Compounds and methods for treating cancer

Abstract

The present invention relates to GSPT1 degrading agent compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods of making and using the compounds or salts in the treatment of certain diseases. The invention also relates to methods of identifying such compounds.

Description

Background Art

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

[0002] The present invention relates to compounds (eg, small molecule compounds), compositions containing one or more compounds, and methods of using the compounds to treat certain diseases in subjects in need thereof. The present invention also relates to methods of identifying or preparing the compounds.

[0003] In some embodiments, the present invention provides a method of treating a subject in need thereof, comprising administering 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, the present invention provides a compound of formula (A):

[0005]

[0006] or a pharmaceutically acceptable salt thereof, wherein:

[0007] W is hydrogen or fluorine;

[0008] Z does not exist, -NR 1a -, or -O-; wherein R 1a is hydrogen or C1-C8 alkyl;

[0009] L is an optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 heteroalkylene, or

[0010] L is in,

[0011] Ring B is an optionally substituted 3-7 membered carbocyclyl, or an optionally substituted 4-7 membered heterocyclyl;

[0012] L 1 Absent, or optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 heteroalkylene;

[0013] L 2 Absent, or optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkyne, or optionally substituted C1-C 10heteroalkylene;

[0014] R 1 is absent or oxo (=O);

[0015] R 2 and R 4 are 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;

[0016] 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,

[0017] R 2 and R 3 , or R 3 and R 4 together form an optionally substituted 3-7 membered partially saturated or unsaturated carbocyclyl, an optionally substituted 4-7 membered partially saturated or unsaturated heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl ring;

[0018] Each R 5 and R 6is 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,

[0019] R 5 and R 6 and together with the atoms to which they are attached, optionally form an optionally substituted 4-7 membered heterocyclyl, or an optionally substituted 5-6 membered heteroaryl ring.

[0020] In some embodiments, the present invention provides a compound of formula (I):

[0021]

[0022] or a pharmaceutically acceptable salt thereof, wherein:

[0023] Z does not exist, -NR 1a -, or -O-; wherein R 1a is hydrogen or C1-C8 alkyl;

[0024] L is an optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 heteroalkylene, or

[0025] L is in,

[0026] Ring B is an optionally substituted 3-7 membered carbocyclyl, or an optionally substituted 4-7 membered heterocyclyl;

[0027] L 1 Absent, or optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 heteroalkylene;

[0028] L 2 Absent, or optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkyne, or optionally substituted C1-C 10 heteroalkylene;

[0029] R 1is absent or oxo (=O);

[0030] R 2 and R 4 are 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;

[0031] 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,

[0032] R 2 and R 3 , or R 3 and R 4 together form an optionally substituted 3-7 membered partially saturated or unsaturated carbocyclyl, an optionally substituted 4-7 membered partially saturated or unsaturated heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl ring;

[0033] Each R 5 and R 6is 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,

[0034] R 5 and R 6 and together with the atoms to which they are attached, optionally form an optionally substituted 4-7 membered heterocyclyl, or an optionally substituted 5-6 membered heteroaryl.

[0035] In some embodiments of Formula (I), R 2 and R 3 Together they form an optionally substituted phenyl group, or an optionally substituted 5-6 membered heteroaryl ring.

[0036] In some embodiments of Formula (I), R 3 and R 4 Together they form an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl ring. In some such embodiments, R 3 and R 4 Together they form Ring A and provide the structure of Formula (II).

[0037] In some embodiments, the compound of formula (I) has the structure shown in formula (II):

[0038]

[0039] or a pharmaceutically acceptable salt thereof, wherein:

[0040] R 1 、R 2 , L and Z are as defined in formula (I);

[0041] Ring A is phenyl or a 5-6 membered heteroaryl group;

[0042] Each R 11 are independently hydrogen, halogen, CN, NO2, OR 5 SR 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

[0043] p1 is 0, 1, 2, 3, or 4.

[0044] In some embodiments, the compound of formula (I) has the structure shown in formula (III):

[0045]

[0046] or a pharmaceutically acceptable salt thereof, wherein:

[0047] R 1 、R 2 , L and Z are as defined in formula (I);

[0048] X 4 、X 5 and X 6 Each independently CR 8 or N;

[0049] Each R 8 are independently hydrogen, halogen, CN, NO2, OR 5 SR 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,

[0050] Two R on adjacent carbon atoms 8 together form an optionally substituted partially unsaturated 3-7 membered carbocyclyl, an optionally substituted partially unsaturated 4-7 membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl; and

[0051] p2 is 0, 1, 2, 3, 4, or 5.

[0052] In some embodiments, the compound of formula (I) has the structure shown in formula (IV):

[0053]

[0054] or a pharmaceutically acceptable salt thereof, wherein:

[0055] R 1 、R 2 , L and Z are as defined in formula (I);

[0056] X 4 CR 8a or N;

[0057] X 5 CR 8b or N;

[0058] X 6 CR 8d or N;

[0059] R 8a 、R 8b 、R 8c 、R 8d and R 8e are independently hydrogen, halogen, CN, NO2, OR 5 SR 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,

[0060] R 8a and R 8b 、R 8b and R 8c 、R 8c and R 8d , or R 8d and R 8e and together with the atoms to which they are attached form an optionally substituted 3-7 membered carbocyclyl, an optionally substituted 4-7 membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl.

[0061] In another aspect, the present invention provides a pharmaceutical composition comprising a compound represented by any chemical formula described in the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0062] On the other hand, the present invention provides a method of treatment comprising administering to a subject in need thereof an effective amount of a compound represented by any of the chemical formulas described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt described herein. In some embodiments, the subject suffers from cancer. In some embodiments, the method further comprises administering to the 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 method further comprises administering to the subject a second compound comprising a chemotherapeutic agent. Other aspects and advantages of the present disclosure will become apparent to those skilled in the art through the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. It should be recognized that the present disclosure may have other and different embodiments, and that several of its details may be modified in various obvious aspects, all without departing from the present disclosure. Accordingly, the drawings and description should be considered illustrative rather than restrictive.

[0063] Incorporation by reference

[0064] All publications, patents, and patent applications mentioned in this specification are incorporated herein 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. If a publication, patent, or patent application incorporated by reference contradicts the disclosure in this specification, this specification is intended to supersede and / or take precedence over any such contradictory material.

[0065] BRIEF DESCRIPTION OF THE DRAWINGS

[0066] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the invention may be obtained by reference to the following detailed description, which sets forth illustrative embodiments in which the principles of the invention are utilized, and the accompanying drawings:

[0067] Figures 1A-1B Small molecule-mediated targeted degradation of GSPT1 is shown. MOLM-13 cells were treated with the indicated concentrations of compounds GS-729, GS-731, GS-697, and GS-788 for 16 hours prior to immunoblotting.

[0068] Figures 2A-2C FLT3 inhibition was shown to sensitize AML cells to the GSPT1 degraders GS-707, GS-749, and GS-750. MOLM-13 cells were treated with the indicated concentrations of GSPT1 degraders after 3-fold serial dilutions in the presence or absence of 20 nM gilteritinib for 3 days.

[0069] Figure 3 The pancreatic cell line KP-4 was shown to be sensitive to the GSPT1 degraders GS-668, GS-676, and GS-766. KP-4 cells were treated with the indicated concentrations of GSPT1 degraders after 3-fold serial dilution for 3 days.

[0070] Figures 4A-4B GSPT1 degraders were shown to reduce GSPT1 protein levels in xenograft tumors. Figure 4A ) nude mice bearing MOLM-13 xenograft tumors or ( Figure 4B Nude mice bearing 22RV1 xenograft tumors were orally administered 30 mg / kg of a GSPT1 degrader or vehicle. Tumors were harvested for immunoblot analysis.

[0071] Figure 5 Small molecule-mediated targeted degradation of GSPT1 is shown. MOLM-13 cells were treated with compounds GS-802 and GS-803 at the indicated concentrations for 16 hours before immunoblotting.

[0072] Figure 6 Small molecule-mediated targeted degradation of GSPT1 is shown. 22RV1 cells were treated with compounds GS-807, GS-813, and GS-814 at the indicated concentrations for 8 hours prior to immunoblotting. Specific embodiments

[0073] Translation termination is a GTP-dependent process regulated by two key proteins, eRF1 and eRF3. The translation termination factor eRF3a (also known as the eukaryotic peptide 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 complexing 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. GSPT1 activates eRF1 in a GTP-dependent manner, and its GTPase activity requires complexing with eRF1 and the ribosome (Frolova, Le Goff et al., 1996). Through translation regulation, GSPT1 plays a variety of important roles in cellular physiology. GSPT1 expression is increased in human lung and gastric cancers, among other malignancies (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 tumor target through which active translation, which contributes to the malignant phenotype of cancer cells, may be disrupted. Recently, Matyskiela and colleagues reported that a 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 is degraded by a series of heterobifunctional compounds derived from phthalimide (Ishoey, Chorn et al., 2018). CC-885 induced significant toxicity in the vast majority of cell lines tested, likely due to degradation of GSPT1 and numerous other proteins (Matyskiela, Lu et al., 2016). Therefore, despite its broad and potent anticancer activity, CC-885 exhibits unacceptable toxicity, hindering further development (Hansen, Correa et al., 2020).

[0074] In one aspect, the present invention discloses compounds. In some embodiments, the compounds include chemical structures or formulas disclosed herein. The compounds include GSPT1 degraders. The GSPT1 degraders are characterized by being able to degrade or reduce cellular protein levels of GSPT1.

[0075] Although various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Numerous variations, modifications, and substitutions may occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be employed.

[0076] I. Compounds of the Present Invention

[0077] In some embodiments, disclosed herein are compounds. In some embodiments, the compound comprises a degradation tag. In some embodiments, the compound comprises a cereblon binding portion. In some embodiments, the degradation tag comprises a cereblon binding portion. In some embodiments, the compound comprises a GSPT1 degrader. For example, the compound can cause GSPT1 degradation. Due to the regulation of cereblon by the degradation tag, the compound can degrade GSPT1. The compound can bind to or regulate GSPT1 or cereblon. In some embodiments, the compound comprises a heterobifunctional compound. In some embodiments, the compound comprises a molecular glue. In some embodiments, the compound is used as a molecular glue. In some embodiments, the compound comprises a linker. In some embodiments, the compound comprises a truncated Janus kinase (JAK) binding portion.

[0078] In one aspect, provided herein are compounds of formula (A):

[0079]

[0080] or a pharmaceutically acceptable salt thereof, wherein:

[0081] W is hydrogen or fluorine;

[0082] Z does not exist, -NR 1a -, or -O-; wherein R 1a is hydrogen or C1-C8 alkyl;

[0083] L is an optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 heteroalkylene, or

[0084] L is wherein Ring B is an optionally substituted 3-7 membered carbocyclic group, or an optionally substituted 4-7 membered heterocyclic group;

[0085] L 1 Absent, or optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10heteroalkylene;

[0086] L 2 Absent, or optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkyne, or optionally substituted C1-C 10 heteroalkylene;

[0087] R 1 is absent or oxo (=O);

[0088] R 2 and R 4 are 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;

[0089] 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,

[0090] R 2 and R 3 , or R 3 and R 4 together form an optionally substituted 3-7 membered partially saturated or unsaturated carbocyclyl, an optionally substituted 4-7 membered partially saturated or unsaturated heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl;

[0091] Each R 5and R 6 is 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,

[0092] R 5 and R 6 and together with the atoms to which they are attached, optionally form an optionally substituted 4-7 membered heterocyclyl, or an optionally substituted 5-6 membered heteroaryl.

[0093] In some embodiments of Formula (A), W is hydrogen. In some embodiments of Formula (A), W is fluoro.

[0094] In another aspect, provided herein are compounds of formula (I):

[0095]

[0096] or a pharmaceutically acceptable salt thereof, wherein:

[0097] Z does not exist, -NR 1a -, or -O-; wherein R 1a is hydrogen or C1-C8 alkyl;

[0098] L is an optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 heteroalkylene, or

[0099] L is wherein Ring B is an optionally substituted 3-7 membered carbocyclic group, or an optionally substituted 4-7 membered heterocyclic group;

[0100] L 1 Absent, or optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 heteroalkylene;

[0101] L 2 Absent, or optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkyne, or optionally substituted C1-C10 heteroalkylene;

[0102] R 1 is absent or oxo (=O);

[0103] R 2 and R 4 are 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;

[0104] 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 3-10 membered carbocyclyl, or optionally substituted saturated or partially unsaturated 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; or,

[0105] R 2 and R 3 , or R 3 and R 4 together form an optionally substituted partially unsaturated 3-7 membered carbocyclyl, an optionally substituted partially unsaturated 4-7 membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl;

[0106] Each R 5 and R 6is 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,

[0107] R 5 and R 6 and together with the atoms to which they are attached, optionally form an optionally substituted 4-7 membered heterocyclyl, or an optionally substituted 5-6 membered heteroaryl.

[0108] In some embodiments of Formula (A) or Formula (I), R 2 and R 3 Together they form an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2 and R 3 Together they form an optionally substituted phenyl group. In some embodiments, R 2 and R 3 Together they form an optionally substituted 5-6 membered heteroaryl. 2 and R 3 Together they form an optionally substituted 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from N and O. In some embodiments, the 6-membered heteroaryl group is pyridinyl or triazinyl. In some embodiments, the 6-membered heteroaryl group is pyridinyl.

[0109] In some such embodiments, R 2 and R 3 Together they form an optionally substituted partially unsaturated 3-7 membered carbocyclyl. In some such embodiments, R 2 and R 3 Together they form an optionally substituted partially unsaturated 4-7 membered heterocyclyl group comprising 1 to 3 heteroatoms selected from N, O and S. In some such embodiments, R 2 and R 3 Together they form an optionally substituted partially unsaturated 3-7 membered carbocyclyl. 2 and R 3 Together they form an optionally substituted partially unsaturated 4-7 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O and S.

[0110] In some embodiments of Formula (A) or Formula (I), R3 and R 4 Together they form an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 3 and R 4 Together they form an optionally substituted phenyl group. In some embodiments, R 3 and R 4 Together they form an optionally substituted 5-6 membered heteroaryl. 3 and R 4 Together they form an optionally substituted 6-membered heteroaryl. In some embodiments, the 6-membered heteroaryl includes 1 to 3 heteroatoms selected from N and O. In some embodiments, the 6-membered heteroaryl is pyridyl or triazinyl. In some embodiments, the 6-membered heteroaryl is pyrimidinyl, pyrazinyl, or pyridazinyl.

[0111] In some such embodiments, R 3 and R 4 Together they form an optionally substituted partially unsaturated 3-7 membered carbocyclyl. 3 and R 4 Together they form an optionally substituted partially unsaturated 4-7 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O and S.

[0112] The embodiments described herein for Formula (A) or Formula (I) also apply to any of Formulas (II), (III), or (IV) (including (II-A), (IV-A), (IV-B), (IV-C), or (IV-D) for clarity), provided there are no inconsistencies in these embodiments.

[0113] In some embodiments of Formula (I), when R 3 and R 4 When taken together to form an optionally substituted phenyl group or an optionally substituted 5- to 6-membered heteroaromatic ring, the ring corresponds to Ring A in the compound of formula (II).

[0114] In some embodiments, the compound of formula (I) has the structure shown in formula (II):

[0115]

[0116] or a pharmaceutically acceptable salt thereof, wherein:

[0117] R 1 、R 2 , L and Z are as defined in formula (I);

[0118] Ring A is phenyl or a 5-6 membered heteroaryl group;

[0119] Each R 11are independently hydrogen, halogen, CN, NO2, OR 5 SR 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

[0120] p1 is 0, 1, 2, 3, or 4;

[0121] In some embodiments of Formula (II), Ring A is phenyl, pyridyl, or triazinyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyridyl. 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.

[0122] The embodiments described herein for Formula (II) also apply to Formula (II-A) to the extent there is no inconsistency between these embodiments.

[0123] In some embodiments, the compound of formula (II) has the structure shown in formula (II-A):

[0124]

[0125] or a pharmaceutically acceptable salt thereof, wherein:

[0126] R 1 、R 2 , L and Z are as defined in formula (I); and

[0127] X 1 、X 2 and X 3 Each independently CR 11 or N.

[0128] In some embodiments of Formula (II-A), X 1 、X 2 and X 3 Each independently CR 11 .

[0129] In some embodiments of Formula (II-A), X1 、X 2 and X 3 Each is independently N.

[0130] In some embodiments of Formula (II-A), X 1 is N; and X 2 and X 3 Each independently CR 11 .

[0131] In some embodiments of Formula (II-A), X 1 and X 2 Each is N; and X 3 CR 11 .

[0132] In some embodiments of Formula (II-A), X 1 and X 3 Each is N; and X 2 CR 11 .

[0133] In some such embodiments, each R 11 are independently hydrogen, halogen, CN, NO2, OR 5 SR 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. In some embodiments, each R 11 R is independently hydrogen, halogen, or optionally substituted C1-C8 alkyl. 11 are independently hydrogen. In some embodiments, each R 11 R is independently methyl, ethyl, n-propyl, isopropyl, or tert-butyl. 11 In some embodiments, each R 11 R is independently an optionally substituted 3-10 membered carbocyclyl, or an optionally substituted 3-10 membered heterocyclyl. 11 R is independently optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. 11 R is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 11R is independently oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, or piperazine. 11 R is independently H, Cl, F, Br, CN, NO2, OH, OCH3, methyl, ethyl, or isopropyl. 11 R is independently H, Cl, F, Br, CN, NO2, NH2, OH, OCH3, methyl, ethyl, or isopropyl. 11 R is independently H, Cl, F, Br, OH, OCH3, methyl, or isopropyl. 11 R is independently H, Cl, F, Br, NH2, OH, OCH3, methyl, or isopropyl. 11 In some embodiments, each R 11 N(R 5 )R 6 In some embodiments, each R 11 is NH2. In some embodiments, each R 11 N(R 5 )R 6 , where R 5 and R 6 and together with the nitrogen to which they are attached form a 3-10 membered heterocyclyl. In some embodiments, each R 11 N(R 5 )R 6 , where R 5 and R 6 and together with the N to which they are attached form piperazine.

[0134] In some embodiments of Formula (A) or Formula (I), R 3 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 3-10 membered carbocyclyl, or optionally substituted saturated or partially unsaturated 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0135] In some such embodiments, R3 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. 3 is an optionally substituted phenyl or an optionally substituted 6-10 membered heteroaryl. 3 In some embodiments, R 3 is an optionally substituted 5-10 membered heteroaryl. 3 is an optionally substituted 6-10 membered heteroaryl. 3 is a substituted 6-10 membered heteroaryl. In some such embodiments, the 6-10 membered heteroaryl is selected from pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, benzofuroyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. In some such embodiments, the 6-10 membered heteroaryl is pyridyl, pyrimidinyl or pyrazinyl. In some such embodiments, the 6-10 membered heteroaryl is pyridyl. 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.

[0136] In some embodiments of Formula (A) or Formula (I), R 3 For hydrogen.

[0137] 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), R 3 In some embodiments of Formula (A) or Formula (I), R 3 It is benzyl.

[0138] In some embodiments of Formula (A) or Formula (I), R 3 is an optionally substituted 3-10 membered carbocyclyl. In some embodiments of Formula (A) or Formula (I), R 3 is optionally substituted In some embodiments of Formula (A) or Formula (I), R 3 for In some embodiments of Formula (A) or Formula (I), R 3 for

[0139] In some such embodiments, R 3 N(R 5 )R 6 In some embodiments, R 3 NHR 6 In some embodiments, R 3 NHR 6 , where R 6 is an optionally substituted 3-10 membered carbocyclyl. 3 is optionally substituted In some such embodiments, R 3 for In some embodiments, R 3 NHR 6 , where R 6 is an optionally substituted 3-10 membered heterocyclyl. 3 NHR 6 , where R 6 is an optionally substituted 6-membered heterocyclic group. 3 is optionally substituted In some embodiments, R 3 is optionally substituted In some embodiments, R 3 for In some embodiments, R 3 NHR 6 , where R 6 is an optionally substituted 6-10 membered aryl. 3 NHR 6 , where R 6 is an optionally substituted phenyl. 3 NHR 6 , where R 6 is an optionally substituted 5-10 membered heteroaryl. 3 NHR 6 , where R6 is an optionally substituted 5- or 6-membered heteroaryl. 3 NHR 6 , where R 6 is an optionally substituted 5- or 6-membered heteroaryl group comprising 1, 2, or 3 nitrogen atoms. 3 NHR 6 , where R 6 is an optionally substituted 5-membered heteroaryl. 3 is optionally substituted In some embodiments, R 3 for In some embodiments, R 3 NHR 6 , where R 6 is an optionally substituted 6-membered heteroaryl. 3 is optionally substituted In some embodiments, R 3 is optionally substituted In some embodiments, R 3 is optionally substituted

[0140] In some embodiments of Formula (A) or Formula (I), R 4 For hydrogen, halogen, CN, NO2, OR 5 SR 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. In some embodiments, R 4 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. In some embodiments, R 4 is hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl. 4 is methyl, ethyl, n-propyl, isopropyl, or tert-butyl. 4 In some embodiments, R 4In some embodiments, R 4 is an optionally substituted 3-10 membered carbocyclyl. 4 is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 N(R 5 )R 6 In some embodiments, R 4 NHR 6 In some embodiments, R 4 NHR 6 , where R 6 is an optionally substituted 6-10 membered aryl. 4 is NH(optionally substituted phenyl). In some embodiments, R 4 is NH (phenyl). In some embodiments, R 4 is an optionally substituted C1-C8 haloalkyl. 4 For CHF2.

[0141] In some such embodiments, R 4 For hydrogen.

[0142] In some such embodiments, R 4 is hydrogen; and R 3 N(R 5 )R 6 , an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 6-10 membered aryl, or an optionally substituted 5-10 membered heteroaryl.

[0143] In some such embodiments, R 4 is hydrogen; and R 3 is an optionally substituted phenyl, or an 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 an optionally substituted quinoxalinyl, naphthyridinyl, pyrazolopyridinyl, imidazopyridinyl or pyrrolopyridinyl. In some such embodiments, R4 is hydrogen; and R 3 is an optionally substituted quinoxalinyl. In some such embodiments, R 4 is hydrogen; and R 3 is an optionally substituted naphthyridinyl. In some such embodiments, R 4 is hydrogen; and R 3 is an optionally substituted pyrazolopyridinyl. In some such embodiments, R 4 is hydrogen; and R 3 is an optionally substituted imidazopyridinyl. In some such embodiments, R 4 is hydrogen; and R 3 is an optionally substituted pyrrolopyridinyl group.

[0144] In some embodiments of Formula (A) or Formula (I), each R 5 and R 6 and 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.

[0145] In some embodiments of Formula (A) or Formula (I), R 5 and R 6 and together with the atoms to which they are attached, optionally form an optionally substituted 4-7 membered heterocyclyl, or an optionally substituted 5-6 membered heteroaryl.

[0146] In one embodiment, the compound of formula (I) has the structure shown in formula (III):

[0147]

[0148] or a pharmaceutically acceptable salt thereof, wherein:

[0149] R 1 、R 2 , L and Z are as defined in formula (I);

[0150] X 4 、X 5 and X 6 Each independently CR 8 or N;

[0151] Each R 8 are independently hydrogen, halogen, CN, NO2, OR 5 SR 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

[0152] Two R on adjacent carbon atoms 8 together form an optionally substituted partially unsaturated 3-7 membered carbocyclyl, an optionally substituted partially unsaturated 4-7 membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5-6 membered heteroaryl; and

[0153] p2 is 0, 1, 2, 3, 4, or 5.

[0154] In some embodiments of Formula (III), X 4 、X 5 and X 6 Each independently CR 8 In some embodiments, X 4 、X 5 and X 6 Each is independently N.

[0155] In some embodiments of Formula (III), X 4 is N; and X 5 and X 6 Each independently CR 8 .

[0156] In some embodiments of Formula (III), X 5 is N; and X 4 and X 6 Each independently CR 8 .

[0157] In some embodiments of Formula (III), X 6 is N; and X 4 and X 5 Each independently CR 8 .

[0158] In some embodiments of Formula (III), X 4 CR8 ; and X 5 and X 6 Each is independently N.

[0159] In some embodiments of Formula (III), X 5 CR 8 ; and X 4 and X 6 Each is independently N.

[0160] In some embodiments of Formula (III), X 6 CR 8 ; and X 4 and X 5 Each is independently N.

[0161] 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.

[0162] In some embodiments of Formula (III), each R 8 are independently hydrogen, halogen, CN, NO2, OR 5 SR 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. In some embodiments, each R 8 R is independently hydrogen, halogen, or optionally substituted C1-C8 alkyl. 8 are independently hydrogen, halogen, or C1-C4 alkyl. 8 R is independently methyl, ethyl, n-propyl, isopropyl, or tert-butyl. 8 R is independently hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, or tert-butyl. 8 R is independently an optionally substituted 3-10 membered carbocyclyl, or an optionally substituted 3-10 membered heterocyclyl. 8 R is independently optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. 8R is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 8 R is independently oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, or piperazine. 8 R is independently H, Cl, F, Br, CN, NO2, OH, OCH3, methyl, ethyl, or isopropyl. 8 Independently OR 5 、N(R 5 )R 6 , or optionally substituted C1-C8 haloalkyl. In some embodiments, each R 8 are independently cyclopropyloxy, amino, methylamino, dimethylamino, CHF2 or CF3.

[0163] In some such embodiments, each R 8 is independently halogen. In some such embodiments, each R 8 is independently F. In some embodiments, each R 8 are independently Cl.

[0164] In some such embodiments, each R 8 is independently an optionally substituted C1-C8 alkyl. In some such embodiments, each R 8 is independently an optionally substituted C1-C3 alkyl. In some such embodiments, each R 8 is independently C1-C3 haloalkyl. In some such embodiments, each R 8 are independently CH3. In some such embodiments, each R 8 is independently CHF2. In some such embodiments, each R 8 is independently CF3.

[0165] In some such embodiments, each R 8 is independently an optionally substituted 3-10 membered carbocyclyl. 8 R is independently optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. 8 is independently optionally substituted cyclobutyl. In some embodiments, each R 8 Independently

[0166] In some such embodiments, each R 8 is independently an optionally substituted 3-10 membered heterocyclyl. In some such embodiments, each R8 is independently an optionally substituted 3-10 membered heterocyclyl including 1 or 2 nitrogen atoms. 8 is independently an optionally substituted 3-10 membered heterocyclyl including 1 nitrogen. In some such embodiments, each R 8 is independently an optionally substituted 4-, 5-, or 6-membered heterocyclyl. 8 Independently In some embodiments, each R 8 Independently

[0167] In some embodiments, each R 8 Independently OR 5 In some such embodiments, R 5 is hydrogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl. 5 is an optionally substituted 3-10 membered carbocyclyl. In some such embodiments, R 5 is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. 8 Independently

[0168] In some such embodiments, each R 8 are independently N(R 5 )R 6 In some such embodiments, each R 8 is independently NH2. In some such embodiments, each R 8 is independently -NHCH3. In some such embodiments, each R 8 is independently -N(CH3)2. In some such embodiments, R 5 and R 6 and together with the nitrogen to which they are attached form an optionally substituted 4-7 membered heterocyclyl. In some such embodiments, R 5 and R 6 and together with the nitrogen to which they are attached form an optionally substituted 4-7 membered heterocyclyl comprising 1 to 3 heteroatoms. In some such embodiments, R 5 and R 6 and together with the nitrogen to which they are attached form an optionally substituted 4-7 membered heterocyclyl including 1 nitrogen. In some such embodiments, R 5 and R 6and together with the nitrogen to which they are attached form an optionally substituted 4-7 membered heterocyclyl including 2 nitrogens. In some such embodiments, R 5 and R 6 and together with the nitrogen to which they are attached form an optionally substituted 4, 5 or 6 membered heterocyclyl. 8 Independently In some embodiments, each R 8 Independently In some embodiments, each R 8 Independently In some embodiments, each R 8 Independently In some such embodiments, two R 8 Together they form an optionally substituted partially unsaturated 3-7 membered carbocyclyl, an optionally substituted partially unsaturated 4-7 membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl. In some embodiments, two R on adjacent carbon atoms 8 Together they form an optionally substituted phenyl group.

[0169] In some such embodiments, the two R 8 Together they form an optionally substituted partially unsaturated 3-7 membered carbocyclyl. In some such embodiments, two R on adjacent carbon atoms 8 Together they form an optionally substituted 5-membered carbocyclyl. In some such embodiments, two R on adjacent carbon atoms 8 Together they form a 5-membered carbocyclyl substituted with hydroxy. In some such embodiments, two R on adjacent carbon atoms 8 Formed together

[0170] In some such embodiments, two R 8 Together they form an optionally substituted partially unsaturated 4-7 membered heterocyclyl. In some such embodiments, two R on adjacent carbon atoms 8 Together they form an optionally substituted 6-membered heterocyclyl. In some such embodiments, two R on adjacent carbon atoms 8 Together they form an optionally substituted 6-membered heterocyclyl including 1 or 2 nitrogen atoms. In some such embodiments, two R 8 Together they form an optionally substituted 6-membered heterocyclyl including 1 nitrogen. In some such embodiments, two R on adjacent carbon atoms 8 Together to form optionally substituted In some such embodiments, two R 8 Formed together

[0171] In some embodiments, two R 8 In some embodiments, two R on adjacent carbon atoms 8 In some embodiments, two R on adjacent carbon atoms 8 Together to form In some embodiments, two R 8 Together to form In some embodiments, two R 8 Together to form In some embodiments, two R 8 Together to form In some embodiments, two R 8 Together to form In some embodiments, two R 8 Together to form In some embodiments, two R 8 Together to form In some embodiments, two R 8 Together to form In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together

[0172] In some embodiments, two R 8 Together they form an optionally substituted 5-membered heteroaryl. In some embodiments, two R 8 Together they form an optionally substituted 5-membered heteroaryl group comprising 1 to 3 nitrogen atoms. In some embodiments, two R 8 Together they form an optionally substituted 5-membered heteroaryl group including one nitrogen atom. In some embodiments, two R 8 Together they form an optionally substituted 5-membered heteroaryl group comprising two nitrogen atoms. In some embodiments, two R 8 Together they form an optionally substituted 5-membered heteroaryl group comprising 3 nitrogen atoms. In some embodiments, two R 8 Together they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is substituted with methyl. In some embodiments, two R 8 Together they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is substituted by isopropyl. In some embodiments, two R 8 Together, they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is In some embodiments, two R on adjacent carbon atoms 8 Together, they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is In some embodiments, two R on adjacent carbon atoms 8 Together, they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is In some embodiments, two R on adjacent carbon atoms 8 Together, they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is In some embodiments, two R on adjacent carbon atoms 8 Together, they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is In some embodiments, two R on adjacent carbon atoms 8 Together, they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is In some embodiments, two R on adjacent carbon atoms 8 Together, they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is In some embodiments, two R on adjacent carbon atoms 8 Together, they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is In some embodiments, two R on adjacent carbon atoms 8 Together, they form a substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is In some embodiments, two R on adjacent carbon atoms 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R 8 Formed together In some embodiments, two R8 Formed together In some embodiments, two R 8 Formed together

[0173] In some embodiments, two R 8 Together they form an optionally substituted 6-membered heteroaryl. In some embodiments, two R 8 Together they form an optionally substituted 6-membered heteroaryl group comprising 1 to 3 nitrogen atoms. In some embodiments, two R 8 Together they form an optionally substituted 6-membered heteroaryl group comprising 1 or 2 nitrogen atoms. In some embodiments, two R 8 Together they form an optionally substituted 6-membered heteroaryl group (i.e., pyridinyl) including one nitrogen atom. In some embodiments, two R 8 Together to form optionally substituted

[0174] In some embodiments, the compound of formula (I) has the structure shown in formula (IV):

[0175]

[0176] or a pharmaceutically acceptable salt thereof, wherein:

[0177] R 1 、R 2 , L and Z are as defined in formula (I);

[0178] X 4 CR 8a or N;

[0179] X 5 CR 8b or N;

[0180] X 6 CR 8d or N;

[0181] R 8a 、R 8b 、R 8c 、R 8d and R 8e are independently hydrogen, halogen, CN, NO2, OR 5 SR 5 、N(R 5 )R 6 、C(O)R 5 、C(O)OR 5 、C(O)N(R5 )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,

[0182] R 8a and R 8b 、R 8b and R 8c 、R 8c and R 8d , or R 8d and R 8e and together with the atoms to which they are attached form an optionally substituted 3-7 membered carbocyclyl, an optionally substituted 4-7 membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl.

[0183] In some embodiments of Formula (IV), X 4 CR 8a , X 5 CR 8b , and X 6 CR 8d In some embodiments of Formula (IV), X 4 N, X 5 CR 8b , and X 6 CR 8d In some embodiments of Formula (IV), X 5 N, X 4 CR 8a , and X 6 CR 8d In some of the above embodiments, R 8a 、R 8b 、R 8c 、R 8d and R 8e Each is independently hydrogen, halogen, or optionally substituted C1-C8 alkyl. 8a 、R 8b and R 8c Each is independently hydrogen, halogen or C1-C4 alkyl. In some such embodiments, R 8d and R 8e In some embodiments of Formula (IV), X 4 N, X 5 CR 8b , and X 6 CR 8d , and R 8b、R 8c 、R 8d , and R 8e are each independently hydrogen, halogen, or optionally substituted C1-C8 alkyl. In some such embodiments, R 8b and R 8c are each independently hydrogen, halogen or C1-C4 alkyl, and R 8d and R 8e For hydrogen.

[0184] In some embodiments of Formula (IV), R 8a and R 8b and together with the atoms to which they are attached form an optionally substituted phenyl group. In some embodiments, R 8a and R 8b and together with the atoms to which they are attached form an optionally substituted 5-membered heteroaryl. 8a and R 8b and together with the atoms to which they are attached form an optionally substituted 6-membered heteroaryl group comprising 1 to 3 nitrogen atoms.

[0185] In some embodiments of Formula (IV), R 8b and R 8c and together with the atoms to which they are attached form an optionally substituted phenyl group. In some embodiments, R 8b and R 8c and together with the atoms to which they are attached form an optionally substituted 5-membered heteroaryl. In some such embodiments, R 8b and R 8c and together with the atoms to which they are attached form an optionally substituted 6-membered heteroaryl group comprising 1 to 3 nitrogen atoms.

[0186] In some embodiments of Formula (IV), R 8c and R 8d and together with the atoms to which they are attached form an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl. 8c and R 8d and together with the atoms to which they are attached form an optionally substituted phenyl group. In some embodiments, R 8c and R 8d and together with the atoms to which they are attached form an optionally substituted 5-membered heteroaryl. 8c and R 8d and together with the atoms to which they are attached form an optionally substituted 6-membered heteroaryl group comprising 1 to 3 nitrogen atoms.

[0187] In some embodiments of Formula (IV), R 8d and R 8eand together with the atoms to which they are attached form an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl. 8d and R 8e and together with the atoms to which they are attached form an optionally substituted phenyl group. In some embodiments, R 8d and R 8e and together with the atoms to which they are attached form an optionally substituted 5-membered heteroaryl. 8d and R 8e and together with the atoms to which they are attached form an optionally substituted 6-membered heteroaryl group comprising 1 to 3 nitrogen atoms.

[0188] In some embodiments of Formula (IV), X 4 N; and R 8c and R 8b and together with the atoms to which they are attached form an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl.

[0189] The embodiments described herein for Formula (IV) also apply to Formula (IV-A), (IV-B), (IV-C), or (IV-D) to the extent there are no inconsistencies between these embodiments.

[0190] In some embodiments, the compound of formula (IV) has the structure shown in formula (IV-A):

[0191]

[0192] or a pharmaceutically acceptable salt thereof, wherein:

[0193] R 1 、R 2 , L and Z are as defined in formula (I);

[0194] X 4 CR 8a or N;

[0195] X 6 CR 8d or N;

[0196] Each R 9 are independently hydrogen, halogen, CN, NO2, OR 5 SR 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

[0197] q1 is 0, 1, 2, or 3.

[0198] In some such embodiments of Formula (IV-A), each R 9 are independently hydrogen, halogen, CN, NO2, OR 5 SR 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. In some embodiments, each R 9 R is independently hydrogen, halogen, or optionally substituted C1-C8 alkyl. 9 R is independently methyl, ethyl, n-propyl, isopropyl, or tert-butyl. 9 R is independently an optionally substituted 3-10 membered carbocyclyl, or an optionally substituted 3-10 membered heterocyclyl. 9 R is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 9 R is independently optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. 9 R is independently oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, or piperazine. 9 R is independently hydrogen, Cl, F, Br, CN, NO2, OH, OCH3, methyl, ethyl, or isopropyl. 9 is independently an optionally substituted C1-C8 alkylamino group. 9 independently NH(CH2OH)2 or NHCH2CH(OH)CH2OH.

[0199] 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.

[0200] In some embodiments, X 4 is N, and X 6 is N. In some embodiments, X 4 is N, and X 6 CR 8d In some embodiments, X 4 CR 8a , and X 6 is N. In some embodiments, X 4 CR 8a , and X 6 CR 8d .

[0201] In some embodiments, the compound of formula (IV) has the structure shown in formula (IV-B):

[0202]

[0203] or a pharmaceutically acceptable salt thereof, wherein:

[0204] R 1 、R 2 , L and Z are as defined in formula (I);

[0205] X 4 CR 8a or N;

[0206] X 5 CR 8b or N;

[0207] Y 1 、Y 2 and Y 3 Each independently CR 10 NR 10a or N; where Y 1 、Y 2 and Y 3 At least one of them is CR 10 ;

[0208] Each R 10is 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; and

[0209] Each R 10a are 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl.

[0210] In some embodiments of Formula (IV-B), X 4 is N, and X 5 CR 8b In some embodiments, X 5 is N, and X 4 CR 8a In some embodiments, X 4 is N, and X 5 is N. In some embodiments, X 4 CR 8a , and X 5 CR 8b .

[0211] In some embodiments, the compound of formula (IV) has the structure shown in formula (IV-C):

[0212]

[0213] or a pharmaceutically acceptable salt thereof, wherein:

[0214] R 1 、R 2 , L and Z are as defined in formula (I);

[0215] X 4 CR 8a or N;

[0216] X 6 CR 8d or N;

[0217] Y 1 、Y 2 and Y 3 Each independently CR 10 NR 10a or N; where Y 1 、Y 2 and Y3 At least one of them is CR 10 ;

[0218] Each R 10 is 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; and

[0219] Each R 10a are 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl.

[0220] In some such embodiments of Formula (IV-C), X 4 is N, and X 6 CR 8d In some embodiments, X 4 CR 8a , and X 6 is N. In some embodiments, X 4 is N, and X 6 is N.

[0221] In some embodiments, the compound of formula (IV) has the structure shown in formula (IV-D):

[0222]

[0223] or a pharmaceutically acceptable salt thereof, wherein:

[0224] R 1 、R 2 , L and Z are as defined in formula (I);

[0225] X 4 CR 8a or N;

[0226] X 5 CR 8b or N;

[0227] Y 1 、Y 2 and Y 3 Each independently CR 10 NR 10a or N; where Y 1 、Y 2and Y 3 At least one of them is CR 10 ;

[0228] Each R 10 is 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; and

[0229] Each R 10a are 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl.

[0230] In some such embodiments of Formula (IV-D), X 4 is N, and X 5 CR 8b In some embodiments, X 4 CR 8a , and X 5 is N. In some embodiments, X 4 is N, and X 5 is N.

[0231] In some embodiments 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 SR 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. In some such embodiments, R 8a 、R 8b 、R 8c 、R 8d and R 8e are each independently hydrogen, halogen, or optionally substituted C1-C8 alkyl. In some such embodiments, R8a 、R 8b 、R 8c 、R 8d and R 8e are each independently hydrogen, halogen, or C1-C4 alkyl. In some such embodiments, R 8a 、R 8b 、R 8c 、R 8d and R 8e Each is independently hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl or tert-butyl. In some such embodiments, R 8a 、R 8b 、R 8c 、R 8d and R 8e Each is independently methyl, ethyl, n-propyl, isopropyl or tert-butyl. 8a 、R 8b 、R 8c 、R 8d and R 8e Each is independently an optionally substituted 3-10 membered carbocyclyl, or an optionally substituted 3-10 membered heterocyclyl. 8a 、R 8b 、R 8c 、R 8d and R 8e Each is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R 8a 、R 8b 、R 8c 、R 8d and R 8e R is independently hydrogen, Cl, F, Br, CN, NO2, OH, OCH3, methyl, ethyl, or isopropyl. 8a 、R 8b 、R 8c 、R 8d and R 8e are each independently hydrogen or F.

[0232] In some embodiments of Formula (IV-B), (IV-C), or (IV-D), Y 1 and Y 3 Each independently is NR 10a or N; and Y 2 CR 10 .

[0233] In some embodiments of Formula (IV-B), (IV-C), or (IV-D), Y 2 and Y 3 Each independently is NR10a or N; and Y 1 CR 10 .

[0234] In some embodiments of Formula (IV-B), (IV-C), or (IV-D), Y 1 and Y 2 Each independently is NR 10a or N; and Y 3 CR 10 .

[0235] In some embodiments of Formula (IV-B), (IV-C), or (IV-D), each R 10 R is 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. In some embodiments, each R 10 R is independently hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl. 10 R is independently methyl, ethyl, n-propyl, isopropyl, or tert-butyl. 10 R is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 10 are independently hydrogen. In some embodiments, each R 10 In some embodiments, each R 10 is independently F, Cl, or Br. In some embodiments, each R 10 is independently F.

[0236] In some embodiments of Formula (IV-B), (IV-C), or (IV-D), each R 10a R is independently hydrogen, or optionally substituted C1-C8 alkyl, or optionally substituted C1-C8 haloalkyl. 10a R is independently methyl, ethyl, n-propyl, isopropyl, or tert-butyl. 10a are independently hydrogen. In some embodiments, each R 10a is independently an optionally substituted C1-C8 haloalkyl. 10a is independently CF3, CHF2, or CH2CF3. In some embodiments, each R 10a is independently an optionally substituted 3-6 membered carbocyclyl.10a R is independently optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. 10a is independently an optionally substituted 3-6 membered heterocyclyl. 10a is 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.

[0237] In some embodiments of any of the formulas described herein, R 2 For hydrogen, halogen, CN, NO2, OR 5 SR 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. In some embodiments, R 2 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.

[0238] In some embodiments of any of the formulas described herein, each R 2 is hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl. 2 is methyl, ethyl, n-propyl, isopropyl, or tert-butyl. 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is an optionally substituted 3-10 membered heterocyclyl. 2 is oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, or piperazine. In some embodiments, R 2 is an optionally substituted 3-10 membered carbocyclyl. 2is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is an optionally substituted C1-C8 haloalkyl. 2 is CF3, CHF2, or CH2CF3. In some embodiments, R 2 For CHF2.

[0239] In some embodiments of any of the formulae 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, where R 1a In some embodiments, Z is -NR 1a -, where R 1a In some embodiments, Z is -NH-.

[0240] In some embodiments of any of the formulas described herein, L is an optionally substituted C1-C 10 Alkylene or optionally substituted C1-C 10 In some embodiments, L is an optionally substituted C1-C 10 In some embodiments, L is an optionally substituted C1-C 10 Heteroalkylene, wherein the heteroatom is N or O. In some embodiments, the heteroalkylene is polyethylene glycol (PEG).

[0241] In some embodiments of any of the formulas described herein, L is in,

[0242] Ring B is an optionally substituted 3-7 membered carbocyclyl, or an optionally substituted 4-7 membered heterocyclyl;

[0243] L 1 Absent, or optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 heteroalkylene; and

[0244] L 2 Absent, or optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C10 Alkyne, or optionally substituted C1-C 10 Heteroalkylene.

[0245] In some such embodiments, L is in,

[0246] Ring B is an optionally substituted 3-7 membered carbocyclyl;

[0247] L 1 Absent, or optionally substituted C1-C 10 alkylene; and

[0248] L 2 Absent, or optionally substituted C1-C 10 Alkylene.

[0249] In some embodiments, L is Among them, L 1 does not exist; and L 2 C1-C 10 In some such embodiments, L 2 is C1-C4 alkylene, preferably, L 2 It is a C1-C2 alkylene group.

[0250] In some embodiments, L is Among them, L 2 does not exist; and L 1 C1-C 10 In some such embodiments, L 1 is C1-C4 alkylene, preferably, L 1 It is a C1-C2 alkylene group.

[0251] In some embodiments, Ring B is an optionally substituted 3-7 membered carbocyclyl. In some embodiments, Ring B is an optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted optionally substituted spiro[3.3]heptyl, optionally substituted spiro[4.4]nonyl, or optionally substituted spiro[3.4]octyl 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 an optionally substituted cyclopropyl. In some embodiments, Ring B is an optionally substituted cyclobutyl. In some embodiments, Ring B is an optionally substituted cyclopentyl. In some embodiments, Ring B is an optionally substituted cyclohexyl. In some embodiments, Ring B is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. In some embodiments, Ring B is an optionally substituted spiro[3.3]heptyl, optionally substituted spiro[4.4]nonyl, or optionally substituted spiro[3.4]octyl ring. In some embodiments, Ring B is an optionally substituted spiro[3.3]heptyl or optionally substituted spiro[4.4]nonyl ring. 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.

[0252] In some embodiments of any of the formulas described herein, L 1 In some embodiments, L 1 is an optionally substituted C1-C 10 In some embodiments, L 1 is an optionally substituted C1-C4 alkylene. 1 is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, L 1 is an optionally substituted C1-C 10 wherein the heteroatom is N or O. In some embodiments, L 1 is polyethylene glycol (PEG). In some embodiments, L 1 is –(CH2CH2O) n -, wherein n is an integer from 1 to 20. In some embodiments, n is 1-15, 1-10, 1-8, 1-6, 1-4, or 1-2.

[0253] In some embodiments of any of the formulas described herein, L 2 is an optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkyne, or optionally substituted C1-C 10In some embodiments of any of the formulas described herein, L 2 L is optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, optionally substituted C2-C4 alkynylene, or optionally substituted C1-C4 heteroalkylene. 2 In some embodiments, L 2 is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, L 2 is an optionally substituted C1-C 10 wherein the heteroatom is N or O. In some embodiments, L 2 is polyethylene glycol (PEG). In some such embodiments, L 2 is –(CH2CH2O) n -, wherein n is an integer from 1 to 20. In some embodiments, n is 1-15, 1-10, 1-8, 1-6, 1-4, or 1-2.

[0254] In some embodiments of any of the formulas described herein, R 1 does not exist. When R 1 does not exist, the portion has the following structure:

[0255]

[0256] In some embodiments of any of the formulas described herein, R 1 is an oxo group (=O). 1 is an oxo group, and the moiety has the following structure:

[0257]

[0258] 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.

[0259] 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.

[0260] Certain preferred embodiments of formula (III) have any combination of one, two, three, four, five or more of the following options, as long as these embodiments do not conflict with each other:

[0261] R 2 is hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl;

[0262] R 2 is an optionally substituted 3-10 membered carbocyclic group;

[0263] R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0264] R 2 is cyclopropyl;

[0265] X 4 is N; and X 5 and X 6 Each independently CR 8 ;

[0266] X 4 N, X 5 is N, and X 6 CR 8 ;

[0267] p2 is 1 or 2;

[0268] p2 is 2;

[0269] Each R 8 are independently hydrogen, halogen, or optionally substituted C1-C8 alkyl;

[0270] Each R 8 are independently hydrogen, F, or C 1-4 alkyl;

[0271] Each R 8 are independently F or methyl;

[0272] L is in:

[0273] L 1 does not exist; and L 2 C1-C 10 alkylene;

[0274] L 1 does not exist; and L 2 is C1-C4 alkylene; or

[0275] L 1 does not exist; and L 2 is a C1-C2 alkylene group;

[0276] L is in:

[0277] L 2 does not exist; and L 1 C1-C 10 alkylene;

[0278] L 2 does not exist; and L 1 is C1-C4 alkylene; or

[0279] L 2 does not exist; and L 1 is a C1-C2 alkylene group;

[0280] Ring B is an optionally substituted 3-7 membered carbocyclyl;

[0281] Ring B is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl;

[0282] Ring B is optionally substituted cyclobutyl;

[0283] Ring B is an optionally substituted spiro[3.3]heptyl, optionally substituted spiro[4.4]nonyl or optionally substituted spiro[3.4]octyl ring;

[0284] Z is -NR 1a -, where R 1a is hydrogen or C1-C4 alkyl;

[0285] Z is -NR 1a -, where R 1a is hydrogen;

[0286] Z is -NH-;

[0287] R 1 does not exist;

[0288] R 1 It is an oxo group.

[0289] Certain preferred embodiments of formula (IV) have any combination of one, two, three, four, five or more of the following options, as long as these embodiments do not conflict with each other:

[0290] R 2 is hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl;

[0291] R 2 is an optionally substituted 3-10 membered carbocyclic group;

[0292] R 2is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0293] R 2 is cyclopropyl;

[0294] X 4 N, X 5 CR 8b , and X 6 CR 8d ;

[0295] X 4 N, X 5 is N, and X 6 CR 8d ;

[0296] X 5 N, X 4 CR 8a , and X 6 CR 8d ;

[0297] R 8a 、R 8b 、R 8c 、R 8d and R 8e are each independently hydrogen, halogen, or optionally substituted C1-C8 alkyl;

[0298] R 8a 、R 8b 、R 8c 、R 8d and R 8e Each is independently hydrogen, halogen, or C1-C4 alkyl;

[0299] R 8a 、R 8b 、R 8c 、R 8d and R 8e are each independently hydrogen, F, or C1-C4 alkyl;

[0300] R 8a and R 8b and together with the atoms to which they are attached form an optionally substituted 5-6 membered heteroaryl;

[0301] R 8b and R 8c and together with the atoms to which they are attached form an optionally substituted phenyl group;

[0302] R 8b and R 8c and together with the atoms to which they are attached form an optionally substituted 5-6 membered heteroaryl;

[0303] R8c and R 8d and together with the atoms to which they are attached form an optionally substituted 5-6 membered heteroaryl;

[0304] L is in:

[0305] L 1 does not exist; and L 2 C1-C 10 alkylene;

[0306] L 1 does not exist; and L 2 is C1-C4 alkylene; or

[0307] L 1 does not exist; and L 2 is a C1-C2 alkylene group;

[0308] L is in:

[0309] L 2 does not exist; and L 1 C1-C 10 alkylene;

[0310] L 2 does not exist; and L 1 is C1-C4 alkylene; or

[0311] L 2 does not exist; and L 1 is a C1-C2 alkylene group;

[0312] Ring B is an optionally substituted 3-7 membered carbocyclyl;

[0313] Ring B is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl;

[0314] Ring B is optionally substituted cyclobutyl;

[0315] Ring B is an optionally substituted spiro[3.3]heptyl, optionally substituted spiro[4.4]nonyl or optionally substituted spiro[3.4]octyl ring;

[0316] Z is -NR 1a -, where R 1a is hydrogen or C1-C4 alkyl;

[0317] Z is -NR 1a -, where R 1a is hydrogen;

[0318] Z is -NH-;

[0319] R1 does not exist;

[0320] R 1 It is an oxo group.

[0321] Certain preferred embodiments of formula (IV-A), (IV-B), (IV-C) or (IV-D) have any combination of one, two, three, four, five or more of the following options, as long as these embodiments do not conflict:

[0322] R 2 is hydrogen, halogen, optionally substituted C1-C8 alkyl, or optionally substituted 3-10 membered carbocyclyl;

[0323] R 2 is an optionally substituted 3-10 membered carbocyclic group;

[0324] R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0325] R 2 is cyclopropyl;

[0326] Formula (IV-A) or (IV-C):

[0327] X 4 is N, and X 6 CR 8d ;

[0328] X 4 is N, and X 6 is N;

[0329] Formula (IV-B) or (IV-D):

[0330] X 4 is N, and X 5 CR 8b ;

[0331] X 4 is N, and X 5 is N;

[0332] Formula (IV-B), (IV-C) or (IV-D):

[0333] Y 1 and Y 3 Each independently is NR 10a or N; and Y 2 CR 10 ;

[0334] Y 2 and Y 3 Each independently is NR 10a or N; and Y1 CR 10 ;

[0335] Y 1 and Y 2 Each independently is NR 10a or N; and Y 3 CR 10 ;

[0336] L is in:

[0337] L 1 does not exist; and L 2 C1-C 10 alkylene;

[0338] L 1 does not exist; and L 2 is C1-C4 alkylene; or

[0339] L 1 does not exist; and L 2 is a C1-C2 alkylene group;

[0340] L is in:

[0341] L 2 does not exist; and L 1 C1-C 10 alkylene;

[0342] L 2 does not exist; and L 1 is C1-C4 alkylene; or

[0343] L 2 does not exist; and L 1 is a C1-C2 alkylene group;

[0344] Ring B is an optionally substituted 3-7 membered carbocyclyl;

[0345] Ring B is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl;

[0346] Ring B is optionally substituted cyclobutyl;

[0347] Ring B is an optionally substituted spiro[3.3]heptyl, optionally substituted spiro[4.4]nonyl or optionally substituted spiro[3.4]octyl ring;

[0348] Z is -NR 1a -, where R 1a is hydrogen or C1-C4 alkyl;

[0349] Z is -NR 1a-, where R 1a is hydrogen;

[0350] Z is -NH-;

[0351] R 1 does not exist;

[0352] R 1 It is an oxo group.

[0353] 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, as a downstream effect of cereblon binding and modulation, the compounds degrade GSPT1. Table 1 shows some examples of GSPT1 degraders.

[0354] Table 1. Example compounds of the present invention

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377] II. Synthesis and other forms of compounds

[0378] As non-limiting examples, synthetic schemes for specific exemplary compounds are described in detail in the Examples.

[0379] The present disclosure includes all stereoisomers, geometric isomers, tautomers and isotopes of the compounds described herein and the structures named herein. The present disclosure also includes the compounds described herein, no matter how they are prepared, for example, synthetically, by biological processes (for example, metabolism or enzymatic conversion), or combinations thereof. The present disclosure includes pharmaceutically acceptable salts of the compounds described herein and the structures named herein.

[0380] Pharmaceutically acceptable isotopic variants 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 variants of those reagents). Specifically, an isotopic variant is a compound in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Useful isotopes are known in the art and include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. 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 Cl.

[0381] Isotopic variants (e.g., containing 2H isotopic variants) may afford therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).

[0382] In addition, certain isotopic variants (particularly those containing radioactive isotopes) are useful in drug or substrate tissue distribution studies. In particular, the radioactive isotope tritium ( 3 H) and carbon 14 ( 14 C), can be used for this purpose given their ease of binding and existing detection methods.

[0383] Pharmaceutically acceptable solvates of the compounds disclosed herein are contemplated. Solvates can be produced, for example, by replacing the solvent used to crystallize the compounds disclosed herein with an isotopic variant (e.g., D2O instead of H2O, d6-acetone instead of acetone, or d6-DMSO instead of DMSO).

[0384] Pharmaceutically acceptable fluorinated variants 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 (replacing appropriate reagents with appropriate fluorinated variants of those reagents). Specifically, fluorinated variants are compounds in which at least one hydrogen atom is replaced by a fluorine atom. Fluorinated variants may provide therapeutic advantages resulting from greater metabolic stability (e.g., increased half-life in vivo or reduced dosage requirements).

[0385] One or more constituent atoms of the compounds provided herein may be replaced or substituted by atomic isotopes of natural abundance or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5 or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted by deuterium atoms. In some embodiments, the compound includes at least one fluorine atom. In some embodiments, the compound includes two or more fluorine atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5 or 1-6 fluorine atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted by fluorine atoms.

[0386] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z or E form (or cis or trans). In addition, some chemical entities may exist in various tautomeric forms. Unless otherwise indicated, the compounds described herein are intended to include all Z-, E- and tautomeric forms.

[0387] "Tautomers" refer to molecules in which a proton can be transferred from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomers. Where tautomerism is possible, chemical equilibrium exists between the tautomers. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.

[0388] The compounds of the present invention also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs and amorphous forms of the compounds, and mixtures thereof.

[0389] In some cases, the compounds described herein may exist as diastereomers, enantiomers or other stereoisomeric forms. If absolute stereochemistry is not specified, the compounds described herein include all diastereomers, enantiomers and epimers and their appropriate mixtures. The separation of stereoisomers can be carried out by chromatography or by forming diastereomers and separating by recrystallization or chromatography or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981, incorporated herein by reference). Stereoisomers can also be obtained by stereoselective synthesis.

[0390] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Likewise, in some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. In addition, the compounds described herein may exist in the form of unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). Solvated forms of the compounds described herein are also considered to be disclosed herein.

[0391] In some embodiments, the salt of compound or compound can be a prodrug, for example, wherein the hydroxyl group in the parent compound exists in the form of an ester or carbonate, or the carboxylic acid present in the parent compound exists in the form of an ester. The term "prodrug" is intended to include compounds that are converted into medicaments of the present disclosure under physiological conditions. A method for preparing a prodrug is to include one or more selected parts that are hydrolyzed under physiological conditions to display the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal (for example, a specific target cell in the host animal). For example, esters or carbonates (for example, esters of alcohol or carboxylic acid or esters of carbonate and phosphonic acid) are preferred prodrugs of the present disclosure.

[0392] Prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce the compound as hereinbefore described, are included within the scope of the claims. In certain instances, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0393] Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they can be bioavailable via oral administration, whereas the parent drug cannot. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. Prodrugs in pharmaceutical compositions also have improved solubility compared to the parent drug. Prodrugs can be designed as reversible drug derivatives and used as modifiers to enhance drug transport to specific tissue locations or increase drug residence time within cells.

[0394] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. 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. Systems, Volume 14 of the ACS Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, Pergamon Press, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference. According to another embodiment, the present disclosure provides methods for producing the above-mentioned compounds. The compounds can be synthesized using conventional techniques. Advantageously, these compounds can be conveniently synthesized from readily available starting materials.

[0395] Synthetic chemistry transformations and methods 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. Wuts, Protective Groups in Organic Synthesis, 2nd 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).

[0396] In some aspects, provided herein is a method for identifying a compound that mediates GSPT1 degradation or reduction, the method comprising: providing a compound comprising a CRBN binder; contacting the compound with a cell comprising a ubiquitin ligase and GSPT1; determining whether GSPT1 levels in the cell are reduced; and identifying the compound as a compound that mediates GSPT1 degradation or reduction. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cancer cell is a GSPT1-mediated cancer cell.

[0397] III. Characterization of Exemplary Compounds

[0398] The binding affinity of the compounds described herein or their pharmaceutically acceptable salts can be assessed 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 assess the ability of the compounds to induce GSPT1 degradation and inhibit cancer cell proliferation. In addition to assessing compound-induced changes in GSPT1 protein levels. Assays suitable for 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, xenografts, orthotopic and patient-derived xenograft models. Cell lines suitable for any or all of these steps 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. Mouse models suitable for any or all of these steps are known in the art and include subcutaneous xenograft models, orthotopic models, patient-derived xenograft models, and patient-derived orthotopic models.

[0399] A cell viability assay was used to characterize specific exemplary compounds. In the assay, MV4;11 and MOLM-13 cells were treated with compounds for three days. 50 Values ​​range from 1 nM to 10 μM.

[0400] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are effective at an IC of less than 50 nM. 50 In some embodiments, the compound inhibits cell growth with an IC value of less than 25 nM. 50 In some embodiments, the compound inhibits cell growth with an IC value of less than 10 nM. 50 In some embodiments, the compound inhibits cell growth with an IC value of less than 8 nM. 50 In some embodiments, the compound inhibits cell growth with an IC value of less than 2 nM. 50 In some embodiments, the cells include MV4;11 or MOLM-13 cells. In some embodiments, the cells are MV4;11 cells. In some embodiments, the cells are MOLM-13 cells.

[0401] IV. Pharmaceutical Compositions

[0402] In some aspects, the compositions and methods described herein include the manufacture and use of pharmaceutical compositions and drugs comprising one or more compounds disclosed herein (such as heterobifunctional compounds). Also included are the pharmaceutical compositions themselves. In some embodiments, the pharmaceutical composition includes a compound as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition includes a compound as described herein, such as a GSPT1 degrader. In some embodiments, the pharmaceutical composition includes a second compound, such as a FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or agonist. The second compound can be a FLT3 pathway inhibitor or a FLT3 inhibitor such as Gilteritinib.

[0403] In some aspects, the compositions disclosed herein may include other compounds, drugs or agents for treating cancer. For example, in some cases, the pharmaceutical compositions disclosed herein may be combined with one or more (e.g., one, two, three, four, five or less than ten) compounds. Such additional compounds may include, for example, conventional chemotherapeutics or any other cancer treatment known in the art. When co-administered, the compounds disclosed herein may act in conjunction with conventional chemotherapeutics or any other cancer treatment known in the art to produce a mechanical additive or synergistic therapeutic effect.

[0404] In some aspects, 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.

[0405] Pharmaceutical compositions typically include a pharmaceutically acceptable excipient, adjuvant, or carrier. As used herein, the phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally considered to be physiologically tolerable and that generally do not produce allergic or similar adverse reactions, such as stomach upset, dizziness, etc., when administered to a human. A pharmaceutically acceptable excipient, adjuvant, or carrier refers to a substance that can be administered to a subject together with the compound of the present invention and does not impair its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound. Exemplary conventional non-toxic pharmaceutically acceptable excipients, adjuvants, and carriers include, but are not limited to, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents that are compatible with drug administration.

[0406] In particular, pharmaceutically acceptable excipients, adjuvants and carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopheryl polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as Tween or other similar polymer 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, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrins can also be advantageously used to enhance the delivery of the various compounds described herein.

[0407] Depending on the dosage form selected for delivering the compounds disclosed herein, different pharmaceutically acceptable excipients, adjuvants and carriers can be used. In the case of oral tablets, pharmaceutically acceptable excipients, adjuvants and carriers that can be used include lactose and corn starch. Lubricants such as magnesium stearate are usually also added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension or emulsion is taken orally, the active ingredient can be suspended or dissolved in an oil phase and mixed with an emulsifier or suspending agent. If necessary, certain sweeteners, flavorings or coloring agents can be added.

[0408] As used herein, compounds disclosed herein are defined as including pharmaceutically acceptable derivatives thereof or their prodrugs. "Pharmaceutically acceptable derivatives" refers to any pharmaceutically acceptable salt, solvate or prodrug of a compound disclosed herein or a medicament, such as a carbamate, ester, phosphate, salt or other derivative of an ester, which can provide (directly or indirectly) a compound as described herein or its active metabolite or residue after being applied to a recipient. Particularly preferred derivatives and prodrugs are compounds that increase the bioavailability of a compound disclosed herein when the compound disclosed herein is applied to a subject (e.g., by making the compound administered orally more easily absorbed into the blood), or compounds that enhance the delivery of the parent compound to a biological compartment (e.g., brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives in which a group that enhances water solubility or active transport by the intestinal membrane is attached to a formula structure as described herein. Those skilled in the art can identify such derivatives without excessive experimentation. Nevertheless, reference is made to Burger's Medicinal Chemistry and Drug Discovery, 5th edition, Volume 1: Principles and Practices, which are incorporated herein by reference within the scope of teaching such derivatives.

[0409] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions 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 can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0410] The phrase "pharmaceutically acceptable" as used herein refers to 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 excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0411] The compounds disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and meso forms, and pharmaceutically acceptable salts, solvate complexes, morphological forms or deuterated derivatives thereof.

[0412] In some aspects, the pharmaceutical compositions disclosed herein may comprise an effective amount of one or more compounds. As used herein, the terms "effective amount" and "effective treatment" refer to the amount or concentration of one or more compounds or pharmaceutical compositions described herein that effectively causes a desired effect or physiological result (e.g., treating or preventing cell growth, cell proliferation, or cancer) within the scope of its administration over a period of time (including acute or chronic administration and regular or continuous administration).

[0413] In some aspects, the pharmaceutical composition may further comprise one or more other compounds, drugs, or agents used to treat cancer (e.g., conventional chemotherapeutic agents) in an amount effective to cause a desired effect or physiological outcome (e.g., treating or preventing cell growth, cell proliferation, or cancer).

[0414] In some embodiments, the present disclosure relates to pharmaceutical formulations comprising: (a) a therapeutically effective amount of a compound described herein (eg, Formula (I)), or a pharmaceutically acceptable salt thereof; and (b) a second therapeutic agent.

[0415] In some embodiments, the present disclosure relates to pharmaceutical formulations comprising: (a) a therapeutically effective amount of a compound described herein (eg, Formula (I)) or a pharmaceutically acceptable salt thereof; and (b) one or more therapeutic agents.

[0416] In some embodiments, the present disclosure relates to pharmaceutical formulations 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.

[0417] In some embodiments, the second or more therapeutic agents are anticancer drugs. In some embodiments, the second or more therapeutic agents are antiproliferative 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.

[0418] 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 can be gilteritinib.

[0419] 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 compound is an inhibitor or activator of the PI3K-AKT-mTOR pathway.

[0420] 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.

[0421] V. Administration of Pharmaceutical Compositions

[0422] Pharmaceutical composition disclosed herein can be formulated or adjusted for any approach, such as any approach approved by the Food and Drug Administration (FDA) and applied to a subject. Exemplary methods are described in the FDA Data Standards Manual (DSM) (available at www.fda.gov / Drugs / DevelopmentApprovalProcess / FormsSubmissionRequirements / Electronic Submissions / DataStandardsManualmonographs). In particular, the pharmaceutical composition can be formulated for oral, parenteral or transdermal delivery and delivered orally, 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.

[0423] The pharmaceutical compositions disclosed herein can be administered, for example, topically, rectally, nasally (e.g., by inhalation spray or nebulizer), orally, vaginally, subcutaneously (e.g., by injection or via an implanted reservoir), or ophthalmically.

[0424] In some embodiments, the pharmaceutical compositions of the present invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.

[0425] In some embodiments, the pharmaceutical compositions of the present invention can be used for rectal administration in the form of suppositories. These compositions can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients that are solid at room temperature (rt) but liquid at rectal temperature and therefore will melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0426] In some embodiments, the pharmaceutical compositions of the present invention can be 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 saline solutions, using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons or other solubilizing or dispersing agents known in the art.

[0427] In some embodiments, the pharmaceutical compositions of the present invention can be administered by injection (e.g., as a solution or powder). Such compositions can be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among acceptable carriers and solvents, mannitol, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile, fixed oils are commonly 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, can be used to prepare injectable formulations, as can natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethylcellulose or similar dispersants, which are commonly used to formulate pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. Other commonly used surfactants, such as Tweens, Spans or other similar emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0428] In some aspects, effective doses of the pharmaceutical compositions of the present invention include, but are not limited to, for example, 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, 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 / kg / day, or as required for a particular pharmaceutical composition.

[0429] When the pharmaceutical compositions disclosed herein comprise a combination of a compound described herein and one or more additional compounds (e.g., one or more additional compounds, drugs, or agents that are useful in treating cancer or any other condition or disease, including conditions or diseases known to be associated with or caused by cancer), the dosage levels of both the compound and the additional compound may be between about 1% and 100%, more preferably between about 5% and 95% of the dose typically administered in a single-drug treatment regimen. The additional agents may be administered separately from the compounds of the invention as part of a multiple-dose regimen. Alternatively, these agents may be part of a single dosage form, mixed with the compounds of the invention in a single composition.

[0430] In some aspects, a pharmaceutical composition disclosed herein may be included in a container, pack, or dispenser together with instructions for administration.

[0431] VI. Treatment Methods

[0432] In some embodiments, disclosed herein are methods of administering a composition described herein to a subject. Some embodiments relate to using a composition described herein, such as administering the composition to a subject. Some embodiments relate to methods of treating a disease in a subject in need thereof. Some embodiments relate to the use of a composition described herein in the treatment of a disease.

[0433] In one embodiment, provided herein is a method for treating a disease or condition associated with abnormal cell growth (such as cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as shown in any one of Formula (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof. In another embodiment, provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound as shown in any one of Formula (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof.

[0434] In some embodiments, the method further comprises administering to the subject a second therapeutic agent (e.g., an anticancer therapeutic agent). In another embodiment, a method for treating a disease or condition associated with abnormal cell growth (e.g., cancer) in a subject in need thereof is provided, comprising administering to the subject an amount of a compound as shown in any of Formulas (I)-(IV) or (A), or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional therapeutic agent (e.g., an anticancer therapeutic agent), wherein the amounts together are effective to treat the abnormal cell growth (e.g., cancer).

[0435] In another embodiment, a compound as shown in any one of Formula (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof, is provided for use in treating abnormal cell growth (e.g., cancer) in a subject. In a further embodiment, a compound as shown in any one of Formula (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof, is provided for use in treating abnormal cell growth (e.g., cancer) in a subject.

[0436] In a further embodiment, provided is the use of a compound as represented by any one of formula (I)-(IV) or formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a medicament (e.g., a medicament for treating abnormal cell growth (e.g., cancer)).

[0437] In some embodiments of the compounds, compositions, methods, and uses described herein, a compound such as any one of Formula (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof, degrades GSPT1. In common embodiments of each of the methods and uses described herein, the abnormal cell growth is cancer. In some such embodiments, the cancer is mediated by GSPT1.

[0438] In some embodiments, the treatment method includes administering to a subject in need thereof a first compound comprising a GSPT1 degrader as shown in any one of Formula (I)-(IV) or Formula (A) or a pharmaceutically acceptable salt thereof 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. Some embodiments include administering a composition as described herein to a subject suffering from the disease. In some embodiments, the subject is treated for the disease. In some embodiments, the composition treats the subject's disease. In some embodiments, the treatment includes preventing, inhibiting, or reversing the subject's disease. In some embodiments, the subject suffers from cancer.

[0439] According to one aspect of the present disclosure, the methods disclosed herein for treating a GSPT1-mediated disease comprise administering a compound disclosed herein (e.g., a compound as shown in any one of Formula (I)-(IV) or Formula (A)) or a pharmaceutically acceptable salt thereof to a subject suffering from a GSPT1-mediated disease. In some embodiments, the compound is a compound disclosed in Table 1 or a pharmaceutically acceptable salt thereof.

[0440] The methods disclosed herein contemplate administering an effective amount of a compound or composition to achieve the desired or prescribed effect. Typically, the compound or composition of the present invention is administered about 1 to about 6 times a day, or, alternatively or in addition as a continuous infusion. This administration can be used as a chronic or acute treatment. The amount of the active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. A typical formulation will contain about 5% to about 95% active compound (w / w). Alternatively, such formulations may contain about 20% to about 80% active compound. In some embodiments, the first compound and the second compound are administered to a subject together. In some embodiments, the first compound and the second compound are administered to a subject separately. In some embodiments, the subject is a mammal. In some embodiments, the subject is human.

[0441] In some aspects, provided herein are compounds or pharmaceutically acceptable salts thereof for use in preventing or treating a disease or condition. In some aspects, provided herein are heterobifunctional compounds described herein for use in preventing or treating a disease or condition.

[0442] In some aspects, provided herein are compounds or pharmaceutically acceptable salts thereof for use in treating or preventing one or more diseases or conditions disclosed herein in a subject in need thereof. 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, stomach cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, hematopoietic system cancer, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin 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.

[0443] In some embodiments, the GSPT1-mediated cancer is selected from the group consisting of mesothelioma, leukemia, and lymphoma such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotropic virus (HTLV) 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 lymphoma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), Hodgkin lymphoma, Burkitt lymphoma, adult T-cell Myelodysplastic syndrome (MDS), childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms tumor, bone tumors and soft tissue sarcomas, common solid tumors in adults such as head and neck cancer (such as oral cancer, laryngeal cancer and nasopharyngeal cancer), esophageal cancer, genitourinary cancer (such as prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, testicular cancer), lung cancer (such as small cell carcinoma and non-small cell carcinoma), breast cancer, pancreatic cancer, melanoma, and other skin cancers, stomach cancer, brain tumors, and Gorlin's syndrome. syndrome-associated tumors (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 tumors (GIST), skeletal muscle or smooth muscle cancer, gastric cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0444] In some embodiments, the GSPT1 -mediated disease is recurrent cancer.

[0445] In some embodiments, the GSPT1 -mediated disease is refractory to one or more prior therapies.

[0446] In some embodiments, the methods include administering a therapeutically effective amount of one or more compounds or compositions described herein to a subject (e.g., a mammalian subject, such as a human subject) in need or determined to be in need of such treatment. In some embodiments, the disclosed methods include selecting a subject and administering to the subject an effective amount of one or more compounds or compositions described herein, and optionally repeating the administration as needed to prevent or treat cancer.

[0447] In some embodiments, the selection of subject may include obtaining a sample and testing the sample from a subject (e.g., candidate subject), and obtaining an indication that the subject is suitable for selecting a subject. In some embodiments, it is possible, for example, by a healthcare professional, to confirm or identify that a subject is high in risk of having, about to have, or suffering from a certain condition or disease. In some embodiments, suitable subjects include, for example, suffering from or having suffered from a condition or disease but having resolved the disease or its aspects, presenting a subject whose disease symptoms are alleviated (e.g., relative to other subjects (e.g., most subjects) suffering from the same condition or disease), or surviving a long time in a condition or disease (e.g., relative to other subjects (e.g., most subjects) suffering from the same condition or disease), for example, being in an asymptomatic state (e.g., relative to other subjects (e.g., most subjects) suffering from the same condition or disease). In some embodiments, the display of a positive immune response for a condition or disease can be made by patient records, family history, or detecting an indication of a positive immune response. In some embodiments, multiple parties may be included in the subject's selection. For example, the first party may obtain a sample from a candidate subject, and the second party may test the sample. In some embodiments, the subject may be selected or mentioned by a medical practitioner (e.g., general practitioner). In some embodiments, selection of a subject may include obtaining a sample from the selected subject and storing the sample or using the sample in the methods disclosed herein. The sample may include, for example, a cell or a population of cells.

[0448] In some embodiments, the methods of treatment may include single administration, multiple administration, and repeated administration of one or more compounds disclosed herein as needed to prevent or treat a disease or condition disclosed herein (e.g., a GSPT1-mediated disease). In some embodiments, the methods of treatment may include assessing the subject's disease level before, during, or after treatment. In some embodiments, treatment may continue until a decrease in the subject's disease level is detected.

[0449] As used herein, the term "subject" or "patient" refers to any animal subject. In some cases, the subject is a mammal. In some cases, the term "subject" as used herein refers to a human (e.g., a man, woman, or child). A subject can include, for example, a human or veterinary patient, or a human or veterinary subject participating in a clinical trial.

[0450] As used herein, the terms "administer," "apply," or "administering" refer to implanting, ingesting, injecting, inhaling, or otherwise absorbing a compound or composition, regardless of its form. For example, the methods disclosed herein include administering an effective amount of a compound or composition to achieve a desired or prescribed effect.

[0451] As used herein, the terms "treat," "treated," or "therapy" refer to partial or complete alleviation, inhibition, improvement, or alleviation of a disease or condition suffered by a subject. This means any manner in which one or more symptoms of a disease or condition (e.g., cancer) are improved or otherwise beneficially altered. As used herein, improvement of the symptoms of a particular condition (e.g., cancer) refers to any alleviation, whether permanent or temporary, long-lasting or short-lived, attributable to or associated with the treatment with the compounds, compositions, and methods of the invention. In some embodiments, treatment can promote or result in, for example, a decrease in the number of tumor cells (e.g., in a subject) relative to the number of tumor cells before treatment; a decrease in the viability (e.g., average / mean viability) of tumor cells (e.g., in a subject) relative to the viability of tumor cells before treatment; a decrease in the growth rate of tumor cells; a decrease in the rate of local or distant tumor metastasis; a reduction in one or more symptoms associated with one or more tumors compared to the symptoms of the subject before treatment.

[0452] As used herein, the terms "prevent," "preventing," and "prophylaxis" shall refer to a reduction in the occurrence of a disease or a decrease in the risk of developing a disease or its associated symptoms in a subject. 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 disease or pathological cells in the subject occur less frequently, appear later, or progress more slowly than would occur in the absence of the present invention. In certain embodiments, the subject is at increased risk for developing one or more GSPT1-mediated diseases. Exemplary GSPT1-mediated diseases that can be treated with the compounds include, for example, brain cancer, stomach cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, and hematopoietic cancers such as myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, myeloma, and other hematological malignancies.

[0453] In some embodiments, the compounds are more effective than existing drugs in treating diseases such as cancer. For example, the compounds may be effective at lower doses than existing drugs. In some embodiments, the compounds are more effective than known cereblon modulators. In some embodiments, the compounds are more effective than CC-90009. In some embodiments, the compounds are more effective than known drugs in reducing cell viability. For example, the compounds are more effective than CC-90009 in reducing cancer cell viability.

[0454] In some embodiments, the combination of the compound and a second compound (e.g., a FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, a PI3K-AKT-mTOR pathway inhibitor or activator) is more effective in treating conditions such as cancer compared to existing drugs. The second compound can be a FLT3 pathway inhibitor or a FLT3 inhibitor. In some embodiments, the second compound includes a FLT3 pathway inhibitor. In some embodiments, the second compound includes a FLT3 inhibitor. In some embodiments, examples of the FLT3 inhibitor include: Gilteritinib, Midostaurin, Sorafenib, Sunitinib, Lestaurtinib, Quizartinib, Crenolanib, or Sitravatinib. In some embodiments, the FLT3 inhibitor includes Gilteritinib. In some embodiments, the compound used in combination with the second compound is effective at a lower dose than existing drugs. In some embodiments, the compound used in combination with the second compound is more effective than a known cereblon modulator. In some embodiments, the compound used in combination with the second compound is more effective than CC-90009. In some embodiments, the compound used in combination with the second compound is more effective at reducing cell viability than known drugs. For example, the compound used in combination with the second compound may be more effective than CC-90009 at reducing cancer cell viability. In some embodiments, the compound used in combination with the second compound achieves enhanced therapeutic efficacy compared to another drug.

[0455] In some embodiments, the second compound includes a RAS-RAF-MEK-ERK pathway inhibitor. In some embodiments, the RAS-RAF-MEK-ERK pathway inhibitor includes Vemurafenib, Dabrafenib, Encorafenib, SB590885, PLX4720, XL281, RAF265, Trametinib, Binimetinib, Cobimetinib, Selumetinib, CI-1040 or PD0325901. In some embodiments, the second compound includes a PI3K-AKT-mTOR pathway inhibitor or activator. In some embodiments, the PI3K-AKT-mTOR pathway inhibitors or activators include: Apitolisib, Idelalisib, Copanlisib, Duvelisib, MK-2206, ARQ-092, Gedatolisib, Apitolisib, VQD-002, Perifosine, AZD5363, Ipatasertib, Rapamycin, mycin), temsirolimus, everolimus, ridaforolimus, Rapalogs, sirolimus, dactolisib, BGT226, SF1126, PKI-587, NVPBE235, sapanisertib, AZD8055, and AZD2014, wortmannin, LY294002, hibiscone C C), Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, bisper oxovanadium, or Sarcopoterium.

[0456] In some embodiments, the second compound is a chemotherapeutic agent, including, for example, an alkylating agent (e.g., thiotepa or cyclophosphamide), an antimetabolite (e.g., 5'-azacitidine, 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 chemotherapeutic agent is 5'-azacitidine.

[0457] In some embodiments, the compounds disclosed herein selectively affect GSPT1-mediated disease cells compared to WT (wild-type) cells (i.e., the heterobifunctional compound is able to kill or inhibit the growth of GSPT1-mediated disease cells while also having a relatively low ability to lyse or inhibit the growth of WT cells), for example, having a GI of 1.5-fold or more, 2-fold or more, 2.5-fold or more, 3-fold or more, 4-fold or more, 5-fold or more, 6-fold or more, 7-fold or more, 8-fold or more, 9-fold or more, 10-fold or more, 15-fold or more, or 20-fold or more against one or more GSPT1-mediated disease cells. 50 , compared to the GI of one or more WT cells (e.g., WT cells of the same species and tissue type as the GSPT1-mediated disease cells) 50 .

[0458] In some embodiments, the compound has an IC of 50 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, the IC of the compound is 50 In some cases, the IC of the compound is determined based on treatment of cells with the compound alone. 50 In some cases, the IC 50 In some cases, the IC 50 Below 75 nM. 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 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 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 Table 2 shows the IC values ​​of the compounds. 50 Some examples of values ​​and ranges.

[0459] In some embodiments, the compound is used in combination with a second compound (e.g., a FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or agonist) to inhibit the IC 50 IC value lower than CC-90009 50 value. 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 by treating cells with the compound in combination with a second compound (e.g., gilteritinib). In some cases, the IC of a compound used in combination with a second compound is 50 In some cases, the IC of a compound used in combination with a second compound is less than 100 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 100 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 75 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 50 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 25 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 10 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 9 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 8 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 7 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 6 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 5 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 4 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 3 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 2 nM. 50In some cases, the IC of a compound used in combination with a second compound is less than 1 nM. 50 In some cases, the IC of a compound used in combination with a second compound is less than 0.5 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 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 Above 0.25nM.

[0460] 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, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, disorder or symptom, the patient's predisposition to the disease, disorder or symptom, and the judgment of the treating physician.

[0461] The effective amount can be administered in single or multiple administrations, applications or dosages. The therapeutically effective amount (i.e., effective dose) of the therapeutic compound depends on the selected therapeutic compound. In addition, treating a subject with a therapeutically effective amount of a compound or composition as described herein may 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 once or more per day to once or more per week; including once every other day. It will be understood by those skilled in the art that certain factors may affect the dosage and time required to effectively treat the subject, including but not limited to the severity of the disease or condition, previous treatment, the general health or age of the subject, and other diseases present.

[0462] After administration, the subject can be assessed to detect, evaluate or determine their disease level. In some cases, treatment can continue until a change (such as a reduction) in the subject's disease level is detected. After the patient's condition improves (for example, the subject's disease level changes (for example, decreases)), if necessary, a maintenance dose of a compound or composition disclosed herein can be administered. Subsequently, the dosage or frequency of administration or both can be reduced (for example, as a function of symptoms) to a level that maintains the improved condition. However, once any disease symptoms recur, the patient may need long-term intermittent treatment.

[0463] The method can include administering the compound to the subject by any of the routes of administration described herein. In one embodiment, the compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.

[0464] 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.

[0465] In some embodiments, the additional treatment regimen is selected from surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy.

[0466] Some embodiments involve the administration of additional compounds.Such additional compounds may preferably be kinase inhibitors, in particular, FLT3 pathway inhibitors (e.g., Gilteritinib, Midostaurin, Sorafenib, Sunitinib, Lestaurtinib, Quizartinib, Crenolanib or Sitravatinib), MAPK pathway inhibitors, RAS-RAF-MEK-ER K pathway inhibitors (e.g., vemurafenib, dabrafenib; encorafenib, SB590885, PLX4720, XL281, RAF265, trametinib, binimetinib, cobimetinib, selumetinib, CI-1040, or PD0325901), or PI3K-AKT-mTOR pathway inhibition agents or agonists (e.g., Apitolisib, Idelalisib, Copanlisib, Duvelisib, MK-2206, ARQ-092, gedatolisib, Apitolisib, VQD-002, Perifosine, AZD5363, Ipatasertib, Rapamycin, Temsirolimus, msirolimus), everolimus, ridaforolimus, Rapalogs, sirolimus, dactolisib, BGT226, SF1126, PKI-587, NVPBE235, sapanisertib, AZD8055, and AZD2014, wortmannin, LY294002, hibiscone C, taselisib, perifosine, buparlisib, umbralisib, PX-866, dactolisib, CUDC-907, voxtalisib, bisper oxovanadium, or sarcopoterium.

[0467] Some embodiments include administering a first compound to a subject in need thereof. 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 as shown in any of Formulas (I)-(IV) or (A), or a pharmaceutically acceptable salt thereof. In some embodiments, the first compound includes any one of the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

[0468] In some embodiments, the first compound does not bind to JAK. In some embodiments, the first compound includes a truncated JAK binding portion. In some embodiments, the first compound does not include a JAK binding portion. Some implementations include administering to the 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 includes a FLT3 pathway inhibitor. In some embodiments, the second compound includes a RAS-RAF-MEK-ERK pathway inhibitor. In some embodiments, the second compound includes a PI3K-AKT-mTOR pathway inhibitor or activator. Some embodiments include a method of treatment comprising administering to a subject in need thereof 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 the subject as a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In some embodiments, the first compound and the second compound are administered to the subject together. In some embodiments, the first compound and the second compound are administered separately to the subject.

[0469] Some embodiments include methods of treating or preventing cancer comprising administering to a subject in need thereof a compound that has degrader activity against GSPT1 in combination with one or more additional therapeutic agents, wherein the additional therapeutic agent is selected from an inhibitor of an inhibitory molecule, an activator of a co-stimulatory molecule, a chemotherapeutic agent, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, or a combination thereof.

[0470] In some embodiments, a method of treating or preventing cancer is provided, comprising administering to a subject in need thereof a combination comprising (a) a compound as shown in any one of Formula (I)-(IV) or Formula (A), or a pharmaceutically acceptable salt thereof; and (b) a second therapeutic agent.

[0471] 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 includes Gilteritinib. In some embodiments, the second compound includes a FLT3 pathway inhibitor (such as Gilteritinib).

[0472] In some embodiments, the second or multiple 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 includes 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 includes a RAS-RAF-MEK-ERK pathway inhibitor.

[0473] 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, n), temsirolimus, everolimus, ridaforolimus, Rapalogs, sirolimus, dactolisib, BGT226, SF1126, PKI-587, NVPBE235, sapanisertib, AZD8055, and AZD2014, wortmannin, LY294002, hibiscone C 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.

[0474] definition

[0475] Unless defined otherwise, 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.

[0476] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0477] The terms "including" and "comprising" are used in their open, non-limiting sense.

[0478] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably containing from one to fifteen carbon atoms (i.e., C1-C 15 In certain embodiments, the alkyl group contains from one to thirteen carbon atoms (i.e., C1-C 13 In certain embodiments, the alkyl group comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In certain embodiments, the alkyl group comprises one to five carbon atoms (i.e., C1-C5 alkyl). In certain embodiments, the alkyl group comprises one to four carbon atoms (i.e., C1-C4 alkyl). In certain embodiments, the alkyl group comprises one to three carbon atoms (i.e., C1-C3 alkyl). In certain embodiments, the alkyl group comprises one to two carbon atoms (i.e., C1-C2 alkyl). In certain embodiments, the alkyl group comprises one carbon atom (i.e., C1 alkyl). In certain embodiments, the alkyl group comprises five to fifteen carbon atoms (i.e., C5-C 15 Alkyl). In certain embodiments, the alkyl group comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In certain embodiments, the alkyl group comprises two to five carbon atoms (i.e., C2-C5 alkyl). In certain embodiments, the alkyl group comprises three to five carbon atoms (i.e., C3-C5 alkyl). In certain embodiments, the 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 (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise expressly stated in this specification, the alkyl group may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0479] The term "C x-y " when used in conjunction with a chemical moiety such as an alkyl, alkenyl, or alkynyl group, is intended to include groups containing from x to y carbons in the chain. For example, "C 1-6The term "alkyl" refers to an alkyl group which may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and includes straight-chain alkyl groups and branched-chain alkyl groups.

[0480] As used herein, "allyl" refers to a -CH2CH=CH2 group.

[0481] "Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C 12 In some embodiments, the alkenyl group comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In some embodiments, the alkenyl group comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In some embodiments, the alkenyl group comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl group is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Unless otherwise expressly stated in this specification, the alkenyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0482] "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C 12 Alkynyl). In certain embodiments, the alkynyl group contains two to eight carbon atoms (i.e., C2-C8 alkynyl). In certain embodiments, the alkynyl group contains two to six carbon atoms (i.e., C2-C6 alkynyl). In certain embodiments, the alkynyl group contains two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl group is connected to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise expressly stated in this specification, the alkynyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0483] The term "C x-y Alkenyl" and "C x-y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group similar in length and possible substituents to the alkyl groups above, but containing at least one double or triple bond, respectively. The term -C x-y Alkenylene- refers to a substituted or unsubstituted alkenylene chain having from x to y carbon atoms in the alkenylene chain. For example, –C 2-6Alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene and hexenylene, any of which is optionally substituted. The alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. Term - C x-y Alkyne- refers to a substituted or unsubstituted alkenylene chain having from x to y carbon atoms in the alkynyl chain. For example, –C 2-6 Alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene and hexynylene, any of which are optionally substituted. The alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0484] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, which consists only of carbon and hydrogen, does not contain unsaturation, and preferably has one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. The connection point of the alkylene chain to the rest of the molecule and the group can be through any two carbon atoms in the chain. In certain embodiments, the alkylene group comprises one to ten carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, the alkylene group comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, the alkylene group comprises one to five carbon atoms (i.e., C1-C5 alkylene). In certain embodiments, the alkylene group comprises one to four carbon atoms (i.e., C1-C4 alkylene). In certain embodiments, the alkylene group comprises one to three carbon atoms (i.e., C1-C3 alkylene). In certain embodiments, the alkylene group comprises one to two carbon atoms (i.e., C1-C2 alkylene). In certain embodiments, the alkylene group comprises one carbon atom (i.e., C1 alkylene). In certain embodiments, the alkylene group comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In certain embodiments, the alkylene group comprises two to five carbon atoms (i.e., C2-C5 alkylene). In certain embodiments, the alkylene group comprises three to five carbon atoms (i.e., C3-C5 alkylene). x-y Alkylene- refers to a substituted or unsubstituted alkylene chain having from 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 of which is optionally substituted.

[0485] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a radical, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having two to twelve carbon atoms. The alkenylene chain is connected to the rest of the molecule by a single bond and to the radical by a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and the radical can be through any two carbon atoms in the chain. In certain embodiments, the alkenylene group comprises two to ten carbon atoms (i.e., C2-C 10 In certain embodiments, the alkenylene group comprises two to eight carbon atoms (i.e., C2-C8 alkenylene). In certain embodiments, the alkenylene group comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In certain embodiments, the alkenylene group comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In certain embodiments, the alkenylene group comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In certain embodiments, the alkenylene group comprises two carbon atoms (i.e., C2 alkenylene). In certain embodiments, the alkenylene group comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In certain embodiments, the alkenylene group comprises three to five carbon atoms (i.e., C3-C5 alkenylene).

[0486] "Alkynylidene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a radical, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having two to twelve carbon atoms. The alkynylene chain is connected to the rest of the molecule by a single bond and to the radical by a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and the radical can be through any two carbon atoms in the chain. In certain embodiments, the alkynylene group comprises two to ten carbon atoms (i.e., C2-C 10 In certain embodiments, the alkynylene group comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In certain embodiments, the alkynylene group comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In certain embodiments, the alkynylene group comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In certain embodiments, the alkynylene group comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In certain embodiments, the alkynylene group comprises two carbon atoms (i.e., C2 alkynylene). In certain embodiments, the alkynylene group comprises five to eight carbon atoms (i.e., C5-C8 alkynylene). In certain embodiments, the alkynylene group comprises three to five carbon atoms (i.e., C3-C5 alkynylene).

[0487] As used herein, the term "alkoxy" refers to an alkyl group, as defined herein, attached to the remainder of the molecule via an oxygen atom. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0488] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom, wherein the ring system contains at least one aromatic ring. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon and contains from 5 to 18 carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system consistent with 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. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, groups derived from anthracene, naphthylene, phenanthrenyl, anthracene, azulene, benzene, The aromatic hydrocarbon ring system of fluoranthene, fluorene, as-indane, s-indane, indane, indene, naphthalene, perobenzonaphthalene, phenanthrene, pleiadene, pyrene and triphenylene. Unless otherwise specified in the specification, the aromatic hydrocarbon ring system may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0489] " assorted alkyl " refers to that one or more skeleton atoms in alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (such as-NH-,-N (alkyl)-), sulphur, phosphorus, or their combination.Assorted alkyl is connected with the remainder of molecule at the carbon atom of assorted alkyl. In one aspect, assorted alkyl is C1-C6 assorted alkyl, wherein assorted alkyl is by 1 to 6 carbon atom and one or more atoms (such as oxygen, nitrogen (such as-NH-,-N (alkyl)-), sulphur, phosphorus, or its combination) composition except carbon, wherein assorted alkyl is connected with the remainder of molecule at the carbon atom of assorted alkyl. The example of assorted alkyl is, such as-CH2OCH3,-CH2CH2OCH3,-CH2CH2OCH2CH2OCH3,-CH(CH3)OCH3,-CH2NHCH3,-CH2N(CH3)2,-CH2CH2NHCH3, or-CH2CH2N(CH3)2.

[0490] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic group (i.e., a 3-18 membered heteroaryl) comprising 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it comprises a cyclic, delocalized (4n+2)π-electron system consistent with the Hückel theory. In certain embodiments, heteroaryl refers to a group derived from a 3- to 10-membered aromatic ring group (3-10 membered heteroaryl). In certain embodiments, heteroaryl refers to a group derived from a 5- to 7-membered aromatic ring (5-7 membered heteroaryl). Heteroaryl includes fused rings or bridged ring systems. The heteroatoms in the heteroaryl are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl is connected to the rest of the molecule through any atom of the ring. Examples of such groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, etc. In certain embodiments, heteroaryl is connected to the rest of the molecule via a ring carbon atom. In certain embodiments, heteroaryl is connected to the rest of the molecule via a nitrogen atom (N- connected) or a carbon atom (C- connected). For example, a group derived from pyrrole can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). For example, a group derived from imidazole can be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).

[0491] As used herein, the term "heterocyclyl" refers to a non-aromatic, monocyclic, bicyclic, tricyclic or tetracyclic group having a total of 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 atoms in its ring system and containing 3 to 12 carbon atoms and 1 to 4 heteroatoms independently selected from O, S and N, with the proviso that the ring of the group does not contain two adjacent O atoms or two adjacent S atoms. The heterocyclyl group may include a fused ring, a bridged ring or a spiro ring system. In certain embodiments, the heterocyclyl group includes 3 to 10 ring atoms (3-10 membered heterocyclyl). In certain embodiments, the heterocyclyl group includes 3 to 8 ring atoms (3-8 membered heterocyclyl). In certain embodiments, the heterocyclyl group includes 4 to 10 ring atoms (4-10 membered heterocyclyl). In certain embodiments, the heterocyclyl group includes 4 to 8 ring atoms (4-8 membered heterocyclyl). The heterocyclyl group may include an oxo substituent on any available atom that can produce a stable compound. For example, such a group can include an oxo group at an available carbon atom or nitrogen atom. If chemically feasible, such a group can include more than one oxo group. In addition, it should be understood that when such a heterocyclic group contains a sulfur atom, the sulfur atom can be oxidized by one or two oxygen atoms to provide a sulfoxide or sulfone. An example of a 4-membered heterocyclic 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-quinolinyl. Other examples of such heterocyclic groups are, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidine, morpholine, thiomorpholine, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine, diazepine, thiazepine, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl Heteroaryl groups include, but are not limited to, 1,3-dioxolane, 1,4-dioxolanyl, 1,6-dioxolane, 1,7-dioxolane, 1,8-dioxolane, 1,9-dioxolane, 2,10-dihydro-1,2-dihydro-1,3-dihydro-1,3-dihydro-2,4-dihydro-3,4-dihydro-4,4-dihydro-5,6-dihydro-6,6-dihydro-7,4-dihydro-8,6-dihydro-1,3-dihydro-2,4-dihydro-3,4-dihydro-4,4-dihydro-5,6 ...

[0492] "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 monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, such as phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as long as the valence permits, is included in the definition of carbocycle. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. In some embodiments, the carbocycle is aryl. In some embodiments, the carbocycle is cycloalkyl. In some embodiments, the carbocycle is cycloalkenyl. In some embodiments, the carbocycle contains a triple bond. Unless otherwise expressly stated in this specification, a carbocycle may be optionally substituted.

[0493] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, and preferably having 3 to 12 carbon atoms. In certain embodiments, the cycloalkyl group comprises 3 to 10 carbon atoms. In certain embodiments, the cycloalkyl group comprises 3 to 7 carbon atoms. The cycloalkyl group is connected to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like.

[0494] "Cycloalkylene" is a bidentate group obtained by removing a hydrogen atom from a cycloalkyl group as defined above. Examples of such groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cycloheptylene, and the like.

[0495] As used herein, "spirocycle" has its conventional meaning, i.e., any ring system comprising two or more rings, wherein both rings have a common ring carbon. As defined herein, each ring of a spirocycle system independently contains 3 to 20 ring atoms. Preferably, it has 3 to 10 ring atoms. Non-limiting examples of spirocycle systems include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.

[0496] The term "cyano" refers to a -C≡N group.

[0497] An "aldehyde" group refers to a -C(O)H group.

[0498] "Alkoxy" refers to an -O-alkyl group, as defined herein.

[0499] "Alkoxycarbonyl" refers to a -C(O)-alkoxy group, as defined herein.

[0500] "Alkylaminoalkyl" refers to an -alkyl-NR-alkyl group, as defined herein.

[0501] "Alkylsulfonyl" refers to a -SO2 alkyl group, as defined herein.

[0502] "Amino" refers to an optionally substituted -NH2.

[0503] "Aminoalkyl" means an -alkyl-amino group, as defined herein.

[0504] "Aminocarbonyl" refers to a -C(O)-amino group, as defined herein.

[0505] "Arylalkyl" means an -alkylaryl group in which alkyl and aryl are as defined herein.

[0506] An "aryloxy" group refers to both -O-aryl and -O-heteroaryl groups, as defined herein.

[0507] "Aryloxycarbonyl" means a -C(O)-aryloxy group, as defined herein.

[0508] "Arylsulfonyl" means a -SO2 aryl group, as defined herein.

[0509] "Carbonyl" means a -C(O)- group, as defined herein.

[0510] A "carboxylic acid" group refers to a -C(O)OH group.

[0511] "Cycloalkoxy" refers to an -O-carbocyclic group, as defined herein.

[0512] A "halo" or "halogen" group refers to fluoro, chloro, bromo, or iodo.

[0513] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above that is substituted with one or more halogen groups, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group may be optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include methyl halides (e.g., methyl chloride, methyl bromide, methyl fluoride, methyl iodide), 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 group, each halogen group can be independently selected, for example, 1-chloro, 2-fluoroethane.

[0514] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluorine groups, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2fluoro-ethyl, and the like.

[0515] "Hydroxy" refers to an -OH group.

[0516] A "nitro" group refers to a -NO2 group.

[0517] An "oxo" group refers to a =0 substituent.

[0518] When referring to a moiety, the term "length" refers to the minimum number of carbon and / or heteroatoms from one end of the moiety to its other end. When referring to a linker, it means the minimum number of atoms from the end attached to the TRK ligand to the end attached to the degradation tag. This applies whether the linker is linear or branched, as well as when the linker contains a ring system.

[0519] The term "substituted" means that the designated group or moiety bears one or more substituents independently selected from the group consisting of 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, halogen, -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) -C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -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), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl).

[0520] The term "none" or "absent" refers to the absence of an atom or moiety and the presence of bonds between adjacent atoms in the structure.

[0521] The term "optionally substituted" means that the specified group may be unsubstituted or substituted with one or more substituents as defined herein. It should be understood that in the compounds of the present invention, when a group is referred to as "unsubstituted," or "substituted" with a group that is less than the valence of all atoms in the compound, the remaining valences of the group are filled with hydrogen. For example, if a C6 aryl group, also referred to herein as "phenyl," is substituted with an additional substituent, one of ordinary skill in the art will understand that such a group has 4 open positions on the carbon atoms of the C6 aromatic ring (6 initial positions, minus one position and one additional substituent to which the rest of the compounds of the present invention are attached, leaving 4 positions open). In this case, each of the remaining 4 carbon atoms is combined with a hydrogen atom to fill their valences. Similarly, if a C6 aryl group in a compound of the present invention is referred to as "disubstituted," one of ordinary skill in the art will understand that it means that the C6 aryl group has 3 unsubstituted remaining carbon atoms. Each of these three unsubstituted carbon atoms is combined with a hydrogen atom to fill their valences. Unless otherwise indicated, an optionally substituted group may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, CN, NO2, OR m SR m NR n R o 、COR m 、CO2R m 、CONR n R o 、SOR m 、SO2R m 、SO2NR n R o NR n COR o NR m C(O)NR n R o NR n SOR o NR n SO2R o , C1-C8 alkyl, C1-C8 alkoxy C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino C1-C8 alkyl, C3-C7 carbocyclyl, 3-7 membered heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and heteroaryl, wherein R m 、R n and R o are independently selected from: none, hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 carbocyclyl, 3-7 membered heterocyclyl, aryl and heteroaryl, or R n and R oTogether with the atoms to which they are attached, they form a 3-8 membered cycloalkyl ring or heterocyclyl ring.

[0522] The term "combination therapy" or "combination" or "in combination with" refers to the administration of two or more therapeutic agents to treat the conditions or diseases described in this disclosure (e.g., cancer). Such administration includes co-administering these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration includes co-administering each active ingredient in multiple containers or in separate containers (e.g., capsules, powders, and liquids). The powders and / or liquids can be reconstituted or diluted to the desired dose prior to administration. In addition, such administration also includes using each type of therapeutic agent in a sequential manner, at approximately the same time or at different times. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or diseases described herein.

[0523] Combination therapy can provide "synergy" and demonstrate "synergy," that is, the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by the compounds when used alone. A synergistic effect can be achieved when the active ingredients are: (1) formulated and administered or delivered simultaneously in a combined unit dosage formulation; (2) delivered in alternation or parallel delivery as separate formulations; or (3) delivered by some other regimen. When delivered in alternation therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, by different injections in separate syringes. Generally, during alternation therapy, an effective dose of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective doses of two or more active ingredients are administered together.

[0524] As used herein, the term "pharmaceutical combination" refers to a fixed combination in one dosage unit form, or a non-fixed combination or kit for combined administration wherein two or more therapeutic agents may be administered independently simultaneously or separately within time intervals, particularly when these time intervals allow the combination partners to exhibit a synergistic effect (e.g., a synergistic effect).

[0525] As used herein, "therapeutic agent" refers to a therapy (e.g., a molecule) including but not limited to a compound, peptide, antibody, antibody fragment, antibody conjugate, or nucleic acid; gene or cell therapy; or radiation therapy, that has therapeutic activity or enhances therapeutic activity when administered to a subject in combination with a compound of the disclosure, or reduces one or more side effects of a compound of the disclosure when administered to a subject in combination with a compound of the disclosure.

[0526] "Cancer" refers to any cancer caused by the uncontrolled proliferation of abnormal cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc. Cancer cells can spread locally or spread to other parts of the body through the blood and lymphatic system. For example, cancer includes but is 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 lymphotropic virus (HTLV) 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 lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include: myelodysplastic syndrome, solid tumors in children such as brain tumors, neuroblastoma, retinoblastoma, Wilms tumor, bone tumors and soft tissue sarcomas, common solid tumors in adults such as head and neck cancer (e.g., oral cancer, laryngeal cancer and nasopharyngeal cancer), esophageal cancer, genitourinary cancer (e.g., prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, testicular cancer), lung cancer (e.g., small cell carcinoma and non-small cell carcinoma), breast cancer, pancreatic cancer, melanoma, and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin's 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). Other exemplary cancer types that can be treated by the compounds and compositions described herein include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0527] The second agent can be an anticancer agent. The term "anticancer" or "anticancer agent" refers to an agent for treating cancer (i.e., a compound, antibody, etc. that can be used to treat cancer). The anticancer effect may be produced by 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 infiltration (the spread of tumor cells to adjacent normal structures), inhibiting checkpoint molecules, or promoting apoptosis.

[0528] The anticancer agent is an antiproliferative agent or an immunomodulatory agent. In one embodiment, the second agent is an immunomodulatory agent.

[0529] As used herein, the term "antiproliferative" or "antiproliferative agent" 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-targeted drugs, topoisomerase poisons, inhibitors of molecular targets or enzymes.

[0530] The term "immunomodulator" is an agent that alters the immune response or immune system function (such as by stimulating antibody formation or inhibiting leukocyte activity). The immunomodulator can be an immunomodulator, a cytokine, a vaccine, or an antibody.

[0531] The term "immunomodulator" refers to inhibitors of immune checkpoint molecules.

[0532] Other cancers for which the compounds and compositions described herein can be used for prevention, treatment, and research include, for example, colon cancer, familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, or melanoma. In addition, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary system cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors, gallbladder cancer, bronchogenic carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0533] Example

[0534] The present disclosure is further described and demonstrated by the following examples. However, the use of these and other examples anywhere in the specification is illustrative only and in no way limits the scope and meaning of the present invention or any exemplary term. Likewise, the present invention is not limited to any particular preferred embodiment or aspect described herein. Indeed, many modifications and variations will be apparent to those skilled in the art upon reading this specification, and such changes may be made without departing from the spirit or scope of the present invention. Therefore, the present invention is limited only by the terms of the appended claims and the full scope of equivalents to which those claims are entitled.

[0535] General Chemical Methods: All chemicals and reagents were purchased commercially from suppliers and used without further purification. LCMS spectra of all compounds were obtained using a Waters LC-MS AcQuity H UPLC-class system. The Waters LC-MS H UPLC-class system included a pump with a degasser (quaternary solvent manager), an autosampler (FTN), a column oven (40°C, unless otherwise stated), and a photodiode array PDA detector. Chromatography was performed on an AcQuity UPLC BEHC18 (1.7 μm 2.1 x 50 mm) using water with 0.1% formic acid as solvent A and acetonitrile with 0.1% formic acid as solvent B at a flow rate of 0.6 mL / min. The liquid flow from the column was split to the MS spectrometer. The MS detector was equipped with an electrospray ionization source. Nitrogen was used as the nebulizer gas. Data acquisition was performed using a MassLynx data system. The nuclear magnetic resonance spectra were recorded on a Bruker AvanceⅢ400 spectrometer. Chemical shifts are expressed in parts per million (ppm) and reported as δ values ​​(chemical shift δ). Coupling constants are in Hertz (J value, Hertz; integration and splitting mode: where s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet). Purification of intermediates or final products was carried out on an Agilent Prep 1260 series with the UV detector set to 254 nm or 220 nm. The sample was injected onto a Phenomenex Luna C18 column (5 μm, 30x75 mm) at room temperature. The flow rate was 40 mL / min. A linear gradient of 10% or 50% MeOH in H2O containing 0.1% TFA was used as solvent A and 100% MeOH as solvent B. Alternatively, the product was purified by HPLC. Purification was performed on a NextGen 300 system with UV detection set to 254 nm, 220 nm, or 280 nm. The flow rate was 40 mL / min. A linear gradient of 0.05% TFA in H2O was used as solvent A, and 0.05% TFA in 100% MeOH was used as solvent B. All compounds were >95% pure using LCMS.

[0536] 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)

[0537]

[0538] 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 K2CO3 (40.8 mg, 295 μmol). After stirring the reaction mixture at 60°C for 12 h, the reaction mixture was purified by reverse phase chromatography to give the desired product (2.1 mg, yield: 3%) as a yellow solid. MS (ESI) m / z = 577.3 [M+H] + .

[0539] Example 2. 5-(((trans-3-(4-(3-cyclopropyloxypyridin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-641)

[0540]

[0541] Step 1. Synthesis of 2-bromo-3-cyclopropyloxypyridine

[0542] To a solution of cyclopropanol (1.98 g, 34.09 mmol) in DMF (20 mL) was slowly added NaH (2.73 g, 68.19 mmol) at 0°C. After the reaction was stirred at 0°C for 1 h, 2-bromo-3-fluoro-piperidine (3 g, 17.05 mmol) was added dropwise. The resulting mixture was stirred at 70°C for 16 h. After the reaction mixture was cooled to room temperature, it was poured into a saturated aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (3x60 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 flash chromatography on silica gel to give the desired product (600 mg, yield: 17%) as a light yellow oil. MS (ESI) m / z = 214.0 [M+H] + .

[0543] Step 2. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((trans-3-(4-(3-(cyclopropyloxy)-2-pyridinyl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0544] To a solution of 2-bromo-3-(cyclopropyloxy)pyridine (100.0 mg, 0.467 mmol) in MeCN (6.0 mL) and water (4.0 mL) was added tert-butyl N-tert-butyloxycarbonyl-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 G (45.1 mg, 0.0467 mmol), and KCO (128.9 mg, 0.934 mmol) at room temperature. The reaction mixture was stirred at 100 ° C. under an inert atmosphere for 16 h. 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 afford the desired product (171.0 mg, yield: 70%) as a pale white solid. MS (ESI) m / z = 525.2 [M+H] + .

[0545] Step 3. Synthesis of (trans-3-(4-(3-cyclopropyloxypyridin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methanamine

[0546] To a solution of tert-butyl N-tert-butyloxycarbonyl-N-((trans-3-(4-(3-(cyclopropyloxy)-2-pyridinyl)-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, yield: 95%) as a light yellow oil. MS (ESI) m / z = 325.0 [M+H] + .

[0547] Step 4. Synthesis of 5-(((trans-3-(4-(3-cyclopropyloxypyridin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0548] To a solution of (trans-3-(4-(3-cyclopropyloxypyridin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)methanamine (180.0 mg, 0.555 mmol) and 2-(2,6-dioxo-3-piperidinyl)-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 h under microwave irradiation. After cooling to room temperature, the mixture was poured into water (15 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were 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, yield: 14%) as a yellow solid. MS (ESI) m / z = 581.7 [M+H] + .

[0549] 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)

[0550]

[0551] Step 1. Synthesis of tert-butyl (3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)propyl)carbamate

[0552] 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, yield: 60%) as a light yellow solid. MS (ESI) m / z = 394.5 [M+H] + .

[0553] Step 2. Synthesis of 3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)propan-1-amine

[0554] 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 at room temperature for 1 hour. The resulting mixture was concentrated to give the crude product (30 mg, 100% yield) as a light yellow solid. This compound was used in the next step without further purification. MS (ESI) m / z = 294.5 [M+H] + .

[0555] 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

[0556] 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. for 1 h under microwave irradiation. After cooling to room temperature, the mixture was purified by reverse phase chromatography to give the desired product (15 mg, yield: 27%) as a light yellow solid. MS (ESI) m / z = 550.6 [M + H] + .

[0557] 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)

[0558]

[0559] Step 1. Synthesis of tert-butyldimethyl((trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methoxy)silane

[0560] 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 at 0°C for 30 min, CHI (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 another 2 h. The reaction was quenched with aqueous NH4Cl 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, yield: 64%) as a colorless oil.

[0561] Step 2. Synthesis of (trans-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)boronic acid

[0562] 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) was added NaIO4 (3.29 g, 15.36 mmol) and AcONH4 (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, yield: 81%) as a yellow oil.

[0563] Step 3. Synthesis of 6-(1-(trans-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-3-cyclopropyl-1H-pyrazol-4-yl)-3-fluoro-2-methylpyridine

[0564] 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) were added Cu(OAc)2 (200 mg, 1.10 mmol), Cs2CO 3( 538 mg, 1.65 mmol), bipyridine (172 mg, 1.10 mmol) and 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 x 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 obtain the desired product (45 mg, yield: 20%) as a yellow solid. MS (ESI) m / z = 402.5 [M + H] + .

[0565] Step 4. Synthesis of (trans-2-(3-cyclopropyl-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)methanol

[0566] 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, yield: 93%) as a light yellow solid. MS (ESI) m / z = 288.2 [M+H] + .

[0567] Step 5. Synthesis of (trans-2-(3-cyclopropyl-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)methyl 4-methylbenzenesulfonate

[0568] 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), Et3N (50 mg, 0.50 mmol) and DMAP (18 mg, 0.15 mmol) at 0°C. After the reaction mixture was stirred at room temperature for 1 h, it was poured into water (50 mL) and extracted with DCM (3x20 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 flash chromatography on silica gel to give the desired product (35 mg, yield: 76%) as a white solid. MS (ESI) m / z = 442.3 [M+H] + .

[0569] Step 6. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((trans-2-(3-cyclopropyl-4-(5-fluoro-6-methyl-2-pyridyl)pyrazol-1-yl)cyclopropyl)methyl)carbamate

[0570] 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 H0 (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were 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, yield: 90%) as a yellow oil. MS (ESI) m / z = 487.3 [M+H] + .

[0571] The remaining steps were carried out according to steps 2 to 3 of GS-642 to obtain the desired product (2 mg, two-step yield: 11%) as a yellow solid. MS (ESI) m / z = 543.3 [M+H] + .

[0572] 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)

[0573]

[0574] Step 1. Synthesis of tert-butyl N-((trans-3-(4-(7-bromoquinoxalin-2-yl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)-N-tert-butyloxycarbonyl-carbamate

[0575] To a solution of 7-bromo-2-chloro-quinoxaline (650 mg, 2.67 mmol) in dioxane (10 mL) and water (2 mL) was added tert-butyl N-tert-butyloxycarbonyl-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) at room temperature. The reaction mixture was stirred at 100°C for 4 h under an inert atmosphere. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 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, yield: 15%) as a pale white solid. MS (ESI) m / z = 598.3 [M+H] + .

[0576] Step 2. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(7-(3-hydroxyazetidin-1-yl)quinoxalin-2-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0577] 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 for 2 h under an inert atmosphere. After cooling to room temperature, the mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 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 obtain the desired product (50 mg, yield: 46%) as a pale white solid. MS (ESI) m / z = 591.7 [M+H] + .

[0578] The remaining steps were carried out according to the procedures of steps 3 to 4 in GS-641 to obtain the desired product (0.88 mg, two-step yield: 1%) as a light yellow solid. MS (ESI) m / z = 647.7 [M+H] + .

[0579] 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)

[0580]

[0581] Step 1. Synthesis of ethyl 2-(aminomethyl)cyclopropane-1-carboxylate

[0582] At room temperature, to a solution of ethyl 2-cyanocyclopropane-1-carboxylate (400 mg, 2.88 mmol) in MeOH (10 mL) was added Raney nickel (100 mg). Under a hydrogen atmosphere, the reaction mixture was stirred at room temperature for 4 h. The mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain the desired product (300 mg, 73% yield) as a colorless oil.

[0583] Step 2. Synthesis of ethyl 2-(((tert-butoxycarbonyl)amino)methyl)cyclopropane-1-carboxylate

[0584] To a solution of ethyl 2-(aminomethyl)cyclopropane-1-carboxylate (300 mg, 2.10 mmol) in dichloromethane (20 mL) was added Boc2O (900 mg, 4.20 mmol) and DMAP (384 mg, 3.15 mmol). After the reaction mixture was stirred at room temperature for 6 h, it was quenched with water (20 mL) and extracted with dichloromethane (3 mL × 20). The combined organic layer was 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.

[0585] Step 3. Synthesis of tert-butyl ((2-(hydroxymethyl)cyclopropyl)methyl)carbamate

[0586] To a solution of ethyl 2-(((tert-butoxycarbonyl)amino)methyl)cyclopropane-1-carboxylate (300 mg, 1.23 mmol) in THF (10 mL) was added LiAlH4 (140 mg, 3.70 mmol) at 0 ° C. The reaction mixture was stirred at room temperature under argon for 2 h, after which it was quenched with solid Na2SO4 and diluted with EtOAc (25 mL). The suspension was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (200 mg, 81% yield). The compound was used in the next step without further purification.

[0587] Step 4. Synthesis of methyl (2-(((tert-Butyloxycarbonyl)amino)methyl)cyclopropyl)4-methylbenzenesulfonate

[0588] To a solution of tert-butyl ((2-(hydroxymethyl)cyclopropyl)methyl)carbamate (200mg, 0.99mmol) and 4-methylbenzenesulfonyl chloride (474mg, 2.48mmol) in dichloromethane (20mL) was added EtN (500mg, 4.97mmol) and DMAP (121mg, 0.99mmol). After the reaction mixture was stirred at room temperature for 10h, it was quenched with water (20mL) and extracted with dichloromethane (2x20 mL). The combined organic layer was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain the desired product (120mg, yield: 34%) as a white solid.

[0589] Step 5. Synthesis of tert-butyl ((2-((3-cyclopropyl-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)carbamate

[0590] 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 at 80 ° C for 3 h. 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, yield: 66%) as a brown solid. MS (ESI) m / z=401.8[M+H] + .

[0591] The remaining steps were carried out according to the procedures of steps 2 to 3 of GS-642 to obtain the desired product (7 mg, 2-step yield: 25%) as a yellow solid. MS (ESI) m / z = 557.6 [M+H] + .

[0592] 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)

[0593]

[0594] Step 1. Synthesis of 6-methoxycyclohex-1-en-1-yl trifluoromethanesulfonate

[0595] To a solution of 2-methoxycyclohexen-1-one (1.5 g, 11.70 mmol) in dry THF (10 mL) was added LiHMDS (1 M, 15.21 mL) at -78°C. The reaction was stirred at -78°C for 30 minutes, followed by the dropwise addition of a solution of N-phenyl-bis(trifluoromethanesulfonimide) (4.60 g, 12.87 mmol) in anhydrous THF (5.0 mL). The reaction mixture was stirred at 25°C for 12 hours. The mixture was quenched with H2O (20 mL) and extracted with petroleum ether (30 mL x 3). The combined organic phases were washed with brine, dried over aqueous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product (3 g, 98% yield), which was used directly in the next step without purification.

[0596] Step 2. Synthesis of 2-(6-methoxycyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0597] 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 at 90°C for 12 h. The reaction was quenched with H2O (20 mL) and extracted with ethyl acetate (20 mL x 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, yield: 44%) as a yellow oil.

[0598] Step 3. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(6-methoxycyclohexen-1-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0599] 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-butyloxycarbonyl-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 H0 (1 mL) was added Pd(dppf)Cl (61.4 mg, 0.084 mmol) at room temperature. The reaction mixture was stirred at 90°C for 12 h. The reaction was quenched with H0 (20 mL) and extracted with ethyl acetate (20 mL x 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 obtain the desired product (100 mg, yield: 24%) as a yellow oil. MS (ESI) m / z = 502.9 [M+H] + .

[0600] Step 4. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(2-methoxycyclohexyl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0601] To a solution of tert-butyl N-tert-butyloxycarbonyl-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 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the desired product (100 mg, yield: 99%) as a yellow oil. The compound was used directly in the next step without further purification. MS (ESI) m / z = 504.8 [M+H] + .

[0602] The remaining steps were carried out according to the procedures of steps 3 to 4 of GS-641 to obtain the desired product (0.9 mg, two-step yield: 2%) as a yellow solid. MS (ESI) m / z = 560.6 [M+H] + .

[0603] 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)

[0604]

[0605] Step 1. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((trans-3-(3-cyclopropyl-4-[6-(3-hydroxyazetidin-1-yl)-2-pyridinyl)pyrazol-1-yl)cyclobutyl)methyl]carbamate

[0606] To a solution of azetidin-3-ol (43.6 mg, 0.40 mmol), N-tert-butyloxycarbonyl-N-((trans-3-(4-(6-chloro-2-pyridinyl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)carbamic acid tert-butyl ester (100 mg, 0.20 mmol), XantPhos (23.0 mg, 0.04 mmol) and Cs2CO3 (194.3 mg, 0.60 mmol) in toluene (10 mL) was added Pd2(dba)3 (18.2 mg, 0.02 mmol) at room temperature. The reaction mixture was stirred at 100 ° C for 12 h. The reaction was quenched with H2O (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 obtain the desired product (13 mg, yield: 12%) as a yellow oil. MS (ESI) m / z = 540.6 [M+H] + .

[0607] The remaining steps were carried out according to the procedures of steps 3 to 4 of GS-641 to obtain the desired product (0.8 mg, two-step yield: 6%) as a yellow solid. MS (ESI) m / z = 596.6 [M+H] + .

[0608] 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)

[0609]

[0610] Step 1. Synthesis of 3-chloro-N-methoxy-N-methylpyrazine-2-carboxamide

[0611] 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, yield: 93%) as a white solid. MS (ESI) m / z = 202.2 [M+H]+ .

[0612] Step 2. Synthesis of (3-chloropyrazin-2-yl)(cyclopropyl)methanone

[0613] 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 saturated ammonium chloride solution and diluted with water (20 mL). The resulting mixture was stirred at room temperature until both layers were 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, yield: 39%) as a colorless oil. MS (ESI) m / z = 183.1 [M+H] + .

[0614] Step 3. Synthesis of 3-cyclopropyl-1H-pyrazolo[3,4-b]pyrazine

[0615] 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 h 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 layer was 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, yield: 60%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ13.55(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] + .

[0616] Step 4. Synthesis of (trans-3-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutyl)methanol

[0617] 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 Cs2CO3 (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 H2O (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain two isomers. The desired trans isomer (90 mg, yield: 39%) was obtained as a yellow solid. MS (ESI) m / z = 245.5 [M+H] + .

[0618] The remaining steps were carried out according to steps 5 to 6 of GS-643 and steps 3 to 4 of GS-641 to obtain the desired product (4.2 mg, 10% yield over 4 steps) as a yellow solid. MS (ESI) m / z = 500.5 [M+H] + .

[0619] 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)

[0620]

[0621] 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

[0622] A solution of tert-butyl N-tert-butyloxycarbonyl-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 h. 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] + .

[0623] 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

[0624] 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), KCO (74.1 mg, 0.537 mmol), and Pd(dppf)Cl (26.2 mg, 0.0358 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 100° C. for 1 h under microwave irradiation. After cooling to room temperature, the mixture was concentrated and purified by reverse phase chromatography to give the desired product (20 mg, yield: 35%) as a colorless oil. MS (ESI) m / z = 323.4 [M+H] + .

[0625] 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

[0626] 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, yield: 18%) as a yellow solid. MS (ESI) m / z = 579.8 [M+H] + .

[0627] 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)

[0628]

[0629] Step 1. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((3-(3-cyclopropyl-4-(2-(dimethylamino)phenyl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0630] To a solution of 2-bromo-N,N-dimethyl-aniline (50 mg, 0.25 mmol) in dioxane (8 mL) and H2O (2 mL) were added K2CO3 (51.7 mg, 0.38 mmol) and Pd(dppf)Cl2 (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 H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography to give the desired product (50 mg, yield: 40%) as a light yellow solid. MS (ESI) m / z = 511.5 [M+H] + .

[0631] The remaining steps were carried out according to the procedures of steps 2 to 3 of GS-642 (5.0 mg, two-step yield: 13%), resulting in a light yellow solid. MS (ESI) m / z = 567.8 [M+H] + .

[0632] 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)

[0633]

[0634] Step 1. Synthesis of trans-3-(3-cyclopropyl-4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde

[0635] 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 periodate (516.3 mg, 1.22 mmol). The reaction mixture was stirred at 25° C. for 2 h, then quenched with H O (20 mL) and extracted with dichloromethane (20 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (80 mg, yield: 62%) as a yellow oil. MS (ESI) m / z=319.4 [M+H] + .

[0636] 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

[0637] 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-methylpyridine borane complex (20.2 mg, 0.19 mmol). The reaction mixture was stirred at 25°C for 12 h, then quenched with H₂O (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield the desired product (3.4 mg, 5% yield) as a yellow solid. MS (ESI) m / z = 562.7 [M+H] + .

[0638] 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)

[0639]

[0640] GS-652 (6.5 mg, 3-step yield: 7%) was synthesized as a yellow solid according to steps 1 to 3 of GS-649. MS (ESI) m / z = 608.7 [M+H] + .

[0641] 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)

[0642]

[0643] Step 1. Synthesis of tert-butyl N-((3-(4-(3-bromophenyl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)-N-tert-butyloxycarbonyl-carbamate

[0644] To a mixture of 1-bromo-3-iodo-benzene (50 mg, 0.177 mmol) and tert-butyl N-tert-butyloxycarbonyl-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 H₂O (1 mL) was added Pd(dppf)Cl₂ (25.8 mg, 0.035 mmol) and K₂CO₃ (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 H₂O (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography to obtain the desired product (50 mg, yield: 52%) as a light yellow solid. MS (ESI) m / z = 546.5 [M+H] + .

[0645] Step 2. Synthesis of tert-butyl N-((3-(4-(3-(azetidin-1-yl)phenyl)-3-cyclopropyl-pyrazol-1-yl)cyclobutyl)methyl)-N-tert-butyloxycarbonyl-carbamate

[0646] 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), Pd2(dba)3 (8.4 mg, 0.0092 mmol) and Cs2CO3 (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 H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography to give the desired product (30 mg, yield: 63%) as a yellow solid. MS (ESI) m / z = 523.5 [M+H] + .

[0647] The remaining steps were carried out according to the procedures of steps 2 to 3 of GS-642 (3 mg, two-step yield: 11%), resulting in a light yellow solid. MS (ESI) m / z = 579.7 [M+H] + .

[0648] 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)

[0649]

[0650] 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

[0651] The title compound (30 mg, yield: 45%) was synthesized as a yellow solid according to Step 2 of GS-649. MS (ESI) m / z = 449.6 [M+H] + .

[0652] Step 2. Synthesis of tert-butyl 4-(2-(1-(trans-3-(aminomethyl)cyclobutyl)-3-cyclopropyl-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxylate

[0653] 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 min. The mixture was filtered through celite and the filter cake was washed with EtOAc (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give the desired product (20 mg, 66% yield) as a yellow solid.

[0654] The remaining steps were carried out according to the procedures of steps 2 to 3 of GS-642 (3 mg, two-step yield: 11%), resulting in a yellow solid. MS (ESI) m / z = 607.7 [M+H] + .

[0655] 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)

[0656]

[0657] 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

[0658] At room temperature, under N2, 1,2-dibromoethane (45 mg, 0.23 mmol) was added to a suspension of Zn powder (382 mg, 5.85 mmol) in dry DMF (20 mL). After stirring at 80 ° C for 10 min, the reaction mixture was cooled to room temperature. A solution of 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, after which 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 trans-3-(4-(7-bromoquinoxalin-2-yl)-3-cyclopropyl-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid methyl ester (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 x 150 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the desired product (270 mg, yield: 46%) as a brown solid. MS (ESI) m / z = 504.7 [M+H] + .

[0659] 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

[0660] 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 LiAlH4 (26 mg, 0.7 mmol) at 0°C under N2. After the reaction mixture was stirred at room temperature for 1 h, H2O (0.1 mL) and anhydrous Na2SO4 were added to the mixture. The precipitate was filtered, and the filtrate was concentrated under reduced pressure to give the desired crude product (110 mg, yield: 89%) as a yellow oil. MS (ESI) m / z = 476.6 [M+H] + .

[0661] 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

[0662] 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. After the reaction mixture was stirred at room temperature for 16 h, it was poured into water (20 mL) and extracted with dichloromethane (3x20 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 flash chromatography on silica gel to give the desired product (130 mg, yield: 89%) as a white solid. MS (ESI) m / z=630.6[M+H] + .

[0663] 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

[0664] 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 phthalimide (76 mg, 0.42 mmol) at room temperature. The reaction mixture was stirred at 80 ° C for 2 h. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3x20 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 flash chromatography on silica gel to give the desired product (110 mg, yield: 88%) as a colorless oil. MS (ESI) m / z=605.7[M+H] + .

[0665] 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

[0666] 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 in the next step without further purification. MS (ESI) m / z = 505.5 [M+H] + .

[0667] 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

[0668] 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 H2O, 328 mg, 3.57 mmol) and NaBH(OAc)3 (756.0 mg, 3.57 mmol). The reaction mixture was stirred at room temperature for 3 days and then concentrated under reduced pressure. The 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] + .

[0669] Step 7. Synthesis of (trans-3-(3-cyclopropyl-4-(7-(1-methylazetidin-3-yl)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine

[0670] 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 h and then concentrated under reduced pressure. The 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] + .

[0671] 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

[0672] 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-piperidinyl)-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. for 30 min under microwave irradiation. After cooling to room temperature, the mixture was purified by reverse phase chromatography to give the desired product (1.2 mg, yield: 6%) as a yellow solid. MS (ESI) m / z = 645.7 [M + H] + .

[0673] 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)

[0674]

[0675] GS-656 (2 mg, 7-step yield: 1%) was synthesized as a yellow solid according to steps 1 to 3 of GS-677 and steps 5 to 8 of GS-643. MS (ESI) m / z = 617.7 [M+H] + .

[0676] 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)

[0677]

[0678] GS-657 (4 mg, 7-step yield: 3%) was synthesized as a yellow solid according to steps 1 to 3 of GS-677 and steps 5 to 8 of GS-643. MS (ESI) m / z = 589.7 [M+H] + .

[0679] 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)

[0680]

[0681] Step 1. Synthesis of 6-chloro-1-methyl-1H-imidazo[4,5-c]pyridine

[0682] 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 CH3I (554.5 mg, 3.91 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h, after which it was quenched with ice water (20 mL) and extracted with ethyl acetate (3x20 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, yield: 34%) as a white solid. MS (ESI) m / z = 168.1 [M+H] + .

[0683] The remaining steps were carried out according to the procedures of steps 2 to 3 of GS-649 to obtain the desired product (6.5 mg, two-step yield: 6%) as a yellow solid. MS (ESI) m / z = 579.5 [M+H] + .

[0684] 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)

[0685]

[0686] Step 1. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(7-(3-hydroxypyrrolidin-1-yl)quinoxalin-2-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0687] 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 G (43.4 mg, 0.05 mmol) and Cs CO (163.4 mg, 0.50 mmol) at room temperature. The reaction mixture was stirred at 100 ° C for 16 h under nitrogen. After cooling to room temperature, the mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 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 obtain the desired product (120 mg, yield: 79%) as a red solid. MS (ESI) m / z = 605.8 [M+H] + .

[0688] The remaining steps were carried out according to the procedures of steps 3 to 4 of GS-641 to obtain the desired product (1.5 mg, two-step yield: 10%) as a light yellow solid. MS (ESI) m / z = 661.6 [M+H] + .

[0689] 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)

[0690]

[0691] Step 1. Synthesis of 7-chloro-2-isopropyl-2H-pyrazolo[3,4-c]pyridine

[0692] 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) in portions at 0°C under N2. After the reaction was stirred at 0°C for 30 min, a solution of 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, after which it was slowly quenched with water (30 mL) and extracted with ethyl acetate (3 x 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] + .

[0693] Step 2. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(2-isopropylpyrazolo[3,4-c]pyridin-7-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0694] To a solution of 7-chloro-2-isopropyl-pyrazolo[3,4-c]pyridine (100 mg, 0.5 mmol) and tert-butyl 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 H2O (1 mL) was added Cs2CO3 (497 mg, 1.53 mmol) and Pd(PPh3)4 (59 mg, 0.05 mmol) at room temperature under N2. 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 x 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 obtain the desired product (32 mg, 11% yield) as a brown oil. MS (ESI) m / z = 551.6 [M+H] + .

[0695] The remaining steps were carried out according to the procedures of steps 2 to 3 of GS-642 to obtain the desired product (1.3 mg, 2-step yield: 3%) as a yellow solid. MS (ESI) m / z = 607.8 [M+H] + .

[0696] 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)

[0697]

[0698] GS-661 (0.9 mg, 4-step yield: 1%) was synthesized as a yellow solid according to steps 1 to 2 of GS-660 and steps 2 to 3 of GS-642. MS (ESI) m / z = 607.8 [M+H] + .

[0699] 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)

[0700]

[0701] GS-662 (17.9 mg, yield: 25%) was synthesized according to the procedure of step 2 of GS-651 as an off-white solid. MS (ESI) m / z = 562.5 [M+H] + .

[0702] 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)

[0703]

[0704] Step 1. Synthesis of cyclopropyl(4,6-dichloropyrimidin-5-yl)methanol

[0705] 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 min, 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 min, after which cyclopropanecarboxaldehyde (2.37 g, 33.8 mmol) was added dropwise. After the reaction mixture was warmed to room temperature, it was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 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 obtain the desired product (4.25 g, yield: 58%) as a colorless oil. MS (ESI) m / z = 219.0 [M+H] + .

[0706] Step 2. Synthesis of cyclopropyl(4,6-dichloropyrimidin-5-yl)methanone

[0707] 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 periodate (8.3 g, 19.59 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous sodium bicarbonate solution (50 mL) and 10% aqueous sodium sulfite solution (50 mL). After stirring for 15 min, 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, yield: 69%) as a colorless oil. MS (ESI) m / z = 217.0 [M+H] + .

[0708] Step 3. Synthesis of 4-chloro-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine

[0709] 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 h under microwave irradiation. After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane (20 mL x 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 obtain the desired product (2.4 g, yield: 92%) as a white solid.1 H NMR(400MHz, DMSO-d6)δ14.01(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] + .

[0710] Step 4. Synthesis of 3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine

[0711] 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 an atmosphere of H2. 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 obtain the desired product (600 mg, yield: 52%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ13.58(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] + .

[0712] The remaining steps were carried out according to the procedures of step 4 of GS-648 and steps 5 to 8 of GS-643 to obtain the desired product (1.5 mg, 5-step yield: 1%) as a yellow solid. MS (ESI) m / z = 500.5 [M+H] + .

[0713] 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)

[0714]

[0715] GS-664 (3.1 mg, 2% yield over 4 steps) was synthesized as a light yellow solid according to the standard procedures of steps 1 to 2 of GS-660 and steps 2 to 3 of GS-642. MS (ESI) m / z = 607.5 [M+H] + .

[0716] 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)

[0717]

[0718] Step 1. Synthesis of tert-butyl 2-chloro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0719] 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 H2O (2 mL) was added Pd(dppf)Cl2 (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 H2O (20 mL) and extracted with ethyl acetate (20 mL x 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 obtain the desired product (2.4 g, yield: 78%) as a yellow oil. MS (ESI) m / z = 295.3 [M+H] + .

[0720] Step 2. Synthesis of tert-butyl 2-(1-(tert-butyloxycarbonyl)-3-cyclopropyl-1H-pyrazol-4-yl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0721] 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 H2O (2 mL) was added Pd(PPh3)4 (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 H2O (20 mL) and extracted with ethyl acetate (20 mL x 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 obtain the desired product (1 g, yield: 63%) as a yellow oil. MS (ESI) m / z = 467.8 [M+H] + .

[0722] Step 3. Synthesis of tert-butyl 2-(3-cyclopropyl-1H-pyrazol-4-yl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0723] 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). After the reaction mixture was stirred at 25°C for 1 h, it was quenched with H2O (20 mL) and extracted with dichloromethane (20 mL x 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, yield: 44%) as a yellow solid. MS (ESI) m / z = 367.5 [M+H] + .

[0724] Step 4. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)piperidine-1-carboxylate

[0725] 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 at 40 ° C for 12 h under a hydrogen atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the desired product (300 mg, yield: 90%) as a yellow oil. The compound was used directly in the next step without further purification. MS (ESI) m / z = 369.6 [M+H] + .

[0726] 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

[0727] 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 Cs2CO3 (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 H2O (20 mL) and extracted with ethyl acetate (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 trans isomer (200 mg, yield: 58%) as a yellow solid. MS (ESI) m / z=453.6[M+H] + .

[0728] 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

[0729] 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 p-toluenesulfonyl chloride (168.5 mg, 0.88 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h, then quenched with H2O (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 (140 mg, yield: 52%) as a yellow oil. MS (ESI) m / z=607.6[M+H] + .

[0730] 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

[0731] 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 H2O (20 mL) and extracted with dichloromethane (20 mL x 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 (80 mg, yield: 78%) as a yellow oil. MS (ESI) m / z = 478.7 [M+H] + .

[0732] 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

[0733] 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 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the desired product (35 mg, yield: 92%) as a yellow oil. The compound was used in the next step without further purification. MS (ESI) m / z=452.5[M+H] + .

[0734] 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

[0735] 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-piperidinyl)-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. for 0.5 h under microwave irradiation. After cooling to room temperature, the mixture was purified by reverse phase chromatography to give the desired product (20 mg, yield: 36%) as a yellow solid. MS (ESI) m / z = 708.6 [M+H] + .

[0736] 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

[0737] 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). After the reaction mixture was stirred at room temperature for 1 hour, it was 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] + .

[0738] 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)

[0739]

[0740] Step 1. Synthesis of tert-butyl N-((trans-3-(3-cyclopropyl-4-((1-methyl-4-piperidinyl)amino)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0741] To a mixture of tert-butyl N-tert-butyloxycarbonyl-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 Pd2(dba)3 (19.2 mg, 0.021 mmol) at room temperature. The reaction mixture was purged with N2 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, yield: 17%) as a yellow solid. MS (ESI) m / z = 404.5 [M+H] + .

[0742] The remaining steps were carried out according to the procedures of steps 2 to 3 of GS-642 to obtain the desired product (3.8 mg, two-step yield: 9%) as a yellow solid. MS (ESI) m / z = 560.7 [M+H] + .

[0743] 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)

[0744]

[0745] GS-667 (2.4 mg, 3-step yield: 4%) was synthesized as a yellow solid according to the standard procedure of step 1 of GS-666 and steps 2 to 3 of GS-642. MS (ESI) m / z = 545.7 [M+H] + .

[0746] 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)

[0747]

[0748] GS-668 (30 mg, 5-step yield: 6%) was synthesized as a yellow solid according to the standard procedure of steps 1 to 5 for preparing GS-667. MS (ESI) m / z = 553.5 [M+H] + .

[0749] 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)

[0750]

[0751] Step 1. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(2-pyridylamino)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0752] To a solution of pyridin-2-amine (60.0 mg, 0.64 mmol) in dioxane (5 mL) was added tert-butyl N-tert-butyloxycarbonyl-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 h under nitrogen. After cooling to room temperature, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 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 obtain the desired product (60.0 mg, yield: 19%) as a pale white solid. MS (ESI) m / z = 484.6 [M+H] + .

[0753] The remaining steps were carried out according to the procedures of steps 3 to 4 of GS-641 to obtain the desired product (4.1 mg, two-step yield: 2%) as a yellow solid. MS (ESI) m / z = 540.5 [M+H] + .

[0754] 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)

[0755]

[0756] GS-670 (9.6 mg, 3-step yield: 1%) was synthesized as a yellow solid according to the standard procedure of GS-669 step 1 and GS-641 steps 3 to 4. MS (ESI) m / z = 540.5 [M+H] + .

[0757] 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)

[0758]

[0759] GS-671 (10 mg, 3-step yield: 17%) was synthesized as a yellow solid according to the standard procedure of step 1 of GS-669 and steps 3 to 4 of GS-641. MS (ESI) m / z = 540.5 [M+H] + .

[0760] 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)

[0761]

[0762] Step 1. Synthesis of 2-chloro-N-methoxy-N,6-dimethylnicotinamide

[0763] 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 at room temperature overnight. The reaction was quenched with water (100 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 residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2: 1) to give the desired product (2.14 g, yield: 86%) as a yellow solid. MS (ESI) m / z = 215.1 [M+H] + .

[0764] Step 2. Synthesis of (2-chloro-6-methylpyridin-3-yl)(cyclopropyl)methanone

[0765] 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, after which it was quenched with aqueous NH4Cl (50 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 residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the desired product (1.68 g, yield: 93%) as a yellow oil. MS (ESI) m / z = 196.0 [M+H] + .

[0766] Step 3. Synthesis of 3-cyclopropyl-6-methyl-1H-pyrazolo[3,4-b]pyridine

[0767] 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 h 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 layer was 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 obtain the desired product (1.5 g, yield: 70%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.89(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] + .

[0768] The remaining steps were carried out according to the procedures of step 4 of GS-648 and steps 5 to 8 of GS-643 to obtain the desired product (7.4 mg, 5-step yield: 2%) as a yellow solid. MS (ESI) m / z = 513.5 [M+H] + .

[0769] 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)

[0770]

[0771] GS-673 (8.9 mg, 7-step yield: 1%) was synthesized as a yellow solid according to the standard procedures of GS-672, GS-648, and GS-643. MS (ESI) m / z = 513.5 [M+H] + .

[0772] 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)

[0773]

[0774] GS-674 (22.3 mg, 7-step yield: 5%) was synthesized as a yellow solid according to the standard procedures of GS-672, steps 1 to 3, GS-648, and steps 5 to 8 of GS-643. MS (ESI) m / z = 529.5 [M+H] + .

[0775] 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)

[0776]

[0777] Step 1. Synthesis of tert-butyl 3-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate

[0778] 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 Cs2CO3 (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 H2O (100 mL) and extracted with ethyl acetate (100 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 (1.7 g, yield: 28%) as a yellow solid. MS (ESI) m / z=309.2[M+H] + .

[0779] The remaining steps were carried out according to the procedures of steps 2 to 9 of GS-665 to obtain the desired product (1.3 mg, 8-step yield: 1%) as a yellow solid. MS (ESI) m / z = 620.5 [M+H] + .

[0780] 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)

[0781]

[0782] GS-676 (19 mg, 5-step yield: 2%) was synthesized as a yellow solid according to steps 1 to 4 of GS-678. MS (ESI) m / z = 543.7 [M+H] + .

[0783] 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)

[0784]

[0785] Step 1. Synthesis of trans-3-(4-(5-fluoro-6-methylpyridin-2-yl)-3-formyl-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid methyl ester

[0786] 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) at room temperature were added 6-bromo-3-fluoro-2-methylpyridine (377 mg, 1.98 mmol), KCO (820 mg, 5.95 mmol), and Pd(dppf)Cl (145 mg, 0.19 mmol). 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 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired trans isomer (180 mg, 28% yield) as a white solid. MS (ESI) m / z = 318.4 [M+H] + .

[0787] Step 2. Synthesis of trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid methyl ester

[0788] To a solution of trans-3-(4-(5-fluoro-6-methylpyridin-2-yl)-3-formyl-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid methyl ester (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, after which it was quenched with aqueous NaHCO3 and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (150 mg, yield: 78%) as a white solid. MS (ESI) m / z=340.4[M+H] + .

[0789] Step 3. Synthesis of (trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol

[0790] To a solution of trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid methyl ester (150 mg, 0.44 mmol) in THF (10 mL) was added LiAlH4 (34 mg, 0.88 mmol). After the reaction mixture was stirred at 0°C under nitrogen for 2 h, it was carefully quenched with aqueous NaOH solution (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 Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (110 mg, yield: 80%) as a colorless oil. MS (ESI) m / z=312.4[M+H] + .

[0791] Step 4. Synthesis of trans-3-(3-(difluoromethyl)-4-(5-fluoro-6-methylpyridin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde

[0792] 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 periodate (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 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (60 mg, yield: 55%) as a colorless oil. MS (ESI) m / z = 310.2 [M+H] + .

[0793] 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

[0794] 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 2-methylpyridine borane complex (41 mg, 0.38 mmol) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 5 h. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (3x20 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] + .

[0795] 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)

[0796]

[0797] Step 1. Synthesis of 6-(3-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridine

[0798] To a solution of 6-chloro-1-methyl-1H-pyrazolo[4,3-c]pyridine (3 g, 17.90 mmol) in dioxane (100 mL) and H₂O (20 mL) was added 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)Cl₂ (654.2 mg, 895.01 μmol), and K₂CO₃ (4.94 g, 35.80 mmol) 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 x 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, yield: 58%) as an off-white solid. MS (ESI) m / z = 240.4 [M+H] + .

[0799] 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

[0800] 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 Cs2CO3 (6.81 g, 20.90 mmol) at room temperature. The reaction mixture was stirred at 100°C for 3 h. After cooling to room temperature, the mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 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, yield: 33%) as an off-white solid. MS (ESI) m / z = 324.3 [M+H] + .

[0801] 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

[0802] 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 periodate (786.6 mg, 1.86 mmol) in three portions at 0°C. The reaction mixture was stirred at room temperature for 2 h, after which it was poured into water (50 mL) and extracted with dichloromethane (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 (450 mg, yield: 90%) as an off-white solid. MS (ESI) m / z = 322.5 [M+H] + .

[0803] 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

[0804] 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 2-methylpyridine borane complex (86.8 mg, 0.93 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 4 h. 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 residue was purified by silica gel chromatography to obtain the desired product (120 mg, yield: 46%) as a white solid. MS (ESI) m / z = 565.4 [M+H] + .

[0805] 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)

[0806]

[0807] GS-679 (5.8 mg, 7-step yield: 1%) was synthesized as a yellow solid according to the standard procedures of GS-672, Steps 2 to 3 of GS-663, Steps 4 of GS-648, and Steps 5 to 8 of GS-643. MS (ESI) m / z = 513.5 [M+H] + .

[0808] 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)

[0809]

[0810] Step 1. Synthesis of tert-butyl 3-(6-chloro-2H-pyrazolo[4,3-c]pyridin-2-yl)azetidine-1-carboxylate

[0811] 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 Cs2CO3 (8.49 g, 26.05 mmol). The reaction mixture was stirred at 90 ° C for 12 h. 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, yield: 50%) as a light yellow solid. MS (ESI) m / z = 309.2 [M + H] + .

[0812] Step 2. Synthesis of 2-(azetidin-3-yl)-6-chloro-2H-pyrazolo[4,3-c]pyridine

[0813] 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 at 25 °C for 1 h. The mixture was concentrated in vacuo to give the desired product (670 mg, yield: 99%) as a yellow oil. MS (ESI) m / z = 209.1 [M+H] + .

[0814] Step 3. Synthesis of 6-chloro-2-(1-methylazetidin-3-yl)-2H-pyrazolo[4,3-c]pyridine

[0815] To a solution of 2-(azetidin-3-yl)-6-chloro-2H-pyrazolo[4,3-c]pyridine (670 mg, 3.2 mmol), two drops of acetic acid, and formaldehyde solution (37 wt% in H₂O, 482.1 mg, 16.0 mmol) in methanol (10 mL) was added 2-methylpyridine borane complex (687 mg, 6.4 mmol). The reaction mixture was stirred at 25°C for 12 h. The mixture was quenched with H₂O (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the desired product (600 mg, yield: 84%) as a white solid. MS (ESI) m / z = 223.1 [M+H] + .

[0816] Step 4. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-((trans-3-(3-cyclopropyl-4-(2-(1-methylazetidin-3-yl)pyrazolo[4,3-c]pyridin-6-yl)pyrazol-1-yl)cyclobutyl)methyl)carbamate

[0817] 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-butyloxycarbonyl-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 K3PO4 (476.6 mg, 2.25 mmol) in dioxane (10 mL) and H2O (2 mL) was added XPhosPdG2 (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 H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the desired product (150 mg, yield: 23%) as a yellow oil. MS (ESI) m / z = 578.5 [M+H] + .

[0818] 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

[0819] To a solution of tert-butyl N-tert-butyloxycarbonyl-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 at 25 ° C for 1 h. The mixture was concentrated in vacuo to give the desired product (98 mg, yield: 99%) as a yellow oil. MS (ESI) m / z = 378.4 [M + H] + .

[0820] 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

[0821] 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-piperidinyl)-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, yield: 1%) as a yellow solid. MS (ESI) m / z = 634.5 [M+H] + .

[0822] 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)

[0823]

[0824] Step 1. Synthesis of 4-chloro-3-iodo-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridine

[0825] 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 at room temperature overnight, quenched with water (100 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases 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 obtain the desired product (5.1 g, yield: 24%) as a colorless oil. MS (ESI) m / z = 364.1 [M+H] + .

[0826] Step 2. Synthesis of 4-chloro-3-cyclopropyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridine

[0827] Under nitrogen, a mixture of 4-chloro-3-iodo-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridine (5 g, 13.8 mmol), cyclopropylboronic acid (1.72 g, 20.7 mmol), Pd(OAc)2 (310.5 mg, 1.38 mmol), SPhos (1.13 g, 2.76 mmol), and K3PO4 (8.8 g, 41.4 mmol) in toluene (40 mL) and H2O (4 mL) was stirred at 95°C for 12 h. After cooling to room temperature, the reaction mixture was quenched with H2O (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases 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 obtain the desired product (2.32 g, yield: 61%) as a white solid. MS (ESI) m / z = 278.1 [M+H] + .

[0828] Step 3. Synthesis of 3-cyclopropyl-4-methoxy-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridine

[0829] 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 under 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, yield: 72%) as a white solid. MS (ESI) m / z = 274.1 [M+H] + .

[0830] Step 4. Synthesis of 3-cyclopropyl-4-methoxy-1H-pyrazolo[3,4-b]pyridine

[0831] At 0 ° C, 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). 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 NaHCO3. The mixture was extracted with dichloromethane (20 mL x3). The combined organic layers were dried over anhydrous Na2SO4, 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, yield: 85%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.98(s,1H),8.30(d,J=5.6Hz,1H),6.65(d,J=5.6Hz,1 H),4.00(s,3H),2.42-2.36(m,1H),0.97-0.89(m,4H).MS(ESI)m / z=190.1[M+H] + .

[0832] The remaining steps were carried out according to the procedure of step 4 of GS-648 and steps 5 to 8 of GS-643 to obtain the desired product (3.2 mg, 5-step yield: 3%) as a yellow solid. MS (ESI) m / z = 529.4 [M+H] + .

[0833] 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)

[0834]

[0835] Step 1. Synthesis of 5-bromo-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine

[0836] To a solution of 5-bromo-3-cyclopropyl-1H-pyrazolo[3,4-b]pyridine (4.12 g, 17.4 mmol) in DMF (30 mL) at 0°C was added NaH (60% in oil, 695 mg, 17.4 mmol). The reaction was stirred at 0°C for 1 h, and then SEMCl (3.2 g, 19.1 mmol) was added dropwise. The resulting mixture was stirred at 0°C for an additional 2 h, quenched with H₂O (15 mL), and extracted with EtOAc (50 mL x 2). 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 (5.7 g, yield: 89%) as a white solid. MS (ESI) m / z = 368.1 [M+H] + .

[0837] Step 2. Synthesis of 3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-ol

[0838] 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) and pinacol diboron (7.87 g, 31 mmol) in dioxane (50 mL) was added KOAc (3.04 g, 31 mmol) and Pd(dppf)Cl2 (2.26 g, 3.1 mmol) at room temperature. The reaction mixture was stirred at 80°C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in MeOH (50 mL) and filtered. H2O2 (20 mL) was added to the filtrate, 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 Na2SO4, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the desired product (2.88 g, yield: 61%) as a white solid. MS (ESI) m / z = 306.1 [M+H] + .

[0839] Step 3. Synthesis of 3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine 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) were added MeI (1.60 g, 11.33 mmol) and KCO (2.60 g, 18.88 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). 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 obtain the desired product (2.05 g, yield: 68%) as a white solid. MS (ESI) m / z = 320.1 [M+H] +

[0840] Step 4. Synthesis of 3-cyclopropyl-5-methoxy-1H-pyrazolo[3,4-b]pyridine

[0841] 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 (3N, 15 mL) at room temperature. The reaction mixture was stirred at 80°C overnight. 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 x 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, yield: 63%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.97(s,1H),8.23(d,J=2.8Hz,1H),7.71(d,J=2.8Hz,1 H),3.86(s,3H),2.30-2.24(m,1H),1.00-0.92(m,4H).MS(ESI)m / z=190.1[M+H] + .

[0842] The remaining steps were carried out according to the procedures of step 4 of GS-648 and steps 5 to 8 of GS-643 to obtain the desired product (9.7 mg, 5-step yield: 4%) as a yellow solid. MS (ESI) m / z = 529.4 [M+H] + .

[0843] 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)

[0844]

[0845] Step 1. Synthesis of tert-butyl 4-(2-chloro-5-fluoropyridin-3-yl)piperazine-1-carboxylate

[0846] In a nitrogen atmosphere, 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), Pd2(dba)3 (18.3 mg, 0.02 mmol) and Cs2CO3 (195.6 mg, 0.6 mmol) in DMSO (3 mL) was stirred at 100 ° C in a nitrogen atmosphere for 12 h. 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, yield: 25%) as a white solid. MS (ESI) m / z = 315.8 [M+H] + .

[0847] Step 2. Synthesis of tert-butyl 4-(2-(3-cyclopropyl-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate

[0848] In a nitrogen atmosphere, 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(PPh3)4 (349.8 mg, 0.32 mmol) and K2CO3 (1.33 g, 9.6 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was stirred at 100 ° C for 2 h in 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, yield: 24%) as a white solid. MS (ESI) m / z = 387.4 [M+H] + .

[0849] 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

[0850] 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). After the reaction was stirred at 100 ° C for 2 h, it was cooled to room temperature and quenched with H O (100 mL). The mixture was extracted with EtOAc (30 mL x 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, yield: 44%) as a white solid. MS (ESI) m / z=471.7[M+H] + .

[0851] 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

[0852] 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). After the reaction was stirred at 25 ° C for 1 h, it was diluted with DCM (20 mL) and washed with H2O 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] + .

[0853] 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

[0854] 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 phthalimide (88.61 mg, 0.478 mmol) in DMSO (3 mL) was stirred at 70° C. for one hour. The mixture was then diluted with DCM (10 mL) and washed with H O and brine. The organic layer was concentrated to give the desired product (130 mg, yield: 59%) as a white solid. MS (ESI) m / z = 600.7 [M+H] + .

[0855] 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

[0856] 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% aqueous solution) in EtOH (5 mL) was stirred at 80°C for one hour. The mixture was then 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] + .

[0857] 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

[0858] 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-piperidinyl)-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 h and then purified by ISCO on C18 to give the desired product (60 mg, 28% yield) as a yellow solid. MS (ESI) m / z = 726.8 [M+H]+ .

[0859] 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

[0860] 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). After the reaction was stirred at room temperature for 1 hour, it was 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] + .

[0861] 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)

[0862]

[0863] Step 1. Synthesis of 5-(3-cyclopropyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

[0864] 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) were 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. under N for 12 h and then purified by reverse phase chromatography (CHCN / H0 / TFA) to give the desired product (485 mg, 75% yield) as a brown solid.

[0865] 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

[0866] 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 Cs2CO3 (1.5 g, 4.71 mmol) and [3-(hydroxymethyl)cyclobutyl]4-methylbenzenesulfonate (486 mg, 1.88 mmol). The mixture was stirred at 100 ° C. under N2 for 2.5 h. The mixture was poured into water and extracted with EtOAc (4x). The combined organic layers were washed with brine, dried, concentrated and purified by flash chromatography on silica gel to give the title compound (270 mg, yield: 44%) as a white solid. MS (ESI) m / z = 394.7 [M+H] + .

[0867] Step 3. Synthesis of methyl 4-methylbenzenesulfonate (trans-3-(3-cyclopropyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)cyclobutyl)

[0868] 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). After the mixture was stirred at 25° C. for 2 h, it was purified by silica gel flash chromatography to give the title compound (270 mg, yield: 72%) as a white solid. MS (ESI) m / z = 548.7 [M+H] + .

[0869] Step 4. Synthesis of tert-butyl N-tert-butyloxycarbonyl-N-[[trans-3-[3-cyclopropyl-4-(1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-yl)pyrazol-1-yl]cyclobutyl]methyl]carbamate

[0870] To a solution of methyl 4-benzenesulfonate (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 ester (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, yield: 86%) as a yellow solid. MS (ESI) m / z = 593.8 [M+H] + .

[0871] Step 5. Synthesis of (trans-3-(3-cyclopropyl-4-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)cyclobutyl)methanamine

[0872] A mixture of tert-butyl N-tert-butyloxycarbonyl-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 afford the desired product (120 mg, 93% yield) as a white solid. MS (ESI) m / z = 309.4 [M+H] + .

[0873] 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

[0874] 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-piperidinyl)-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. under microwave conditions for 2.5 h. The mixture was purified by reverse phase chromatography (CH 3 CN / H 2 O / 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]+ .

[0875] 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)

[0876]

[0877] Step 1. Synthesis of 8-(3-cyclopropyl-1H-pyrazol-4-yl)-1,7-naphthyridine

[0878] To a solution of 8-chloro-1,7-naphthyridine (500 mg, 3.04 mmol) in dioxane (15 mL) and H₂O (5 mL) were added Pd(dppf)Cl₂ (222.06 mg, 303.78 μmol), K₂CO₃ (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 under N₂ for 12 h. 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 chromatography (MeOH / H₂O / TFA) to afford the desired product (348 mg, 48% yield) as a black oil. MS (ESI) m / z = 237.4 [M+H] + .

[0879] Step 2. Synthesis of (trans-3-(3-cyclopropyl-4-(1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol

[0880] 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 Cs2CO3 (1.44 g, 4.42 mmol). The mixture was stirred at 90°C under N2 for 6 h. The mixture was purified by reverse phase chromatography (MeOH / H2O / TFA) and preparative TLC (DCM:MeOH = 12:1) to obtain the desired trans isomer (202 mg, yield: 43%) as a white solid. MS (ESI) m / z = 321.6 [M+H] + .

[0881] Step 3. Synthesis of trans-3-(3-cyclopropyl-4-(1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbaldehyde

[0882] 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 h. 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] + .

[0883] Step 4. Synthesis of (E)-3-(trans-3-(3-cyclopropyl-4-(1,7-naphthyridin-8-yl)-1H-pyrazol-1-yl)cyclobutyl)acrylonitrile

[0884] 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-(triphenylphosphinidylidene)acetonitrile (340.72 mg, 1.13 mmol). The mixture was stirred at room temperature for 0.5 hours, and then the solvent was removed. The resulting residue was diluted with DMF and purified by reverse phase column chromatography (CH3CN / H2O / TFA) to afford the title compound (260 mg, yield: 91%) as a white solid. MS (ESI) m / z = 342.5 [M+H] + .

[0885] 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

[0886] 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 h. The reaction solution was filtered and concentrated to give the title compound (20 mg, yield: 87%). MS (ESI) m / z = 352.6 [M+H] + .

[0887] 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

[0888] 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-piperidinyl)-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. under microwave for 2.5 h. The mixture was purified by reverse phase chromatography (CH 3 CN / H 2 O / TFA) to give the title compound (4.6 mg, yield: 14%) as a yellow solid.

[0889] 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-dioxocyclohexane)isoindoline-1,3-dione (GS-686)

[0890]

[0891] Step 1. Synthesis of tert-butyl 2-chloro-5-fluoro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0892] 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)Cl2 (350.9 mg, 0.48 mmol) and K2CO3 (1.98 g, 14.44 mmol) in 1,4-dioxane (20 mL) and H2O (4 mL) was stirred at 100 ° C under N2 for 2 h. The reaction was diluted with EtOAc (40 mL) and H2O (20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography to give the desired product (1.25 g, yield: 83%) as a white solid. MS (ESI) m / z = 313.3 [M+H] + .

[0893] Step 2. Synthesis of 2-chloro-5-fluoro-1',2',3',6'-tetrahydro-3,4'-bipyridine

[0894] 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 afford the desired product (1.46 g, 95% yield) as a white solid. MS (ESI) m / z = 212.6 [M+H] + .

[0895] Step 3. Synthesis of 2-chloro-5-fluoro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid benzyl ester

[0896] 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 at 0°C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 hours and then concentrated. The residue was purified by flash column chromatography to give the desired product (700 mg, yield: 82%) as a white solid. MS (ESI) m / z = 346.4 [M+H] + .

[0897] Step 4. Synthesis of 4-[2-[1-[trans-3-[[bis(tert-butyloxycarbonyl)amino]methyl]cyclobutyl]-3-cyclopropyl-pyrazol-4-yl]-5-fluoro-3-pyridinyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester

[0898] 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-butyloxycarbonyl-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(PPh3)4 (100.53 mg, 0.087 mmol), and K2CO3 (360.18 mg, 2.61 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was stirred at 100° C. for 15 h. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was concentrated and the residue was purified by flash column chromatography to give the desired product (92 mg, yield: 10%) as a white solid. MS (ESI) m / z = 702.8 [M+H] + .

[0899] 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

[0900] To a solution of benzyl 4-[2-[1-[trans-3-[[bis(tert-butyloxycarbonyl)amino]methyl]cyclobutyl]-3-cyclopropyl-pyrazol-4-yl]-5-fluoro-3-pyridinyl]-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 afford the title compound (70 mg, 99% yield) as a white solid. MS (ESI) m / z = 502.8 [M+H] + .

[0901] 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-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0902] To a solution 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 (70 mg, 0.13 mmol) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (35.88 mg, 0.13 mmol) in DMSO (2 mL) was added DIEA (166.4 mg, 1.3 mmol) at room temperature. The reaction was stirred at 130 °C under microwave irradiation for 1 h and then purified by ISCO to give the desired product (35 mg, 36% yield) as a yellow solid. MS (ESI) m / z = 756.7 [M+H] + .

[0903] Step 7. Synthesis of 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-dioxocyclohexane)isoindoline-1,3-dione

[0904] A mixture 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-[3,4'-bipyridine]-1'(2'H)-carboxylate (35 mg, 0.046 mmol) and Pd / C (10 mg, 10%) in EtOH (5 mL) was stirred at 25 ° C. under a H2 atmosphere for 1 h. The mixture was then filtered and the filtrate was concentrated. The residue was purified by preparative TLC to give the desired product (14 mg, yield: 49%) as a yellow solid. MS (ESI) m / z = 624.7 [M+H] + .

[0905] Example 48: 5-(((trans-3-(3-cyclopropyl-4-(1-methyl-1H-imidazol-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-687)

[0906]

[0907] Step 1. Synthesis of tert-butyl 3-cyclopropyl-4-(1-methyl-1H-imidazol-2-yl)-1H-pyrazole-1-carboxylate

[0908] Under a nitrogen atmosphere, a mixture of 2-bromo-1-methyl-1H-imidazole (350 mg, 2.17 mmol), 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (943.9 mg, 2.83 mmol), Pd(PPh3)4 (250.74 mg, 0.217 mmol) and K2CO3 (898.4 mg, 6.51 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was stirred at 100 ° C in N2 for 2 h. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was concentrated and the residue was purified by flash column chromatography to give the desired product (250 mg, yield: 40%) as a white solid. MS (ESI) m / z = 288.3 [M+H] + .

[0909] Step 2. Synthesis of 3-cyclopropyl-4-(1-methyl-1H-imidazol-2-yl)-1H-pyrazole

[0910] To a solution of tert-butyl 3-cyclopropyl-4-(1-methyl-1H-imidazol-2-yl)-1H-pyrazole-1-carboxylate (250 mg, 0.87 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction was stirred at 25°C for 1 h. The reaction mixture was concentrated to give the desired product (167 mg, yield: 99%) as a white solid. MS (ESI) m / z = 188.3 [M+H] + .

[0911] The remaining steps were carried out according to the procedures of steps 2 to 6 of GS-684 to obtain the desired product (12 mg, 5-step yield: 6%) as a yellow solid. MS (ESI) m / z = 528.7 [M+H] + .

[0912] Example 49: 2-(2,6-dioxopiperidin-3-yl)-5-(((trans-3-(3-methyl-2H-indazol-2-yl)cyclobutyl)methyl)amino)isoindoline-1,3-dione (GS-688)

[0913]

[0914] GS-688 was synthesized according to the procedure of steps 2 to 6 of GS-684 to obtain the title compound (75 mg, 5-step yield: 8%) as a yellow solid. MS (ESI) m / z = 472.7 [M+H] + .

[0915] Example 50: 2-(2,6-dioxopiperidin-3-yl)-5-(((trans-3-(3-methyl-1H-indazol-1-yl)cyclobutyl)methyl)amino)isoindoline-1,3-dione (GS-689)

[0916]

[0917] GS-689 was synthesized according to the procedure of steps 2 to 6 of GS-684 to obtain the title compound (87 mg, 5-step yield: 25%) as a yellow solid. MS (ESI) m / z = 472.6 [M+H] + .

[0918] Example 51: 5-(((trans-3-(3'-cyclopropyl-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-690)

[0919]

[0920] Step 1. Synthesis of 3'-cyclopropyl-2-methyl-1'H,2H-3,4'-bipyrazole

[0921] To a mixture of tert-butyl 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (600 mg, 1.80 mmol) and 5-bromo-1-methyl-pyrazole (289.03 mg, 1.80 mmol) in 1,4-dioxane (10 mL) was added K2CO3 (743.23 mg, 5.39 mmol), Pd(dppf)Cl2 (131.36 mg, 179.52 μmol) and water (1 mL). The resulting mixture was purged with N2 and heated to 100°C for 16 h. The mixture was then filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by C18 column to give the title compound (120 mg, yield: 35%) as a colorless oil. MS (ESI) m / z = 189.4 [M+H] + .

[0922] The remaining steps were carried out according to the procedures of steps 2 to 6 of GS-684 to obtain the desired product (5 mg, 5-step yield: 1%) as a yellow solid. MS (ESI) m / z = 528.7 [M+H] + .

[0923] Example 52: 5-(((trans-3-(3-cyclopropyl-4-(1-methyl-1H-imidazol-5-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-691)

[0924]

[0925] Step 1. Synthesis of 3-cyclopropyl-4-(1-methyl-1H-imidazol-5-yl)-1H-pyrazole

[0926] To a mixture of tert-butyl 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (1000 mg, 2.99 mmol) and 5-bromo-1-methyl-imidazole (481.72 mg, 2.99 mmol) in 1,4-dioxane (10 mL) was added K2CO3 (1.24 g, 8.98 mmol), Pd(dppf)Cl2 (218.93 mg, 299.21 μmol) and water (1 mL). The resulting mixture was purged with N2 and heated to 100°C for 16 h. The mixture was then filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by C18 column to give the title compound as an anhydrous oil. MS (ESI) m / z = 189.4 [M+H] + .

[0927] The remaining steps were carried out according to the procedures of steps 2 to 6 of GS-684 to obtain the desired product (4 mg, 5-step yield: 1%) as a light yellow solid. MS (ESI) m / z = 528.7 [M+H] + .

[0928] Example 53: 2-(2,6-dioxopiperidin-3-yl)-5-(((trans-3-(7-methyl-1H-indazol-1-yl)cyclobutyl)methyl)amino)isoindoline-1,3-dione (GS-693)

[0929]

[0930] GS-693 was synthesized according to the procedure of steps 2 to 6 of GS-684 to obtain the ...

Claims

1. A compound of formula (A): or a pharmaceutically acceptable salt thereof, wherein: W is hydrogen or fluorine; Z does not exist, -NR 1a -, or -O-; where R 1a is hydrogen or C1-C8 alkyl; L is an optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 Heteroalkylene, or L is in: Ring B is an optionally substituted 3-7 membered carbocyclic group, or an optionally substituted 4-7 membered heterocyclic group; L 1 Absent, or optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 heteroalkylene; L 2 Absent, or optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkyne, or optionally substituted C1-C 10 heteroalkylene; R 1 is absent or oxo (=O); R 2 and R 4 are 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 they form an optionally substituted 3-7 membered partially saturated or unsaturated carbocyclic group, an optionally substituted 4-7 membered partially saturated or unsaturated heterocyclic group, an optionally substituted phenyl group, or an optionally substituted 5-6 membered heteroaromatic ring; Each R 5 and R 6 is 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 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl C1-C8 alkyl, optionally substituted 3-10 membered heterocyclyl C1-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 and together with the atoms to which they are attached, optionally form an optionally substituted 4-7 membered heterocyclyl, or an optionally substituted 5-6 membered heteroaryl ring.

2. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z does not exist, -NR 1a -, or -O-; where R 1a is hydrogen or C1-C8 alkyl; L is an optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 Heteroalkylene, or L is in: Ring B is an optionally substituted 3-7 membered carbocyclic group, or an optionally substituted 4-7 membered heterocyclic group; L 1 Absent, or optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 heteroalkylene; L 2 Absent, or optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkyne, or optionally substituted C1-C 10 heteroalkylene; R 1 is absent or oxo (=O); R 2 and R 4 are 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 partially unsaturated 3-7 membered carbocyclyl, an optionally substituted partially unsaturated 4-7 membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl ring; Each R 5 and R 6 is 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 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl C1-C8 alkyl, optionally substituted 3-10 membered heterocyclyl C1-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 and together with the atoms to which they are attached, optionally form an optionally substituted 4-7 membered heterocyclyl, or an optionally substituted 5-6 membered heteroaryl ring.

3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, characterized in that: R 2 and R 3 Together they form an optionally substituted phenyl group, or an optionally substituted 5-6 membered heteroaryl ring.

4. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, characterized in that: R 3 and R 4 Together they form an optionally substituted phenyl group, or an optionally substituted 5-6 membered heteroaryl ring.

5. The compound according to claim 1, 2 or 4, characterized in that The compound has a structure shown in formula (II) Structure: or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 11 are independently hydrogen, halogen, CN, NO2, OR 5 , SR 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.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, characterized in that Ring A is phenyl, pyridyl or triazine.

7. The compound according to claim 5, characterized in that The compound has a structure shown in formula (II-A): or a pharmaceutically acceptable salt thereof, wherein: X 1 , X 2 and X 3 Each independently is CR 11 or N.

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that X 1 is N; and X 2 and X 3 Each independently is CR 11 .

9. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that X 1 and X 2 respective is N; and X 3 CR 11 .

10. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that X 1 and X 3 respective is N; and X 2 CR 11 .

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that: R 4 is hydrogen; And R 3 N(R 5 )R 6 , an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 6-10 membered aryl, or an optionally substituted 5-10 membered heteroaryl.

12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, characterized in that R 3 For optional The invention also comprises an optionally substituted phenyl group, or an optionally substituted 5-10 membered heteroaryl group.

13. The compound according to any one of claims 1, 2, 11 or 12, characterized in that The compound has a structure shown in formula (III): or a pharmaceutically acceptable salt thereof, wherein: X 4 , X 5 and X 6 Each independently is CR 8 or N; Each R 8 are independently hydrogen, halogen, CN, NO2, OR 5 , SR 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 3-7 membered carbocyclyl, an optionally substituted partially unsaturated 4-7 membered heterocyclyl, an optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl ring; and p2 is 0, 1, 2, 3, 4 or 5.

14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, characterized in thatX 4 , X 5 and X 6 Each independently is CR 8 .

15. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, characterized in that X 4 is N; and X 5 and X 6 Each independently is CR 8 .

16. A compound as claimed in any one of claims 13 to 15, or a pharmaceutically acceptable salt thereof, characterized in that In each R 8 are independently hydrogen, halogen, or optionally substituted C1-C8 alkyl.

17. The compound according to any one of claims 1, 2, 11 or 12, characterized in that The compound has a structure shown in formula (IV): or a pharmaceutically acceptable salt thereof, wherein: X 4 CR 8a or N; X 5 CR 8b or N; X 6 CR 8d or N; R 8a , R 8b , R 8c , R 8d and R 8e Each independently is hydrogen, halogen, CN, NO2, OR 5 , SR 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, R 8a and R 8b , R 8b and R 8c , R 8c and R 8d , or R 8d and R 8e and together with the atoms to which they are attached form an optionally substituted 3-7 membered carbocyclyl, an optionally substituted 4-7 membered heterocyclyl, an optionally substituted 6 membered aryl, or an optionally substituted 5-6 membered heteroaryl ring.

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, characterized in that X 4 for N, X 5 CR 8b , and X 6 CR 8d .

19. The compound according to claim 17 or 18, or a pharmaceutically acceptable salt thereof, characterized in that R 8b , R 8c , R 8d and R 8e Each is independently hydrogen, halogen, or optionally substituted C1-C8 alkyl.

20. The compound according to claim 17, characterized in that The compound has a structure shown in formula (IV-A): or a pharmaceutically acceptable salt thereof, wherein: Each R 9 are independently hydrogen, halogen, CN, NO2, OR 5 , SR 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 q1 is 0, 1, 2, 3, or 3.

21. The compound according to claim 17, characterized in that The compound has a structure shown in formula (IV-B): or a pharmaceutically acceptable salt thereof, in: Y 1 , Y 2 and Y 3 Each independently is CR 10 NR 10a or N; where Y 1 , Y 2 and Y 3 At least one of them is CR 10 ; Each R 10 is 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; and Each R 10a are 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl.

22. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, characterized in thatX 4 is N, and X 5 CR 8b .

23. The compound according to claim 17, characterized in that The compound has a structure shown in formula (IV-C): or a pharmaceutically acceptable salt thereof, wherein: Y 1 , Y 2 and Y 3 Each independently is CR 10 NR 10a or N; where Y 1 , Y 2 and Y 3 At least one of them is CR 10 ; Each R 10 is 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; and Each R 10a are 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl.

24. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, characterized in that X 4 is N, and X 6 CR 8d .

25. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein X 4 CR 8a , And X 6 is N.

26. The compound according to claim 17, characterized in that The compound has a structure shown in formula (IV-D): or a pharmaceutically acceptable salt thereof, wherein: Y 1 , Y 2 and Y 3 Each independently is CR 10 NR 10a or N; where Y 1 , Y 2 and Y 3 At least one of them is CR 10 ; Each R 10 is 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; and Each R 10a are 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 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl.

27. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, characterized in that X 4 is N, and X 5 CR 8b .

28. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, characterized in that X 4 CR 8a , And X 5 is N.

29. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, characterized in that X 4 is N, and X 5 is N.

30. A compound as described in any one of claims 21 to 29, or a pharmaceutically acceptable salt thereof, characterized in that Yu, Y 1 and Y 3 Each independently is NR 10a or N; and Y 2 CR 10 .

31. A compound as described in any one of claims 21 to 29, or a pharmaceutically acceptable salt thereof, characterized in that Yu, Y 2 and Y 3 Each independently is NR 10a or N; and Y 1 CR 10 .

32. A compound as described in any one of claims 21 to 29, or a pharmaceutically acceptable salt thereof, characterized in that Yu, Y 1 and Y 2 Each independently is NR 10a or N; and Y 3 CR 10 .

33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, characterized in that Z is absent or -O-.

34. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, characterized in that Z is -NR 1a -.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein Z is -NH-.

36. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, characterized in that L is in, Ring B is an optionally substituted 3-7 membered carbocyclic group, or an optionally substituted 4-7 membered heterocyclic group; L 1 Absent, or optionally substituted C1-C 10 Alkylene, or optionally substituted C1-C 10 Heteroalkylene; and L 2 Absent, or optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkyne, or optionally substituted C1-C 10 Heteroalkylene.

37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 3-7 membered carbocyclic group; L 1 Absent, or optionally substituted C1-C 10 Alkylene; and L 2 Absent, or optionally substituted C1-C 10 Alkylene.

38. A compound as claimed in claim 36 or claim 37, or a pharmaceutically acceptable salt thereof, characterized in that At, L 1 is not present; and L 2 C1-C 10 Alkylene.

39. A compound as described in any one of claims 36 to 38, or a pharmaceutically acceptable salt thereof, characterized in that wherein Ring B is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptyl, spiro[4.4]nonyl, or Spiro[3.4]octyl ring.

40. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, characterized in that R 2 Halogen, CN, OR 5 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclic group, or optionally substituted 3-10 membered heterocyclic group.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally substituted 3-10 membered carbocyclic group.

42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, characterized in that R 1 Does not exist.

43. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, characterized in that R 1 It is an oxo group (=O).

44. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

45. A method of treating abnormal cell growth in a subject in need thereof, comprising: An effective amount of the compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, or the composition of claim 40 is administered to the subject.

46. ​​The method of claim 45, wherein: The subject suffers from cancer.

47. The method of claim 45 or claim 46, wherein: Also includes: A second compound comprising a FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator is administered to the subject.

48. The method of claim 47, wherein: The FLT3 pathway inhibitor is gilteritinib The invention relates to gilteritinib, midostaurin, sorafenib, sunitinib, lestaurtinib, quizartinib, crenolanib or sitravatinib, or a pharmaceutically acceptable salt thereof.

49. The method of claim 48, wherein: The FLT3 pathway inhibitor is gilteritinib, or a pharmaceutically acceptable salt thereof.

50. A compound as claimed in any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

51. A compound as claimed in any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating cancer.

52. A combination comprising: A compound as described in any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, 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.

53. The combination of claim 52, wherein: The FLT3 pathway inhibitor is gilteritinib, midostaurin, sorafenib, sunitinib, lestaurtinib, quizartinib, clelanib or sitritinib, or a pharmaceutically acceptable salt thereof.

54. The method of claim 52 or claim 53, wherein: The FLT3 pathway inhibitor is gilteritinib, or a pharmaceutically acceptable salt thereof.

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