Multi-kinase degradation agents, compositions comprising same and methods of use thereof

Abstract

The present disclosure provides a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, a pharmaceutically acceptable salt of the foregoing, a composition comprising a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, # imgabs0 # and methods of using the same to treat diseases, disorders or conditions, e.g., mediated by degradation of protein kinases such as hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1), mitogen-activated protein kinase 1 / 2 (MEK 1 / 2), human Fms-like tyrosine kinase 3 receptor (FLT3) and aurora kinase A

Description

[0001] Inventors: Tianwei MA, Lichao FANG, Miao LIU and Ling SONG. Technical Field

[0002] The present disclosure provides a compound of formula I, a tautomer thereof, a deuterated derivative of the compound or the tautomer, and a pharmaceutically acceptable salt of the foregoing; a composition comprising a compound of formula I, a tautomer thereof, a deuterated derivative of the compound or the tautomer, and / or a pharmaceutically acceptable salt of the foregoing, and a method of using the above-mentioned substances to treat diseases, disorders or conditions mediated by degradation of protein kinases such as hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1), mitogen-activated protein kinase 1 / 2 (MEK 1 / 2), human Fms-like tyrosine kinase 3 receptor (FLT3) and Aurora kinase. Background Art

[0003] Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine, and threonine residues of proteins. Serine / threonine kinases constitute an important family of protein kinases, which are specific for the phosphorylation of serine and threonine residues. Another major family of protein kinases are tyrosine kinases, which are specific for the phosphorylation of tyrosine residues. In addition, there are dual-specific kinases, which can phosphorylate both tyrosine and serine / threonine residues.

[0004] Protein kinases play key roles in many cellular functions such as proliferation, survival, metabolism and differentiation. In addition, dysregulated protein kinases are disease drivers in many pathological conditions, including immune, neoplastic, metabolic, neurological and infectious diseases. Protein kinases involved in cell proliferation and survival are frequently mutated or overexpressed in cancer. They are attractive targets for anticancer drugs.

[0005] Hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1) is a serine / threonine kinase and a member of the MAP4K family. HPK1 is primarily expressed in hematopoietic cell lines and acts as a negative regulator in T lymphocyte and dendritic cell activation. Therefore, HPK1 inhibition is expected to prolong T cell activation and enhance the APC function of dendritic cells. Thus, HPK1 has been identified as a novel anticancer immunotherapy and a new intracellular checkpoint molecule as well as a potential combination therapy with current checkpoint molecules. Small molecule degraders targeting HPK1 can eliminate its scaffold function to achieve better efficacy and / or overcome resistance to inhibitors.

[0006] Mitogen-activated protein kinase 1 / 2 (MEK 1 / 2) are dual-specific (threonine and tyrosine) protein kinases that function downstream of RAS in the MAP kinase (MAPK) signaling pathway. They are responsible for transmitting growth signals from various extracellular stimuli to the downstream effector ERK1 / 2. When RAS binds to RAF, it phosphorylates MEK1 / 2 and activates it. When phosphorylated, MEK1 / 2 further activates the only downstream substrate ERK1 / 2. The MAPK pathway is an important pathway that controls cell proliferation, survival, and differentiation. MEK1 / 2 inhibitors have been used to treat cancers with overactivation of the MAPK pathway. To date, four MEK inhibitors (MEKi) have been approved by the FDA, but their application is limited due to acquired resistance and side effects under long-term treatment. Small molecule degraders that can effectively eliminate MEK protein are expected to address the limitations of current anti-MEK therapies and bring new breakthroughs to cancer treatment.

[0007] Human Fms-like tyrosine kinase 3 receptor (FLT3), also known as fetal liver kinase 2 (FLK-2) or CD135, is a member of the class III receptor tyrosine kinase. FLT3 is overexpressed in the primitive cell crisis phase of about 90% of acute myeloid leukemia (AML), most acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (BC-CML). FLT3 is one of the most commonly mutated genes in hematological malignancies. FLT3 mutations are found in 1-3% of ALL patients, 5-10% of myelodysplasia patients and 15-35% of AML patients. FLT3 mutations can be subdivided into: internal tandem duplications (ITD) present in about 25% of patients; and point mutations (e.g., D835 and I836) in the tyrosine kinase domain (TKD) present in about 5% of patients. Both FLT3-ITD and FLT3-TKD mutations are constitutively active, resulting in ligand-independent FLT3 signal transduction and cell proliferation. Current small molecule FLT3 inhibitors have not brought significant clinical benefits as monotherapy. A FLT3 degrader that can induce rapid degradation of FLT3 is needed to effectively downregulate the downstream STAT5 pathway. Such a Flt3 degrader would provide a new option for patients who have failed all currently available drug therapies and stem cell transplantation.

[0008] Aurora kinases are key cell cycle regulators implicated in the pathogenesis of a variety of tumors. In humans, there are three isoforms of Aurora kinases: Aurora kinase A, Aurora kinase B, and Aurora kinase C. Aurora kinase A and Aurora kinase B play key roles in mitosis, whereas Aurora kinase C activity is primarily restricted to meiotic cells. Aurora kinase A and Aurora kinase B are closely related in structure but have distinct roles in mitosis. The Aurora kinase A gene (AURKA) is localized to chromosome 20ql3.2 and is frequently amplified or overexpressed in a variety of cancers. The encoded protein is present at the centrosomes of interphase cells and at the spindle poles of mitosis. Aurora kinase A kinase interacts with and phosphorylates a variety of proteins that function together in regulating mitotic progression and cell division. Aurora kinase A is functionally associated with several tumor suppressors and oncogenes. It promotes transcription of the c-Myc oncogene and protects the N-Myc protein from ubiquitination and subsequent degradation. It also downregulates p53 and inhibits the function of BRCA1 / 2 tumor suppressors. Overexpression of Aurora A kinase causes a stoichiometric imbalance between Aurora A and its interacting partners, leading to oncogenic transformation. The potential oncogenic role of Aurora A has generated great interest in targeting this kinase to treat cancers with genetic instability, aneuploidy, or genetic alterations of oncogenes (e.g., Myc, RAS, PKA) or tumor suppressors (e.g., TP53, BRCA1 / 2). Although different Aurora A inhibitors have been tested in clinical trials, limited efficacy and significant toxicity have been observed. Novel Aurora A degraders have the potential to improve clinical outcomes.

[0009] In view of the above-mentioned importance of protein kinases in tumorigenesis, small molecule degraders can be used as single agents or in combination to treat solid tumors, including but not limited to brain cancer, breast cancer, respiratory tract cancer and / or lung cancer, reproductive organ cancer, bone cancer, digestive tract cancer, urethral cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer and parathyroid cancer. For example, small molecule degraders can be used as single agents or in combination to treat blood cancers, including but not limited to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), T-cell lymphoma (TCL), Burkitt lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and myelodysplastic syndrome (MDS). Summary of the invention

[0010] One aspect of the present disclosure provides a compound selected from Formula I, its tautomer, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substance, which can be used to treat diseases mediated by the degradation of protein kinases such as hematopoietic progenitor kinase 1 (HPK1, MAP4K1), mitogen-activated protein kinase 1 / 2 (MEK 1 / 2), human Fms-like tyrosine kinase 3 receptor (FLT3) and Aurora kinase. For example, the following compound of structural formula I is disclosed herein:

[0011]

[0012] Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, wherein:

[0013] (i)R 1 Selected from: straight chain, branched chain and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, straight chain, branched chain and cyclic alkenyl groups, straight chain and branched heteroalkenyl groups, straight chain, branched chain and cyclic alkynyl groups, CO2R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2,OC(O)R w NR x R y ,S(O)R y and SO2R y ;

[0014] (ii) R 2 and R 3 Independently selected from: hydrogen, halogen groups, OR x , SR x 、NHR x 、N(R x 2. CHR x and C(R x )2;

[0015] (iii) each R' is independently selected from: hydrogen, a halogen group, a linear, branched and cyclic alkyl group;

[0016] (iv) m and n are independently selected from: 0, 1 and 2;

[0017] (v) X is absent or selected from the group consisting of: linear, branched, cyclic alkylene groups, linear, branched, and cyclic heteroalkylene groups;

[0018] (vi) Y and Z are independently absent or selected from: -O-, -C(O)-, -C(O)R x -、-C(S)-、-C(S)R x -、-[C(R x R y )] p -、-S(O)2-、-S(O)2R x -、NR x -and-NR x C(O)-; wherein p is selected from: 1, 2, 3, 4, 5 and 6; wherein, if X is absent, Y is not -O-, -S(O)2-, -S(O)2R x -、NR x -and-NR x C(O)-;

[0019] (vii) R x , R y and R w are each independently selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups and heteroaryl groups;

[0020] (viii) Ring A is selected from: an optionally substituted aryl group and a heteroaryl group,

[0021] (ix) Ring B is absent or selected from a cycloalkyl group and a heterocycloalkyl group;

[0022] (x) Ring C is selected from:

[0023]

[0024] Among them, R c is hydrogen; R" is selected from: hydrogen, halogen groups, OR x , straight chain, branched chain and cyclic alkyl groups;

[0025] Wherein, the straight chain, branched chain and cyclic alkyl groups, straight chain, branched chain and cyclic alkenyl groups, straight chain, branched chain and cyclic alkylene groups, carbocyclic groups, straight chain and branched heteroalkenyl groups, straight chain, branched chain and cyclic alkynyl groups, heterocyclic groups, aryl groups and heteroaryl groups are optionally substituted by at least one group selected from the following groups:

[0026] Halogen groups,

[0027] Hydroxyl,

[0028] Thiols,

[0029] Amino,

[0030] Cyano,

[0031] -OC(O)C1-C6 straight chain, branched and cyclic alkyl groups,

[0032] -C(O)OC1-C6 straight chain, branched and cyclic alkyl groups,

[0033] -NHC1-C6 straight chain, branched and cyclic alkyl groups,

[0034] -N(C1-C6 straight chain, branched chain and cyclic alkyl group)2,

[0035] -NHC(O)C1-C6 straight chain, branched and cyclic alkyl groups,

[0036] -C(O)NHC1-C6 straight chain, branched and cyclic alkyl groups,

[0037] -NH aryl group,

[0038] -N(aryl group)2,

[0039] -NHC(O)aryl group,

[0040] -C(O)NH aryl group,

[0041] -NH heteroaryl group,

[0042] -N(heteroaryl group)2,

[0043] -NHC(O)heteroaryl group,

[0044] -C(O)NH heteroaryl group,

[0045] C1-C6 straight chain, branched and cyclic alkyl groups,

[0046] C2-C6 straight chain, branched and cyclic alkenyl groups,

[0047] C1-C6 straight chain, branched and cyclic hydroxyalkyl groups,

[0048] C1-C6 straight chain, branched and cyclic aminoalkyl groups,

[0049] C1-C6 straight chain, branched and cyclic alkoxy groups,

[0050] C1-C6 straight chain, branched and cyclic thioalkyl groups,

[0051] C1-C6 straight chain, branched and cyclic haloalkyl groups,

[0052] C1-C6 straight chain, branched and cyclic halogenated aminoalkyl groups,

[0053] C1-C6 straight chain, branched chain and cyclic halogenated thioalkyl groups,

[0054] C1-C6 straight chain, branched and cyclic haloalkoxy groups,

[0055] benzyloxy, benzylamino and benzylthio groups,

[0056] 3- to 6-membered heterocycloalkenyl group,

[0057] a 3- to 6-membered heterocyclic group, and

[0058] 5- and 6-membered heteroaryl groups.

[0059] In one aspect of the present disclosure, the compound of Formula I is selected from Compounds 1 to 18 shown below, tautomers thereof, deuterated derivatives of the compound or the tautomer, and pharmaceutically acceptable salts of the foregoing.

[0060] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing substance, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise a compound selected from compounds 1 to 18 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing substance. These compositions may also comprise additional active agents.

[0061] Another aspect of the present disclosure provides a method for treating a disease, disorder or condition mediated by the degradation of protein kinase in a subject, comprising administering a therapeutically effective amount of a compound of formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances, or a pharmaceutical composition comprising any of the foregoing substances. In some embodiments, the method of treatment comprises administering to the subject a therapeutically effective amount of a compound selected from compounds 1 to 18 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances, or a pharmaceutical composition comprising any of the foregoing substances.

[0062] In some embodiments disclosed herein, the method of treatment includes administering an additional active agent to a subject in need thereof, which may be in the same pharmaceutical composition with the compound of Formula I, its tautomer, the deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, or in a separate composition. In some embodiments disclosed herein, the method of treatment includes administering a compound selected from compounds 1 to 18 shown below, its tautomer, the deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing and an additional active agent in the same composition or a separate composition.

[0063] Also disclosed herein is a method for reducing protein kinase activity, comprising administering to a subject a therapeutically effective amount of a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0064] In some embodiments disclosed herein, the method of degrading protein kinase comprises administering to a subject a compound selected from Compounds 1 to 18 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] The foregoing summary of the invention and the following detailed description of the present disclosure will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the present disclosure, the accompanying drawings illustrate some but not all alternative embodiments. However, it should be understood that the present disclosure is not limited to the precise arrangements and means shown. These drawings are incorporated into the specification and constitute a part thereof and help explain the principles of the present disclosure.

[0066] Figure 1 Western blot showing that Example 2 of the present disclosure degrades HPK1, FLT3, and MEK 1 / 2.

[0067] Figure 2 Graphical data showing degradation of HPK1, FLT3 and MEK 1 / 2 by Example 2 of the present disclosure are shown.

[0068] Figure 3 Western blot showing that Example 8 of the present disclosure degrades HPK1, FLT3, Aurora A, and MEK 1 / 2.

[0069] Figure 4 The graphical data showing the degradation of HPK1 and FLT3 by Example 8 of the present disclosure are shown.

[0070] Figure 5 Plot data showing the degradation of Aurora A and MEK 1 / 2 by Example 8 of the present disclosure.

[0071] Figure 6 Western blot showing degradation of FLT3 and Aurora A by Example 14 of the present disclosure.

[0072] Figure 7 Graphical data showing degradation of FLT3 and Aurora A by Example 14 of the present disclosure. DETAILED DESCRIPTION

[0073] I. Definitions

[0074] As used herein, the terms "a" or "an" when referring to a noun include the expression "at least one" and thus include both the singular and plural units of the noun. For example, "an additional agent" refers to a single or two or more additional agents.

[0075] The term "protein kinase" is an enzyme that catalyzes the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. Serine / threonine kinases constitute an important family of protein kinases, which are specific for the phosphorylation of serine and threonine residues. Another major family of protein kinases is the tyrosine kinases, which are specific for the phosphorylation of tyrosine residues. In addition, there are also dual-specific kinases, which can phosphorylate both tyrosine and serine / threonine residues. Examples of protein kinases include, but are not limited to, hematopoietic progenitor cell kinases, mitogen-activated protein kinases 1 / 2, human Fms-like tyrosine kinase 3 and aurora kinases.

[0076] As used herein, the term "HPK1" or "hematopoietic progenitor kinase 1", also known as MAP4K1, is a serine / threonine kinase that is primarily expressed in hematopoietic cells such as T cells, B cells, and dendritic cells (DCs). HPK1 is involved in the regulation of multiple downstream signal transduction pathways associated with the regulation of cell proliferation and immune cell activation, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB).

[0077] As used herein, the term "MEK 1 / 2" or "mitogen-activated protein kinase 1 / 2" is a dual-specificity (threonine and tyrosine) protein kinase that functions downstream of RAS in the MAP kinase (MAPK) signal transduction pathway. They are responsible for transmitting growth signals from various extracellular stimuli to the downstream effector ERK1 / 2. When RAS binds to RAF, it phosphorylates MEK1 / 2 and activates it. When phosphorylated, MEK1 / 2 further activates the only downstream substrate ERK1 / 2. The MAPK pathway is an important pathway that controls cell proliferation, survival, and differentiation. MEK1 / 2 inhibitors have been used to treat cancers in which the MAPK pathway is overactivated.

[0078] As used herein, the term "FLT3" or "human Fms-like tyrosine kinase 3 receptor", also known as fetal liver kinase 2 (FLK-2) or CD135, is a member of the class III receptor tyrosine kinase. FLT3 is overexpressed in the primitive cell crisis phase of about 90% of acute myeloid leukemia (AML), most acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (BC-CML). FLT3 is one of the most common mutated genes in hematological malignancies. FLT3 mutations are found in 1-3% of ALL patients, 5-10% of myelodysplasia patients and 15-35% of AML patients. FLT3 mutations can be subdivided into: internal tandem duplications (ITD) present in about 25% of patients; and point mutations (e.g., D835 and I836) in the tyrosine kinase domain (TKD) present in about 5% of patients. Both FLT3-ITD and FLT3-TKD mutations are constitutively active, resulting in ligand-independent FLT3 signal transduction and cell proliferation.

[0079] As used herein, the term "Aurora kinase" is a key cell cycle regulator associated with the pathogenesis of a variety of tumors. In humans, there are three subtypes of Aurora kinase: Aurora kinase A, Aurora kinase B and Aurora kinase C. Aurora kinase A and Aurora kinase B play a key role in mitosis, while Aurora kinase C activity is mainly limited to meiotic cells. Aurora kinase A and Aurora kinase B are closely related in structure, but have different roles in mitosis. The Aurora kinase A gene (AURKA) is located on chromosome 20ql3.2, which is often amplified or overexpressed in a variety of cancers. The encoded protein is present in the centrosomes of interphase cells and the spindle poles of mitosis. Aurora kinase A kinase interacts with and phosphorylates a variety of proteins that play a role in regulating mitotic progression and cell division. Aurora kinase A is functionally associated with several tumor suppressors and oncogenes. It promotes the transcription of the c-Myc oncogene and protects the N-Myc protein from ubiquitination and subsequent degradation. It also downregulates p53 and inhibits the function of BRCA1 / 2 tumor suppressors. Overexpression of Aurora A kinase causes a stoichiometric imbalance between Aurora A and its interacting partners, leading to oncogenic transformation. The potential oncogenic role of Aurora A has generated great interest in targeting this kinase to treat cancers with genetic instability, aneuploidy or genetic alterations of oncogenes (e.g. Myc, RAS, PKA) or tumor suppressors (e.g. TP53, BRCA1 / 2).

[0080] The compounds disclosed herein can degrade protein kinases. Thus, the compounds disclosed herein can generally be used to treat diseases or conditions associated with such kinases. In one embodiment, the compounds disclosed herein are HPK1 degraders, MEK1 / 2 degraders, FLT3 degraders, or Aurora kinase A degraders, and can be used to treat diseases associated with such kinases, such as cancer.

[0081] As used herein, the term "degrader" refers to a molecular agent that binds to a protein kinase, such as hematopoietic progenitor kinase 1, and subsequently reduces the steady-state protein level of the kinase. In some embodiments, the degraders disclosed herein reduce the steady-state protein kinase level by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the degraders disclosed herein reduce the steady-state protein kinase level by at least 65%. In some embodiments, the degraders disclosed herein reduce the steady-state protein kinase level by at least 85%.

[0082] When referring to the compounds of the present disclosure, unless otherwise specified as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), the term "compound" refers to a collection of molecules having the same chemical structure, except for isotopic variations between the constituent atoms of the molecules. Therefore, it will be clear to those skilled in the art that a compound represented by a specific chemical structure containing a specified deuterium atom will also contain a smaller amount of isotopologues having hydrogen atoms at one or more specified deuterium positions in the structure. The relative amount of such isotopologues in the compounds of the present disclosure will depend on many factors, including, for example, the isotopic purity of the reagents used to prepare the compound and the incorporation efficiency of the isotopes in the various synthetic steps used to prepare the compound. However, as described above, the relative total amount of such isotopologues will be less than 49.9% of the compound. In other embodiments, the relative total amount of such isotopologues is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0083] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise specified, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent at each position may be the same or different. Combinations of substituents contemplated by the present disclosure are those that result in the formation of stable or chemically feasible compounds.

[0084] The term "isotopic configuration" refers to species of chemical structures that differ only in their isotopic composition. In addition, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or replacing 13 C or 14 Compounds having structures of the present disclosure other than C replacing a carbon are within the scope of the present disclosure.

[0085] Unless otherwise stated, structures described herein are also meant to include all isomeric forms of the structure, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers such as (Z) and (E) double bond isomers and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the compounds of the present disclosure are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0086] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that coexist in equilibrium and are readily interchangeable by migration of atoms (eg, hydrogen atoms) or groups within a molecule.

[0087] As used herein, "stereoisomers" refers to enantiomers and diastereomers.

[0088] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as the reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ("D" or " 2H”). It should be recognized that some variation in natural isotopic abundance in synthesized compounds depends on the source of the chemical materials used in the synthesis. Despite this variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the extent of stable isotopic substitution of the deuterated derivatives disclosed herein. Therefore, unless otherwise specified, when referring to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen has been replaced with deuterium at a level well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have at least 3500 (in each reference) per deuterium atom. The isotopic enrichment factor of at least 4500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4500 (67.5% deuterium incorporation at each designated deuterium atom), at least 5000 (75% deuterium incorporation at each designated deuterium atom), at least 5500 (82.5% deuterium incorporation at each designated deuterium atom), at least 6000 (90% deuterium incorporation at each designated deuterium atom), at least 6333.3 (95% deuterium incorporation at each designated deuterium atom), at least 6466.7 (97% deuterium incorporation at each designated deuterium atom), or at least 6600 (99% deuterium incorporation at each designated deuterium atom).

[0089] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0090] As used herein, the term "alkyl" refers to a fully saturated straight or branched, substituted or unsubstituted hydrocarbon chain. Unless otherwise specified, the alkyl group contains 1 to 30 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 20 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 10 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1 to 8 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1 to 6 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 4 alkyl carbon atoms. In other embodiments, the alkyl group contains 1 to 3 alkyl carbon atoms. In other embodiments, the alkyl group contains 1 to 2 alkyl carbon atoms. In some embodiments, the alkyl group is substituted. In some embodiments, the alkyl group is unsubstituted. In some embodiments, the alkyl group is linear or straight or unbranched. In some embodiments, the alkyl group is branched.

[0091] The term "cycloalkyl" refers to a fully saturated monocyclic C 3-8 Hydrocarbon or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14In some embodiments, the cycloalkyl group is C3 to C4. 12 Cycloalkyl. In some embodiments, the cycloalkyl is a C3 to C8 cycloalkyl. In some embodiments, the cycloalkyl is a C3 to C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0092] The term "carbocyclyl" encompasses the term "cycloalkyl" and refers to a monocyclic C 3-8 Hydrocarbon or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 Hydrocarbon, it is fully saturated or partially saturated (because it contains one or more unsaturated units but is not aromatic), wherein any single ring in the bicyclic system has 3 to 7 members. Bicyclic carbocyclyl includes a combination of monocyclic carbocyclic rings fused to, for example, phenyl. In some embodiments, the carbocyclyl group is substituted. In some embodiments, the carbocyclyl group is unsubstituted. In some embodiments, the carbocyclyl group is C3 to C 12 In some embodiments, the carbocyclic group is C3 to C 10 Carbocyclyl. In some embodiments, the carbocyclyl is a C3 to C8 carbocyclyl. Non-limiting examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like.

[0093] As used herein, the term "alkylene" refers to a divalent alkyl radical. 1-10 Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, and n-decylene.

[0094] As used herein, the term "alkenyl" refers to a straight or branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, the alkenyl group is substituted. In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is linear, straight or unbranched. In some embodiments, the alkenyl group is branched.

[0095] As used herein, the term "alkynyl" refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched chain group of 2 to 8 carbon atoms, referred to herein as C 2-8Alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

[0096] As used herein, the term "heterocyclyl" refers to a non-aromatic (i.e., fully saturated or partially saturated, because it contains one or more unsaturated units but is not aromatic), monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system, wherein one or more ring members are independently selected heteroatoms. Bicyclic heterocyclic groups include, for example, a combination of the following monocyclic rings: a monocyclic heteroaryl fused to a monocyclic heterocyclic group; a monocyclic heterocyclic group fused to another monocyclic heterocyclic group; a monocyclic heterocyclic group fused to a phenyl group; a monocyclic heterocyclic group fused to a monocyclic carbocyclic group / cycloalkyl group; and a monocyclic heteroaryl group fused to a monocyclic carbocyclic group / cycloalkyl group. In some embodiments, the "heterocyclic" group contains 3 to 14 ring members, wherein one or more ring members are independently selected from heteroatoms such as oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has a heteroatom independently selected from oxygen, sulfur, nitrogen and phosphorus. In some embodiments, the heterocycle has a heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has a heteroatom that is an oxygen atom. In some embodiments, the heterocycle has two heteroatoms each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle is substituted. In some embodiments, the heterocycle is unsubstituted. In some embodiments, the heterocyclyl is a 3 to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4 to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3 to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5 to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5 to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5 or 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, tetrahydrothiophenyl, dihydropyranyl, tetrahydropyridinyl, and the like.

[0097] The term "heteroatom" refers to one or more of oxygen, sulfur and nitrogen, including any oxidized form of nitrogen or sulfur or silicon; any quaternized form of a basic nitrogen; a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).

[0098] As used herein, the term "unsaturated" refers to a moiety having one or more unsaturated units or degrees of unsaturation. Unsaturation is the state in which not all available valences in a compound are satisfied by substituents, thus the compound contains double or triple bonds.

[0099] As used herein, the term "alkoxy" refers to an alkyl group as defined above wherein one of the carbons of the alkyl group is replaced with an oxygen ("alkoxy") atom, provided that the oxygen atom is attached between two carbon atoms.

[0100] The term "halogen" includes F, Cl, Br and I, ie fluorine, chlorine, bromine and iodine, respectively.

[0101] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0102] As used herein, "aromatic ring" refers to a carbocyclic or heterocyclic ring containing a conjugated planar ring system having a delocalized π electron orbital consisting of [4n+2]p orbital electrons, where n is an integer from 0 to 6. A "non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the above requirements for an aromatic ring and may be fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, which are further defined below.

[0103] The term "aryl", used alone or as part of a larger moiety as in "arylalkyl", "arylalkoxy", or "aryloxyalkyl", refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having a total of five to fourteen ring members, wherein each ring in the system is an aromatic ring containing only carbon atoms, and wherein each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) rings and naphthyl (C 10 ) ring. In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0104] The term "heteroaryl" refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Bicyclic heteroaryl includes, for example, a combination of the following monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has one heteroatom. In some embodiments, the heteroaryl group has two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic ring system with five ring members. In some embodiments, the heteroaryl group is a monocyclic ring system with six ring members. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl group is a 3 to 12-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls are pyridyl, pyrimidinyl, thienyl, thiazolyl, isoxazolyl, and the like.

[0105] "Spirocyclic ring system" refers to a ring system having two or more cyclic rings wherein every two rings share only one common atom.

[0106] The term "prodrug group" refers to a group that is covalently linked to a compound and causes the compound to have improved oral bioavailability and / or tumor targeting and / or is more active in vivo. Certain compounds of Formula I may include a prodrug group, such as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (see Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). The prodrug of the compound described herein is a structurally modified form of the compound that is susceptible to chemical changes under physiological conditions to provide an active compound. Prodrugs are generally useful because, in some cases, they are easier to administer than the parent drug. They can be, for example, bioavailable by oral administration, while the parent drug cannot. A variety of prodrug derivatives are known in the art, such as derivatives that rely on hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug group is a part of a compound such as an ester, but is then metabolically hydrolyzed to a carboxylic acid to release an active entity. Other examples of prodrug groups include peptidyl derivatives of the compounds.

[0107] Non-limiting examples of suitable solvents that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropanol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0108] Non-limiting examples of suitable bases that can be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropylethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCH3).

[0109] Disclosed herein are pharmaceutically acceptable salts of the disclosed compounds. Salts of a compound are formed between an acid and a basic group of the compound (eg, an amino functional group), or between a base and an acidic group of the compound (eg, a carboxyl functional group).

[0110] As used herein, the term "pharmaceutically acceptable" refers to components that are suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, etc., within the scope of reasonable medical judgment, and are commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" refers to any non-toxic salt that can directly or indirectly provide a compound of the present disclosure when administered to a recipient. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge, et al. J. Pharmaceutical Sciences, 1977, 66, pp. 1-19.

[0111] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propionates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dimethoxybenzene, 1,2 ... Pharmaceutically acceptable acid addition salts include, but are not limited to, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0112] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali metal salts and alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0113] The term "subject" refers to animals, including but not limited to humans.

[0114] The term "therapeutically effective amount" refers to the amount of a compound that produces the desired effect of the administered compound (e.g., ameliorating symptoms of diseases, disorders and conditions mediated by degradation of HPK1, lessening the severity of diseases, disorders and conditions mediated by degradation of HPK1 or their symptoms, and / or reducing the progression of diseases, disorders and conditions mediated by degradation of HPK1 or their symptoms). The exact amount of a therapeutically effective amount will depend on the purpose of the treatment and can be determined by one skilled in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0115] As used herein, the term "treat" and its cognates refer to slowing or stopping the progression of a disease. "Treatment" and its cognates as used herein include, but are not limited to, the following: complete or partial relief and risk reduction of diseases, disorders and conditions mediated by the degradation of HPK1 and complications associated with the disease. The improvement or reduction of the severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0116] The term "cancer" includes, but is not limited to, the following cancers: oral cavity such as epidermoid carcinoma of the buccal cavity, lip, tongue, mouth, pharynx; cardiac cancer such as sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer such as bronchial cancer (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatosis hamartoma, mesothelioma; gastrointestinal cancer such as esophageal (squamous cell carcinoma, laryngeal carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreatic (ductal adenocarcinoma, insulinoma) Cancers of the small intestine or large intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon or large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, colorectum; genitourinary tract cancers, including kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma cancers such as osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; cancers of the nervous system, including the skull (osteomas, hemangiomas, granulomas, xanthomas, Osteitis deformans), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecological cancers including uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical atypia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), ovarian granulosa-follicular cell tumor (granulosathecal cell tumors), ovarian Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast;Blood cancers such as blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) hair cells; lymphatic system diseases; skin cancers including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; thyroid cancers such as papillary thyroid cancer, follicular thyroid cancer; medullary thyroid cancer, anaplastic thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and adrenal gland cancers such as neuroblastoma. ;

[0117] The compounds and compositions of the present application can be administered in combination therapy with one or more therapeutic agents (drug combinations) or treatment methods (such as antiproliferative agents, anticancer agents, immunomodulators or anti-inflammatory agents and / or non-drug therapy combinations, etc.) in a therapeutically effective amount. For example, a synergistic effect can be produced with antiproliferative, anticancer, immunomodulatory or anti-inflammatory substances. When the compounds of the present application are administered in combination with other therapies, the dosage of the co-administered compound will of course vary according to the type of combined drug used, the specific drug used, the condition treated, etc. Combination therapy includes further administering the test compound in combination with one or more other biologically active ingredients (such as but not limited to a second kinase inhibitor, a second different antitumor agent) and non-drug therapy (such as but not limited to surgery or radiotherapy). For example, the compounds of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effect of the compounds of the present application. The compounds of the present application can be administered simultaneously (as a single preparation or a separate preparation) or in sequence with other drug therapies or treatment methods. In general, combination therapy envisions administering two or more drugs in a single treatment cycle or course of treatment. In another aspect of the present application, the compounds may be administered in combination with one or more separate agents (eg, chemotherapeutic agents, immunotherapeutic agents, or adjuvant therapeutic agents).In one embodiment, the single agent is selected from the group consisting of an anti-PD1 antibody (e.g., pembrolizumab), an HDAC inhibitor r (e.g., panobinostat, romidepsin, vorinostat, or sitastat), a BCL-2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor r (e.g., idelalisib), a PKCβ inhibitor (e.g., enzastaurin), a SYK inhibitor (e.g., fostamatinib), JAK2 inhibitors (e.g., fidartinib, paclitinib, ruxolitinib, baricitinib, tucatinib, lestaurtinib, or molotinib), Aurora kinase inhibitors (e.g., aleceptinib), EZF12 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaadenine A, EPZ005687, Ell, UNC1999, or sinefungin), BET inhibitors (e.g., bilaricevse), hypomethylating agents (e.g., 5-azacytidine or decitabine), DO T1L inhibitors (e.g., pinostat), FIAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., compound C or celidestat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420FU / F12 inhibitors (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JF1295), MEK inhibitors (e.g., trametinib, bemetinib, cobimetinib, selumetinib), PF1F19 inhibitors, PIM inhibitors (e.g., LGF1-447), IGF-IR inhibitors (e.g., linsetinib), XP01 inhibitors (e.g., selinexor), BIRC5 inhibitors (e.g., YM1 55), PARP inhibitors (e.g., olaparib), EGFR inhibitors (e.g., osimertinib), HER2 / NEU inhibitors (e.g., tucatinib), SRC inhibitors (e.g., dasatinib), AKT inhibitors (e.g., patasertib), KRAS (G12C) inhibitors (e.g., sotracib), KRAS (G12D) inhibitors (e.g., MRTX1133), platinum or chemotherapy drugs (e.g., bendamustine, bleomycin, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, cisplatin, taxanes or dexamethasone).

[0118] When used in conjunction with a dose, amount, or weight percentage of an ingredient of a composition or dosage form, the terms "about" and "approximately" include either the value of the specified dose, amount, or weight percentage or a range of doses, amounts, or weight percentages that one of ordinary skill in the art recognizes provides a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage.

[0119] II. Compounds and Compositions

[0120] In a first embodiment, the compound of the present disclosure is a compound of the following structural formula I:

[0121]

[0122]

[0123] Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, wherein:

[0124] (i)R 1 Selected from: straight chain, branched chain and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, straight chain, branched chain and cyclic alkenyl groups, straight chain and branched heteroalkenyl groups, straight chain, branched chain and cyclic alkynyl groups, CO2R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2,OC(O)R w NR x R y ,S(O)R y and SO2R y ;

[0125] (ii) R 2 and R 3 Independently selected from: hydrogen, halogen groups, OR x , SR x 、NHR x 、N(R x 2. CHR x and C(R x )2;

[0126] (iii) each R' is independently selected from: hydrogen, a halogen group, a linear, branched and cyclic alkyl group;

[0127] (iv) m and n are independently selected from: 0, 1 and 2;

[0128] (v) X is absent or selected from the group consisting of: linear, branched, cyclic alkylene groups, linear, branched, and cyclic heteroalkylene groups;

[0129] (vi) Y and Z are independently absent or selected from: -O-, -C(O)-, -C(O)R x -、-C(S)-、-C(S)R x -、-[C(R x R y )] p -、-S(O)2-、-S(O)2R x -、NR x -and-NR x C(O)-; wherein p is selected from: 1, 2, 3, 4, 5 and 6; wherein, if X is absent, Y is not -O-, -S(O)2-, -S(O)2R x -、NR x -and-NR x C(O)-;

[0130] (vii) R x , R y and R w are each independently selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups and heteroaryl groups;

[0131] (viii) Ring A is selected from: an optionally substituted aryl group and a heteroaryl group,

[0132] (ix) Ring B is absent or selected from a cycloalkyl group and a heterocycloalkyl group;

[0133] (x) Ring C is selected from:

[0134]

[0135] Among them, R c is hydrogen; R" is selected from: hydrogen, a halogen group, OR x , linear, branched and cyclic alkyl groups;

[0136] Wherein, the straight chain, branched chain and cyclic alkyl groups, straight chain, branched chain and cyclic alkenyl groups, straight chain, branched chain and cyclic alkylene groups, carbocyclic groups, straight chain and branched heteroalkenyl groups, straight chain, branched chain and cyclic alkynyl groups, heterocyclic groups, aryl groups and heteroaryl groups are optionally substituted by at least one group selected from the following groups:

[0137] Halogen groups,

[0138] Hydroxyl,

[0139] Thiols,

[0140] Amino,

[0141] Cyano,

[0142] -OC(O)C1-C6 straight chain, branched and cyclic alkyl groups,

[0143] -C(O)OC1-C6 straight chain, branched and cyclic alkyl groups,

[0144] -NHC1-C6 straight chain, branched and cyclic alkyl groups,

[0145] -N(C1-C6 straight chain, branched chain and cyclic alkyl group)2,

[0146] -NHC(O)C1-C6 straight chain, branched and cyclic alkyl groups,

[0147] -C(O)NHC1-C6 straight chain, branched and cyclic alkyl groups,

[0148] -NH aryl group,

[0149] -N(aryl group)2,

[0150] -NHC(O)aryl group,

[0151] -C(O)NH aryl group,

[0152] -NH heteroaryl group,

[0153] -N(heteroaryl group)2,

[0154] -NHC(O)heteroaryl group,

[0155] -C(O)NH heteroaryl group,

[0156] C1-C6 straight chain, branched and cyclic alkyl groups,

[0157] C2-C6 straight chain, branched and cyclic alkenyl groups,

[0158] C1-C6 straight chain, branched and cyclic hydroxyalkyl groups,

[0159] C1-C6 straight chain, branched and cyclic aminoalkyl groups,

[0160] C1-C6 straight chain, branched and cyclic alkoxy groups,

[0161] C1-C6 straight chain, branched and cyclic thioalkyl groups,

[0162] C1-C6 straight chain, branched and cyclic haloalkyl groups,

[0163] C1-C6 straight chain, branched and cyclic halogenated aminoalkyl groups,

[0164] C1-C6 straight chain, branched chain and cyclic halogenated thioalkyl groups,

[0165] C1-C6 straight chain, branched and cyclic haloalkoxy groups,

[0166] benzyloxy, benzylamino and benzylthio groups,

[0167] 3- to 6-membered heterocycloalkenyl group,

[0168] a 3- to 6-membered heterocyclic group, and

[0169] 5- and 6-membered heteroaryl groups.

[0170] In a second embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R 1 is selected from linear, branched and cyclic alkyl groups; R 2 is a halogen group; R 3 is selected from hydrogen, linear, branched and cyclic alkyl; all other variables not specifically defined herein are as defined in the first embodiment.

[0171] In a third embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R 1 selected from C1-C6 linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the first embodiment or the second embodiment.

[0172] In a fourth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R 1 is selected from the group consisting of methyl, ethyl, cyclopropyl, and cyclobutyl; all other variables not specifically defined herein are as defined in the third embodiment.

[0173] In a fifth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R 2 is a halogen group; all other variables not specifically defined herein are as defined in the preceding embodiments.

[0174] In a sixth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R 2 is chlorine; all other variables not specifically defined herein are as defined in the fifth embodiment.

[0175] In a seventh embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R 2is hydrogen; all other variables not specifically defined herein are as defined in any of the first to fourth embodiments.

[0176] In an eighth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R 3 is a halogen group; all other variables not specifically defined herein are as defined in the preceding embodiments.

[0177] In a ninth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R 3 is chlorine; all other variables not specifically defined herein are as defined in the eighth embodiment.

[0178] In a tenth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R 3 is hydrogen; all other variables not specifically defined herein are as defined in any of the first to seventh embodiments.

[0179] In an eleventh embodiment, in a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of the present disclosure, m is 1, n is 1; and all other variables not specifically defined herein are as defined in the preceding embodiments.

[0180] In a twelfth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R' is hydrogen; all other variables not specifically defined herein are as defined in the eleventh embodiment.

[0181] In a thirteenth embodiment, in a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of the present disclosure, m is 2, n is 1; and all other variables not specifically defined herein are as defined in the preceding embodiments.

[0182] In the fourteenth embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R' is hydrogen; all other variables not specifically defined herein are as defined in the thirteenth embodiment.

[0183] In a fifteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is absent; all other variables not specifically defined herein are as defined in the preceding embodiments.

[0184] In a sixteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is a straight chain alkylene group; all other variables not specifically defined herein are as defined in the preceding embodiments.

[0185] In the seventeenth embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, X is a methylene group; all other variables not specifically defined herein are as defined in the sixteenth embodiment.

[0186] In an eighteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is an ethylene group; all other variables not specifically defined herein are as defined in the sixteenth embodiment.

[0187] In a nineteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Y is absent; all other variables not specifically defined herein are as defined in the preceding embodiments.

[0188] In a twentieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring B is selected from optionally substituted heterocycloalkyl; all other variables not specifically defined herein are as defined in the preceding embodiments.

[0189] In a twenty-first embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, Ring B is selected from:

[0190] All other variables not specifically defined herein are as defined in the twentieth embodiment.

[0191] In a twenty-second embodiment, in a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of the present disclosure, wherein Z is absent; all other variables not specifically defined herein are as defined in the preceding embodiments.

[0192] In the twenty-third embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is All other variables not specifically defined herein are as defined in the preceding embodiments.

[0193] In a twenty-fourth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is hydrogen; all other variables not specifically defined herein are as defined in the twenty-third embodiment.

[0194] In a twenty-fifth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R cis selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the twenty-third embodiment.

[0195] In a twenty-sixth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the twenty-third embodiment.

[0196] In the twenty-seventh embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, Ring C is All other variables not specifically defined herein are as defined in any of Embodiments 1-22.

[0197] In a twenty-eighth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is hydrogen; all other variables not specifically defined herein are as defined in the twenty-seventh embodiment.

[0198] In the twenty-ninth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the twenty-seventh embodiment.

[0199] In the thirtieth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the twenty-seventh embodiment.

[0200] In a thirty-first embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is All other variables not specifically defined herein are as defined in any of Embodiments 1-22.

[0201] In a thirty-second embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is hydrogen; and all other variables not specifically defined herein are as defined in the thirty-first embodiment.

[0202] In the thirty-third embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the thirty-first embodiment.

[0203] In a thirty-fourth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the thirty-first embodiment.

[0204] In a thirty-fifth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, Ring C is All other variables not specifically defined herein are as defined in any of Embodiments 1-22.

[0205] In a thirty-sixth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is hydrogen; and all other variables not specifically defined herein are as defined in the thirty-fifth embodiment.

[0206] In a thirty-seventh embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the thirty-fifth embodiment.

[0207] In a thirty-eighth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the thirty-fifth embodiment.

[0208] In the thirty-ninth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is All other variables not specifically defined herein are as defined in any of Embodiments 1-22.

[0209] In the fortieth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is hydrogen; all other variables not specifically defined herein are as defined in the thirty-ninth embodiment.

[0210] In a 41st embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the thirty-ninth embodiment.

[0211] In a 42nd embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the thirty-ninth embodiment.

[0212] In the 43rd embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is All other variables not specifically defined herein are as defined in any of Embodiments 1-22.

[0213] In the 44th embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is hydrogen; and all other variables not specifically defined herein are as defined in the forty-third embodiment.

[0214] In a 45th embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is selected from linear, branched, and cyclic alkyl groups; all other variables not specifically defined herein are as defined in the forty-third embodiment.

[0215] In a 46th embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R c is a prodrug group; all other variables not specifically defined herein are as defined in the forty-third embodiment.

[0216] In certain embodiments, at least one compound of the present disclosure is selected from Compounds 1 to 18 shown in Table 1 below, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing.

[0217] Table 1

[0218]

[0219]

[0220] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Formula I, Compounds 1 to 18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, and at least one pharmaceutically acceptable carrier.

[0221] In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable excipient and a pharmaceutically acceptable adjuvant. In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable filler, a disintegrant, a surfactant, a binder and a lubricant.

[0222] It should also be understood that the pharmaceutical compositions of the present disclosure can be used for combination therapy; that is, the pharmaceutical compositions of the present disclosure can further comprise additional active agents. Alternatively, a composition comprising a compound selected from Formula I, Compounds 1 to 18, tautomers thereof, deuterated derivatives of the compound or tautomers, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing, can be administered as a separate composition simultaneously with, before, or after, a composition comprising an additional active agent.

[0223] As mentioned above, the pharmaceutical composition disclosed herein comprises a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be selected from adjuvants and carriers. As used herein, a pharmaceutically acceptable carrier can be selected from, for example, any and all solvents, diluents, other liquid carriers, dispersing aids, suspension aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders and lubricants suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988 to 1999, Marcel Dekker, New York discloses various carriers for preparing pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compound of the present disclosure (such as by producing any undesirable biological effect or interacting with any other component (one or more) of the pharmaceutical composition in a harmful manner), its use is covered within the scope of the present disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars (e.g., lactose, glucose and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer solution, nontoxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives and antioxidants.

[0224] III. Methods of treatment and use

[0225] In another aspect of the present disclosure, a compound of Formula I, compounds 1 to 18, tautomers thereof, deuterated derivatives of the compound or tautomers, or pharmaceutically acceptable salts of the foregoing, as disclosed herein, a compound, tautomer, deuterated derivatives, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, is used to treat a disease, disorder, or condition mediated by the degradation of a protein kinase. In another aspect, disclosed herein is a compound of Formula I, compounds 1 to 18, tautomers thereof, deuterated derivatives of the compound or tautomers, or pharmaceutically acceptable salts of the foregoing, as disclosed herein, a compound, tautomer, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease, disorder, or condition mediated by the degradation of a protein kinase. In yet another aspect, disclosed herein is a method for treating a disease, disorder or condition mediated by degradation of a protein kinase in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, Compounds 1 to 18, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, as disclosed herein, a tautomer, a deuterated derivative and / or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the protein kinase is selected from the group consisting of: hematopoietic progenitor cell kinase 1 (HPK1), mitogen-activated protein kinase 1 / 2 (MEK 1 / 2), Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora kinase A.

[0227] In some embodiments, the disease, disorder or condition is selected from a protein kinase-related disease. In some embodiments, the disease, disorder or condition is selected from a MEK 1 / 2-related disease. In some embodiments, the disease, disorder or condition is selected from a FLT3-related disease. In some embodiments, the disease, disorder or condition is selected from an Aurora kinase A-related disease.

[0228] In some embodiments, the disease, illness or condition is cancer. In some embodiments, cancer is a solid tumor. In some embodiments, solid tumors are selected from brain cancer, breast cancer, respiratory tract cancer and / or lung cancer, reproductive organ cancer, bone cancer, digestive tract cancer, urethral cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer and parathyroid cancer. In some embodiments, cancer is a blood cancer. In some embodiments, blood cancer is selected from acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma mesothelioma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and myelodysplastic syndrome (MDS).

[0229] In some embodiments, the cancer is selected from: oral cavity such as buccal cavity, lip, tongue, mouth, pharyngeal epidermoid cancer; cardiac cancer such as sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer such as bronchial cancer (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, enchondromatosis hamartoma, mesothelioma; gastrointestinal cancer such as esophageal (squamous cell carcinoma, laryngeal cancer, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreatic (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilatory intestinal cancer, etc. Cancers of the ovary or rectum (including pancreatic cancer, ... ), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bile duct; bone cancer, such as osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system cancer, including skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pineal tumors) Gynecological cancers include uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), ovarian granulosa cell-follicular cell tumor, ovarian supporting cell-stromal cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast cancer;Blood cancers, such as blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), hair cells; lymphatic system diseases; skin cancers, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; thyroid cancers, such as papillary thyroid cancer, follicular thyroid cancer; medullary thyroid cancer, anaplastic thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and adrenal gland cancers, such as neuroblastoma. ;

[0230] In another aspect of the present disclosure, compounds of Formula I, compounds 1 to 18, tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, as disclosed herein, tautomers, deuterated derivatives and / or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof are used to reduce protein kinase activity. In another aspect, disclosed herein are compounds of Formula I, compounds 1 to 18, tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, as disclosed herein, tautomers, deuterated derivatives and / or pharmaceutically acceptable salts thereof, in the preparation of a medicament for reducing protein kinase activity. In another aspect, disclosed herein is a method for reducing protein kinase activity, comprising administering to a subject a therapeutically effective amount of a compound of Formula I, Compounds 1 to 18, tautomers thereof, deuterated derivatives of the compound or tautomers, and / or a pharmaceutically acceptable salt of the foregoing, as disclosed herein, a compound, tautomer, deuterated derivatives, and / or a pharmaceutically acceptable salt thereof. In another aspect, disclosed herein is a method for reducing protein kinase activity, comprising contacting the protein kinase with a compound of Formula I, Compounds 1 to 18, tautomers thereof, deuterated derivatives of the compound or tautomers, and / or a pharmaceutically acceptable salt thereof, as disclosed herein, a compound, tautomer, deuterated derivatives, and / or a pharmaceutically acceptable salt thereof, as disclosed herein, or a pharmaceutically acceptable salt thereof, administered to a subject.

[0231] For example, a compound of Formula I, Compounds 1 to 18, tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof can be administered once a day, twice a day, or three times a day for the treatment of a disease, disorder, or condition mediated by the degradation of a protein kinase.

[0232] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formula I, Compounds 1 to 18, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, is administered once daily, twice daily, or three times daily.

[0233] The compound of formula I, compound 1 to 18, its tautomer, the deuterated derivative of the compound or tautomer, and / or the pharmaceutically acceptable salt of the aforementioned substance, or its pharmaceutical composition can be, for example, administered orally, parenterally, sublingually, topically, rectally, nasally, buccally, vaginally, transdermally, by patch, pump or via implanted reservoirs, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes, for example, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and local modes of administration. Parenteral administration can be, for example, performed by continuous infusion over a selected time period. Other administration forms encompassed in the present disclosure are described in International Patent Application Nos. WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142 and WO 2015 / 023915.

[0234] The useful dose or therapeutically effective amount of the compounds disclosed herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known in the art. See, for example, U.S. Patent No. 4,938,949.

[0235] One of ordinary skill in the art will recognize that when an amount of a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of the compounds, tautomers, pharmaceutically acceptable salts, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "1000 mg of at least one compound selected from the group consisting of a compound of Formula I and a pharmaceutically acceptable salt thereof" includes 1000 mg of a compound of Formula I and a concentration of a pharmaceutically acceptable salt of a compound of Formula I equivalent to 1000 mg of a compound of Formula I.

[0236] In another aspect of the present disclosure, the compounds and compositions disclosed herein can be administered in combination therapy with one or more therapeutic agents (drug combinations) or treatment modalities (e.g., antiproliferative agents, anticancer agents, immunomodulators or anti-inflammatory agents and / or non-drug therapies, etc.) in a therapeutically effective amount. For example, a synergistic effect can be produced with antiproliferative, anticancer, immunomodulatory or anti-inflammatory substances. When the compounds disclosed herein are administered in combination with other therapies, the dose of the co-administered compound will of course vary according to the type of combined drug used, the specific drug used, the condition treated, etc. Combination therapy includes further administering the test compound in combination with one or more other biologically active ingredients (e.g., a second kinase inhibitor, a second different antitumor agent) and non-drug therapy (e.g., surgery or radiotherapy). For example, the compounds disclosed herein can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compounds disclosed herein. The compounds disclosed herein can be administered simultaneously (as a single preparation or separate preparations) or sequentially with other drug therapies or treatment modalities. In general, combination therapy envisions administering two or more drugs within a single treatment cycle or course of treatment. In another aspect of the disclosure, the compounds may be administered in combination with one or more separate agents (eg, chemotherapeutic agents, immunotherapeutic agents, or adjuvant therapeutic agents).In one embodiment, the single agent is selected from: anti-PD1 antibodies (e.g., pembrolizumab), HDAC inhibitors r (e.g., panobinostat, romidepsin, vorinostat or sitastat), BCL-2 inhibitors (e.g., venetoclax), BTK inhibitors (e.g., ibrutinib or acalabrutinib), mTOR inhibitors (e.g., everolimus), PI3K inhibitors r (e.g., idelalisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), J AK2 inhibitors (e.g., fidartinib, paclitinib, ruxolitinib, baricitinib, tucatinib, lestaurtinib, or molotinib), Aurora kinase inhibitors (e.g., aleceptinib), EZF12 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaadenine A, EPZ005687, Ell, UNC1999, or sinefungin), BET inhibitors (e.g., bilaricev), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT 1L inhibitors (e.g., pinostat), FIAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., compound C or celidestat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420FU / F12 inhibitors (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JF1295), MEK inhibitors (e.g., trametinib, bemetinib, cobimetinib, selumetinib), PF1F19 inhibitors, PIM inhibitors (e.g., LGF1-447), IGF-IR inhibitors (e.g., linsetinib), XP01 inhibitors (e.g., selinexor), BIRC5 inhibitors (e.g., YM1 55), PARP inhibitors (e.g., olaparib), EGFR inhibitors (e.g., osimertinib), HER2 / NEU inhibitors (e.g., tucatinib), SRC inhibitors (e.g., dasatinib), AKT inhibitors (e.g., patasertib), KRAS (G12C) inhibitors (e.g., sotracib), KRAS (G12D) inhibitors (e.g., MRTX1133), platinum or chemotherapy drugs (e.g., bendamustine, bleomycin, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, cisplatin, taxanes or dexamethasone).

[0237] Non-limiting exemplary embodiments

[0238] 1. Compounds of formula (I):

[0239]

[0240] Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, wherein:

[0241] (i)R 1 Selected from: straight chain, branched chain and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, straight chain, branched chain and cyclic alkenyl groups, straight chain and branched heteroalkenyl groups, straight chain, branched chain and cyclic alkynyl groups, CO2R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2,OC(O)R w NR x R y ,S(O)R y and SO2R y ;

[0242] (ii) R 2 and R 3 Independently selected from: hydrogen, halogen groups, OR x , SR x 、NHR x 、N(R x 2. CHR x and C(R x )2;

[0243] (iii) each R' is independently selected from: hydrogen, a halogen group, a linear, branched and cyclic alkyl group;

[0244] (iv) m and n are independently selected from: 0, 1 and 2;

[0245] (v) X is absent or selected from the group consisting of: linear, branched, cyclic alkylene groups, linear, branched, and cyclic heteroalkylene groups;

[0246] (vi) Y and Z are independently absent or selected from: -O-, -C(O)-, -C(O)R x -、-C(S)-、-C(S)R x -、-[C(R x R y )] p -、-S(O)2-、-S(O)2R x -、NR x -and-NR xC(O)-; wherein p is selected from: 1, 2, 3, 4, 5 and 6; wherein, if X is absent, Y is not -O-, -S(O)2-, -S(O)2R x -、NR x -and-NR x C(O)-;

[0247] (vii) R x , R y and R w are each independently selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups and heteroaryl groups;

[0248] (viii) Ring A is selected from: an optionally substituted aryl group and a heteroaryl group,

[0249] (ix) Ring B is absent or selected from a cycloalkyl group and a heterocycloalkyl group;

[0250] (x) Ring C is selected from:

[0251]

[0252] Among them, R c R is selected from the group consisting of hydrogen, linear, branched and cyclic alkyl groups, and prodrug groups; R" is selected from the group consisting of hydrogen, halogen groups, OR x , linear, branched and cyclic alkyl groups;

[0253] Wherein, the straight chain, branched chain and cyclic alkyl groups, straight chain, branched chain and cyclic alkenyl groups, straight chain, branched chain and cyclic alkylene groups, carbocyclic groups, straight chain and branched heteroalkenyl groups, straight chain, branched chain and cyclic alkynyl groups, heterocyclic groups, aryl groups and heteroaryl groups are optionally substituted by at least one group selected from the following groups:

[0254] Halogen groups,

[0255] Hydroxyl,

[0256] Thiols,

[0257] Amino,

[0258] Cyano,

[0259] -OC(O)C1-C6 straight chain, branched and cyclic alkyl groups,

[0260] -C(O)OC1-C6 straight chain, branched and cyclic alkyl groups,

[0261] -NHC1-C6 straight chain, branched and cyclic alkyl groups,

[0262] -N(C1-C6 straight chain, branched chain and cyclic alkyl group)2,

[0263] -NHC(O)C1-C6 straight chain, branched and cyclic alkyl groups,

[0264] -C(O)NHC1-C6 straight chain, branched and cyclic alkyl groups,

[0265] -NH aryl group,

[0266] -N(aryl group)2,

[0267] -NHC(O)aryl group,

[0268] -C(O)NH aryl group,

[0269] -NH heteroaryl group,

[0270] -N(heteroaryl group)2,

[0271] -NHC(O)heteroaryl group,

[0272] -C(O)NH heteroaryl group,

[0273] C1-C6 straight chain, branched and cyclic alkyl groups,

[0274] C2-C6 straight chain, branched and cyclic alkenyl groups,

[0275] C1-C6 straight chain, branched and cyclic hydroxyalkyl groups,

[0276] C1-C6 straight chain, branched and cyclic aminoalkyl groups,

[0277] C1-C6 straight chain, branched and cyclic alkoxy groups,

[0278] C1-C6 straight chain, branched and cyclic thioalkyl groups,

[0279] C1-C6 straight chain, branched and cyclic haloalkyl groups,

[0280] C1-C6 straight chain, branched and cyclic halogenated aminoalkyl groups,

[0281] C1-C6 straight chain, branched chain and cyclic halogenated thioalkyl groups,

[0282] C1-C6 straight chain, branched and cyclic haloalkoxy groups,

[0283] benzyloxy, benzylamino and benzylthio groups,

[0284] 3- to 6-membered heterocycloalkenyl group,

[0285] a 3- to 6-membered heterocyclic group, and

[0286] 5- and 6-membered heteroaryl groups.

[0287] 2. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 1, wherein R 1 is selected from linear, branched and cyclic alkyl groups; R 2 is a halogen group; R 3 Selected from hydrogen, straight chain, branched chain and cyclic alkyl groups.

[0288] 3. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 1 or 2, wherein R 1 Selected from C1-C6 straight chain, branched chain and cyclic alkyl groups.

[0289] 4. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 3, wherein R 1 Selected from methyl, ethyl, cyclopropyl and cyclobutyl.

[0290] 5. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-4, wherein R 2 is a halogen group.

[0291] 6. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 5, wherein R 2 It's chlorine.

[0292] 7. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-5, wherein R 2 It's hydrogen.

[0293] 8. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-7, wherein R 3 is a halogen group.

[0294] 9. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 8, wherein R 3 It's chlorine.

[0295] 10. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-7, wherein R 3 It's hydrogen.

[0296] 11. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-10, wherein m is 1 and n is 1.

[0297] 12. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 11, wherein R' is hydrogen.

[0298] 13. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-10, wherein m is 2 and n is 1.

[0299] 14. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 11, wherein each R' is hydrogen.

[0300] 15. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-14, wherein X is absent.

[0301] 16. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-14, wherein X is a straight chain alkylene group.

[0302] 17. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 16, wherein X is a methylene group.

[0303] 18. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 16, wherein X is an ethylene group.

[0304] 19. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-18, wherein Y is absent.

[0305] 20. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-19, wherein Ring B is selected from optionally substituted heterocycloalkyl.

[0306] 21. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 20, wherein ring B is selected from

[0307] 22. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-21, wherein Z is absent.

[0308] 23. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-22, wherein ring C is

[0309] 24. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 23, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

[0310] 25. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-22, wherein ring C is

[0311] 26. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 25, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

[0312] 27. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-22, wherein ring C is

[0313] 28. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 27, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

[0314] 29. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-22, wherein ring C is

[0315] 30. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 29, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

[0316] 31. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-22, wherein ring C is

[0317] 32. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 31, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

[0318] 33. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-22, wherein ring C is

[0319] 34. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 33, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

[0320] 35. A compound selected from the group consisting of

[0321]

[0322]

[0323]

[0324] Its tautomer, deuterated derivative of the compound or tautomer, or pharmaceutically acceptable salt of the foregoing substance.

[0325] 36. A pharmaceutical composition comprising: a compound, a tautomer, a deuterated derivative and / or a pharmaceutically acceptable salt of any one of embodiments 1-35, and at least one pharmaceutically acceptable carrier.

[0326] 37. A method for treating or alleviating a disease, disorder or condition mediated by degradation of a protein kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative and / or pharmaceutically acceptable salt of any one of embodiments 1-35 or a pharmaceutical composition of embodiment 36.

[0327] 38. The method of embodiment 37, wherein the protein kinase is selected from the group consisting of: hematopoietic progenitor kinase 1 (HPK1), mitogen-activated protein kinase 1 / 2 (MEK 1 / 2), Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora kinase A.

[0328] 39. A method of reducing protein kinase activity in a disease, disorder or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative and / or pharmaceutically acceptable salt of any one of embodiments 1-35 or a pharmaceutical composition of embodiment 36.

[0329] 40. The method of embodiment 39, wherein the disease, disorder or condition is selected from a protein kinase-associated disease.

[0330] 41. The method of embodiment 40, wherein the protein kinase-associated disease is cancer.

[0331] 42. The method of embodiment 41, wherein the cancer is a solid tumor.

[0332] 43. The method of embodiment 42, wherein the solid tumor is selected from: brain cancer, breast cancer, respiratory tract cancer and / or lung cancer, reproductive organ cancer, bone cancer, digestive tract cancer, urethral cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer and parathyroid cancer.

[0333] 44. The method of embodiment 41, wherein the cancer is a blood cancer.

[0334] 45. The method of embodiment 44, wherein the blood cancer is selected from: acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma mesothelioma (HL), T-cell lymphoma (TCL), Burkitt lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and myelodysplastic syndrome (MDS).

[0335] 46. ​​The method of embodiment 41, wherein the cancer is selected from: oral cavity such as buccal cavity, lip, tongue, mouth, pharyngeal epidermoid carcinoma; cardiac cancer such as sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer such as bronchial cancer (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatosis hamartoma, mesothelioma; gastrointestinal cancer such as esophageal (squamous cell carcinoma, laryngeal carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreatic (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor , vasodilator peptide tumor), small intestine or small intestinal tract (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine or large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, colorectum, rectum; genitourinary tract cancers, including kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver cancer, such as hepatocellular carcinoma ( hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bile duct; bone cancers, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; cancers of the nervous system, including skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors ( Gynecological cancers include uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), ovarian granulosa cell-follicular cell tumor, ovarian supporting cell-stromal cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast cancer;Blood cancers, such as blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), hair cells; lymphatic system diseases; skin cancers, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; thyroid cancers, such as papillary thyroid cancer, follicular thyroid cancer; medullary thyroid cancer, anaplastic thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and adrenal gland cancers, such as neuroblastoma. ;

[0336] 47. The method of embodiment 39, further comprising administering to the subject an existing standard of care or an FDA-approved therapy.

[0337] 48. The method of embodiment 39, further comprising administering one or more separate agents to the subject.

[0338] 49. The method of embodiment 48, wherein the separate agent is selected from the group consisting of a chemotherapeutic agent, an immunotherapeutic agent, and an adjuvant therapeutic agent.

[0339] Example

[0340] Synthesis of compounds

[0341] In order to fully understand the present disclosure, the following examples are disclosed. It should be understood that these examples are only for illustrative purposes and should not be construed as limiting the present disclosure in any way.

[0342] All specific and generic compounds, as well as intermediates disclosed for the preparation of such compounds, are considered to be part of this disclosure.

[0343] The compounds of the present disclosure can be prepared according to standard chemical practices or as disclosed herein. Throughout the following synthetic schemes and descriptions for preparing compounds of Formula I, compounds 1 to 18, pharmaceutically acceptable salts of any of these compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, the following abbreviations are used:

[0344] abbreviation

[0345]

[0346] Ac = acetyl

[0347] Ac2O = acetic anhydride

[0348] Boc2O=di-tert-butyl dicarbonate

[0349] DCM = dichloromethane

[0350] DIEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propane-2-amine

[0351] DMAP = dimethylaminopyridine

[0352] DMA = dimethylacetamide

[0353] DME = dimethoxyethane

[0354] DMF = dimethylformamide

[0355] DMSO = dimethyl sulfoxide

[0356] EtOAc / EA=Ethyl acetate

[0357] EtOH = ethanol

[0358] HOAc=acetic acid

[0359] KOAc = Potassium acetate

[0360] LiHMDS = Lithium Bis(trimethylsilyl)amide

[0361] MeMgBr = methylmagnesium bromide

[0362] MeOH = methanol

[0363] NaOAc = Sodium acetate

[0364] NBS = N-bromosuccinimide

[0365] Pd(ppf)Cl2=[1,1'-bis(phenylphosphino)ferrocene]dichloropalladium(II)

[0366] PTSA = p-toluenesulfonic acid monohydrate

[0367] rt = room temperature (ambient temperature)

[0368] T3P=2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide

[0369] TEA = triethylamine

[0370] TFA = trifluoroacetic acid

[0371] THF = Tetrahydrofuran

[0372] TsCl = p-Toluenesulfonyl chloride

[0373] UV = Ultraviolet

[0374] X-Phos=2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0375] Synthesis of intermediate compounds:

[0376] Intermediate A1: 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine

[0377]

[0378] Step 1. Preparation of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one:

[0379] To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (50 g, 0.25 mol) in DCM (550 mL) was added AlCl (101.27 g, 0.76 mol) and acetyl chloride (21.92 g, 0.28 mol) at 0 ° C and N2. The reaction mixture was stirred at room temperature for 7 hours under N2. MeOH (300 mL) was added to the reaction mixture and the solvent was removed under reduced pressure. The reaction solution was adjusted to pH 6-7 with 3N NaOH aqueous solution and extracted with EA (500 mL x 3). The combined organic layer was washed with brine (300 mL x 3) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the crude product was purified by Combiflash (PE / EtOAc=2:1) ​​to obtain a yellow solid product 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (43.24 g, 71%). Mass (m / z): 241.0 [M+H] + .

[0380] Step 2. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine:

[0381] To a solution of AlCl3 (27.8 g, 0.20 mol) in DME (200 mL) was added LiAlH4 (4.39 g, 0.1 mol) and 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (10 g, 0.04 mol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours under N2. After the reaction was completed, H2O (500 mL) was added to the reaction mixture, which was then extracted with EA (200 mL x 3). The combined organic layers were washed with brine (100 mL x 2) and then dried over anhydrous Na2SO4. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the compound product 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (11.5 g, 74%) as a yellow solid. Mass (m / z): 225.0 [M+H] + .

[0382] Step 3. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide:

[0383] To a solution of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (25 g, 0.11 mol) in EA (100 mL) was added meta-chloroperbenzoic acid (26.84 g, 0.155 mol). The reaction mixture was stirred at room temperature for 3 hours. Washed with saturated Na2CO3 (20 mL) and brine (20 mL), then dried over anhydrous Na2SO4. The reaction mixture was filtered and the filtrate was concentrated to dryness to give the desired product as a white solid (17.4 g, yield: 64.6%). Mass (m / z): 240.7 [M+H] + .

[0384] Step 4. Preparation of 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine:

[0385] Phosphorus oxychloride (55.05 g, 35.9 mmol) was added to a solution of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide (17.3 g, 71.8 mmol) in NMP (15 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with water (50 mL), extracted with EA (30 mL x 3), washed with saturated brine, filtered, concentrated, and the residue was purified by flash column (PE / EA=5:1) to give the desired product as a white solid (4.1 g, yield: 22%). Mass (m / z): 258.7 [M+H] + .

[0386] Intermediate A2: 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine

[0387]

[0388] Step 1. Preparation of 5-bromo-4-chloropyridin-2-amine:

[0389] NBS (458 g, 2.57 mol, 1.1 eq) was added to a solution of compound 4-chloropyridine-2-amine (300 g, 2.34 mol, 1.0 eq) in acetonitrile (3000 mL) in several portions. The reaction mixture was stirred at room temperature for 6 hours. The reactant was then poured into water and filtered. The filter cake was washed with PE and dried to obtain compound 5-bromo-4-chloropyridine-2-amine (407 g, 83.9% yield) as a yellow solid. Mass (m / z): 207 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ8.10(s,1H),6.67(s,1H),6.45(s,2H).

[0390] Step 2. Preparation of 5-bromo-4-chloro-3-iodopyridin-2-amine:

[0391] NIS (666 g, 2.96 mol, 1.5 eq) was added to a solution of compound 5-bromo-4-chloropyridine-2-amine (407 g, 1.97 mol, 1.0 eq) in AcOH (2000 mL) in several portions. The reaction mixture was stirred at 80 ° C for 4 hours. The reaction was cooled to room temperature, poured into ice water (5000 mL), adjusted to pH>7 with K2CO3, extracted with EA (5000 mL x 3), and washed with Na2SO3 solution (5000 mL) and brine (5000 mL). The organic phase was concentrated in vacuo to obtain compound 5-bromo-4-chloro-3-iodopyridine-2-amine (500 g, 76.3% yield) as a yellow solid. Mass (m / z): 332.7 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.10 (s, 1H), 6.62 (s, 2H).

[0392] Step 3. Preparation of 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine:

[0393] Pd(PPh3)2Cl2(21.1g, 0.03mol, 0.1eq) was added to a solution of compound 5-bromo-4-chloro-3-iodopyridine-2-amine (100g, 0.300mol, 1.0eq) and DABCO (101g, 0.900mol, 3.0eq) in DMF (2000mL) under N2. Compound (cyclopropylethynyl)trimethylsilane (166g, 1.20mol, 4.0eq) was then added. The reaction was degassed 3 times under N2. The reaction mixture was stirred at 120°C for 10 hours. The reactant was filtered, quenched with water (2000mL), extracted with EA (2000mL x 3), washed with brine (2000mL), dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography with THF / PE (1:15) to give compound 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (27 g, 26.2% yield) as a yellow solid. Mass (m / z): 344.9 [m+H]+.

[0394] Step 4. Preparation of 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine:

[0395] To the mixture of THF (237mL) of compound 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo [2,3-b] pyridine (27g, 79.0mmol, 1.0eq) was added TBAF (1.0M, 237mL, 3.0eq) and H in THF2O (4.27g, 237mmol, 3.0eq). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (1000mL), extracted with EA (1000mL x 3), washed with brine (1000ml), dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography with THF / PE (1:4) to obtain the product compound 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo [2,3-b] pyridine (15g, 70.4% yield) as a light yellow solid. Mass (m / z): 272.9 [m+H] + . 1 HNMR (400MHz, DMSO-d6) δ11.92(s,1H),8.36(s,1H),7.33–7.34(d,J=4.0Hz,1H),2.11–2.16(m,1H),0.84–0.86(m,2H),0.62–0.64(m,2H).

[0396] Intermediate A3: 5-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine

[0397]

[0398] Step 1. Preparation of 1-{5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2-difluoroethanone

[0399] To a solution of 3-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.16 mol) in DCM (10 mL) was added AlCl3 (863.78 mg, 6.48 mmol) and ethyl 2,2-difluoroacetyl 2,2-difluoroacetate (751.9 mg, 4.32 mol) at 0 ° C. The reaction mixture was stirred at 25 ° C under N2 for 7 hours. MeOH (30 mL) was added to the reaction mixture, and the solvent was removed under reduced pressure. The residue was adjusted to pH 6-7 with 3N NaOH aqueous solution and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and then dried over Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (eluted with PE / EtOAc=2:1) ​​to give the product as a yellow solid (200 mg, 11.7%). Mass (m / z): 308.7 [m+H] + .

[0400] Step 2. Preparation of 3-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine:

[0401] To a solution of AlCl3 (200 g, 0.65 mol) in DME (10 mL) was added LiAlH4 (64.62 mg, 1.62 mol) and 1-{5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2-difluoroethanone (430.69 g, 3.23 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 3 hours under N2. After the reaction was complete, H2O (100 mL) was added, followed by extraction with EA (200 mL x 3). The combined organic layers were washed with brine (100 mL x 2) and then dried over anhydrous Na2SO4. The reaction mixture was filtered, the filtrate was concentrated under vacuum and purified by combiflash (eluted with PE / EA (1:1)) to give the compound product 3-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 13.1%) as a brown solid compound. Mass (m / z): 295.0 [M+H] + .

[0402] Intermediate A4: 2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)acetaldehyde

[0403]

[0404] Step 1. Preparation of {3-[(3-bromophenyl)amino]propyl}(2,2-dimethoxyethyl)amine:

[0405] A solution of N-(3-aminopropyl)-3-bromoaniline (5.8 g, 25.3 mmol) and 2,2-dimethoxyacetaldehyde (2.9 g, 27.8 mmol) in MeOH (100 mL) and AcOH (1 mL) was stirred at 25 ° C under nitrogen for 0.5 hours. NaBH3CN (4.8 g, 75.9 mmol) was then added at 0 ° C. The reaction mixture was stirred at 25 ° C for 16 hours. The solution was concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=30:1) to give the product (4.2 g, 47%) as a light yellow oil. Mass (m / z): 317.2 [M+H] + .

[0406] Step 2. Preparation of 1-(3-bromophenyl)-3-(2,2-dimethoxyethyl)-1,3-diazinan-2-one:

[0407] A solution of triphosgene (1.53 g, 5.16 mmol) in DCM (20 mL) was added dropwise to a stirred solution of {3-[(3-bromophenyl)amino]propyl}(2,2-dimethoxyethyl)amine (4.1 g, 12.9 mmol) and DIEA (3.33 g, 25.8 mmol) in DCM (40 mL) at 0 ° C. over 30 minutes. The solution was stirred at 25 ° C. for 2 hours. The solution was concentrated under reduced pressure. The residue was purified by flash column (PE / EA=1:1) to give the product (1.8 g, 36%) as a light yellow oil. Mass (m / z): 343.1 [M+H] + .

[0408] Step 3. Preparation of 1-(2,2-dimethoxyethyl)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-dioxazin-2-one:

[0409] Pd(dppf)Cl2 (320 mg, 0.44 mmol) was added to a solution of 1-(3-bromophenyl)-3-(2,2-dimethoxyethyl)-1,3-dioxaborolan-2-one (1.5 g, 4.4 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.13 g, 12.3 mmol) and KOAc (1.3 g, 13.2 mmol) in 1,4-dioxane (50 mL). The mixture was stirred at 90 °C under nitrogen for 5 hours. Water (100 mL) was added and the mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by column chromatography (PE / EA=1:1) to give the product as a brown oil (1.1 g, 57%). Mass (m / z): 391.3 [M+H] + .

[0410] Step 4. Preparation of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-(2,2-dimethoxyethyl)-1,3-dioxazin-2-one:

[0411] Pd(dppf)Cl2 (37 mg, 0.051 mmol) was added to a solution of 1-(2,2-dimethoxyethyl)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-dioxazoline-2-one (200 mg, 0.51 mmol), 3-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (146 mg, 0.56 mmol) and K2CO3 (212 mg, 1.53 mmol) in 1,4-dioxane / H2O (10:1, 10 mL). The solution was stirred at 90°C under nitrogen for 6 hours. Water (15 mL) was added and the mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by column chromatography (PE / EA=1:1) to obtain the product as a yellow solid compound (200 mg, 79% yield). Mass (m / z): 443.2 [M+H] + .

[0412] Step 5. Preparation of 2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazolin-1-yl]acetaldehyde:

[0413] To a solution of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-(2,2-dimethoxyethyl)-1,3-dioxadiazine-2-one (180 mg, 0.41 mmol) in DCM (20 mL) was added TFA (1 mL) and H2O (1 mL). The reaction mixture was stirred at 25 °C for 16 hours. Water (15 mL) was added, and the mixture was extracted with DCM (20 mL×2). The combined DCM layers were washed with saturated NaHCO3 (15 mL×2) and brine (20 mL), dried over Na2SO4 and concentrated to give the product as a brown oil (220 mg, 82%). Mass (m / z): 397.2 [M+H] + .

[0414] Intermediate A5: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0415]

[0416] To a mixture of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (1 g, 3 mmol), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]carboxylic acid tert-butyl ester (1.12 g, 3.6 mmol) and K3PO4 (0.76 g, 3.6 mmol) in dioxane / H2O (10:1, 20 mL) was added Pd(dppf)Cl2 (0.12 g, 0.1 mmol). The reaction mixture was stirred at 90 °C under N2 for 18 hours. Water (20 mL) was added and the mixture was extracted with DCM (20 mL x 2). The organic layer was washed with brine (20 mL x 2), dried over Na2SO4 and concentrated. The residue was purified by combiflash (DCM / MeOH=10:1) to give the product as a brown solid (1 g, 73%). Mass (m / z): 462.1 [M+Na] + .

[0417] Intermediate A6: tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)naphthalen-2-yl)piperazine-1-carboxylate

[0418]

[0419] Step 1. Preparation of 6-bromonaphthalene-1-amine:

[0420] To a mixture of 6-bromo-1-nitronaphthalene (5.00 g, 0.0198 mol) in EtOH / H2O (3:1, 50 mL) was added NH4Cl (7.73 g, 0.145 mol). The reaction mixture was heated to 60°C and zinc powder (9.45 g, 0.145 mol) was added in batches. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water (200 mL), then extracted with EtOAc (150 mL x 3), washed with brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE / EA=0-40%) to give the product 6-bromonaphthalene-1-amine (3.87 g, 83%) as a brown solid. Mass (m / z): 221.9 [M+H] + .

[0421] Step 2. Preparation of 3-[(6-bromonaphthalen-1-yl)amino]propionic acid:

[0422] To a mixture of 6-bromonaphthalene-1-amine (3.87 g, 0.0174 mol) in toluene (40.0 mL) was added acrylic acid (7.52 g, 0.104 mol). The reaction was degassed with N2 and stirred at 110°C for 21 hours. The reaction mixture was concentrated under reduced pressure to give the product 3-[(6-bromonaphthalene-1-yl)amino]propionic acid (8.00 g, 93%) as a brown solid. Mass (m / z): 293.9 [M+H] + .

[0423] Step 3. Preparation of 1-(6-bromonaphthalene-1-yl)-1,3-diazinone-2,4-dione:

[0424] To a mixture of 3-[(6-bromonaphthalene-1-yl)amino]propionic acid (8.7 g, 0.0296 mol) in AcOH (180 mL) was added urea (4.44 g, 0.0740 mol). The reaction mixture was stirred at 120 ° C for 16 hours under N2. The reaction mixture was slowly poured into water (200 mL) at 0 ° C and then filtered. The filter cake was dried under reduced pressure to give the product 1-(6-bromonaphthalene-1-yl)-1,3-diazinone-2,4-dione (7.5 g, 71%) as a brown solid. Mass (m / z): 318.8 [M+H] + .

[0425] Step 4. Preparation of tert-butyl {4-[5-(2,4-dioxo-1,3-dioxadiazin-1-yl)naphthalen-2-yl]piperazin-1-yl}carboxylate:

[0426] To a mixture of 1-(6-bromonaphthalene-1-yl)-1,3-dioxazoline-2,4-dione (500 mg, 1.57 mmol) in dioxane (10.0 mL) was added K3PO4 (998 mg, 4.70 mmol), piperazine-1-yl-tert-butyl formate (586 mg, 3.133 mmol) and RuPhos Pd G3 (262 mg, 0.313 mmol). The reaction was degassed 3 times with N2 and stirred at 90 ° C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EA (25 mL) and H2O (50 mL), then extracted with EA (50 mL x3), washed with brine (100 mL), dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE / EA=0-30%) to obtain the product {4-[5-(2,4-dioxo-1,3-dioxazo-1-yl)naphthalen-2-yl]piperazin-1-yl}carboxylic acid tert-butyl ester (360 mg, 49%) as a white solid. Mass (m / z): 424.9 [M+H] + .

[0427] Intermediates A7 and A8: 3-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-dioxaborolan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione and 3-(1-oxo-5-(4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0428]

[0429] Step 1. Preparation of 5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-dioxopiperidin-1-yl]methyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione:

[0430] TFA (2 mL) and H2O (2 mL) were added to a solution of tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (1.3 g, 2.8 mmol) in DCM (40 mL). The reaction mixture was stirred at 25 ° C for 16 hours. Water (30 mL) was added, and the mixture was extracted with DCM (40 mL×2). The combined DCM layer was washed with saturated NaHCO3 (30 mL×2) and brine (40 mL), dried over Na2SO4 and concentrated to give a crude product. A solution of the crude product 1-(3-bromophenyl)-3-(piperidin-4-ylmethyl)-1,3-diazin-2-one (1 g, 2.8 mmol) and DIEA (1.09 g, 8.4 mmol) in DMSO (20 mL) was stirred at 120 ° C for 2 hours under nitrogen protection. Water (50 mL) was added and the mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by flash chromatography (PE / EA=1:1) to give the product (1.1 g, 57%) as a brown solid. Mass (m / z): 607.7 [M+H] + .

[0431] Step 2. Preparation of 3-[5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-dioxadiazin-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione and 3-(5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione:

[0432] To a solution of 5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-dioxopiperidin-1-yl]methyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (1.4 g, 2.3 mmol) in AcOH (20 mL) was added Zn powder (1.5 g, 2.3 mmol) and the reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. Water (30 mL) was added and the mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by Prep-HPLC [Gemini-C18, 150 x 21.2 mm, 5 um; ACN--H2O (0.1% TFA), 55-60] to give the product:

[0433] 3-[5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-dioxadiazin-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (430 mg, 27%). Mass (m / z): 680.3 [M+H] + .

[0434] 3-(5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180 mg, 11%). Mass (m / z): 680.3 [M+H] + .

[0435] Step 3. Preparation of 3-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-dioxaborolan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione and 3-(1-oxo-5-(4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione:

[0436] To a solution of 3-[6-(4-{[3-(3-bromophenyl)-2-oxo-1,3-dioxazoin-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (430 mg, 0.72 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (275 mg, 1.08 mmol) and KOAc (213 mg, 2.17 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2 (53 mg, 0.072 mmol). The mixture was stirred at 110° C. under nitrogen for 2 hours. Water (15 mL) was added and the mixture was extracted with EA (10 mL×3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by flash chromatography (DCM / MeOH=20:1) to give product A7 (300 mg, 58%) as a brown solid. Mass (m / z): 642.4 [M+H] + .

[0437] According to the same process, the product A8 (140 mg, 64%) was obtained as a brown solid from 3-(5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. Mass (m / z): 642.3 [M+H] + .

[0438] General synthesis process I:

[0439]

[0440] Step 1. Preparation of G1-2:

[0441] TFA (1 mL) was added to a solution of G1-1 (0.25 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 3 hours. Methyl tert-butyl ether (50 mL) was added and the mixture was filtered. The filter cake was dried to obtain the product G1-2, which was used directly in the next step.

[0442] Step 2. Preparation of G1-3:

[0443] To a solution of 2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-dioxazoline-1-yl]acetaldehyde (110 mg, 0.28 mmol) in THF (3 mL) was added G1-2 (0.26 mmol), silanol (146 mg, 0.83 mmol) and AcOH (one drop). The reaction mixture was stirred at 70° C. for 16 hours. The solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC [Gemini-C18, 150× 21.2 mm, 5 um; ACN--H2O (0.1% FA), 30-40] to give the product.

[0444] General Synthesis Process II:

[0445]

[0446] Step 1. Preparation of G2-2:

[0447] To a solution of 1,3-dibromobenzene (18 g, 63.63 mmol) and propane-1,3-diamine (14.1 g, 190.87 mmol) and KOH (7.14 g, 127.25 mmol) and CuCl (630 mg, 6.36 mmol), the resulting mixture was stirred at 0 ° C for 16 hours under N2. After the reaction was completed, H2O (500 mL) was added to the reaction mixture, which was then extracted with DCM (500 mL×3). The combined organic layers were washed with brine (300 mL x 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash [DCM / MeOH (10% NH3) = 0~10%] to give the product as a brown oil (10.7 g, 73%). Mass (m / z): 231.1 [M+H] + .

[0448] Step 2. Preparation of G2-4:

[0449] At 0℃, N 1 G2-3 (46.96 mmol), AcOH (0.5 mL) and NaCNBH3 (8.85 g, 140.88 mmol) were added to a solution of -(3-bromophenyl)propane-1,3-diamine (10.7 g, 46.96 mmol) in MeOH (200 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by Combiflash column [DCM / MeOH (10% NH3) = 0-10%] to obtain the product.

[0450] Step 3. Preparation of G2-5:

[0451] To a solution of G2-4 (42.19 mmol) in DCM (200 mL) was added TEA (8.5 g, 84.37 mmol) and triphosgene (6.25 g, 21.09 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, H2O (500 mL) was added to the reaction mixture, which was then extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (300 mL x 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product.

[0452] Example 1

[0453] 3-[6-(1-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazoin-1-yl]ethyl}azetidin-3-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

[0454]

[0455] Step 1. Preparation of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidine-1-carboxylate:

[0456] A solution of 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (626 mg, 2 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (400 mL, 2.4 mmol), TTMSS (750 mL, 2.4 mmol), NiCl2-glyme (22 mg, 0.1 mmol), dtbpy (27 mg, 0.1 mmol), Ir[dF(CF3)ppy](dtbpy)PF6 (23 mg, 0.02 mmol), Na2CO3 (424 mg, 4 mmol) in DME (10 mL) was stirred at 25 ° C under nitrogen and irradiated with a blue LED for 16 hours. The solution was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=40:1) to give the product (466 mg, 58%) as a light purple solid. Mass (m / z): 400.2 [M+H] + .

[0457] Step 2. Following the general synthetic procedure I, starting from tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)azetidine-1-carboxylate, the product 3-[6-(1-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazin-1-yl]ethyl}azetidine-3-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (17 mg, 8.6%) was obtained as a yellow solid. Mass (m / z): 680.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),11.01(d,J=4.6Hz,1H),9.80-9.53(m,1H),8.11(d,J=5.8Hz,1 H),7.94(d,J=22.2Hz,1H),7.62(dd,J=21.4,7.6Hz,2H),7.42(dd,J=14.0,7.2Hz,4H),7.23(t,J=6.8 Hz,1H),5.13(dd,J=13.2,4.8Hz,1H),4.48(d,J=8.6Hz,2H),4.43(s,1H),4.34–4.22(m,4H),3.55(s, 4H), 3.48 (s, 2H), 3.42 (d, J = 5.6Hz, 2H), 2.96–2.85 (m, 4H), 2.02-1.99 (m, 4H), 1.27 (t, J = 7.2Hz, 3H).

[0458] Example 2

[0459] 3-[5-(1-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazoin-1-yl]ethyl}azetidin-3-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

[0460]

[0461] Step 1. Preparation of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate:

[0462] 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (517 mg, 1.6 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (315 mL, 1.9 mmol), TTMSS (600 mL, 1.9 mmol), NiCl2-glyme (18 mg, 0.08 mmol), dtbpy (22 mg, 0.08 mmol), Ir[dF(CF3)ppy](dtbpy)PF6 (18 mg, 0.016 mmol), Na2CO3 (339 mg, 3.2 mmol) DME (8 mL) solution was stirred at 25 ° C under nitrogen and irradiated with a blue LED for 16 hours. The solution was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=40:1) to give the product (458 mg, 71%) as a light pink solid. Mass (m / z): 400.2 [M+H] + .

[0463] Step 2. Following the general synthetic procedure I, starting from tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate, the product 3-[5-(1-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazin-1-yl]ethyl}azetidine-3-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (13 mg, 6.6%) was obtained as a yellow solid. Mass (m / z): 680.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),11.00(s,1H),9.83-9.55(m,1H),8.11(d,J=4.8Hz,1H),7.73(d,J=7.8Hz ,1H),7.67(s,1H),7.56(d,J=7.8Hz,1H),7.42(dd,J=15.8,9.0Hz,4H),7.24(d,J=6.6Hz,1H),5.12(dd,J=13.2, 5.0Hz,1H),4.51(d,J=5.2Hz,2H),4.41(d,J=5.8Hz,1H),4.28(dd,J=29.2,10.6Hz,4H),3.56(s,4H),3.45(d,J =17.2Hz,2H),3.42–3.36(m,2H),2.91(td,J=12.4,5.4Hz,4H),2.19–1.88(m,4H),1.26(dd,J=14.4,7.2Hz,3H).

[0464] Example 3

[0465] 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0466]

[0467] Step 1. Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-1-carboxylate:

[0468] To a solution of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 1.13 mmol) in MeOH (10 mL) and THF (10 mL) was added 10% Pd / C (50 mg, 10% wt / wt). The reaction was then stirred at 40 °C under 1 atm of H2 for 18 hours. The mixture was filtered and the filtrate was concentrated to give the desired product as a gray solid (400 mg, 75%). Mass (m / z): 464.0 [M+Na] + .

[0469] Step 2. Following the general synthetic procedure I, starting from tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-1-carboxylate, the desired product 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (16 mg, 9%) was obtained as a white solid. Mass (m / z): 722.0 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ11.73(s,1H),11.09(s,1H),8.09(s,1H),8.06(s,1H),7.80–7.74(m ,2H),7.70(d,J=7.8Hz,1H),7.37–7.32(m,3H),7.30(d,J=8.0Hz,1H),7.17(d,J=6.4Hz,1H), 5.19–5.04(m,1H),3.69(d,J=4.8Hz,2H),3.41(dd,J=14.0,8.4Hz,8H),2.88–2.82(m,3H),2. 56(d,J=17.8Hz,4H),2.02(d,J=4.6Hz,4H),1.81(s,2H),1.73(s,2H),1.21(t,J=7.4Hz,3H).

[0470] Example 4

[0471] 1-(6-(4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperazin-1-yl)naphthalen-1-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0472]

[0473] According to the general synthetic procedure I, starting from tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)naphthalen-2-yl)piperazine-1-carboxylate, the desired product 1-(6-(4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperazin-1-yl)naphthalen-1-yl)dihydropyrimidine-2,4(1H,3H)-dione (12 mg, 8%) was obtained as a white solid. Mass (m / z): 704.8 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ11.78(s,1H),10.43(s,1H),8.13(d,J=15.2Hz,2H),7.72(dd,J=18 .8,8.8Hz,2H),7.41(dd,J=14.6,7.2Hz,4H),7.33(d,J=8.0Hz,1H),7.22(dd,J=14.6,7.8Hz, 3H),3.85(d,J=4.8Hz,1H),3.76–3.68(m,2H),3.67–3.54(m,2H),3.46(d,J=5.2Hz,4H),3.26 (s,3H),2.91(dd,J=15.0,7.6Hz,3H),2.77–2.52(m,7H),2.05(s,2H),1.26(t,J=7.4Hz,3H).

[0474] Example 5

[0475] 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0476]

[0477] Following the general synthetic procedure I, starting from tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate, the desired product 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (31 mg, 17%) was obtained as a white solid. Mass (m / z): 720.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.78(d,J=2.2Hz,1H),11.15(s,1H),8.10(s,1H),7.98(s,1 H),7.89(dd,J=18.0,7.8Hz,2H),7.38(tt,J=16.0,8.0Hz,4H),7.22(d,J=7.6Hz,1H), 6.56(s,1H),5.16(dd,J=12.8,5.2Hz,1H),3.73(s,4H),3.58(s,2H),3.45(t,J=5.8Hz ,4H),2.97–2.82(m,4H),2.80–2.52(m,5H),2.13–1.95(m,3H),1.26(t,J=7.4Hz,3H).

[0478] Example 6

[0479] 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0480]

[0481] Step 1. Preparation of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-1-carboxylate:

[0482] A solution of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (337 mg, 1 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (246 mL, 1.5 mmol), TTMSS (466 mL, 1.5 mmol), NiCl2-glyme (11 mg, 0.05 mmol), dtbpy (14 mg, 0.05 mmol), Ir[dF(CF3)ppy](dtbpy)PF6 (11 mg, 0.01 mmol), 2,6-dimethylpyridine (580 mL, 5 mmol) in DME (5 mL) was stirred at 25 ° C under nitrogen and irradiated with a blue LED for 16 hours. The solution was concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=40:1) to give the product (220 mg, 53%) as a light yellow solid. Mass (m / z): 414.2 [M+H] + .

[0483] Step 2. Following the general synthetic procedure I, starting from tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-1-carboxylate, the product 5-(1-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (7 mg, yield: 4%) was obtained as a white solid. Mass (m / z): 694.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.77(d,J=2.4Hz,1H),11.14(s,1H),8.10(s,1H),8.00(s,1H),7.8 5(s,2H),7.43–7.29(m,4H),7.20(d,J=7.4Hz,1H),5.14(dd,J=12.8,5.4Hz,1H),3.80(d,J=6 .8Hz,1H),3.70(dt,J=13.8,5.8Hz,4H),3.44(t,J=5.8Hz,2H),3.28(dd,J=15.2,8.8Hz,5H), 2.97–2.80(m,3H),2.59(dd,J=31.8,13.6Hz,3H),2.06(s,3H),1.26(dd,J=13.8,6.2Hz,3H).

[0484] Example 7

[0485] 3-(5-(4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0486]

[0487] Step 1. Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate:

[0488] A solution of 3-(5-bromo-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (171 mg, 0.5 mmol), tert-butyl piperazine-1-carboxylate (186 mg, 1 mmol), Ruphos-Pd-GII (77 mg, 0.1 mmol), Ruphos (47 mg, 0.1 mmol), Cs2CO3 (489 mg, 1.5 mmol), 4AMS (100 mg) in dioxane (10 mL) was stirred at 100 ° C for 24 hours under nitrogen. The solution was filtered through celite and concentrated under reduced pressure. The residue was purified by flash column (DCM / MeOH=40:1) to give the product as a white solid (70 mg, 31%). Mass (m / z): 447.2 [M+H] + .

[0489] Step 2. Following the general synthetic procedure I, starting from tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate, the product 3-(5-(4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15 mg, 11%) was obtained as a white solid. Mass (m / z): 727.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.77(s,1H),10.99(s,1H),8.11(s,1H),7.50(d,J=11.2Hz,1H),7.45(s,1H),7.42(d,J=7.6 Hz,1H),7.40–7.32(m,3H),7.24(d,J=7.4Hz,1H),5.09(dd,J=13.2,4.8Hz,1H),4.36(d,J=17.2Hz,2H),4.25(d,J=17. 4Hz,2H),3.77(d,J=5.8Hz,3H),3.71(s,2H),3.45(dd,J=14.8,9.4Hz,4H),3.30(d,J=10.8Hz,2H),3.16(d,J=11.8Hz ,2H),2.96–2.82(m,3H),2.67–2.55(m,2H),2.40–2.35(m,1H),2.10(s,2H),2.03–1.94(m,1H),1.23(t,J=7.4Hz,3H).

[0490] Example 8

[0491] 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0492]

[0493] Step 1. According to the general synthetic process II, starting from tert-butyl 4-formylpiperidine-1-carboxylate, the product tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (11.1 g, 58%) was obtained as a yellow oil. Mass (m / z): 473.9 [M+H] + .

[0494] Step 2. Preparation of tert-butyl 4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate:

[0495] To a solution of tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (11.1 g, 24.48 mmol) in dioxane (200 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (9.3 g, 36.72 mmol), KOAc (7.2 g, 73.45 mmol) and Pd(dppf)Cl2 (1.79 g, 2.45 mmol). The reaction mixture was stirred at 90°C under N2 for 2 hours. The solvent was removed under reduced pressure and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product as a brown oil (12.3 g, 80%). Mass (m / z): 522.0 [M+H] + .

[0496] Step 3. Preparation of tert-butyl 4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate:

[0497] To a solution of tert-butyl 4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (12.3 g, 24.58 mmol) in dioxane / H2O (10:1, 200 mL) was added 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (6.37 g, 24.58 mmol), K2CO3 (10.19 g, 73.73 mmol) and Pd(dppf)Cl2 (1.79 g, 2.46 mmol). The reaction mixture was stirred at 90°C under N2 for 4 hours. After the reaction was completed, H2O (300 mL) was added to the reaction mixture, which was then extracted with DCM (200 mL×3). The combined organic layers were washed with brine (300 mL x 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product as a brown solid (5.83 g, 39%). Mass (m / z): 552.0 [M+H] + .

[0498] Step 4. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one:

[0499] 4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (5.83 g, 12.9 mmol) was added to a DCM / TFA (3:1, 50 mL) solution. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product as a brown oil (9.58 g, purity: 60%). Mass (m / z): 451.9 [M+H] + .

[0500] Step 5. Preparation of 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione:

[0501] To a solution of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one (4.23 g, 9.36 mmol) in DMSO (100 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.585 g, 9.36 mmol) and DIEA (3.63 g, 20.08 mmol). The reaction mixture was stirred at 120 °C for 2 hours under N2. After the reaction was completed, H2O (300 mL) was added to the reaction mixture, which was then extracted with EA (200 mL×3). The combined organic layers were washed with brine (300 mL x 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to obtain the product as a yellow solid (1.45 g, 21%). Mass (m / z): 707.7 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.79(s,1H),11.08(s,1H),8.11(s,1H),7.64(d,J=8.6Hz,1H),7.37( ddd,J=25.2,13.8,8.2Hz,5H),7.22(t,J=9.8Hz,2H),5.06(dd,J=12.8,5.4Hz,1H),4.07(d,J=1 2.8Hz,2H),3.77–3.70(m,2H),3.39(t,J=5.8Hz,2H),3.20(d,J=7.2Hz,2H),3.02–2.82(m,5H), 2.62–2.53(m,2H), 2.03(dd,J=12.8,7.2Hz,4H), 1.71(d,J=11.8Hz,2H), 1.28(t,J=7.4Hz,3H).

[0502] Example 9

[0503] 5-(4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0504]

[0505] Step 1. According to the general synthetic procedure II, starting from tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate, the product tert-butyl 4-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (660 mg, 56%) was obtained as a yellow oil. Mass (m / z): 488.2 [M+H] + .

[0506] Step 2. Preparation of tert-butyl 4-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate:

[0507] To a solution of tert-butyl 4-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (660 mg, 1.41 mmol) in dioxane (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (538 mg, 2.12 mmol), KOAc (416 mg, 4.24 mmol) and Pd(dppf)Cl2 (103 mg, 0.14 mmol). The reaction mixture was stirred at 90°C under N2 for 2 hours. The solvent was removed under reduced pressure and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product as a brown oil (650 mg, 89%). Mass (m / z): 536.0 [M+H] + .

[0508] Step 3. Preparation of tert-butyl 4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate:

[0509] To a solution of tert-butyl 4-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (650 mg, 1.26 mmol) in dioxane / H2O (10:1, 15 mL) was added 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (343 mg, 1.26 mmol), K2CO3 (523 mg, 3.79 mmol) and Pd(dppf)Cl2 (92 mg, 0.13 mmol). The reaction mixture was stirred at 90 °C under N2 for 4 h. After the reaction was completed, H2O (20 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum and the residue was purified by Combiflash (DCM / MeOH=0-10%) to obtain the product as a yellow oil (250 mg, 34%). Mass (m / z): 578.3 [M+H] + .

[0510] Step 4. Preparation of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(2-(piperidin-4-yl)ethyl)tetrahydropyrimidin-2(1H)-one:

[0511] Tert-butyl 4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (250 mg, 0.43 mmol) was dissolved in TFA / DCM (3:1, 10 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product as a brown oil (230 mg, purity: 89%). Mass (m / z): 477.9 [M+H] + .

[0512] Step 5. Preparation of 5-(4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione:

[0513] 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (142 mg, 0.48 mmol) and DIEA (187 mg, 1.44 mmol) were added to a solution of 1-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(2-(piperidin-4-yl)ethyl)tetrahydropyrimidin-2(1H)-one (230 mg, 0.48 mmol) in DMSO (10 mL). The reaction mixture was stirred at 120 ° C for 2 hours under N2. After the reaction was completed, H2O (20 mL) was added to the reaction mixture, which was then extracted with EA (20 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to obtain the product as a yellow solid (85 mg, 23%). Mass (m / z): 751.7 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.73(d,J=2.4Hz,1H),11.11(s,1H),8.11(s,1H),7.69(d,J=11.6Hz,1H),7.44–7.36(m,3H) ,7.34–7.28(m,2H),7.23–7.19(m,1H),5.10(dd,J=12.8,5.4Hz,1H),3.75–3.69(m,2H),3.59(d,J=12.4Hz,2H),3.36( d,J=10.2Hz,4H),2.90–2.82(m,3H),2.56(dd,J=19.8,10.6Hz,2H),2.23–2.15(m,1H),2.04(dd,J=14.6,9.2Hz,3H),1 .84(d,J=11.8Hz,2H),1.50(d,J=6.8Hz,3H),1.37–1.28(m,2H),0.83(ddd,J=8.2,6.0,4.0Hz,2H),0.66–0.60(m,2H).

[0514] Example 10

[0515] 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0516]

[0517] Step 1. Preparation of 5-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione:

[0518] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.3 g, 4.7 mmol) in DMF (20 mL) was added NaH (60% in oil, 226 mg, 9.41 mmol) at 0°C. The mixture was stirred at 0°C under N2 for 0.5 h. CH3I (1002 mg, 7.06 mmol) was then added. The reaction mixture was stirred at room temperature under N2 for 2.5 h. The reaction mixture was poured into ice water (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (100 mL x 3) and dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo and the residue was purified by Combiflash column (DCM / MeOH=0-10%) to give the product as a yellow solid (375 mg, 27%). Mass (m / z): 291.0 [M+H] + .

[0519] Step 2. Preparation of 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione:

[0520] 5-Fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (257 mg, 0.89 mmol) and DIEA (343 mg, 2.66 mmol) were added to a solution of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one (400 mg, 0.89 mmol) in DMSO (5 mL). The reaction mixture was stirred at 120 ° C for 2 hours under N2. After the reaction was completed, the reaction mixture was poured into water (15 mL) and then extracted with EA (15 mL x 3). The combined organic layers were washed with brine (20 mL x 3) and then dried over anhydrous Na2SO4. The filtrate was then concentrated by filtration and the residue was purified by Prep-HPLC [Gemini-C18, 150 x 21.2 mm, 5 um; ACN-H2O (0.1% FA) 30-50] to give the product 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (59 mg, 9%) as a yellow solid. Mass (m / z): 722.2 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ11.79(d,J=2.4Hz,1H),8.11(s,1H),7.64(d,J=8.4Hz,1H),7.36(dd d,J=19.0,7.8,2.3Hz,5H),7.26–7.18(m,2H),5.13(dd,J=13.0,5.4Hz,1H),4.07(d,J=13.2H z,2H),3.77–3.70(m,2H),3.39(t,J=5.8Hz,2H),3.20(d,J=7.2Hz,2H),3.01(s,3H),2.99–2 .87(m,5H),2.55(d,J=5.0Hz,1H),2.05(d,J=5.2Hz,4H),1.70(s,2H),1.28(t,J=7.4Hz,3H).

[0521] Embodiment 11

[0522] 3-[6-(4-{[3-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-dioxadiazin-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

[0523]

[0524] To a solution of 33-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazin-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (100 mg, 0.15 mmol), 3-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (50.8 mg, 0.18 mmol) and K3PO4 (99 mg, 0.46 mmol) in 1,4-dioxane / H2O (10:1, 3 mL) was added Pd(dppf)Cl2 (11 mg, 0.015 mmol). The solution was stirred at 85°C under nitrogen for 16 hours. The reaction was cooled to room temperature. Water (15 mL) was added and the mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by Prep-HPLC [Gemini-C18, 150 x 21.2 mm, 5 um; ACN--H2O (0.1% TFA), 30-50] to give the product as a yellow solid (2.3 mg, 2%). Mass (m / z): 706.3 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ11.75(s,1H),10.97(s,1H),8.11(s,1H),7.54(s,2H),7.45–7.36(m,2H),7.31(dd,J=22.0,12.8 Hz,2H),7.25–7.19(m,1H),7.15(s,1H),5.20–4.96(m,1H),4.32(d,J=16.7Hz,1H),4.19(d,J=16.6Hz,1H),3.75(dd,J=14 .0,9.0Hz,4H),3.40(s,2H),3.22(d,J=7.2Hz,2H),3.00–2.88(m,2H),2.77–2.64(m,2H),2.24(dd,J=28.6,23.6Hz,2H),2 .12–2.00(m,2H),1.91(d,J=39.8Hz,2H),1.72(d,J=11.2Hz,2H),1.32–1.21(m,2H),0.90–0.79(m,2H),0.73–0.59(m,2H).

[0525] Example 12

[0526] 3-[5-(4-{[3-(3-{4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-dioxadiazin-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

[0527]

[0528] To a solution of 3-{1-oxo-5-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazin-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (70 mg, 0.11 mmol), 3-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (30 mg, 0.11 mmol) and K3PO4 (69 mg, 0.33 mmol) in 1,4-dioxane / H2O (10:1, 3 mL) was added Pd(dppf)Cl2 (8 mg, 0.011 mmol). The solution was stirred at 85°C under nitrogen for 16 hours. The reaction was cooled to room temperature. Water (15 mL) was added, and the mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by Prep-HPLC [Gemini-C18, 150 x 21.2 mm, 5 um; ACN--H2O (0.1% TFA), 35-50] to give the product as a yellow solid (1.3 mg, 1.5%). Mass (m / z): 706.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.74(s,1H),10.94(s,1H),8.10(s,1H),7.56(s,1H),7.49(d,J=8.6Hz,1H),7.37(s,2H), 7.35–7.28(m,2H),7.21(d,J=7.4Hz,1H),7.05(s,1H),5.03(dd,J=13.4,5.2Hz,1H),4.31(d,J=16.8Hz,2H),4.18( d,J=16.6Hz,2H),3.89(d,J=11.6Hz,2H),3.74(s,2H),3.21(d,J=6.8Hz,2H),2.85(d,J=10.6Hz,2H),2.20(d,J=4. 6Hz,2H),2.06(s,2H),1.94(s,2H),1.70(d,J=10.8Hz,2H),1.23(s,4H),0.88–0.80(m,2H),0.64(d,J=3.4Hz,2H).

[0529] Example 13

[0530] 3-(6-{4-[(3-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-2-oxo-1,3-dioxadiazin-1-yl)methyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

[0531]

[0532] To a solution of 3-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazin-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (100 mg, 0.15 mmol), 3-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.18 mmol) and K3PO4 (99 mg, 0.46 mmol) in 1,4-dioxane / H2O (5 mL) was added Pd(dppf)Cl2 (11 mg, 0.015 mmol). The solution was stirred at 85°C under nitrogen for 16 hours. The reaction was cooled to room temperature. Water (15 mL) was added and the mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na2SO4. The filtrate was then concentrated by filtration. The crude product was purified by Prep-HPLC [Gemini-C18, 150 x 21.2 mm, 5 um; ACN--H2O (0.1% FA), 30-50] to give the product as a yellow solid (6 mg, 5.1%). Mass (m / z): 730.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.10(d,J=1.8Hz,1H),10.97(s,1H),8.15(d,J=12.4Hz,1H),7.58(d,J=2.0Hz,1H),7.38(td,J=15.2,7.8Hz, 4H),7.23(dd,J=16.4,8.0Hz,2H),7.15(s,1H),6.48–6.12(m,1H),5.09(dd,J=13.2,5.0Hz,1H),4.32(d,J=16.8Hz,1H),4.19(d,J=16 .8Hz,1H),3.86–3.66(m,4H),3.52(td,J=17.2,4.2Hz,2H),3.44–3.37(m,2H),3.22(d,J=7.2Hz,2H),2.96–2.85(m,1H),2.71(t,J=11 .5Hz,2H),2.58(d,J=17.0Hz,1H),2.42–2.29(m,1H),2.10–2.00(m,2H),1.98-1.85(m,2H),1.71(d,J=11.2Hz,2H),1.32-1.23(m,2H).

[0533] Embodiment 14

[0534] 3-(5-{4-[(3-{3-[4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-2-oxo-1,3-dioxadiazin-1-yl)methyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

[0535]

[0536] To a solution of 3-{1-oxo-5-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-dioxazoin-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (70 mg, 0.11 mmol), 5-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine (39 mg, 0.11 mmol) and K3PO4 (69 mg, 0.33 mmol) in 1,4-dioxane / H2O (10:1, mL) was added Pd(dppf)Cl2 (8 mg, 0.011 mmol). The solution was stirred at 85°C under nitrogen for 16 hours. The reaction was cooled to room temperature. Water (15 mL) was added, and the mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by Prep-HPLC [Gemini-C18, 150 x 21.2 mm, 5 um; ACN--H2O (0.1% FA), 30-50] to give the product as a yellow solid (2 mg, 2.5%). Mass (m / z): 730.3 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ12.09(s,1H),10.93(s,1H),8.40(s,1H),8.16(s,1H),7.58(s,1H),7.49(d,J=8.6Hz,1H),7.43 –7.27(m,3H),7.21(d,J=7.6Hz,1H),7.03(d,J=7.8Hz,1H),6.30(s,1H),5.03(d,J=12.6Hz,1H),4.31(d,J=17.0Hz,1H), 4.18(d,J=17.2Hz,1H),3.89(d,J=11.4Hz,2H),3.74(s,2H),3.54(d,J=16.6Hz,2H),3.40(s,2H),3.20(s,2H),2.85(dd, J=25.6,13.0Hz,2H),2.63(d,J=28.0Hz,2H),2.33(s,1H),2.06(s,2H),1.93(s,2H),1.70(d,J=11.0Hz,2H),1.24(s,2H).

[0537] Embodiment 15

[0538] 3-((4-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0539]

[0540] Step 1. Preparation of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl}-1,3-dioxazin-2-one:

[0541] 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-(piperidin-4-ylmethyl)-1,3-dioxadiazine-2-one (700mg, 1.55mmol) in DMSO (20mL) was added 1,2-difluoro-4-nitrobenzene (246mg, 1.55mmol) and DIEA (1001mg, 7.75mmol). The reaction mixture was stirred at 120°C for 1 hour under N2. After the reaction was completed, H2O (100mL) was added to the reaction mixture, which was then extracted with EA (50mL x 3). The combined organic layer was washed with brine (50mL x 3) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl}-1,3-dioxazin-2-one (660 mg, 72%) as a yellow solid. Mass (m / z): 590.9 [M+H] + .

[0542] Step 2. Preparation of 1-{[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-dioxazin-2-one:

[0543] A solution of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl}-1,3-dioxazin-2-one (650 mg, 1.1 mmol) in EA (10 mL) was stirred at 80° C. for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by Combiflash [DCM / MeOH (10% NH3·H2O)=0~10%] to give the product 1-{[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-dioxazin-2-one (450 mg, 72%) as a brown solid. Mass (m / z): 561.0 [M+H] + .

[0544] Step 3. Preparation of 3-((4-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione:

[0545] 3-Bromopiperidine-2,6-dione (342 mg, 1.8 mmol) and NaHCO3 (90 mg, 1.07 mmol) were added to a solution of 1-{[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-dioxazin-2-one (200 mg, 0.36 mmol) in DMF (10 mL). The reaction mixture was stirred at 80° C. for 16 hours under N2. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product 3-((4-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (4 mg, 1%) as a white solid. Mass (m / z): 672.0 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.11(s,1H),7.47(t,J=7.8Hz,1H),7.38(s,1H),7.33(t,J=7.2Hz,2H) ,7.26(s,1H),6.99(s,1H),6.54(d,J=17.8Hz,2H),4.24(s,1H),3.84–3.75(m,2H),3.52(t ,J=5.8Hz,2H),3.34(d,J=7.2Hz,4H),3.01(q,J=7.4Hz,2H),2.86–2.68(m,4H),2.28(s,1H ), 2.18 (dd, J = 13.4, 7.4Hz, 2H), 1.88 (d, J = 20.2Hz, 4H), 1.53 (s, 2H), 1.33 (t, J = 7.4Hz, 4H).

[0546] Example 16

[0547] 3-((4-(4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0548]

[0549] Step 1. Preparation of tert-butyl 4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate:

[0550] To a solution of tert-butyl 4-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (1200 mg, 2.33 mmol) in dioxane / H2O (10:1, 30 mL) was added 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (605 mg, 2.33 mmol), Na2CO3 (742 mg, 7.0 mmol) and Pd(dppf)Cl2 (170 mg, 0.23 mmol). The reaction mixture was stirred at 90 °C under N2 for 4 h. After the reaction was complete, H2O (20 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product as a yellow oil (600 mg, 45%). Mass (m / z): 566.3 [M+H] + .

[0551] Step 2. Preparation of 1-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(2-(piperidin-4-yl)ethyl)tetrahydropyrimidin-2(1H)-one:

[0552] Tert-butyl 4-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (600 mg, 1.06 mmol) was dissolved in a solution of TFA / DCM (3:1, 10 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product as a brown oil (560 mg, purity: 89%). Mass (m / z): 466.2 [M+H] + .

[0553] Step 3. Preparation of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl}-1,3-dioxazin-2-one:

[0554] 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-[2-(piperidin-4-yl)ethyl]-1,3-dioxadiazole-2-one (500mg, 1.72mmol) in DMSO (10mL) was added 1,2-difluoro-4-nitrobenzene (474mg, 1.72mmol) and DIEA (692mg, 5.36mmol). The reaction mixture was stirred at 80°C for 1 hour under N2. After the reaction was completed, H2O (100mL) was added to the reaction mixture, which was then extracted with EA (50mL x 3). The combined organic layer was washed with brine (50mL x 3) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl}-1,3-dioxazin-2-one (436 mg, 67%) as a yellow solid. Mass (m / z): 605.1 [M+H] + .

[0555] Step 4. Preparation of 1-{2-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]ethyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-dioxazin-2-one:

[0556] A solution of 1-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-{2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl}-1,3-oxazin-2-one (436 mg, 0.72 mmol) in EA (10 mL) was stirred at 80 °C for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash [DCM / MeOH (10% NH3·H2O=0-10%] to give the product 1-{2-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]ethyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-dioxazin-2-one (300 mg, 72%) as a brown solid. Mass (m / z): 575.2 [M+H]+ .

[0557] Step 5. Preparation of 3-{[4-(4-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazin-1-yl]ethyl}piperidin-1-yl)-3-fluorophenyl]amino}piperidine-2,6-dione:

[0558] 3-Bromopiperidine-2,6-dione (415 mg, 2.15 mmol) and NaHCO3 (110 mg, 1.30 mmol) were added to a solution of 1-{2-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]ethyl}-3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-1,3-dioxazin-2-one (250 mg, 0.43 mmol) in DMF (10 mL). The reaction mixture was stirred at 80° C. for 16 hours under N2. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product 3-{[4-(4-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazin-1-yl]ethyl}piperidin-1-yl)-3-fluorophenyl]amino}piperidine-2,6-dione (30 mg, 10%) as a white solid. Mass (m / z): 686.0 [M+H] + . 1 H NMR (400MHz, MeOD) δ8.10(d,J=8.2Hz,1H),7.46(t,J=7.8Hz,1H),7.38(d,J=1.6Hz,1H),7.32(t,J= 7.4Hz,2H),7.25(s,1H),6.88(s,1H),6.56–6.42(m,2H),4.61(s,1H),4.23(d,J=8.2Hz,1H),3.81– 3.74(m,2H),3.47(t,J=7.6Hz,4H),3.22(d,J=10.8Hz,2H),3.00(q,J=7.4Hz,2H),2.85–2.72(m,2H ),2.62(s,2H),2.29(s,1H),2.20–2.12(m,2H),1.86(s,2H),1.59(s,2H),1.44(s,2H),1.32(s,4H).

[0559] Embodiment 17

[0560] 3-[4-(4-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-dioxazoline-1-yl]ethyl}piperazin-1-yl)phenyl]piperidine-2,6-dione

[0561]

[0562] To a solution of 2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-dioxazo-1-yl]acetaldehyde (200 mg, 0.50 mmol) in THF (5 mL) was added 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione hydrochloride (156 mg, 0.50 mmol) and silane (265 mg, 1.5 mmol) and AcOH (one drop). The reaction mixture was stirred at 70 °C under N2 for 18 hours. The solution was concentrated under reduced pressure. The residue was purified by prep-HPLC [Gemini-C18, 150 x 21.2 mm, 5 um; ACN-H2O (0.1% FA), 20-50] to give the desired product (20 mg, 6%) as a white solid. Mass (m / z): 654.1 [M+H] + . 1 HNMR(400MHz,MeOD)δ8.00(s,1H),7.36(t,J=7.8Hz,1H),7.30(d,J=1.6Hz,1H),7.22(t,J= 7.8Hz,2H),7.16(s,1H),7.00(d,J=8.6Hz,2H),6.83(d,J=8.6Hz,2H),3.71–3.65(m,3H),3 .51(t,J=6.8Hz,2H),3.44(t,J=5.8Hz,2H),3.14–3.07(m,4H),2.89(q,J=7.4Hz,2H),2.72 (s,4H),2.65(t,J=6.6Hz,2H),2.58–2.46(m,2H),2.11–2.04(m,4H),1.22(t,J=7.4Hz,3H).

[0563] Embodiment 18

[0564] 3-{[4-(4-{2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazoin-1-yl]ethyl}piperazin-1-yl)-3-fluorophenyl]amino}piperidine-2,6-dione

[0565]

[0566] To a solution of 2-[3-(3-{4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-dioxazo-1-yl]acetaldehyde (200 mg, 0.50 mmol) in THF (5 mL) was added 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione hydrochloride (173 mg, 0.50 mmol) and silane (265 mg, 1.5 mmol) and AcOH (one drop). The reaction mixture was stirred at 70 °C under N2 for 18 hours. The solution was concentrated under reduced pressure. The residue was purified by prep-HPLC [Gemini-C18, 150 x 21.2 mm, 5 um; ACN-H2O (0.1% FA), 20-50] to give the desired product (8 mg, 2%) as a white solid. Mass (m / z): 687.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),10.79(s,1H),8.11(s,1H),7.37(dd,J=14.6,8.4Hz,4H),7.20( d,J=7.4Hz,1H),6.79(s,1H),6.50(d,J=14.8Hz,1H),6.39(d,J=8.6Hz,1H),5.80(d,J=7.6Hz,1H),4. 29–4.21(m,1H),3.73–3.69(m,2H),3.42(d,J=6.0Hz,4H),2.92(q,J=7.4Hz,2H),2.84(s,4H),2.69(d ,J=11.2Hz,1H),2.54(s,6H),2.13–1.96(m,4H),1.84(dd,J=12.2,4.4Hz,1H),1.26(t,J=7.4Hz,3H).

[0567] General testing process:

[0568] HPK1 enzyme inhibition assay

[0569] The compounds were dissolved in 100% DMSO at a concentration of 10 mM. HPK1 protein was purchased from Signal Chem (M23-11G-10). 2X HPK1 protein was added to the test plate containing the test compound at 2.5 μL / well, centrifuged at 1500 rpm for 1 minute, and then incubated at 25°C for 60 minutes. MBP protein was purchased from Signal Chem (M42-51N) and ATP was purchased from Promega (V9102). A mixture of 2X MBP (0.2 ug / ul) and ATP (20 μM) was added at 2.5 μL / well, centrifuged at 1500 rpm for 1 minute, and then incubated at 25°C for 60 minutes. Then 5 μL of ADP-Glo ​​(V9102) from Promega was added to the test plate, and the unconsumed ATP was depleted for 60 minutes. Then centrifuged at 1500 rpm for 1 minute and incubated at 25°C for 60 minutes. Finally, 10 μL of kinase assay reagent (V9102) from PPromega was added to the assay plate to convert ADP to ATP, centrifuged at 1500 rpm for 1 minute, and incubated at 25°C for 40 minutes. After 40 minutes of incubation, the fluorescence was measured. Based on the results, the IC of the compound was calculated. 50 Value. IC 50 The results are shown in Table 2 below.

[0570] FLT3-ITD enzyme inhibition assay

[0571] The compound was dissolved in 100% DMSO at a concentration of 10 mM. FLT3-ITD protein was purchased from Invitrogen (PV6191). 2.5X FLT3-ITD protein was added to the test plate containing the test compound at 10 μL / well, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. Peptide 2 was purchased from GL Biochem (112394) and ATP was purchased from Promega (V9102). A mixture of 1.67X peptide 2 (final concentration of 3 μM) and ATP (final concentration of 97.2 μM) was added at 15 μL / well, centrifuged at 1000 rpm for 1 minute, and then incubated at 25°C for 40 minutes. Then, 30 μL of stop buffer (100 mM HEPES pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent 3, 50 mM EDTA) was added to the test plate, and the product was measured by centrifugation at 1000 rpm for 1 minute. Based on the results, the IC value of the compound was calculated. 50 Value. IC 50 The results are shown in Table 2 below.

[0572] Aurora Kinase A Inhibition Assay

[0573] The compounds were dissolved in 100% DMSO at a concentration of 10 mM. Aurora A protein was purchased from Carna (05-101). 2.5X Aurora A protein was added to the assay plate containing the test compound at 10 μL / well, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. Peptide 21 was purchased from GL Biochem (116370), and ATP was purchased from Promega (V9102). A mixture of 1.67X peptide 21 (final concentration of 3 μM) and ATP (final concentration of 14.58 μM) was added at 15 μL / well, centrifuged at 1000 rpm for 1 minute, and then incubated at 25°C for 40 minutes. Then, 30 μL of stop buffer (100 mM HEPES pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent 3, 50 mM EDTA) was added to the test plate, and the product was measured by centrifugation at 1000 rpm for 1 minute. Based on the results, the IC value of the compound was calculated. 50 Value. IC 50 The results are shown in Table 2 below.

[0574] Table 2. Results of compounds in enzyme inhibition assays

[0575]

[0576]

[0577] ND: Not Determined

[0578] HPK1 degradation assay

[0579] Frozen human PBMCs were purchased from Shanghai OribioTech and recovered with culture medium (RMPI1640) before use. The cells were then incubated with different concentrations of the compounds. After incubation, the cells were collected and lysed. Protein concentration was determined by BCA protein assay kit (23227) from Thermo. HPK1 protein levels were determined by Western blotting using anti-human HPK1 polyclonal antibody (4472S) from CST. The proteins were loaded into each well of the precast gel and separated by electrophoresis by SDS-PAGE. The SDS-PAGE-separated proteins were transferred to PVDF, blocked with 5% skim milk, and detected using standard Western blotting procedures with anti-human HPK1 antibody or β-actin antibody (3700S) from CST.

[0580] MEK 1 / 2 degradation assay

[0581] Prior to use, MV-411 cells were cultured with culture medium (IMDM) and IMR32 cells were cultured with culture medium (MEM). The cells were then incubated with various concentrations of the compounds. After incubation, the cells were collected and lysed. Protein concentration was determined by BCA protein assay kit (23227) from Thermo. FLT3 protein levels were determined by Western blotting using anti-human MEK 1 / 2 polyclonal antibody (9122S) from CST. Proteins were loaded into each well of the precast gel and separated by SDS-PAGE electrophoresis. The SDS-PAGE separated proteins were transferred to PVDF, blocked with 5% skim milk, and detected using standard Western blotting procedures with anti-human MEK1 / 2 antibody or β-actin antibody (3700S) from CST and COX IV antibody (4850S) from CST.

[0582] FLT3 degradation assay

[0583] MV-411 cells were cultured with culture medium (IMDM) before use. The cells were then incubated with various concentrations of the compounds. After incubation, the cells were collected and lysed. Protein concentration was determined by BCA protein assay kit (23227) from Thermo. FLT3 protein levels were determined by Western blotting using anti-human FLT3 monoclonal antibody (3462S) from CST. The proteins were loaded into each well of the precast gel and separated by electrophoresis by SDS-PAGE. The proteins separated by SDS-PAGE were transferred to PVDF, blocked with 5% skim milk, and detected using standard Western blotting procedures with anti-human FLT3 antibody or β-actin antibody (3700S) from CST.

[0584] Aurora kinase A degradation assay

[0585] Before use, IMR32 cells were cultured with culture medium (MEM), Huh7 cells were cultured with culture medium (DMEM), and HL-60 cells were cultured with culture medium (IMDM). The cells were then incubated with various concentrations of the compounds. After incubation, the cells were collected and lysed. The protein concentration was determined using the BCA protein assay kit (23227) from Thermo. The AURKA protein level was determined by Western blotting using an anti-human AURKA monoclonal antibody (14475S) from CST. The proteins were loaded into each well of the precast gel and separated by SDS-PAGE electrophoresis. The proteins separated by SDS-PAGE were transferred to PVDF, blocked with 5% skim milk, and detected using a standard Western blotting procedure with an anti-human AURKA antibody or β-actin antibody (3700S) or COX IV antibody (4850S) from CST.

[0586] The results for HPK1, FLT3, Aurora kinase, and MEK are shown in Table 3 .

[0587] Table 3. Results of compounds in protein degradation assays

[0588]

[0589]

[0590] +: No activity detected up to 10 uM.

[0591] Other Implementations

[0592] The present disclosure provides only exemplary embodiments. Those skilled in the art will readily recognize from the present disclosure and claims that various changes, modifications and variations may be made therein without departing from the spirit and scope of the present disclosure as defined in the appended claims.

Claims

1. A compound of formula (I): Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, wherein: (i)R 1 Selected from: straight chain, branched chain and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, straight chain, branched chain and cyclic alkenyl groups, straight chain and branched heteroalkenyl groups, straight chain, branched chain and cyclic alkynyl groups, CO2R x , C(O)NR x R y , C(O)R x OR y , C(O)R w N(R x R y )2,OC(O)R w NR x R y ,S(O)R y and SO2R y ; (ii) R 2 and R 3 Independently selected from: hydrogen, halogen groups, OR x , SR x 、NHR x 、N(R x 2. CHR x and C(R x )2; (iii) each R' is independently selected from: hydrogen, a halogen group, a linear, branched and cyclic alkyl group; (iv) m and n are independently selected from: 0, 1 and 2; (v) X is absent or selected from the group consisting of: linear, branched, cyclic alkylene groups, linear, branched, and cyclic heteroalkylene groups; (vi) Y and Z are independently absent or selected from: -O-, -C(O)-, -C(O)R x -、-C(S)-、-C(S)R x -、-[C(R x R y )] p -、-S(O)2-、-S(O)2R x -、NR x -and-NR x C(O)-; wherein p is selected from: 1, 2, 3, 4, 5 and 6; wherein, if X is absent, Y is not -O-, -S(O)2-, -S(O)2R x -、NR x -and-NR x C(O)-; (vii) R x , R y and R w are each independently selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups and heteroaryl groups; (viii) Ring A is selected from: optionally substituted aryl groups and heteroaryl groups, (ix) Ring B is absent or selected from a cycloalkyl group and a heterocycloalkyl group; (vii) Ring C is selected from: Among them, R c R is selected from the group consisting of hydrogen, linear, branched and cyclic alkyl groups, and prodrug groups; R" is selected from the group consisting of hydrogen, halogen groups, OR x , linear, branched and cyclic alkyl groups; Wherein, the straight chain, branched chain and cyclic alkyl groups, straight chain, branched chain and cyclic alkenyl groups, straight chain, branched chain and cyclic alkylene groups, carbocyclic groups, straight chain and branched heteroalkenyl groups, straight chain, branched chain and cyclic alkynyl groups, heterocyclic groups, aryl groups and heteroaryl groups are optionally substituted by at least one group selected from the following groups: Halogen groups, Hydroxyl, Thiols, Amino, Cyano, -OC(O)C1-C6 straight chain, branched and cyclic alkyl groups, -C(O)OC1-C6 straight chain, branched and cyclic alkyl groups, -NHC1-C6 straight chain, branched and cyclic alkyl groups, -N(C1-C6 straight chain, branched chain and cyclic alkyl group)2, -NHC(O)C1-C6 straight chain, branched and cyclic alkyl groups, -C(O)NHC1-C6 straight chain, branched and cyclic alkyl groups, -NH aryl group, -N(aryl group)2, -NHC(O)aryl group, -C(O)NH aryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O)heteroaryl group, -C(O)NH heteroaryl group, C1-C6 straight chain, branched and cyclic alkyl groups, C2-C6 straight chain, branched and cyclic alkenyl groups, C1-C6 straight chain, branched and cyclic hydroxyalkyl groups, C1-C6 straight chain, branched and cyclic aminoalkyl groups, C1-C6 straight chain, branched and cyclic alkoxy groups, C1-C6 straight chain, branched and cyclic thioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkyl groups, C1-C6 straight chain, branched and cyclic halogenated aminoalkyl groups, C1-C6 straight chain, branched chain and cyclic halogenated thioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino and benzylthio groups, 3- to 6-membered heterocycloalkenyl group, a 3- to 6-membered heterocyclic group, and 5- and 6-membered heteroaryl groups.

2. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 1 Selected from: linear, branched and cyclic alkyl groups; R 2 is a halogen group; R 3 Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups.

3. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1 or 2, wherein R 1 Selected from: C1-C6 straight chain, branched chain and cyclic alkyl groups.

4. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 3, wherein R 1 Selected from: methyl, ethyl, cyclopropyl and cyclobutyl.

5. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein R 2 is a halogen group.

6. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 5, wherein R 2 It's chlorine.

7. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein R 2 It's hydrogen.

8. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein R 3 is a halogen group.

9. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 8, wherein R 3 It's chlorine.

10. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein R 3 It's hydrogen.

11. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein m is 1 and n is 1.

12. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 11, wherein each R' is hydrogen.

13. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein m is 2 and n is 1.

14. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 11, wherein each R' is hydrogen.

15. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1-14, wherein X is absent.

16. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1 to 14, wherein X is a straight chain alkylene group.

17. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 16, wherein X is a methylene group.

18. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 16, wherein X is an ethylene group.

19. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1-18, wherein Y is absent.

20. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 19, wherein Ring B is selected from optionally substituted heterocycloalkyl.

21. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 20, wherein Ring B is selected from:

22. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1-21, wherein Z is absent.

23. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 22, wherein ring C is 24. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 23, wherein Rc Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

25. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 22, wherein ring C is 26. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 25, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

27. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 22, wherein ring C is 28. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 27, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

29. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 22, wherein ring C is 30. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 29, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

31. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 22, wherein ring C is 32. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 31, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

33. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 22, wherein ring C is 34. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 33, wherein R c Selected from: hydrogen, straight chain, branched chain and cyclic alkyl groups, and prodrug groups.

35. A compound selected from the group consisting of: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substance.

36. A pharmaceutical composition comprising: a compound, tautomer, deuterated derivative and / or pharmaceutically acceptable salt according to any one of claims 1 to 35, and at least one pharmaceutically acceptable carrier.

37. A method for treating or alleviating a disease, disorder or condition mediated by degradation of a protein kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative and / or pharmaceutically acceptable salt of any one of claims 1-35 or a pharmaceutical composition of claim 36.

38. The method of claim 37, wherein the protein kinase is selected from the group consisting of: hematopoietic progenitor kinase 1 (HPK1), mitogen-activated protein kinase 1 / 2 (MEK 1 / 2), Fms-like tyrosine kinase 3 receptor (FLT3), and Aurora kinase A.

39. A method of reducing protein kinase activity in a disease, disorder or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative and / or pharmaceutically acceptable salt of any one of claims 1-35 or a pharmaceutical composition of claim 36.

40. The method of claim 39, wherein the disease, disorder or condition is selected from a protein kinase-associated disease.

41. The method of claim 40, wherein the protein kinase-related disease is cancer.

42. The method of claim 41, wherein the cancer is a solid tumor.

43. The method of claim 42, wherein the solid tumor is selected from the group consisting of brain cancer, breast cancer, respiratory and / or lung cancer, reproductive organ cancer, bone cancer, digestive tract cancer, urethral cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, anal cancer, nervous system cancer, thyroid cancer and parathyroid cancer.

44. The method of claim 41, wherein the cancer is a hematological cancer.

45. The method of claim 44, wherein the blood cancer is selected from the group consisting of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma mesothelioma (HL), T-cell lymphoma (TCL), Burkitt lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and myelodysplastic syndrome (MDS).

46. ​​The method of claim 41, wherein the cancer is selected from: oral cavity, such as buccal cavity, lip, tongue, mouth, pharyngeal epidermoid cancer; cardiac cancer, such as sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung cancer, such as bronchial cancer (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, enchondromatosis hamartoma, mesothelioma; Gastrointestinal cancer, such as esophagus (squamous cell carcinoma, laryngeal carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine or small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine or large intestine tract (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, colorectum, rectum; genitourinary tract cancers, including kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver cancers, such as hepatoma (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; Bone cancers, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system cancers, including skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealoma), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal cord neurofibromas, meningiomas, gliomas, sarcomas); gynecological cancers, including uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), ovarian granulosa-follicular cell tumors, ovarian Sertoli-Leydig cell tumors, dysgerminomas, malignant teratomas), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast cancer; blood cancers, such as blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) hair cell; lymphatic system diseases; skin cancers, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; thyroid cancers, such as papillary thyroid cancer, follicular thyroid cancer; medullary thyroid cancer, anaplastic thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and adrenal gland cancers, such as neuroblastoma.

47. The method of claim 39, further comprising administering to the subject an existing standard of care or an FDA-approved therapy.

48. The method of claim 39, further comprising administering one or more separate pharmaceutical agents to the subject.

49. The method of claim 48, wherein the separate agent is selected from the group consisting of a chemotherapeutic agent, an immunotherapeutic agent, and an adjuvant therapeutic agent.

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