c , R 8c and R 8d , or R 8d and R 8e together with the atoms to which they are attached form an optionally substituted 3- to 7-membered carbocyclyl, an optionally substituted 4- to 7-membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered heteroaryl.

[0157] In some embodiments of Formula (IV), X 4 is CR 8a and X 5 is CR 8b and X 6 is CR 8d In some embodiments of formula (IV), X 4 is N and X 5 is CR 8b and X 6 is CR 8d In some embodiments of formula (IV), X 5 is N and X 4 is CR 8a and X 6 is CR 8d In some such embodiments described above, R 8a , R 8b , R 8c , R 8d , and R 8eare each independently hydrogen, halogen, or optionally substituted C-C alkyl. In some such embodiments, R 8a , R 8b , and R 8c are each independently hydrogen, halogen, or C1-C4 alkyl. In some such embodiments, R 8d and R 8e is hydrogen. In some embodiments of Formula (IV), X 4 is N and X 5 is CR 8b and X 6 is CR 8d and R 8b , R 8c , R 8d , and R 8e are each independently hydrogen, halogen, or optionally substituted C-C alkyl. In some such embodiments, R 8b and R 8c are each independently hydrogen, halogen, or C1-C4 alkyl; R 8d and R 8c is hydrogen.

[0158] In some embodiments of Formula (IV), R 8a and R 8b taken together with the atom to which they are attached form an optionally substituted phenyl. In some embodiments, R 8a and R 8b taken together with the atom to which they are attached form an optionally substituted 5-membered heteroaryl. In some embodiments, R 8a and R 8b together with the atom to which they are attached form an optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms.

[0159] In some embodiments of Formula (IV), R 8b and R 8ctaken together with the atom to which they are attached form an optionally substituted phenyl. In some embodiments, R 8b and R 8c together with the atom to which they are attached form an optionally substituted 5-membered heteroaryl. In some such embodiments, R 8b and R 8c together with the atom to which they are attached form an optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms.

[0160] In some embodiments of Formula (IV), R 8c and R 8d together with the atoms to which they are attached form an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 8c and R 8d taken together with the atom to which they are attached form an optionally substituted phenyl. In some embodiments, R 8c and R 8d taken together with the atom to which they are attached form an optionally substituted 5-membered heteroaryl. In some embodiments, R 8c and R 8d together with the atom to which they are attached form an optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms.

[0161] In some embodiments of Formula (IV), R 8d and R 8e together with the atoms to which they are attached form an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 8d and R 8e taken together with the atom to which they are attached form an optionally substituted phenyl. In some embodiments, R 8d and R 8etaken together with the atom to which they are attached form an optionally substituted 5-membered heteroaryl. In some embodiments, R 8d and R 8e together with the atom to which they are attached form an optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms.

[0162] In some embodiments of Formula (IV), X 4 is N and R 8b and R 8c together with the atoms to which they are attached form an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl.

[0163] Embodiments described herein for formula (IV) are also applicable to formulas (IV-A), (IV-B), (IV-C), or (IV-D) to the extent such embodiments are not inconsistent.

[0164] In some embodiments, the compound of formula (IV) has the formula (IV-A):

[0165] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , L, and Z are defined as in formula (I), X 4 is CR 8a or N, X 6 is CR 8d or N, R 9 are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R6 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl, and q1 is 0, 1, 2, or 3.

[0166] In some such embodiments of formula (IV-A), R 9 are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R 5 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl. 9 are each independently hydrogen, halogen, or optionally substituted C1-C8 alkyl. In some embodiments, R 9 are each independently methyl, ethyl, n-propyl, iso-propyl, or tert-butyl. 9 are each independently an optionally substituted 3- to 10-membered carbocyclyl or an optionally substituted 3- to 10-membered heterocyclyl. 9 are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 9 are each independently optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, R 9are each independently oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, or piperazine. 9 are each independently hydrogen, Cl, F, Br, CN, NO, OH, OCH, methyl, ethyl, or iso-propyl. 9 are each independently an optionally substituted C1-C8 alkylamino. In some embodiments, R 9 are each independently NH(CHOH) or NHCHCH(OH)CHOH.

[0167] In some embodiments of Formula (IV-A), q1 is 1, 2, or 3. In some embodiments, q1 is 1 or 2. In some embodiments, q1 is 0. In some embodiments, q1 is 1. In some embodiments, q1 is 2. In some embodiments, q1 is 3.

[0168] In some embodiments, X 4 is N and X 6 is N. In some embodiments, X 4 is N and X 6 is CR 8d In some embodiments, X 4 is CR 8a and X 6 is N. In some embodiments, X 4 is CR 8a and X 6 is CR 8d is.

[0169] In some embodiments, the compound of formula (IV) has the formula (IV-B):

[0170] [ka] or a pharmaceutically acceptable salt thereof, wherein: R1 , R 2 , L, and Z are defined as in formula (I), X 4 is CR 8a or N, X 5 is CR 8b or N, Y 1 , Y 2 , and Y 3 are each independently, CR 10 , N.R. 10a , or N, where Y 1 , Y 2 , and Y 3 At least one of the following is CR 10 and R 10 are each independently hydrogen, halogen, CN, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, or optionally substituted C1-C8 alkylamino, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, and R 10a are each independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3- to 10-membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl.

[0171] In some such embodiments of formula (IV-B), X 4 is N and X 5 is CR 8b In some embodiments, X 5 is N and X 4 is CR 8a In some embodiments, X 4 is N and X 5is N. In some embodiments, X 4 is CR 8a and X 5 is CR 8b is.

[0172] In some embodiments, the compound of formula (IV) has the formula (IV-C):

[0173] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , L, and Z are defined as in formula (I), X 4 is CR 8a or N, X 6 is CR 8d or N, Y 1 , Y 2 , and Y 3 are each independently, CR 10 , N.R. 10a , or N, where Y 1 , Y 2 , and Y 3 At least one of the following is CR 10 and R 10 are each independently hydrogen, halogen, CN, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, or optionally substituted C1-C8 alkylamino, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, and R 10aare each independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3- to 10-membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl.

[0174] In some such embodiments of formula (IV-C), X 4 is N and X 6 is CR 8d In some embodiments, X 4 is CR 8a and X 6 is N. In some embodiments, X 4 is N and X 6 is N.

[0175] In some embodiments, the compound of formula (IV) has the formula (IV-D):

[0176] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , L, and Z are defined as in formula (I), X 4 is CR 8a or N, X 5 is CR 8b or N, Y 1 , Y 2 , and Y 3 are each independently, CR 10 , N.R. 10a , or N, where Y 1 , Y 2 , and Y 3 At least one of the following is CR 10 and R 10are each independently hydrogen, halogen, CN, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, or optionally substituted C1-C8 alkylamino, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, and R 10a are each independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3- to 10-membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl.

[0177] In some such embodiments of formula (IV-D), X 4 is N and X 5 is CR 8b In some embodiments, X 4 is CR 8a and X 5 is N. In some embodiments, X 4 is N and X 5 is N.

[0178] In some embodiments of any of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 8a , R 8b , R 8c , R 8d , and R 8e are independently hydrogen, halogen, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R 5, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl. 8a , R 8b , R 8c , R 8d , and R 8e are each independently hydrogen, halogen, or optionally substituted C-C alkyl. In some such embodiments, R 8a , R 8b , R 8c , R 8d , and R 8e are each independently hydrogen, halogen, or C1-C4 alkyl. 8a , R 8b , R 8c , R 8d , and R 8e are each independently hydrogen, halogen, methyl, ethyl, n-propyl, iso-propyl, or tert-butyl. 8a , R 8b , R 8c , R 8d , and R 8e are each independently methyl, ethyl, n-propyl, iso-propyl, or tert-butyl. 8a , R 8b , R 8c , R 8d , and R 8e are each independently an optionally substituted 3- to 10-membered carbocyclyl or an optionally substituted 3- to 10-membered heterocyclyl. 8a , R 8b , R 8c , R 8d , and R 8eare each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 8a , R 8b , R 8c , R 8d , and R 8e are each independently hydrogen, Cl, F, Br, CN, NO, OH, OCH, methyl, ethyl, or iso-propyl. 8a , R 8b , R 8c , R 8d , and R 8e are each independently hydrogen or F.

[0179] In some embodiments of formula (IV-B), (IV-C), or (IV-D), Y 1 and Y 3 are each independently, NR 10a or N and Y 2 is CR 10 is.

[0180] In some embodiments of formula (IV-B), (IV-C), or (IV-D), Y 2 and Y 3 are each independently, NR 10a or N and Y 1 is CR 10 is.

[0181] In some embodiments of formula (IV-B), (IV-C), or (IV-D), Y 1 and Y 2 are each independently, NR 10a or N and Y 3 is CR 10 is.

[0182] In some embodiments of formula (IV-B), (IV-C), or (IV-D), R 10are each independently hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, or optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl. 10 are each independently hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl. 10 are each independently methyl, ethyl, n-propyl, iso-propyl, or tert-butyl. 10 are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 10 are each independently hydrogen. In some embodiments, R 10 are each independently halogen. In some embodiments, R 10 are each independently F, Cl, or Br. In some embodiments, R 10 are each independently F.

[0183] In some embodiments of formula (IV-B), (IV-C), or (IV-D), R 10a are each independently hydrogen, or optionally substituted C-C alkyl, optionally substituted C-C haloalkyl. 10a are each independently methyl, ethyl, n-propyl, iso-propyl, or tert-butyl. 10a are each independently hydrogen. 10a are each independently an optionally substituted C-C haloalkyl. In some embodiments, R 10aare each independently CF, CHF, or CHCF. In some embodiments, R 10a are each independently an optionally substituted 3- to 6-membered carbocyclyl. In some embodiments, R 10a are each independently optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, R 10a are each independently an optionally substituted 3- to 6-membered heterocyclyl. In some embodiments, R 10a are each independently optionally substituted oxetanyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydro-2H-pyranyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted piperazinyl.

[0184] In some embodiments of any of the formulas described herein, R 2 are hydrogen, halogens, CN, NO2, OR 5 , S.R. 5 , N(R 5 )R 6 , C(O)R 5 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl. 2 is halogen, CN, OR 5, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl.

[0185] In some such embodiments of any of the formulas described herein, R 2 Each is hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl. 2 is methyl, ethyl, n-propyl, iso-propyl, or tert-butyl. 2 is methyl or ethyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is iso-propyl. In some embodiments, R 2 is an optionally substituted 3-10 membered heterocyclyl. In some embodiments, R 2 is oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, or piperazine. 2 is an optionally substituted 3- to 10-membered carbocyclyl. In some embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is an optionally substituted C-C haloalkyl. In some embodiments, R 2is CF, CHF, or CHCF. In some embodiments, R 2 is CHF2. In some embodiments of any of the formulas described herein, Z is absent or -O-. In some embodiments, Z is absent. In some embodiments, Z is -O-. In some embodiments, Z is -NR 1a In some embodiments, Z is -NR 1a -Z and R 1a is hydrogen or C1-C4 alkyl. In some embodiments, Z is -NR 1a and R 1a is hydrogen. In some embodiments, Z is -NH-.

[0186] In some embodiments of any of the formulas described herein, L is an optionally substituted C-C 10 Alkylene, or optionally substituted C-C 10 In some embodiments, L is an optionally substituted C-C 10 In some embodiments, L is an optionally substituted C-C alkylene. 10 It is heteroalkylene, wherein the heteroatom is N or O. In some embodiments, the heteroalkylene is polyethylene glycol (PEG).

[0187] In some embodiments of any of the formulas described herein, L is

[0188] [ka] wherein: Ring B is an optionally substituted 3- to 7-membered carbocyclyl or an optionally substituted 4- to 7-membered heterocyclyl; L 1 is absent or optionally substituted C1-C 10Alkylene or optionally substituted C-C 10 is heteroalkylene, L 2 is absent or optionally substituted C1-C 10 Alkylene, optionally substituted C-C 10 Alkenylene, optionally substituted C-C 10 Alkynylene, or optionally substituted C-C 10 It is heteroalkylene.

[0189] In some such embodiments, L is

[0190] [ka] wherein: Ring B is an optionally substituted 3- to 7-membered carbocyclyl; L 1 is absent or optionally substituted C1-C 10 alkylene, and L 2 is absent or optionally substituted C1-C 10 It is alkylene.

[0191] In some embodiments, L is

[0192] [ka] where L 1 does not exist, and L 2 is C1-C 10 In some such embodiments, L is alkylene. 2 is C1-C4 alkylene, preferably L 2 is C1-C2 alkylene.

[0193] In some embodiments, L is

[0194] [ka] where L 2 does not exist, and L 1 is C1-C 10 In some such embodiments, L is alkylene. 1 is C1-C4 alkylene, preferably L 1 is C1-C2 alkylene.

[0195] In some embodiments, Ring B is an optionally substituted 3- to 7-membered carbocyclyl. In some embodiments, Ring B is an optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted spiro[3.3]heptyl, optionally substituted spiro[4.4]nonyl, or optionally substituted spiro[3.4]octanyl ring. In some embodiments, Ring B is an optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, Ring B is optionally substituted cyclopropyl. In some embodiments, Ring B is optionally substituted cyclobutyl. In some embodiments, Ring B is optionally substituted cyclopentyl. In some embodiments, Ring B is optionally substituted cyclohexyl. In some embodiments, Ring B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, ring B is an optionally substituted spiro[3.3]heptyl, an optionally substituted spiro[4.4]nonyl, or an optionally substituted spiro[3.4]octanyl ring. In some embodiments, ring B is an optionally substituted spiro[3.3]heptyl, or an optionally substituted spiro[4.4]nonyl. In some embodiments, ring B is an optionally substituted spiro[3.3]heptyl ring. In some embodiments, ring B is an optionally substituted spiro[4.4]nonyl ring.

[0196] In some embodiments of any of the formulas described herein, L 1 is absent. In some embodiments, L 1 is optionally substituted C1-C 10 In some embodiments, L is alkylene. 1 is an optionally substituted C1-C4 alkylene. In some embodiments, L 1 is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, L 1 is optionally substituted C1-C 10 heteroalkylene, wherein the heteroatom is N or O. In some embodiments, L 1 is polyethylene glycol (PEG). In some embodiments, L 1 Ha-(CH2CH2O) n -, and n is an integer from 1 to 20. In some embodiments, n is 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2.

[0197] In some embodiments of any of the formulas described herein, L 2 is an optionally substituted C1-C 10 Alkylene, optionally substituted C-C 10 Alkenylene, optionally substituted C-C 10 Alkynylene or optionally substituted C-C 10 In some embodiments of any of the formulas described herein, L is heteroalkylene. 2 is an optionally substituted C1-C4 alkylene, an optionally substituted C2-C4 alkenylene, an optionally substituted C2-C4 alkynylene, or an optionally substituted C1-C4 heteroalkylene. In some embodiments, L 2 is absent. In some embodiments, L 2 is -CH2-, -CH2CH2, or -CH2CH2CH2-. In some embodiments, L2 is optionally substituted C1-C 10 heteroalkylene, wherein the heteroatom is N or O. In some embodiments, L 2 is polyethylene glycol (PEG). In some such embodiments, L 2 Ha-(CH2CH2O) n -, and n is an integer from 1 to 20. In some embodiments, n is 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2.

[0198] In some embodiments of any of the formulas described herein, R 1 does not exist. R 1 If there is no

[0199] [ka] It has.

[0200] In some embodiments of any of the formulas described herein, R 1 is oxo (=O). R 1 is oxo, the moiety has the structure

[0201] [ka] It has.

[0202] In some embodiments of Formula (II) or (II-A), p1 is 1, 2, or 3. In some embodiments, p1 is 1 or 2. In some embodiments, p1 is 0. In some embodiments, p1 is 1. In some embodiments, p1 is 2. In some embodiments, p1 is 3.

[0203] In some embodiments of Formula (III), p2 is 1, 2, 3, or 4. In some embodiments, p2 is 1 or 2. In some embodiments, p2 is 0. In some embodiments, p2 is 1. In some embodiments, p2 is 2. In some embodiments, p2 is 3. In some embodiments, p2 is 4.

[0204] Some preferred embodiments of formula (III) have any combination of one, two, three, four, five, or more than five of the following options, to the extent that such embodiments are not incompatible: (R 2 is hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3- to 10-membered carbocyclyl; R 2 is an optionally substituted 3- to 10-membered carbocyclyl; R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 2 is cyclopropyl, X 4 is N and X 5 and X 6 are each independently, CR 8 and X 4 is N and X 5 is N and X 6 is CR 8 and p2 is 1 or 2, p2 is 2, R 8 are each independently hydrogen, halogen, or optionally substituted C1-C8 alkyl; R 8 are each independently hydrogen, F, or C1-C4 alkyl; R 8 are each independently F or methyl; L is

[0205] [ka] wherein: L 1 does not exist, and L 2 is C1-C 10 is alkylene, L 1 does not exist, and L 2 is C1-C4 alkylene, or L 1 does not exist, and L 2 is C1-C2 alkylene, L is

[0206] [ka] wherein: L 2 does not exist, and L 1 is C1-C 10 is alkylene, L 2 does not exist, and L 1 is C1-C4 alkylene, or L 2 does not exist, and L 1 is C1-C2 alkylene, Ring B is an optionally substituted 3- to 7-membered carbocyclyl; Ring B is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl; Ring B is an optionally substituted cyclobutyl; Ring B is an optionally substituted spiro[3.3]heptyl, an optionally substituted spiro[4.4]nonyl, or an optionally substituted spiro[3.4]octanyl ring; Z is -NR 1a - and R 1a is hydrogen or C1-C4 alkyl, Z is -NR 1a - and R 1a is hydrogen, Z is -NH-; R 1 does not exist, R 1 is oxo).

[0207] Some preferred embodiments of formula (IV) have any combination of one, two, three, four, five, or more than five of the following options, to the extent that such embodiments are not incompatible: (R 2 is hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3- to 10-membered carbocyclyl; R 2 is an optionally substituted 3- to 10-membered carbocyclyl; R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 2 is cyclopropyl, X 4 is N and X 5 is CR 8b and X 6 is CR 8d and X 4 is N and X 5 is N and X 6 is CR 8d and X 5 is N and X 4 is CR 8a and X 6 is CR 8d and R 8a , R 8b , R 8c , R 8d , and R 8e are each independently hydrogen, halogen, or optionally substituted C1-C8 alkyl; R 8a , R 8b , R 8c , R 8d , and R 8eare each independently hydrogen, halogen, or C1-C4 alkyl; R 8a , R 8b , R 8c , R 8d , and R 8e are each independently hydrogen, F, or C1-C4 alkyl; R 8a and R 8b taken together with the atom to which they are attached form an optionally substituted 5-6 membered heteroaryl; R 8b and R 8c taken together with the atom to which they are attached form an optionally substituted phenyl; R 8b and R 8c taken together with the atom to which they are attached form an optionally substituted 5-6 membered heteroaryl; R 8c and R 8d taken together with the atom to which they are attached form an optionally substituted 5-6 membered heteroaryl; L is

[0208] [ka] wherein: L 1 does not exist, and L 2 is C1-C 10 is alkylene, L 1 does not exist, and L 2 is C1-C4 alkylene, or L 1 does not exist, and L 2 is C1-C2 alkylene, L is

[0209] [ka] wherein: L 2does not exist, and L 1 is C1-C 10 is alkylene, L 2 does not exist, and L 1 is C1-C4 alkylene, or L 2 does not exist, and L 1 is C1-C2 alkylene, Ring B is an optionally substituted 3- to 7-membered carbocyclyl; Ring B is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl; Ring B is an optionally substituted cyclobutyl; Ring B is an optionally substituted spiro[3.3]heptyl, an optionally substituted spiro[4.4]nonyl, or an optionally substituted spiro[3.4]octanyl ring; Z is -NR 1a - and R 1a is hydrogen or C1-C4 alkyl, Z is -NR 1a - and R 1a is hydrogen, Z is -NH-; R 1 does not exist, R 1 is oxo).

[0210] Some preferred embodiments of formula (IV-A), (IV-B), (IV-C), or (IV-D) have any combination of one, two, three, four, five, or more than five of the following options, to the extent that such an embodiment is not incompatible: (R 2 is hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3- to 10-membered carbocyclyl; R 2 is an optionally substituted 3- to 10-membered carbocyclyl; R 2is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 2 is cyclopropyl, Formula (IV-A) or (IV-C): X 4 is N and X 6 is CR 8d and X 4 is N and X 6 is N, Formula (IV-B) or (IV-D): X 4 is N and X 5 is CR 8b and X 4 is N and X 5 is N, Formula (IV-B), (IV-C), or (IV-D): Y 1 and Y 3 are each independently, NR 10a or N and Y 2 is CR 10 and Y 2 and Y 3 are each independently, NR 10a or N and Y 1 is CR 10 and Y 1 and Y 2 are each independently, NR 10a or N and Y 3 is CR 10 and L is

[0211] [ka] wherein: L 1 does not exist, and L 2 is C1-C 10 is alkylene, L 1 does not exist, and L 2is C1-C4 alkylene, or L 1 does not exist, and L 2 is C1-C2 alkylene, L is

[0212] [ka] wherein: L 2 does not exist, and L 1 is C1-C 10 is alkylene, L 2 does not exist, and L 1 is C1-C4 alkylene, or L 2 does not exist, and L 1 is C1-C2 alkylene, Ring B is an optionally substituted 3- to 7-membered carbocyclyl; Ring B is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl; Ring B is an optionally substituted cyclobutyl; Ring B is an optionally substituted spiro[3.3]heptyl, an optionally substituted spiro[4.4]nonyl, or an optionally substituted spiro[3.4]octanyl ring; Z is -NR 1a - and R 1a is hydrogen or C1-C4 alkyl, Z is -NR 1a - and R 1a is hydrogen, Z is -NH-; R 1 does not exist, R 1 is oxo).

[0213] Disclosed herein are GSPT1 degraders. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, degrade GSPT1. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, reduce cellular GSPT1 protein levels. In some embodiments, the compounds bind to cereblon. In some embodiments, the compounds modulate cereblon. In some embodiments, the compounds degrade GSPT1 as a downstream effect of cereblon binding and modulation. Some examples of GSPT1 degraders are shown in Table 1.

[0214] [Table 1-1]

[0215] [Table 1-2]

[0216] [Table 1-3]

[0217] [Table 1-4]

[0218] [Table 1-5]

[0219] [Table 1-6]

[0220] [Table 1-7]

[0221]

Table 1-8

[0222]

Table 1-9

[0223]

Table 1-10

[0224]

Table 1-11

[0225]

Table 1-12

[0226]

Table 1-13

[0227]

Table 1-14

[0228]

Table 1-15

[0229]

Table 1-16

[0230]

Table 1-17

[0231]

Table 1-18

[0232] [Table 1-19]

[0233] [Table 1-20]

[0234] [Table 1-21]

[0235] [Table 1-22]

[0236] II. Synthesis and Further Forms of the Compounds By way of non-limiting example, detailed synthetic protocols are described in the Examples for certain exemplary compounds.

[0237] The present disclosure includes all stereoisomers, geometric isomers, tautomers, and isotopes of the compounds whose structures and names are shown herein. The present disclosure also includes the compounds described herein, regardless of how they are prepared, for example, synthetically, by biological processes (e.g., metabolic or enzymatic conversion), or by a combination thereof. The present disclosure includes pharmaceutically acceptable salts of the compounds whose structures and names are shown herein.

[0238] Pharmaceutically acceptable isotopic variations of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or methods corresponding to those described in the examples (substituting appropriate reagents with appropriate isotopic variations of those reagents).Specifically, isotopic variations are compounds in which at least one atom has the same atomic number, but is replaced with an atom that has an atomic mass different from the atomic mass that is usually found in nature.Useful isotopes are known in the art, and are, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine.Therefore, exemplary isotopes include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 35 S, 18 F, and 36 Examples include Cl.

[0239] Isotopic variations (e.g., 2 Isotopic variations including H) can offer therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0240] Additionally, certain isotopic variations, particularly those containing radioactive isotopes, can be used in drug or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0241] The pharmaceutically acceptable solvate of the compound disclosed herein is intended.Solvate can be produced by, for example, using the solvent that is used to crystallize the compound disclosed herein with isotopic variation (for example, H2O is substituted with D2O, acetone is substituted with d6-acetone, or DMSO is substituted with d6-DMSO).

[0242] Pharmaceutically acceptable fluorinated variations of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or methods corresponding to those described in Examples (substituting appropriate reagents with appropriate fluorinated variations of those reagents).Specifically, fluorinated variations are compounds in which at least one hydrogen atom is replaced with a fluoro atom.Fluorinated variations can provide therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced required dose.

[0243] One or more constituent atoms of the compounds presented herein may be replaced or substituted with an isotope of the atom at natural or non-natural abundance. In some embodiments, the compounds contain at least one deuterium atom. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 deuterium atoms. In some embodiments, all of the hydrogen atoms in the compounds may be replaced or substituted with deuterium atoms. In some embodiments, the compounds contain at least one fluorine atom. In some embodiments, the compounds contain two or more fluorine atoms. In some embodiments, the compounds contain 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 fluorine atoms. In some embodiments, all of the hydrogen atoms in the compounds may be replaced or substituted with fluorine atoms.

[0244] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z or E forms (or cis or trans forms). Additionally, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z, E, and tautomeric forms as well.

[0245] "Tautomer" refers to a molecule that can undergo proton transfer from one atom of a molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH.

[0246] The compounds of the present invention include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of the compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), stereopolymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0247] The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms. When absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, and the appropriate mixtures thereof. Separation of stereoisomers can be carried out by chromatography, or diastereomeric formation and recrystallization or chromatographic separation, or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, incorporated by reference for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0248] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of such compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated forms as well as solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0249] In some embodiments, a compound or a salt of a compound may be a prodrug, for example, where a hydroxyl group in the parent compound is presented as an ester or carbonate, or a carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted into pharmaceuticals of the present disclosure under physiological conditions. One method for creating a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal, such as a specific target cell in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0250] Prodrug forms of the compounds described herein (which prodrugs are metabolized in vivo to produce compounds as defined herein) are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0251] Prodrugs are often useful because they can be easier to administer than the parent drug in some situations. Prodrugs may be bioavailable, for example, by oral administration, while the parent drug is not. Prodrugs can help enhance the cell permeability of compounds compared to the parent drug. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs may be designed as reversible drug derivatives to enhance drug transport to site-specific tissues or to be used as modifiers to increase drug retention inside cells.

[0252] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical agent, hi some embodiments, the prodrug design increases the effective aqueous solubility. For example, Fedorak et al.,Am. Pharmaceutics,37,87 (1987); J. Larsen et al.,Int. J. Pharmaceutics,47,103 (1988); Sinkula et al.,J. Pharm. Sci.,64:181-210 (1975); T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems,Vol. 14 of the ACS Symposium Series, and Edward B. Roche, Bioreversible See Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference. According to another embodiment, the present disclosure provides a method for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0253] Synthetic chemical transformations and methodologies useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0254] In some aspects, provided herein is a method for identifying a compound that mediates the degradation or reduction of GSPT1, the method comprising: providing a compound comprising a CRBN binding agent; contacting the compound with a cell that comprises ubiquitin ligase and GSPT1; determining whether GSPT1 level is reduced in the cell; and identifying the compound as a compound that mediates the degradation or reduction of GSPT1.In certain embodiments, the cell is a cancer cell.In certain embodiments, the cancer cell is a GSPT1-mediated cancer cell.

[0255] III. Characterization of Exemplary Compounds The binding affinity of the compounds disclosed herein or their pharmaceutically acceptable salts can be evaluated using standard biophysical assays known in the art (e.g., isothermal titration calorimetry (ITC), surface plasmon resonance (SPR)). Cellular assays can then be used to evaluate the ability of the compounds to induce GSPT1 degradation and inhibit cancer cell growth. Furthermore, the compound's induced changes in GSPT1 protein levels are evaluated. Assays suitable for use in any or all of these steps are known in the art and include, for example, Western blotting, quantitative mass spectrometry (MS) analysis, flow cytometry, enzyme activity assays, ITC, SPR, cell growth inhibition, xenograft, orthotopic, and patient-derived xenograft models. Suitable cell lines for use in any or all of these processes are known in the art and include HEL, RS4;11, MV4;11, MOLT-4, CCRF-CEM, Kasumi-1, MM.1S, HL-60, WSU-DLCL2, Pfeiffer, and SU-DHL-1 cancer cell lines. Suitable mouse models for use in any or all of these processes are known in the art and include subcutaneous xenograft models, orthotopic models, patient-derived xenograft models, and patient-derived orthotopic models.

[0256] Cell viability assays were used to characterize certain exemplary compounds. In the assays, MV4;11 and MOLM-13 cells were treated with compounds for 3 days. IC 50 Values ​​ranged from 1 nM to greater than 10 μM.

[0257] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, have an IC of less than 50 nM. 50 In some embodiments, the compound inhibits cell proliferation at an IC value of less than 25 nM. 50 In some embodiments, the compound inhibits cell proliferation with an IC value of less than 10 nM. 50 In some embodiments, the compound inhibits cell proliferation with an IC value of less than 8 nM. 50In some embodiments, the compound inhibits cell proliferation with an IC value of less than 2 nM. 50 In some embodiments, the cells comprise MV4;11 or MOLM-13 cells. In some embodiments, the cells are MV4;11 cells. In some embodiments, the cells are MOLM-13 cells.

[0258] IV. Pharmaceutical Compositions In some aspects, the compositions and methods described herein include the manufacture and use of pharmaceutical compositions and medicaments comprising one or more compounds (e.g., heterobifunctional compounds) disclosed herein. Also included are pharmaceutical compositions themselves. In some embodiments, the pharmaceutical composition comprises a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound described herein, such as a GSPT1 degrader. In some embodiments, the pharmaceutical composition comprises a second compound, such as an FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator. The second compound can be a FLT3 pathway inhibitor or a FLT3 inhibitor, such as gilteritinib.

[0259] In some embodiments, the compositions disclosed herein can contain other compounds, drugs, or agents used in the treatment of cancer. For example, in some instances, the pharmaceutical compositions disclosed herein can be combined with one or more (e.g., 1, 2, 3, 4, 5, or less than 10) compounds. Such additional compounds may include, for example, conventional chemotherapeutic agents or other cancer therapeutic agents known in the art. When co-administered, the compounds disclosed herein can act in conjunction with conventional chemotherapeutic agents or any other cancer therapeutic agents known in the art to produce mechanistically additive or synergistic therapeutic effects.

[0260] In some embodiments, the pH of the compositions disclosed herein can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the compound or its delivery form.

[0261] Pharmaceutical compositions typically contain a pharmaceutically acceptable excipient, adjuvant, or vehicle. As used herein, the phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally considered physiologically acceptable when administered to humans and typically do not cause allergic or similar adverse reactions, such as gastric upset or dizziness. A pharmaceutically acceptable excipient, adjuvant, or vehicle is a substance that can be administered to a subject together with a compound of the present disclosure and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound without impairing its pharmacological activity. Exemplary conventional non-toxic pharmaceutically acceptable excipients, adjuvants, and vehicles include, but are not limited to, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., compatible with pharmaceutical administration.

[0262] In particular, pharmaceutically acceptable excipients, adjuvants, and vehicles that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0263] Depending on the dosage form selected for delivering the compounds disclosed herein, various pharmaceutically acceptable excipients, adjuvants and vehicles can be used.For oral use tablets, pharmaceutically acceptable excipients, adjuvants and vehicles can be used, and can include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.For oral administration in aqueous suspension or emulsion, active ingredient can be suspended or dissolved in oil phase, and combined with emulsifier or suspending agent.If necessary, certain sweeteners, flavorings or colorings can be added.

[0264] As used herein, the compounds disclosed herein are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. "Pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt, solvate, or prodrug, such as a carbamate, ester, phosphate ester, salt of an ester, or other derivative of a compound or drug disclosed herein, which, upon administration to a recipient, can provide (directly or indirectly) a compound described herein, or an active metabolite or residue thereof. Particularly preferred derivatives and prodrugs are those that increase the bioavailability of a compound disclosed herein when administered to a subject (e.g., by facilitating absorption of an orally administered compound into the blood) or enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) compared to the parent species. Preferred prodrugs include derivatives in which groups that enhance water solubility or active transport across intestinal membranes are added to the structures of the formulas described herein. Such derivatives are recognizable to those skilled in the art without undue experimentation. Nevertheless, reference is made to the teachings of Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Vol. 1: Principles and Practice, which is incorporated herein by reference to the extent of its teaching of such derivatives.

[0265] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, substituted amines including basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0266] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0267] The compounds disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, as well as meso forms and pharmaceutically acceptable salts, solvent complexes, morphological forms, or deuterated derivatives thereof.

[0268] In some embodiments, the pharmaceutical compositions disclosed herein may contain an effective amount of one or more compounds. The terms "effective amount" and "effective for treatment," as used herein, refer to an amount or concentration of one or more compounds or pharmaceutical compositions described herein utilized over a period of time (including acute or chronic administration, and regular or continuous administration) that is effective within the context of its administration to produce an intended effect or physiological result (e.g., cell growth, cell proliferation, or cancer treatment or prevention).

[0269] In some embodiments, the pharmaceutical composition may further comprise one or more additional compounds, drugs, or agents used in the treatment of cancer (e.g., conventional chemotherapeutic agents) in an amount effective to produce an intended effect or physiological result (e.g., cell growth, cell proliferation, or treatment or prevention of cancer).

[0270] In some embodiments, the present disclosure relates to a pharmaceutical formulation comprising: (a) a therapeutically effective amount of a compound described herein (e.g., Formula (I)) or a pharmaceutically acceptable salt thereof; and (b) a second therapeutic agent.

[0271] In some embodiments, the present disclosure relates to a pharmaceutical formulation comprising: (a) a therapeutically effective amount of a compound described herein (e.g., Formula (I)) or a pharmaceutically acceptable salt thereof; and (b) one or more therapeutic agents.

[0272] In some embodiments, the present disclosure relates to a pharmaceutical formulation comprising a therapeutically effective amount of (a) a compound of FORMULA 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and (b) one or more therapeutic agents.

[0273] In some embodiments, the second or more therapeutic agents are anti-cancer agents. In some embodiments, the second or more therapeutic agents are anti-proliferative agents. In some embodiments, the second or more therapeutic agents are immunomodulatory agents. In some embodiments, the second or more therapeutic agents are kinase inhibitors or activators. In some embodiments, the second or more therapeutic agents are kinase inhibitors.

[0274] In some embodiments, the second or more therapeutic agents inhibit the FMS-like tyrosine kinase 3 gene (FLT3) pathway. In some embodiments, the second or more therapeutic agents inhibit FLT3. In some embodiments, the second compound is a FLT3 pathway inhibitor. The second compound may be gilteritinib.

[0275] In some embodiments, the second or more therapeutic agents inhibit the PI3K / AKT / mTOR pathway. In some embodiments, the second or more therapeutic agents inhibit PI3K. In some embodiments, the second or more therapeutic agents inhibit AKT. In some embodiments, the second or more therapeutic agents inhibit mTOR. In some embodiments, the second or more therapeutic agents are PI3K-AKT-mTOR pathway inhibitors or activators.

[0276] In some embodiments, the second or more therapeutic agents inhibit the MAPK pathway. In some embodiments, the second or more therapeutic agents inhibit the RAS / RAF / MEK / ERK pathway. In some embodiments, the second or more therapeutic agents inhibit RAS. In some embodiments, the second or more therapeutic agents inhibit RAF. In some embodiments, the second or more therapeutic agents inhibit MEK. In some embodiments, the second or more therapeutic agents inhibit ERK. In some embodiments, the second compound is a RAS-RAF-MEK-ERK pathway inhibitor.

[0277] V. Administration of Pharmaceutical Compositions The pharmaceutical compositions disclosed herein are formulated or adapted for administration to a subject via any route, for example, any route approved by the US Food and Drug Administration (FDA). Exemplary methods are described in the FDA Data Standards Manual (DSM) (available at www.fda.gov / Drugs / DevelopmentApprovalProcess / FormsSubmissionRequirements / ElectronicSubmissions / DataStandardsManualmonographs). In particular, the pharmaceutical compositions can be formulated for oral, parenteral, or transdermal delivery and administered via oral, parenteral, or transdermal delivery. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0278] The pharmaceutical compositions disclosed herein may be administered, for example, topically, rectally, nasally (e.g., by inhalation spray or nebulizer), buccally, vaginally, subcutaneously (e.g., by injection or via an implanted reservoir), or ophthalmically.

[0279] In some embodiments, the pharmaceutical compositions of the present disclosure are orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions.

[0280] In some embodiments, the pharmaceutical compositions of the present disclosure are administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present disclosure with suitable non-irritating excipients that are solid at room temperature (RT) but liquid at rectal temperature, and therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0281] In some embodiments, the pharmaceutical compositions of the present disclosure are administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and can be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers which enhance bioavailability, fluorocarbons, or other solubilizing or dispersing agents known in the art.

[0282] In some embodiments, the pharmaceutical compositions of the present disclosure can be administered by injection (e.g., as a solution or powder). Such compositions can be formulated according to techniques known in the art using suitable dispersants or wetting agents (e.g., Tween 80, etc.) and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic saline. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants, commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. Other commonly used surfactants, such as Tween, Spans, or other similar emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for the formulation.

[0283] In some embodiments, an effective dose of a pharmaceutical composition of the present disclosure may be, but is not limited to, about 0.00001, 0.0001, 0.001, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, or more per kg per day, or according to the requirements of the particular pharmaceutical composition. , 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2500, 5000, or 10000 mg.

[0284] When the pharmaceutical compositions disclosed herein include a combination of a compound described herein and one or more additional compounds (e.g., one or more additional compounds, drugs, or agents used in the treatment of cancer or any other disease or disorder, including diseases or disorders known to be associated with or caused by cancer), both the compound and the additional compounds may be present at dosage levels of about 1-100%, more preferably about 5-95%, of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately from the compounds of the present disclosure as part of a multiple-dosing regimen. Alternatively, these agents may be part of a single dosage form, mixed with the compounds of the present disclosure in a single composition.

[0285] In some embodiments, the pharmaceutical compositions disclosed herein may be included in a container, pack, or dispenser together with instructions for administration.

[0286] VI. Treatment Method Disclosed herein in some embodiments are methods for administering the compositions described herein to a subject. Some embodiments relate to the use of the compositions described herein, such as administering the compositions to a subject. Some embodiments relate to methods for treating disorders in a subject in need of treatment. Some embodiments relate to the use of the compositions described herein in treatment methods.

[0287] In one embodiment, provided herein is a method of treating a disease or disorder associated with abnormal cell proliferation, such as cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of Formulas (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof. In another embodiment, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any of Formulas (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the method further comprises administering to the subject a second therapeutic agent (e.g., an anti-cancer therapeutic agent). In another embodiment, provided herein is a method of treating a disease or disorder associated with abnormal cell proliferation, such as cancer, in a subject in need thereof, comprising administering to the subject an amount of a compound of any of Formulas (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional therapeutic agent (e.g., an anti-cancer therapeutic agent), wherein said amounts are together effective to treat said abnormal cell proliferation, such as cancer.

[0289] In another embodiment, there is provided a compound of any of Formulas (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof, for use in treating abnormal cell growth, such as cancer, in a subject. In a further embodiment, there is provided the use of a compound of any of Formulas (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof, for treating abnormal cell growth, such as cancer, in a subject.

[0290] In a further embodiment, there is provided the use of a compound of any of Formulas (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for example, a medicament for the treatment of abnormal cell growth, such as cancer.

[0291] In some embodiments of the compounds, compositions, methods, and uses described herein, the compound of any of Formulas (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof, degrades GSPT1. In frequent embodiments of each of the methods and uses herein, the abnormal cell growth is cancer. In some such embodiments, the cancer is mediated by GSPT1.

[0292] In some embodiments, a method of treatment comprises administering to a subject in need thereof a first compound comprising a GSPT1 degrader of any of Formulas (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof, and a second compound comprising an FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator. Some embodiments comprise administering to a subject having a disorder a composition described herein. In some embodiments, the administration treats the subject's disorder. In some embodiments, the composition treats the subject's disorder. In some embodiments, the treatment comprises preventing, inhibiting, or ameliorating the subject's disorder. In some embodiments, the subject has cancer.

[0293] According to one aspect of the present disclosure, the method of treating a GSPT1-mediated disease disclosed herein comprises administering to a subject having a GSPT1-mediated disease a compound disclosed herein (e.g., a compound of any of Formulas (I)-(IV) or Formula (A)) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound disclosed in Table 1, or a pharmaceutically acceptable salt thereof.

[0294] The methods disclosed herein contemplate administration of an effective amount of a compound or composition to achieve the desired or described effect. Typically, the disclosed compounds or compositions are administered about 1 to about 6 times per day, or alternatively or additionally, as a continuous infusion. Such administration can be used as a chronic or acute treatment. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Typical preparations contain about 5% to about 95% active compound (w / w). Alternatively, such preparations may contain about 20% to about 80% active compound. In some embodiments, a first compound and a second compound are administered simultaneously to a subject. In some embodiments, a first compound and a second compound are each administered separately to a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0295] In some embodiments, provided herein are compounds or pharmaceutically acceptable salts thereof for preventing or treating a disease or condition. In some embodiments, provided herein are heterobifunctional compounds described herein for preventing or treating a disease or condition.

[0296] In some embodiments, provided herein is a compound or a pharmaceutically acceptable salt thereof for treating or preventing one or more diseases or conditions disclosed herein in a subject. In some embodiments, the disease or condition is a GSPT1-mediated disease or condition. In some embodiments, the disease or condition is cancer, inflammation, autoimmune disease, viral infection, and immune disease. In some embodiments, the GSPT1-mediated cancer is selected from the group consisting of brain cancer, gastric cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, hematopoietic cancer, myeloproliferative neoplasm, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin's lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, and myeloma. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is GSPT1-mediated cancer.

[0297] In some embodiments, the GSPT1 mediated cancer is mesothelioma, leukemia, and lymphoma, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, human T-cell lymphotrophic virus (HTLV) associated lymphoma, such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma, myelodysplastic syndrome, pediatric solid tumor, such as brain tumor, neuroblastoma, retinoblastoma, Wilms' tumor. tumors, bone tumors, and soft tissue sarcomas, common adult solid tumors such as head and neck cancer (e.g., oral cavity, larynx, and nasopharynx), esophageal cancer, genitourinary cancer (e.g., prostate, bladder, kidney, uterus, ovary, testis), lung cancer (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.), liver cancer, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST), cancer of skeletal or smooth muscle, gastric cancer, cancer of the small intestine, cancer of the rectum, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and cancer of the pituitary gland.

[0298] In some embodiments, the GSPT1-mediated disease is recurrent cancer.

[0299] In some embodiments, the GSPT1-mediated disease is refractory to one or more previous treatments.

[0300] In some embodiments, the methods include administering a therapeutically effective amount of one or more of the compounds or compositions described herein to a subject (e.g., a mammalian subject, e.g., a human subject) in need of, or determined to be in need of, such treatment. In some embodiments, the disclosed methods include selecting a subject, administering to the subject an effective amount of one or more of the compounds or compositions described herein, and optionally repeating the administration as necessary to prevent or treat the cancer.

[0301] In some embodiments, subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection. In some embodiments, the subject can be confirmed or identified, e.g., by a health care professional, as having, being at risk for, or having a disease or disorder. In some embodiments, suitable subjects include, e.g., subjects who have or have had a disease or disorder but have resolved the disease or aspects thereof, or have exhibited a reduction in symptoms of the disease (e.g., compared to other subjects (e.g., the majority of subjects) with the same disease or disorder), or who survive long-term with the disease or disorder (e.g., compared to other subjects (e.g., the majority of subjects) with the same disease or disorder), e.g., in an asymptomatic state (e.g., compared to other subjects (e.g., the majority of subjects) with the same disease or disorder). In some embodiments, the display of a positive immune response to the disease or disorder can be obtained from patient records, family history, or from detecting indicators of a positive immune response. In some embodiments, multiple parties can be involved in subject selection. For example, one party can obtain a sample from a candidate subject, and a second party can test the sample. In some embodiments, the subject can be selected or referred by a physician (e.g., a general practitioner). In some embodiments, subject selection can include obtaining a sample from the selected subject and storing the sample or using the sample in a method disclosed herein. The sample can include, for example, a cell or population of cells.

[0302] In some embodiments, treatment methods can include single, multiple, and repeated administration of one or more compounds disclosed herein necessary for the prevention or treatment of a disease or condition disclosed herein (e.g., a GSPT1-mediated disease). In some embodiments, treatment methods can include assessing the subject's level of disease before, during, or after treatment. In some embodiments, treatment can be continued until a decrease in the subject's level of disease is detected.

[0303] The term "subject" or "patient" as used herein refers to any animal subject. In some examples, the subject is a mammal. In some examples, the term "subject" as used herein refers to a human (e.g., a male, female, or child). A subject can include, for example, a human or veterinary patient, or a human or veterinary subject participating in a clinical trial.

[0304] The terms "administer," "administering," or "administration," as used herein, refer to implanting, ingesting, injecting, inhaling, or otherwise absorbing a compound or composition, regardless of the form. For example, the methods disclosed herein include administering an effective amount of a compound or composition to achieve a desired or described effect.

[0305] The terms "treat," "treating," or "treatment," as used herein, refer to partially or completely alleviating, inhibiting, ameliorating, or relieving a disease or condition from which a subject is afflicted. This refers to any manner in which one or more of the symptoms of a disease or condition (e.g., cancer) are improved or otherwise beneficially altered. As used herein, amelioration of symptoms of a particular disorder (e.g., cancer) refers to any alleviation, whether permanent or temporary, persistent or transient, that can result from or be associated with treatment with the disclosed compounds, compositions, and methods. In some embodiments, treatment can promote or result in, for example, a reduction in the number of tumor cells (e.g., in a subject) relative to the number of tumor cells before treatment, a reduction in the survival rate (e.g., mean / average survival rate) of tumor cells (e.g., in a subject) relative to the survival rate of tumor cells before treatment, a reduction in the growth rate of tumor cells, a reduction in the rate of local or distant tumor metastasis, or a reduction in one or more symptoms associated with one or more tumors in the subject relative to the subject's symptoms before treatment.

[0306] The terms "prevent," "preventing," or "prevention," as used herein, refer to a reduction in the occurrence of a disease or a reduction in a subject's risk of acquiring a disease or its associated symptoms. Prevention can be complete (e.g., the complete absence of disease or pathological cells in the subject). Prevention can also be partial, such that the development of disease or pathological cells in the subject occurs less frequently, occurs later, or progresses more slowly than the disease or pathological cells would have occurred in the absence of the present disclosure. In certain embodiments, the subject is at high risk of developing one or more GSPT1-mediated diseases. Exemplary GSPT1 mediated diseases that can be treated with the compounds include, for example, cancers of the brain, stomach, gastrointestinal tract, liver, biliary tract, breast, ovary, cervix, prostate, testis, penis, urogenital tract, esophagus, larynx, skin, lung, pancreas, thyroid, gland, bladder, kidney, muscle, bone, and cancers of the hematopoietic system such as myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin's lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, myeloma, and other hematologic malignancies.

[0307] In some embodiments, the compound is more effective at treating a disease such as cancer than existing drugs. For example, the compound may be effective at a lower dose than existing drugs. In some embodiments, the compound is more effective than known cereblon modulators. In some embodiments, the compound is more effective than CC-90009. In some embodiments, the compound is more effective than known drugs at reducing cell viability. For example, the compound may be more effective than CC-90009 at reducing cancer cell viability.

[0308] In some embodiments, a compound combined with a second compound, such as a FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator, is more effective in treating diseases such as cancer than existing drugs. The second compound can be a FLT3 pathway inhibitor or a FLT3 inhibitor. In some embodiments, the second compound comprises a FLT3 pathway inhibitor. In some embodiments, the second compound comprises a FLT3 inhibitor. In some embodiments, the FLT3 inhibitor comprises gilteritinib, midostaurin, sorafenib, sunitinib, lestaurtinib, quizartinib, crenolanib, or sitravatinib. In some embodiments, the FLT3 inhibitor comprises gilteritinib. In some embodiments, the compound combined with the second compound is effective at a lower dose than existing drugs. In some embodiments, the compound combined with the second compound is more effective than known cereblon modulators. In some embodiments, the compound combined with the second compound is more effective than CC-90009. In some embodiments, the compound combined with the second compound is more effective than a known drug in reducing cell viability. For example, the compound combined with the second compound may be more effective than CC-90009 in reducing cancer cell viability. In some embodiments, the effectiveness of the compound combined with the second compound is increased compared to another drug.

[0309] In some embodiments, the second compound comprises a RAS-RAF-MEK-ERK pathway inhibitor. In some embodiments, the RAS-RAF-MEK-ERK pathway inhibitor comprises vemurafenib, dabrafenib, encorafenib, SB590885, PLX4720, XL281, RAF265, trametinib, binimetinib, cobimetinib, selumetinib, CI-1040, or PD0325901. In some embodiments, the second compound comprises a PI3K-AKT-mTOR pathway inhibitor or activator. In some embodiments, the PI3K-AKT-mTOR pathway inhibitor or activator is apitolisib, idelalisib, copanlisib, duvelisib, MK-2206, ARQ-092, gedatolisib, apitolisib, VQD-002, perifosine, AZD5363, ipatasertib, rapamycin, temsirolimus, everolimus, ridaforolimus, rapalogs, sirolimus, dactolisib ib, BGT226, SF1126, PKI-587, NVPBE235, sapanisertib, AZD8055 and AZD2014, wortmannin, LY294002, hibiscon C, taselisib, perifosine, bupallisib, umbralisib, PX-866, dactolisib, CUDC-907, voxtalisib, bisper oxovanadium, or sarcopoterium.

[0310] In some embodiments, the second compound is a chemotherapy agent, including, for example, an alkylating agent (e.g., thiotepa or cyclophosphamide), an antimetabolite (e.g., 5'-azacytidine, 5-fluorouracil, gemcitabine, capecitabine, cladribine, clofarabine, cytarabine, or fludarabine), an antitumor antibiotic (e.g., doxorubicin or daunorubicin), a topoisomerase inhibitor (e.g., etoposide, topotecan, or irinotecan), a mitotic inhibitor (e.g., paclitaxel, docetaxel, vincristine, vinorelbine, or vinblastine), or a plant alkaloid (e.g., a vinca alkaloid). In some embodiments, the chemotherapy agent is 5'-azacytidine.

[0311] In some embodiments, the compounds disclosed herein can selectively affect GSPT1-mediated disease cells relative to WT (wild-type) cells (i.e., heterobifunctional compounds that can kill or inhibit the growth of GSPT1-mediated disease cells but have a relatively reduced ability to lyse or inhibit the growth of WT cells), e.g., by inhibiting its GI activity against one or more WT cells, e.g., WT cells of the same species and tissue type as the GSPT1-mediated disease cells. 50 a GI that is more than 1.5-fold lower, more than 2-fold lower, more than 2.5-fold lower, more than 3-fold lower, more than 4-fold lower, more than 5-fold lower, more than 6-fold lower, more than 7-fold lower, more than 8-fold lower, more than 9-fold lower, more than 10-fold lower, more than 15-fold lower, or more than 20-fold lower for one or more GSPT1-mediated disease cells than 50 It has.

[0312] In some embodiments, the compound exhibits an IC 50 Lower IC 50 In some embodiments, the cell comprises a cell line. Optionally, the cell line comprises MV4;11 cells. Optionally, the cell line comprises MOLM-13 cells. Optionally, the compound has an IC 50 is determined based on treating cells with the compound alone. In some cases, the IC 50In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC of the compound is less than 0.25 nM. 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 The IC of the compound is greater than 0.25 nM. 50 Some example values ​​and ranges are shown in Table 2.

[0313] In some embodiments, the compound in combination with a second compound, such as a FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, a PI3K-AKT-mTOR pathway inhibitor or activator, reduces the IC of CC-90009 in cells. 50 Less than IC 50 The second compound can be a FLT3 pathway inhibitor or a FLT3 inhibitor, such as gilteritinib. In some embodiments, the cell comprises a cell line. In some cases, the cell line comprises MV4;11 cells. In some cases, the cell line comprises MOLM-13 cells. In some cases, IC 50 is determined based on treating cells with the compound in combination with a second compound (e.g., gilteritinib). In some cases, the IC of the compound in combination with the second compound is 50 is less than 100 nM. In some cases, the IC 50 is less than 100 nM. In some cases, the IC 50 In some cases, the IC of the compound in combination with the second compound is less than 75 nM. 50 is less than 50 nM. In some cases, the IC 50 In some cases, the IC of the compound in combination with the second compound is less than 25 nM. 50In some cases, the IC of the compound in combination with the second compound is less than 10 nM. 50 In some cases, the IC of the compound in combination with the second compound is less than 9 nM. 50 In some cases, the IC of the compound in combination with the second compound is less than 8 nM. 50 In some cases, the IC of the compound in combination with the second compound is less than 7 nM. 50 In some cases, the IC of the compound in combination with the second compound is less than 6 nM. 50 In some cases, the IC of the compound in combination with the second compound is less than 5 nM. 50 In some cases, the IC of the compound in combination with the second compound is less than 4 nM. 50 In some cases, the IC of the compound in combination with the second compound is less than 3 nM. 50 In some cases, the IC of the compound in combination with the second compound is less than 2 nM. 50 In some cases, the IC of the compound in combination with the second compound is less than 1 nM. 50 In some cases, the IC of the compound in combination with the second compound is less than 0.5 nM. 50 In some cases, the IC of the compound is less than 0.25 nM. 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 In some cases, the IC 50 is greater than 0.25 nM.

[0314] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, disorder, or condition, predisposition of the patient to the disease, disorder, or condition, and the judgment of the treating physician.

[0315] An effective amount can be administered in one or more administrations, applications, or dosages. The therapeutically effective amount (i.e., effective dosage) of a therapeutic compound will depend on the therapeutic compound selected. Furthermore, treatment of a subject with a therapeutically effective amount of a compound or composition described herein can include a single treatment or a series of treatments. For example, an effective amount can be administered at least once. The composition can be administered one or more times per week, including one or more times per day to every other day. One of skill in the art will understand that certain factors, including, but not limited to, the severity of the disease or disorder, previous treatments, the subject's overall health or age, and other diseases present, can affect the dosage and timing required to effectively treat a subject.

[0316] After administration, the subject can be evaluated to detect, assess, or determine the level of disease. In some examples, treatment can be continued until a change (e.g., a decrease) in the subject's level of disease is detected. Once the patient's condition (e.g., a change (e.g., a decrease) in the subject's level of disease) has improved, a maintenance dose of a compound or composition disclosed herein can be administered, if necessary. Thereafter, the dosage or frequency of administration, or both, can be reduced, for example, depending on the symptoms, to a level at which the improved disease is maintained. However, the patient may require intermittent treatment over a long period of time if the symptoms of the disease recur.

[0317] The method can include administering the compound to the subject by any route of administration described herein. In one embodiment, the compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.

[0318] In some embodiments, the method further comprises administering to the subject an additional therapeutic regimen for treating cancer, an inflammatory disorder, or an autoimmune disease.

[0319] In some embodiments, the additional therapeutic regimen is selected from the group consisting of surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy.

[0320] Some embodiments include administering an additional compound. Such additional compounds are preferably kinase inhibitors, in particular FLT3 pathway inhibitors (e.g., gilteritinib, midostaurin, sorafenib, sunitinib, lestaurtinib, quizartinib, crenolanib, or sitravatinib), MAPK pathway inhibitors, RAS-RAF-MEK-ERK pathway inhibitors (e.g., vemurafenib, dabrafenib, encorafenib, SB590885, PLX4720, XL281, RAF265, trametinib, binimetinib, cobimetinib, selumetinib, CI-1040, or PD0325901), or PI3K-AKT-mTOR pathway inhibitors or activators (e.g., apitolisib, idelalisib, copanlisib, duvelisib, MK-2206, ARQ-092, gedat Gedatolisib, Apitolisib, VQD-002, Perifosine, AZD5363, Ipatasertib, Rapalogs, Sirolimus, Dactolisib, BGT226, SF1126, PKI-587, NVPBE235, Sapanisertib, AZD8055 and AZD2014, Wortmannin, LY294002, Hibiscon C, Taselisib, Perifosine, Bupalisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, Bisperoxovanadium oxovanadium, or Sarcopoterium.

[0321] Some embodiments include administering a first compound to a subject. In some embodiments, the first compound is a GSPT1 degrader. In some embodiments, the first compound is a compound described herein (e.g., a compound of any of Formulas (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof). In some embodiments, the first compound comprises any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0322] In some embodiments, the first compound does not bind to JAK. In some embodiments, the first compound comprises a truncated JAK-binding moiety. In some embodiments, the first compound does not comprise a JAK-binding moiety. Some embodiments include administering to a subject a second compound comprising a FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator. In some embodiments, the second compound comprises a FLT3 pathway inhibitor. In some embodiments, the second compound comprises a RAS-RAF-MEK-ERK pathway inhibitor. In some embodiments, the second compound comprises a PI3K-AKT-mTOR pathway inhibitor or activator. Some embodiments include a method of treatment comprising administering to a subject in need of treatment a first compound comprising a GSPT1 degrader and a second compound comprising a FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator. In some embodiments, the first compound and / or the second compound are administered to a subject as a pharmaceutical composition comprising a pharmaceutically acceptable carrier.In some embodiments, the first compound and the second compound are administered to a subject simultaneously.In some embodiments, the first compound and the second compound are each administered to a subject separately.

[0323] Some embodiments include a method of treating or preventing cancer, comprising administering to a subject in need thereof a compound having degrader activity against GSPT1 in combination with one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from an inhibitor of an inhibitory molecule, an activator of a costimulatory molecule, a chemotherapeutic agent, a targeted anti-cancer therapy, an oncolytic agent, a cytotoxic agent, or a combination thereof.

[0324] In some embodiments, provided is a method for treating or preventing cancer, the method comprising administering to a subject in need thereof a combination comprising: (a) a compound of any of Formulas (I)-(IV) or Formula (A) or a pharmaceutically acceptable salt thereof; and (b) a second therapeutic agent.

[0325] In some embodiments, the second or more therapeutic agents inhibit the FMS-like tyrosine kinase 3 gene (FLT3) pathway. In one embodiment, the second or more therapeutic agents inhibit FLT3. Examples of FLT3 inhibitors include gilteritinib, midostaurin, sorafenib, sunitinib, lestaurtinib, quizartinib, crenolanib, or sitravatinib. In some embodiments, the FLT3 inhibitor comprises gilteritinib. In some embodiments, the second compound comprises a FLT3 pathway inhibitor (e.g., gilteritinib).

[0326] In some embodiments, the second or more therapeutic agents inhibit the PI3K / AKT / mTOR pathway. In one embodiment, the second or more therapeutic agents inhibit PI3K. In one embodiment, the second or more therapeutic agents inhibit AKT. In one embodiment, the second or more therapeutic agents inhibit mTOR. In some embodiments, the second compound comprises a PI3K-AKT-mTOR pathway inhibitor or activator. Examples of RAS-RAF-MEK-ERK pathway inhibitors include vemurafenib, dabrafenib, encorafenib, SB590885, PLX4720, XL281, RAF265, trametinib, binimetinib, cobimetinib, selumetinib, CI-1040, or PD0325901. In some embodiments, the second compound comprises a RAS-RAF-MEK-ERK pathway inhibitor.

[0327] In some embodiments, the second or more therapeutic agents inhibit the MAPK pathway. In some embodiments, the second or more therapeutic agents inhibit the RAS / RAF / MEK / ERK pathway. In some embodiments, the second or more therapeutic agents inhibit RAS. In some embodiments, the second or more therapeutic agents inhibit RAF. In some embodiments, the second or more therapeutic agents inhibit MEK. In some embodiments, the second or more therapeutic agents inhibit ERK. In some embodiments, the second compound comprises a RAS-RAF-MEK-ERK pathway inhibitor. Examples of PI3K-AKT-mTOR pathway inhibitors or activators include apitolisib, idelalisib, copanlisib, duvelisib, MK-2206, ARQ-092, gedatolisib, apitolisib, VQD-002, perifosine, AZD5363, ipatasertib, rapamycin, temsirolimus, everolimus, ridaforolimus, rapalogs, sirolimus, dactolisib, BG The second compound may comprise T226, SF1126, PKI-587, NVPBE235, sapanisertib, AZD8055 and AZD2014, wortmannin, LY294002, hibiscon C, taselisib, perifosine, bupallisib, umbralisib, PX-866, dactolisib, CUDC-907, voxtalisib, bisper oxovanadium, or sarcopoterium. In some embodiments, the second compound comprises a PI3K-AKT-mTOR pathway inhibitor. In some embodiments, the second compound comprises a PI3K-AKT-mTOR pathway activator.

[0328] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.

[0329] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0330] As used herein, the terms "comprising" and "including" are used in an open, non-limiting sense.

[0331] "Alkyl" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having 1 to 15 carbon atoms (i.e., C1-C 15 Alkyl) refers to a straight or branched hydrocarbon chain radical. In certain embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1-C 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15In other embodiments, an alkyl comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In certain embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, an alkyl group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0332] "C x-y The term "C" when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include groups containing x to y carbons in the chain. For example, "C 1-6 The term "alkyl" refers to alkyl groups that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, including straight chain alkyl groups and branched chain alkyl groups.

[0333] "Allyl," as used herein, refers to the group -CH2CH=CH2.

[0334] "Alkenyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having 2 to 12 carbon atoms (i.e., C-C 12Alkenyl refers to a straight or branched hydrocarbon chain radical group. In certain embodiments, alkenyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, alkenyl contains 2 to 6 carbon atoms (i.e., C2-C8 alkenyl). In other embodiments, alkenyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). Alkenyl is attached to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless otherwise specified in the specification, alkenyl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0335] "Alkynyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having 2 to 12 carbon atoms (i.e., C-C 12 Alkynyl refers to a straight or branched hydrocarbon chain radical group. In certain embodiments, alkynyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, alkynyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, alkynyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). Alkynyl is attached to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise specified in the specification, alkynyl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0336] "C x-y alkenyl" and "Cx-y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively. x-y The term alkenylene- refers to a substituted or unsubstituted alkenylene chain having x to y carbons in the chain. For example, -C 2-6 Alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. The alkenylene chain may have one double bond or more than two double bonds in the alkenylene chain. -C x-y The term alkynylene- refers to a substituted or unsubstituted alkynylene chain having x to y carbons in the chain. For example, -C 2-6 Alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. The alkynylene chain may have one triple bond or more than two triple bonds within the alkynylene chain.

[0337] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the radical group to the rest of the molecule, consists solely of carbon and hydrogen, contains no unsaturation, and preferably has 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkylene contains 1 to 10 carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, alkylene contains 1 to 8 carbon atoms (i.e., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). -C x-y The term alkylene- refers to a substituted or unsubstituted alkylene chain having x to y carbon atoms in the alkylene chain. For example, -C 1-6 Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0338] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having 2 to 12 carbon atoms, that connects the radical group to the rest of the molecule. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkenylene contains 2 to 10 carbon atoms (i.e., C2-C 10 alkenylene). In certain embodiments, alkenylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, alkenylene contains 2 carbon atoms (i.e., C2 alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkenylene).

[0339] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having 2 to 12 carbon atoms, connecting the rest of the molecule to a radical group. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkynylene contains 2 to 10 carbon atoms (i.e., C2-C 10alkynylene). In certain embodiments, alkynylene comprises 2 to 8 carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, alkynylene comprises 2 to 5 carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, alkynylene comprises 2 to 4 carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, alkynylene comprises 2 to 3 carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, alkynylene comprises 2 carbon atoms (i.e., C2 alkynylene). In other embodiments, alkynylene comprises 5 to 8 carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, alkynylene comprises 3 to 5 carbon atoms (i.e., C3-C5 alkynylene).

[0340] The term "alkoxy," as used herein, means an alkyl group, as defined herein, attached to the remainder of the molecule by an oxygen atom. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0341] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom, where the ring system contains at least one aromatic ring. The aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms from 5 to 18 carbon atoms, and at least one ring in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. The aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified in the specification, aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0342] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH3, -CHCHOCH3, -CHCHOCHCHOCH3, -CH(CH3)OCH3, -CHNHCH3, -CHN(CH3)2, -CHCH2NHCH3, or -CHCH2N(CH3)2.

[0343] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur (i.e., a 3- to 18-membered heteroaryl). As used herein, a heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, in which at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. In certain embodiments, heteroaryl refers to a radical derived from a 3- to 10-membered aromatic ring radical (a 3- to 10-membered heteroaryl). In certain embodiments, heteroaryl refers to a radical derived from a 5- to 7-membered aromatic ring (a 5- to 7-membered heteroaryl). Heteroaryl includes fused or bridged ring systems. The heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of such groups include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and the like. In certain embodiments, a heteroaryl is attached to the remainder of the molecule by a ring carbon atom. In certain embodiments, a heteroaryl is attached to the remainder of the molecule by a nitrogen atom (N-bonded) or a carbon atom (C-bonded). For example, a group derived from pyrrole can be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked), and a group derived from imidazole can be imidazol-1-yl (N-linked) or imidazol-3-yl (C-linked).

[0344] The term "heterocyclyl," as used herein, refers to a non-aromatic monocyclic, bicyclic, tricyclic, or tetracyclic radical having a total of 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 atoms in its ring system, containing 3 to 12 carbon atoms and 1 to 4 heteroatoms, each independently selected from O, S, and N, provided that no ring of the group contains two adjacent O atoms or two adjacent S atoms. Heterocyclyl groups can include fused, bridged, or spirocyclic ring systems. In certain embodiments, heterocyclyl groups contain 3 to 10 ring atoms (3- to 10-membered heterocyclyl). In certain embodiments, heterocyclyl groups contain 3 to 8 ring atoms (3- to 8-membered heterocyclyl). In certain embodiments, heterocyclyl groups contain 4 to 10 ring atoms (4- to 10-membered heterocyclyl). In certain embodiments, heterocyclyl groups contain 4 to 8 ring atoms (4-8-membered heterocyclyl). Heterocyclyl groups can contain an oxo substituent at any available atom that results in a stable compound. For example, such groups can contain an oxo atom at an available carbon or nitrogen atom. Such groups can contain more than one oxo substituent, if chemically feasible. Additionally, when such heterocyclyl groups contain a sulfur atom, it is understood that the sulfur atom can be oxidized with one or two oxygen atoms to provide either a sulfoxide or a sulfone. An example of a 4-membered heterocyclyl group is azetidinyl (derived from azetidine). An example of a 5-membered cycloheteroalkyl group is pyrrolidinyl. An example of a 6-membered cycloheteroalkyl group is piperidinyl. An example of a 9-membered cycloheteroalkyl group is indolinyl. An example of a 10-membered cycloheteroalkyl group is 4H-quinolidinyl.Further examples of such heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2-pyrr ... Examples of heteroaryl groups include H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, quinolizinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, and 1-oxo-2,8,diazaspiro[4.5]dec-8-yl. Heteroaryl groups can be bonded to the rest of the molecule by a carbon atom (C-bond) or a nitrogen atom (N-bond). For example, a group derived from piperazine can be piperazin-1-yl (N-bond) or piperazin-2-yl (C-bond).

[0345] "Carbocycle" or "carbocyclyl" refers to a saturated, unsaturated, or aromatic ring system in which each ring atom of the ring system is carbon. Carbocycles can include 3- to 10-membered monocycles, 6- to 12-membered bicycles, and 6- to 12-membered bridged rings. Each ring in a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, valence permitting. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. In some embodiments, a carbocycle is aryl. In some embodiments, a carbocycle is cycloalkyl. In some embodiments, a carbocycle is cycloalkenyl. In some embodiments, a carbocycle contains a triple bond. Unless stated otherwise in the specification, carbocycles may be optionally substituted.

[0346] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon group, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having 3 to 12 carbon atoms. In certain embodiments, cycloalkyls contain 3 to 10 carbon atoms. In other embodiments, cycloalkyls contain 5 to 7 carbon atoms. A cycloalkyl can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like.

[0347] A "cycloalkylene" is a bidentate radical obtained by removing a hydrogen atom from a cycloalkyl ring as defined above. Examples of such groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cycloheptylene, and the like.

[0348] "Spirocyclic ring," as used herein, has its conventional meaning, i.e., any ring system containing two or more rings, two of which have one ring carbon in common. Each ring of a spirocyclic ring system, as defined herein, independently contains 3 to 20 ring atoms. Preferably, they have 3 to 10 ring atoms. Non-limiting examples of spirocyclic ring systems include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.

[0349] The term "cyano" refers to the group --C.ident.N.

[0350] An "aldehyde" group refers to a -C(O)H group.

[0351] An "alkoxy" group refers to both an --O-alkyl group, as defined herein.

[0352] "Alkoxycarbonyl" refers to -C(O)-alkoxy, as defined herein.

[0353] An "alkylaminoalkyl" group refers to an -alkyl-NR-alkyl group, as defined herein.

[0354] An "alkylsulfonyl" group refers to an -SO2 alkyl, as defined herein.

[0355] An "amino" group refers to an optionally substituted -NH2.

[0356] An "aminoalkyl" group refers to an -alkyl-amino group, as defined herein.

[0357] "Aminocarbonyl" refers to --C(O)-amino, as defined herein.

[0358] An "arylalkyl" group refers to an -alkylaryl, where alkyl and aryl are defined herein.

[0359] An "aryloxy" group refers to both an --O-aryl and an --O-heteroaryl group, as defined herein.

[0360] "Aryloxycarbonyl" refers to -C(O)-aryloxy, as defined herein.

[0361] An "arylsulfonyl" group refers to an -SO2aryl, as defined herein.

[0362] A "carbonyl" group refers to a -C(O)- group, as defined herein.

[0363] A "carboxylic acid" group refers to a -C(O)OH group.

[0364] "Cycloalkoxy" refers to an --O-carbocyclyl group, as defined herein.

[0365] A "halo" or "halogen" group refers to fluorine, chlorine, bromine, or iodine.

[0366] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radical, each halogen may be independently selected, for example, 1-chloro, 2-fluoroethane.

[0367] "Fluoroalkyl" refers to an alkyl radical that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0368] A "hydroxy" group refers to an --OH group.

[0369] A "nitro" group refers to a -NO2 group.

[0370] An "oxo" group refers to a =O substituent.

[0371] The term "length," when referring to a moiety, refers to the minimum number of carbon atoms and / or heteroatoms from one end of the moiety to the other. When referring to a linker, it refers to the minimum number of atoms that connect the end to the TRK ligand and the end to the degradation tag. This applies both to situations where the linker is linear or branched, and to situations where the linker contains a ring system.

[0372] The term "substituted" means that the particular group or moiety is substituted with any of the following: C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo, -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-

[0023] This means that the aryl group has one or more substituents independently selected from -C1-C4 alkyl, -CONH, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SONH, -SONH(C1-C4 alkyl), -SONH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl).

[0373] The term "null" or "absent" means that an atom or moiety is not present and there is a bond between adjacent atoms in the structure.

[0374] The term "optionally substituted" means that a particular group may be unsubstituted or substituted with one or more substituents as defined herein. In the compounds of the present disclosure, when a group is described as "unsubstituted" or "substituted" with fewer groups than satisfy the valences of all atoms in the compound, it is understood that the remaining valences on such group are satisfied with hydrogen. For example, when a C aryl group, also referred to herein as "phenyl," is substituted with one additional substituent, one skilled in the art would understand that such a group has four open positions remaining on the carbon atoms of the C aryl ring (the six original positions minus one to which the remainder of the disclosed compound is attached plus the additional substituent, leaving four open positions). In such cases, each of the remaining four carbon atoms is bonded to one hydrogen atom to satisfy their valences. Similarly, when a C aryl group in the compounds is described as "disubstituted," one skilled in the art would understand that this means that the C aryl has three remaining carbon atoms that are unsubstituted. Each of the three unsubstituted carbon atoms is bonded to one hydrogen atom to satisfy their valence. Unless otherwise specified, an optionally substituted radical may be unsubstituted or a halogen, CN, NO, OR m , S.R. m , N.R. n R o , C.O.R. m , CO2R m ,CONR n R o , SOR m , SO2R m , SO2NR n R o , N.R. n COR o , N.R. m C(O)NR n R o , N.R. n SOR o , N.R. n SO2R o, C1-C8 alkyl, C1-C8 alkoxyC1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkylaminoC1-C8 alkyl, C3-C7 carbocyclyl, 3- to 7-membered heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and heteroaryl; R m , R n , and R o is independently selected from null, hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 carbocyclyl, 3- to 7-membered heterocyclyl, aryl, and heteroaryl, or R n and R o together with the atoms to which they are attached form a 3- to 8-membered carbocyclyl or heterocyclyl ring.

[0375] The terms "combination therapy" or "combination" or "in combination with" refer to the administration of two or more therapeutic agents to treat a disease or disorder (e.g., cancer) described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple or separate containers (e.g., capsules, powder, and liquid) for each active ingredient. The powder and / or liquid may be reconstituted or diluted to the desired dose prior to administration. In addition, such administration further encompasses the use of each type of therapeutic agent in a sequential manner, at about the same time or at different times. In either case, the treatment regimen provides the beneficial effects of the drug combination in treating the disease or disorder described herein.

[0376] Combination therapy can provide "synergistic effects" and be proven to be "synergistic," i.e., an effect achieved when the active ingredients used together are greater than the sum of the effects produced by using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined unit dose formulation, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, by different injections in separate syringes. Generally, during alternation therapy, effective doses of each active ingredient are administered sequentially, i.e., consecutively, whereas in combination therapy, effective doses of two or more active ingredients are administered together.

[0377] The term "pharmaceutical combination," as used herein, refers either to a fixed combination in one dosage unit form, or to a non-fixed combination or kit of parts for combined administration in which two or more therapeutic agents can be independently administered separately at the same time or within a time interval, among other things, such time interval allowing the combination partners to exhibit a cooperative, e.g., synergistic, effect.

[0378] As used herein, "therapeutic agent" refers to a therapy, for example, a molecule, including but not limited to, a chemical compound, a peptide, an antibody, an antibody fragment, an antibody conjugate, or a nucleic acid, gene or cell therapy, or radiation therapy, that is therapeutically active when administered to a subject in combination with a compound of the present disclosure, or that enhances the therapeutic activity, or that reduces one or more side effects of a compound of the present disclosure when administered to a subject in combination with a compound of the present disclosure.

[0379] "Cancer" means any cancer caused by the uncontrolled growth of abnormal cells, such as a tumor, neoplasm, carcinoma, sarcoma, leukemia, lymphoma, etc. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. For example, cancers include, but are not limited to, mesothelioma, leukemia, and lymphomas, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphomas associated with human T-cell lymphotrophic virus (HTLV), such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, pediatric solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas, common adult solid tumors such as head and neck cancer (e.g., oral cavity, larynx, and nasopharynx), esophageal cancer, genitourinary cancer (e.g., prostate, bladder, kidney, uterus, ovary, testis), lung cancer (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.), liver cancer, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST). Further exemplary forms of cancer that may be treated by the compounds and compositions described herein include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, cancer of the small intestine, rectal cancer, cancer of the salivary glands, endometrial cancer, adrenal gland cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0380] The second agent may be an anti-cancer agent. The term "anti-cancer" or "anti-cancer agent" refers to an agent that treats cancer (i.e., a compound, antibody, etc. that is useful in treating cancer). The anti-cancer effect may occur through one or more mechanisms, including, but not limited to, regulating cell growth or proliferation, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of tumors from their origin), inhibiting invasion (the spread of tumor cells to adjacent normal structures), inhibiting checkpoint molecules, or promoting apoptosis.

[0381] The anti-cancer agent can be an anti-proliferative agent or an immunomodulatory agent. In one embodiment, the second agent is an immunomodulatory agent.

[0382] The term "antiproliferative" or "antiproliferative agent" as used herein refers to an agent that inhibits cell growth or cell proliferation. Antiproliferative agents can be cytotoxic agents (e.g., alkylating agents, antimetabolites, etc.), targeted agents (e.g., EGF inhibitors, tyrosine protein kinase inhibitors, angiogenesis inhibitors, etc.), or hormonal agents (e.g., estrogen-selective estrogen receptor modulators, etc.). Examples of antiproliferative agents include alkylating agents, antimetabolites, antibiotics, antidotes, EGFR inhibitors, HER2 inhibitors, histone deacetylase inhibitors, hormones, mitotic inhibitors, MTOR inhibitors, multikinase inhibitors, serine / threonine inhibitors, tyrosine kinase inhibitors, VEGF / VEGFR inhibitors, taxanes or taxane derivatives, aromatase inhibitors, anthracyclines, microtubule-targeting drugs, topoisomerase poison drugs, and inhibitors of molecular targets or enzymes.

[0383] The term "immunomodulator" refers to an agent that modulates the immune response or function of the immune system (by stimulating antibody formation or inhibiting leukocyte activity). An immunomodulator can be an immunomodulator, cytokine, vaccine, or antibody.

[0384] The term "immunomodulatory agent" refers to an inhibitor of an immune checkpoint molecule.

[0385] Additional cancers that the compounds and compositions described herein may be useful for preventing, treating, and studying are, for example, colon cancer, familial adenomatous polyposis cancer, and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, kidney parenchyma carcinoma, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors, gallbladder cancer, bronchial carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. [Example]

[0386] The present disclosure is further described and illustrated by the following examples. However, the use of these examples, and other examples anywhere in the specification, is illustrative only and in no way limits the scope and meaning of the disclosure or the scope and meaning of any exemplified term. Likewise, the present disclosure is not limited to any particular preferred embodiment or aspect described herein. Indeed, many modifications and variations may become apparent to those skilled in the art upon reading this specification, and such variations can be made without departing from the invention in spirit or scope. Therefore, the present invention is to be limited only by the appended claims, along with the full range of equivalents to which such claims are entitled.

[0387] General Chemical Methods: All chemicals and reagents were purchased from commercial sources and used without further purification. LCMS spectra of all compounds were acquired using a Waters LC-MS AcQuity H UPLC-class system. The Waters LC-MS AcQuity H UPLC-class system includes a pump with a degasser (Quaternary Solvent Manager), an autosampler (FTN), a column oven (40 °C unless otherwise indicated), and a photodiode array PDA detector. Chromatography was performed on an AcQuity UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) column using water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B at a flow rate of 0.6 mL / min. The column flow was split to the MS spectrometer. The MS detector was configured with an electrospray ion source. Nitrogen was used as the nebulizer gas. Data acquisition was performed using a MassLynx data system. Nuclear magnetic resonance spectra were recorded on a Bruker Avance III400 spectrometer. Chemical shifts are expressed in parts per million (ppm) and reported as δ values ​​(chemical shift δ). Coupling constants are reported in units of hertz (J value, Hz; integration and splitting patterns: s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet). Purification of intermediates or final products was performed on an Agilent Prep 1260 series with the UV detector set at 254 nm or 220 nm. Samples were injected onto a Phenomenex Luna C18 column (5 μm, 30 × 75 mm) at room temperature. The flow rate was 40 mL / min. A linear gradient was used with 10% or 50% MeOH in HO containing 0.1% TFA as solvent A and 100% MeOH as solvent B. Alternatively, products were purified on a CombiFlash® NextGen 300 system with a UV detector set at 254 nm, 220 nm, or 280 nm. The flow rate was 40 mL / min. A linear gradient was used with HO containing 0.05% TFA as solvent A and 100% MeOH containing 0.05% TFA as solvent B.All compounds showed >95% purity using LCMS methods.

[0388] Example 1. 5-((trans-3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-640)

[0389] [ka]

[0390] To a solution of (trans-3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl 4-methylbenzenesulfonate (70 mg, 147.5 μmol) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (40.4 mg, 147.5 μmol) in DMF (3 mL) was added KCO (40.8 mg, 295 μmol). The reaction mixture was stirred for 12 h at 60 °C and then purified by reverse-phase chromatography to give the desired product (2.1 mg, 3% yield) as a yellow solid. MS (ESI) m / z = 577.3 [M+H] + .

[0391] Example 2. 5-(((trans-3-(4-(3-cyclopropoxypyridin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-641)

[0392] [ka]

[0393] Step 1. Synthesis of 2-bromo-3-cyclopropoxypyridine

[0394] To a solution of cyclopropanol (1.98 g, 34.09 mmol) in DMF (20 mL) was added NaH (2.73 g, 68.19 mmol) slowly at 0 °C. The reaction was stirred at 0 °C for 1 h, and then 2-bromo-3-fluoro-pyridine (3 g, 17.05 mmol) was added dropwise. The resulting mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to room temperature and then poured into saturated aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel flash chromatography to give the desired product (600 mg, 17% yield) as a pale yellow oil. MS (ESI) m / z = 214.0 [M+H] + .

[0395] Step 2. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(4-(3-(cyclopropoxy)-2-pyridyl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0396] To a solution of 2-bromo-3-(cyclopropoxy)pyridine (100.0 mg, 0.467 mmol) in MeCN (6.0 mL) and water (4.0 mL), tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate (290.1 ​​mg, 0.56 mmol), Sphos Pd G3 (45.1 mg, 0.0467 mmol), and K2CO3 (128.9 mg, 0.934 mmol) were added at room temperature. The reaction mixture was stirred at 100 °C under an inert atmosphere for 16 hours. After cooling to room temperature, the mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give the desired product (171.0 mg, 70% yield) as a pale white solid. MS (ESI) m / z = 525.2 [M+H] + .

[0397] Step 3. Synthesis of (trans-3-(4-(3-cyclopropoxypyridin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methanamine

[0398] To a solution of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(4-(3-(cyclopropoxy)-2-pyridyl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)carbamate (220.0 mg, 0.418 mmol) in DCM (6 mL) was added TFA (3 mL) at room temperature. After stirring at room temperature for 1 h, the reaction mixture was concentrated and purified by reverse phase chromatography to give the desired product (130.0 mg, 95% yield) as a pale yellow oil. MS (ESI) m / z = 325.0 [M+H] + .

[0399] Step 4. Synthesis of 5-(((trans-3-(4-(3-cyclopropoxypyridin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0400] To a solution of (trans-3-(4-(3-cyclopropoxypyridin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methanamine (180.0 mg, 0.555 mmol) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (183.9 mg, 0.666 mmol) in DMSO (3 mL) was added DIPEA (0.72 g, 5.55 mmol) at room temperature. The reaction mixture was stirred at 130° C. for 2 hours under microwave irradiation. After cooling to room temperature, the mixture was poured into water (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give the desired product (45.0 mg, 14% yield) as a yellow solid. MS(ESI) m / z=581.7[M+H] + .

[0401] Example 3. 5-((3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-642)

[0402] [ka]

[0403] Step 1. Synthesis of tert-butyl (3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)propyl)carbamate

[0404] To a solution of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (40 mg, 0.17 mmol) and tert-butyl (3-bromopropyl)carbamate (85 mg, 0.34 mmol) in DMSO (3 mL) was added CsCO (166 mg, 0.51 mmol) at room temperature. The reaction mixture was then stirred at 80 °C for 3 h. The mixture was purified by reverse-phase chromatography to give the desired product (40 mg, 60% yield) as a pale yellow solid. MS (ESI) m / z = 394.5 [M+H] + .

[0405] Step 2. Synthesis of 3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)propan-1-amine

[0406] A mixture of tert-butyl (3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)propyl)carbamate (40 mg, 0.10 mmol) in TFA / DCM (1:1, 4 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated to give the crude product (30 mg, 100% yield) as a pale yellow solid. This compound was used directly in the next step without further purification. MS (ESI) m / z = 294.5 [M+H] + .

[0407] Step 3. Synthesis of 5-((3-(3-cyclopropyl-4-(quinoxalin-2-yl-1H-pyrazol-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0408] To a solution of 3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)propan-1-amine (30 mg, 0.10 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (28 mg, 0.10 mmol) in DMSO (2 mL) was added KF (30 mg, 0.50 mmol) at room temperature. The reaction mixture was then stirred at 130° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was purified by reverse-phase chromatography to give the desired product (15 mg, 27% yield) as a pale yellow solid. MS (ESI) m / z=550.6 [M+H] + .

[0409] Example 4. 5-(((trans-2-(3-cyclopropyl-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-643)

[0410] [ka]

[0411] Step 1. Synthesis of tert-butyldimethyl((trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methoxy)silane

[0412] To a solution of (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (1.2 g, 4.02 mmol) in DCM (50 mL) was added EtZn (2.48 g, 20.13 mmol) at 0 °C. After the reaction was stirred for 30 min at 0 °C, CHCl (5.4 g, 20.13 mmol) and TFA (2.3 g, 20.13 mmol) were added to the above solution at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and at room temperature for an additional 2 h. The reaction was quenched with aqueous NHCl and extracted with DCM (2 × 100 mL). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (800 mg, 64% yield) as a colorless oil.

[0413] Step 2. Synthesis of (trans-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)boronic acid

[0414] To a solution of tert-butyldimethyl((trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methoxy)silane (800 mg, 2.56 mmol) in acetone (40 mL) and water (20 mL) were added NaIO (3.29 g, 15.36 mmol) and AcONH (1.18 mg, 15.36 mmol) at room temperature. After stirring at room temperature for 10 h, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (2 × 100 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (480 mg, 81% yield) as a yellow oil.

[0415] Step 3. Synthesis of 6-(1-(trans-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-3-cyclopropyl-1H-pyrazol-4-yl)-3-fluoro-2-methylpyridine

[0416] To a solution of 6-(3-cyclopropyl-1H-pyrazol-4-yl)-3-fluoro-2-methylpyridine (120 mg, 0.55 mmol) and (trans-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)boronic acid (250 mg, 1.10 mmol) in DMF (10 mL) was added Cu(OAc) (200 mg, 1.10 mmol), CsCO (538 mg, 1.65 mmol), bipyridine (172 mg, 1.10 mmol), and 4Å MS (100 mg). The reaction mixture was stirred at 100 °C for 10 h under argon. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (45 mg, 20% yield) as a yellow solid. MS (ESI) m / z = 402.5 [M+H] + .

[0417] Step 4. Synthesis of (trans-2-(3-cyclopropyl-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)methanol

[0418] To a solution of 6-(1-(trans-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-3-cyclopropyl-1H-pyrazol-4-yl)-3-fluoro-2-methylpyridine (45 mg, 0.11 mmol) in DCM (10 mL) was added TBAF (1 M in THF, 1.0 mL) at room temperature. After stirring at room temperature for 6 h, the reaction mixture was concentrated and purified by reverse phase chromatography to give the desired product (30 mg, 93% yield) as a pale yellow solid. MS (ESI) m / z = 288.2 [M+H] + .

[0419] Step 5. Synthesis of (trans-2-(3-cyclopropyl-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)methyl 4-methylbenzenesulfonate

[0420] To a solution of (trans-2-(3-cyclopropyl-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)methanol (30 mg, 0.10 mmol) in DCM (5 mL) was added TsCl (38 mg, 0.20 mmol), EtN (50 mg, 0.50 mmol), and DMAP (18 mg, 0.15 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, then poured into water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel flash chromatography to give the desired product (35 mg, 76% yield) as a white solid. MS (ESI) m / z = 442.3 [M+H] + .

[0421] Step 6. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((trans-2-(3-cyclopropyl-4-(5-fluoro-6-methyl-2-pyridyl)pyrazol-1-yl)cyclopropyl)methyl)carbamate

[0422] To a solution of (trans-2-(3-cyclopropyl-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)methyl 4-methylbenzenesulfonate (35 mg, 0.08 mmol) and tert-butyl N-tert-butoxycarbonylcarbamate (34 mg, 0.16 mmol) in DMF (4 mL) was added CsCO (78 mg, 0.24 mmol) at room temperature. The reaction was stirred at 90 °C for 1 h, then quenched with HO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (35 mg, 90% yield) as a yellow oil. MS (ESI) m / z = 487.3 [M+H] + .

[0423] The remaining steps were carried out according to the procedure of steps 2-3 of GS-642 to give the desired product (2 mg, 11% yield over two steps) as a yellow solid. MS (ESI) m / z = 543.3 [M+H] + .

[0424] Example 5. 5-(((trans-3-(3-cyclopropyl-4-(7-(3-hydroxyazetidin-1-yl)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-644)

[0425] [ka]

[0426] Step 1. Synthesis of tert-butyl N-((trans-3-(4-(7-bromoquinoxalin-2-yl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)-N-tert-butoxycarbonyl-carbamate

[0427] To a solution of 7-bromo-2-chloroquinoxaline (650 mg, 2.67 mmol) in dioxane (10 mL) and water (2 mL), tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate (1.66 g, 3.20 mmol), Pd(PPh3)4 (308.3 mg, 0.267 mmol), and Cs2CO3 (1.74 g, 5.34 mmol) were added at room temperature. The reaction mixture was stirred at 100 °C under an inert atmosphere for 4 hours. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give the desired product (400 mg, 15% yield) as a pale white solid. MS (ESI) m / z = 598.3 [M+H] + .

[0428] Step 2. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(7-(3-hydroxyazetidin-1-yl)quinoxalin-2-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0429] To a solution of tert-butyl N-((trans-3-(4-(7-bromoquinoxalin-2-yl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)-N-tert-butoxycarbonyl-carbamate (110.0 mg, 0.184 mmol) in THF (10 mL) was added azetidin-3-ol (53.7 mg, 0.735 mmol), Sphos Pd G3 (15.9 mg, 0.018 mmol), and t-BuONa (53.0 mg, 0.551 mmol) at room temperature. The reaction mixture was then stirred at 100° C. under an inert atmosphere for 2 hours. After cooling to room temperature, the mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by reverse phase chromatography to give the desired product (50 mg, 46% yield) as a pale white solid. MS (ESI) m / z = 591.7 [M+H] + .

[0430] The remaining steps were carried out according to the procedure of steps 3-4 of GS-641 to give the desired product (0.88 mg, 1% yield over two steps) as a pale yellow solid. MS (ESI) m / z = 647.7 [M+H] + .

[0431] Example 6. 5-(((2-((3-cyclopropyl-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-645)

[0432] [ka]

[0433] Step 1. Synthesis of ethyl 2-(aminomethyl)cyclopropane-1-carboxylate

[0434] To a solution of ethyl 2-cyanocyclopropane-1-carboxylate (400 mg, 2.88 mmol) in MeOH (10 mL) was added Raney nickel (Ni) (100 mg) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give the desired product (300 mg, 73% yield) as a colorless oil.

[0435] Step 2. Synthesis of ethyl 2-(((tert-butoxycarbonyl)amino)methyl)cyclopropane-1-carboxylate

[0436] To a solution of ethyl 2-(aminomethyl)cyclopropane-1-carboxylate (300 mg, 2.10 mmol) in dichloromethane (20 mL) was added BocO (900 mg, 4.20 mmol) and DMAP (384 mg, 3.15 mmol). The reaction mixture was stirred at room temperature for 6 hours, then quenched with water (20 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were then washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (300 mg, 59% yield) as a colorless oil.

[0437] Step 3. Synthesis of tert-butyl ((2-(hydroxymethyl)cyclopropyl)methyl)carbamate

[0438] To a solution of ethyl 2-(((tert-butoxycarbonyl)amino)methyl)cyclopropane-1-carboxylate (300 mg, 1.23 mmol) in THF (10 mL) was added LiAlH (140 mg, 3.70 mmol) at 0 °C. The reaction mixture was stirred at room temperature under argon for 2 h, then quenched with solid NaSO and diluted with EtOAc (25 mL). The suspension was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the crude product (200 mg, 81% yield). This compound was used directly in the next step without further purification.

[0439] Step 4. Synthesis of (2-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate

[0440] To a solution of tert-butyl ((2-(hydroxymethyl)cyclopropyl)methyl)carbamate (200 mg, 0.99 mmol) and 4-methylbenzenesulfonyl chloride (474 ​​mg, 2.48 mmol) in dichloromethane (20 mL) was added EtN (500 mg, 4.97 mmol) and DMAP (121 mg, 0.99 mmol). The reaction mixture was stirred at room temperature for 10 hours, then quenched with water (20 mL) and extracted with dichloromethane (2 × 20 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (120 mg, 34% yield) as a white solid.

[0441] Step 5. Synthesis of tert-butyl ((2-((3-cyclopropyl-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)carbamate

[0442] To a solution of (2-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (100 mg, 0.28 mmol) and 6-(3-cyclopropyl-1H-pyrazol-4-yl)-3-fluoro-2-methylpyridine (20 mg, 0.09 mmol) in DMF (10 mL) was added K2CO3 (65 mg, 0.47 mmol). The reaction mixture was stirred for 3 h at 80 °C. After cooling to room temperature, the reaction was poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (25 mg, 66% yield) as a brown solid. MS (ESI) m / z = 401.8 [M+H] + .

[0443] The remaining steps were carried out according to the procedure of steps 2 and 3 of GS-642 to give the desired product (7 mg, 25% yield over two steps) as a yellow solid. MS (ESI) m / z = 557.6 [M+H] + .

[0444] Example 7. 5-(((trans-3-(3-cyclopropyl-4-(2-methoxycyclohexyl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-646)

[0445] [ka]

[0446] Step 1. Synthesis of 6-methoxycyclohex-1-en-1-yl trifluoromethanesulfonate

[0447] To a solution of 2-methoxycyclohexan-1-one (1.5 g, 11.70 mmol) in dry THF (10 mL) was added LiHMDS (1 M, 15.21 mL) at −78° C. After the reaction was stirred at −78° C. for 30 minutes, a solution of N-phenyl-bis(trifluoromethanesulfonimide) (4.60 g, 12.87 mmol) in dry THF (5.0 mL) was added dropwise. The reaction mixture was stirred at 25° C. for 12 hours. The mixture was quenched with HO (20 mL) and extracted with petroleum ether (30 mL × 3). The combined organic phases were washed with brine, dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to give the crude product (3 g, 98% yield), which was used directly in the next step without further purification.

[0448] Step 2. Synthesis of 2-(6-methoxycyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0449] To a solution of 6-methoxycyclohex-1-en-1-yl trifluoromethanesulfonate (500 mg, 1.92 mmol), KOAc (565.7 mg, 5.76 mmol), and B2Pin2 (585.5 mg, 2.31 mmol) in DMF (10 mL) was added Pd(dppf)Cl2 (140.6 mg, 0.192 mmol) at room temperature. The reaction mixture was stirred for 12 hours at 90 °C. The reaction was quenched with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (200 mg, 44% yield) as a yellow oil.

[0450] Step 3. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(6-methoxycyclohexen-1-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0451] To a solution of 2-(6-methoxycyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.84 mmol), tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-iodo-pyrazol-1-yl)cyclobutyl)methyl)carbamate (434.6 mg, 0.84 mmol), and KCO (232.2 mg, 1.68 mmol) in dioxane (5 mL) and HO (1 mL), Pd(dppf)Cl (61.4 mg, 0.084 mmol) was added at room temperature. The reaction mixture was stirred at 90 °C for 12 h. The reaction was quenched with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (100 mg, 24% yield) as a yellow oil. MS (ESI) m / z = 502.9 [M+H] + .

[0452] Step 4. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(2-methoxycyclohexyl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0453] To a solution of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(6-methoxycyclohexen-1-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate (100 mg, 0.2 mmol) in methanol (5 mL) was added 10% Pd / C (24.2 mg). The reaction mixture was purged with hydrogen three times and stirred under a hydrogen atmosphere for 12 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the desired product (100 mg, 99% yield) as a yellow oil. This compound was used directly in the next step without further purification. MS (ESI) m / z = 504.8 [M+H] + .

[0454] The remaining steps were carried out according to the procedure of steps 3 and 4 of GS-641 to give the desired product (0.9 mg, 2% yield over two steps) as a yellow solid. MS (ESI) m / z = 560.6 [M+H] + .

[0455] Example 8. 5-(((trans-3-(3-cyclopropyl-4-(6-(3-hydroxyazetidin-1-yl)pyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-647)

[0456] [ka]

[0457] Step 1. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-[6-(3-hydroxyazetidin-1-yl)-2-pyridyl]pyrazol-1-yl)cyclobutyl)methyl]carbamate

[0458] To a solution of azetidin-3-ol (43.6 mg, 0.40 mmol), tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(4-(6-chloro-2-pyridyl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)carbamate (100 mg, 0.20 mmol), XantPhos (23.0 mg, 0.04 mmol), and CsCO (194.3 mg, 0.60 mmol) in toluene (10 mL) was added Pd(dba) (18.2 mg, 0.02 mmol) at room temperature. The reaction mixture was stirred for 12 hours at 100 °C. The reaction was quenched with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (13 mg, 12% yield) as a yellow oil. MS (ESI) m / z = 540.6 [M+H] + .

[0459] The remaining steps were carried out according to the procedure of steps 3 and 4 of GS-641 to give the desired product (0.8 mg, 6% yield over two steps) as a yellow solid. MS (ESI) m / z = 596.6 [M+H] + .

[0460] Example 9. 5-(((trans-3-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-648)

[0461] [ka]

[0462] Step 1. Synthesis of 3-chloro-N-methoxy-N-methylpyrazine-2-carboxamide

[0463] To a solution of 3-chloropyrazine-2-carboxylic acid (5.0 g, 31.6 mmol) in DMF (50 mL) was added HATU (14.4 g, 37.9 mmol), DIPEA (8.2 g, 63.3 mmol), and N,O-dimethylhydroxylamine (6.1 g, 63.3 mmol) at room temperature. After stirring overnight at room temperature, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the desired product (5.9 g, 93% yield) as a white solid. MS (ESI) m / z = 202.2 [M+H] + .

[0464] Step 2. Synthesis of (3-chloropyrazin-2-yl)(cyclopropyl)methanone

[0465] To a solution of 3-chloro-N-methoxy-N-methylpyrazine-2-carboxamide (5.9 g, 29.4 mmol) in THF (50 mL) was added dropwise a solution of cyclopropylmagnesium bromide (1.0 M, 35.2 mL, 35.2 mmol) in THF at 0 °C. The reaction mixture was warmed to room temperature and stirred at the same temperature overnight. The reaction was quenched with a saturated solution of ammonium chloride and diluted with water (20 mL). The resulting mixture was stirred at room temperature until both layers became clear. The aqueous layer was separated and extracted with diethyl ether (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2:1) to give the desired product (2.08 g, 39% yield) as a colorless oil. MS (ESI) m / z = 183.1 [M+H] + .

[0466] Step 3. Synthesis of 3-cyclopropyl-1H-pyrazolo[3,4-b]pyrazine

[0467] A solution of (3-chloropyrazin-2-yl)(cyclopropyl)methanone (2.08 g, 11.4 mmol) in hydrazine hydrate (20 mL) was heated at 100° C. for 1.5 hours under microwave irradiation. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL×4). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=1:1) to give the desired product (1.09 g, 60% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 13.55(s,1H),8.53(s,2H),2.39-2.32(m,1H),1.21-1.17(m,2H),1.08-1.03(m,2H).MS(ESI)m / z=161.1[M+H] + .

[0468] Step 4. Synthesis of (trans-3-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutyl)methanol

[0469] To a solution of 3-cyclopropyl-1H-pyrazolo[3,4-b]pyrazine (150 mg, 0.94 mmol) and 3-(hydroxymethyl)cyclobutyl 4-methylbenzenesulfonate (432 mg, 1.96 mmol) in DMF (5 mL) was added CsCO (610.6 mg, 1.87 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 4 h. After cooling to room temperature, the reaction was quenched with HO (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give two isomers. The desired trans isomer (90 mg, 39% yield) was obtained as a yellow solid. MS (ESI) m / z = 245.5 [M+H]+ .

[0470] The remaining steps were carried out according to the procedures of steps 5-6 of GS-643 and steps 3-4 of GS-641 to give the desired product (4.2 mg, 10% yield over 4 steps) as a yellow solid. MS (ESI) m / z = 500.5 [M+H] + .

[0471] Example 10. 5-(((trans-3-(3-cyclopropyl-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-649)

[0472] [ka]

[0473] Step 1. Synthesis of (trans-3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine

[0474] A solution of tert-butyl N-tert-butoxycarbonyl-N-(trans-3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate (180 mg, 0.348 mmol) in TFA (1.5 mL) and dichloromethane (1.5 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by reverse-phase chromatography to give the desired product (50 mg, 45% yield) as a colorless oil. MS (ESI) m / z = 318.3 [M+H] + .

[0475] Step 2. Synthesis of (trans-3-(3-cyclopropyl-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine

[0476] A mixture of 7-chloro-1-methyl-pyrazolo[3,4-c]pyridine (30 mg, 0.18 mmol), (trans-3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine (56.8 mg, 0.18 mmol), K2CO3 (74.1 mg, 0.537 mmol), and Pd(dppf)Cl2 (26.2 mg, 0.0358 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 100 °C under microwave irradiation for 1 h. After cooling to room temperature, the mixture was concentrated and purified by reverse-phase chromatography to give the desired product (20 mg, 35% yield) as a colorless oil. MS (ESI) m / z = 323.4 [M+H] + .

[0477] Step 3. Synthesis of 5-(((trans-3-(3-cyclopropyl-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0478] To a solution of (trans-3-(3-cyclopropyl-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine (20 mg, 0.062 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (25.7 mg, 0.093 mmol) in DMSO (1 mL) was added DIPEA (32.0 mg, 0.25 mmol). The mixture was stirred at 125° C. under microwave irradiation for 45 minutes. After cooling to room temperature, the mixture was purified by reverse-phase chromatography to give the desired product (6.5 mg, 18% yield) as a yellow solid. MS (ESI) m / z=579.8 [M+H] + .

[0479] Example 11. 5-(((trans-3-(3-cyclopropyl-4-(2-(dimethylamino)phenyl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-650)

[0480] [ka]

[0481] Step 1. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((3-(3-cyclopropyl-4-(2-(dimethylamino)phenyl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0482] To a solution of 2-bromo-N,N-dimethyl-aniline (50 mg, 0.25 mmol) in dioxane (8 mL) and HO (2 mL) was added KCO (51.7 mg, 0.38 mmol) and Pd(dppf)Cl (17.8 mg, 0.025 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 1 h. After cooling to room temperature, the reaction was quenched with HO (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give the desired product (50 mg, 40% yield) as a pale yellow solid. MS (ESI) m / z = 511.5 [M+H] + .

[0483] The remaining steps were carried out according to the procedure of steps 2-3 of GS642 to give a pale yellow solid (5.0 mg, 13% yield over two steps). MS (ESI) m / z = 567.8 [M+H] + .

[0484] Example 12. 3-(5-(((trans-3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GS-651)

[0485] [ka]

[0486] Step 1. Synthesis of trans-3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde

[0487] To a solution of (trans-3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol (130 mg, 0.40 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (516.3 mg, 1.22 mmol). The reaction mixture was stirred at 25 °C for 2 h, then quenched with HO (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (80 mg, 62% yield) as a yellow oil. MS (ESI) m / z = 319.4 [M+H] + .

[0488] Step 2. Synthesis of 3-(5-(((trans-3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0489] To a solution of trans-3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde (40 mg, 0.12 mmol), two drops of acetic acid, and 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (32.6 mg, 0.12 mmol) in methanol (2 mL) was added 2-picoline borane complex (20.2 mg, 0.19 mmol). The reaction mixture was stirred at 25 °C for 12 h, then quenched with HO (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (3.4 mg, 5% yield) as a yellow solid. MS(ESI) m / z=562.7[M+H] + .

[0490] Example 13. 5-(((trans-3-(3-cyclopropyl-4-(2-(piperazin-1-yl)phenyl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-652)

[0491] [ka]

[0492] GS-652 was synthesized as a yellow solid (6.5 mg, 7% yield over 3 steps) following the procedure for GS649, steps 1-3. MS (ESI) m / z = 608.7 [M+H] + .

[0493] Example 14. 5-(((trans-3-(4-(3-(azetidin-1-yl)phenyl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-653)

[0494] [ka]

[0495] Step 1. Synthesis of tert-butyl N-((3-(4-(3-bromophenyl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)-N-tert-butoxycarbonyl-carbamate

[0496] To a mixture of 1-bromo-3-iodo-benzene (50 mg, 0.177 mmol) and tert-butyl N-tert-butoxycarbonyl-N-((3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate (91.5 mg, 0.177 mmol) in dioxane (3 mL) and HO (1 mL) was added Pd(dppf)Cl (25.8 mg, 0.035 mmol) and KCO (73.2 mg, 0.53 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 1 h. After cooling to room temperature, the reaction was quenched with HO (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography to give the desired product (50 mg, 52% yield) as a pale yellow solid. MS (ESI) m / z = 546.5 [M+H] + .

[0497] Step 2. Synthesis of tert-butyl N-((3-(4-(3-(azetidin-1-yl)phenyl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)-N-tert-butoxycarbonyl-carbamate

[0498] To a solution of tert-butyl N-((3-(4-(3-bromophenyl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)-N-tert-butoxycarbonyl-carbamate (50 mg, 0.092 mmol) in dioxane (3 mL) was added S-Phos (37.60 mg, 0.092 mmol), Pd(dba) (8.4 mg, 0.0092 mmol), and CsCO (89.2 mg, 0.27 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 3 h. After cooling to room temperature, the reaction was quenched with HO (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to afford the desired product (30 mg, 63% yield) as a yellow solid. MS(ESI) m / z=523.5[M+H] + .

[0499] The remaining steps were carried out according to the procedure of steps 2-3 of GS642 to give a pale yellow solid (3 mg, 11% yield over two steps). MS (ESI) m / z = 579.7 [M+H] + .

[0500] Example 15. 5-(((trans-3-(3-cyclopropyl-4-(2-(piperidin-4-yl)phenyl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-654)

[0501] [ka]

[0502] Step 1. Synthesis of tert-butyl 4-(2-(1-(trans-3-(aminomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0503] The title compound was synthesized as a yellow solid (30 mg, 45% yield) following Step 2 of GS-649. MS (ESI) m / z = 449.6 [M+H] + .

[0504] Step 2. Synthesis of tert-butyl 4-(2-(1-(trans-3-(aminomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxylate

[0505] To a solution of tert-butyl 4-(2-(1-(trans-3-(aminomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (30 mg, 0.067 mmol) in ethyl acetate (3 mL) was added Pd / C (12.2 mg, 10 wt%) at room temperature. The reaction mixture was purged with hydrogen three times and stirred at room temperature under a hydrogen balloon for 20 minutes. The mixture was filtered through Celite, and the filter cake was washed with EtOAc (10 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give the desired product (20 mg, 66% yield) as a yellow solid.

[0506] The remaining steps were carried out according to the procedure of steps 2-3 of GS642 to give a yellow solid (3 mg, 11% yield over two steps). MS (ESI) m / z = 607.7 [M+H] + .

[0507] Example 16. 5-(((trans-3-(3-cyclopropyl-4-(7-(1-methylazetidin-3-yl)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-655)

[0508] [ka]

[0509] Step 1. Synthesis of tert-butyl 3-(3-(3-cyclopropyl-1-(trans-3-(methoxycarbonyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)azetidine-1-carboxylate

[0510] To a suspension of Zn dust (382 mg, 5.85 mmol) in dry DMF (20 mL) was added 1,2-dibromoethane (45 mg, 0.23 mmol) at room temperature under a N2 atmosphere. After stirring at 80 °C for 10 min, the reaction mixture was cooled to room temperature. Trimethylsilyl chloride (25 mg, 0.23 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 45 min, and then a solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.6 g, 5.85 mmol) in DMF (5 mL) was added dropwise. The resulting mixture was stirred at 45 °C for an additional 2 h, after which a solution of methyl trans-3-(4-(7-bromoquinoxalin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (500 mg, 1.17 mmol) and Pd(PPh3)4 (135 mg, 0.11 mmol) in DMF (20 mL) was added. After stirring at 70 °C for 16 h, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the desired product (270 mg, 46% yield) as a brown solid. MS (ESI) m / z = 504.7 [M+H] + .

[0511] Step 2. Synthesis of tert-butyl 3-(3-(3-cyclopropyl-1-(trans-3-(hydroxymethyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)azetidine-1-carboxylate

[0512] To a solution of tert-butyl 3-(3-(3-cyclopropyl-1-(trans-3-(methoxycarbonyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)azetidine-1-carboxylate (130 mg, 0.26 mmol) in THF (20 mL) was added LiAlH (26 mg, 0.7 mmol) at 0 °C under N. After the reaction mixture was stirred at room temperature for 1 h, HO (0.1 mL) and anhydrous NaSO were added to the mixture. The precipitate was filtered, and the filtrate was concentrated to give the desired crude product (110 mg, 89% yield) as a yellow oil. MS (ESI) m / z = 476.6 [M+H] + .

[0513] Step 3. Synthesis of tert-butyl 3-(3-(3-cyclopropyl-1-(trans-3-((tosyloxy)methyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)azetidine-1-carboxylate

[0514] To a solution of tert-butyl 3-(3-(3-cyclopropyl-1-(trans-3-(hydroxymethyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)azetidine-1-carboxylate (110 mg, 0.23 mmol) in dichloromethane (20 mL) was added TsCl (88 mg, 0.46 mmol) and DMAP (56 mg, 0.46 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours, then poured into water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel flash chromatography to give the desired product (130 mg, 89% yield) as a white solid. MS (ESI) m / z=630.6 [M+H] + .

[0515] Step 4. Synthesis of tert-butyl 3-(3-(3-cyclopropyl-1-(trans-3-((1,3-dioxoisoindolin-2-yl)methyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)azetidine-1-carboxylate

[0516] To a solution of tert-butyl 3-(3-(3-cyclopropyl-1-(trans-3-((tosyloxy)methyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)azetidine-1-carboxylate (130 mg, 0.21 mmol) in DMSO (10 mL) was added potassium 1,3-dioxoisoindolin-2-ide (76 mg, 0.42 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel flash chromatography to give the desired product (110 mg, 88% yield) as a colorless oil. MS (ESI) m / z=605.7 [M+H] + .

[0517] Step 5. Synthesis of 2-((trans-3-(4-(7-(azetidin-3-yl)quinoxalin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methyl)isoindoline-1,3-dione

[0518] To a solution of tert-butyl 3-(3-(3-cyclopropyl-1-(trans-3-((1,3-dioxoisoindolin-2-yl)methyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)azetidine-1-carboxylate (110 mg, 0.18 mmol) in DCM (2 mL) was added TFA (1 mL) at 0° C. After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo to give the crude product, which was used directly in the next step without further purification. MS (ESI) m / z=505.5 [M+H] + .

[0519] Step 6. Synthesis of 2-((trans-3-(3-cyclopropyl-4-(7-(1-methylazetidin-3-yl)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)isoindoline-1,3-dione

[0520] To a solution of 2-((trans-3-(4-(7-(azetidin-3-yl)quinoxalin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methyl)isoindoline-1,3-dione (90 mg, 0.18 mmol) in MeOH (10 mL) and AcOH (1 mL) was added formaldehyde solution (37 wt% in HO, 328 mg, 3.57 mmol) and NaBH(OAc) (756.0 mg, 3.57 mmol). The reaction mixture was stirred at room temperature for 3 days and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give the desired product (85 mg, 91% yield) as a yellow solid. MS (ESI) m / z = 519.6 [M+H] + .

[0521] Step 7. Synthesis of (trans-3-(3-cyclopropyl-4-(7-(1-methylazetidin-3-yl)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine

[0522] To a solution of 2-((trans-3-(3-cyclopropyl-4-(7-(1-methylazetidin-3-yl)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)isoindoline-1,3-dione (85 mg, 0.16 mmol) in EtOH (10 mL) was added hydrazine hydrate (164 mg, 3.28 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography to give the desired product (45 mg, 71% yield) as a yellow solid. MS (ESI) m / z=389.4 [M+H] + .

[0523] Step 8. Synthesis of 5-(((trans-3-(3-cyclopropyl-4-(7-(1-methylazetidin-3-yl)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0524] To a solution of (trans-3-(3-cyclopropyl-4-(7-(1-methylazetidin-3-yl)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine (10 mg, 0.02 mmol) in DMSO (2 mL) was added 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (14 mg, 0.04 mmol) and DIPEA (33 mg, 0.25 mmol). The reaction mixture was stirred at 130° C. under microwave irradiation for 30 minutes. After cooling to room temperature, the mixture was purified by reverse-phase chromatography to give the desired product (1.2 mg, 6% yield) as a yellow solid. MS (ESI) m / z=645.7 [M+H] + .

[0525] Example 17. 5-(((trans-3-(3-(difluoromethyl)-4-(1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-656)

[0526] [ka]

[0527] GS-656 was synthesized as a yellow solid (2 mg, 1% yield over 7 steps) following the procedure for GS677, steps 1-3, and GS643, steps 5-8. MS (ESI) m / z = 617.7 [M+H] + .

[0528] Example 18. 5-(((trans-3-(3-(difluoromethyl)-4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-657)

[0529] [ka]

[0530] GS-657 was synthesized as a yellow solid (4 mg, 3% yield over 7 steps) following the procedure for GS677, steps 1-3, and GS643, steps 5-8. MS (ESI) m / z = 589.7 [M+H] + .

[0531] Example 19. 5-(((trans-3-(3-cyclopropyl-4-(1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-658)

[0532] [ka]

[0533] Step 1. Synthesis of 6-chloro-1-methyl-1H-imidazo[4,5-c]pyridine

[0534] To a stirred solution of 6-chloro-1H-imidazo[4,5-c]pyridine (200 mg, 1.30 mmol) and NaH (93.7 mg, 3.91 mmol) in DMF (4 mL) was added dropwise CHCl (554.5 mg, 3.91 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then quenched with ice-water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the desired product (75 mg, 34% yield) as a white solid. MS (ESI) m / z = 168.1 [M+H] + .

[0535] The remaining steps were carried out according to the procedure of steps 2 and 3 of GS-649 to give the desired product (6.5 mg, 6% yield over two steps) as a yellow solid. MS (ESI) m / z = 579.5 [M+H] + .

[0536] Example 20. 5-(((trans-3-(3-cyclopropyl-4-(7-(3-hydroxypyrrolidin-1-yl)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-659)

[0537] [ka]

[0538] Step 1. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(7-(3-hydroxypyrrolidin-1-yl)quinoxalin-2-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0539] To a solution of tert-butyl N-((trans-3-(4-(7-bromoquinoxalin-2-yl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)-N-tert-butoxycarbonyl-carbamate (150 mg, 0.25 mmol) in dioxane (10 mL) was added pyrrolidin-3-ol (43.7 mg, 0.50 mmol), Sphos Pd G3 (43.4 mg, 0.05 mmol), and Cs2CO3 (163.4 mg, 0.50 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. After cooling to room temperature, the mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by reverse phase chromatography to give the desired product (120 mg, 79% yield) as a red solid. MS (ESI) m / z = 605.8 [M+H] + .

[0540] The remaining steps were carried out according to the procedure of steps 3-4 of GS-641 to give the desired product (1.5 mg, 10% yield over two steps) as a pale yellow solid. MS (ESI) m / z = 661.6 [M+H] + .

[0541] Example 21. 5-(((trans-3-(3-cyclopropyl-4-(2-isopropyl-2H-pyrazolo[3,4-c]pyridin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-660)

[0542] [ka]

[0543] Step 1. Synthesis of 7-chloro-2-isopropyl-2H-pyrazolo[3,4-c]pyridine

[0544] To a solution of 7-chloro-1H-pyrazolo[3,4-c]pyridine (600 mg, 3.91 mmol) in DMF (10 mL) was added NaH (312 mg, 7.81 mmol) portionwise at 0 °C under N2. The reaction was stirred at 0 °C for 30 min, and then 2-bromopropane (961 mg, 7.81 mmol) in DMF (2 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 50 °C for 2 h, then slowly quenched with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give the desired isomer (420 mg, 54% yield) as a colorless oil. MS (ESI) m / z = 196.2 [M+H] + .

[0545] Step 2. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(2-isopropylpyrazolo[3,4-c]pyridin-7-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0546] To a solution of 7-chloro-2-isopropyl-pyrazolo[3,4-c]pyridine (100 mg, 0.5 mmol) and tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate) (528 mg, 1.02 mmol) in dioxane (10 mL) and HO (1 mL), CsCO (497 mg, 1.53 mmol) and Pd(PPh) (59 mg, 0.05 mmol) were added at room temperature under N. The reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give the desired product (32 mg, 11% yield) as a brown oil. MS (ESI) m / z = 551.6 [M+H]+ .

[0547] The remaining steps were carried out according to the procedure of steps 2 and 3 of GS-642 to give the desired product (1.3 mg, 3% yield over two steps) as a yellow solid. MS (ESI) m / z = 607.8 [M+H] + .

[0548] Example 22. 5-((((trans-3-(3-cyclopropyl-4-(1-isopropyl-1H-pyrazolo[3,4-c]pyridin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-661)

[0549] [ka]

[0550] GS-661 was synthesized as a yellow solid (0.9 mg, 1% yield over 4 steps) following the procedure for GS-660, steps 1-2, and GS-642, steps 2-3. MS (ESI) m / z = 607.8 [M+H] + .

[0551] Example 23. 3-(6-(((trans-3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GS-662)

[0552] [ka]

[0553] GS-662 was synthesized as an off-white solid (17.9 mg, 25% yield) following the procedure in Step 2 of GS-651. MS (ESI) m / z = 562.5 [M+H] + .

[0554] Example 24. 5-(((trans-3-(3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-663)

[0555] [ka]

[0556] Step 1. Synthesis of cyclopropyl(4,6-dichloropyrimidin-5-yl)methanol

[0557] To a solution of diisopropylamine (3.75 g, 37.2 mmol) in THF (50 mL) was added n-BuLi (2.5 M, 15 mL, 37.2 mmol) dropwise at −78° C. under nitrogen. The reaction mixture was stirred at the same temperature for 30 minutes, after which a solution of 4,6-dichloropyrimidine (5.0 g, 33.8 mmol) in THF (15 mL) was added dropwise. The reaction mixture was stirred at −78° C. for another 30 minutes, after which cyclopropanecarbaldehyde (2.37 g, 33.8 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the desired product (4.25 g, 58% yield) as a colorless oil. MS(ESI)m / z=219.0[M+H] + .

[0558] Step 2. Synthesis of cyclopropyl(4,6-dichloropyrimidin-5-yl)methanone

[0559] To a solution of cyclopropyl(2,4-dichloropyridin-3-yl)methanol (4.25 g, 19.59 mmol) in dichloromethane (50 mL) was added Dess-Martin periodinane (8.3 g, 19.59 mmol). The reaction mixture was stirred overnight at room temperature and then quenched with saturated aqueous sodium bicarbonate (50 mL) and 10% aqueous sodium sulfite (50 mL). After stirring for 15 minutes, the reaction mixture was extracted with dichloromethane (50 mL × 4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the desired product (2.9 g, 69% yield) as a colorless oil. MS (ESI) m / z = 217.0 [M+H] + .

[0560] Step 3. Synthesis of 4-chloro-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine

[0561] A solution of cyclopropyl(4,6-dichloropyrimidin-5-yl)methanone (2.9 g, 13.4 mmol) in hydrazine hydrate (20 mL) was heated at 100° C. for 1.5 hours under microwave irradiation. After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane (20 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5:1) to give the desired product (2.4 g, 92% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 14.01(s,1H),8.75(s,1H),2.51-2.46(m,1H),1.09-0.94(m,4H). MS(ESI)m / z=195.1[M+H] + .

[0562] Step 4. Synthesis of 3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine

[0563] To a solution of 4-chloro-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine (1.4 g, 7.2 mmol) in 1,4-dioxane (30 mL) was added triethylamine (729 mg, 7.2 mmol) and Pd / C (300 mg). The reaction mixture was stirred overnight at room temperature under a H atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the desired product (600 mg, 52% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 13.58(s,1H),9.31(s,1H),8.91(s,1H),2.42-2.35(m,1H),1.10-1.02(m,4H). MS(ESI)m / z=161.1[M+H] + .

[0564] The remaining steps were carried out according to the procedures of Step 4 of GS-648 and Steps 5-8 of GS-643 to give the desired product (1.5 mg, 1% yield over 5 steps) as a yellow solid. MS (ESI) m / z = 500.5 [M+H] + .

[0565] Example 25. 5-(((trans-3-(3-cyclopropyl-4-(1-isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-664)

[0566] [ka]

[0567] GS-664 was synthesized as a pale yellow solid (3.1 mg, 2% yield over 4 steps) following the standard procedure for GS-660, steps 1-2, and GS-642, steps 2-3. MS(ESI) m / z = 607.5 [M+H] + .

[0568] Example 26. 5-(((trans-3-(3-cyclopropyl-4-(3-(piperidin-4-yl)pyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-665)

[0569] [ka]

[0570] Step 1. Synthesis of tert-butyl 2-chloro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0571] To a solution of 3-bromo-2-chloropyridine (2 g, 10.39 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.18 g, 13.51 mmol), and KPO (4.41 g, 20.79 mmol) in dioxane (15 mL) and HO (2 mL) was added Pd(dppf)Cl (760.4 mg, 1.04 mmol). The reaction mixture was stirred at 90 °C for 12 h. After cooling to room temperature, the mixture was quenched with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (2.4 g, 78% yield) as a yellow oil. MS (ESI) m / z = 295.3 [M+H] + .

[0572] Step 2. Synthesis of tert-butyl 2-(1-(tert-butoxycarbonyl)-3-cyclopropyl-1H-pyrazol-4-yl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0573] To a solution of tert-butyl 2-chloro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (1 g, 3.39 mmol), tert-butyl 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.7 g, 5.09 mmol), and KCO (1.41 g, 10.18 mmol) in DME (20 mL) and HO (2 mL) was added Pd(PPh) (392.0 mg, 0.34 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 12 h. After cooling to room temperature, the mixture was quenched with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (1 g, 63% yield) as a yellow oil. MS (ESI) m / z = 467.8 [M+H] + .

[0574] Step 3. Synthesis of tert-butyl 2-(3-cyclopropyl-1H-pyrazol-4-yl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0575] To a solution of tert-butyl 2-(1-(tert-butoxycarbonyl)-3-cyclopropyl-1H-pyrazol-4-yl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (1 g, 2.14 mmol) in methanol (5 mL) was added K2CO3 (888.6 mg, 6.43 mmol). The reaction mixture was stirred at 25 °C for 1 h, then quenched with HO (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (350 mg, 44% yield) as a yellow solid. MS (ESI) m / z = 367.5 [M+H] + .

[0576] Step 4. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate

[0577] To a solution of tert-butyl 2-(3-cyclopropyl-1H-pyrazol-4-yl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (330 mg, 0.9 mmol) in methanol (10 mL) was added 10% Pd / C (30 mg). The reaction mixture was purged with hydrogen three times and stirred under a hydrogen atmosphere at 40 °C for 12 h. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the desired product (300 mg, 90% yield) as a yellow oil. This compound was used directly in the next step without further purification. MS (ESI) m / z = 369.6 [M+H] + .

[0578] Step 5. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-(hydroxymethyl)cyclobutyl)-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate

[0579] To a solution of tert-butyl 4-(2-(3-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate (280 mg, 0.76 mmol) and 3-(hydroxymethyl)cyclobutyl 4-methylbenzenesulfonate (292.16 mg, 1.14 mmol) in DMF (5 mL) was added CsCO (495.2 mg, 1.52 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 12 h. After cooling to room temperature, the mixture was quenched with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired trans isomer (200 mg, 58% yield) as a yellow solid. MS (ESI) m / z = 453.6 [M+H] + .

[0580] Step 6. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-((tosyloxy)methyl)cyclobutyl)-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate

[0581] To a solution of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-(hydroxymethyl)cyclobutyl)-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate (200 mg, 0.44 mmol), DMAP (54.0 mg, 0.44 mmol), and DIPEA (0.2 mL) in dichloromethane (10 mL) was added tosyl chloride (168.5 mg, 0.88 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours, then quenched with HO (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (140 mg, 52% yield) as a yellow oil. MS (ESI) m / z = 607.6 [M+H] + .

[0582] Step 7. Synthesis of tert-butyl 4-(2-(1-(trans-3-(azidomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate

[0583] To a solution of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-(hydroxymethyl)cyclobutyl)-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate (130 mg, 0.21 mmol) and TMSN3 (74.1 mg, 0.63 mmol) in THF (10 mL) was added TBAF (1 M, 0.6 mL) at room temperature. The reaction mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the mixture was quenched with HO (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (80 mg, 78% yield) as a yellow oil. MS (ESI) m / z = 478.7 [M+H] + .

[0584] Step 8. Synthesis of tert-butyl 4-(2-(1-(trans-3-(aminomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate

[0585] To a solution of tert-butyl 4-(2-(1-(trans-3-(azidomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate (40 mg, 0.084 mmol) in methanol (2 mL) was added 10% Pd / C (10 mg). The reaction mixture was purged with hydrogen three times and stirred at room temperature under a hydrogen atmosphere for 12 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the desired product (35 mg, 92% yield) as a yellow oil. This compound was used directly in the next step without further purification. MS (ESI) m / z = 452.5 [M+H] + .

[0586] Step 9. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)cyclobutyl)-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate

[0587] A mixture of tert-butyl 4-(2-(1-(trans-3-(aminomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate (35 mg, 0.078 mmol), 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (25.7 mg, 0.093 mmol), and DIPEA (0.1 mL) in DMSO (1 mL) was stirred at 130° C. under microwave irradiation for 0.5 h. After cooling to room temperature, the mixture was purified by reverse-phase chromatography to give the desired product (20 mg, 36% yield) as a yellow solid. MS (ESI) m / z=708.6 [M+H] + .

[0588] Step 10. Synthesis of 5-(((trans-3-(3-cyclopropyl-4-(3-(piperidin-4-yl)pyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0589] To a solution of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)cyclobutyl)-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate (20 mg, 0.028 mmol) in dichloromethane (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give the desired product (2.1 mg, 11% yield) as a yellow solid. MS (ESI) m / z = 608.6 [M+H]+ .

[0590] Example 27. 5-(((trans-3-(3-cyclopropyl-4-((1-methylpiperidin-4-yl)amino)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-666)

[0591] [ka]

[0592] Step 1. Synthesis of tert-butyl N-((trans-3-(3-cyclopropyl-4-((1-methyl-4-piperidyl)amino)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0593] To a mixture of tert-butyl-N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-iodo-pyrazol-1-yl)cyclobutyl)methyl)carbamate (150 mg, 0.29 mmol), 1-methylpiperidin-4-amine (99.3 mg, 0.87 mmol), t-BuOK (80.5 mg, 0.72 mmol), and t-BuDavephos (122.3 mg, 0.29 mmol) in m-xylene (8 mL) was added Pd(dba) (19.2 mg, 0.021 mmol) at room temperature. The reaction mixture was purged with N and stirred at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL) and filtered through Celite. The filtrate was concentrated and purified by reverse-phase chromatography to give the desired product (20 mg, 17% yield) as a yellow solid. MS(ESI) m / z=404.5[M+H] + .

[0594] The remaining steps were carried out according to the procedure of steps 2 and 3 of GS-642 to give the desired product (3.8 mg, 9% yield over two steps) as a yellow solid. MS (ESI) m / z = 560.7 [M+H] + .

[0595] Example 28. 5-(((trans-3-(4-(cyclohexylamino)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-667)

[0596] [ka]

[0597] GS-667 was synthesized as a yellow solid (2.4 mg, 4% yield over 3 steps) following the standard procedure for GS-666, step 1, and GS-642, steps 2-3. MS(ESI) m / z = 545.7 [M+H] + .

[0598] Example 29. 3-(5-(((trans-3-(3-(difluoromethyl)-4-(5-fluoro-3-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GS-668)

[0599] [ka]

[0600] GS-668 was synthesized as a yellow solid (30 mg, 6% yield over 5 steps) following the standard procedure for GS-677, steps 1-5. MS (ESI) m / z = 553.5 [M+H] + .

[0601] Example 30. 5-(((trans-3-(3-cyclopropyl-4-(pyridin-2-ylamino)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-669)

[0602] [ka]

[0603] Step 1. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(2-pyridylamino)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0604] To a solution of pyridin-2-amine (60.0 mg, 0.64 mmol) in dioxane (5 mL) was added tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-iodo-pyrazol-1-yl)cyclobutyl)methyl)carbamate (329.8 mg, 0.64 mmol), t-BuBrettPhos Pd G3 (54.5 mg, 0.064 mmol), and Cs2CO3 (415.7 mg, 1.28 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen. After cooling to room temperature, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by reverse phase chromatography to give the desired product (60.0 mg, 19% yield) as a pale white solid. MS (ESI) m / z = 484.6 [M+H] + .

[0605] The remaining steps were carried out according to the procedure of steps 3 and 4 of GS-641 to give the desired product (4.1 mg, 2% yield over two steps) as a yellow solid. MS (ESI) m / z = 540.5 [M+H] + .

[0606] Example 31. 5-(((trans-3-(3-cyclopropyl-4-(pyridin-3-ylamino)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-670)

[0607] [ka]

[0608] GS-670 was synthesized as a yellow solid (9.6 mg, 1% yield over 3 steps) following the standard procedure for GS-669, step 1, and GS-641, steps 3-4. MS(ESI) m / z = 540.5 [M+H] + .

[0609] Example 32. 5-(((trans-3-(3-cyclopropyl-4-(pyridin-4-ylamino)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-671)

[0610] [ka]

[0611] GS-671 was synthesized as a yellow solid (10 mg, 17% yield over three steps) following the standard procedure for GS-669, step 1, and GS-641, steps 3-4. MS(ESI) m / z = 540.5 [M+H] + .

[0612] Example 33. 5-(((trans-3-(3-cyclopropyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-672)

[0613] [ka]

[0614] Step 1. Synthesis of 2-chloro-N-methoxy-N,6-dimethylnicotinamide

[0615] To a solution of 2-chloro-6-methylnicotinic acid (2.0 g, 11.7 mmol) in DMF (20 mL) was added HATU (6.7 g, 17.6 mmol), DIEA (4.5 g, 35.1 mmol), and N,O-dimethylhydroxylamine (1.3 g, 12.9 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the desired product (2.14 g, 86% yield) as a yellow solid. MS (ESI) m / z = 215.1 [M+H] + .

[0616] Step 2. Synthesis of (2-chloro-6-methylpyridin-3-yl)(cyclopropyl)methanone

[0617] To a solution of 2-chloro-N-methoxy-N,6-dimethylnicotinamide (2 g, 9.3 mmol) in THF (20 mL) was added dropwise a solution of cyclopropylmagnesium bromide (1.0 M in THF, 47 mL, 47 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h, then slowly quenched with aqueous NHCl (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the desired product (1.68 g, 93% yield) as a yellow oil. MS (ESI) m / z = 196.0 [M+H] + .

[0618] Step 3. Synthesis of 3-cyclopropyl-6-methyl-1H-pyrazolo[3,4-b]pyridine

[0619] A solution of (3-chloropyrazin-2-yl)(cyclopropyl)methanone (2.3 g, 12 mmol) in hydrazine hydrate (5 mL) was heated at 100° C. for 1.5 hours under microwave irradiation. After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane (20 mL×4). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5:1) to give the desired product (1.5 g, 70% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 12.89(s,1H),8.06(d,J=8.4Hz,1H),6.99(d,J=8Hz,1H),2.54(s,3H),2.23-2.21(m,1H),1.01-0.92(m,4H).MS(ESI)m / z=174.2[M+H] + .

[0620] The remaining steps were carried out according to the procedures of Step 4 of GS-648 and Steps 5-8 of GS-643 to give the desired product (7.4 mg, 2% yield over 5 steps) as a yellow solid. MS (ESI) m / z = 513.5 [M+H] + .

[0621] Example 34. 5-(((trans-3-(3-cyclopropyl-5-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-673)

[0622] [ka]

[0623] GS-673 was synthesized as a yellow solid (8.9 mg, 1% yield over 7 steps) following standard procedures for GS-672 (steps 1-3), GS-648 (step 4), and GS-643 (steps 5-8). MS(ESI) m / z = 513.5 [M+H] + .

[0624] Example 35. 5-(((trans-3-(3-cyclopropyl-6-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-674)

[0625] [ka]

[0626] GS-674 was synthesized as a yellow solid (22.3 mg, 5% yield over 7 steps) following the standard procedures for GS-672 steps 1-3, GS-648 step 4, and GS-643 steps 5-8. MS(ESI) m / z = 529.5 [M+H] + .

[0627] Example 36. 5-(((trans-3-(4-(1-(azetidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-675)

[0628] [ka]

[0629] Step 1. Synthesis of tert-butyl 3-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate

[0630] To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (3 g, 19.54 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (6.08 g, 21.49 mmol) in DMF (30 mL) was added CsCO (12.73 g, 39.07 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 12 h. After cooling to room temperature, the mixture was quenched with HO (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (1.7 g, 28% yield) as a yellow solid. MS (ESI) m / z = 309.2 [M+H] + .

[0631] The remaining steps were carried out according to the procedure of steps 2-9 of GS-665 to give the desired product (1.3 mg, 1% yield over 8 steps) as a yellow solid. MS (ESI) m / z = 620.5 [M+H] + .

[0632] Example 37. 3-(5-(((trans-3-(3-cyclopropyl-4-(5-fluoro-3-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GS-676)

[0633] [ka]

[0634] GS-676 was synthesized as a yellow solid (19 mg, 2% yield over 5 steps) following the procedure for GS-678, steps 1-4. MS (ESI) m / z = 543.7 [M+H] + .

[0635] Example 38. 3-(5-(((trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GS-677)

[0636] [ka]

[0637] Step 1. Synthesis of methyl trans-3-(4-(5-fluoro-6-methylpyridin-2-yl)-3-formyl-1H-pyrazol-1-yl)cyclobutane-1-carboxylate

[0638] To a solution of (3-formyl-1-(3-(methoxycarbonyl)cyclobutyl)-1H-pyrazol-4-yl)boronic acid (500 mg, 1.98 mmol) in dioxane (30 mL) and water (6 mL), 6-bromo-3-fluoro-2-methylpyridine (377 mg, 1.98 mmol), K2CO3 (820 mg, 5.95 mmol), and Pd(dppf)Cl2 (145 mg, 0.19 mmol) were added at room temperature. The reaction mixture was stirred at 90 °C under nitrogen for 2 h. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired trans isomer (180 mg, 28% yield) as a white solid. MS(ESI)m / z=318.4[M+H] + .

[0639] Step 2. Synthesis of methyl trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate

[0640] To a solution of methyl trans-3-(4-(5-fluoro-6-methylpyridin-2-yl)-3-formyl-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (180 mg, 0.57 mmol) in dichloromethane (10 mL) was added DAST (914 mg, 5.67 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 2 h, then quenched with aqueous NaHCO and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (150 mg, 78% yield) as a white solid. MS (ESI) m / z=340.4 [M+H] + .

[0641] Step 3. Synthesis of (trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol

[0642] To a solution of methyl trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (150 mg, 0.44 mmol) in THF (10 mL) was added LiAlH (34 mg, 0.88 mmol). The reaction mixture was stirred under nitrogen at 0 °C for 2 h and then carefully quenched with water and aqueous NaOH (1 N). The solid was filtered, and the filtrate was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the desired product (110 mg, 80% yield) as a colorless oil. MS (ESI) m / z = 312.4 [M+H] + .

[0643] Step 4. Synthesis of trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde

[0644] To a solution of (trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol (110 mg, 0.35 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (450 mg, 1.06 mmol). The reaction mixture was stirred at 30 °C for 4 h, then quenched with aqueous sodium bicarbonate and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na SO , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (60 mg, 55% yield) as a colorless oil. MS (ESI) m / z = 310.2 [M+H] + .

[0645] Step 5. Synthesis of 3-(5-(((trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0646] To a solution of trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde (60 mg, 0.19 mmol) in MeOH (5 mL) was added 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.19 mmol) and borane-2-picoline complex (41 mg, 0.38 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 5 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by reverse-phase chromatography to give the desired product (11 mg, 10% yield) as a white solid. MS(ESI) m / z=553.5[M+H] + .

[0647] Example 39. 3-(5-(((trans-3-(3-cyclopropyl-4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GS-678)

[0648] [ka]

[0649] Step 1. Synthesis of 6-(3-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridine

[0650] To a solution of 6-chloro-1-methyl-1H-pyrazolo[4,3-c]pyridine (3 g, 17.90 mmol) in dioxane (100 mL) and HO (20 mL), tert-butyl 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (8.97 g, 26.85 mmol), Pd(dppf)Cl (654.2 mg, 895.01 μmol), and KCO (4.94 g, 35.80 mmol) were added at room temperature. The reaction mixture was stirred at 100 °C under an inert atmosphere for 6 h. After cooling to room temperature, the mixture was poured into water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (2.5 g, 58% yield) as a pale white solid. MS (ESI) m / z = 240.4 [M+H] + .

[0651] Step 2. Synthesis of (trans-3-(3-cyclopropyl-4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol

[0652] To a solution of 6-(3-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridine (2.5 g, 10.45 mmol) in DMF (20 mL) was added 3-(hydroxymethyl)cyclobutyl 4-methylbenzenesulfonate (3.21 g, 12.54 mmol) and CsCO (6.81 g, 20.90 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was poured into water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (1.1 g, 33% yield) as a pale white solid. MS (ESI) m / z = 324.3 [M+H] + .

[0653] Step 3. Synthesis of trans-3-(3-cyclopropyl-4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde

[0654] To a solution of (trans-3-(3-cyclopropyl-4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol (500 mg, 1.55 mmol) in dichloromethane (15 mL) was added Dess-Martin periodinane (786.6 mg, 1.86 mmol) in three portions at 0° C. The reaction mixture was stirred at room temperature for 2 hours, then poured into water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (450 mg, 90% yield) as a pale white solid. MS (ESI) m / z=322.5 [M+H] + .

[0655] Step 4. Synthesis of 3-(5-(((trans-3-(3-cyclopropyl-4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0656] To a solution of trans-3-(3-cyclopropyl-4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde (150 mg, 0.466 mmol) in MeOH (10 mL) was added 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (181.51 mg, 0.70 mmol), AcOH (1 mL), and borane-2-picoline complex (86.8 mg, 0.70 mmol). 0.93 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 4 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (120 mg, 46% yield) as a white solid. MS (ESI) m / z = 565.4 [M+H] + .

[0657] Example 40. 5-(((trans-3-(3-cyclopropyl-4-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-679)

[0658] [ka]

[0659] GS-679 was synthesized as a yellow solid (5.8 mg, 1% yield over 7 steps) following the standard procedure for GS-672, step 2, GS-663, steps 2-3, GS-648, and steps 5-8. MS(ESI) m / z = 513.5 [M+H]. + .

[0660] Example 41. 5-(((trans-3-(3-cyclopropyl-4-(2-(1-methylazetidin-3-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-680)

[0661] [ka]

[0662] Step 1. Synthesis of tert-butyl 3-(6-chloro-2H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate

[0663] To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.0 g, 13.02 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (5.53 g, 19.54 mmol) in DMF (30 mL) was added CsCO (8.49 g, 26.05 mmol). The reaction mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (2.0 g, 50% yield) as a yellow solid. MS (ESI) m / z = 309.2 [M+H] + .

[0664] Step 2. Synthesis of 2-(azetidin-3-yl)-6-chloro-2H-pyrazolo[4,3-c]pyridine

[0665] To a solution of tert-butyl 3-(6-chloro-2H-pyrazolo[4,3-c]pyridin-2-yl)azetidine-1-carboxylate (1.0 g, 3.24 mmol) in DCM (10 mL) was added TFA (2 mL). The reaction mixture was stirred for 1 hour at 25° C. The mixture was concentrated in vacuo to give the desired product (670 mg, 99% yield) as a yellow oil. MS (ESI) m / z = 209.1 [M+H] + .

[0666] Step 3. Synthesis of 6-chloro-2-(1-methylazetidin-3-yl)-2H-pyrazolo[4,3-c]pyridine

[0667] To a solution of 2-(azetidin-3-yl)-6-chloro-2H-pyrazolo[4,3-c]pyridine (670 mg, 3.2 mmol), 2 drops of acetic acid, and formaldehyde solution (37 wt % in HO, 482.1 mg, 16.0 mmol) in methanol (10 mL) was added 2-picoline borane complex (687 mg, 6.4 mmol). The reaction mixture was stirred at 25 °C for 12 h. The mixture was quenched with HO (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (600 mg, 84% yield) as a white solid. MS (ESI) m / z = 223.1 [M+H] + .

[0668] Step 4. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(2-(1-methylazetidin-3-yl)pyrazolo[4,3-c]pyridin-6-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0669] To a solution of 6-chloro-2-(1-methylazetidin-3-yl)-2H-pyrazolo[4,3-c]pyridine (250 mg, 1.12 mmol), tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate (871.4 mg, 1.68 mmol), and KPO (476.6 mg, 2.25 mmol) in dioxane (10 mL) and HO (2 mL) was added XPhos Pd G (88.2 mg, 0.11 mmol). The reaction mixture was stirred at 90 °C for 12 h. After cooling to room temperature, the mixture was quenched with HO (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (150 mg, 23% yield) as a yellow oil. MS (ESI) m / z = 578.5 [M+H] + .

[0670] Step 5. Synthesis of (trans-3-(3-cyclopropyl-4-(2-(1-methylazetidin-3-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine

[0671] To a solution of tert-butyl N-tert-butoxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(2-(1-methylazetidin-3-yl)pyrazolo[4,3-c]pyridin-6-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate (150 mg, 0.26 mmol) in DCM (10 mL) was added TFA (2 mL). The reaction mixture was stirred for 1 h at 25 °C. The mixture was concentrated in vacuo to give the desired product (98 mg, 99% yield) as a yellow oil. MS (ESI) m / z = 378.4 [M+H] + .

[0672] Step 6. Synthesis of 5-(((trans-3-(3-cyclopropyl-4-(2-(1-methylazetidin-3-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0673] A mixture of (trans-3-(3-cyclopropyl-4-(2-(1-methylazetidin-3-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine (98 mg, 0.26 mmol), 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (73.2 mg, 0.26 mmol), and DIPEA (0.2 mL) in DMSO (1 mL) was heated at 130 °C for 30 min under microwave irradiation. After cooling to room temperature, the mixture was purified by reverse-phase chromatography to give the desired product (2.0 mg, 1% yield) as a yellow solid. MS (ESI) m / z = 634.5 [M+H] + .

[0674] Example 42. 5-(((trans-3-(3-cyclopropyl-4-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-681)

[0675] [ka]

[0676] Step 1. Synthesis of 4-chloro-3-iodo-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridine

[0677] To a mixture of 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (16 g, 57.3 mmol) and 4-methylbenzenesulfonic acid (1.97 g, 11.5 mmol) in dichloromethane (150 mL) was added 3,4-dihydro-2H-pyran (9.63 g, 114.6 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature, quenched with water (100 mL), and extracted with dichloromethane (100 × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give the desired product (5.1 g, 24% yield) as a colorless oil. MS (ESI) m / z = 364.1 [M+H] + .

[0678] Step 2. Synthesis of 4-chloro-3-cyclopropyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridine

[0679] A mixture of 4-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (5 g, 13.8 mmol), cyclopropylboronic acid (1.72 g, 20.7 mmol), Pd(OAc) (310.5 mg, 1.38 mmol), SPhos (1.13 g, 2.76 mmol), and KPO (8.8 g, 41.4 mmol) in toluene (40 mL) and HO (4 mL) was stirred at 95 °C under nitrogen for 12 h. After cooling to room temperature, the reaction mixture was quenched with HO (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10:1) to give the desired product (2.32 g, 61% yield) as a white solid. MS (ESI) m / z=278.1 [M+H] + .

[0680] Step 3. Synthesis of 3-cyclopropyl-4-methoxy-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridine

[0681] To a solution of 4-chloro-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (2.32 g, 8.38 mmol) in MeOH (20 mL) was added MeONa (2 M, 8.38 mL, 16.8 mmol) at room temperature. The reaction mixture was heated to reflux for 3.5 hours. The mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give the desired product (1.65 g, 72% yield) as a white solid. MS (ESI) m / z = 274.1 [M+H] + .

[0682] Step 4. Synthesis of 3-cyclopropyl-4-methoxy-1H-pyrazolo[3,4-b]pyridine

[0683] To a solution of 3-cyclopropyl-4-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (1.65 g, 6.04 mmol) in dichloromethane (15 mL) was added TFA (5 mL) at 0 °C. After stirring at room temperature for 1 hour, the reaction mixture was quenched with water (10 mL) and the pH was adjusted to 8 with saturated NaHCO . The mixture was extracted with dichloromethane (20 mL × 3). The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane / MeOH = 20:1) to give the desired product (977 mg, 85% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ 12.98(s,1H),8.30(d,J=5.6Hz,1H),6.65(d,J=5.6Hz,1H),4.00(s,3H),2.42-2.36(m,1H),0.97-0.89(m,4H). MS(ESI)m / z=190.1[M+H] + .

[0684] The remaining steps were carried out according to the procedures of Step 4 of GS-648 and Steps 5-8 of GS-643 to give the desired product (3.2 mg, 3% yield over 5 steps) as a yellow solid. MS (ESI) m / z = 529.4 [M+H] + .

[0685] Example 43. 5-(((trans-3-(3-cyclopropyl-5-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-682)

[0686] [ka]

[0687] Step 1. Synthesis of 5-bromo-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine

[0688] To a solution of 5-bromo-3-cyclopropyl-1H-pyrazolo[3,4-b]pyridine (4.12 g, 17.4 mmol) in DMF (30 mL) was added NaH (60% in oil, 695 mg, 17.4 mmol) at 0 °C. The reaction was stirred for 1 h at 0 °C, and then SEMCl (3.2 g, 19.1 mmol) was added dropwise. The resulting mixture was stirred for an additional 2 h at 0 °C, then quenched with HO (15 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give the desired product (5.7 g, 89% yield) as a white solid. MS (ESI) m / z = 368.1 [M+H] + .

[0689] Step 2. Synthesis of 3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-ol

[0690] To a solution of 5-bromo-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (5.7 g, 15.5 mmol), bis(pinacolato)diboron (7.87 g, 31 mmol) in dioxane (50 mL) was added KOAc (3.04 g, 31 mmol) and Pd(dppf)Cl (2.26 g, 3.1 mmol) at room temperature. The reaction mixture was stirred overnight at 80 °C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in MeOH (50 mL) and filtered. To the filtrate was added HO (20 mL), and the resulting solution was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (100 mL), washed with brine (50 mL), dried over NaSO, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=5:1) to give the desired product (2.88 g, 61% yield) as a white solid. MS (ESI) m / z=306.1 [M+H] + .

[0691] Step 3. Synthesis of 3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine

[0692] To a solution of 3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-ol (2.88 g, 9.44 mmol) in DMF (20 mL) was added MeI (1.60 g, 11.33 mmol) and K2CO3 (2.60 g, 18.88 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give the desired product (2.05 g, 68% yield) as a white solid. MS (ESI) m / z = 320.1 [M+H] +

[0693] Step 4. Synthesis of 3-cyclopropyl-5-methoxy-1H-pyrazolo[3,4-b]pyridine

[0694] To a stirred solution of 3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (2.05 g, 6.4 mmol) in EtOH (15 mL) was added HCl (3 N, 15 mL) at room temperature. The reaction mixture was stirred overnight at 80 °C. After cooling to room temperature, the reaction mixture was poured into water (15 mL) and the pH was adjusted to 8 with saturated NaHCO3. The mixture was extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane / methanol = 20:1) to give the desired product (750 mg, 63% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ 12.97(s,1H),8.23(d,J=2.8Hz,1H),7.71(d,J=2.8Hz,1H),3.86(s,3H),2.30-2.24(m,1H),1.00-0.92(m,4H).MS(ESI)m / z=190.1[M+H] + .

[0695] The remaining steps were carried out according to the procedures of Step 4 of GS-648 and Steps 5-8 of GS-643 to give the desired product (9.7 mg, 4% yield over 5 steps) as a yellow solid. MS (ESI) m / z = 529.4 [M+H] + .

[0696] Example 44. 5-(((trans-3-(3-cyclopropyl-4-(5-fluoro-3-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-683)

[0697] [ka]

[0698] Step 1. Synthesis of tert-butyl 4-(2-chloro-5-fluoropyridin-3-yl)piperazine-1-carboxylate

[0699] A mixture of 3-bromo-2-chloro-5-fluoropyridine (41.6 mg, 0.2 mmol), tert-butyl piperazine-1-carboxylate (37.23 mg, 0.2 mmol), Pd(dba) (18.3 mg, 0.02 mmol), and CsCO (195.6 mg, 0.6 mmol) in DMSO (3 mL) was stirred at 100 °C for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was concentrated, and the residue was purified by flash column chromatography to give the desired product (15.7 mg, 25% yield) as a white solid. MS (ESI) m / z = 315.8 [M+H] + .

[0700] Step 2. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate

[0701] A mixture of tert-butyl 4-(2-chloro-5-fluoropyridin-3-yl)piperazine-1-carboxylate (1 g, 3.2 mmol), tert-butyl 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.27 g, 3.8 mmol), Pd(PPh) (349.8 mg, 0.32 mmol), and KCO (1.33 g, 9.6 mmol) in 1,4-dioxane (10 mL) and HO (2 mL) was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was concentrated, and the residue was purified by flash column chromatography to give the desired product (300 mg, 24% yield) as a white solid. MS(ESI) m / z=387.4[M+H] + .

[0702] Step 3. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-(hydroxymethyl)cyclobutyl)-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate

[0703] To a solution of tert-butyl 4-(2-(3-cyclopropyl-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate (300 mg, 0.78 mmol) and 3-(hydroxymethyl)cyclobutyl 4-methylbenzenesulfonate (198 mg, 0.78 mmol) in DMSO (5 mL) was added CsCO (762.84 mg, 2.34 mmol). The reaction was stirred at 100 °C for 2 h, then cooled to room temperature and quenched with HO (100 mL). The mixture was extracted with EtOAc (30 mL × 3). The organic layers were combined, dried, and concentrated. The residue was purified by flash column chromatography to give the desired trans isomer (160 mg, 44% yield) as a white solid. MS (ESI) m / z = 471.7 [M+H] + .

[0704] Step 4. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-((tosyloxy)methyl)cyclobutyl)-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate

[0705] To a solution of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-(hydroxymethyl)cyclobutyl)-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate (160 mg, 0.34 mmol) and DMAP (4.14 mg, 0.034 mmol) in DCM (10 mL) was added TsCl (130 mg, 0.68 mmol) and TEA (171.7 mg, 1.7 mmol). The reaction was stirred at 25 °C for 1 h, then diluted with DCM (20 mL) and washed with HO and brine. The organic layer was concentrated, and the residue was purified by flash column chromatography to give the desired product (150 mg, yield: 70%) as a white solid. MS (ESI) m / z = 625.8 [M+H] + .

[0706] Step 5. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-((1,3-dioxoisoindolin-2-yl)methyl)cyclobutyl)-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate

[0707] A mixture of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-((tosyloxy)methyl)cyclobutyl)-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate (230 mg, 0.368 mmol) and potassium 1,3-dioxoisoindolin-2-ide (88.61 mg, 0.478 mmol) in DMSO (3 mL) was stirred at 70 °C for 1 h. The mixture was then diluted with DCM (10 mL) and washed with HO and brine. The organic layer was concentrated to give the desired product (130 mg, 59% yield) as a white solid. MS (ESI) m / z = 600.7 [M+H] + .

[0708] Step 6. Synthesis of tert-butyl 4-(2-(1-(trans-3-(aminomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate

[0709] A mixture of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-((1,3-dioxoisoindolin-2-yl)methyl)cyclobutyl)-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate (130 mg, 0.21 mmol) and N2H4 (3 mL, 80% in water) in EtOH (5 mL) was stirred at 80 °C for 1 h. Then the mixture was concentrated and the residue was purified by ISCO to give the desired product (60 mg, yield: 61%) as a white solid. MS (ESI) m / z = 470.7 [M+H] + .

[0710] Step 7. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)cyclobutyl)-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate

[0711] To a solution of tert-butyl 4-(2-(1-(trans-3-(aminomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate (130 mg, 0.29 mmol) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (118.99 mg, 0.43 mmol) in DMSO (2 mL) was added DIEA (371.2 mg, 2.9 mmol). The reaction was stirred in a microwave at 130° C. for 2 hours and then purified by ISCO on a C18 column to give the desired product (60 mg, 28% yield) as a yellow solid. MS (ESI) m / z=726.8 [M+H] + .

[0712] Step 8. Synthesis of 5-(((trans-3-(3-cyclopropyl-4-(5-fluoro-3-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0713] To a solution of tert-butyl 4-(2-(3-cyclopropyl-1-(trans-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)cyclobutyl)-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate (60 mg, 0.082 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by preparative HPLC to give the desired product (45 mg, yield: 88%) as a yellow solid. MS (ESI) m / z=626.8 [M+H] + .

[0714] Example 45. 5-(((trans-3-(3-cyclopropyl-4-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-684)

[0715] [ka]

[0716] Step 1. Synthesis of 5-(3-cyclopropyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

[0717] To a solution of 5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.1 mmol) in dioxane (10 mL) and water (2 mL) was added KCO (871 mg, 6.3 mmol), Pd(dppf)Cl (134 mg, 0.21 mmol), and tert-butyl 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (843 mg, 2.5 mmol). The mixture was stirred at 100 °C for 12 h under N and then purified by reverse-phase chromatography (CHCN / HO / TFA) to give the desired product (485 mg, 75% yield) as a brown solid.

[0718] Step 2. Synthesis of (trans-3-(3-cyclopropyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol

[0719] To a solution of 5-(3-cyclopropyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (485 mg, 1.57 mmol) in DMSO (5 mL) was added CsCO (1.5 g, 4.71 mmol) and [3-(hydroxymethyl)cyclobutyl]4-methylbenzenesulfonate (486 mg, 1.88 mmol). The mixture was stirred at 100 °C for 2.5 h under N. The mixture was poured into water and extracted with EtOAc (4x). The combined organic layers were washed with brine, dried, concentrated, and purified by silica gel flash chromatography to give the title compound (270 mg, yield: 44%) as a white solid. MS (ESI) m / z = 394.7 [M+H] + .

[0720] Step 3. Synthesis of (trans-3-(3-cyclopropyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl 4-methylbenzenesulfonate

[0721] To a solution of (trans-3-(3-cyclopropyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol (270 mg, 0.69 mmol) in DCM (8 mL) was added DMAP (84 mg, 0.69 mmol), TEA (209 mg, 2.07 mmol), and 4-methylbenzenesulfonyl chloride (331 mg, 1.72 mmol). The mixture was stirred at 25° C. for 2 h and then purified by silica gel flash chromatography to give the title compound (270 mg, 72% yield) as a white solid. MS (ESI) m / z=548.7 [M+H] + .

[0722] Step 4. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[[trans-3-[3-cyclopropyl-4-(1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-yl]pyrazol-1-yl]cyclobutyl]methyl]carbamate

[0723] To a solution of (trans-3-(3-cyclopropyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl 4-methylbenzenesulfonate (270 mg, 0.49 mmol) in DMSO (5 mL) was added CsCO (479 mg, 1.47 mmol) and tert-butyl N-tert-butoxycarbonylcarbamate (139 mg, 0.64 mmol). The mixture was stirred at 90 °C under N for 1.3 h and then purified by silica gel flash chromatography to give the title compound (250 mg, 86% yield) as a yellow solid. MS (ESI) m / z = 593.8 [M+H] + .

[0724] Step 5. Synthesis of (trans-3-(3-cyclopropyl-4-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine

[0725] A mixture of tert-butyl N-tert-butoxycarbonyl-N-[[trans-3-[3-cyclopropyl-4-(1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-yl]pyrazol-1-yl]cyclobutyl]methyl]carbamate (250 mg, 0.42 mmol) and TFA (1.5 mL) in DCM (3 mL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the desired product (120 mg, yield: 93%) as a white solid. MS (ESI) m / z = 309.4 [M+H] + .

[0726] Step 6. Synthesis of 5-(((trans-3-(3-cyclopropyl-4-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0727] A mixture of (trans-3-(3-cyclopropyl-4-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine (60 mg, 0.19 mmol), 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (54 mg, 0.19 mmol), and DIPEA (490 mg, 3.8 mmol) in DMSO (7 mL) was heated to 130 °C for 2.5 h under microwave heating. The mixture was purified by reverse-phase column purification (CHCN / HO / TFA) and preparative TLC (DCM:MeOH = 18:1) to give the title compound (25 mg, yield: 23%) as a yellow solid. MS (ESI) m / z = 565.37 [M+H] + .

[0728] Example 46. 5-((3-(trans-3-(3-cyclopropyl-4-(1,2,3,4-tetrahydro-1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutyl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-685)

[0729] [ka]

[0730] Step 1. Synthesis of 8-(3-cyclopropyl-1H-pyrazol-4-yl)-1,7-naphthyridine

[0731] To a solution of 8-chloro-1,7-naphthyridine (500 mg, 3.04 mmol) in dioxane (15 mL) and HO (5 mL) was added Pd(dppf)Cl (222.06 mg, 303.78 μmol), KCO (2.10 g, 15.19 mmol), and tert-butyl 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.12 g, 3.34 mmol). The mixture was stirred at 90 °C for 12 h under N. The mixture was poured into water and extracted with a mixed solvent (EtOAc:MeOH = 10:1). The organic layer was dried, concentrated, and purified by reverse-phase column chromatography (MeOH / HO / TFA) to give the desired product (348 mg, yield: 48%) as a black oil. MS(ESI) m / z=237.4[M+H] + .

[0732] Step 2. Synthesis of (trans-3-(3-cyclopropyl-4-(1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol

[0733] To a solution of 8-(3-cyclopropyl-1H-pyrazol-4-yl)-1,7-naphthyridine (348 mg, 1.47 mmol) in DMF (5 mL) was added 3-(hydroxymethyl)cyclobutyl 4-methylbenzenesulfonate (679.55 mg, 2.65 mmol) and CsCO (1.44 g, 4.42 mmol). The mixture was stirred at 90 °C for 6 h under N. The mixture was purified by reverse-phase column (MeOH / HO / TFA) and preparative TLC (DCM:MeOH = 12:1) to give the desired trans isomer (202 mg, 43% yield) as a white solid. MS (ESI) m / z = 321.6 [M+H] + .

[0734] Step 3. Synthesis of trans-3-(3-cyclopropyl-4-(1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde

[0735] To a solution of (trans-3-(3-cyclopropyl-4-(1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol (202 mg, 630.49 μmol) in DCM (5 mL) was added Dess-Martin reagent (534.83 mg, 1.26 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was filtered and the filter cake was washed with DCM and EtOAc. The solvent was evaporated in vacuo to give the title compound (190 mg, yield: 97%) as a crude brown oil. MS (ESI) m / z = 319.4 [M+H] + .

[0736] Step 4. Synthesis of (E)-3-(trans-3-(3-cyclopropyl-4-(1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutyl)acrylonitrile

[0737] To a solution of trans-3-(3-cyclopropyl-4-(1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde (200 mg, 628.20 μmol) in DCM (8 mL) was added 2-(triphenyl-phosphanylidene)acetonitrile (340.72 mg, 1.13 mmol). The mixture was stirred at room temperature for 0.5 h, and then the solvent was removed. The resulting residue was diluted with DMF and purified by reverse-phase column purification (CHCN / HO / TFA) to give the title compound (260 mg, yield: 91%) as a white solid. MS (ESI) m / z = 342.5 [M+H] + .

[0738] Step 5. Synthesis of 3-(trans-3-(3-cyclopropyl-4-(1,2,3,4-tetrahydro-1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutyl)propan-1-amine

[0739] To a solution of (E)-3-(trans-3-(3-cyclopropyl-4-(1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutyl)acrylonitrile (30 mg, 65.87 μmol) in MeOH (6 mL) was added NH3-MeOH (0.5 mL) and Raney nickel (60 mg). The reaction mixture was stirred at room temperature under H2 for 2 hours. The reaction solution was filtered and concentrated to give the title compound (20 mg, yield: 87%). MS (ESI) m / z = 352.6 [M+H] + .

[0740] Step 6. Synthesis of 5-((3-(trans-3-(3-cyclopropyl-4-(1,2,3,4-tetrahydro-1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutyl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0741] A mixture of 3-(trans-3-(3-cyclopropyl-4-(1,2,3,4-tetrahydro-1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutyl)propan-1-amine (19 mg, 0.054 mmol), 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (22 mg, 0.081 mmol) and DIPEA (139 mg, 1.08 mmol) in DMSO (0.5 mL) was heated to 130 °C for 2.5 hours under microwave heating. The mixture was purified by reverse phase column chromatography (CHCN / HO / TFA) to give the title compound (4.6 mg, yield: 14%) as a yellow solid.

[0742] Example 47. 5-(((trans-3-(3-cyclopropyl-4-(5-fluoro-3-(piperidin-4-yl)pyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,4-dioxocyclohexyl)isoindoline-1,3-dione (GS-686)

[0743] [ka]

[0744] Step 1. Synthesis of tert-butyl 2-chloro-5-fluoro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0745] A mixture of 3-bromo-2-chloro-5-fluoropyridine (1.0 g, 4.8 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.48 g, 4.8 mmol), Pd(dppf)Cl (350.9 mg, 0.48 mmol), and KCO (1.98 g, 14.44 mmol) in 1,4-dioxane (20 mL) and HO (4 mL) was stirred at 100 °C under N for 2 h. The reaction was diluted with EtOAc (40 mL) and HO (20 mL). The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated. The resulting residue was purified by flash column chromatography to give the desired product (1.25 g, 83% yield) as a white solid. MS(ESI) m / z=313.3[M+H] + .

[0746] Step 2. Synthesis of 2-chloro-5-fluoro-1',2',3',6'-tetrahydro-3,4'-bipyridine

[0747] To a solution of tert-butyl 2-chloro-5-fluoro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (1.4 g, 4.49 mmol) in DCM (20 mL) was added TFA (10 mL). The reaction was stirred at room temperature for 30 minutes and then concentrated to give the desired product (1.46 g, 95% yield) as a white solid. MS (ESI) m / z = 212.6 [M+H] + .

[0748] Step 3. Synthesis of benzyl 2-chloro-5-fluoro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0749] To a solution of 2-chloro-5-fluoro-1',2',3',6'-tetrahydro-3,4'-bipyridine (522.9 mg, 2.46 mmol) and TEA (3 mL) in DCM (10 mL) was added CbzCl (838.9 mg, 4.93 mmol) dropwise under a nitrogen atmosphere at 0 °C. The reaction was stirred at room temperature for 2 h and then concentrated. The residue was purified by flash column chromatography to give the desired product (700 mg, 82% yield) as a white solid. MS (ESI) m / z = 346.4 [M+H] + .

[0750] Step 4. Synthesis of benzyl 4-[2-[1-[trans-3-[[bis(tert-butoxycarbonyl)amino]methyl]cyclobutyl]-3-cyclopropyl-pyrazol-4-yl]-5-fluoro-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate

[0751] A mixture of benzyl 2-chloro-5-fluoro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (300 mg, 0.87 mmol), tert-butyl N-tert-butoxycarbonyl-N-[[trans-3-[3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclobutyl]methyl]carbamate (675.2 mg, 1.31 mmol), Pd(PPh) (100.53 mg, 0.087 mmol), and KCO (360.18 mg, 2.61 mmol) in 1,4-dioxane (10 mL) and HO (2.5 mL) was stirred at 100 °C for 15 h. The reaction mixture was diluted with EtOAc and washed with HO and brine. The organic layer was concentrated and the residue was purified by flash column chromatography to give the desired product (92 mg, 10% yield) as a white solid. MS (ESI) m / z = 702.8 [M+H] + .

[0752] Step 5. Synthesis of benzyl 2-(1-(trans-3-(aminomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)-5-fluoro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0753] To a solution of benzyl 4-[2-[1-[trans-3-[[bis(tert-butoxycarbonyl)amino]methyl]cyclobutyl]-3-cyclopropyl-pyrazol-4-yl]-5-fluoro-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate] (92 mg, 0.13 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction was stirred at 25 °C for 1 h and then concentrated to give the title compound (70 mg, 99% yield) as a white solid. MS (ESI) m / z = 502.8 [M+H] + .

[0754] Step 6. Synthesis of benzyl 2-(3-cyclopropyl-1-(trans-3-(((2-(2,4-dioxocyclohexyl)-1,3-dioxoisoindolin-5-yl)amino)methyl)cyclobutyl)-1H-pyrazol-4-yl)-5-fluoro-3',6'-dihydro-[...

Claims

1. Formula (IV) 【Chemistry 1】 A compound thereof, or a pharmaceutically acceptable salt thereof, During the ceremony, Z is -NR1a-, where R1a is hydrogen or C1-C4 alkyl. L is 【Chemistry 2】 And, Ring B is a 3- to 7-membered carbocyclyl that has been optionally substituted. L1 does not exist, and L2 is either C1-C4 alkylene, or L2 does not exist, and L1 is a C1-C4 alkylene. R 1 does not exist. R2 is a 3- to 10-membered carbocyclyl that has been optionally substituted. X 4 is CR 8a or N, X 5 is CR 8b or N, X 6 is CR 8d or N, A compound, or a pharmaceutically acceptable salt thereof, in which R 8a, R 8b, R 8c, R 8d, and R 8e are each independently hydrogen, a halogen, or a C1-C4 alkyl group.

2. (1) L1 does not exist, L2 is a C1-C2 alkylene, Is Z -NH- or (2) L2 does not exist, L1 is a C1-C2 alkylene, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is -NH-.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein ring B is cyclobutyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is cyclopropyl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X4 is N, X5 is CR8b, and X6 is CR8d.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R8b, R8c, R8d, and R8e are each independently hydrogen, F, or C1-C4 alkyl.

8. 3-(5-(((trans-3-(3-(difluoromethyl)-4-(5-fluoro-3-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-668), 3-(5-(((Trans-3-(3-cyclopropyl-4-(5-fluoro-3-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-676), 3-(5-(((Trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-677), 3-(5-(((Trans-3-(3-cyclopropyl-4-(5-fluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-731), (S)-3-(5-(((Trans-3-(3-cyclopropyl-4-(5-fluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-800), (R)-3-(5-(((Trans-3-(3-cyclopropyl-4-(5-fluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-801), 3-(5-(((Trans-3-(3-cyclopropyl-4-(6-(difluoromethyl)-5-fluoropyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-802), 3-(5-(((Trans-3-(4-(3-chloro-6-methylpyridine-2-yl)-3-cyclopropyl-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-805), 3-(5-(((Trans-3-(3-cyclopropyl-4-(3-fluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-807), 3-(5-(((Trans-3-(3-cyclopropyl-4-(3,5-difluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-809), 3-(5-(((Trans-3-(4-(3-chloro-5-fluoro-6-methylpyridine-2-yl)-3-cyclopropyl-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-812), (S)-3-(5-(((Trans-3-(3-cyclopropyl-4-(3-fluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-813), and The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is (R)-3-(5-(((trans-3-(3-cyclopropyl-4-(3-fluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-814).

9. The compound according to claim 1, which is 3-(5-(((trans-3-(3-cyclopropyl-4-(5-fluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-731), or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein (S)-3-(5-(((trans-3-(3-cyclopropyl-4-(5-fluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-800).

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein (R)-3-(5-(((trans-3-(3-cyclopropyl-4-(5-fluoro-6-methylpyridine-2-yl)-1H-pyrazole-1-yl)cyclobutyl)methyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (GS-801).

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

14. The pharmaceutical composition according to claim 12, further comprising a second therapeutic agent, the second therapeutic agent being an FLT3 pathway inhibitor selected from gilteritinib, midostaurin, sorafenib, sunitinib, restaurtinib, quizartinib, clenolanib, and citravatinib, or pharmaceutically acceptable salts thereof.

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